Lipoxygenase inhibitor

Abstract

To provide a lipoxygenase inhibitor.SOLUTION: Compounds of Formula 1 are provided: Wherein n is 0-2, when n is 0, B and the NH group are directly linked, and R3 is absent, and when n is 1 or 2, the carbon atom in the linkage is optionally substituted by one R3 group, and A is 6-membered heteroaryl or 6-membered aryl; The 6-membered ring heteroaryl or 6-membered ring aryl is independently further substituted by 1 to 3 R1 groups, and B is a 6-membered heterocycle, a 6-membered aryl, or a 6-membered cyclohexyl, wherein the 6-membered heterocycle, the 6-membered aryl, or the 6-membered cyclohexyl is unsubstituted or independently substituted by up to 3 R2 groups.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [Background technology] Lipoxygenases (LOXs) and their catalytic products, such as inflammatory leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), are implicated in the pathogenesis of various human diseases, including inflammatory disorders, cancer, and neurodegenerative diseases. Lipoxygenase inhibitors are known to be useful in the treatment of a wide range of LOX-associated inflammatory diseases, including neurodegenerative diseases such as Alzheimer's disease. Summary of the Invention

[0002] The present disclosure is directed to overcoming the above-mentioned problems and others with respect to compounds, such as compounds that are LOX inhibitors.

[0003] Various embodiments of the present disclosure are directed to compounds of Formula 1 and pharmaceutically acceptable salts thereof: [ka] wherein n is 0 to 2, when n is 0, B and the NH group are directly bonded, and R3 is absent, and when n is 1 or 2, the carbon at the bond is optionally substituted with one R3 group; A is a 6-membered heteroaryl or a 6-membered aryl, and the 6-membered heteroaryl or 6-membered aryl is independently further substituted with one to three R1 groups; B is a 5- to 6-membered heterocycle, a 5- to 6-membered aryl, or a 5- to 6-membered cyclohexyl, and the 5- to 6-membered heterocycle, the 5- to 6-membered aryl, or the 5- to 6-membered cyclohexyl is unsubstituted or independently substituted with up to three R2 groups; each X1, X2, X3, X4, X5, and X6 is independently C, N, or O; each R1 is independently halo, C, or O. 1~4 Alkyl, -NR x R y , -O(CH2)2R x , -O(CH2)2NR x R y , -NHC(O)-C 2~4 Alkyl, -(CH2)3NR x R y, -NH(CH2)2NR x R y , -NHCH2CR x R y R z , 5-6 membered aryl, 5-10 membered heterocycle, 5-10 membered heteroaryl, or 5-10 membered heteroaryl, and one to three R groups are optionally selected from R a and / or R b and two R groups optionally together form a 5- to 6-membered heteroaryl, [5- to 6-membered heterocyclic ring, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl], and the 5- to 6-membered heteroaryl, [5- to 6-membered heterocyclic ring, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl] is optionally further substituted by 1 to 3 R a groups; each R2 is independently halo, C 1~2 Methoxy, or C(O)OR x two R groups on adjacent atoms optionally together form a 5- to 6-membered aryl ring, and the 5- to 6-membered heteroaryl ring optionally comprises 1 to 3 R a R3 is further substituted by a C 1~3 haloalkyl or oxo; each R x , R y , R z are independently H, halo, and C 1~2 Alkyl, C 1~2 Alcohol, C 1~2 Alkoxy, C 1~2 Haloalkyl or NR a R b Contains R x , R y , R z Any two of R optionally together form a 4- to 6-membered heterocycle or a 5- or 6-membered aryl ring, and each R x , R y , R z is optionally R a and R b and each R a and R b are H, halo, cyano, oxo, and C, respectively. 1~3 Alkyl, -C(O)OR', C 1~3haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle; R a and R b are each further substituted by R', and R' is C 1~3 Alkyl, C 1~3 Alkyl haloalkyl, or C 5~6 It is heteroaryl.

[0004] In some embodiments, each R is independently: [ka] [ka] is selected from.

[0005] In some embodiments, each R2 is independently: [ka] is selected from.

[0006] In some embodiments, the compound (of Formula 1) is [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0007] Various embodiments of the present disclosure are directed to compounds of formula 2 and pharmaceutically acceptable salts thereof: [ka] wherein A is a 6-membered heteroaryl or a 6-membered aryl, wherein the 6-membered heteroaryl or the 6-membered aryl is further independently substituted with one to three R groups; B is a 6-membered heterocycle, a 6-membered aryl, or a 6-membered cyclohexyl, wherein the 6-membered heterocycle, the 6-membered aryl, or the 6-membered cyclohexyl is either unsubstituted or each substituted with up to two R groups; each X, X, X, and X is C, N, or O; each R is independently halo, C, N, or O. 1~4 Alkyl, -NR x R y , -O(CH2)2R x R y , -O(CH2)2NR x R y , -NHC(O)-alkyl 2~4 , -(CH2)3NR x R y , -NH(CH2)2NR x R y , -NHCH2CR x R y R z , 5-6 membered aryl, 5-10 membered heterocycle, 5-10 membered heteroaryl, or 5-10 membered heterocyclic aryl; two R groups optionally together form a 5-6 membered heteroaryl, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl]; the 5-6 membered heteroaryl, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl] optionally can be joined by 1 to 3 R a each of 1 to 3 R is independently optionally further substituted by R a and R b and each R2 is independently halo, C 1~2 Methoxy, or C(O)OR x Each R x , R y , R z are independently H, halo, and C 1~2 Alkyl, C 1~2 Alcohol, C 1~2 Alkoxy, C 1~2 Haloalkyl or NR a Rb Contains R x , R y , R z Any two of R together form a 4- to 6-membered heterocycle or a 5- to 6-membered aryl ring, x , R y , R z is optionally R a and R b and each R a and R b are independently H, halo, cyano, oxo, C 1~3 Alkyl, -C(O)OR', C 1~3 haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle; R a and R b is independently optionally further substituted by R', where R' is C 1~3 Alkyl, C 1~3 Alkyl haloalkyl, or C 5~6 It is heteroaryl.

[0008] In some embodiments, each R is independently: [ka] [ka] is selected from.

[0009] In some embodiments, each R2 is independently: [ka] is selected from.

[0010] In some embodiments, the compound (of Formula 2) is [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0011] Various embodiments are directed to compounds of formula 2A and pharmaceutically acceptable salts thereof: [ka] wherein B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each of X, X, and X is independently C, N, or O; and R is -C 1~3 Alkyl-R x , -(CH2)2NR x R y , -CH2C ( R x R y )R a , -CH2C ( R x R y )NR a R b or a 6-membered aryl, and R is optionally R a or R b R2 is H, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 and R1 and R2 groups optionally together form a 5- to 6-membered aryl ring, which is optionally further substituted by R a or R b , or R a and R b R4 is further substituted by halo or C 1~3 alkyl; each R x and R y are independently 5- to 6-membered heterocycles, and each R a and R b independently, C 1~3 Alkyl or C 1~3 haloalkyl, and R a and R bis optionally further substituted with an R' group, which is a 5-membered heteroaryl or a 5- to 6-membered heterocycle.

[0012] In some embodiments, R1 is [ka] is selected from.

[0013] In some embodiments, each R2 is independently: [ka] is selected from.

[0014] In some embodiments, the compound (of Formula 2A) is [ka] [ka] and pharmaceutically acceptable salts thereof.

[0015] Various embodiments are directed to compounds of formula 2B and pharmaceutically acceptable salts thereof: [ka] wherein B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each X is independently C, N, or O; R is H, -C 1~3 Alkyl, 5- to 6-membered heterocycle, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 5- to 10-membered cycloheteroaryl, 5- to 10-membered heteroaryl, or -C(O)R x ;Each R 2a and R 2b are independently H, -C 1~3 Alkyl, 5-6 membered aryl, -NR x (CH2)2R y , -NR x (CH2)3R y , -NRx C(O)(CH2)2R x R y , -O(CH2)2R x , -NH(CH2)CR x R y CH2R a , -NH(CH2)CR x R y CH2NR a R b , -(CH2)3NR x R y , 5- to 10-membered cycloheteroaryl, or —NR x R y R'2 is H or halo; R3 is H, halo, C 1~3 Alkyl, -O(CH2)2NR x R y , -NR x (CH2)2R y , -NR x R y , or -(CH2)3NR x R y R4 is halo; and R1 is optionally R 2a or R 2b and R a or R b and each R, R 2a , R 2b , R'2, and R3 optionally independently represent one or more R a is replaced by R x and R y are independently H, C 1~4 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, -NR a R b and each R x and R y is optionally a 4- to 5-membered heterocycle, and R x and R y are optionally, independently, R a and / or R b each R a and R b are independently H, halo, oxo, cyano, C 1~3 Alkyl, C1~3 Alcohol, C 1~3 Alkoxy, phenyl, -(CH2)2R', 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycle, where R' is a 5-membered heteroaryl.

[0016] In some embodiments, R1 is [ka] is selected from.

[0017] In some embodiments, each R 2a and R 2b is, independently, [ka] is selected from.

[0018] In some embodiments, each R3 is independently: [ka] is.

[0019] In some embodiments, the compound (of Formula 2B) and pharmaceutically acceptable salts thereof are [ka] [ka] is selected from.

[0020] Various embodiments are directed to compounds of formula 3 and pharmaceutically acceptable salts thereof: [ka] wherein n is 1 to 2; B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each of X1, X2, X3, X4, and X5 is independently C, N, or O; R1 is halo, -C 1~4 Alkyl, -NRx R y , -O(CH2)2NR x R y , 6-membered cyclohexyl, 6-membered heterocycle, 6-membered aryl, 6-membered heteroaryl, or 5-10-membered cycloalkyl, and when there are two R groups, the two R groups optionally together form a 6-membered heteroaryl; each (one or more) R groups optionally independently selects one or more R a each R2 is halo or C 1~3 alkoxy; each R3 is independently H, oxo, C 1~3 haloalkyl, or hydroxyalkyl, and when one or more R are hydroxyalkyl, one or more of R optionally form a four-membered heterocycle together with C in formula 3, and each R x and R y are independently H, C 1~3 alkyl, 6-membered aryl, or 6-membered heteroaryl, and each R x and R y optionally, independently, one or more R a Further substituted by R a H, halo, oxo, cyano, C 1~3 haloalkyl, -NR' R', 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycle, and one or more R a optionally, together form a 4- to 5-membered heterocycle; R' is C 1~3 It is alkyl.

[0021] In some embodiments, each R is independently: [ka] [ka] is selected from.

[0022] In some embodiments, each R2 is independently: [ka] is selected from.

[0023] In some embodiments, R3 is [ka] is selected from.

[0024] In some embodiments, the compound (of Formula 3) and pharmaceutically acceptable salts thereof are [ka] [ka] [ka] is selected from.

[0025] Various embodiments are directed to compounds of formula 3A and pharmaceutically acceptable salts thereof: [ka] wherein n is 1 to 2; B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each of X1, X2, and X3 is independently C, N, or O; R1 is C 1~3 alkyl, and R2 is H, halo, C 1~3 Haloalkyl, C 1~4 alkyl, 5-6 membered aryl, 5-6 membered cycloaryl, 5-6 membered heterocycle, 5-10 membered heteroaryl, 5-6 membered cycloaryl; R3 is H or halo; each R4 is independently H, oxo, C 1~3 haloalkyl, or hydroxyalkyl, and when one or more of R4 are hydroxyalkyl, one or more of R4 together with C of Formula 3A optionally form a 4-membered heterocycle; R5 is halo or a 4- to 5-membered heterocycle; each of R1, R2, R4, and R5 optionally independently comprises up to two R a or R b and each R a and R b independently, C1~3 Alkyl, C 1~3 haloalkyl, 5-6 membered heterocycle, 5-6 membered heteroaryl, -N / -NR' R', and R a and R b optionally, together form a 4- to 5-membered heterocycle, R a and R b is optionally further substituted independently by one or more R′ groups, where R′ is halo or C 1~3 It is alkyl.

[0026] In some embodiments, R1 is [ka] is selected from.

[0027] In some embodiments, R2 is [ka] is selected from.

[0028] In some embodiments, R3 is H or F.

[0029] In some embodiments, R4 is [ka] is.

[0030] In some embodiments, R5 is [ka] is.

[0031] In some embodiments, the compound (of Formula 3A) and pharmaceutically acceptable salts thereof are [ka] [ka] is selected from.

[0032] Various embodiments are directed to compounds of formula 3B and pharmaceutically acceptable salts thereof: [ka] where n is 1 to 2; B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each of X1, X2, X3, and X4 is independently C, N, or O; R1 is H, C 1~3 alkyl, or 5- to 6-membered aryl; R1 is optionally one or more R a or R b and each R 2a and R 2b independently, C 1~4 alkyl or 5-6 membered heteroaryl; R and R 2a or R 2b optionally, together form a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, and the optional 5- or 6-membered aryl or 5- or 6-membered heteroaryl may optionally be joined by R a or R b each R3 is independently H, halo, or C 1~3 each R4 is independently H or oxo; each R5 is independently halo or a 4- to 5-membered heterocycle; each R1, R 2a , R 2b , R3, and R5 are optionally independently selected from R a and R b and each R a and R b are independently H, halo, oxo, cyano, or C 1~3 alkyl, and 5- to 6-membered heteroaryl.

[0033] In some embodiments, R1 is [ka] is.

[0034] In some embodiments, each R2a and R 2b is, independently, [ka]

[0035] In some embodiments, each R3 is independently: [ka] is.

[0036] In some embodiments, R4 is H or oxo.

[0037] In some embodiments, R5 is independently: [ka] is.

[0038] In some embodiments, the compound (of Formula 3B) and its pharmaceutically acceptable salts and / or hydrates thereof is [ka] is selected from.

[0039] Various embodiments are directed to methods for inhibiting lipoxygenase activity in cells determined to be in need of lipoxygenase inhibition, the method comprising contacting or administering to the cells a compound having a structure as disclosed in any of the claims, such as claim 1. In some embodiments, the cells are human cells, either in vivo or isolated in vitro. In some embodiments, the cells are cells of a human being determined to be in need of lipoxygenase inhibition or who is suffering from a disorder associated with pathogenic lipoxygenase activity, the disorder being an acute or chronic inflammatory disorder or a neurodegenerative disorder.

[0040] In some embodiments, the disease is (i) an acute or chronic inflammatory disease such as asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherothrombotic stroke, or cardiovascular disease, or (ii) a neurodegenerative disease such as age-related neurodegeneration, amyloid beta-related disease, Alzheimer's disease, ischemia-related disorders, Creutzfeldt-Jakob disease / prion peptide neurotoxicity, ALS, dementia, or Parkinson's disease.

[0041] In some embodiments, the method further includes (i) measuring lipoxygenase activity in a sample from the person; (ii) determining the level of a lipoxygenase metabolite in the sample from the person; and (iii) determining whether the person is ill.

[0042] Various embodiments are directed to pharmaceutical compositions comprising a compound of claim 1 that inhibits lipoxygenase activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0043] Various embodiments are directed to pharmaceutical compositions comprising a compound of claim 4 that inhibits lipoxygenase activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0044] Various embodiments are directed to compositions comprising a compound of Formula 1 above and a second anti-neurodegenerative disease agent.

[0045] Various embodiments are directed to methods of identifying lipoxygenase inhibitors, comprising screening compounds of Formula 1 and / or claim 44 for lipoxygenase inhibitory activity.

[0046]

[0013] Embodiments according to the present disclosure include all combinations of the specific embodiments described. Furthermore, the applicability of the embodiments and the full scope of the invention will become apparent from the detailed description provided herein. However, it will be understood that the detailed description and specific embodiments, while indicating preferred embodiments of the invention, are intended for illustration only, and that various modifications and variations within the spirit and scope of the invention will be apparent to those skilled in the art from the detailed description. The publications, patents, and patent applications mentioned herein, together with the references therein, are incorporated herein in their entirety for all purposes.

[0047] [Detailed Description of the Invention] The following description is provided with the understanding that the present disclosure is an example of the claimed subject matter and is not intended to limit the scope of the appended claims to the particular embodiments set forth. Headings used throughout this disclosure are provided for convenience and should not be construed as limiting the scope of the claims in any way. Embodiments described in any heading may be combined with embodiments described in any other heading.

[0048] As used in the specification and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, reference to "the assay" includes reference to one or more assays, and so forth.

[0049] "C x-y The prefix "" indicates that the following group has x (e.g., 1) to y (e.g., 6) carbon atoms, one or more of which may be replaced by one or more heteroatoms or heteroatom groups in the specified group (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.). For example, "C 1~6"Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "xy-membered" ring, such as "3- to 12-membered heterocycle," refers to a ring containing xy (e.g., 3-12) atoms, up to half of which are heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon, where x and y are numerical ranges. Also, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may use "alkylene" groups, "alkylenyl" groups, or "alkylyl" groups, or "arylene" groups, "arylenyl" groups, or arylyl groups, respectively.

[0050] "Alkyl" refers to any group derived from a straight or branched chain saturated hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propan-1-yl, propan-2-yl (isopropyl), butyl such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), pentyl, hexyl, octyl, decyl, and the like. Unless specifically specified, alkyl groups have 1 to 10 carbon atoms, e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms.

[0051] "Alkenyl" refers to any group derived from a straight or branched chain saturated hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless specifically specified, alkenyl groups have 2 to 10 carbon atoms, e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms.

[0052] "Alkynyl" refers to any group derived from a straight or branched chain saturated hydrocarbon with at least one carbon-carbon triple bond, including groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-CH≡CH), propargyl (-CHC≡CH), (E)-pent-3-en-1-ynyl, and the like. Unless specifically specified, alkenyl groups have 2 to 10 carbon atoms, e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms.

[0053] "Amino" is -NH2. Amino groups may also be substituted with alkyl, carbonyl, and other amino groups as described herein. The term "alkylamino" refers to an amino group substituted with one or two alkyl substituents (e.g., dimethylamino or propylamino).

[0054] "Aryl" refers to any group derived from one or more aromatic rings, i.e., a single aromatic ring, a bicyclic, or a polycyclic system. Aryl groups include, but are not limited to, acenaphthylene, anthracene, azulene, benzene, chrysene, cyclopentadienyl, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, pyrene, and others.

[0055] "Arylalkyl (also aralkyl)" refers to any combination of an aryl group and an alkyl group. Arylalkyls include, but are not limited to, benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl, and the like. Alkylaryl groups contain 6 to 30 carbon atoms; for example, the alkyl group may contain 5 to 10 carbon atoms and the aryl group may contain 5 to 20 carbon atoms.

[0056] "Cycloaryl" is a combination of an aryl group and a ring. Some representative examples of cycloaryl are 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene, 3a,5,6,7-tetrahydro-4H-indene, and the like.

[0057] "Heterocycloaryl" is a combination of an aryl group and a heterocyclic group. Some representative examples of heterocycloaryl are 1,2,3,4-tetrahydroisoquinoline, isochroman, 1,3-dihydroisobenzofuran, isoindoline, and the like.

[0058] "Cycloalkyl" refers to cyclic alkyl and alkenyl groups. Cycloalkyl groups have one or more rings and are fully saturated or partially unsaturated, including fused and bridged groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcyclopropyl (cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl, and the like. Another example is C 5~7 It is a cycloalkenyl.

[0059] "Halo" and "halogen" are fluoro, chloro, bromo, and iodo.

[0060] "Haloalkyl" is an alkyl in which one or more hydrogen atoms have each been replaced by a halogen. Examples include, but are not limited to, alkyl groups such as -CH2Cl, -CH2F, -CH2Br, -CFClBr, -CH2CH2Cl, -CH2CH2F, -CF3, -CH2CF3, -CH2CCl3, etc., as well as perfluoroalkyl groups in which all hydrogen atoms have been replaced by fluorine ions.

[0061] A "hydroxyalkyl" is an alkyl in which one or more hydrogen atoms are respectively replaced by a hydroxy group. Examples include, but are not limited to, -CHOH, -CHCHOH, and -C(CH)OH.

[0062] "Halo 3- to 6-membered heterocyclyl" is a heterocyclyl group substituted with at least one halogen atom at a carbon atom, and may contain multiple halogen atoms, such as 3,3-fluoroacetidinyl.

[0063] "Heteroalkyl" refers to an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom(s) or heteroatom group. Heteroatoms include, but are not limited to, N, P, O, S, etc. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -PH-, -P(O)-, -S(O)-, -S(O)-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or cycloheteroalkyl. Heteroalkyl includes, but is not limited to, -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, -CHNRCH, -CHOH, etc., where R is H, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. Heteroalkyl groups contain 1 to 10 carbons and up to 3 heteroatoms, for example, 1 to 6 carbons and 1 to 2 heteroatoms.

[0064] "Heteroaryl" refers to a monocyclic or polycyclic aryl group, as defined above, in which one or more aromatic carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms or heteroatom groups. Polycyclic systems are included within heteroaryl and may be attached to the ring containing the heteroatom or aryl ring. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthan, etc. Heteroaryl groups may be 5-14, 5-10, or 5-6 membered rings.

[0065] "Heterocycle," "heterocyclic," and "heterocyclyl" refer to saturated or partially unsaturated non-aromatic rings or partially non-aromatic polycyclic ring systems containing at least one heteroatom or heteroatom group, as defined above. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, thiomorpholine, tetrahydro-2H-thiopyran, 1-iminotetrahydro-2H-thiopyran-1-oxide, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazodaline, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems containing one aromatic and one non-aromatic ring, but do not include fully aromatic ring systems. Examples include dihydroquinolines such as 3,4-dihydroquinoline, dihydroisoquinolines such as 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, indoline, isoindoline, isoindolone (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindolin]-3'-one, etc. The heterocyclic group may have a 3- to 12-membered ring, or a 3- to 10-membered ring, or a 3- to 7-membered ring, or a 5- to 6-membered ring.

[0066] "Hydroxyl" and "hydroxy" are used interchangeably and are -OH. "Oxo" is =O, or oxide, and exists as an N-oxide and an S-oxide. When a compound has tautomers, the hydroxyl and oxy groups are interchangeable.

[0067] It is understood that combinations of chemical groups may be used and will be recognized by those skilled in the art. For example, "hydroxyalkyl" refers to an alkyl group with a hydroxy group attached. Many such combinations can be readily envisioned. As used herein, the combinations of substituents are defined as follows: C 1~6Alkylaminocarbonyl (e.g., CH3CH2NHC(O)), C 1~6 Alkoxycarbonyl (e.g., CHO-C(O)-), 5- to 7-membered heterocyclyl-C 1~6 Alkyl (e.g., piperazinyl-CH2-), C 1~6 Alkylsulfonyl-5- to 7-membered heterocyclyl (e.g., CH3S(O)2-morpholinyl), 5- to 7-membered heterocyclyl-C 1~6 Alkoxy (e.g., pyrrolidinyl-O-), 5- to 7-membered heterocyclyloxy, (4- to 7-membered heterocyclyl)-4- to 7-membered heterocyclyl (e.g., oxetanylpyrrolidinyl-), C 3~6 Cycloalkylaminocarbonyl (e.g., cyclopropyl-NH-C(O)-), 5- to 7-membered heterocyclyl-C 2~6 Alkenyl (e.g., N-piperazinyl-CHC≡CCH—), and C 6~10 Includes arylaminocarbonyl (e.g., phenyl-NH-C(O)-).

[0068] A "pharmaceutically acceptable salt" is a salt of a compound that is pharmaceutically acceptable and that possesses (or is convertible into a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, tosylic acid, pivalic acid, etc., and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or by coordination with an organic base, such as diethanolamine, triethanolamine, N-methylglucamine, etc. Also included within this definition are ammonium and substituted or quaternized ammonium salts. Non-limiting representative examples of pharmaceutically acceptable salts are described in S. M. Berge et al. (1977) J. Pharma Sci 66(1), 1-19, and in Remington: The Science and Practice of Pharmacy (2005), 21st Edition, R. Hendrickson, ed., Lippincott, Williams & Wilkins, Inc., Philadelphia, PA, p. 723, Table 38-5, which are incorporated herein by reference.

[0069] As used herein and in the claims, "hydrogen" and "H," "oxygen" and "O," "carbon" and "C," and "nitrogen" and "N" are used interchangeably and refer to a hydrogen atom, an oxygen atom, a carbon atom, and / or a nitrogen atom, respectively. As used herein and in the claims, various rings of compounds are referred to by "ring A" and "A" and "ring B" and "B," each referring to a specific ring. Similarly, as used herein and in the claims, various groups of compounds may often be referred to interchangeably by the suffix "atom" or "group," such as "R" and "R group," each referring to a specific atom or chemical group.

[0070] "Subject" and "subjects" refer to humans, domestic animals (e.g., dogs and cats), livestock (e.g., cows, horses, sheep, goats, pigs), laboratory animals (e.g., rats, hamsters, guinea pigs, pigs, pocket pets, dogs, monkeys), and others.

[0071] "Treating" a disease and "treatment" of a disease are as follows: (1) Preventing or reducing the risk of disease progression, i.e., preventing the progression of clinical symptoms of disease in subjects who have been exposed to or are susceptible to the disease but have not yet experienced or manifested symptoms of the disease; (2) inhibiting the disease, i.e., preventing or reducing the progression of the disease or its clinical symptoms; (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms; Includes:

[0072] "Effective amount" refers to an amount that may be effective to elicit a desired biological, clinical, or medical response, including the amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in that treatment. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. An effective amount includes a range of amounts.

[0073] The compounds of the present disclosure include solvates, hydrates, tautomers, stereoisomers, and salts thereof.

[0074] Pharmaceutical compositions of compounds of the disclosed formulae may be administered in single or multiple doses by any acceptable pharmaceutical administration technique with similar utility, including, for example, rectally, orally, nasally, transdermally, by intraarterial, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, or topical injection, as an inhalant, or via an impregnated or coated device such as a stent or a tubular polymer inserted into an artery, as described in the incorporated patents and patent applications. In one embodiment, the compounds described herein may be administered orally. Oral administration may be, for example, via capsules or enteric-coated tablets.

[0075] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0076] In certain embodiments, the compound of the present disclosure is a compound of formula 1: [ka] where n is either 0, 1, or 2. When n is 0, B and the NH group connected to ring A (as shown) are directly bonded, and R3 is absent. When n is 1 or 2, the R3 group may be replaced by any of the CH atoms. For example, each of the 1 or 2 CH atoms is independently substituted or unsubstituted by an R3 group.

[0077] In some embodiments, ring A is a 6-membered heteroaryl. In some embodiments, ring A is a 6-membered aryl. In some embodiments, ring A is a 6-membered heteroaryl substituted with 1, 2, or 3 R groups, which may be the same or different. In some embodiments, ring A is a 6-membered aryl substituted with 1, 2, or 3 R groups, which may be the same or different. In some embodiments, ring A is a heteroaryl, and X, X, and X are independently C, N, or O.

[0078] In some embodiments, ring B is a 5- to 6-membered heterocycle, a 5- to 6-membered aryl, or a 5- to 6-membered cyclohexyl. In some embodiments, it can be a 5- to 6-membered heterocycle independently substituted with up to three R groups. In some embodiments, ring B can be a 5- to 6-membered aryl independently substituted with up to three R groups. In some embodiments, it can be a 5- to 6-membered cyclohexyl independently substituted with up to three R groups. In some embodiments, ring B is a 5- to 6-membered aryl, and X4, X5, and X6 are all carbon. In some embodiments, ring B is a 5- to 6-membered heterocycle or a 5- to 6-membered aryl, and each of X4, X5, and X6 can independently be C, N, or O.

[0079] In some embodiments, R is halo, C 1~4 Alkyl, -NR x R y , -O(CH2)2R x , -O(CH2)2NR x R y , -NHC(O)-C 2~4 Alkyl, -(CH2)3NR x R y , -NH(CH2)2NR x R y , -NHCH2CR x R y R z, 5-6 membered aryl, 5-10 membered heterocycle, 5-10 membered heteroaryl, or 5-10 membered heterocyclic aryl. As used herein, heterocyclic aryl refers to two rings, such as a heterocycle, fused to an aryl. In some embodiments, R1 is independently one, two, or three R a or R b In some embodiments, two R groups may together form a 5- to 6-membered heteroaryl, a 5- to 6-membered heterocycle, a 5- to 6-membered cycloalkyl, or a 5- to 6-membered aryl, and when two R groups together form a 5- to 6-membered heteroaryl, a 5- to 6-membered heterocycle, a 5- to 6-membered cycloalkyl, or a 5- to 6-membered aryl, the formed 5- to 6-membered heteroaryl, a 5- to 6-membered heterocycle, a 5- to 6-membered cycloalkyl, or a 5- to 6-membered aryl may be further substituted by one, two, or three R a It may be further substituted by groups.

[0080] In some embodiments, R1 is [ka] [ka] is.

[0081] In some embodiments, each R is independently a halogen atom, C 1~2 Methoxy, or C(O)OR x In some embodiments, two R groups on adjacent atoms optionally together form a 5- to 6-membered aryl ring. A 5- to 6-membered heteroaryl ring may independently be one, two, or three R a It may be unsubstituted or further substituted with groups.

[0082] In some embodiments, R2 is [ka] is.

[0083] In some embodiments, R3 is C 1~3 It is either haloalkyl or oxo.

[0084] In some embodiments, each R x , R y , R z are independently hydrogen, halogen atoms, C 1~2 Alkyl, C 1~2 Alcohol, C 1~2 Alkoxy, C 1~2 Haloalkyl or NR a R b In some embodiments, each R x , R y , R z are independently a cyano group, oxygen or oxo, C 1~3 Alkyl, -C(O)OR', C 1~3 In some embodiments, R may be haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle. x , R y , R z Any two of may together form a 4- to 6-membered heterocycle or a 5- to 6-membered aryl ring. x , R y , R z is R a and / or R b It may be further substituted by:

[0085] In some embodiments, each R a and R b are independently a hydrogen atom, a halogen atom, a cyano group, an oxygen atom, or C 1~3 Alkyl, -C(O)OR', C 1~3 In some embodiments, R is haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle. a and / or R b may be independently further substituted by R'.

[0086] In some embodiments, R' is C 1~3 Alkyl, C1~3 Haloalkyl, or C 5~6 It may be heteroaryl.

[0087] In some embodiments, the disclosed compounds are pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula 1.

[0088] A compound having the structure of Formula 1 is [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0089] In some embodiments, the disclosed compounds have a structure corresponding to Formula 2: [ka]

[0090] In some embodiments of Formula 2, ring A is either a 6-membered heteroaryl or a 6-membered aryl. In some embodiments of Formula 2, ring A is either a 6-membered heteroaryl or a 6-membered aryl, and ring A is independently substituted with 1, 2, or 3 R groups. In some embodiments of Formula 2, ring A is either an unsubstituted 6-membered heteroaryl or an unsubstituted 6-membered aryl. In some embodiments of Ring A, ring A is a 6-membered heteroaryl, and X, X, and X are independently C, N, or O.

[0091] In some embodiments of Formula 2, Ring B is either a 6-membered heterocycle, a 6-membered aryl, or a 6-membered cyclohexyl. In some embodiments of Formula 2, Ring B is either a 6-membered heterocycle, a 6-membered aryl, or a 6-membered cyclohexyl, and Ring B is unsubstituted. In some embodiments of Formula 2, Ring B is either a 6-membered heterocycle, a 6-membered aryl, or a 6-membered cyclohexyl, and Ring B is independently substituted with up to two R groups. Further, in embodiments of Ring B, Ring B is a 6-membered heterocycle, and X4 can be C, N, or O.

[0092] In some embodiments of Formula 2, R is a halogen atom, C 1~4 Alkyl, -NR x R y , -O(CH2)2R x R y , -O(CH2)2NR x R y , -NHC(O)-alkyl 2~4 , -(CH2)3NR x R y , -NH(CH2)2NR x R y , -NHCH2CR x R y R z , 5-6 membered aryl, 5-10 membered heterocycle, 5-10 membered heteroaryl, or 5-10 membered heterocyclic aryl. In some embodiments, two R1 groups together may form a 5-6 membered heteroaryl, a 5-6 membered heterocycle, a 5-6 membered cycloalkyl, or a 5-6 membered aryl. In some embodiments, two R1 groups together may form a 5-6 membered heteroaryl, a 5-6 membered heterocycle, a 5-6 membered cycloalkyl, or a 5-6 membered aryl, and the 5-6 membered heteroaryl, 5-6 membered heterocycle, 5-6 membered cycloalkyl, and 5-6 membered aryl are each independently selected from 1 to 3 R1 groups. a In some embodiments, each of the 1 to 3 R groups is independently selected from the group consisting of 1 to 3 R a group and / or 1 to 3 R bIt may be further substituted by groups.

[0093] In some embodiments of Formula 2, R1 is [ka] is.

[0094] In some embodiments of Formula 2, each R is independently a halogen atom, C 1~2 Methoxy, or C(O)OR x It may be.

[0095] In some embodiments of Formula 2, each R2 is independently: [ka] It may be.

[0096] In some embodiments of Formula 2, R and / or R can be one or more R x , R y , and / or R z groups, and each R x , R y , and R z The groups are independently hydrogen atoms, halogen atoms, C 1~2 Alkyl, C 1~2 Alcohol, C 1~2 Alkoxy, C 1~2 Haloalkyl, or -NR a R b In some embodiments of Formula 2, R x , R y , or R z If there are two, R x , R y , or R z Any two of may together form a 4- to 6-membered heterocycle or a 5- to 6-membered aryl ring. In some embodiments of Formula 2, each R x , R y , or R z is R a group or R a Groups and R bIt may be further substituted by groups.

[0097] In some embodiments of Formula 2, each R a and R b are independently a hydrogen atom, a halogen atom, a cyano group, an oxygen atom, or C 1~3 Alkyl, -C(O)OR', C 1~3 In some embodiments of Formula 2, R may be haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle. a and / or R b independently, C 1~3 Alkyl, -C(O)OR', C 1~3 haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle; R a and / or R b may be further substituted by R'. In some embodiments of Formula 2, the disclosed compounds are either pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula 2.

[0098] In some embodiments, exemplary compounds of Formula 2 and pharmaceutically acceptable salts thereof have the following structure: [ka] [ka] [ka]

[0099] In some embodiments, the disclosed compounds have a structure corresponding to Formula 2A. [ka] wherein, in some embodiments, Ring B can be cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl. In some embodiments of Formula 2A, Ring B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and X can be any of C, N, or O. In some embodiments of Formula 2A, Ring B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and Ring B can be independently substituted with up to two R groups.

[0100] In some embodiments, R1 and R3 of ring A may be independently C, N, or O.

[0101] In some embodiments, R1 is -C 1~3 Alkyl-R x , -(CH2)2NR x R y , -CH2C ( R x R y )R a , -CH2C ( R x R y )NR a R b or a 6-membered aryl. In some embodiments, R is substituted and R is R a and / or R b In some embodiments, R2 is a hydrogen atom, a halogen atom, a C 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~2 In some embodiments, each R x and R y may independently be a 5- or 6-membered heterocycle. In some embodiments, R1 and R2 may together form a 5- or 6-membered heterocycle. In some embodiments, when R1 and R2 together form a 5- or 6-membered heterocycle, the 5- or 6-membered heterocycle is a and / or R bIn some embodiments, R3 is a hydrogen atom or a halogen atom. In some embodiments, R4 is a halogen atom or a C 1~3 In some embodiments, R1, R2, R3, and / or R4 can independently be one or more R a and / or R b In some embodiments, each R a and R b independently, C 1~3 Alkyl or C 1~3 haloalkyl, and R a and R b may be further substituted with an R' group. In some embodiments, R' may be a 5-membered heteroaryl or a 5-6 membered heterocycle. The disclosed compounds are either pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula 2A.

[0102] In some embodiments of Formula 2A, R1 is [ka] is selected from.

[0103] In some embodiments of Formula 2A, R2 is [ka] is selected from.

[0104] In some embodiments, compound 2A and its pharmaceutically acceptable salts have the following structure: [ka] [ka]

[0105] In some embodiments, the disclosed compounds have a structure corresponding to Formula 2B. [ka] wherein Ring B is either cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl. In some embodiments, Ring B is either cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and the cyclohexyl, 6-membered heterocycle, 6-membered aryl, or 6-membered heteroaryl may be further substituted independently with up to two R groups.

[0106] In some embodiments, X is either N or O when ring B is a 6-membered heterocycle or a 6-membered heteroaryl.

[0107] In some embodiments, each X in ring A and / or ring B can independently be C, N, or O. In some embodiments, ring A can be independently substituted with R, R', and / or one or two R.

[0108] In some embodiments, R is a hydrogen atom, —C 1~3 Alkyl, 5- to 6-membered heterocycle, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 5- to 10-membered cycloheteroaryl, 5- to 10-membered heteroaryl, or -C(O)R x It may be.

[0109] In some embodiments, each R 2a and R 2b are independently a hydrogen atom, -C 1~3 Alkyl, 5-6 membered aryl, -NR x (CH2)2R y , -NR x (CH2)3R y , -NR x C(O)(CH2)2R x R y , -O(CH2)2R x , -NH(CH2)CR x R y CH2R a , -NH(CH2)CR x Ry CH2NR a R b , -(CH2)3NR x R y , 5- to 10-membered cycloheteroaryl, or —NR x R y It may be.

[0110] In some embodiments, R'2 can be a hydrogen atom or a halogen atom.

[0111] In some embodiments, each R is independently a hydrogen atom, a halo atom, C 1~3 Alkyl, -O(CH2)2NR x R y , -NR x (CH2)2R y , -NR x R y , or -(CH2)3NR x R y It may be.

[0112] In some embodiments, R4 is a halogen atom.

[0113] In some embodiments, R is R 2a or R 2b may form a 5- or 6-membered heterocycle together with any one of the following.

[0114] In some embodiments, R is R 2a or R 2b and form a 5- or 6-membered heterocycle together with any one of R a or R b It may be further substituted by:

[0115] In some embodiments, each R, R′, R 2a , R 2b and / or R3 is one or more R a It may be further substituted by groups.

[0116] In some embodiments, each R x and Ry are independently hydrogen atoms, C 1~4 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, -NR a R b In some embodiments, R x and R y together form a 4- to 5-membered heterocycle, and / or R x and R y The 4- to 5-membered heterocycle formed by R a or R b may be replaced by

[0117] In some embodiments, each R a and R b are independently a hydrogen atom, a halogen atom, an oxygen atom, a cyano group, or C 1~3 Alkyl, C 1~3 Alcohol, C 1~3 It may be alkoxy, phenyl, -(CH2)2R', a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocycle.

[0118] In some embodiments, R' is a 5-membered heteroaryl.

[0119] In some embodiments, the disclosed compounds are either pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula 2B. In some embodiments of Formula 2B, R1 is: [ka] [ka] is.

[0120] In some embodiments of Formula 2B, each R 2a and R 2b is, independently, [ka] is selected from.

[0121] In some embodiments of Formula 2B, R3 is [ka] is.

[0122] In some embodiments of Formula 2B, the compound and its pharmaceutically acceptable salts and hydrates have the following structure: [ka] [ka] [ka]

[0123] In some embodiments, the disclosed compounds have a structure corresponding to Formula 3: [ka]

[0124] In some embodiments, n is 1-2.

[0125] In some embodiments, each X1, X2, X3, and X4 of ring A may independently be C, N, or O.

[0126] In some embodiments, ring A may be independently substituted with 1, 2, or 3 R 1 groups.

[0127] In some embodiments, Ring B can be either cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl.

[0128] In some embodiments, ring B is a 6-membered heterocycle or a 6-membered heteroaryl, and X5 can be N or O. In some embodiments, X5 can be C.

[0129] In some embodiments, R is a halo atom, C 1~4 Alkyl, -NR x R y , -O(CH2)2NR x R y , a 6-membered cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, a 6-membered heteroaryl, or a 5- to 10-membered cycloalkyl.

[0130] In some embodiments, when there are two R groups, the two R groups together may form a 6-membered heteroaryl ring. In some embodiments, when there are two R groups, the two R groups together may form a 6-membered heteroaryl ring, and either of the two R groups may be joined by one or more R a It may be substituted by a group.

[0131] In some embodiments, each R2 is a halogen atom or C 1~3 It is an alkoxy group.

[0132] In some embodiments, the or each R is independently a hydrogen atom, an oxygen atom, C 1~3 In some embodiments, when one or more R3 is hydroxyalkyl, one or more of R3 optionally form a four-membered heterocycle together with C in formula 3.

[0133] In some embodiments, each R x and R y are independently hydrogen atoms, C 1~3 In some embodiments, R may be alkyl, a 6-membered aryl, or a 6-membered heteroaryl. x and R y is C 1~3 alkyl, 6-membered aryl, or 6-membered heteroaryl; R x and / or R y is one or more R a It may be further substituted by:

[0134] In some embodiments, R a is a halogen atom, an oxygen atom, a cyano group, C 1~3 In some embodiments, one or more R is haloalkyl, —NR′ R′, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycle. a may together form a 4- or 5-membered heterocycle.

[0135] In some embodiments, R' is C 1~3 In some embodiments, the disclosed compounds are either pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula 3.

[0136] In some embodiments, Formula 3 is: [ka] is.

[0137] In some embodiments of Formula 3, R1 is [ka] [ka] is.

[0138] In some embodiments of Formula 3, R2 is [ka] is.

[0139] In some embodiments of Formula 3, R3 is [ka] is.

[0140] In some embodiments of Formula 3, the compound and its pharmaceutically acceptable salts have the following structure: [ka] [ka] [ka]

[0141] In certain embodiments, compounds of the present disclosure are compounds of formula 3A: [ka] is.

[0142] In some embodiments, n is 1-2.

[0143] In some embodiments, Ring B is either cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl.

[0144] In some embodiments, each X1, X2, and X3 may independently be C, N, or O.

[0145] In some embodiments, R is C 1~3 In some embodiments, R is C 1~3 alkyl and one or more R a or R b It may be further substituted by:

[0146] In some embodiments, R2 is a hydrogen atom, a halogen atom, C 1~3 Haloalkyl, C 1~4 In some embodiments, R3 is a hydrogen atom or a halogen atom. In some embodiments, R4 or each R4 is independently a hydrogen atom, an oxygen atom, a C 1~3In some embodiments, when one or more of R4 is hydroxyalkyl, one or more of R4 may optionally form a 4-membered heterocycle together with C in Formula 3A. In some embodiments, R5 may be a halogen atom or a 4- to 5-membered heterocycle. In some embodiments, R1, R2, R4, and R5 may be joined by up to two R a or R b groups, and each R a and R b The group is C 1~3 Alkyl, C 1~3 haloalkyl, 5-6 membered heterocycle, 5-6 membered heteroaryl, -N / -NR'R'. In some embodiments, R1, R2, R4, and R5 are R a or R b substituted by R a or R b may together form a 4- to 5-membered heterocycle. a and R b is further independently substituted with one or more R' groups, and when there is more than one R' group, the R' groups can be either the same or different. In some embodiments, the R' groups are halogen atoms or C 1~3 In some embodiments, the disclosed compounds are either pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of formula 3A:

[0147] In some embodiments of Formula 3A, R1 is [ka] is.

[0148] In some embodiments of Formula 3A, R2 is [ka] is.

[0149] In some embodiments of Formula 3A, R3 and R5 are independently H or F atoms. In some embodiments, R3 is an F atom. In some embodiments of Formula 3A, R4 is [ka] is.

[0150] In some embodiments, the compound of formula 3A is [ka] is.

[0151] In some embodiments of Formula 3A, the compounds and pharmaceutically acceptable salts thereof have the following structure: [ka] [ka]

[0152] In certain embodiments, the compound of the present disclosure is a compound of formula 3B. [ka]

[0153] In some embodiments, n is 1-2.

[0154] In some embodiments, Ring B can be cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl. In some embodiments, Ring B can be cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and can be further substituted with up to two R groups.

[0155] In some embodiments, each X1, X2, X3, and X4 may independently be C or N.

[0156] In some embodiments, R is a hydrogen atom, C 1~3 In some embodiments, R is a hydrogen atom, C 1~3 alkyl, or 5- to 6-membered aryl, and R1 is C 1~3 When R1 is alkyl or 5- to 6-membered aryl, R1 may be one or more R a or R b may be replaced by

[0157] In some embodiments, each R 2a and R 2b independently, C 1~4 In some embodiments, R and R are alkyl or 5- to 6-membered heteroaryl. 2a or R 2b may optionally together form a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, and the optional 5- or 6-membered aryl or 5- or 6-membered heteroaryl may optionally be joined by R a or R b is further substituted by

[0158] In some embodiments, each R is a hydrogen atom, a halogen atom, or C 1~3 It is an alkoxy.

[0159] In some embodiments, the or each R is independently a hydrogen atom or an oxygen atom. In some embodiments, R is a halogen atom or a 4- to 5-membered heterocycle. In some embodiments, each R, R 2a , R 2b , R3, and R5 independently represent up to two R a and R b is further substituted by R a and R b is a hydrogen atom, a halogen atom, an oxygen atom, a cyano group, or C 1~3 alkyl, 5-6 membered heteroaryl. In some embodiments, the disclosed compounds are either pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula 3B:

[0160] In some embodiments of Formula 3B, R1 is [ka] is.

[0161] In some embodiments of Formula 3B, each R 2a and R 2b is, independently, [ka] is.

[0162] In some embodiments of Formula 3B, each R3 is [ka] is.

[0163] In some embodiments of Formula 3B, R4 is a hydrogen atom or an oxygen atom. In some embodiments of Formula 3B, R5 is [ka] In some embodiments of Formula 3B, R5 is [ka] is.

[0164] In some embodiments, Formula 3B is: [ka] is.

[0165] In some embodiments of Formula 3B, the compound and its pharmaceutically acceptable salts have the following structure: [ka]

[0166] Some embodiments are directed to methods for inhibiting lipoxygenase in cells determined to be in need of lipoxygenase inhibition, the methods comprising contacting (or administering to) the cells with a compound having any of the structures disclosed above, wherein the cells are human cells, either in vivo or isolated in vitro. In some embodiments, the cells are cells from a human being determined to be in need of lipoxygenase inhibition or from a human being suffering from a disease associated with pathogenic lipoxygenase activity, the disease being an acute or chronic inflammatory disease or a neurodegenerative disease. Some methods further comprise (i) measuring lipoxygenase activity in a sample from the human being; (ii) determining the level of a lipoxygenase metabolite in the sample from the human being; and (iii) determining whether the human being is afflicted with the disease. In some methods, the disease is (i) an acute or chronic inflammatory disease such as asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherothrombotic stroke, or cardiovascular disease, or (ii) a neurodegenerative disease such as age-related neurodegeneration, amyloid beta-related disease, Alzheimer's disease, ischemia-related disorders, Creutzfeldt-Jakob disease / prion peptide neurotoxicity, ALS, dementia, or Parkinson's disease.

[0167] Further contemplated are pharmaceutical compositions comprising the above-disclosed compounds that inhibit lipoxygenase activity, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. Further contemplated are pharmaceutical compositions comprising the above-disclosed compounds that inhibit lipoxygenase activity, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. Further contemplated are compositions comprising the above-disclosed compounds of Formula 1 and a second anti-neurodegenerative disease agent. Further contemplated are methods for identifying lipoxygenase inhibitors, comprising screening one or more of the above-disclosed compounds for lipoxygenase inhibitory activity.

[0168] As described in more detail herein, the subject compounds may be used in pharmaceutically acceptable alternative forms, such as pharmaceutically acceptable salts, prodrugs (e.g., sulfamates, phosphates, esters, ethers, amides, etc.), and the like. Unless specified, all descriptions of compounds according to Formula 1 herein include such alternative forms. Pharmaceutically acceptable and pharmaceutically active combinations of such forms, such as salts of prodrugs, are also possible and are included within the scope of the present disclosure. Some examples of salts and prodrugs are described herein.

[0169] In some embodiments, the subject compounds are used to prepare compositions effective against neurodegenerative diseases (also known as neurodegenerative conditions). Examples of neurodegenerative diseases include neuroinflammation-associated neurodegeneration, Alzheimer's disease, ischemia-related disorders, Creutzfeldt-Jakob disease / prion peptide neurotoxicity, ALS, dementia, or Parkinson's disease. In some embodiments, treating a neurodegenerative disease involves administering a formulation containing the subject compounds. As described in more detail herein, the compositions may include one or more active agents and one or more pharmaceutically acceptable excipients. Furthermore, the compositions may be formulated into any suitable dosage form.

[0170] In some embodiments, the subject compounds comprise a compound according to Formula 1 as the only active agent; such formulations may also contain pharmaceutically inactive ingredients, such as carriers.

[0171] In some embodiments, the subject compound is administered in combination with one or more additional anti-neurodegenerative disease drugs. The additional drugs may be administered together with the subject compound in a single formulation, and thus simultaneously. Alternatively, the additional drugs may be administered in separate formulations, with a dosing regimen separate from that of the formulation containing the subject compound. In such embodiments, the two dosing regimens may be related, e.g., the second formulation may be administered simultaneously with, immediately before, or immediately after the administration of the first formulation. Examples of additional anti-neurodegenerative disease drugs include acetylcholinesterase inhibitors (e.g., tacrine, rivastigmine, galantamine, donepezil), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), huperzine A, latrepirdine, hypothalamic proline-rich peptide 1 (RPR-1), and others.

[0172] The subject compounds may be administered as a free base or in the form of salts, esters, amides, prodrugs, active metabolites, or analogs, where the salts, prodrugs, active metabolites, or analogs are pharmaceutically acceptable and pharmacologically active as currently defined. Salts, esters, amides, prodrugs, active metabolites, or analogs, and other derivatives of active drugs, may be prepared by standard methods known in the art of synthetic organic chemistry, as described, for example, in J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structures," 5th Edition (New York: Wiley-Interscience, 2001), and Green, "Protective Groups in Organic Synthesis," 3rd Edition (New York: Wiley-Interscience, 1999).

[0173] Pharmaceutically acceptable salts may be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or a combination thereof.

[0174] Suitable organic acids for preparing acid addition salts include, for example, acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, phthalic acid, terephthalic acid, and the like. 1~6 Alkyl and C6-C 12 Acid addition salts include arylcarboxylic acids, dicarboxylic acids, tricarboxylic acids, and aryl and alkylsulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc. Suitable inorganic acids for preparing acid addition salts include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Acid addition salts may be reconverted to the free base by treatment with a suitable base.

[0175] Suitable organic acids for preparing base addition salts include salts of primary, secondary, and tertiary amines such as trimethylamine, triethylamine, tripropylamine, N,N-dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins; cyclic amines such as caffeine, N-ethylmorpholine, N-ethylpiperidine, and purines; and amines such as betaine, choline, and procaine. Suitable inorganic acids for preparing base addition salts include salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium, or zinc, such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, etc. A base addition salt may be reconverted to the free base by treatment with a suitable acid.

[0176] Prodrugs and active metabolites may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system. For example, a compound according to Formula 1 may be in the form of a medically acceptable prodrug, such as a sulfamate prodrug.

[0177] Other derivatives and analogs of the active agents may be prepared using standard methods known in the art of synthetic organic chemistry, or may be deduced by reference to the relevant literature.

[0178] Any compound of the present disclosure may be the active agent in a subject formulation. Formulations containing a compound of the present disclosure may contain one, two, or three or more subject compounds and may include one or more additional additives, such as analgesics and other antibiotics. "Any compound of the present disclosure" refers to any compound selected from the subject compound itself (i.e., as the free base), its salt, prodrug, etc.

[0179] The amount of active agent in the formulation is typically about 0.05 wt% to about 95 wt% based on the total weight of the formulation. For example, the amount of active agent may be about 0.05 wt% to about 50 wt%, or about 0.1 wt% to about 25 wt%. Alternatively, the amount of active agent in the formulation may be adjusted to achieve a desired dosage.

[0180] Formulations containing the subject compounds may be presented in unit dosage form or in multi-dose containers with an optional preservative to enhance shelf life.

[0181] The compositions of the present disclosure may be administered to a patient by any suitable method. Generally, both systemic and local administration methods are possible. It will be apparent to those skilled in the art that the administration method to be selected will be influenced by many factors, such as the treatment condition, administration frequency, dosage, and the patient's wishes and requirements. For example, some methods are suitable for rapidly administering a large amount of active agent, while other methods are suitable for slowly and steadily administering the active agent. Examples of administration methods suitable for providing the compounds of the present disclosure include parenteral and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery by these methods are known in the art.

[0182] For example, formulations containing compounds of the present disclosure may be administered parenterally, such as via intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using a bolus injection and / or continuous infusion. Generally, liquid formulations are used for parenteral administration.

[0183] The compositions may also be administered via the digestive tract, such as orally or rectally. Examples of formulations suitable for administration via the digestive tract include tablets, capsules, troches, chewing gum, aqueous solutions, and suppositories.

[0184] The formulations may also be administered transmucosally. Transmucosal administration includes oral (including buccal and sublingual), nasal, vaginal, and rectal administration. Formulations suitable for transmucosal administration are known and include tablets, chewing gum, mouthwashes, lozenges, suppositories, gels, creams, liquids, and pastes.

[0185] The formulations may also be administered transdermally, which may be accomplished, for example, using topically applied creams, liquids, pastes, gels, and what are often referred to as transdermal "patches."

[0186] The formulations may also be administered via the respiratory tract. Respiratory administration may be achieved via oral or nasal inhalation using aerosol, dry powder, or liquid formulations, etc. Aerosol inhalers and imitation cigarettes are examples of respiratory dosage forms.

[0187] Liquid formulations include solutions, suspensions, and emulsions. For example, a solution may be an aqueous solution of the active agent, which may contain one or more of propylene glycol, polyethylene glycol, etc. Aqueous suspensions can be prepared by dispersing finely divided active ingredients in water containing a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents. Also included are solid formulations that are converted to liquids shortly before use.

[0188] Tablets and lozenges comprise, for example, compressed sucrose, lactose, and a flavored base such as acacia or tragacanth, and an effective amount of the active agent. Generally, lozenges contain the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia.

[0189] The subject compounds inhibit one or more lipoxygenases, for example, by at least 50%, at least 75%, at least 85%, at least 95%, or at least 98%. In some embodiments, the compounds are selective inhibitors, i.e., inhibitors of a subsection of the LOX family of enzymes. In some embodiments, the subject compounds may inhibit 5-LOX, 12-LOX, or 15-LOX. In some embodiments, the subject compounds may inhibit various combinations of 5-LOX, 12-LOX, and 15-LOX, such as inhibiting 5-LOX and 12-LOX, inhibiting 5-LOX and 15-LOX, inhibiting 12-LOX and 15-LOX, and / or inhibiting 5-LOX, 12-LOX, and 15-LOX.

[0190] The subject compounds are particularly useful therapeutically for the treatment of diseases associated with pathogenic lipoxygenase activity, such as acute or chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherothrombotic stroke, or cardiovascular disease, and neurodegenerative diseases, such as age-related neurodegeneration, amyloid beta-related diseases, Alzheimer's disease, ischemia-related disorders, Creutzfeldt-Jakob disease / prion peptide neurotoxicity, ALS, dementia, or Parkinson's disease.

[0191] For example, the method includes administering the subject compound to a patient suffering from, at risk of, or exhibiting a neurodegenerative disease such as Alzheimer's disease, etc., that has a deficiency of the subject compound. In some embodiments, the subject compound is used in a method for reducing or eliminating symptoms associated with the subject disease. For example, the method includes contacting a nervous system cell or a cell located in the nervous system, or contacting a tissue associated with the nervous system, where the contacting results in one or more of inhibiting further neurodegeneration, inhibiting the growth and development of abnormal cells, inhibiting the growth of non-cellular matter in the nervous system, reducing neuroinflammation, reducing symptoms associated with the neurodegenerative disease, etc.

[0192] In some embodiments, the subject compounds are used to prepare compositions effective in treating a subject disease, which compositions include one or more active agents and one or more pharmaceutically acceptable salts, as described in more detail herein.

[0193] In some embodiments, treating a target condition involves administering a formulation comprising a target compound. As described in more detail herein, the formulation may include any of a number of additives and / or additional active agents and may be prepared in any of a variety of dosage forms. In some embodiments, treating a target condition using a compound involves determining that a person has a target condition associated with pathogenic lipoxygenase activity. This determination may be made by any means appropriate for the particular condition, including blood tests or imaging studies.

[0194] In some embodiments, the methods involve measuring the patient's lipoxygenase activity (such as 5-LOX, 12-LO, 15-LOX, and / or various combinations) before, after, or both before and after treatment with a compound of interest. In some embodiments, the methods involve measuring the patient's level of a lipoxygenase metabolite. An example metabolite is 5-HETE. In these methods, measuring the enzyme activity or measuring the metabolite level may be performed using any suitable sample from the person, such as a bodily fluid (e.g., blood, urine).

[0195] Various embodiments are made in accordance with and claim the benefit of the basic provisional patent application (Serial No. 62 / 953,023) entitled "Lipoxygenase Inhibitors," filed December 23, 2019, the general description and specific teachings of which are incorporated herein by reference in their entirety. For example, embodiments of the present application and / or the provisional application may be combined to different degrees (including in their entirety). Reference may be made to the experimental teachings and underlying references provided in the basic provisional application. The embodiments described in the provisional application are not intended to be limiting in any way to the entire technical disclosure or any portion of the claimed disclosure, unless specifically stated otherwise.

[0196] All patents, patent applications, and publications mentioned herein are incorporated herein by reference in their entirety. However, when patents, patent applications, and publications containing definitions of terms are incorporated, it is understood that the definitions of those terms apply to the patents, patent applications, and publications in which they are incorporated, and not to the remainder of the specification, particularly the claims of this application.

[0197] While the present disclosure will be described in conjunction with certain specific embodiments, it will be understood that the descriptions and the examples that follow are for illustrative purposes only and are not intended to limit the scope of the present disclosure. It will be understood by those skilled in the art that various modifications and equivalent substitutions may be made thereto without departing from the scope of the present disclosure, and other aspects, advantages, and modifications will be apparent to those skilled in the art. DETAILED DESCRIPTION OF THE INVENTION

[0198] The compounds disclosed herein have been discovered to inhibit the activity of Akt and ERK by inhibiting the metabolism of arachidonic acid by 12-LOX.

[0199] 5-LOX FI assay fluorescence assay

[0200] The enzyme assay (100 μL) contained 50 mM Tris, 0.1 mM pH 7.5 EDTA, 0.3 mM CaCl2, 20 μM AA, 100 μM ATP, 1 μM DHR123, and recombinant 5-LOX cell lysate (0.5 μL / 100 μL). 1 μL of inhibitor (dissolved in DMSO) was placed in a 96-well assay microplate, followed by the addition of 40 μL of a solution containing 5-LOX enzyme. The enzyme was preincubated with the compound for 15 minutes. The assay was initiated by adding 40 μL of a substrate solution containing AA and ATP and 20 μL of a solution containing DHR23. The enzyme reaction proceeded for 30 minutes, and kinetic readings were performed on a SpectraMax Paradigm (Molecular Devices) at 500 nm excitation and 536 nm emission. The inhibition rate was calculated for each compound dose using a four-parameter logistic model or a sigmoidal dose-response logistic model. 50 was calculated for curve fitting.

[0201] 12-LOX / 15-LOX assay fluorescence assay

[0202] The enzyme assay (100 μL) contained 50 mM Tris, 0.1 mM pH 7.5, 0.05% Tween-20, 20 μM AA, 1 μM DHR123, and 100 nM recombinant 12-LOX enzyme / 100 nM recombinant 15-LOX enzyme. Inhibitor (dissolved in DMSO) was placed in a 96-well assay microplate at 1 μL, followed by the addition of 40 μL of a solution containing 12-LOX / 15-LOX enzyme. The enzyme was preincubated with the compound for 15 minutes. The assay was initiated by adding 40 μL of a substrate solution containing AA / LA and 20 μL of a solution containing DHR23. The enzyme reaction proceeded for 30 minutes, and kinetic measurements were performed at 500 nm excitation and 536 nm emission on a SpectraMax Paradigm (Molecular Devices). The inhibition rate was calculated for each compound dose using a four-parameter logistic model or a sigmoidal dose-response logistic model. 50 was calculated for curve fitting.

[0203] Inhibitory activity against a panel of lipoxygenases was demonstrated in cell-based assays, e.g., for 5-LOX, a human 5-LOX luminescence-based enzyme assay (Anal. Biochem., 364:204) was used, and for 12-LOX, a colorimetric method for determining platelet 12-LOX activity (Anal. Biochem., 231:354) was used. Table 1 shows the results for example compounds on 5-LOX, 12-LOX, and 15-LOX.

[0204] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15

[0205] General information on examples All evaporations were performed in vacuo on a rotary evaporator. Analytical examples were dried under vacuum (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized under UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (200-300 mesh). Solvent systems were reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (600 MHz) spectrometer. 1H chemical shifts are reported in δ values ​​in ppm using deuterated solvents as internal standards. Data are reported by chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration.

[0206] Example 1 [ka]

[0207] Example Routes for Example 1 [ka]

[0208] Synthesis of 2-(2-bromo-6-nitrophenoxy)-N,N-dimethylethanamine (25-1): [ka] A mixture of 25-1 (4.0 g, 18.4 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (5.3 g, 36.8 mmol), and K2CO3 (7.6 g, 55.2 mmol) in acetone (50 mL) was heated to reflux for 16 h. The mixture was diluted with EtOAc (150 mL). The organic layer was washed with water (100 mL), saturated aqueous bicarbonate solution, and brine (100 mL). The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc = 1 / 4) on silica gel to give 25-2 (2.3 g, 43% yield) as an oil. MS Calcd: 288.0; MS Found: 289.1 [M+H] + It was.

[0209] Synthesis of 2-(2-(dimethylamino)ethoxy)-N-(4-methoxybenzyl)-3-nitroaniline (25-3): [ka] A mixture of 25-2 (600 mg, 2.1 mmol), (4-methoxyphenyl)methanamine (288 mg, 2.1 mmol), Pd(dba) (183 mg, 0.2 mmol), X-phos (173 mg, 0.3 mmol), and CsCO (1.4 g, 4.2 mmol) in dioxane (20 mL) was stirred at 95 °C for 16 h under nitrogen. The reaction mixture was cooled to room temperature, and then filtered and washed with EtOAc (50 mL). The organic phase was washed successfully with water (50 mL) and brine (50 mL). The ethyl acetate was dried over MgSO and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc = 1 / 5) on silica gel to give 25-3 (230 mg, approximately 32% yield) as a solid. MS Calcd:345.2;MS Found:346.3[M+H] + It was.

[0210] Synthesis of 2-(2-(dimethylamino)ethoxy)-N1-(4-methoxybenzyl)benzene-1,3-diamine (SS20308-0025-01): [ka] A solution of 25-3 (200 mg, 0.6 mmol), Zn powder (195 mg, 3.0 mmol) in HOAc (0.1 mL) and MeOH (10 mL) was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature, then filtered and washed with MeOH (20 mL). The organic phase was concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford SS20308-0015-01 (62 mg, approximately 34% yield) as a solid.

[0211] 1 H NMR (400MHz, CdCl3) δ7.30(d,J=8.4Hz,2H), 6.87(d,J=8.8Hz,2H), 6.77(dd,J=8.0,8.0Hz,1H), 6.12(dd,J=8.0,1. 2Hz,1H), 6.08(d,J=8.4Hz,1H), 4.24(s,2H), 3.93(t,J=5.0Hz,2H), 3.80(s.3H), 2.55(t,J=5.0Hz,2H), 2.17(s,6H)

[0212] Example 2 [ka]

[0213] Example Routes for Example 2 [ka]

[0214] Synthesis of 2-(2-(dimethylamino)ethoxy)-3-nitro-N-phenylaniline (52-2): [ka] A mixture of 52-1 (500 mg, 1.73 mmol), aniline (322 mg, 3.46 mmol), Pd2dba3 (79 mg, 0.09 mmol), Xant-Phos (98 mg, 0.17 mmol), and Cs2CO3 (845 mg, 2.56 mmol) in toluene (25 mL) was heated to reflux overnight under nitrogen. The mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 8 / 1) to afford 52-2 (500 mg, 96% yield) as a solid. MS Calcd: 301.1; MS Found: 302.4 [M+H] + It was.

[0215] 2-(2-(dimethylamino)ethoxy)-N 1 Synthesis of -phenylbenzene-1,3-diamine (52-3): [ka] To a solution of 52-2 (500 mg, 1.66 mmol) in MeOH (20 mL) was added PD / C (10%, 50 mg). The mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction mixture was then filtered. The filtrate was concentrated to afford 52-3 (370 mg, approximately 82% yield) as an oil. MS Calcd: 271.2; MS Found: 272.4 [M+H] + It was.

[0216] 2-(2-(dimethylamino)ethoxy)-N 1 Synthesis of -(4-methoxybenzyl)-1,3-diamine (SS20308-0052-01): [ka] A solution of 52-3 (290 mg, 1.07 mmol) and p-methoxybenzaldehyde (146 mg, 1.07 mmol) in HOAc (1 mL) and MeOH (20 mL) was stirred at 70 °C for 2 h. After cooling to room temperature, NaBH (40 mg, 1.07 mmol) was added, and the mixture was stirred for 30 min at room temperature. The mixture was then poured into water and basified with 1 N NaOH until the pH reached 9. The mixture was then extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by prep-HPLC to afford SS20308-0052-01 (60 mg, approximately 14% yield) as a solid, MS Calcd: 391.2; MS Found: 392.2 [M+H]. + It was.

[0217] 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H), 7.26(d,J=8.8Hz,2H), 7.16(dd,J=8.4,7.2Hz,2H), 6.98(d,J=7.6Hz,2H), 6.87(dd,J=8.8Hz,2H), 6.74(dd,J=7.6 ,7.2,Hz,1H), 6.69(t,J=8.4Hz,1H)6.45(dd,J=8.0,0.8Hz,1H),6.12~6.05 (m,2H), 4.21(d,J=6.0Hz,2H), 3.87(t,J=4.8Hz), 3.70(s,3H), 2.14(s,6H)

[0218] Example 3 [ka]

[0219] Example Routes for Example 2 [ka]

[0220] Synthesis of 3-bromo-2-(2-(dimethylamino)ethoxy)aniline (53-1): [ka] A mixture of 52-1 (1.0 g, 3.46 mmol), iron powder (1.9 g, 34.59 mmol), and NH4Cl (93 mg, 1.74 mmol) in ethanol (16 mL) and water (4 mL) was stirred at 85 °C for 2 h. The reaction mixture was then filtered through celite. The filtrate was basified with NaOH until the pH reached 10.0-11.0 and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated to afford 53-1 (0.7 g, approximately 78% yield) as a solid. MS Calcd: 258.0; MS Found: 259.2 [M+H] + It was.

[0221] Synthesis of N-(3-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-3-oxo-3-phenylpropanamide (53-2): [ka] A mixture of 53-1 (410 mg, 1.58 mmol) and ethyl benzoylacetate (760 mg, 3.95 mmol) was stirred and heated at 140 °C for 30 min under microwave irradiation and nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1, 5 / 1, 3 / 1, 1 / 1, CHCl / MeOH = 20 / 1) to afford 53-2 (400 mg, approximately 62% yield) as a solid. MS Calcd: 404.1; MS Found: 405.3 [M+H] + It was.

[0222] Synthesis of 7-bromo-8-(2-(dimethylamino)ethoxy)-4-phenylquinolin-2(1H)-one (53-3): [ka] 53-2 (500 mg, 1.23 mmol) in H2SO4 (5 mL) was stirred and heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured onto ice, basified with NaOH (40%) until the pH reached 9.0-10.0, and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by prep-TLC (CHCl2 / MeOH = 20 / 1) to afford 53-3 (70 mg, approximately 15% yield) as an oil. MS Calcd: 386.1; MS Found: 387.2 [M+H] + It was.

[0223] Synthesis of 8-(2-(dimethylamino)ethoxy)-7-(4-methoxybenzylamino)-4-phenylquinolin-2(1H)-one (SS20308-0053-01): [ka] A mixture of 53-3 (85 mg, 0.22 mmol), (4-methoxyphenyl)methanamine (151 mg, 1.1 mmol), Xantphos (13 mg, 0.022 mmol), Pd(dba) (10 mg, 0.011 mmol), and anhydrous cesium carbonate (108 mg, 0.33 mmol) was suspended in toluene (4 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere overnight and then filtered, rinsing with EtOAc. The filtrate was concentrated and purified by prep-TLC (CHCl / MeOH = 20 / 1) to afford SS20308-0053-01 (61 mg, approximately 63% yield) as a solid. MS Calcd: 443.2; MS Found: 444.3 [M+H] + It was.

[0224] 1H NMR (400MHz, DMSO-d6) δ12.58(brs,1H), 7.51~7.44(m,3H), 7.41~7.36(m,2H), 7.26(d,J=8.8Hz,2H), 6.88~6.83(m,3H), 6.77(t,J=6.2Hz, 1H), 6.44(d,J=9.2Hz,1H), 5.97(d,J=1.6Hz,1H), 4.34(d,J=6.4Hz,2H), 4.01~4.09(m,2H), 3.70(s,3H), 2.66(t,J=4.2Hz,2H), 2.35(s,6H)

[0225] Example 4 [ka]

[0226] Example Routes for Example 4 [ka]

[0227] Synthesis of 2-(2-bromo-6-nitrophenoxy)-N,N-dimethylethanamine (71-1): [ka] A mixture of 71-1 (3.0 g, 13.6 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (2.2 g, 15.0 mmol), K2CO3 (3.8 g, 27.3 mmol), and NaI (1.0 g, 6.8 mmol) in acetone (25 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (50 mL) and then extracted with EtOAc (30 mL × 5). The organic layer was washed with brine and concentrated to dryness to afford 71-2 (1.1 g, approximately 28% yield) as an oil. MS Calcd: 288.0; MS Found: 289.1 [M+H] + It was.

[0228] Synthesis of N-benzyl-2-(2-(dimethylamino)ethoxy)-3-nitroaniline (71-3): [ka] To a solution of 71-2 (300 mg, 1.0 mmol) in toluene (3 mL), benzylamine (111 mg, 1.0 mmol), Cs2CO3 (696 mg, 2.0 mmol), XantPhos (62 mg, 0.1 mmol), and Pd2dba3 (98 mg, 0.1 mmol) were added, and the reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and then diluted with EtOAc (20 mL). The organic layer was washed with brine and concentrated to dryness. The residue was purified by column chromatography (EtOAc / petroleum ether = 1 / 1 to 1 / 0) to afford 71-3 (200 mg, 59% yield) as a solid. MS Calcd: 315.2; MS Found: 316.3 [M+H] + It was.

[0229] N 1 Synthesis of -benzyl-2-(2-(dimethylamino)ethoxy)benzene-1,3-diamine (71-4): [ka] To a solution of 71-3 (200 mg, 0.63 mmol) in MeOH (6 mL) was added Zn powder (166 mg, 2.5 mmol) and HOAc (152 mg, 2.5 mmol), and the reaction mixture was then stirred at 60 °C for 4 h. The mixture was diluted with water and then extracted with EtOAc (150 mL). The organic layer was washed with brine and concentrated to dryness to afford 71-4 (200 mg, crude) as an oil. MS Calcd: 285.2; MS Found: 286.2 [M+H] + It was.

[0230] N 1 -Benzyl-N 3Synthesis of -(3-chloropyridin-2-yl)-2-(2-(dimethylamino)ethoxy)benzene-1,3-diamine (SS20308-0071-01): [ka] To a solution of 71-4 (380 mg, 1.33 mmol) in toluene (15 mL), 2,3-dichloropyridine (237 mg, 1.60 mmol), Cs2CO3 (868 mg, 2.66 mmol), XantPhos (77 mg, 0.1 mmol), and Pd2dba3 (61 mg, 0.13 mmol) were added, and the reaction mixture was then stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by prep-TLC (EtOAc) to afford SS20308-0071-01 (420 mg, approximately 80% yield) as an oil. MS Calcd: 396.2; MS Found: 397.3 [M+H] + It was.

[0231] 1 H NMR (400MHz, CDCl3) δ8.08(dd,J=4.8,1.6Hz,1H), 7.69~7.67(m,2H), 7.49(dd,J=7. 6,1.6Hz,1H), 7.34~7.32(m,2H), 7.28~7.24(m,2H), 7.20~7.19(m,1H), 6.90(dd,J= 8.4,8.0Hz,1H), 6.61(dd,J=8.0,6.4Hz,1H), 6.26(dd,J=8.0,1.2Hz,1H), 5.93(t,J =5.2Hz,1H), 4.28(d,J=5.6Hz,2H), 3.94(d,J=4.4Hz,2H), 2.56(br,2H), 2.09(s,6H)

[0232] Example 5 [ka]

[0233] Example Routes for Example 4 [ka]

[0234] Synthesis of 4-bromo-2-nitrobiphenyl (95-2): [ka] A mixture of 95-1 (6.00 g, 21.36 mmol), phenylboronic acid (2.60 g, 21.36 mmol), Pd(PPh) and NaCO in toluene / HO (60 mL, 5 / 1) was stirred overnight at 90 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether) to afford 95-2 (3.70 g, approximately 62% yield) as an oil.

[0235] 1 H NMR (400MHz, CDCl3) δ8.00(d,J=2.0Hz,1H), 7.75(dd,J=8.4Hz,2.0Hz,1H), 7.45~7.40(m,3H), 7.33(d,J=8.4Hz,1H), 7.31~7.27(m,2H)

[0236] Synthesis of 4-bromobiphenyl-2-amine (95-3): [ka] A mixture of 95-2 (3.70 g, 13.30 mmol), Zn powder (8.70 g, 133.00 mmol), and HOAc (35 mL) in EtOH (35 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water. The mixture was basified with 40% NaOH until the pH reached 10. The resulting mixture was filtered through celite and washed with MeOH. The filtrate was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 95-3 (1.90 g, approximately 58% yield) as an oil. MS Calcd: 247.0; MS Found: 248.1 [M+H] + It was.

[0237] Synthesis of 4-bromo-N-(2-chloroethyl)biphenyl-2-amine (95-4): [ka] To a solution of 95-3 (1.75 g, 7.05 mmol) in MeOH (20 mL), 2-chloroacetaldehyde (2.77 g, 14.11 mmol, 40%), AcOH (846 mg, 14.11 mmol), and NaBHCN (887 mg, 14.11 mmol) were added, and the reaction mixture was then stirred overnight at 40 °C. Next, the reaction mixture was poured into water and basified with 1 N NaOH until the pH reached 10. The mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 95-4 (2.00 g, approximately 91% yield) as an oil. MS Calcd: 309.0; MS Found: 309.8 [M+H] + It was.

[0238] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromobiphenyl-2-amine (95-5): [ka] A mixture of 95-4 (2.00 g, 6.44 mmol), 1H-1,2,4-triazole (677 mg, 9.66 mmol), and CsCO (4.20 g, 12.88 mmol) in CHCN (40 mL) was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to afford 95-5 (2.10 g, approximately 95% yield) as an oil. MS Calcd: 342.1; MS Found: 342.8 [M+H] + It was.

[0239] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -benzylbiphenyl-2,4-diamine (SS20308-0096-01): [ka] A mixture of 95-5 (200 mg, 0.58 mmol), benzylamine (75 mg, 0.70 mmol), Pd2dba3 (53 mg, 0.06 mmol), XantPhos (67 mg, 0.12 mmol), and Cs2CO3 (378 mg, 1.16 mmol) in toluene (20 mL) was stirred overnight at 110 °C under a N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-TLC to afford SS20308-0096-01 (25 mg, approximately 12% yield) as a solid. MS Calcd: 396.2; MS Found: 370.1 [M+H] + It was.

[0240] 1H NMR (400MHz, CDCl3) δ7.88(s,1H), 7.86(s,1H), 7.44~7.40(m,2H), 7.40~7.33(m,4H), 7.31~7.26(m,2H), 7.23~7.19(m,2H), 6.93(d,J=8.0Hz,1H) ), 6.15(dd,J=8.0Hz,2.0Hz,1H), 5.92(d,J=2.0Hz,1H), 4.39(s,2H), 4.19(t,J=6.0Hz,2H), 4.14(s,2H), 4.09(t,J=6.0Hz,2H), 3.55~3.48(m,2H)

[0241] Example 6 [ka]

[0242] Example Routes for Example 4 [ka]

[0243] Synthesis of N-(4-bromo-3-nitrophenyl)benzamide (135-2): [ka] To a solution of 135-1 (432 mg, 2 mmol) in DCM (50 mL) was added benzoyl chloride (420 mg, 3 mmol). The mixture was stirred at room temperature for 2 h, and the solution was washed with HO (40 mL) and brine (40 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 5 / 1 to 1 / 1) to afford 135-2 (350 mg, approximately 54% yield) as a solid. MS Calcd: 320.0; MS Found: 321.2 [M+H] + It was.

[0244] Synthesis of N-(2-nitro-[1,1'-biphenyl]-4-yl)benzamide (135-2): [ka] To a mixture of 135-2 (320 mg, 1 mmol) and phenylboronic acid (146 mg, 1.2 mmol) in toluene / HO (30 mL, 3 mL) was added CsCO (652 mg, 2 mmol) and xphosPdG (20 mg). The mixture was heated to reflux for 6 h. The mixture was diluted with EtOAc (50 mL), and the organic layer was washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) on silica gel to afford 135-3 (230 mg, approximately 72% yield) as an oil. MS Calcd: 318.1; MS Found: 319.2 [M+H] + It was.

[0245] Synthesis of N-(2-amino-[1,1'-biphenyl]-4-yl)benzamide (135-4): [ka] To a mixture of 135-3 (230 mg, 0.72 mmol) in DCM (50 mL) was added HOAc (5 mL) and Zn powder (150 mg) at room temperature. The mixture was stirred at room temperature for 4 h, and the organic layer was concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 1) to afford 135-4 (140 mg, approximately 68% yield) as a solid. MS Calcd: 288.1; MS Found: 288.2 [M+H] + It was.

[0246] Synthesis of N-(2-((2-chloroethyl)amino)-[1,1'-biphenyl]-4-yl)benzamide (135-5): [ka] To a mixture of 135-4 (144 mg, 0.5 mmol) in EtOH (30 mL), 2-chloroacetaldehyde (1 mL) and HOAc (1 mL) were added at room temperature, followed by the addition of NaBH3CN. The mixture was stirred for 6 h at room temperature, filtered, and the filtrate was purified by column chromatography (hexane / EtOAc = 2 / 1) on silica gel to afford 135-5 (85 mg, approximately 48% yield) as a solid. MS Calcd: 350.1; MS Found: 350.2 [M+H] + It was.

[0247] Synthesis of N-(2-((2-(1H-1,2,4-triazol-1-yl)ethyl)amino)-[1,1'-biphenyl]-4-yl)benzamide (SS20038-0135): [ka] To a mixture of 135-5 (85 mg, 0.24 mmol) in DCF (15 mL) was added 1H-1,2,4-triazole (60 mg, 1 mmol) and CsCO (326 mg, 1 mmol) at room temperature. The mixture was stirred at 80 °C for 8 h, filtered, and the solid was washed with DCM (50 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (DCM / MeOH = 15 / 1) to afford SS20038-0135 (25 mg, approximately 27% yield) as a solid. MS Calcd: 383.5; MS Found: 384.2 [M+H] + It was.

[0248] 1H NMR (400MHz, DMSO-d6) δ3.50(br,J=5.77Hz,2H), 4.42(t,J=6.02Hz,2H), 4.80(s,1H), 6.97(d,J=8.53Hz,1H), 7.23~7.28(m,4H), 7.34(s,1H), 6.93(d,J=8.0Hz,1H), 6.15(dd,J=8.0Hz,2.0Hz,1H), 7.41(d,J=7.53Hz,2H), 7.53~7.63(m,3H), 7.96~8.00(m,3H), 8.48(s,1H), 10.12(s,2H)

[0249] Example 7 [ka]

[0250] Example Routes for Example 7 [ka]

[0251] Synthesis of 5-bromobiphenyl-2-amine (145-2): [ka] A mixture of 145-1 (6.40 g, 37.82 mmol) and NBS (6.70 g, 37.82 mmol) in DMF (10 mL) was stirred overnight at 0 °C. Then, the mixture was poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 145-2 (5.7 g, approximately 57.6% yield) as an oil. MS Calcd: 247.0; MS Found: 248.2 [M+H] + It was.

[0252] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (145-3): [ka] A mixture of 145-2 (5.70 g, 22.97 mmol), 2-chloroacetaldehyde (2.1 g, 27.56 mmol), and NaBHCN (1.44 g, 22.97 mmol) in EtOH / AcOH (60 mL, 5 / 1) was stirred overnight at room temperature. The resulting mixture was washed with EtOAc (30 mL × 3), and the organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 145-3 (6.0 g, approximately 84% yield) as a solid. MS Calcd: 309.0; MS Found: 310.0 [M+H] + It was.

[0253] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (145-4): [ka] A solution of 145-3 (5.00 g, 16.10 mmol), 1H-1,2,4-triazole (1.33 g, 19.32 mmol), and CsCO (15.73 g, 48.30 mmol) in CHCN (15 mL) was stirred at 80 °C for 4 h. The mixture was then poured into water and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 145-4 (3.8 g, approximately 70% yield) as a solid. MS Calcd: 342.1; MS Found: 343.9 [M+H] + It was.

[0254] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of -benzylbiphenyl-2,5-diamine (SS20308-0145-01): [ka] A mixture of 145-4 (450 mg, 1.31 mmol), benzylamine (420 mg, 3.93 mmol), Pd(OAc) (29 mg, 0.13 mmol), P(tBu)HBF (76 mg, 0.26 mmol), and NaOtBu (378 mg, 3.93 mmol) in toluene (5 mL) was stirred overnight at 110 °C under a N atmosphere. The reaction mixture was then filtered and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0145-01 (100 mg, approximately 21% yield) as an oil. MS Calcd: 369.2; MS Found: 370.3 [M+H] + It was.

[0255] 1 H NMR (400MHz, CDCl3) δ7.93(s,1H), 7.89(s,1H), 7.39~7.43(m,5H), 7.32~7.37(m,3H), 7.29~7.31(m,1H), 7.25~ 7.28(m,1H), 6.64(d,J=2Hz,1H), 6.56~6.7(m,1H), 4.30(t,J=5.6Hz,4H), 3.66(brs,1H), 3.55(t,J=5.2Hz,2H)

[0256] Example 8 [ka]

[0257] Example Routes for Example 8

[0258] Synthesis of 5-bromobiphenyl-2-amine (146-2): [ka] A mixture of 146-1 (6.40 g, 37.82 mmol) and NBS (6.70 g, 37.82 mmol) in DMF (10 mL) was stirred overnight at 0 °C. Then, the mixture was poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 146-2 (5.7 g, approximately 57.6% yield) as an oil. MS Calcd: 247.0; MS Found: 248.2 [M+H] + It was.

[0259] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (146-3): [ka] A mixture of 146-2 (5.70 g, 22.97 mmol), 2-chloroacetaldehyde (2.1 g, 27.56 mmol), and NaBHCN (1.44 g, 22.97 mmol) in EtOH / AcOH (60 mL, 5 / 1) was stirred overnight at room temperature. The resulting mixture was washed with ethyl acetate (30 mL × 3), and the organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 146-3 (6.0 g, approximately 84% yield) as a solid. MS Calcd: 309.0; MS Found: 310.0 [M+H] + It was.

[0260] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (146-4): [ka] A solution of 146-3 (5.00 g, 16.10 mmol), 1H-1,2,4-triazole (1.33 g, 19.32 mmol), and CsCO (15.73 g, 48.30 mmol) in CHCN (15 mL) was stirred at 80 °C for 4 h. The mixture was then poured into water and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 146-4 (3.8 g, approximately 70% yield) as a solid. MS Calcd: 342.1; MS Found: 343.9 [M+H] + It was.

[0261] Synthesis of N-(6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)biphenyl-3-yl)benzamide (SS20308-0146-01): [ka] A mixture of 146-4 (350 mg, 1.02 mmol), benzamide (372 mg, 3.06 mmol), Pd(OAc) (22 mg, 0.10 mmol), t-Bu-Bretphos (97 mg, 0.20 mmol), and CsCO (997 mg, 3.06 mmol) in t-BuOH (5 mL) was stirred at 130 °C by MW under a N atmosphere for 1 h. The reaction mixture was then filtered and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0146-01 (50 mg, approximately 13% yield) as an oil. MS Calcd: 384.2; MS Found: 384.2 [M+H] + It was.

[0262] 1H NMR (400MHz, DMSO-d6) δ9.99(s,1H), 8.46(s,1H), 7.96(s,1H), 7.91~7.93(m,2H), 7.43~7.59(m,7H), 7.37(d,J=7.2Hz) ,1H), 7.28(d,J=6.8Hz,2H), 6.72(d,J=8.8Hz,1H), 4.66(t,J=6.4Hz,1H), 4.36(t,J=6.0Hz,2H), 3.49(q,J=6.0Hz,2H)

[0263] Example 9 [ka]

[0264] Example Routes for Example 9 (SS20308-0211-01 & SS20308-0225-01) [ka]

[0265] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-4-nitroaniline (111-2): [ka] A solution of 211-1 (2.20 g, 10.00 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine hydrochloride (1.78 g, 12.00 mmol), and K2CO3 (4.15 g, 30.00 mmol) in DMSO (10 mL) was stirred overnight at room temperature. The mixture was then poured into water and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 211-2 (2.00 g, approximately 64% yield) as a solid. MS Calcd: 311.0; MS Found: 312.0 [M+H] + It was.

[0266] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)-4-nitroaniline (211-3): [ka] A mixture of 211-2 (2.00 g, 6.41 mmol), 7-(4,4,5,5-tetramethyl-(1,3,2-dioxaborolan-2-yl)-1H-indole (2.34 g, 9.61 mmol), Pd(dppf)Cl (469 mg, 0.64 mmol), and NaBHCN (2.66 g, 19.23 mmol) in DME / HO (10 mL, 5 / 1) was stirred at 80 °C for 2 h under a N atmosphere. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 211-3 (1.80 g, approximately 81% yield) as a solid. MS Calcd: 348.1; MS Found:394.4[M+H] + It was.

[0267] N 1 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)benzene-1,4-diamine (211-4): [ka] A mixture of 211-3 (1.00 g, 2.87 mmol) and 10% Pd / C (339 mg, 1.38 mmol) in MeOH (10 mL) was stirred at room temperature under an H atmosphere for 3 h. The reaction mixture was then cooled to room temperature and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 211-4 (0.78 g, approximately 86% yield) as a solid. MS Calcd: 318.2; MS Found: 319.0 [M+H] + It was.

[0268] N 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(1H-indol-7-yl)benzene-1,4-diamine (SS20308-0225-01): [ka] A mixture of 211-4 (600 mg, 1.88 mmol), 4-fluorobenzaldehyde (281 mg, 2.26 mmol), and NaBH(CHCOO) (479 mg, 2.26 mmol) in DCM (10 mL) was stirred overnight at room temperature. The mixture was then poured into water and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0225-01 (360 mg, approximately 45% yield) as a solid. MS Calcd: 426.2; MS Found: 427.0 [M+H] + It was.

[0269] 1 H NMR (400MHz, CD3OD-d4) δ8.12(s,1H), 7.80(s,1H), 7.55(d,J=8.0Hz,1H), 7.40(q,J=5.6Hz,2H), 7.16(d,J=3.2Hz,1H), 7.01~7.08(m,3H), 6.88(d,J=6.8Hz,1H), 6.65~6.62(m,3H), 6.49(d,J=3.2Hz,1H), 4.20~4.26(m,4H), 3.46~3.50(m,2H)

[0270] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(1H-indolin-7-yl)benzene-1,4-diamine (SS20308-0211-01): [ka] A mixture of SS20308-0225-01 (50 mg, 0.117 mmol) and NaBHCN (8 mg, 0.117 mmol) in AcOH (2 mL) was stirred overnight at 0 °C. The residue was then purified by Prep-HPLC to afford SS20308-0211-01 (20 mg, approximately 40% yield) as a solid. MS Calcd: 428.2; MS Found: 429.0 [M+H] + It was.

[0271] 1 H NMR (400MHz, DMSO-d4) δ8.43(s,1H), 7.94(s,1H), 7.36~7.40(m,2H), 7.11~7.15(t,2 H), 7.01(d,J=7.2Hz,1H), 6.71~6.73(d,J=8.0Hz,1H), 6.56~6.62(m,1H), 6.49(q,J= 2.4Hz,1H), 6.39(d,J=2.4Hz,1H), 5.63~5.66(m,1H), 4.69(s,2H), 4.28~4.30(m,2H) , 4.17(d,J=5.6Hz,1H), 4.08~4.11(d,J=m,1H), 3.24~3.29(m,4H), 2.92~2.94(m,2H)

[0272] Example 10 [ka]

[0273] Example Routes for Example 10 [ka]

[0274] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-bromo-5-chloropyridin-2-amine (212-2): [ka] To a solution of 212-1 (500 mg, 2.38 mmol) in DMF (6 mL) was added KCO (1.31 g, 9.50 mmol) and 1H-1,2,4-triazole-1-ethanamine:hydrochloride (1:2) (355 g, 2.38 mmol), and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO, and concentrated in vacuo to afford 212-2, which was used in the next step without further purification.

[0275] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-3-phenylpyridin-2-amine (212-3): [ka] A mixture of 212-2 (300 mg, 0.99 mmol), phenylboronic acid (121 mg, 0.99 mmol), Pd(Phh3)4 (115 mg, 0.10 mmol), and K2CO3 (274 mg, 1.98 mmol) in DME (20 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 212-3 (170 mg, approximately 57% yield) as an oil. MS Calcd: 299.1; MS Found: 300.1 [M+H] + It was.

[0276] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of -benzyl-3-phenylpyridine-2,5-diamine (SS20308-0212-01): [ka] A mixture of 212-3 (100 mg, 0.33 mmol), phenylmethanamine (71 mg, 0.67 mmol), Pd(dba) (31 mg, 0.03 mmol), X-phos (32 mg, 0.07 mmol), and CsCO (217 mg, 0.67 mmol) in Tol (10 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO, and concentrated in vacuo. The residue was purified by prep-HPLC to afford SS20308-0212-01 (7 mg, 6% yield) as an oil. MS Calcd: 370.2; MS Found: 371.0 [M+H] + It was.

[0277] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H), 7.92(s,1H), 7.50(d,J=2.8Hz,1H), 7.43~7.21(m,10H), 6.80(d,J=2.8Hz,1 H), 6.66(t,J=6.4Hz,1H), 5.01(t,J=6.0Hz,1H), 4.31(t,J=6.0Hz,2H), 4.23(d,J=6.0Hz,2H), 3.59~3.54(m,2H)

[0278] Example 11 [ka]

[0279] Example Routes for Example 11 [ka]

[0280] Synthesis of 5-nitro-4-phenylpyridin-2(1H)-one (213-2): [ka] A mixture of phenylboronic acid (1.3 g, 11.0 mmol), 213-1 (2.0 g, 7.3 mmol), Pd(dppf)Cl (534 mg, 0.73 mmol), and CsCO (3.0 g, 21.9 mmol) in DME (50 mL) and water (5 mL) was stirred at 100 °C for 18 h. After the reaction was completed, the reaction mixture was concentrated and quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over NaSO, concentrated in vacuo, and then purified by CC (petroleum ether / EtOAc = 5 / 1) to afford 213-2 (800 mg, approximately 51% yield) as a solid. MS Calcd: 216.1; MS Found: 217.4 [M+H] + It was.

[0281] Synthesis of 2-chloro-5-nitro-4-phenylpyridine (213-3): [ka] A solution of 213-2 (800 mg, 3.7 mmol) in POCl (10 mL) was stirred at 80 °C for 18 h. After the reaction was completed, the reaction mixture was concentrated and quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined layers were dried over NaSO, concentrated in vacuo, and then purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 213-3 (700 mg, approximately 81% yield) as a solid. MS Calcd: 234.0; MS Found: 235.3 [M+H] + It was.

[0282] Synthesis of N-benzyl-5-nitro-4-phenylpyridin-2-amine (213-4): [ka] A mixture of phenylmethanamine (385 mg, 3.6 mmol), 213-3 (700 mg, 3 mmol), and K2CO3 (828 mg, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. After the reaction was completed, the reaction mixture was concentrated and quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined layers were dried over Na2SO4, concentrated in vacuo, and then purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 213-4 (600 mg, approximately 66% yield) as a solid. MS Calcd: 305.1; MS Found: 306.4 [M+H] + It was.

[0283] N 2 Synthesis of -benzyl-4-phenylpyridine-2,5-diamine (213-5): [ka] A mixture of 213-4 (800 mg, 2.6 mmol), Fe (728 mg, 13 mol), and NH4CL (aq, 2 mL) in EtOH (20 mL) was stirred at 70 °C for 18 h. After the reaction was completed, the reaction mixture was concentrated and quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to afford 213-5 (500 mg, approximately 70% yield) as a solid. MS Calcd: 275.1; MS Found: 276.4 [M+H] + It was.

[0284] N 2 -Benzyl-N 5 Synthesis of -(2-chloroethyl)-4-phenylpyridine-2,5-diamine (213-6): [ka] A mixture of 213-5 (250 mg, 0.91 mmol), 2-chloroacetaldehyde (213 mg, 2.73 mmol), and NaBHCN (118 mg, 1.82 mmol) in EtOH (10 mL) was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated and quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to afford 213-6 (180 mg, approximately 53% yield) as a solid. MS Calcd: 337.1; MS Found: 338.4 [M+H] + It was.

[0285] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -benzyl-3-phenylpyridine-2,5-diamine (SS20308-0213-01): [ka] A mixture of 1H-1,2,4-triazole (40 mg, 0.6 mmol), 213-6 (100 mg, 0.3 mmol), and KCO (120 mg, 0.9 mmol) in CHCN (5 mL) was stirred at 80 °C for 2 days. After the reaction was complete, the reaction mixture was concentrated, quenched with water (10 mL), and extracted with EtOAc (10 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by Prep-HPLC to afford SS20308-0213-01 (14 mg, approximately 13% yield) as a solid. MS Calcd: 370.5; MS Found: 371.3 [M+H] + It was.

[0286] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H), 7.93(s,1H), 7.54(s,1H), 7.45~7.38(m,3H), 7.36~7.27(m,6H), 7.22~7.18(m,1H) , 6.46~6.44(m,1H), 6.31(s,1H), 4.42(d,J=6.4Hz,2H), 4.30(t,J=6.0Hz,2H), 4.06(t,J=6.4Hz,1H), 3.33~3.31(m,2H)

[0287] Example 12 [ka]

[0288] Example Routes for Example 12 [ka]

[0289] Synthesis of 6-chloro-2-phenylpyridin-3-amine (214-2): [ka] A solution of 214-1 (2.0 g, 9.64 mmol), phenylboronic acid (1.18 g, 9.64 mmol), Pd(dppf)Cl (394 mg, 0.48 mmol), and potassium carbonate (4.0 g, 28.92 mmol) was suspended in DME (20 mL) and water (4 mL). The reaction mixture was heated at 80 °C overnight, then filtered and rinsed with EtOAc. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1, 5 / 1) to afford compound 214-2 (1.4 g, approximately 71% yield) as a solid. MS Calcd: 204.1; MS Found: 205.1 [M+H] + It was.

[0290] Synthesis of 6-chloro-N-(2-chloroethyl)-2-phenylpyridin-3-amine (214-3): [ka] A mixture of 214-2 (1.0 g, 4.89 mmol), 2-chloroacetaldehyde (3.84 g, 19.55 mmol, 40% in water), NaBHCN (461 mg, 7.34 mmol), and AcOH (2 mL) in EtOH (20 mL) was stirred overnight at room temperature. The reaction mixture was basified with NaHCO solution and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was used in the next step without further purification. MS Calcd: 266.0; MS Found: 267.0 [M+H] + It was.

[0291] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-chloro-2-phenylpyridin-3-amine (214-4): [ka] A mixture of 214-3 (1.31 g, 4.9 mmol), 1H-1,2,4-triazole (508 mg, 7.36 mmol), and KCO (1.02 g, 7.36 mmol) in CHCN (40 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (EtOAc / petroleum ether = 1 / 1, EtOAc) to afford compound 214-4 (1.2 g, approximately 82% yield over two steps) as a solid. MS Calcd: 299.1; MS Found: 300.4 [M+H] + It was.

[0292] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -benzyl-6-phenylpyridine-2,5-diamine (SS20308-0214-01): [ka] A solution of 214-4 (50 mg, 0.17 mmol), benzylamine (36 mg, 0.035 mmol), XantPhos (20 mg, 0.034 mmol), Pd(dba) (16 mg, 0.017 mmol), and anhydrous cesium carbonate (163 mg, 0.5 mmol) was suspended in toluene (2 mL). The reaction mixture was heated at 110 °C under N overnight, then filtered and rinsed with EtOAc. The filtrate was concentrated and purified by Prep-HPLC to afford SS20308-0214-01 (6 mg, approximately 10% yield) as a semi-solid. MS Calcd: 370.2; MS Found: 371.0 [M+H] + It was.

[0293] 1 H NMR (400MHz, CD3OD) δ8.32(s,1H), 7.92(s,1H), 7.43~7.35(m,7H), 7.34~7.29(m,2H), 7.26~7.20(m,1H) , 7.11(d,J=8.8Hz,1H), 6.47(d,J=8.8Hz,1H), 4.44(s,2H), 4.33(d,J=5.8Hz,2H), 3.48(t,J=5.6Hz,2H)

[0294] Example 13 [ka]

[0295] Example Routes for Example 13 [ka]

[0296] Synthesis of N-benzyl-3-bromo-4-nitroaniline (215-2): [ka] To a solution of 214-1 (5.00 g, 22.73 mmol) and phenylmethanamine (2.43 g, 22.73 mmol) in DMSO (50 mL) was added K2CO3 (6.27 g, 45.46 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1, 10 / 1) to afford compound 215-2 (6.2 g, approximately 89% yield) as a solid. MS Calcd: 306.0; MS Found: 307.0 [M+H] + It was.

[0297] Synthesis of tert-butyl benzyl(3-bromo-4-nitrophenyl)carbamate (215-3): [ka] To a solution of 215-2 (5.00 g, 16.29 mmol) in DCM (50 mL), TEA (3.29 g, 32.57 mmol) and DMAP (1.99 g, 16.29 mmol) were added, and the solution was cooled to 0 °C. Then, (Boc)2O (5.33 g, 24.44 mmol) was added dropwise over 10 min. The solution was then stirred overnight at room temperature. Water was added to the solution, and the mixture was extracted with DCM (50 mL × 3). The combined organic layer was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1, 10 / 1) to afford compound 215-3 (6.0 g, approximately 91% yield) as a solid. MS Calcd: 406.0; MS Found: 351.0 [M+H] + It was.

[0298] Synthesis of tert-butyl 4-amino-3-bromophenyl(benzyl)carbamate (215-4): [ka] To a solution of 214-3 (6.00 g, 14.74 mmol) in EtOH (60 mL) was added AcOH (6 mL) and Zn powder (9.58 g, 147.40 mmol). The mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1, 5 / 1) to afford compound 215-4 (4.2 g, approximately 75% yield) as a solid. MS Calcd: 376.0; MS Found: 377.0 [M+H] + It was.

[0299] Synthesis of tert-butyl benzyl(3-bromo-4-(2-chloroethylamino)phenyl)carbamate (215-5): [ka] To 215-4 (4.00 g, 14.44 mmol) in EtOH (50 mL) was added 2-chloroacetaldehyde (40 wt% aq, 5.66 g, 28.88 mmol), NaBHCN (1.81 g, 28.88 mmol), and AcOH (5 mL). The reaction mixture was stirred overnight at room temperature. The solution was concentrated, and the solvent was removed. The residue was dissolved in EtOAc and water and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with water and brine, dried over NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1, 10 / 1) to afford compound 215-5 (3.6 g, approximately 78% yield) as a solid. MS Calcd: 438.0; MS Found: 439.0 [M+H] + It was.

[0300] Synthesis of tert-butyl 4-(1H-1,2,4-triazol-1-yl)ethylamino)-3-bromophenyl(benzyl)carbamate (215-6): [ka] To a solution of 215-5 (3.60 g, 8.22 mmol) in CHCN (50 mL) was added 1H-1,2,4-triazole (40 wt% aq, 0.68 g, 9.86 mmol) and CsCO (5.36 g, 16.44 mmol). The mixture was stirred at 80 °C for 4 h. The solution was cooled to room temperature, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1, 1 / 1) to afford 215-6 (3.5 g, approximately 90% yield) as a solid.

[0301] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H), 7.97(s,1H), 7.33~7.29(m,7H), 7.25~7.17(m,4H), 6.95(d,J=8.8Hz,1H) , 6.61(d,J=8.8Hz,1H)5.35~5.32(m,1H), 4.72(s,2H), 4.37(t,J=6.0Hz,2H), 3.51(q,J=6Hz,2H), 1.37(s,9H)

[0302] Synthesis of tert-butyl 4-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-4-yl)phenyl(benzyl)-carbamate (215-7): [ka] To a solution of 215-6 (200 mg, 0.42 mmol) in 1,4-dioxane / HO (5 mL / 0.5 mL) was added pyridin-4-ylboronic acid (104 mg, 0.84 mmol), KCO (116 g, 0.84 mmol), and Pd(dppf)Cl (30 mg, 0.04 mmol). The mixture was stirred at 120 °C for 1 h under microwave irradiation. The solution was filtered, and the filtrate was purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1, 1 / 1) to afford 215-7 (120 mg, approximately 60% yield) as a solid. MS Calcd: 470.0; MS Found: 471.0 [M+H] + It was.

[0303] Synthesis of N1-2(1H-1,2,4-triazol-1-yl)ethyl)-N4-benzyl-2-(pyridin-4-yl)benzene-1,4-diamine (SS20308-0215-01): [ka] To a solution of 215-7 (120 mg, 0.25 mmol) in DCM (5 mL) was added TFA (1 mL). The solution was stirred overnight at room temperature. The solution was basified with NaHCO3 and extracted with DCM (10 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified by Prep-HPLC to afford SS20308-215-01 (50 mg, approximately 52% yield) as a solid. MS Calcd: 370.0; MS Found: 371.0 [M+H] + It was.

[0304] 1 H NMR (400MHz, DMSO-d6) δ8.55~8.53(m,2H), 8.42(s,1H), 7.94(s,1H), 7.36~7.29(m,4H), 7.26~7.20(m, 3H), 6.58~6.56(m,2H) 6.43(d,J=2.4Hz,1H), 4.29(t,J=6.0Hz,2H), 4.20(s,2H), 3.31(t,J=5.6Hz,2H)

[0305] Example 14 [ka]

[0306] Example Routes for Example 14 [ka]

[0307] Synthesis of tert-butyl 4-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-3-yl)phenyl(benzyl)carbamate (SS20308-0216-02): [ka] A mixture of 215-6 (300 mg, 0.64 mmol), pyridin-3-ylboronic acid (117 mg, 0.95 mmol), Pd(dppf)Cl (47 mg, 0.064 mmol), and NaCO (203 mg, 1.92 mmol) in DMF / HO (10 mL, 5 / 1) was stirred overnight at 90 °C under a N atmosphere. The mixture was then poured into water and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by prep-TLC to afford 216-2 (200 mg, approximately 66.8% yield) as an oil. MS Calcd: 470.2; MS Found: 471.0 [M+H] + It was.

[0308] N 1 -(2(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -benzyl-2-(pyridin-3-yl)benzene-1,4-diamine (SS20308-0216-01): [ka] A mixture of 216-2 (200 mg, 0.43 mmol) and TFA (0.1 mL, 1.26 mmol) in DCM (5 mL) was stirred for 2 h at room temperature. Then, the mixture was poured into water and extracted with CHCl (3×30 mL). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by prep-TLC to afford SS20308-0216-01 (126 g, approximately 80% yield) as a solid. MS Calcd: 370.2; MS Found: 371.0 [M+H] + It was.

[0309] 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=1,6Hz,1H), 8.43(d,J=1.6Hz,1H), 8.41(s,1H), 7.92(s,1H), 7.62~7.65(m,1H), 7.29~7.41( m,5H)7.21(t,J=7.2Hz,1H), 6.52~6.59(m,2H), 6.40(d,J=2.8Hz,2H), 5.67~5.70(m,1H), 4.20~4.29(m,4H), 3.28~3.30(m,2H)

[0310] Example 15 [ka]

[0311] Example Routes for Example 15 [ka]

[0312] Synthesis of 3-bromo-N-(cyclohexylmethyl)-4-nitroaniline (271-1): [ka] To a solution of 215-1 (30 g, 12.4 mmol) in DMSO (20.0 mL), cyclohexylmethanamine (1.7 g, 15.0 mmol) and K2CO3 (3.6 g, 27.0 mmol) were added. The mixture was then stirred for 4 h. After the reaction was completed, the reaction mixture was quenched with water and extracted with EtOAc (20.0 mL x 3). The organic layer was washed with brine, dried over Mg2SO4, and concentrated to afford 217-1 (3.5 g, approximately 83% yield) as an oil. MS Calcd: 312.0; MS Found: 313.0 [M+H] + It was.

[0313] Synthesis of tert-butyl 3-bromo-4-nitrophenyl(cyclohexylmethyl)carbamate (217-2): [ka] A mixture of 217-1 (3.5 g, 11.2 mmol), (Boc)O (3.2 g, 15.0 mmol), DMAP (600.0 g, 5.0 mmol), and TEA (2.0 g, 20.0 mmol) in DCM (20.0 mL) was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water and then extracted with EtOAc (20.0 mL × 3). The organic layer was separated, dried over MgSO, and concentrated to afford 217-2 (3.8 g, approximately 89% yield) as an oil.

[0314] Synthesis of tert-butyl 4-amino-3-bromophenyl(cyclohexylmethyl)carbamate (217-3): [ka] A mixture of 217-2 (3.8 g, 9.2 mmol), Zn powder (2.9 mg, 45.0 mmol), and HOAc (2.8 g, 45.0 mmol) in EtOH (20.0 mL) was stirred overnight at room temperature. After the reaction was completed, the mixture was quenched with water and NaHCO3, and then extracted with EtOAc (20.0 mL × 3). The organic layer was separated, dried over Mg2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 217-3 (2.2 g, approximately 63% yield) as a solid. MS Calcd: 382.0; MS Found: 328.0 [M+H] + It was.

[0315] Synthesis of tert-butyl 3-bromo-4-(2-chloroethylamino)phenyl(cyclohexylmethyl)carbamate (217-4): [ka] To a solution of 217-3 (1.2 g, 3.0 mmol) and 2-chloroacetaldehyde (1.0 g, 4 mmol) in EtOH (10.0 mL), NaBHCN (372.0 mg, 6.0 mmol) and AcOH (2.0 mL) were added. The solution was then stirred overnight. After the reaction was complete, the reaction mixture was purified by column chromatography to afford 217-4 (770.0 mg, approximately 59% yield) as an oil. MS Calcd: 444.0; MS Found: 445.0 [M+H] + It was.

[0316] Synthesis of tert-butyl 4-(1H-1,2,4-triazol-1-yl)ethylamino)-3-bromophenyl(cyclohexylmethyl)carbamate (217-5): [ka] To a mixture of 217-4 (777.0 mg, 1.73 mmol) and 1H-1,2,4-triazole (320 mg, 4.4 mmol) in ACN (10.0 mL) was added Cs2CO3 (1.1 g, 3.5 mmol), and then the solution was stirred at 80 °C overnight. The reaction mixture was then quenched with H2O and extracted with EtOAc (20.0 mL x 3). The organic layer was washed with water and brine, dried over Mg2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 217-5 (420.0 mg, yield approximately 51%) as an oil. MS Calcd: 477.0; MS Found: 478.0 [M+H] + It was.

[0317] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-3-yl)phenyl(cyclohexylmethyl)carbamate (217-6): [ka] A mixture of 217-5 (300.0 mg, 0.6 mmol), pyridin-4-ylboronic acid (200.0 mg, 1.6 mmol), Pd(dppf)Cl (10.0 mg, 0.1 mmol), and KCO (150.0 mg, 1.1 mmol) in dioxane (3.0 mL) was stirred at 120 °C for 1 h under MW. After the reaction was completed, the mixture was quenched with water and then extracted with EtOAc (5.0 mL × 3). The organic layer was separated, dried over MgSO, and concentrated. The reaction mixture was purified by column chromatography to afford 217-6 (80 mg, approximately 27% yield) as a solid. MS Calcd:477.2;MS Found:478.0[M+H] + It was.

[0318] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(cyclohexylmethyl)-2-(pyridin-3-yl)benzene-1,4-diamine (217-01): [ka] A solution of 217-6 (50.0 mg, 0.1 mmol) in HCl / EA (10.0 mL of 1 M) was stirred overnight. The reaction mixture was then quenched with HO and extracted with EtOAc (5 mL × 3). The organic layer was washed with water and brine, dried over MgSO, and concentrated. The residue was purified by Prep-HPLC to afford 217 (20.0 mg, approximately 51% yield) as an oil. MS Calcd: 376.0; MS Found: 377.0 [M+H] + It was.

[0319] 1H NMR (400MHz, DMSO-d6+D2O) δ8.60(s,2H), 8.42(s,1H), 7.97(s,1H), 7.32(s,2H), 6.66(s,2H), 6.45(s,1 H)4.32(s,2H), 3.58(s,2H), 2.81(s,2H), 1.75~1.52(m,5H), 1.50(s,1H), 1.23~1.96(m,3H), 0.93(s, 2H)

[0320] Example 16 [ka]

[0321] Example Routes for Example 16 [ka]

[0322] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(thiophen-2-yl)phenyl(benzyl)carbamate (218-1): [ka] A mixture of 215-6 (500 mg, 1.06 mmol), 2-thiopheneboronic acid (271 mg, 2.12 mmol), Pd(dppf)Cl (78 mg, 0.11 mmol), and KCO (293 mg, 2.12 mmol) in DMSO (5 mL) was stirred at 120 °C for 2 h in a microwave reactor. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The reaction mixture was then poured into water. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 218-1 (450 mg, approximately 84% yield) as an oil. MS Calcd: 475.2; MS Found: 476.4 [M+H] + It was.

[0323] N1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -benzyl-2-(thiophen-2-yl)benzene-1,4-diamine (SS20308-0218-01): [ka] A mixture of 218-1 (450 mg, 0.94 mmol) and HCl (2 mL, 2 mmol, 1N in dioxane) in dioxane (5 mL) was stirred overnight at room temperature. The reaction mixture was then poured into water and basified with 1N NaOH until the pH reached 10. The mixture was extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) and Prep-HPLC to afford SS20308-0218-01 (31.15 mg, yield approx. 9%) as an oil. MS Calcd: 375.1; MS Found: 376.0 [M+H] + It was.

[0324] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H), 7.94(s,1H), 7.50~7.49(m,1H), 7.36~7.28(m,4H), 7.22~7.18(m,1H), 7.09~7.04(m,2H)6.58~6.56 (m,2H), 6.51~6.49(m,1H), 5.74(t,J=6.0Hz,1H), 4.40(t,J=6.0Hz,1H), 4.35(t,J=6.0Hz,1H), 4,20(d,J=5.6Hz,2H), 3.(t,J=5.8Hz,1H)

[0325] Example 17 [ka]

[0326] Example Routes for Example 17 (SS20308-0173-01 and 0219-01) [ka]

[0327] Synthesis of 5-chloro-2-phenylpyridin-3-amine (173-2): [ka] A mixture of 173-1 (500 mg, 2.42 mmol), phenylboronic acid (590 mg, 4.84 mmol), Pd(PPh3)4 (277 mg, 0.24 mmol), and K2CO3 (668 mg, 4.84 mmol) in DME (10 mL) and water (1 mL) was stirred at 80 °C overnight under a N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 10 / 1) to afford 173-2 (440 mg, approximately 91% yield) as an oil. MS Calcd: 204.0; MS Found: 205.1 [M+H] + It was.

[0328] Synthesis of 5-chloro-N-(2-chloroethyl)-2-phenylpyridin-3-amine (173-3): [ka] To a solution of 173-2 (450 mg, 2.20 mmol) in MeOH (10 mL), 2-chloroacetaldehyde (432 mg, 4.40 mmol, 40% in water), AcOH (264 mg, 4.40 mmol), and NaBHCN (275 mg, 4.40 mmol) were added, and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was then poured into water and basified with 1N NaOH until the pH reached 10. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 173-3 (100 mg, approximately 17% yield) as a solid. MS Calcd: 266.0; MS Found: 237.1 [M+H] + It was.

[0329] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-2-phenylpyridin-3-amine (173-4): [ka] A mixture of 173-3 (100 mg, 0.37 mmol), 1H-1,2,4-triazole (52 mg, 0.74 mmol), and CsCO (240 mg, 0.74 mmol) in CHCN (10 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature, filtered through diatomaceous earth, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 173-4 (77 mg, approximately 68% yield) as a solid. MS Calcd: 299.1; MS Found: 300.2 [M+H] + It was.

[0330] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2-diphenylpyridine-3,5-diamine (SS20308-0219-01): [ka] A mixture of 173-4 (300 mg, 1.00 mmol), phenylmethanamine (214 mg, 2.00 mmol), Pd(OAc) (23 mg, 0.10 mmol), X-phos (95 mg, 0.20 mmol), and t-BuONa (186 mg, 2.00 mmol) in toluene (5 mL) was stirred at 150 °C for 2 h in a microwave reactor. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-HPLC (petroleum ether / EtOAc = 1 / 3) to afford SS20308-0219-01 (21 mg, approximately 6% yield) as a solid. MS Calcd:370.2;MS Found:371.3[M+H] + It was.

[0331] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H), 7.97(s,1H), 7.41~7.39(m,9H), 7.27~7.21(m,2H), 6.40(t,J=6. 0Hz,1H), 6.25(t,J=2.0Hz,1H), 4.97(t,J=6.0Hz,1H), 4.32~4.28(m,4H), 3.40(dd,J=12.0, 6.0Hz,2H)

[0332] Example 18 [ka]

[0333] Example Routes for Example 18 [ka]

[0334] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of -benzyl-3-phenylpyridine-2,6-diamine (SS20308-0221-01): [ka] A mixture of 175-3 (130 mg, 0.43 mmol), phenylmethanamine (93 mg, 0.87 mmol), Pd(dba) (40 mg, 0.04 mmol), CsCO (282 mg, 0.87 mmol), and X-phos (41 mg, 0.09 mmol) in Tol (10 mL) was stirred at 110 °C overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL x 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified twice by Prep-HPLC to afford SS20308-0221-01 (8 mg, approximately 5% yield) as a solid. MS Calcd: 370.2; MS Found: 371.3 [M+H] + It was.

[0335] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H), 7.94(s,1H), 7.37~7.28(m,6H), 7.24~7.18(m,4H), 7.02(d,J=8.0Hz,1H), 6.91(t,J =6.0Hz,1H), 5.86(d,J=8.0Hz,1H), 5.55(t,J=5.6Hz,1H), 4.49(d,J=6.0Hz,2H), 4.24(t,J=6.0Hz,2H), 3.61~3.60(m, 2H)

[0336] Example 19 [ka]

[0337] Example Routes for Example 19 [ka]

[0338] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-4-nitroaniline (211-2): [ka] A solution of 211-1 (2.20 g, 10.00 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine hydrochloride (1.78 g, 12.00 mmol), and K2CO3 (4.15 g, 30.00 mmol) in DMSO (10 mL) was stirred overnight at room temperature. The mixture was then poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 211-2 (2.00 g, approximately 64% yield) as a solid. MS Calcd: 311.0; MS Found: 312.0 [M+H] + It was.

[0339] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)-4-nitroaniline (211-3): [ka] A mixture of 211-2 (2.00 g, 6.41 mmol), 7-(4,4,5,5-tetramethyl-(1,3,2-dioxaborolan-2-yl)-1H-indole (2.34 g, 9.61 mmol), Pd(dppf)Cl (469 mg, 0.64 mmol), and KCO (2.66 g, 19.23 mmol) in DME / HO (10 mL, 5 / 1) was stirred at 80 °C for 2 h under a N atmosphere. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 211-3 (1.80 g, approximately 81% yield) as a solid. MS Calcd: 348.1; MS Found:349.4[M+H] + It was.

[0340] N 1 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)benzene-1,4-diamine (211-4): [ka] A mixture of 211-3 (1.00 g, 2.87 mmol) and 10% Pd / C (339 mg, 1.38 mmol) in MeOH (10 mL) was stirred at room temperature under an H atmosphere for 3 h. The reaction mixture was then cooled to room temperature and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 211-4 (0.78 g, approximately 86% yield) as a solid. MS Calcd: 318.2; MS Found: 319.0 [M+H] + It was.

[0341] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(1H-indol-7-yl)benzene-1,4-diamine (SS20308-0225-01): [ka] A mixture of 211-4 (600 mg, 1.88 mmol), 4-fluorobenzaldehyde (281 mg, 2.26 mmol), and NaBH(CHCOO) (479 mg, 2.26 mmol) in DCM (10 mL) was stirred overnight at room temperature. The mixture was then poured into water and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0225-01 (360 mg, approximately 45% yield) as a solid. MS Calcd: 426.2; MS Found: 427.0 [M+H] + It was.

[0342] 1 H NMR (400MHz, CD3OD-d4) δ8.12(s,1H), 7.80(s,1H), 7.55(d,J=8.0Hz,1H), 7.40(q,J=5.6Hz,2H), 7.16(d,J=3.2Hz,1H), 7.01~7.08(m,3H), 6.88(d,J=6.8Hz,1H), 6.65~6.62(m,3H), 6.49(d,J=3.2Hz,1H), 4.20~4.26(m,4H), 3.46~3.50(m,2H)

[0343] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(1H-indolin-7-yl)benzene-1,4-diamine (SS20308-0211-01): [ka] A mixture of SS20308-0225-01 (50 mg, 0.117 mmol) and NaBHCN (8 mg, 0.117 mmol) in AcOH (2 mL) was stirred overnight at 0 °C. The residue was then purified by Prep-HPLC to afford SS20308-0211-01 (20 mg, approximately 40% yield) as a solid. MS Calcd: 428.2; MS Found: 429.0 [M+H] + It was.

[0344] 1 H NMR (400MHz, DMSO-d4) δ8.43(s,1H), 7.94(s,1H), 7.36~7.40(m,2H), 7.11~7.15(t,2 H), 7.01(d,J=7.2Hz,1H), 6.71~6.73(d,J=8.0Hz,1H), 6.56~6.62(m,2H), 6.49(q,J= 2.4Hz,1H), 6.39(d,J=2.4Hz,1H), 5.63~5.66(m,1H), 4.69(s,2H), 4.28~4.30(m,2H) , 4.17(d,J=5.6Hz,2H), 4.08~4.11(d,J=m,1H), 3.24~3.29(m,4H), 2.92~2.94(m,2H)

[0345] Example 20 [ka]

[0346] Example Routes for Example 20 [ka]

[0347] Synthesis of 5-bromobiphenyl-2-amine (226-2): [ka] A mixture of 226-1 (5.0 g, 29.6 mmol) in DMF (30 mL) was stirred at 0 °C, NBS (5.3 g, 29.6 mmol) was added to the mixture, and then the mixture was stirred at room temperature overnight. After pouring into water, the mixture was extracted with ethyl acetate (30 mL × 4). The organic layer was washed with brine and concentrated to dryness to afford 226-2 (5.0 g, approximately 68% yield) as an oil. MS Calcd: 247.0; MS Found: 250.1 [M+H] + It was.

[0348] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (226-3): [ka] To a solution of 226-2 (2.0 g, 8.1 mmol) in EtOH (20 mL), 2-chloroacetaldehyde (950 mg, 12.1 mmol, 40% in water), AcOH (970 mg, 16.1 mmol), and NaBHCN (507 mg, 8.1 mmol) were added, and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was poured into cold water (50 mL) and basified with saturated NaCO solution until the pH reached 9, then extracted with ethyl acetate (150 mL). The organic layer was washed with brine and concentrated to dryness to afford 226-3 (1.7 g, approximately 68% yield) as an oil. MS Calcd: 309.0; MS Found: 310.0 [M+H] + It was.

[0349] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (226-4): [ka] To a solution of 226-3 (1.7 g, 5.5 mmol) in CH3CN (10 mL) was added 1,2,4-triazole (756 mg, 11.0 mmol) and Cs2CO3 (3.6 g, 11.0 mmol), and the reaction mixture was then stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 5) to afford 226-4 (1.0 g, approximately 53% yield) as an oil. MS Calcd: 343.2; MS Found: 345.2 [M+H] + It was.

[0350] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)biphenyl-2,5-diamine (SS20308-0226-01) [ka] To a solution of 226-4 (180.0 mg, 0.5 mmol) in toluene (10.0 mL), 2,2,2-trifluoro-1-phenylethanamine (262.0 mg, 1.5 mmol), Pd(OAc) (10.0 mg, 0.1 mmol), S-Phos (20.0 mg, 0.1 mmol), and NaOBut (100.0 mg, 1.0 mmol) were added. The solution was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (10 mL × 3). The residue was purified twice by Prep-HPLC to afford SS20308-226-01 (20.0 mg, approximately 9% yield) as a solid. MS Calcd: 437.0; MS Found: 438.0 [M+H] + It was.

[0351] 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H), 7.92(s,1H), 7.59(d,J=7.2Hz,2H), 7.29~7.40(m,7H), 7.18~7.20(m,2H), 6.72(dd,J=8.8Hz,2.4Hz,1H), 6 .63(d,J=2.8Hz,1H), 6.53(d,J=8.4Hz,1H), 6.07(t,J=10.8Hz,1H), 5.3 7~5.42(m,1H), 4.27(t,J=6.0Hz,2H), 4.11(d,J=6.0Hz,1H), 3.36(s,2H)

[0352] Example 21 [ka]

[0353] Example Routes for Example 21 [ka]

[0354] Synthesis of 4-bromo-2,3-difluoro-6-nitroaniline (227-2): [ka] To a solution of 227-1 (200 mg, 1.15 mmol) in DMF (5 mL) was added NBS (204 mg, 1.15 mmol), and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 227-2 (180 mg, approximately 62% yield) as a solid. MS Calcd: 251.9; MS Found: 252.9 [M+H] + It was.

[0355] Synthesis of 1-bromo-2,3-difluoro-5-nitrobenzene (227-3): [ka] To a solution of 227-2 (3 g, 11.86 mmol) in THF (20 mL) was added isopentyl nitrite (2.78 g, 23.72 mmol), and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 227-3 (2.3 g, approximately 82% yield) as a solid.

[0356] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-6-fluoro-4-nitroaniline (227-4): [ka] A solution of 227-3 (2.00 g, 8.40 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine hydrochloride (1.56 g, 8.40 mmol), and KCO (4.65 g, 33.62 mmol) in CHCN (30 mL) was stirred at 80 °C for 4 h under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 227-4 (2 g, approximately 72% yield) as a solid. MS Calcd: 329.0; MS Found: 330.0 [M+H] + It was.

[0357] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-5-nitrobiphenyl-2-amine (227-5): [ka] A mixture of 227-4 (1 g, 3.03 mmol), phenylboronic acid (443 mg, 3.64 mmol), Pd(PPh3)4 (700 mg, 0.61 mmol), and Na2CO3 (642 mg, 6.06 mmol) in Tol (20 mL) and water (2 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 227-5 (850 mg, approximately 86% yield) as a solid. MS Calcd: 327.1; MS Found: 328.2 [M+H] + It was.

[0358] N 2 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluorobiphenyl-2,5-diamine (227-6): [ka] To a solution of 227-5 (200 mg, 0.61 mmol) in MeOH (20 mL) was added Pd / C (10%, 50 mg), and the mixture was stirred overnight at room temperature under an H atmosphere. After the reaction was completed, the insoluble material was removed by filtration. The organic layer was concentrated in vacuo and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 227-6 (150 mg, approximately 83% yield) as a solid. MS Calcd: 297.1; MS Found: 298.2 [M+H] + It was.

[0359] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-N 5 Synthesis of -(4-fluorobenzyl)biphenyl-2,5-diamine (SS20308-0227-01): [ka] To a mixture of 227-6 (150 mg, 0.50 mmol) and 4-fluorobenzaldehyde (75 mg, 0.61 mmol) in MeOH (10 mL) was added NaBHCN (95 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by Prep-HPLC to afford SS20308-0227-01 (33 mg, approximately 16% yield) as an oil. MS Calcd: 405.2; MS Found: 406.0 [M+H] + It was.

[0360] 1H NMR (400MHz, DMSO-d6) δ8.26(s,1H), 7.84(s,1H), 7.40~7.30(m,5H), 7.27~7.25(m,2H), 7.17~7.13(m,2H), 6.36(dd,J=13.6Hz,2.4Hz ,1H), 6.23(d,J=2.0Hz,1H), 6.17(t,J=5.6Hz,1H), 4.20(d,J=6.0Hz,1H), 4.08(t,J=6.0Hz,2H), 3.67~3.63(m,1H), 3.06~3.02(m,2H)

[0361] Example 22 [ka]

[0362] Example Routes for Example 22 [ka]

[0363] Synthesis of 3-bromo-2-fluoro-N-(4-fluorobenzyl)-4-nitroaniline (228-2): [ka] A mixture of 228-1 (2.00 g, 8.40 mmol), 4-fluorobenzylamine (2.10 g, 16.8 mmol), and K2CO3 (3.48 g, 25.2 mmol) in DMSO (40 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (160 mL). The resulting solid was collected by filtration and concentrated to afford 228-2 (2.88 g, approximately 100% yield) as a solid. MS Calcd: 342.0; MS Found: 343.2 [M+H] + It was.

[0364] Synthesis of 2-fluoro-N-(4-fluorobenzyl)-6-nitrobiphenyl-3-amine (228-3): [ka] A mixture of 228-2 (2 g, 5.8 mmol), phenylboronic acid (1.42 g, 11.7 mmol), Pd(dppf)Cl (238 mg, 0.3 mmol), and KCO (2.01 g, 14.6 mmol) in DME / HO (48 mL, 5 / 1) was stirred overnight at 80 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1, 10 / 1) to afford 228-3 (1.70 g, approximately 86% yield) as a solid. MS Calcd: 340.1; MS Found: 341.4 [M+H] + It was.

[0365] Synthesis of tert-butyl 2-fluoro-6-nitrobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-4): [ka] To a solution of 228-3 (1.6 g, 4.70 mmol) in DCM (20 mL) was added (Boc)O (1.54 g, 7.05 mmol), DMAP (575 mg, 4.71 mmol), and EtN (952 mg, 9.41 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1, 50 / 1, 20 / 1) to afford 228-4 (2.07 g, approximately 100% yield) as an oil. MS Calcd: 440.2; MS Found: 385.3 [MH] + It was.

[0366] Synthesis of tert-butyl 6-amino-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-5): [ka] A mixture of 228-4 (2.07 g, 4.70 mmol) and Zn powder (3.07 g, 47.00 mmol) in EtOH / AcOH (41 mL, 40 / 1) was stirred overnight at room temperature. The reaction mixture was then filtered through celite and concentrated to afford 228-5 (1.93 g, approximately 100% yield) as a solid. MS Calcd: 410.2; MS Found: 355.3 [M-55] + It was.

[0367] Synthesis of tert-butyl 6-(2-chloroethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-6): [ka] To a solution of 228-5 (500 mg, 1.22 mmol) in DCM (5 mL), 2-chloroacetaldehyde (957 mg, 4.88 mmol, 40% in water), NaBHCN (115 mg, 1.83 mmol), and AcOH (0.5 mL) were added, and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was then poured into water and basified with NaHCO solution until the pH reached 8. The mixture was extracted with DCM (20 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated to afford 228-6 (576 mg, approximately 100% yield) as an oil. MS Calcd: 472.2; MS Found: 417.3 [M-56] + It was.

[0368] Synthesis of tert-butyl 6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-7): [ka] A mixture of 228-6 (576 mg, 1.22 mmol), 1H-1,2,4-triazole (126 mg, 1.83 mmol), and CsCO (595 mg, 1.83 mmol) in DMF (10 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 228-7 (200 mg, approximately 32% yield) as an oil. MS Calcd: 505.2; MS Found: 506.4 [M+H] + It was.

[0369] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-fluoro-N 5 Synthesis of -(4-fluorobenzyl)biphenyl-2,5-diamine (SS20308-0228-01): [ka] 228-7 (400 mg, 1.27 mmol) was dissolved in HCl / dioxane (10 mL, 1N) and stirred overnight at room temperature. The reaction mixture was then poured into water and basified with 1N NaOH until the pH reached 10. The mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by Prep-HPLC to afford SS20308-228-01 (40 mg, approximately 12% yield) as an oil. MS Calcd: 405.2; MS Found: 406.0 [M+H] + It was.

[0370] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H), 7.89(s,1H), 7.46~7.37(m,5H), 7.16~7.11(m,4H), 6.47(d,J=9.2Hz,1 H), 6.34(d,J=8.8Hz,1H), 5.45(t,J=5.8Hz,1H), 4.26~4.23(m,1H), 3.87(t,J=6.2Hz,1H), 3.32~3.29(m,2H)

[0371] Example 23 [ka]

[0372] Example Routes for Example 23 [ka]

[0373] Synthesis of 3-bromo-2-fluoro-N-(4-fluorobenzyl)-4-nitroaniline (229-2): [ka] A mixture of 229-1 (2.00 g, 8.40 mmol), 4-fluorobenzylamine (2.10 g, 16.8 mmol), and K2CO3 (3.48 g, 25.2 mmol) in DMSO (50 mL) was stirred overnight at room temperature. Water (150 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated to afford 229-2 (2.64 g, approximately 91% yield) as a solid. MS Calcd: 342.0; MS Found: 341.9 [M+H] + It was.

[0374] Synthesis of 4-fluoro-N-(4-fluorobenzyl)-6-nitrobiphenyl-3-amine (229-3): [ka] A mixture of 229-2 (2 g, 7.29 mmol), phenylboronic acid (1.78 g, 14.6 mmol), Pd(dppf)Cl (522 mg, 0.73 mmol), and KCO (2.01 g, 14.6 mmol) in DME / HO (60 mL, 5 / 1) was stirred overnight at 80 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford 229-3 (2.25 g, approximately 91% yield) as a solid. MS Calcd: 292.2; MS Found: 293.3 [M+H] + It was.

[0375] Synthesis of tert-butyl 4-fluoro-6-nitrobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-4): [ka] To a solution of 229-3 (2.25 g, 6.61 mmol) in DCM (50 mL) was added (Boc)O (2.88 g, 13.2 mmol), DMAP (168 mg, 1.32 mmol), and EtN (1.34 mg, 13.2 mmol), and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated to afford 229-4 (2.81 g, approximately 96% yield) as a solid. MS Calcd: 440.2; MS Found: 385.1 [M+H] + It was.

[0376] Synthesis of tert-butyl 6-amino-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-5): [ka] A mixture of 229-4 (2.81 g, 6.38 mmol) and Zn powder (4.15 g, 63.8 mmol) in EtOH / AcOH (60 mL, 15 / 1) was stirred overnight at room temperature. The reaction mixture was then filtered through celite and concentrated to afford 229-5 (2.50 g, approximately 95% yield) as a solid. MS Calcd: 410.2; MS Found: 355.1 [M+H] + It was.

[0377] Synthesis of tert-butyl 6-(2-chloroethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-6): [ka] To a solution of 229-5 (2.50 g, 6.09 mmol) in EtOH (40 mL), 2-chloroacetaldehyde (2.39 g, 12.2 mmol, 40% in water), NaBHCN (768 mg, 12.2 mmol), and AcOH (732 mg, 12.2 mmol) were added, and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was then poured into water and basified with 1 N NaOH until the pH reached 10. The mixture was extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated to afford 229-6 (2.50 g, approximately 87% yield) as a solid. MS Calcd: 472.2; MS Found: 317.3 [M+H] + It was.

[0378] Synthesis of tert-butyl 6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-7): [ka] A mixture of 229-6 (600 mg, 1.27 mmol), 1H-1,2,4-triazole (175 mg, 2.54 mmol), and CsCO (825 mg, 2.54 mmol) in DMF (15 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 229-7 (400 mg, approximately 62% yield) as a solid. MS Calcd: 505.2; MS Found: 506.2 [M+H] + It was.

[0379] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-fluoro-N 5 Synthesis of -(4-fluorobenzyl)biphenyl-2,5-diamine (SS20308-0229-01): [ka] 229-7 (400 mg, 1.27 mmol) was dissolved in HCl / dioxane (10 mL, 1N) and stirred overnight at room temperature. The reaction mixture was then poured into water and basified with 1N NaOH until the pH reached 10. The mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by Prep-HPLC to afford SS20308-0229-01 (39 mg, approximately 12% yield) as an oil. MS Calcd: 405.2; MS Found: 406.0 [M+H] + It was.

[0380] 1H NMR (400MHz, DMSO-d6) δ8.42(s,1H), 7.93(s,1H), 7.38~7.28(m,5H), 7.13~7.08(m,4H), 6.55(d,J=14.4Hz,1H) , 6.36(d,J=10.0Hz,1H), 5.44(t,J=6.0Hz,1H), 4.28(t,J=5.8Hz,3H), 4.22(d,J=6.0Hz,2H), 3.38~3.34(m,2H)

[0381] Example 24 [ka]

[0382] Example Routes for Example 24 [ka]

[0383] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)benzene-1,4-diamine (SS20308-0232-01): [ka] To a solution of 239-1 (180 mg, 0.89 mmol) and 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (204 mg, 1.06 mmol) in CHCl (10 mL) was added AlMe (0.89 mL, 1.78 mmol, 2N in THF), and the reaction was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction was cooled, BH-DMS (0.89 mL, 1.78 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO, and concentrated. Purification by prep-HPLC afforded SS20308-0232-01 (23 mg, approximately 7% yield) as an oil. MS Calcd:379.1;MS Found:380.0[M+H] + It was.

[0384] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H), 7.96(s,1H), 7.65~7.61(m,2H), 7.24~7.19(m,2H), 6.63(d,J=8.4Hz,2H), 6.38(d,J= 8.8Hz,2H), 5.97(d,J=11.2Hz,1H), 5.38~5.33(m,1H), 5.05(t,J=6.4Hz,1H), 4.25(d,J=6.0Hz,2H), 3.31(t,J=6.4Hz,2H)

[0385] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)benzene-1,4-diamine (SS20308-0275-01): [ka] To a solution of 239-1 (180 mg, 0.89 mmol) and 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (170 mg, 1.06 mmol) in CHCl (10 mL) was added AlMe (0.89 mL, 1.78 mmol, 2N in THF), and the reaction was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction was cooled, BH-DMS (0.89 mL, 1.78 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO, and concentrated. Purification by prep-HPLC afforded SS20308-0275-01 (26 mg, approximately 8% yield) as an oil. MS Calcd:347.2;MS Found:348.2[M+H] + It was.

[0386] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H), 7.98(s,1H), 7.25~7.21(m,3H), 6.61(d,J=8.8Hz,2H), 6.46(d,J=8.8Hz,2H), 5.04(d,J=8.8H) z,1H), 4.96~4.87(m,2H), 4.31(t,J=6.4Hz,2H), 3.39~3.34(m,2H), 2.35~2.30(m,1H), 1.68~1.63(m,1H), 1.33(s,3H), 1.19(s,3H)

[0387] Example 25 [ka]

[0388] Example Routes for Example 25 [ka]

[0389] Synthesis of tert-butyl 3-(1H-1,2,4-triazol-1-yl)propylcarbamate (236-2): [ka] A mixture of tert-butyl (3-bromopropyl)carbamate (236-1) (5.0 g, 21.0 mmol), 1H-1,2,4-triazole (1.74 g, 25.2 mmol), and potassium carbonate (4.35 g, 31.5 mmol) in acetone (150 mL) was stirred overnight at 60 °C. The reaction mixture was then filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, dichloromethane / methanol = 50 / 1) to afford 236-2 (4.75 g, approximately 100% yield) as an oil. MS Calcd: 226.1; MS Found: 227.2 [M+H] + It was.

[0390] 1 H NMR (400MHz, CDCl3) δ8.16(s,1H), 7.90(s,1H), 4.67(brs,1H), 4.19(t,J=6.6Hz,2H), 3.13~3.03(m,2H), 2.05~1.95(m,2H), 1.38(s,9H)

[0391] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-6-nitrobiphenyl-3-amine dihydrogen chloride (262-3): [ka] A mixture of 236-2 (4.75 g, 21.0 mmol) in THF (80 mL) and 6 N HCl (20 mL) was stirred overnight at 60 °C. The mixture was concentrated in vacuo. Ethanol was added to the residue, and the mixture was concentrated again to afford 236-3 (3.8 g, approximately 92% yield) as a solid.

[0392] 1H NMR (400MHz, DMSO-d6) δ9.16(s,1H), 9.06(brs,1H), 8.40(s,1H), 8.31(brs,3H), 4.41(t,J=6.8Hz,2H), 2.83~2.72(m,2H), 2.19~2.10(m,2H)

[0393] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-4-nitroaniline (236-4): [ka] A mixture of 3,4-difluoronitrobenzene (100 mg, 0.63 mmol), 236-3 (138 mg, 0.69 mmol), and potassium carbonate (261 mg, 1.89 mmol) was suspended in DMSO (2 mL). After stirring overnight at room temperature, the mixture was diluted with water (8 mL). The resulting solid was filtered, washed with water, and concentrated to afford 236-4 (157 mg, approximately 94% yield) as a solid. MS Calcd: 265.1; MS Found: 266.4 [M+H] + It was.

[0394] N 1 Synthesis of -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (236-5): [ka] A solution of 236-4 (157 mg, 0.59 mmol) and Pd / C (30 mg, 10%) in MeOH (5 mL) was stirred under H2 at room temperature for 2 h. The reaction mixture was then filtered through celite. The filtrate was concentrated to afford 236-5 (140 mg) as an oil, which was used directly in the next step. MS Calcd: 235.1; MS Found: 236.4 [M+H] + It was.

[0395] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-N4 Synthesis of -(4-fluorobenzyl)benzene-1,4-diamine (SS20308-0236-01): [ka] A solution of 236-5 (140 mg, 0.6 mmol), 4-fluorobenzaldehyde (74 mg, 0.6 mmol), NaBHCN (56 mg, 0.89 mmol), and AcOH (0.2 mL) in EtOH (2 mL) was stirred overnight at room temperature. The reaction mixture was basified with NaHCO solution and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by prep-TLC (EtOAc) and prep-HPLC to afford SS20308-0236-01 (82.3 mg, approximately 40% yield for two steps) as a solid. MS Calcd: 343.2; MS Found: 344.0 [M+H] + It was.

[0396] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H), 7.96(s,1H), 7.37(dd,J=8.4Hz,5.6Hz,2H), 7.13(dd,J=8.8Hz,8.8Hz,2H), 6.47(dd,J=9.6Hz,8.8Hz,1H), 6.3 6(d,J=14.4Hz,1H), 6.26(d,J=8.4Hz,1H), 5.76(brs,1H), 4.58(brs,1H) , 4.24(t,J=6.8Hz,2H), 4.15(s,2H), 2.95~2.85(m,2H), 2.04~1.95(m,2H)

[0397] Example 26 [ka]

[0398] Example Routes for Example 26 [ka]

[0399] Synthesis of 3-bromo-N-(4-fluorobenzyl)-4-methylaniline (237-2): [ka] A mixture of 237-1 (200 mg, 1.3 mmol), 4-fluorobenzaldehyde (190 mg, 1.6 mmol), AcOH (one drop), and NaBHCN (130 mg, 2.0 mmol) in CHCl (10 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated to afford 237-2 (150 mg, approximately 39% yield) as an oil. MS Calcd: 216.1; MS Found: 294.3 [M+H] + It was.

[0400] N 3 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 1 Synthesis of (4-fluorobenzyl)-4-methylbenzene-1,4-diamine (SS20308-0237-01): [ka] A mixture of 237-2 (130 mg, 0.44 mmol), 1H-1,2,4-triazole-1-propanamine (86 mg, 0.53 mmol), Pd(dba) (20 mg, 0.022 mmol), X-Phos (21 mg, 0.044 mmol), and CsCO (430 mg, 1.32 mmol) in toluene (3 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and evaporated, and the residual crude product was purified by Prep-HPLC to afford SS20308-0237-01 (13.5 mg, approximately 9% yield) as an oil. MS Calcd: 339.2; MS Found: 340.0 [M+H] + It was.

[0401] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H), 7.98(s,1H), 7.96(dd,J=8.8Hz,5.6Hz,2H), 7.10(t,J=8.8Hz,2H), 6.60(d,J=8.0Hz,1H), 5.79 ~5.73(m,3H), 4.59(t,J=5.6Hz,1H), 4.24(t,J=6.8Hz,2H), 4.16(d,J=6.4Hz,2H), 2.96~2.91(m,2H), 2.03~1.99(m,2H), 1.90(s, 3H)

[0402] Example 27 [ka]

[0403] Example Routes for Example 27 [ka]

[0404] Synthesis of 1,3-dibromo-5-fluoro-2-nitrobenzene (239-2): [ka] To a solution of 2,6-dibromo-4-fluoroaniline (5.0 mg, 18.59 mmol) in dichloromethane (100 mL) was added 3-chloroperbenzoic acid (18.4 g, 90.63 mmol, 85 wt%). The mixture was heated to reflux and stirred for 5 hours. The reaction mixture was cooled to 0°C in an ice bath and then filtered. The filtrate was then washed with 1.0 N KOH (3 x 75 mL), and the organic layer was concentrated under reduced pressure to yield a brown solid. The solid was dissolved in 50 mL of glacial acetic acid. To this solution was added 25 mL of 30% H2O2 solution and 4 mL of concentrated nitric acid. The mixture was heated to reflux and stirred for 3 hours, then poured into 250 mL of ice water, the suspension was filtered, and the solid was washed with water and then air-dried on the filter to yield 239-2 (4.4 g, approximately 79% yield) as a solid. MS Calcd: 296.8; MS Found: 298.2 [M+H] + It was.

[0405] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-3,5-dibromo-4-nitroaniline (239-3): [ka] A mixture of compound 239-2 (2.0 g, 6.69 mmol), 236-3 (2.0 g, 10.04 mmol), and potassium carbonate (4.62 g, 33.46 mmol) was suspended in DMSO (20 mL). After stirring overnight at room temperature, the mixture was diluted with water (80 mL). The resulting solid was filtered, washed with water, and dried to afford 239-3 (2.3 g, approximately 85% yield) as a solid. MS Calcd: 402.9; MS Found: 403.9 [M+H] + It was.

[0406] N 1 Synthesis of -(3-(1H-1,2,4-triazol-1-yl)propyl)benzene-1,4-diamine (239-4): [ka] To a solution of 239-3 (1.00 g, 2.47 mmol) in MeOH (5 mL) and EtOAc (5 mL) was added Pd / C (10%, 250 mg). The resulting mixture was stirred overnight at room temperature under an H atmosphere. The mixture was filtered and concentrated to afford 239-4 (700 mg) as a crude oil. MS Calcd: 217.1; MS Found: 218.1 [M+H] + It was.

[0407] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of 4-cyclohexylbenzene-1,4-diamine (SS20308-0239-01): [ka] To a solution of 239-4 (200.00 mg, 0.92 mmol) in EtOH (3 mL) and AcOH (3 mL) was added cyclohexanone (361.37 mg, 3.68 mmol) and NaBHCN (173.54, 2.76 mmol). The resulting mixture was stirred overnight at room temperature. Next, the mixture was basified with NaCO (aq.) until the pH reached 7-8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC to afford SS20308-0239-01 (15 mg, approximately 5% yield) as a solid. MS Calcd: 299.2; MS Found: 300.2 [M+H] + It was.

[0408] 1H NMR (400MHz, DMSO-d6) δ8.50(s,1H), 7.97(s,1H), 6.43~6.37(m,4H), 4.76(t,J=5.8Hz,1H), 4.41(d,J=8.4Hz,1H), 4.27(t,J=6.8Hz,2H), 3.02~2.9 9(m,1H), 2.86(q,J=12.8Hz,2H), 2.03~1.96(m,2H), 1.89~1.86(m,2H), 1 .71~1.67(m,2H), 1.59~1.56(m,1H), 1.32~1.23(m,2H), 1.18~1.01(m,3H)

[0409] Example 28 [ka]

[0410] Example Route for Example 28 [ka]

[0411] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (SS20308-0240-01): [ka] To a solution of 239-4 (250.00 mg, 1.15 mmol) in EtOH (3 mL) and AcOH (3 mL) was added cyclohexanecarbaldehyde (516.27 mg, 4.60 mmol) and NaBHCN (216.93, 3.45 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then basified with NaCO (aq.) until the pH reached 7-8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC to afford SS20308-0240-01 (40 mg, approximately 11% yield) as a solid. MS Calcd: 313.4; MS Found: 314.2 [M+H] + It was.

[0412] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H), 7.97(s,1H), 6.42~6.37(m,4H), 4.76~4.96(m,2H), 4.27(t,J=7.0Hz,2H), 2.85(q,J=6.4Hz,2H), 2 .73(t,J=6.2Hz,2H), 2.08~1.96(m,2H), 1.79~1.76(m,2H), 1.69~1.61(m, 3H), 1.51~1.45(m, 1H), 1.20~1.11(m, 3H), 0.94~0.85(m,2H)

[0413] Example 29 [ka]

[0414] Example Route for Example 29 [ka]

[0415] N 1 Synthesis of -(cyclohexylmethyl)-4-nitroaniline (242-2): [ka] To a solution of 242-1 (2.00 g, 14.48 mmol) and cyclohexanecarbaldehyde (1.95 g, 17.38 mmol) in MeOH (25 mL) was added NaBHCN (2.73 g, 43.44 mmol), and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 242-2 (1.5 g, approximately 44% yield) as a solid.

[0416] N 1 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (242-3): [ka] To a solution of 242-2 (1.00 g, 4.27 mmol) in MeOH (20 mL) was added Pd / C (10%, 100 mg), and the mixture was stirred overnight at room temperature under an H atmosphere. After the reaction was complete, the insoluble material was removed by filtration. The organic layer was concentrated in vacuo and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 242-3 (800 mg, approximately 92% yield) as a solid. MS Calcd: 204.2; MS Found: 205.4 [M+H] + It was.

[0417] N 1 -((3-(bromomethyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (242-4): [ka] To a solution of 242-3 (150 mg, 0.73 mmol) and 3-(bromomethyl)oxetane-3-carbaldehyde (131 mg, 0.73 mmol) in MeOH (20 mL) was added NaBHCN (138 mg, 2.20 mmol), and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mass was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (2 × 30 mL), dried over MgSO, concentrated in vacuo, and simple workup afforded 242-4 (160 mg, approximately 59% yield) as an oil. MS Calcd: 366.1; MS Found: 367.0 [M+H] + It was.

[0418] N 1 -((3-((1H-1,2,4-triazol-1-yl)methyl)oxetan-3-yl)methyl)-N 4 Synthesis of 4-cyclohexylbenzene-1,4-diamine (SS20308-0242-01): [ka] A mixture of 242-4 (160 mg, 0.44 mmol), 1H-1,2,4-triazole (60 mg, 0.87 mmol), and KCO (180 mg, 1.31 mmol) in CHCN (20 mL) was stirred at 80° C. for 4 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water and extracted with EtOAc (20 mL x 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by Prep-HPLC to afford SS20308-0242-01 (13 mg, approximately 8% yield) as an oil. MS Calcd: 355.2; MS Found: 356.1 [M+H] + It was.

[0419] 1H NMR (400MHz, DMSO-d6) δ8.49(s,1H), 8.01(s,1H), 6.50~6.39(m,4H), 4.84(t, J=6.8Hz,1H), 4.77(t,J=5.6Hz,1H), 4.59(s,2H), 4.51(d,J=6.0Hz,2H), 4.38( d,J=6.0Hz,2H,), 2.99(d,J=6.4Hz,2H), 2.74(t,J=6.0Hz,2H), 1.79~1.60(m,2 H), 1.69~1,63(m,3H), 1.51~1.45(m,1H), 1.24~1.11(m,3H), 0.94~0.86(m,2H)

[0420] Example 30 [ka]

[0421] Example Routes for Example 30 [ka]

[0422] Synthesis of 5-nitro-N-(2,2,2-trifluoro-1-phenylethyl)pyridin-2-amine (0245-2): [ka] To 2-bromo-5-nitro-pyridine (245-1) (1.0 g, 4.93 mmol) in toluene (10 mL) was added 2,2,2-trifluoro-1-phenyl-ethanamine (863 mg, 4.93 mmol), followed by palladium(II) acetate (55 mg, 0.25 mmol), tri-tert-butylphosphine tetrafluoroborate (143 mg, 0.49 mmol), and sodium tert-butoxide (710 mg, 7.39 mmol). The reaction mixture was stirred at 120 °C for 1 h under microwave irradiation. The reaction mixture was filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1, 50 / 1, 20 / 1) to afford 245-2 (0.3 g, approximately 20% yield) as a solid. MS Calcd:297.1;MS Found:298.1[M+H] + It was.

[0423] Synthesis of tert-butyl 5-nitropyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-3): [ka] To a solution of 245-2 (300 mg, 1.01 mmol) in DCM (5 mL) was added TEA (102 mg, 1.01 mmol), (Boc)2O (440 mg, 2.02 mmol), and DMAP (62 mg, 0.50 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated and purified by prep-TLC (petroleum ether / EtOAc = 10 / 1) to afford 245-3 (171 mg, approximately 43% yield) as an oil. MS Calcd: 397.1; MS Found: 342.1 [M-55] + It was.

[0424] Synthesis of tert-butyl 5-aminopyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-4): [ka] A suspension of 245-3 (166 mg, 0.42 mmol) and palladium on carbon (166 mg, 10%) in EtOAc (20 mL) was vigorously stirred at room temperature for 5 h under a hydrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to afford crude product 245-4 (153 mg, approximately 100% yield) as a solid. MS Calcd: 367.2; MS Found: 368.1 [M+H] + It was.

[0425] Synthesis of tert-butyl 5-nitropyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-5): [ka] To a solution of 245-4 (159 mg, 0.43 mmol), 2-chloroacetaldehyde (255 mg, 1.30 mmol, 40% in water), and glacial acetic acid (1 mL) was added NaBHCN (55 mg, 0.87 mmol). After stirring at room temperature for 16 h, the reaction mixture was basified with NaHCO solution and extracted with EtOAc (10 mL × 3). The organic layer was washed with water and brine, dried over MgSO, and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 2 / 1) to afford 245-5 (162 mg, approximately 87% yield) as an oil. MS Calcd: 429.1; MS Found: 430.3 [M+H] + It was.

[0426] Synthesis of tert-butyl 5-(2-(1H-1,2,4-triazol-1-yl)ethylamino)pyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-6): [ka] A mixture of 245-5 (162 mg, 0.38 mmol), 1H-1,2,4-triazole (52 mg, 0.75 mmol), and potassium carbonate (104 mg, 0.75 mmol) in DMF (5 mL) was stirred at room temperature for 3 days. The reaction mixture was then poured into cold water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by prep-TLC (petroleum ether / EtOAc = 1 / 2, ethyl acetate, dichloromethane / methanol = 20 / 1) to afford 245-6 (77 mg, approximately 44% yield) as an oil. MS Calcd: 462.2; MS Found: 463.3 [M+H] + It was.

[0427] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)pyridine-2,5-diamine (SS20308-0245-01): [ka] 245-6 (77 mg, 0.17 mmol) in HCl (4 M in dioxane, 10 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and dissolved in water; the pH was adjusted to 10.0-11.0 with NaOH solution and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by prep-TLC (dichloromethane / methanol = 15 / 1) to afford SS20308-0245-01 (38 mg, approximately 63% yield) as an oil. MS Calcd: 362.2; MS Found: 363.3 [M+H] + It was.

[0428] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H), 7.94(s,1H), 7.54(d,J=7.2Hz,2H), 7.42(d,J=2.8Hz,1H), 7.39~7.29(m,3H), 6.99(d,J=10.0Hz,2H) ), 6.87(dd,J=8.8,2.8Hz,2H), 6.59(d,J=8.8Hz,1H,), 5.97~5.86(m,1H), 5.10(t,J=6.0Hz,1H), 4.26(t,J=6.0Hz,2H), 3.37~3.30(m,2H)

[0429] Example 31 [ka]

[0430] Example Routes for Example 31 [ka]

[0431] Synthesis of 5-bromo-N-(4-fluorobenzyl)pyridin-2-amine (246-2): [ka] A mixture of 246-1 (2.00 g, 11.4 mmol), 4-(fluorophenyl)methanamine (2.85 g, 22.8 mmol), and KCO (3.15 g, 22.8 mmol) in DMSO (50 mL) was stirred overnight at room temperature. Water (50 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford 246-2 (500 mg, yield approx. 16%) as a solid. MS Calcd: 280.0; MS Found: 281.2 [M+H] + It was.

[0432] N 5-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -(4-fluorobenzyl)pyridine-2,5-diamine (SS20308-0246-01): [ka] A mixture of 246-2 (250 mg, 0.89 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine (199 mg, 1.78 mmol), BrettPhosPalladacycle (71 mg, 0.089 mmol), and t-BuOK (199 mg, 1.78 mmol) in toluene (5 mL) was stirred at 140 °C for 1 h in a microwave reactor. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by Prep-HPLC to afford SS20308-0246-01 (26 mg, approximately 9% yield) as a solid. MS Calcd: 312.2; MS Found: 313.3 [M+H] + It was.

[0433] 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H), 7.97(s,1H), 7.43(d,J=2.8Hz,1H), 7.36~7.30(m,2H), 7.14~7.07(m,2H), 6.85(dd,J=8.6Hz,3.2Hz ,1H), 6.36(d,J=8.8, 1H), 6.29(t,J=6.2Hz,1H,), 4.97(t,J=6.2Hz, 1H), 4.34(d,J=6.0Hz, 1H), 4.28(t,J=6.2Hz, 2H), 3.38~3.34(m,2H)

[0434] Example 32 [ka]

[0435] Example Routes for Example 32 [ka]

[0436] Synthesis of 5-bromo-N-((4,4-difluorocyclohexyl)methyl)pyridin-2-amine (247-2): [ka] A mixture of 247-1 (50 mg, 0.28 mmol), (4,4-difluorocyclohexyl)methanamine (84 mg, 0.56 mmol), and K2CO3 (116 mg, 0.84 mmol) in DMSO (2 mL) was stirred at 120 °C for 4 h. The reaction mixture was diluted with water (10 mL), and then the mixture was extracted with EtOAc (10 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated to afford 247-2 (80 mg, approximately 92% yield) as an oil. MS Calcd: 304.0; MS Found: 305.2 [M+H] + It was.

[0437] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -(4,4-difluorocyclohexyl)pyridine-2,5-diamine (SS20308-0247-01): [ka] A mixture of 247-2 (80 mg, 0.26 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine (58 mg, 0.52 mmol), BrettPhosPalladacycle (21 mg, 0.026 mmol), and t-BuOK (58 mg, 0.52 mmol) in toluene (3 mL) was stirred at 110 °C overnight under a N atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-HPLC to afford SS20308-0247-01 (7 mg, approximately 8% yield) as an oil. MS Calcd: 336.2; MS Found: 337.3 [M+H] + It was.

[0438] 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H), 7.97(s,1H), 7.44~7.42(m,1H), 6.85~6.80(m,1H), 6.35(d,J=8.8Hz,1H), 5.81(t,J=6.0Hz,1H), 4.90(t ,J=6.4Hz, 1H), 4.29(t,J=6.2Hz,2H,), 3.36(t,J=6.0Hz, 2H), 3.03(t,J=6.0Hz, 2H), 2.05~1.93(m,2H), 1.84~1.58(m,2H), 1.23~1.10(m,2H)

[0439] Example 33 [ka]

[0440] Example Routes for Example 33 [ka]

[0441] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-bromopyridin-2-amine (249-2): [ka] A mixture of 249-1 (600 mg, 3.41 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine hydrochloride (757 mg, 4.09 mmol), and K2CO3 (1.18 g, 8.52 mmol) in DMF (10 mL) was stirred overnight at 120 °C under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 249-2 (300 mg, approximately 33% yield) as a solid. MS Calcd: 267.0; MS Found: 268.0 [M+H]+ It was.

[0442] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of -(4-fluorobenzyl)pyridine-2,6-diamine (SS20308-0249-01): [ka] A mixture of 249-2 (100 mg, 0.37 mmol), (4-fluorophenyl)methanamine (56 mg, 0.45 mmol), Pd(dba) (17 mg, 0.02 mmol), X-phos (18 mg, 0.04 mmol), and CsCO (243 mg, 0.75 mmol) in toluene (10 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by Prep-HPLC to afford SS20308-0249-01 (20 mg, approximately 17% yield) as an oil. MS Calcd: 312.2; MS Found: 313.0 [M+H] + It was.

[0443] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H), 7.96(s,1H), 7.37~7.34(m,2H), 7.13~7.08(m,2H), 7.02(t,J=8.0Hz, 1H), 6.68(t,J=6.0Hz, 1H) , 6.19(t,J=5.6Hz,1H,), 5.66(d,J=7.6Hz, 1H), 5.59(d,J=7.6Hz, 1H), 4.39(d,J=6.4Hz, 2H), 4.22(t,J=6.0Hz, 2H), 3.53~3.49(m, 2H)

[0444] Example 34 [ka]

[0445] Example Routes for Example 34 [ka]

[0446] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of -((4,4-difluorocyclohexyl)methyl)pyridine-2,5-diamine (SS20308-0250-01): [ka] A mixture of 249-2 (100 mg, 0.37 mmol), (4,4-difluorocyclohexyl)methanamine (67 mg, 0.45 mmol), Pd(dba) (17 mg, 0.02 mmol), X-phos (18 mg, 0.04 mmol), and CsCO (243 mg, 0.75 mmol) in toluene (10 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water. The insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by Prep-HPLC to afford SS20308-0250-01 (6 mg, approximately 5% yield) as an oil. MS Calcd:336.2;MS Found:337.3[M+H] + It was.

[0447] 1 H NMR (400MHz, CDCl3 and D2O) δ8.10(s,1H), 7.96(s,1H), 7.29~7.25(m, 1H), 5.73(d,J=8.0Hz,2H), 5.66(d,J=8.0Hz, 1H), 4.42(t,J=5. 2Hz, 2H), 3.77(t,J=5.6Hz,2H,), 3.13(d,J=6.8Hz, 2H), 2.13~2.11(m, 2H), 1.91~1.88(m, 2H), 1.79~1.64(m, 3H), 1.39~1.36(m, 2H)

[0448] Example 35 [ka]

[0449] Example Routes for Example 35 [ka]

[0450] Synthesis of 3-(2-(4-fluorobenzylamino)-6-(1H-indol-7-yl)phenyl)-N,N-dimethylpropanamide (253-1): [ka] A mixture of 171-6 (200 mg, 0.7 mmol), 1-(bromomethyl)-4-fluorobenzene (120 mg, 0.7 mmol), and CsCO (180 mg, 1.4 mmol) in DMF (5 mL) was stirred at 90 °C for 18 h. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and evaporated to give the crude product. This was purified by column chromatography (EtOAc / petroleum ether = 5 / 1) to afford 253-1 (50 mg, approximately 17% yield) as an oil. MS Calcd: 415.2; MS Found: 416.4 [M+H] + It was.

[0451] Synthesis of 2-(3-(dimethylamino)propyl)-N-(4-fluorobenzyl)-3-(indolin-7-yl)aniline (SS20308-0253-01): [ka] 253-1 (40 mg, 100 μmol) and BH3 (0.5 mL) in THF (1 mL) were stirred at room temperature for 18 hours. HCl (0.5 mL, 3N) and MeOH (1 mL) were added to the mixture, and the mixture was stirred at 70 °C for 6 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined layers were dried over Na2SO4 and concentrated in vacuo to afford the crude product, which was then purified by Prep-HPLC to afford SS20308-0253-01 (1.84 mg, approximately 5% yield) as a pale solid. MS Calcd: 403.5; MS Found: 404.3 [M+H] + It was.

[0452] 1 H NMR (400MHz, DMSO-d6) δ7.32~7.29(m,2H), 6.98~6.91(m,3H), 6.89~6.87(m,1H), 6.71(d,J=8.0Hz,2H), 6.61(t,J=7.2Hz, 1H), 6.40~6.35(m,2H), 4.30(s,2H), 3.31(t,J=8.4Hz,2H), 2.93(t,J=8.0Hz,2H), 2.46~2.43(m, 1H), 2.34~2.32(m, 2H), 2.12~2.06(m, 2H), 2.02(s,6H), 1.57~1,46(m,2H)

[0453] Example 36 [ka]

[0454] Example Routes for Example 36 [ka]

[0455] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-4-nitroaniline (265-01): [ka] A mixture of 3,4-difluoronitrobenzene (1.60 g, 10.06 mmol), 236-3 (2.40 g, 12.07 mmol), and K2Co3 (6.55 g, 20.11 mmol) in DMSO (10 mL) was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (PE / EtOAc = 1 / 1) to afford 265-1 (2.20 g, approximately 82% yield) as a solid. MS Calcd: 265.1; MS Found: 266.1 [M+H] + It was.

[0456] N 1 Synthesis of -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (265-2): [ka] To a solution of 265-1 (1.00 g, 3.77 mmol) in MeOH (20 mL) was added Pd / C (10%, 50 mg), and the mixture was stirred overnight at room temperature under an H atmosphere. After the reaction was complete, the insoluble material was removed by filtration. The organic layer was concentrated in vacuo and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 265-01-3 (700 mg, approximately 79% yield) as an oil. MS Calcd: 235.1; MS Found: 236.0 [M+H] + It was.

[0457] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0265-01): [ka] To a solution of 265-2 (250 mg, 1.06 mmol) and 2,2,2-trifluoro-1-fluorophenylethanone (222 mg, 1.28 mmol) in CHCl (10 mL) was added AlMe (1.06 mL, 2.12 mmol, 2N in THF), and the reaction was stirred at 40°C for 2 h under a nitrogen atmosphere. After the reaction was cooled, BH-DMS (1.06 mL, 2.12 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40°C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO, and concentrated in vacuo. Purification by prep-HPLC afforded SS20308-0265-01 (33 mg, approximately 8% yield) as an oil. MS Calcd:393.2;MS Found:394.1[M+H] + It was.

[0458] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H), 7.96(s,1H), 7.59~7.57(m, 2H), 7.40~7.31(m,3H), 6.66(dd,J=14.4Hz,2.4Hz,1H), 6.47~6.42( m,2H), 6.23(d,J=10.8Hz,1H), 5.42~5.33(m,1H), 4.71(t,J=5.6Hz,1H), 4.23(t,J=6.8Hz, 2H), 2.93~2.88(m, 2H), 2.02~1.95(m, 2H)

[0459] Example 37 [ka]

[0460] Example Routes for Example 37 [ka]

[0461] N 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)benzene-1,4-diamine (SS20308-0275-01): [ka] To a solution of 239-1 (180 mg, 0.89 mmol) and 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (170 mg, 1.06 mmol) in CHCl (10 mL) was added AlMe (0.89 mL, 1.78 mmol, 2N in THF), and the reaction was stirred at 40°C for 2 hours under a nitrogen atmosphere. After the reaction was cooled, BH-DMS (0.89 mL, 1.78 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by Prep-HPLC to afford SS20308-0275-01 (26 mg, approximately 8% yield) as an oil. MS Calcd:347.2;MS Found:348.2[M+H] + It was.

[0462] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H), 7.98(s,1H), 7.25~7.21(m,3H), 6.61(d,J=8.8Hz,2H), 6.46(d,J=8.8Hz,2H), 5.04(d,J=8.8H) z,1H), 4.96~4.87(m,2H), 4.31(t,J=6.4Hz,2H), 3.39~3.34(m,2H), 2.35~2.30(m,1H), 1.68~1.63(m,1H), 1.33(s,3H), 1.19(s,3H)

[0463] Example 38 [ka]

[0464] Example Route for Example 38 [ka]

[0465] Synthesis of 3-(2-fluoro-4-nitrophenylamino)propan-1-ol (302-2): [ka] A mixture of 3,4-difluoronitrobenzene (1.60 g, 10.06 mmol), 3-aminopropan-1-ol (302-1) (906 mg, 12.07 mmol), and K2CO3 (2.78 g, 20.11 mmol) in DMSO (10 mL) was stirred at 80 °C for 4 h. After the reaction was completed, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether: EtOAc = 1 / 2) to afford 302-2 (2.00 g, approximately 93% yield) as an oil. MS Calcd: 214.1; MS Found: 215.2 [M+H] + It was.

[0466] Synthesis of 3-(4-amino-2-fluorophenylamino)propan-1-ol (302-2): [ka] To a solution of 302-2 (1.90 g, 8.87 mmol) in EtOAc (20 mL) was added Pd / C (10%, 150 mg), and the mixture was stirred at room temperature for 4 h under an H atmosphere. After the reaction was complete, the insoluble material was removed by filtration. The organic layer was concentrated in vacuo and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 302-3 (1.5 g, approximately 92% yield) as an oil. MS Calcd: 184.1; MS Found: 185.2 [M+H] + It was.

[0467] Synthesis of 3-(2-fluoro-4-(2,2,2-trifluoro-1-phenylethylamino)phenylamino)propan-1-ol (302-4): [ka] To a solution of 302-3 (500 mg, 2.71 mmol) and 2,2,2-trifluoro-1-phenylethanone (614 mg, 353 mmol) in CHCl (10 mL) was added AlMe (2.71 mL, 5.42 mmol, 2N in THF), and the reaction was stirred at 40°C for 2 h under a nitrogen atmosphere. After the reaction was cooled, BH-DMS (2.71 mL, 5.42 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40°C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO, concentrated, and purified by Prep-HPLC to afford 302-4 (400 mg, approximately 43% yield) as an oil. MS Calcd:342.1;MS Found:343.0[M+H] + It was.

[0468] Synthesis of 3-(2-fluoro-4-(2,2,2-trifluoro-1-phenylethylamino)phenylamino)propyl methanesulfonic acid (302-5): [ka] To a solution of 302-4 (250 mg, 0.73 mmol) in CHCl (20 mL) was added MsO (153 mg, 0.88 mmol) and DIPEA (189 mg, 1.46 mmol), and the reaction was stirred for 2 h at room temperature. The mixture was quenched with water and extracted with CHCl (50 mL × 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 302-5 (160 mg, approximately 52% yield) as an oil. MS Calcd: 327.1; MS Found: 328.2 [M+H] + It was.

[0469] N 1 -(3-(dimethylamino)propyl)-2-fluoro-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0302-01): [ka] To a solution of 302-5 (160 mg, 0.38 mmol) in CHCN (20 mL) was added dimethylamine hydrochloride (47 mg, 0.57 mmol) and KCO (210 mg, 1.52 mmol), and the mixture was stirred for 4 h at 80 °C. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL × 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by Prep-HPLC to afford SS20308-0302-01 (24 mg, approximately 17% yield) as an oil. MS Calcd: 369.2; MS Found: 370.2 [M+H] + It was.

[0470] 1H NMR (400MHz, DMSO-d6) δ7.54~7.56(m,2H), 7.29~7.37(m,3H), 6.60~6.64(m,1H), 6.43~6.50(m,2H), 6.15(d,J=10.8H) z,1H), 5.31~5.36(m,1H), 4.63(d,J=5.2Hz,1H), 2.90~2.95(m,2H), 2.20~2.23(m,2H), 2.08(s,6H), 1.55~1.62(m,2H)

[0471] Example 39 [ka]

[0472] Example Routes for Example 39 [ka]

[0473] Synthesis of 2-bromo-N-(3-morpholinopropyl)-4-nitroaniline (315-2): [ka] A mixture of 3-morpholinopropan-1-amine (1.31 g, 9.09 mmol), 315-1 (1 g, 4.55 mmol), and potassium carbonate (1.26 g, 9.09 mmol) was suspended in DMSO (10 mL). After stirring overnight at room temperature, the mixture was diluted with water (40 mL). The resulting solid was filtered, washed with water, dried, and concentrated to afford 0315-2 (1.4 g, approximately 89% yield) as a solid. MS Calcd: 343.1; MS Found: 344.0 [M+H] + It was.

[0474] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(3-morpholinopropyl)-4-nitroaniline (315-3): [ka] To a mixture of 315-2 (1 g, 2.91 mmol), palladium(II) acetate (33 mg, 0.15 mmol), S-phos (120 mg, 0.29 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (672 mg, 3.20 mmol), and potassium phosphate (2.16 g, 10.17 mmol) in toluene (40 mL) was added water (2 mL), and the mixture was stirred at 110 °C for 16 h under a N atmosphere. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, 100% EtOAc, DCM / methanol = 50 / 1) to afford 0315-3 (700 mg, yield approx. 69%) as a solid. MS Calcd: 347.2; MS Found: 348.3 [M+H] + It was.

[0475] N 1 Synthesis of -(3-morpholinopropyl)-2-(tetrahydro-2H-pyran-4-yl)benzene-1,4-diamine (315-4): [ka] A suspension of 315-3 (650 mg, 1.87 mmol) and palladium on activated carbon (10%, 130 mg) in EtOAc (20 mL) was vigorously stirred at room temperature under hydrogen gas (balloon) for 16 h. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to afford crude product 315-4 (597 mg, approximately 100% yield) as an oil. MS Calcd: 319.2; MS Found: 320.3 [M+H] + It was.

[0476] N 1 -(3-morpholinopropyl)-2-(tetrahydro-2H-pyran-4-yl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0315-01): [ka] A solution of 315-4 (100 mg, 0.31 mmol) and tetramethylaluminum (2 M in hexane) (0.23 mL, 0.46 mmol) in dichloromethane (10 mL) was heated at 40 °C for 2 h. The reaction mixture was cooled to room temperature, and borane methyl sulfide complex (2 M in THF) (0.31 mL, 0.62 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was quenched with methanol at 0 °C and then concentrated. The residue was basified with NaHCO solution and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by prep-TLC (DCM / methanol = 20 / 1) to afford SS20308-0315-01 (22.8 mg, approximately 23% yield) as a solid. MS Calcd:477.3;MS Found:478.3[M+H] + It was.

[0477] 1 H NMR (400MHz, DMSO-d6) δ7.59(d,J=7.2Hz,2H), 7.40~7.29(m,3H), 6.66(d,J=2.0Hz) ,1H), 6.53(dd,J=8.4,2.0Hz,1H), 6.35(d,J=8.4Hz,1H), 5.88(d,J=10.8Hz,1H),5 .38~5.27(m,1H), 4.38(brs,1H), 3.96~3.87(m,2H), 3.60~3.53(m,4H), 3.50~3.40 (m,2H), 2.99~2.90(m,2H), 2.86~2.76(m,1H), 2.37~2.28(m,6H), 1.72~1.46(m,6H)

[0478] Example 40 [ka]

[0479] Example 41 [ka]

[0480] Example Routes for Example 41 [ka]

[0481] Synthesis of 2-cyclohexenyl-N-(3-morpholinopropyl)-4-nitroaniline (325-1): [ka] To a mixture of 315-2 (580 mg, 1.69 mmol), cyclohexen-1-ylboronic acid (429 mg, 3.41 mmol), palladium(II) acetate (19 mg, 0.085 mmol), S-phos (70 mg, 0.17 mmol), and potassium phosphate (1.25 g, 5.90 mmol) in toluene (20 mL) was added water (1 mL). After stirring at 100°C under N2 for 16 hours, the reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, 100% EtOAc) to afford 325-1 (548 mg, approximately 94% yield) as an oil. MS Calcd: 345.2; MS Found: 346.2 [M+H] + It was.

[0482] 2-Cyclohexyl-N 1 Synthesis of -(3-morpholinopropyl)benzene-1,4-diamine (325-2): [ka] A suspension of 325-1 (550 mg, 1.59 mmol) and palladium on activated carbon (10%, 55 mg) in EtOAc (10 mL) was vigorously stirred at room temperature under hydrogen gas (balloon) for 16 h. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to afford crude product 325-2 (498 mg, approximately 99% yield) as an oil. MS Calcd: 317.3; MS Found: 318.3 [M+H] + It was.

[0483] 2-Cyclohexyl-N 1 -(3-morpholinopropyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0325-01): [ka] A solution of 325-2 (100 mg, 0.31 mmol) and tetramethylaluminum (2 M in hexane) (0.24 mL, 0.48 mmol) in dichloromethane (10 mL) was heated at 40 °C for 2 h. The reaction mixture was cooled to room temperature, and borane methyl sulfide complex (2 M in THF) (0.8 mL, 1.6 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was quenched with methanol at 0 °C and then concentrated. The residue was basified with NaHCO solution and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by prep-TLC (DCM / methanol = 20 / 1) to afford SS20308-0325-01 (85.4 mg, approximately 57% yield) as a solid. MS Calcd: 475.3; MS Found: 476.4 [M+H] + It was.

[0484] 1H NMR (400MHz, DMSO-d6) δ7.59(d,J=6.8Hz,2H), 7.39~7.29(m,3H), 6.65(d,J=2. 4Hz,1H), 6.48(dd,J=8.6,2.6Hz,1H), 6.32(d,J=8.8Hz,1H), 5.84(d,J=10.8Hz ,1H), 5.32~5.21(m,1H), 4.27(brs,1H), 3.61~3.53(m,4H), 3.32~3.29(m,1H), 2.95(t,J=6.8Hz,2H), 2.39~2.27(m,6H), 1.80~1.60(m,6H), 1.45~1.15(m,6H)

[0485] Example 42 [ka]

[0486] Example Routes for Example 42 [ka]

[0487] Synthesis of 2-bromo-N-(3-morpholinopropyl)-4-nitroaniline (326-1): [ka] A mixture of 3-pyrrolidin-1-ylpropan-1-amine (2.33 g, 18.18 mmol), 315-1 (2.00 g, 9.09 mmol), and potassium carbonate (2.51 g, 18.18 mmol) was suspended in DMSO (20 mL). After stirring overnight at room temperature, the mixture was diluted with water (80 mL). The resulting solid was filtered, washed with water, dried, and concentrated to afford 326-1 (2.95, approximately 99% yield) as a solid. MS Calcd: 327.1; MS Found: 328.0 [M+H] + It was.

[0488] Synthesis of 2-cyclohexenyl-4-nitro-N-(3-(pyrrolidin-1-yl)propyl)nitroaniline (326-2): [ka] To a mixture of 326-1 (1.00 g, 3.05 mmol), cyclohexen-1-ylboronic acid (780 mg, 6.19 mmol), palladium(II) acetate (34 mg, 0.15 mmol), S-phos (125 mg, 0.30 mmol), and potassium phosphate (2.26 g, 10.66 mmol) in toluene (40 mL) was added water (2 mL). After stirring at 100 °C for 3 h under N2, the reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, and the residue was purified by CC (petroleum ether / EtOAc = 1 / 1, 100% EtOAc, ECM / methanol = 20 / 1) to afford compound 326-2 (1.0 g, approximately 100% yield) as an oil. MS Calcd: 329.2; MS Found: 330.3 [M+H] + It was.

[0489] 2-Cyclohexyl-N 1 Synthesis of -(3-(pyrrolidin-1-yl)propyl)benzene-1,4-diamine (326-3): [ka] A suspension of 326-2 (1.00 mg, 3.04 mmol) and palladium on activated carbon (10%, 110 mg) in EtOAc (15 mL) was vigorously stirred at room temperature under hydrogen gas (balloon) for 16 h. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to afford crude product 326-3 (915 mg, approximately 100% yield) as an oil. MS Calcd: 301.3; MS Found: 302.2 [M+H] + It was.

[0490] 2-Cyclohexyl-N 1 -(3-(pyrrolidin-1-yl)propyl)-N 4Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0326-01): [ka] A solution of 326-3 (100 mg, 0.33 mmol) and tetramethylaluminum (2 M in hexane) (0.25 mL, 0.50 mmol) in dichloromethane (10 mL) was heated at 40 °C for 2 h. The reaction mixture was cooled to room temperature, and borane methyl sulfide complex (2 M in THF) (0.9 mL, 1.80 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was quenched with methanol at 0 °C and then concentrated. The residue was basified with NaHCO solution and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by prep-TLC (DCM / methanol = 10 / 1) to afford SS20308-0326-01 (16.3 mg, approximately 11% yield) as an oil. MS Calcd:459.3;MS Found:460.3[M+H] + It was.

[0491] 1 H NMR (400MHz, CD3OD) δ7.52(d,J=6.8Hz,2H), 7.40~7.33(m,3H), 6.64(d,J=2.4Hz,1H), 6.57(dd,J=8.4Hz,1H), 6.51(dd,J=8.8,2.8 Hz,1H), 4.99(q,J=8.0Hz,1H), 3.10(d,J=6.8Hz,2H), 2.74~2.62(m,6H), 2.59~2.50(m,1H), 1.90~1.67(m,10H), 1.50~1.25(m,6H)

[0492] Example 43 [ka]

[0493] Example Routes for Example 43 [ka]

[0494] Synthesis of 1-(2-(2-nitrophenoxy)ethyl)-1H-1,2,4-triazole (33-2): [ka] A mixture of 33-1 (3.7 g, 26.60 mmol), 1-(bromoethyl)-1H-1,2,4-triazole (7.0 g, 39.90 mmol), and K2CO3 (7.4 mg, 53.20 mmol) in DMF (70 mL) was stirred overnight at 70 °C. The reaction mixture was cooled to room temperature, poured into water (150 mL), and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (CHCl2 / MeOH = 100 / 1 to 30 / 1) to afford 0016-01-3 (2.0 g, approximately 32% yield) as a solid. MS Calcd: 234.1; MS Found: 235.2 [M+H] + It was.

[0495] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)aniline (33-3): [ka] To a solution of 33-2 (2.0 g, 8.54 mmol) in MeOH (20 mL) was added Pd / C (200 mg, 10%), and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to remove the solvent. The residue was purified by column chromatography (CHCl / MeOH = 100 / 1 to 20 / 1) to afford 33-3 (1.0 g, approximately 57% yield) as an oil. MS Calcd: 204.1; MS Found: 205.3 [M+H] + It was.

[0496] Synthesis of 4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenylamino)benzoic acid (SS20308-0033-01): [ka] A solution of 33-3 (1.0 g, 4.90 mmol), ethyl 4-bromobenzoate (1.4 g, 5.88 mmol), Pd(OAc) (110 mg, 0.49 mmol), BINAP (610 mg, 0.98 mmol), and CsCO (2.4 g, 7.34 mmol) in toluene (150 mL) was stirred overnight at 110 °C. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL). The organic layer was washed with water (300 mL) and brine (2 × 300 mL), and the solvent was evaporated to afford a solid, which was purified by column chromatography (CHCl / MeOH = 100 / 1 to 20 / 1) and prep-HPLC to afford SS20308-0033-01 (700 mg, approximately 40% yield) as a solid. MS Calcd:352.2;MS Found:353.3[M+H] + It was.

[0497] 1 H NMR (400MHz, CDCl3) δ8.08(s,1H), 7.99(s,1H), 7.96~7.93(m,2H), 7.38~7.36(m,1H), 7.04~6.99(m,2H), 7.98~7.94(m,2H) ), 6.90~6.98(m,1H), 6.29(s,1H), 4.57(t,J=5.2Hz,2H), 4.41(t,J=5.0,2H), 4.57(q,J=7.2Hz,2H), 1.38(t,J=7.2Hz,2H)

[0498] Example 44 [ka]

[0499] Example Routes for Example 44 [ka]

[0500] Synthesis of 1-(2-(2-bromo-6-nitrophenoxy)ethyl)-1H-1,2,4-triazole (55-2): [ka] A mixture of 55-1 (2.2 g, 10.09 mmol), 1-(2-bromoethyl)-1H-1,2,4-triazole (2.1 g, 12.11 mmol), and K2CO3 (2.1 g, 15.14 mmol) in DMF (50 mL) was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (70 mL × 3). The organic layer was washed with brine and concentrated. The residue was purified by column chromatography (CHCl2 / MeOH = 100 / 1 to 20 / 1) to afford 55-2 (2.2 g, approximately 70% yield) as an oil. MS Calcd: 312.0; MS Found: 313.0 [M+H] + It was.

[0501] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-3-nitro-N-phenylaniline (55-3): [ka] A solution of 55-2 (1.1 g, 3.51 mmol), aniline (393 mg, 4.22 mmol), Pd(dba) (321 mg, 0.35 mmol), Xant-Phos (203 mg, 0.35 mmol), and CsCO (1.7 g, 5.27 mmol) in toluene (30 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then poured into water (100 mL) and extracted with EtOAc (40 mL × 4). The organic layer was washed with water (50 mL) and brine (2 × 50 mL), and the solvent was evaporated to give a solid, which was purified by column chromatography (CHCl / MeOH = 100 / 1 to 20 / 1) to give 55-3 (700 mg, approximately 83% yield) as an oil. MS Calcd:325.1;MS Found:326.2[M+H] + It was.

[0502] 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-N 1 Synthesis of -phenylbenzene-1,3-diamine (55-4): [ka] To a solution of 55-3 (550 mg, 1.69 mmol) in MeOH (20 mL) was added Pd / C (10%, 100 mg), and the solution was stirred for 16 h at room temperature. The reaction mixture was filtered, washed with methanol (10 mL × 4), concentrated, and purified by column chromatography (CHCl / MeOH = 100 / 1 to 20 / 1) to afford 55-4 (400 mg, approximately 80% yield) as a solid. MS Calcd: 295.1; MS Found: 296.1 [M+H] + It was.

[0503] Synthesis of 4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-3-((phenylamino)phenylamino)benzoic acid (SS20308-0055-01): [ka] A solution of 55-4 (250 mg, 0.85 mmol), ethyl 4-bromobenzoate (291 mg, 1.27 mmol), Pd(dba) (78 mg, 0.085 mmol), Xant-Phos (49 mg, 0.085 mmol), and CsCO (552 mg, 1.69 mmol) in toluene (6 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction was then poured into water (15 mL) and extracted with EtOAc (10 mL × 5). The organic layer was washed with water (10 mL), brine (2 × 10 mL), and the solvent was evaporated to give a solid, which was purified by column chromatography (CHCl / MeOH = 80 / 1 to 30 / 1) and Prep-HPLC to give SS20308-0055-01 (67 mg, approximately 18% yield) as an oil. MS Calcd: 443.2; MS Found: 444.2 [M+H] + It was.

[0504] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H), δ8.16(s,1H), 7.99(s,1H), 7.78(d,J=8.8 Hz,1H), 7.47(s,1H), 7.24(dd,J=7.6,7.6Hz,1H), 7.08(d,J=8.0Hz,1H), 6.97 ~6.90(m,4H), 6.86(t,J=7.2Hz,2H), 6.80(dd,J=7.6Hz,1.6Hz,1H), 4.40(t, J=4.8Hz,2H), 4.25=4.20(m,2H), 4.12(t,J=4.8Hz,2H), 1.27(t,J=7.0Hz,3H)

[0505] Example 45 [ka]

[0506] Example Routes for Example 45 [ka]

[0507] Synthesis of 3-bromo-2-(2-(dimethylamino)ethoxy)aniline (72-2): [ka] 72-1 (1.0 g, 3.46 mmol), iron powder (1.9 g, 34.59 mmol), and NH4Cl (93 mg, 1.74 mmol) in ethanol (16 mL) and water (4 mL) were stirred at 70 °C for 2 h. The reaction mixture was then filtered through celite. The filtrate was basified with NaOH until the pH reached 10.0-11.0 and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated to afford 72-2 (0.7 g, approximately 78% yield) as a solid. MS Calcd: 258.0; MS Found: 259.2 [M+H] + It was.

[0508] Synthesis of N-(3-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-3-oxo-3-phenylpropanamide (72-3): [ka] A mixture of 72-2 (410 mg, 1.58 mmol) and ethyl 3-oxo-3-phenylpropanoate (760 mg, 3.95 mmol) was stirred and heated at 140 °C for 30 min under microwave irradiation and nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1, 5 / 1, 3 / 1, 1 / 1, CHCl / MeOH = 20 / 1) to afford 72-3 (400 mg, approximately 62% yield) as a solid. MS Calcd: 404.1; MS Found: 405.3 [M+H] + It was.

[0509] Synthesis of 7-bromo-8-(2-(dimethylamino)ethoxy)-4-phenylquinolin-2(1H)-one (72-4): [ka] 72-3 (500 mg, 1.23 mmol) in H2SO4 (5 mL) was stirred and heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured onto ice, basified with NaOH (40%) until the pH reached 9.0-10.0, and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by prep-TLC (CHCl2 / MeOH = 20 / 1) to afford 72-4 (70 mg, approximately 15% yield) as an oil. MS Calcd: 386.1; MS Found: 387.2 [M+H] + It was.

[0510] Synthesis of 8-(2-(dimethylamino)ethoxy)-4-phenyl-7-(phenylamino)quinolin-2(1H)-one (SS20308-0072-01): [ka] A solution of 72-4 (60 mg, 0.25 mmol), aniline (73 mg, 0.78 mmol), Xantphos (9 mg, 0.016 mmol), Pd(dba) (7 mg, 0.0076 mmol), and anhydrous cesium carbonate (76 mg, 0.23 mmol) was suspended in toluene (2 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere overnight and then rinsed with EtOAc. The filtrate was concentrated and purified by prep-TLC (CHCl / MeOH = 20 / 1) to afford SS20308-0072-01 (35 mg, approximately 57% yield) as a solid. MS Calcd: 399.2; MS Found: 400.4 [M+H] + It was.

[0511] 1H NMR (400MHz, DMSO-d6) δ12.67(brs,1H), 8.33(s,1H), 7.55~7.44(m,5H), 7.28(dd,J=8.0,7.6Hz,2H), 7.19(d,J=7.6Hz,2 H), 7.04~6.99(m,2H), 6.95(dd,J=7.2,7.2Hz,1H), 6.14(s,1H), 4.08(t,J=4.2Hz,2H), 2.66(t,J=4.2Hz,2H), 2.38(s,6H)

[0512] Example 46 [ka]

[0513] Example Routes for Example 46 [ka]

[0514] Synthesis of 4-bromo-2-nitrobiphenyl (95-2): [ka] A mixture of 95-1 (6.00 g, 21.36 mmol), phenylboronic acid (2.60 g, 21.36 mmol), Pd(PPh) (1.23 g, 1.07 mmol), and NaCO (7.90 g, 74.76 mmol) in toluene / HO (60 mL, 5 / 1) was stirred overnight at 90 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether) to afford 95-2 (3.70 g, approximately 62% yield) as an oil.

[0515] 1H NMR (400MHz, CDCl3) δ8.00(d,J=2.0Hz,1H), 7.75(dd,J=8.4Hz,2.0Hz,1H), 7.45~7.40(m,3H), 7.33(d,J=8.4Hz,1H), 7.31~7.27(m,2H)

[0516] Synthesis of 4-bromobiphenyl-2-amine (95-3): [ka] A mixture of 95-2 (3.70 g, 13.30 mmol), Zn powder (8.70 g, 133.00 mmol), and HOAc (3.5 mL) in EtOH (35 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water. The mixture was basified with 40% NaOH until the pH reached 10. The resulting mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 95-3 (1.90 g, approximately 58% yield) as an oil. MS Calcd: 247.0; MS Found: 248.1 [M+H] + It was.

[0517] Synthesis of 4-bromo-N-(2-chloroethyl)biphenyl-2-amine (95-4): [ka] To a solution of 95-3 (1.75 g, 7.05 mmol) in MeOH (20 mL), 2-chloroacetaldehyde (2.77 g, 14.11 mmol, 40%), AcOH (846 mg, 14.11 mmol), and NaBHCN (887 mg, 14.11 mmol) were added, and the reaction mixture was then stirred overnight at 40 °C. Next, the reaction mixture was poured into water and basified with 1 N NaOH until the pH reached 10. The mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 95-4 (2.00 g, approximately 91% yield) as an oil. MS Calcd: 309.0; MS Found: 309.8 [M+H] + It was.

[0518] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromobiphenyl-2-amine (95-5): [ka] A mixture of 95-4 (2.00 g, 6.44 mmol), 1H-1,2,4-triazole (677 mg, 9.66 mmol), and CsCO (4.20 g, 12.88 mmol) in CHCN (40 mL) was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to afford 95-5 (2.10 g, approximately 95% yield) as an oil. MS Calcd: 342.1; MS Found: 342.8 [M+H] + It was.

[0519] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -phenylbiphenyl-2,4-diamine (SS20308-0095-01): [ka] A mixture of 95-5 (200 mg, 0.58 mmol), aniline (65 mg, 0.70 mmol), Pd2dba3 (53 mg, 0.06 mmol), XantPhos (67 mg, 0.12 mmol), and Cs2CO3 (378 mg, 1.16 mmol) in toluene (20 mL) was stirred overnight at 110 °C under a N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-HPLC to afford SS20308-0095-01 (45 mg, approximately 22% yield) as a solid. MS Calcd: 355.2; MS Found: 356.1 [M+H] + It was.

[0520] 1 H NMR (400MHz, CDCl3) δ7.95(s,1H), 7.88(s,1H), 7.43~7.37(m,2H), 7.34~7.23(m,5H), 7.14(dd,J=8.4Hz,1.2Hz,2H), 7.02~6.93(m,2 H), 6.54(dd,J=8.0Hz,2.0Hz,1H), 6.39(d,J=2.0Hz,1H), 5.75(s,1H), 4.32(t,J=6.0Hz,2H), 4.18(t,J=6.0Hz,1H), 3.60~3.54(m,2H)

[0521] Example 47 [ka]

[0522] Example Routes for Example 47 [ka]

[0523] Synthesis of 4-chloro-2-nitro-1,1'-biphenyl (129-2): [ka] To a mixture of 129-1 (2.36 g, 10 mmol) and phenylboronic acid (1.22 g, 10 mmol) in toluene / HO (50 mL, 5 mL) was added CsCO (6.52 g, 20 mmol) and Xphos Pd Glu (200 mg). The mixture was heated to reflux for 6 h. The mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL). The organic layer was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc = 15 / 1) on silica gel to give 129-2 (1.2 g, approximately 51% yield) as a solid. MS Calcd: 233.0; MS Found: 234.2 [M+H] + It was.

[0524] Synthesis of 4-chloro-[1,1'-biphenyl]-2-amine (129-3): [ka] To a mixture of 129-2 (1.2 g, 4.3 mmol) in DCM (50 mL) was added HOAc (5 mL) and Zn powder (500 mg) at room temperature. The mixture was then stirred for 4 h at room temperature. The reaction mixture was filtered, and the organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc = 5 / 1) on silica gel to give 129-3 (800 mg, approximately 77% yield) as a solid. MS Calcd: 203.1; MS Found: 204.2 [M+H] + It was.

[0525] Synthesis of 4-chloro-N-(2-chloroethyl)-[1,1'-biphenyl]-2-amine (129-4): [ka] To a mixture of 129-3 (406 mg, 2 mmol) in EtOH (50 mL) was added 2-chloroacetaldehyde (5 mL, 40% in water) and HOAc (2 mL) at room temperature. NaBH3CN (0.5 g) was added to the mixture, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was filtered. The filtrate was concentrated and purified by column chromatography (hexane / EtOAc = 3 / 1) to afford 129-4 (380 mg, approximately 71% yield) as a colorless oil. MS Calcd: 265.0; MS Found: 266.2 [M+H] + It was.

[0526] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-[1,1'-biphenyl]-2-amine (129-5): [ka] To a mixture of 129-4 (380 mg, 1.4 mmol) in DMF (10 mL) was added 1H-1,2,4-triazole (193 mg, 2.8 mmol) and CsCO (913 mg, 2.8 mmol) at room temperature. The mixture was stirred at 80 °C for 8 h. The mixture was diluted with DCM (30 mL). The mixture was washed thoroughly with HO (40 mL) and brine (40 mL). The organic layer was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 5) to give 129-5 (260 mg, approximately 61% yield) as a solid. MS Calcd: 298.1; MS Found: 299.2 [M+H] + It was.

[0527] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0129): [ka] To a solution of 129-5 (130 mg, 0.4 mmol) in dioxane (5 mL) was added aniline (74.4 mg, 0.8 mmol), Cs2CO3 (326 g, 1 mmol), and Xphos Pd G2 (30 mg) at room temperature. The mixture was heated to reflux under nitrogen for 12 h. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (80 mL). The filtrate was washed successfully with water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 5 / 1 to 1 / 5) to afford SS20308-0129 (20 mg, approximately 13% yield) as a solid. MS Calcd: 355.2; MS Found: 356.2 [M+H] + It was.

[0528] 1 H NMR (400MHz, CDCl3) δ3.36~3.44(m,2H), 4.30(t,J=6.02Hz,2H), 4.34~4.38(m,1H), 4.71(brt,J=5.77Hz,5H), 6.24(t,J=2.01H,1H) , 6.39~6.51(m,2H), 6.77~6.89(m,2H), 7.08~7.17(m,2H), 7.19~7.32(m,5H), 7.34~7.46(m,3H), 7.67(d,J=2.01Hz,1H), 8.07(s,1H)

[0529] Example 48 [ka]

[0530] Example Route for Example 48 [ka]

[0531] Synthesis of N1-(4-chloro-[1,1'-biphenyl]-2-yl)-N2,N2-dimethylethane-1,2-diamine (130-1): [ka] To a mixture of 129-4 (380 mg, 1.4 mmol) in DMF (10 mL), dimethylamine (7 mL, 14 mmol) and CsCO (913 mg, 2.8 mmol) were added at room temperature, and the mixture was then stirred at 80 °C for 8 h. The mixture was diluted with DCM (30 mL). The mixture was washed thoroughly with H0 (40 mL) and brine (40 mL). The organic layer was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 5) to give 130-1 (220 mg, approximately 56% yield) as an oil. MS Calcd: 274.1; MS Found: 275.2 [M+H] + It was.

[0532] Synthesis of N2-(2-(dimethylamino)ethyl)-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0130): [ka] To a mixture of 130-1 (137 mg, 0.5 mmol) in dioxane (5 mL) was added aniline (74.4 mg, 0.8 mmol), CsCO (326 g, 1 mmol), and Xphos Pd Glu (30 mg) at room temperature. The mixture was heated to reflux under nitrogen for 12 h. The reaction mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc (40 mL). The filtrate was washed successfully with water (40 mL) and brine (40 mL). The organic layer was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1 to 4 / 1) on silica gel to afford SS20308-0130 (10 mg, approximately 13% yield) as a solid. MS Calcd:331.2;MS Found:332.2[M+H] + It was.

[0533] 1 H NMR (400MHz, DMSO-d6) δ2,81(s,6H), 3.17~3.27(m,2H), 3.36~3.44(m,2H), 6.47(d,J=2.01Hz,1H), 6.53(s,1H), 6.82(s,1H), 6.91(d,J=8.28Hz,1H), 7.08~7.16(m,2H), 7.20~7.27(m,2H), 7.29~7.36(m,1H), 7.39~7.47(m,4H)

[0534] Example 49 [ka]

[0535] Example Route for Example 49 [ka]

[0536] Synthesis of 4-chloro-N-(2-chloroethyl)-N-methyl-[1,1'-biphenyl]-2-amine (131-1): [ka] To a mixture of 129-4 (266 mg, 1 mmol) in EtOH (30 mL) was added HCHO(aq) (3 mL) and HOAc (2 mL) at room temperature, followed by NaBHCN (0.5 mg), and the mixture was stirred at room temperature for 6 h. The mixture was filtered. The filtrate was concentrated and purified by column chromatography (hexane / EtOAc = 1 / 1) on silica gel to afford 131-1 (180 mg, approx. 64% yield) as an oil. MS Calcd: 279.1; MS Found: 280.2 [M+H] + It was.

[0537] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-N-methyl-[1,1'-biphenyl]-2-amine (131-2): [ka] To a mixture of 131-1 (180 mg, 0.6 mmol) in DMF (10 mL) was added 1H-1,2,4-triazole (138 mg, 2 mmol) and CsCO (652 mg, 2 mmol) at room temperature. The mixture was stirred at 80 °C for 8 h. The mixture was diluted with DCM (30 mL) and washed with saturated HO (40 mL) and brine (40 mL). The organic layer was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 6) to afford 131-2 (120 mg, approximately 60% yield) as an oil. MS Calcd:312.1;MS Found:313.2[M+H] + It was.

[0538] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N2-methyl-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0131): [ka] To a mixture of 131-2 (120 mg, 0.4 mmol) in toluene (15 mL) was added aniline (74.4 mg, 0.8 mmol), Cs2CO3 (326 g, 1 mmol), and Xphos Pd Glu (30 mg) at room temperature. The mixture was heated to reflux under nitrogen for 12 h. The reaction mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc (40 mL). The filtrate was washed with water (50 mL) and brine (50 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 5 / 1 to 1 / 4) to afford SS20308-0131 (28 mg, approximately 20% yield) as a solid. MS Calcd: 369.2; MS Found: 370.2 [M+H] + It was.

[0539] 1 H NMR (400MHz, DMSO-d6) δ2,45(s,3H), 3.24(s,2H), 4.16~4.24(m,2H), 6.72~6.78(m,1H), 6.79(t,J=2.13Hz,1H), 6.8 1~6.87(m,1H), 7.00(d,J=8.03Hz,1H), 7.07~7.15(m,2H), 7.17~7.35(m,6H), 7.95(s,1H), 8.20(s,1H), 8.33(s,1H)

[0540] Example 50 [ka]

[0541] Example Routes for Example 50 [ka]

[0542] Synthesis of 4-bromo-2-(2-bromoethoxy)-1-chlorobenzene (132-3): [ka] To a mixture of 132-1 (412 mg, 2 mmol) in acetone (50 mL) was added 1,2-dibromomethane (744 g, 4 mmol) and Cs2CO3 (1.3 g, 4 mmol) at room temperature. The mixture was stirred at 70 °C for 8 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 20 / 1) to afford 132-2 (380 mg, approximately 61% yield) as an oil. MS Calcd: 311.9; MS Found: 312.9 [M+H] + It was.

[0543] Synthesis of 1-(2-(5-bromo-2-chlorophenoxy)ethyl)-1H-1,2,4-triazole (132-2): [ka] To a mixture of 132-2 (312 mg, 1 mmol) in DMF (10 mL) was added 1H-1,2,4-triazole (138 mg, 2.0 mmol) and CsCO (652 mg, 2.0 mmol). The mixture was stirred at 80 °C for 8 h. The mixture was diluted with DCM (30 mL) and washed thoroughly with HO (40 mL) and brine (40 mL). The organic layer was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 3) to afford 132-3 (220 mg, approximately 73% yield) as an oil. MS Calcd: 301.0; MS Found: 302.2 [M+H] + It was.

[0544] Synthesis of 3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-4-chloro-N-phenylaniline (132-4): [ka] To a mixture of 132-3 (220 mg, 0.7 mmol) in toluene (10 mL) was added aniline (65 mg, 0.7 mmol), Cs2CO3 (326 g, 1 mmol), and Xphos Pd Glu (30 mg) at room temperature. The mixture was heated to reflux under nitrogen for 12 h. The reaction mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc (40 mL). The filtrate was washed with water (40 mL) and brine (40 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 5 / 1 to 1 / 5) to afford 132-4 (80 mg, approximately 35% yield) as an oil. MS Calcd: 314.1; MS Found: 315.1 [M+H] + It was.

[0545] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-N-phenyl-[1,1'-biphenyl]-4-amine (SS20308-0132): [ka] To a mixture of 132-4 (80 g, 0.25 mmol) and phenylboronic acid (61 mg, 0.5 mmol) in toluene / HO (15 mL, 3 mL) was added CsCO (326 g, 1 mmol) and Xphos Pd Glu (15 mg). The mixture was heated to reflux for 6 h. The mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with water (30 mL) and brine (30 mL). It was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) on silica gel to afford SS20308-0132 (15 mg, approximately 16% yield) as a solid. MS Calcd: 356.2; MS Found: 357.2 [M+H] + It was.

[0546] 1 H NMR (400MHz, DMSO-d6) δ4.32(t,J=5.02Hz,2H), 4.55(t,J=5.02Hz,2H), 6.75(s,1H), 6.76(d ,J=6.00Hz,2H), 6.87(t,J=7.07Hz,1H), 7.13~7.32(m,11H), 8.01(s,1H), 8.30~8.34(m,2H)

[0547] Example 51 [ka]

[0548] Example Routes for Example 51 [ka]

[0549] Synthesis of 4-chloro-2',6'-dimethyl-2-nitro-1,1'-biphenyl (133-2): [ka] To a mixture of 133-1 (235 mg, 1 mmol) and (2,6-dimethylphenyl)boronic acid (180 mg, 1.2 mmol) in toluene / HO (15 mL / 3 mL) was added CsCO (652 g, 2 mmol) and Xphos Pd Glu (20 mg), and the mixture was heated to reflux for 6 h. The solution was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). It was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc = 15 / 1) on silica gel to afford 133-2 (90 mg, approximately 35% yield) as an oil. MS Calcd: 261.1; MS Found: 262.2 [M+H] + It was.

[0550] Synthesis of 4-chloro-2',6'-dimethyl-2-nitro-[1,1'-biphenyl]-2-amine (133-3): [ka] To a mixture of 133-2 (261 mg, 1 mmol) in DCM (50 mL) was added HOAc (5 mL) and Zn powder (150 mg) at room temperature. The mixture was stirred for 4 h at room temperature, filtered, and the organic layer was concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 4 / 1) to give 133-3 (200 mg, approximately 86% yield) as an oil. MS Calcd: 231.1; MS Found: 232.2 [M+H] + It was.

[0551] Synthesis of 4-chloro-N-(2-chloroethyl)-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-4): [ka] To a mixture of 133-3 (200 mg, 2 mmol) in EtOH (30 mL) was added 2-chloroacetaldehyde (1 mL, 40% in water) and HOAc (1 mL) at room temperature, followed by NaBHCN (0.3 g), and the mixture was stirred at room temperature for 6 h. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (hexane / EtOAc = 1 / 1) to afford 133-4 (160 mg, approximately 63% yield) as a colorless oil. MS Calcd: 293.1; MS Found: 293.2 [M+H] + It was.

[0552] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-5): [ka] To a mixture of 133-4 (160 mg, 0.5 mmol) in DMF (10 mL) was added 1H-1,2,4-triazole (69 mg, 1 mmol) and CsCO (326 mg, 1 mmol) at room temperature. The mixture was stirred at 80 °C for 8 h, diluted with DCM (30 mL), and washed with HO (40 mL) and brine (40 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 3) to give 133-5 (120 mg, approximately 67% yield) as a solid. MS Calcd: 326.1; MS Found: 327.2 [M+H] + It was.

[0553] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2',6'-dimethyl-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0133): [ka] To a mixture of 133-5 (120 mg, 0.37 mmol) in dioxane (15 mL) was added aniline (74.4 mg, 0.8 mmol), Cs2CO3 (326 g, 1 mmol), and Xphos Pd G2 (20 mg) at room temperature. The mixture was heated to reflux under nitrogen for 12 h. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (40 mL). The filtrate was washed successfully with water (40 mL) and brine (40 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (DCM / MeOH = 10 / 1) to afford SS20308-0133 (37 mg, approximately 26% yield) as a solid. MS Calcd: 383.2; MS Found: 384.2 [M+H] + It was.

[0554] 1 H NMR (400MHz, DMSO-d6) δ1.89(s,6H), 3.39~3.47(m,2H), 3.97(s,1H), 4.30(t,J=6.02Hz,2H), 6.39~6.52(m,2H), 6.62 (d,J=7.78Hz,H), 6.76~6.85(m,1H), 7.04~7.18(m,5H), 7.23(t,J=7.14Hz,2H), 7.86(s,1H), 8.02(s,1H), 8.36(s,1H)

[0555] Example 52 [ka]

[0556] Example Routes for Example 52 [ka]

[0557] Synthesis of ethyl 3-(1,2,4-triazol-1-yl)propanoate (134-2): [ka] To a mixture of 134-1 (500 mg, 2.8 mmol) in CHCN (50 mL) was added 1H-1,2,4-triazole (241 mg, 3.5 mmol) and CsCO (1.6 g, 5 mmol) at room temperature. The mixture was stirred at 80 °C for 8 h. The solution was filtered, and the solid was washed with DCM (50 mL). The organic layer was dried over MgSO and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 1 / 5) to afford 134-2 (300 mg, approximately 64% yield) as a colorless oil. MS Calcd: 169.1; MS Found: 170.2 [M+H] + It was.

[0558] Synthesis of 3-(1,2,4-triazol-1-yl)propanoic acid (134-3): [ka] To a mixture of 134-2 (300 mg, 1.9 mmol) in MeOH (30 mL) was added LiOH (228 mg, 6 mmol). The mixture was stirred at room temperature for 6 h. HCl (2 M) was added to the solution until pH = 3-4, and the mixture was concentrated under reduced pressure to give crude product 134-2 (400 mg, approximately 80% yield) as a colorless oil, which was used in the next step without further purification. MS Calcd: 141.1; MS Found: 142.2 [M+H] + It was.

[0559] Synthesis of 4-bromo-3-nitro-N-phenylaniline (134-5): [ka] To a mixture of 134-4 (432 mg, 2 mmol) in DCM (50 mL) was added phenylboronic acid (268 mg, 2.2 mmol), Cu(OAc) (362 g, 2 mmol), and TEA (300 mg, 3 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 12 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (hexane / EtOAc = 15 / 1 to 3 / 1) on silica gel to afford 134-5 (256 mg, approximately 44% yield) as a colorless oil. MS Calcd: 292.0; MS Found: 293.2 [M+H] + It was.

[0560] Synthesis of 2-nitro-N-phenyl-[1,1'-biphenyl]-4-amine (134-6): [ka] To a mixture of 134-5 (292 mg, 1 mmol) and phenylboronic acid (146 mg, 1.2 mmol) in toluene / HO (25 mL / 5 mL) was added KCO (276 mg, 2 mmol) and Sphos Pd Glu (40 mg). The mixture was heated to reflux for 6 h. The mixture was diluted with ethyl acetate (30 mL), and the organic layer was washed with water (30 mL) and brine (30 mL). It was then dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc = 2 / 1) on silica gel to afford 134-6 (220 mg, approximately 76% yield) as a solid. MS Calcd: 290.1; MS Found: 291.2 [M+H] + It was.

[0561] Synthesis of N4-phenyl-[1,1'-biphenyl]-2,4-diamine (134-7): [ka] To a mixture of 134-6 (220 mg, 0.76 mmol) in DCM (50 mL) was added HOAc (5 mL) and Zn powder (150 mg) at room temperature. The mixture was stirred for 4 h at room temperature. The reaction mixture was filtered, and the organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc = 1 / 2) on silica gel to give 134-7 (140 mg, approximately 71% yield) as an oil. MS Calcd: 260.1; MS Found: 261.1 [M+H] + It was.

[0562] Synthesis of N-(4-(phenylamino)-[1,1'-biphenyl]-2-yl)-3-(1H-1,2,4-triazol-1-yl)propanamide (SS20308-0134): [ka] To a solution of 134-3 (140 mg, 1 mmol) in DCM (50 mL) was added SOCl2 (3 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated, and DCM (50 mL), 134-7 (130 mg, 0.5 mmol), and TEA (151 mg, 1.5 mmol) were added. The solution was stirred at room temperature for 3 h, and the mixture was washed with H2O (40 mL) and brine (40 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by column chromatography (hexane / EtOAc = 5 / 1 to 1 / 5) to afford SS20308-0134 (40 mg, approximately 21% yield) as a solid. MS Calcd: 383.5; MS Found: 384.2 [M+H] + It was.

[0563] 1H NMR (400MHz, DMSO-d6) δ2.77(t,J=6.65Hz,2H), 4.41(t,J=6.53Hz,2H), 6.87(t,J=6.94Hz,1H), 6.97(dd,J=8.41,2·13Hz,1H), 7. 12(d,J=7.53Hz,2H), 7.16~7.23(m,2H), 7.24~7.32(m,5H), 7.35~7.40(m,2H), 7.98(s,1H), 8.33(s,1H), 8.41(s,1H), 9.30(s,1H)

[0564] Example 53 [ka]

[0565] Example Routes for Example 53 [ka]

[0566] Synthesis of 4-chloro-3-fluoro-6-nitroaniline (141-2): [ka] To a solution of 141-1 (5.0 g, 32.1 mmol) in DMF (40 mL) was added NCS (4.5 g, 33.7 mmol) at room temperature, and the mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and the solid was collected by filtration, washed with water, and dried in vacuo to afford 141-2 (4.5 g, approximately 74% yield) as a solid.

[0567] Synthesis of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (141-3): [ka] To a solution of 141-2 (900 mg, 4.7 mmol) in CHCN (10 mL) was added CuBr (2.1 g, 9.4 mmol) at room temperature. Then, t-BuONO (2.4 g, 23.5 mmol) was added dropwise at 60 °C, and the mixture was stirred at 60 °C for 2 h under nitrogen. The mixture was washed with EtOAc and filtered. The filtrate was concentrated to a crude oil, which was purified by column chromatography (petroleum ether / EtOAc = 1 / 20) on silica gel to afford 141-3 (620 mg, approximately 52% yield) as an oil.

[0568] Synthesis of 4-chloro-2-fluoro-6-nitrobiphenyl (141-4): [ka] To a mixture of 141-3 (620 mg, 2.44 mmol) and phenylboronic acid (328 mg, 2.69 mmol) in DME (10 mL) and water (2 mL) was added PdCl(dppf) (58 mg, 0.1 mmol) and KCO (673 mg, 4.88 mmol) at room temperature, and then the mixture was stirred at 80 °C for 5 h under nitrogen. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated to an oil and purified by column chromatography (petroleum ether / EtOAc=1 / 10) on silica gel to afford 141-4 (750 mg, yield about 60%) as an oil.

[0569] Synthesis of 2-fluoro-6-nitro-N-phenylbiphenyl-4-amine (141-5): [ka] A mixture of 141-4 (590 mg, 2.35 mmol), aniline (230 mg, 2.47 mmol), Pd(OAc) (45 mg, 0.2 mmol), tBuPHBF (58 mg, 0.2 mmol), and tBuONa (564 mg, 5.88 mmol) in toluene (15 mL) was heated at 110 °C overnight under hydrogen. The mixture was cooled to room temperature, filtered, and washed with EtOAc. The filtrate was concentrated to an oil and purified on silica gel by column chromatography (petroleum ether / EtOAc = 1 / 8) to afford 141-5 (180 mg, approximately 25% yield) as an oil. MS Calcd: 308.1; MS Found: 309.3 [M+H] + It was.

[0570] Synthesis of 6-fluoro-N4-phenylbiphenyl-2,4-diamine (141-6): [ka] To a solution of 141-5 (240 mg, 0.79 mmol) in EtOAc (10 mL) was added Pd / C (10%, 30 mg) at room temperature, and the mixture was stirred overnight at room temperature under hydrogen gas (1 atm). The mixture was filtered and washed with EtOAc. The filtrate was concentrated to afford 141-6 (170 mg, approximately 78% yield) as an oil. MS Calcd: 278.1; MS Found: 279.1 [M+H] + It was.

[0571] Synthesis of 6-fluoro-N4-phenylbiphenyl-2,4-diamine (141-7): [ka] To a solution of 141-6 (170 mg, 0.61 mmol) and 2-chloroacetaldehyde (143 g, 1.83 mmol, 40% in water) in EtOH (5 mL) and HOAc (0.2 mL) was added NaBHCN (77 mg, 1.22 mmol) at room temperature, and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with DCM, and then the DCM phase was dried over NaSO. The filtrate was filtered and concentrated to an oil to afford 141-7 (58 mg, approximately 28% yield) as an oil. MS Calcd: 340.1; MS Found: 341.0 [M+H] + It was.

[0572] Synthesis of N2-2-(1H-1,2,4-triazol-1-yl)ethyl)-6-fluoro-N4-phenylbiphenyl-2,4-diamine (SS20308-0141-01) [ka] To a solution of 141-7 (48 mg, 0.14 mmol) and 1H-1,2,4-triazole (10 mg, 0.14 mmol) in CHCN (8 mL) was added CsCO (91 mg, 0.28 mmol) at room temperature. The mixture was then heated to 80 °C for 7 h, diluted with water, extracted with EtOAc, and the EtOAc phase was then dried over NaSO. The filtrate was filtered and concentrated to an oil, which was purified by Prep-HPLC to afford SS20308-0141-01 (12 mg, approximately 23% yield) as a solid. MS Calcd: 373.2; MS Found: 374.3 [M+H] + It was.

[0573] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H), 8.30(s,1H), 7.93(s,1H), 7.45~7.39(m,2H), 7.37~7.32(m,1H), 7.17~7.11 (m,4H), 6.88(t,J=7.4Hz,5H), 6.23~6.18(m,2H), 4.64(t,J=6.0Hz,1H), 4.33(t,J=6.0Hz,2H), 3.44~3.38(m,2H)

[0574] Example 54 [ka]

[0575] Example Routes for Example 54 [ka]

[0576] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-02142-01): [ka] A mixture of 95-5 (100 mg, 0.29 mmol), 4-fluoroaniline (39 mg, 0.35 mmol), Pd(dba) (26 mg, 0.029 mmol), Xantphos (34 mg, 0.058 mmol), and CsCO (189 mg, 0.58 mmol) in toluene (10 mL) was stirred overnight at 110 °C under a N atmosphere. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated to a crude oil and purified by Prep-HPLC to afford SS20308-0142-01 (14.3 mg, approximately 12% yield) as a solid. MS Calcd: 373.2; MS Found: 374.2 [M+H] + It was.

[0577] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H), 8.04(s,1H), 7.95(s,1H), 7.39(dd,J=7.6,7.2Hz,2H), 7.31~7.26(m,1H), 7.25~7.20(m,2H), 7.14~7.05(m ,4H), 6.85(d,J=8.0Hz,2H), 6.40(dd,J=8.4,2.0Hz,1H), 6.35(d,J=2.0Hz,1H)4.74(t,J=5.8Hz,1H), 4.37(t,J=6.04Hz,2H), 3.46~3.39(m,2H)

[0578] Example 55 [ka]

[0579] Example Routes for Example 55 [ka]

[0580] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-2): [ka] A mixture of 143-1 (1.0 g, 4.6 mmol), phenylboronic acid (1.1 g, 9.2 mmol), Cu(OAc) (833 mg, 4.6 mmol), and EtN (2.3 g, 23 mmol) in CHCl (100 mL) was stirred at room temperature for 2 h. After the reaction was complete, the insoluble material was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by column chromatography to afford 143-2 (1.0 mg, approximately 74% yield) as a solid.

[0581] 4-Bromo-N 1Synthesis of -phenylbenzene-1,3-diamine (143-3): [ka] A mixture of 143-2 (1.0 g, 3.4 mmol), Zn (1.1 g, 17 mmol), and HOAc (1.0 g, 17 mmol) in EtOH (50 mL) was stirred overnight at room temperature. After the reaction was completed, the insoluble material was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 143-3 (800 mg, approximately 90% yield) as a solid. MS Found: 263.2 [M+H] + It was.

[0582] 4-Bromo-N 3 -(2-chloroethyl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (143-4): [ka] A mixture of 143-3 (800 mg, 3.1 mmol), 2-chloroacetaldehyde (244 mg, 3.1 mmol, 40% in water), NaBHCN (1.3 g, 6.2 mmol) and HOAc (2 drops) in MeOH (50 mL) was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (EtOAc) to afford 143-4 (600 mg, approximately 60% yield) as a solid. MS Calcd: 324.0; MS Found: 325.0 [M+H] + It was.

[0583] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-N 1Synthesis of -phenylbenzene 1,3-diamine (143-01-4): [ka] A mixture of 143-4 (600 mg, 1.85 mmol), 1H-1,2,4-triazole (192 mg, 2.78 mmol), and CsCO (1.2 g, 3.7 mmol) in acetone (20 mL) was stirred overnight at 80 °C. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by reverse-phase (silica) column chromatography (DCM / EtOH) to afford 143-5 (450 mg, approximately 68% yield) as a solid. MS Calcd: 357.1; MS Found: 358.3 [M+H] + was

[0584] Synthesis of (2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-phenylamino)biphenyl-2-yl)methanol (SS20308-0143-01): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 2-hydroxymethylphenylboronic acid (32 mg, 0.21 mmol), Pd(PPh) (6 mg, 0.007 mmol), X-Phos (7 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (2 / 0.2 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and evaporated. The crude residue was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to afford SS20308-0143-01 (6.22 mg, approximately 11% yield) as a solid. MS Calcd:385.5;MS Found:386.2[M+H] + It was.

[0585] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H), 8.06(s,1H), 7.89(s,1H), 7.56(d,J=7. 6,7.2Hz,1H), 7.36~7.33(m,1H), 7.28~7.21(m,1H), 7.28~7.21(m,3H), 7.12~ 7.10(m,2H), 6.99~6.97(m,1H), 6.80(t,J=7.2Hz,1H)6.72(d,J=8.0Hz,1H), 6 .46~6.42(m,1H), 4.22~4.20(m,2H), 4.17(t,J=6.0Hz,1H), 3.42~3.38(m,2H)

[0586] Example 56 [ka]

[0587] N 2 (2-(1H-1,2,4-triazol-1-yl)ethyl)-2'-methoxy-N 4 Synthesis of -phenylbiphenyl-2,4-diamine (SS20308-0144-01): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 2-methoxyphenylboronic acid (32 mg, 0.21 mmol), Pd(PPh) (6 mg, 0.007 mmol), X-Phos (7 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (2 / 0.2 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated. The residual crude product was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to afford SS20308-0144-01 (6.22 mg, approximately 11% yield) as a solid. MS Calcd: 385.2; MS Found: 386.2 [M+H] + It was.

[0588] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H), 8.04(s,1H), 7.92(s,1H), 7.32~7.30(m,1H), 7.22(t,J=8.4Hz,1H), 7.10(d,J=7.6Hz,2H) , 7.05~7.02(m,2H), 6.99~6.97(m,1H), 6.81~6.75(m,1H), 6.45~6.38(m,2H), 4.33~4.25(m,3H), 3.64(s,3H), 3.44~3.41(m,2H)

[0589] Example 57 [ka]

[0590] Example Routes for Example 57 [ka]

[0591] Synthesis of 4-bromo-4'-chloro-2-nitrobiphenyl (147-2): [ka] A mixture of 147-1 (2.00 g, 7.12 mmol), 4-chloroboronic acid (1.11 g, 7.12 mmol), Pd(PPh) (0.42 g, 0.36 mmol), and NaCO (1.51 g, 14.24 mmol) in toluene / HO (30 mL, 5 / 1) was stirred overnight at 90 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether) to afford 147-2 (1.70 g, approximately 76% yield) as a solid.

[0592] 1 H NMR (400MHz, CDCl3) δ7.96(d,J=2.0Hz,1H), 7.70(dd,J=8.4,2.0Hz,1H), 7.34(d,J=8.8Hz,1H), 7.23(d,J=8.0Hz,1H), 7.15(d,J=8.8Hz,2H)

[0593] Synthesis of 4-bromo-4'-chlorobiphenyl-2-amine (147-3): [ka] A mixture of 147-2 (1.50 g, 4.80 mmol), Zn powder (3.14 g, 48.00 mmol), and HOAc (3 mL) in EtOH (30 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water. The mixture was basified with 40% NaOH until the pH reached 10. The resulting mixture was filtered through celite and washed with EtOAc. The filtrate was extracted with EtOAc (40 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 147-3 (1.20 g, approximately 88% yield) as a solid. MS Calcd: 280.96; MS Found: 282.0 [M+H] + It was.

[0594] Synthesis of 4-bromo-4'-chloro-N-(2-chloroethyl)biphenyl-2-amine (147-4): [ka] To a solution of 147-3 (1.00 g, 3.54 mmol) in MeOH (20 mL), 2-chloroacetaldehyde (1.11 g, 14.16 mmol, 40%), AcOH (844 mg, 14.16 mmol), and NaBHCN (890 mg, 14.16 mmol) were added, and the reaction mixture was then stirred overnight at 40 °C. The reaction mixture was then poured into water and basified with 1 N NaOH until the pH reached 10. The mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 147-4 (710 mg, approximately 59% yield) as an oil. MS Calcd: 343.0; MS Found: 344.0 [M+H] + It was.

[0595] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-4'-chlorobiphenyl-2-amine (147-5): [ka] A mixture of 147-4 (670 mg, 1.94 mmol), 1H-1,2,4-triazole (201 mg, 2.91 mmol), and CsCO (1.26 g, 3.88 mmol) in CHCN (10 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 147-5 (537 mg, approximately 73% yield) as an oil. MS Calcd: 376.01; MS Found: 379.0 [M+H] + It was.

[0596] N2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4'-chloro-N 4 Synthesis of -phenylbiphenyl-2,4-amine (SS20308-0147-01): [ka] A mixture of 147-5 (150 mg, 0.40 mmol), aniline (45 mg, 0.48 mmol), Pd2dba3 (37 mg, 0.04 mmol), XantPhos (46 mg, 0.08 mmol), and Cs2CO3 (261 mg, 0.80 mmol) in toluene (30 mL) was stirred overnight at 100 °C under a N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-HPLC to afford SS20308-0147-01 (15 mg, approximately 9% yield) as a solid. MS Calcd: 389.1; MS Found: 390.3 [M+H] + It was.

[0597] 1 H NMR (400MHz, CDCl3) δ8.46(s,1H), 8.12(s,1H), 7.97(s,1H), 7.42(d,J=8.4Hz,2H), 7.28~7.21(m,4H), 7.13~7.08(m,2H), 6.86(d,J=8.0Hz) ,1H), 6.84~6.79(m,1H), 6.46(dd,J=8.4,2.0Hz,1H), 6.40(t,J=1.6Hz,1H), 4.84(t,J=5.6Hz,1H), 6.37(t,J=6.0Hz,1H), 3.44~3.38(m,2H)

[0598] Example 58 [ka]

[0599] Example Route for Example 58 [ka]

[0600] Synthesis of 1,4-dibromo-2-fluoro-3-nitrobenzene (148-2): [ka] A mixture of 148-1 (1.0 g, 4.26 mmol) and copper bromide (1.43 g, 6.38 mmol) in CHCN (20 mL) was stirred at 60 °C for 10 min, and tert-butyl nitrate (2.19 g, 21.28 mmol) was slowly added. The mixture was stirred at 60 °C for 30 min and then poured into water (100 mL). Extraction with EtOAc (20 mL × 3) was performed. The combined organic layer was washed with brine (10 mL × 3), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 148-2 (820 mg, approximately 65% ​​yield) as a solid.

[0601] Synthesis of 4-bromo-3-fluoro-2-nitrophenyl (148-3): [ka] A solution of 148-2 (810 mg, 2.71 mmol), phenylboronic acid (331 mg, 2.17 mmol), Pd(PPh) (157 g, 0.136 mmol), and sodium carbonate (1.01 g, 9.49 mmol) was suspended in toluene (20 mL) and water (4 mL). The reaction mixture was heated to 80 °C overnight, then rinsed with EtOAc and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1) to afford 148-3 (622 mg, approximately 78% yield) as an oil.

[0602] Synthesis of 4-bromo-3-fluorobiphenyl-2-amine (148-4): [ka] A mixture of 148-3 (622 mg, 2.10 mmol) and zinc powder (825 mg, 12.61 mmol) in isopropanol (15 mL) and acetic acid (1.5 mL) was stirred overnight at room temperature. The reaction mixture was then filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1) to afford 148-4 (622 mg, approximately 93% yield) as an oil. MS Calcd: 265.0; MS Found: 266.2 [M+H] + It was.

[0603] Synthesis of N-(4-bromo-3-fluorobiphenyl-2-yl)-2-chloroacetamide (148-5): [ka] A solution of 148-4 (470 mg, 1.0 mmol), pyridine (168 mg, 1.2 mmol), and chloroacetyl chloride (220 mg, 1.1 mmol) in DCM (10 mL) was heated at room temperature for 1 h, then washed with brine, dried over sodium sulfate, and concentrated to afford 148-5 (428 mg, approximately 71% yield) as a solid. MS Calcd: 341.0; MS Found: 242.2 [M+H] + It was.

[0604] Synthesis of N-(4-bromo-3-fluorobiphenyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (148-6): [ka] A mixture of 148-5 (430 mg, 1.25 mmol), 1H-1,2,4-triazole (130 mg, 1.88 mmol), and CsCO (6.11 mg, 1.88 mmol) in CHCN (20 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether / EtOAc = 1 / 5, 1 / 1) to afford 148-6 (386 mg, approximately 82% yield) as an oil. MS Calcd: 374.0; MS Found: 375.0 [M+H] + It was.

[0605] Synthesis of N-(3-fluoro-4-(phenylamino)biphenyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (148-7): [ka] A solution of 148-6 (386 mg, 1.03 mmol), aniline (288 mg, 3.09 mmol), XantPhos (119 mg, 0.21 mmol), Pd(dba) (95 mg, 0.10 mmol), and anhydrous cesium carbonate (503 mg, 1.54 mmol) was suspended in toluene (10 mL). The reaction mixture was stirred at 120 °C overnight under N, then filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 5, 1 / 1) to afford 148-7 as an oil. MS Calcd: 387.2; MS Found: 388.3 [M+H] + It was.

[0606] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-N 4 Synthesis of -phenylbiphenyl-2,4-amine (SS20308-0148-01): [ka] To a solution of 148-7 (44 mg, 0.26 mmol) in THF (5 mL) was slowly added borane sulfide dimethyl complex (10 mL, 2 M in THF). The reaction mixture was stirred overnight at room temperature, then quenched with MeOH and acidified to pH ∼1 with 1N HCl. The reaction mixture was then heated to 60 °C and stirred overnight. After cooling to room temperature, the reaction mixture was basified with NaHCO3 solution and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by prep-TLC (EtOAc) to afford SS20308-0148-01 (3.8 mg, ∼9% yield) as an oil. MS Calcd: 373.2; MS Found: 474.3 [M+H] + It was.

[0607] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H), 7.89(brs,1H), 7.88(s,1H), 7.39(dd,J=7.2,7.2Hz,2H), 7.35~7.27(m,3H), 7.23(dd,J=8.4,7.2Hz ,2H), 7.04(d,J=8.0Hz,2H), 6.84(dd,J=7.2,7.2Hz,1H), 6.78~6.73(m,2H), 4.50~4.43(m,1H), 4.20(t,J=6.0Hz,2H), 3.33~3.27(m,2H)

[0608] Example 59 [ka]

[0609] Example of a route for Example 59: Synthesis of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (149-2): [ka] A mixture of 149-1 (300 mg, 1.32 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (368 mg, 1.45 mmol), Pd(dppf)Cl2 (48 mg, 0.07 mmol), and AcOK (259 mg, 2.64 mmol) in 1,4-dioxane (5 mL) was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 149-2 (180 mg, approximately 49% yield) as a solid. MS Calcd:276.2;MS Found:277.4[M+H] + It was.

[0610] Synthesis of methyl 2-(2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)acetate (149-3): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 149-2 (92 mg, 0.33 mmol), Pd(PPh) (10 mg, 0.011 mmol), X-Phos (10 mg, 0.022 mmol), and CsCO (143 mg, 0.44 mmol) in toluene / water (2 / 0.2 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and evaporated. The crude residue was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to afford 149-3 (60 mg, approximately 64% yield) as a solid. MS Calcd: 427.2; MS Found: 428.3 [M+H] + It was.

[0611] Synthesis of 2-(2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)ethanol (SS20308-0149-01): [ka] A mixture of 149-3 (60 mg, 0.14 mmol) and LiAlH in THF (3 mL) was stirred overnight at room temperature. After the reaction was complete, the crude product mixture was poured onto wet NaSO, and the insoluble material was removed by filtration and rinsed with EtO. The filtrate was concentrated in vacuo. The residue was purified by Prep-HPLC to afford SS20308-0149-01 (7.2 mg, approximately 13% yield) as a solid. MS Calcd: 399.2; MS Found: 400.3 [M+H] + It was.

[0612] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H), 8.06(s,1H), 7.88(s,1H), 7.32~7.19(m,2H), 7.11(d,J=7.6Hz,2H), 6.98~6.96(m,2H), 6.80(t,J=7. 2Hz,1H), 6.73(d,J=8.0Hz,1H), 6.48~6.42(m,1H), 4.41(t,J=5.2Hz,1H), 4.29(t,J=6.0Hz,2H), 4.12(d,J=5.6Hz,1H), 3.44~3.30(m,5H)

[0613] Example 60 [ka]

[0614] Example Routes for Example 60 [ka]

[0615] Synthesis of 5-bromobiphenyl-2-amine (151-2): [ka] A mixture of 151-1 (6.40 g, 37.82 mmol) and NBS (6.70 g, 37.82 mmol) in DMF (10 mL) was stirred overnight at 0 °C. Then, the mixture was poured into water and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford 151-2 (5.7 g, approximately 57.6% yield) as an oil. MS Calcd: 247.0; MS Found: 248.2 [M+H] + It was.

[0616] Synthesis of N-(5-bromobiphenyl-2-yl)-3-chloropropanamide (151-3): [ka] A mixture of 151-2 (5.70 g, 22.97 mmol), 3-chloropropanoyl chloride (3.50 g, 27.56 mmol), and pyridine (0.181 g, 22.3 mmol) in DCM (10 mL) was stirred at room temperature for 4 h. The resulting mixture was washed with ethyl acetate (30 mL × 3), and the organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 1151-3 (5.0 g, approximately 64% yield) as a solid. MS Calcd: 337.0; MS Found: 3380.2 [M+H] + It was.

[0617] Synthesis of N-(5-bromobiphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propanamide (151-4): [ka] A solution of 151-3 (5.00 g, 14.77 mmol), 1H-1,2,4-triazole (1.22 g, 17.72 mmol), and CsCO (14.43 g, 44.29 mmol) in CHCN (15 mL) was stirred at 80 °C for 4 h. The mixture was then poured into water and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 151-4 (3.3 g, approximately 60% yield) as a solid. MS Calcd: 370.0; MS Found: 372.3 [M+H] + It was.

[0618] Synthesis of N-(5-(phenylamino)biphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propanamide (151-5): [ka] A mixture of 151-4 (1.00 g, 2.69 mmol), aniline (752 mg, 8.08 mmol), Pd(dba) (247 mg, 0.27 mmol), Xantphos (312 mg, 0.54 mmol), and CsCO (378 mg, 8.07 mmol) in toluene (5 mL) was stirred at 110 °C overnight under a N atmosphere. The reaction mixture was then poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 151-5 (810 mg, yield approximately 60%) as an oil. MS Calcd: 382.2; MS Found: 384.3 [M+H] + It was.

[0619] N 2 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 5 Synthesis of -phenylbiphenyl-2,5-diamine (SS20308-0151-01): [ka] A mixture of 151-5 (50 mg, 0.13 mmol) and BMS (2.5 M in THF) was stirred overnight at room temperature. Then, the mixture was poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0151-01 (30 mg, approximately 62% yield) as a solid. MS Calcd: 369.2; MS Found: 370.3 [M+H] + It was.

[0620] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H), 7.93(s,1H), 7.65(m,1H), 7.40~7.48(m,1H), 7.12(m,2H), 6. 97(m,1H), 6.86(d,J=7.6Hz,2H), 6.79(d,J=7.6Hz,1H), 6.61~6.66(m,2H), 4.36(t,J=6.0Hz,1H). 4.21(t,J=6.8Hz,2H), 3.00(q,J=6.8Hz,2H), 2.00(t,J=6.8Hz,2H)

[0621] Example 61 [ka]

[0622] Example Routes for Example 61 [ka]

[0623] Synthesis of tert-butyl 2-(1H-1,2,4-triazol-1-yl)ethylcarbamate (153-2): [ka] To a mixture of 153-1 (2.2 g, 9.82 mmol) and K2CO3 (2.7 g, 19.63 mmol) in acetone (30 mL), 1H-1,2,4-triazole (1.0 g, 14.73 mmol) was added and then stirred overnight at 60 °C. The reaction mixture was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 153-2 (2.0 g, approximately 96% yield) as an oil. MS Calcd: 212.1; MS Found: 213.2 [M+H] + It was.

[0624] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-6-nitroaniline (153-4): [ka] To a mixture of 153-2 (424 mg, 2.00 mmol) in THF (10 mL) was added HCl (6N, 5 mL) and then stirred overnight at room temperature. The reaction mixture was concentrated to dryness several times, then dissolved in DMSO (10 mL), and 1-bromo-2-fluoro-3-nitrobenzene (440 mg, 2.00 mmol) and K2CO3 (552 mg, 4.00 mmol) were added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (40 mL) and then extracted with EtOAc (20 mL × 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1 to 3 / 1) to afford 153-4 (474 ​​mg, approximately 76% yield over two steps) as an oil. MS Calcd:311.0;MS Found:312.0[M+H] + It was.

[0625] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-nitrobiphenyl-2-amine (153-5): [ka] To a solution of 153-4 (443 mg, 1.42 mmol) in DME / water (10 / 1, 15 mL), phenylboronic acid (260 mg, 2.13 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), and K2CO3 (392 mg, 2.84 mmol) were added and then stirred at 80 °C overnight. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (30 mL) and then extracted with EtOAc (20 mL × 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 4 / 1) to afford 153-5 (400 mg, approximately 90% yield) as an oil. MS Calcd: 309.1; MS Found: 310.0 [M+H] + It was.

[0626] N 2 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)biphenyl-2,3-diamine (153-6): [ka] To a solution of 153-5 (157 mg, 0.59 mmol) in MeOH (5 mL) was added Pd / C (35 mg, 10%), and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was filtered through celite. The filtrate was purified by Prep-TLC (EtOAc) to afford 253-6 (100 mg) as a solid. MS Calcd: 279.1; MS Found: 280.1 [M+H] + It was.

[0627] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 3 Synthesis of -phenylbiphenyl-2,3-diamine (SS20308-0153-01): [ka] To a solution of 153-6 (100 mg, 0.36 mmol) in toluene (10 mL), bromobenzene (84 mg, 0.54 mmol), Pd(dba) (30 mg, 0.03 mmol), Xantphos (29 mg, 0.06 mmol), and CsCO (233 mg, 0.72 mmol) were added, and the reaction mixture was then stirred at 110 °C overnight. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (20 mL) and then extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by prep-TLC (petroleum ether / EtOAc = 1 / 1) to afford SS20308-0153-01 (31 mg, approximately 24% yield) as an oil. MS Calcd:355.2;MS Found:356.0[M+H] + It was.

[0628] 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H), 7.82(s,1H), 7.43~7.32(m,5H), 7.23~7.10(m,3H), 7.11(d,J=6.4Hz,1H), 6.90( t,J=7.6Hz,1H), 6.84~6.82(m,1H), 6.75(t,J=7.2Hz,1H), 4.22~4.18(m,1H), 4.01(t,J=6.0Hz,2H), 3.03~2.98(m,2H)

[0629] Example 62 [ka]

[0630] Example Routes for Example 62

[0631] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of -(2-chloro-4-fluorophenyl)biphenyl-2,5-diamine (SS20308-0165-01): [ka] A solution of 0061-3 (1.0 g, 2.91 mmol), 2-chloro-4-fluoroaniline (637 mg, 4.38 mmol), t-Bu3PHBF4 (169 mg, 0.583 mmol), Pd(OAc)2 (66 mg, 0.294 mmol), and t-BuONa (840 mg, 8.74 mmol) was suspended in toluene (20 mL). The reaction mixture was heated to reflux under N2 overnight, then filtered and rinsed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, 3 / 1, 1 / 1) to afford SS20308-0165-01 (440 mg, approximately 37% yield) as an oil. MS Calcd: 407.1; MS Found: 408.1 [M+H] + It was.

[0632] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H), 7.96(s,1H), 7.45~7.39(m,2H), 7.37~7.30(m,2H), 7.29~7.26(m,2H), 7.14 (s,1H), 7.03~6.93(m,3H), 6.79(d,J=2.8Hz,1H), 6.72(d,J=8.8Hz,1H), 4.59(t,J=6.0Hz,1H), 3.50~3.44(m,2H)

[0633] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1H-indol-7-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (166-1): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (51 mg, 0.21 mmol), Pd(dba) (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine and concentrated. The crude residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 166-1 (50 mg, approximately 91% yield) as a solid. MS Calcd:394.2;MS Found:395.2[M+H] + It was.

[0634] Example 63 [ka]

[0635] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(indolin-7-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (SS20308-0166-01): [ka] A mixture of 166-1 (50 mg, 0.13 mmol) and NaBHCN (25 mg, 0.39 mmol) in AcOH (1 mL) was stirred for 2 h at 0 °C. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (30 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by Prep HPLC to afford SS20308-0166-01 (10.3 mg, approximately 20% yield) as a solid. MS Calcd: 396.5; MS Found: 397.3 [M+H] + It was.

[0636] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H), 8.08(s,1H), 7.96(s,1H), 7.23(t,J=8.4H z,2H), 7.10(d,J=7.6Hz,2H), 7.00(d,J=6.8Hz,1H), 6.90(d,J=8.0Hz,1H), 6.8 2~6.76(m,2H), 6.61(t,J=7.2Hz,1H), 6.50~6.45(m,2H), 4.67(s,1H), 4.62(m, 1H), 4.39~4.36(m,2H), 3.48~3.47(m,2H), 2.29~2.28(m,2H), 2.96~2.92(m,2H)

[0637] Example 64 [ka]

[0638] Synthesis of 2-(3-(dimethylamino)propyl)-3-(1H-indolin-7-yl)-N-phenylaniline (SS20308-0171-01): See synthesis of SS20308-0172-01 below [ka] SS20308-0172-01 (50 mg, 0.13 mmol) and DDQ (59 mg, 0.58 mmol) in dioxane (2 mL) were stirred overnight at room temperature. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine and evaporated, and the crude residue was purified by prep-HPLC to afford SS20308-0171-01 (2.5 mg, approximately 5% yield) as a solid. MS Calcd:369.5;MS Found:370.3[M+H] + It was.

[0639] 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H), 8.19(s,1H), 7.53(d,J=8.0Hz,1H), 7.3 0(d,J=7.2Hz,1H), 7.29~7.17(m,4H), 7.05(t,J=6.8Hz,1H), 6.95(d,J=7.6Hz, 2H), 6.90(d,J=7.2Hz,1H), 6.86~6.85(m,1H), 6.73(t,J=7.2Hz,1H), 6.48~6.4 6(m,1H), 2.36~2.30(m,2H), 1.93(s,6H), 1.89~1.86(m,2H), 1.29~1.23(m,2H)

[0640] Example 65 [ka]

[0641] Example Routes for Example 65 (SS20308-0172-01 and SS20308-0171-01) [ka]

[0642] Synthesis of (E)-methyl 3-(2-bromo-6-nitrobiphenyl)acrylate (171-2): [ka] 171-1 (1.0 g, 4.4 mmol) and methyl (triphenylphosphoranylidene)acetate (2.2 g, 6.6 mmol) in THF (50 mL) were stirred overnight at room temperature. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 171-2 (1.2 g, approximately 95% yield) as a solid. MS Calcd: 285.0; MS Found: 303.0 [M+18] + It was.

[0643] Synthesis of (E)-3-(2-bromo-6-nitrobiphenyl)acrylic acid (171-3): [ka] 171-2 (600 mg, 2.1 mmol) and LiOH (100 mg, 4.2 mmol) in THF (5 mL) and HO (2 mL) were stirred overnight at room temperature. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated to afford 171-3 (500 mg, approximately 88% yield) as a solid. MS Calcd: 271.0; MS Found: 289.0 [M+18] + It was.

[0644] Synthesis of (E)-3-(2-bromo-6-nitrobiphenyl)-N,N-dimethylacrylamide (171-4): [ka] A solution of 171-3 (500 mg, 1.85 mmol), dimethylamine (225 mg, 2.78 mmol), mHOBt (300 mg, 2.22 mmol), EDCI (424 mg, 2.22 mmol), and DIPEA (525 mg, 4.07 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 171-4 (500 mg, approximately 90% yield) as a solid. MS Calcd: 298.0; MS Found: 299.0 [M+18] + It was.

[0645] Synthesis of (E)-3-(2-(1H-indolin-7-yl)-6-nitrobiphenyl)-N,N-dimethylacrylamide (171-5): [ka] A mixture of 171-4 (500 mg, 1.4 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (610 mg, 1.7 mmol), Pd(dba) (80 mg, 0.07 mmol), X-Phos (80 mg, 0.14 mmol), and CsCO (1.1 mg, 2.8 mmol) in toluene (10 mL) and HO (1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (EtOAc) to afford 171-5 (450 mg, approximately 48% yield) as a solid. MS Calcd:335.1;MS Found:336.4[M+H] + It was.

[0646] Synthesis of 3-(2-amino-6-(1H-indol-7-yl)phenyl)-N,N-dimethylpropanamide (171-5): [ka] A mixture of 171-4 (600 mg, 1.4 mmol) and Pd / C (10%, 100 mg) in MeOH (10 mL) was stirred under H2(g) overnight at room temperature. The reaction mixture was then filtered. The filtrate was concentrated and purified by column chromatography (EtOAc) to afford 171-5 (450 mg, approximately 90% yield) as a solid. MS Calcd: 307.2; MS Found: 308.4 [M+H] + It was.

[0647] Synthesis of 3-(2-(1H-indol-7-yl)-6-(phenylamino)phenyl)-N,N-dimethylpropanamide (171-6): [ka] A mixture of 171-5 (450 mg, 1.5 mmol), bromobenzene (281 mg, 1.8 mmol), Pd(dba) (38.7 g, 0.075 mmol), xant-Phos (72 mg, 0.15 mmol), and CsCO (978 mg, 3.0 mmol) in toluene (5 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (EtOAc) to afford 171-6 (320 mg, approximately 56% yield) as a solid. MS Calcd: 383.2; MS Found: 384.3 [M+H] + It was.

[0648] Synthesis of 2-(3-(dimethylamino)propyl)-3-(indolin-7-yl)-N-phenylamine (SS20308-0172-01): [ka] A solution of 171-6 (50 mg, 0.13 mmol), BH3 (0.5 mL, 1 M in THF) in THF (2 mL) was stirred at reflux overnight. Then, HCl (1 N, 2 mL) and MeOH (2 mL) were added, and the final mixture was stirred overnight at room temperature. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by prep-HPLC to afford SS20308-0172-01 (5.1 mg, approximately 10% yield) as a solid. MS Calcd:171.5;MS Found:371.5[M+H] + It was.

[0649] 1H NMR (400MHz, CDCl3) δ10.64(brs,1H), 7.37~7.34(m,1H), 7.31~7.29(m,1H), 7.20~7.11(m,5H), 7.03~7.00(m,2H), 6.79(t,J=7.2 Hz,1H), 3.75~3.73(m,2H), 3.35~3.27(m,1H), 2.91~2.80(m,2H), 2.76~2.68(m,2H), 2.54(m,2H), 2.45(s,3H), 1.73~1.67(m,2H)

[0650] Example 66 [ka]

[0651] Example Routes for Example 66 (SS20308-0173-01 and SS20308-0219-01) [ka]

[0652] Synthesis of 5-chloro-2-phenylpyridin-3-amine (173-2): [ka] A mixture of 273-1 (500 mg, 2.42 mmol), phenylboronic acid (590 mg, 4.84 mmol), Pd(PPh3)4 (277 mg, 0.24 mmol), and K2CO3 (668 mg, 4.84 mmol) in DME (10 mL) and water (1 mL) was stirred overnight at 80 °C under a N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 10 / 1) to afford 173-2 (440 mg, approximately 91% yield) as an oil. MS Calcd: 204.0; MS Found: 205.1 [M+H] + It was.

[0653] Synthesis of 5-chloro-N-(2-chloroethyl)-2-phenylpyridin-3-amine (173-3): [ka] To a solution of 173-2 (450 mg, 2.20 mmol) in MeOH (10 mL), 2-chloroacetaldehyde (432 mg, 4.40 mmol, 40% in water), AcOH (264 mg, 4.40 mmol), and NaBHCN (275 mg, 4.40 mmol) were added, and the reaction mixture was then stirred overnight at room temperature. The reaction mixture was then poured into water and basified with 1N NaOH until the pH reached 10. The mixture was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 173-3 (100 mg, approximately 17% yield) as a solid. MS Calcd: 266.0; MS Found: 337.1 [M+H] + It was.

[0654] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-2-phenylpyridin-3-amine (173-4): [ka] A mixture of 173-3 (100 mg, 0.37 mmol), 1H-1,2,4-triazole (52 mg, 0.74 mmol), and CsCO (240 mg, 10.74 mmol) in CHCN (10 mL) was stirred overnight at 80 °C. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 173-4 (77 mg, approximately 68% yield) as a solid. MS Calcd: 299.1; MS Found: 300.2 [M+H] + It was.

[0655] N 3-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2-diphenylpyridine-3,5-diamine (SS20308-0173-01): [ka] A mixture of 173-4 (20 mg, 0.67 mmol), aniline (13 mg, 0.14 mmol), Pd(OAc) (32 mg, 0.14 mmol), X-phos (138 mg, 0.28 mmol), and t-BuONa (13 mg, 0.14 mmol) in toluene (2 mL) was stirred at 110 °C overnight under a N atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by prep-HPLC (petroleum ether / EtOAc = 1 / 3) to afford SS20308-0173-01 (13 mg, approximately 54% yield) as a solid. MS Calcd: 356.2; MS Found: 357.3 [M+H] + It was.

[0656] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H), 7.95(s,1H), 6.68(d,J=2.4Hz,1H), 7.47~7.45(m,2H), 4.36(t,J=7.4Hz,2H), 7.34~7.25(m,3H), 7.1 4(d,J=7.6Hz,2H), 4.36(t,J=7.2Hz,1H), 7.14(d,J=2.0Hz,2H), 5.17(t,J=6.0Hz,1H), 4.36(t,J=6.0Hz,2H), 3.46(dd,J=12.0,6.0Hz,2H)

[0657] Example 67 [ka]

[0658] Example Routes for Example 67 [ka]

[0659] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-bromopyridin-2-amine (249-2): [ka] A mixture of 175-1 (1.00 g, 4.75 mmol), 2-(1H-1,2,4-triazol-1-yl)ethanamine hydrochloride (847 mg, 5.70 mmol), and K2CO3 (1.97 g, 14.25 mmol) in DMF (10 mL) was stirred overnight at room temperature. The mixture was then poured into water and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 175-2 (1.0 g, approximately 71% yield) as a solid. MS Calcd: 301.0; MS Found: 302.0 [M+H] + It was.

[0660] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-chloro-3-phenylpyridin-2-amine (175-3): [ka] A mixture of 175-2 (300 mg, 0.99 mmol), phenylboronic acid (145 mg, 1.19 mmol), Pd(dppf)Cl (7.3 mg, 0.01 mmol), and KCO (410 mg, 2.97 mmol) in DME (5 mL) was stirred at 80 °C for 4 h under a N atmosphere. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 175-3 (250 mg, approximately 84% yield) as a solid. MS Calcd: 299.1; MS Found: 300.2 [M+H] + It was.

[0661] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of ,3-diphenylpyridine-2,6-diamine (SS20308-0175-01): [ka] A mixture of 175-3 (50 mg, 0.17 mmol), aniline (47 mg, 0.50 mmol), Pd(dba) (16 mg, 0.017 mmol), and Xantphos (20 mg, 0.034 mmol) in toluene (3 mL) was stirred at 110 °C for 3 h under a N atmosphere. The reaction mixture was then cooled to room temperature and purified by Prep-HPLC to afford SS20308-0175-01 (44 mg, approximately 72% yield) as a solid. MS Calcd: 356.2; MS Found: 357.3 [M+H] + It was.

[0662] 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H), 8.43(s,1H), 7.68(d,J=8.8Hz,1H), 7.38~7.42(m,1H), 7.29~7.431(m,3H), 7.22~7.26(m,2H), 7 .18(d,J=8.0Hz,3H), 6.85(t,J=7.2Hz,1H), 6.17(d,J=8.0Hz,1H), 5.80(t,J=5.4Hz,2H), 4.42(t,J=6.0Hz,1H), 3.75(q,J=6.0Hz,2H)

[0663] Example 68 [ka]

[0664] Example Route for Example 68 [ka]

[0665] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1-methyl-1H-imidazol-5-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (SS20308-177-01): [ka] A mixture of 143-5 (70 mg, 0.20 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (63 mg, 0.30 mmol), Pd(dba) (9 mg, 0.01 mmol), X-Phos (9 mg, 0.02 mmol), and CsCO (130 mg, 0.40 mmol) in toluene / water (2 / 0.2 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by prep-HPLC to afford SS20308-177-01 (14 mg, approximately 19% yield) as a solid. MS Calcd:359.4;MS Found:360.3[M+H] + It was.

[0666] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H), 8.16(s,1H), 7.93(s,1H), 7.66(s,1H), 7.24(t,J=8.4Hz,3H), 7.12(d,J=7.6Hz,2H), 6. 85~6.82(m,2H), 6.74(s,1H), 6.43~6.39(m,2H), 4.74(t,J=5.6Hz,2H), 4.35(t,J=6.0Hz,2H), 3.45~3.41(m,2H), 3.28(s,3H)

[0667] Example 69 [ka]

[0668] Example Route for Example 69 [ka]

[0669] Synthesis of 4-bromo-3-nitro-N-phenylaniline (178-2): [ka] A mixture of 178-1 (1.00 g, 4.61 mmol), phenylboronic acid (674 mg, 5.53 mmol), EtN (560 mg, 5.53 mmol), and Cu(OAc) (837 mg, 4.61 mmol) in DCM (10 mL) was stirred at room temperature for 48 h. The mixture was then poured into water and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 178-2 (500 mg, approximately 37% yield) as a solid.

[0670] 1 H NMR (400MHz, CDCl3) δ7.42~7.49(m,1H), 7.37(d,J=2.8Hz,1H), 7.26~7.31(m,2H), 7.02~7.06(m,3H), 6.93~6.96(m,1H), 5.84(brs,1H)

[0671] Synthesis of 2-nitro-N-phenylbiphenyl-4-amine (178-3): [ka] A mixture of 178-2 (500 mg, 1.71 mmol), phenylboronic acid (250 mg, 2.05 mmol), Pd(PPh) (196 mg, 0.17 mmol), and NaCO (544 mg, 5.13 mmol) in DME / HO (5 mL, 5 / 1) was stirred overnight at 90 °C under a N atmosphere. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to afford 178-3 (400 mg, approximately 81% yield) as a solid. MS Calcd: 290.1; MS Found: 191.1 [M+H] + It was.

[0672] N 4 Synthesis of -phenylbiphenyl-2,4-diamine (178-4): [ka] A mixture of 178-3 (400 mg, 1.38 mmol) and 10% Pd / C (47 mg, 1.38 mmol) in MeOH (5 mL) was stirred at room temperature under an atmosphere of H2(g) for 1 h. The reaction mixture was then cooled to room temperature and purified by Prep-TLC to afford 174-8 (320 mg, approximately 89% yield) as a solid. MS Calcd: 260.1; MS Found: 261.4 [M+H] + It was.

[0673] Synthesis of 3-chloro-N-(4-(phenylamino)biphenyl-2-yl)propanamide (178-5): [ka] A mixture of 178-4 (330 mg, 1.27 mmol), 3-chloropropanoyl chloride (161 mg, 1.27 mmol), and TEA (128 mg, 1.27 mmol) in DCM (10 mL) was stirred at room temperature for 1 h. The mixture was then poured into water and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with water and brine, dried over NaSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 178-5 (350 mg, approximately 79% yield) as a solid. MS Calcd: 350.1; MS Found: 351.3 [M+H] + It was.

[0674] Synthesis of N-(4-(phenylamino)biphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propanamide (178-6): [ka] A solution of 178-5 (350 mg, 1.00 mmol), 1H-1,2,4-triazole (207 mg, 3.00 mmol), and CsCO (975 mg, 3.00 mmol) in CHCN (10 mL) was stirred overnight at 80 °C. The mixture was then poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford 178-6 (200 mg, approximately 78% yield) as a solid. MS Calcd: 383.2; MS Found: 384.3 [M+H] + It was.

[0675] N 2 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of -phenylbiphenyl-2,4-diamine (SS20308-0178-01): [ka] A mixture of 178-6 (50 mg, 0.13 mmol) and borane methyl sulfide (2.5 M in THF) (5 mL) was stirred overnight at room temperature. Then, the mixture was poured into water and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0178-01 (28 mg, approximately 59% yield) as a solid. MS Calcd: 369.2; MS Found: 370.0 [M+H] + It was.

[0676] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H), 8.07(s,1H), 7.91(s,1H), 7.37~7.45(m, 4H), 7.28~7.32(m,1H), 7.20~7.24(t,2H), 7.08(d,J=7.2Hz,2H), 6.86(d,J=8. 0Hz,1H), 6.79(t,J=7.2Hz,1H), 6.44~6.46(m,1H), 6.35(d,J=2.0Hz,1H), 4.4 6(t,J=5.6Hz,2H), 4.22(t,J=6.8Hz,2H), 2.98~3.03(m,2H), 2.02~2.08(m,2H)

[0677] Example 70 [ka]

[0678] Example Routes for Example 70 [ka]

[0679] N 2 -(2-(1H-1,2,4-triazol-1-yl)propyl)-4'-chloro-N 4 Synthesis of -(4-fluorophenyl)-2,4-diamine (SS20308-0181-01): [ka] A mixture of 147-5 (50 mg, 0.13 mmol), 4-fluoroaniline (22 mg, 0.20 mmol), Pd2dba3 (26 mg, 0.29 mmol), Xantphos (34 mg, 0.058 mmol), and Cs2CO3 (189 mg, 0.58 mmol) in toluene (2 mL) was stirred overnight at 110 °C under a N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through celite, and concentrated. The residue was purified by Prep-HPLC to afford SS20308-0181-01 (14.3 mg, approximately 13% yield) as a solid. MS Calcd: 407.1; MS Found: 408.2 [M+H] + It was.

[0680] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H), 8.07(s,1H), 7.43(s,1H), 7.43(d,J=8.4Hz,2H), 7.26(d,J=8.4Hz,2H), 7.14~7.05(m,4H), 6.85 (d,J=8.0Hz,1H), 6.39(dd,J=8.0,2.0Hz,1H), 6.33(d,J=2.0Hz,1H), 4.85(t,J=5.8Hz,1H), 4.36(t,J=6.0Hz,2H), 3.37~3.43(m,2H)

[0681] Example 71 [ka]

[0682] Example Route for Example 71 [ka]

[0683] Synthesis of 4-bromo-N-(4-fluorophenyl)-3-nitroaniline (184-2): [ka] A mixture of 184-1 (500 mg, 2.30 mmol), 4-fluorophenylboronic acid (322 mg, 2.30 mmol), EtN (466 mg, 4.61 mmol), and Cu(OAc) (418 mg, 2.30 mmol) in MeOH (20 mL) was stirred at room temperature for 48 h. After the reaction was completed, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc 15 / 1) to afford 184-2 (650 mg, approximately 91% yield) as a solid. MS Calcd: 310.0; MS Found: 311.0 [M+H] + It was.

[0684] Synthesis of N-(4-fluorophenyl)-2-nitrobiphenyl-4-amine (184-3): [ka] A mixture of 184-2 (650 mg, 2.09 mmol), phenylboronic acid (255 mg, 2.09 mmol), Pd(dppf)Cl (76 mg, 0.10 mmol), and KCO (578 mg, 4.18 mmol) in DME (20 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (4 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 184-3 (450 mg, approximately 70% yield) as a solid. MS Calcd: 308.1; MS Found: 309.0 [M+H] + It was.

[0685] N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (184-4): [ka] To a solution of 184-3 (3.00 g, 9.31 mmol) in EtOAc (50 mL) was added 10% Pd / C (6.09 g, 93.13 mmol). The mixture was stirred overnight at room temperature under an atmosphere of H2(g). After the reaction was complete, the insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was used in the next step without further purification. MS Calcd: 178.1; MS Found: 179.2 [M+H] + It was.

[0686] N 2 -((3-(bromoethyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (184-7): [ka] To a solution of 184-5 (200 mg, 1.10 mmol) in CHCl (10 mL) was added Dess-Martin periodinane (937 mg, 2.21 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the insoluble material was removed by filtration, and 184-4 (307 mg, 1.10 mmol) and NaBHCN (137 mg, 2.21 mmol) were added to the filtrate. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (2 x 50 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude product was used in the next step without further purification.

[0687] N 2 -((3-((dimethylamino)methyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0184-01): [ka] A mixture of 184-7 (50 mg, 0.11 mmol), dimethylamine hydrochloride (18 mg, 0.23 mmol), and KCO (63 mg, 0.45 mmol) in CHCN (20 mL) was stirred at 80 °C under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (4 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO, and concentrated in vacuo. The crude product was purified by Prep-HPLC to afford SS20308-0184-01 (6 mg, approximately 13% yield) as a solid. MS Calcd: 405.2; MS Found: 406.0 [M+H] + It was.

[0688] 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H), 8.43~7.40(m,2H), 7.34~7.27(m,3H), 7.13~7.05(m,4H), 6.85(d,J=8.0Hz,1H), 6.48(d,J=2.0Hz,1H), 6.41(dd ,J=8.0Hz,2.0Hz,1H), 5.48(t,J=5.6Hz,1H), 4.33(d,J=6.0Hz,2H), 4.25( d,J=6.4Hz,2H), 3.41(d,J=6.0Hz,2H), 2.48(d,J=6.0Hz,2H), 1,81(s,6H)

[0689] Example 72 [ka]

[0690] Example Routes for Example 72 (SS20308-0189-01 and SS20308-0223-01) [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41 mg, 0.21 mmol), Pd(dba) (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and evaporated, and the residue was purified by prep-HPLC to afford SS20308-189-01 (7.04 mg, approximately 16% yield) as a solid. MS Calcd:345.4;MS Found:346.3[M+H] + It was.

[0691] 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H), 8.47(s,1H), 8.12(s,1H), 7.97(s,1H) , 7.86(t,J=6.0Hz,1H), 7.73(d,J=1.6Hz,1H), 7.45(d,J=8·8Hz,1H), 7.23(t ,J=8.4Hz,2H), 7.11(d,J=7.6Hz,2H), 6.81(t,J=7.2Hz,1H), 6.60~6.59(m,2 H), 6.43~6.41(m,2H), 4.45(t,J=6.0Hz,2H), 3.63~3.58(m,2H), 3.28(s,3H) SS20308-223-01 (8.59 mg, approximately 22% yield) was obtained as a solid. MS Calcd: 279.3; MS Found: 280.0 [M+H] + It was.

[0692] 1H NMR (400MHz, DMSO-d6) δ8.47(s,1H), 7.97(s,1H), 7.91(s,1H), 7.19(t,J=8.4Hz,1H), 7.03(d,J=7.6Hz,3H), 6.93(d,J=7.6Hz,1 H), 6.77(t,J=7.6Hz,1H), 6.32~6.30(m,2H), 6.10~6.08(m,1H), 5.67(t,J=2.0Hz,2H), 4.32(t,J=6.4Hz,2H), 3.44~3.40(m,2H)

[0693] Examples 73-79 all use the same initial synthetic steps, which are not repeated in each example. [ka]

[0694] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-2): [ka] A mixture of 143-1 (1.0 g, 4.6 mmol), phenylboronic acid (1.1 g, 9.2 mmol), Cu(OAc) (833 mg, 4.6 mmol), and EtN (2.3 g, 23 mmol) in CHCl (100 mL) was stirred at room temperature for 2 h. After the reaction was complete, the insoluble material was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by column chromatography to afford 143-2 (1.0 mg, approximately 74% yield) as a solid.

[0695] 4-Bromo-N 1 Synthesis of -phenylbenzene-1,3-diamine (143-3): [ka] A mixture of 143-2 (1.0 g, 3.4 mmol), Zn powder (1.1 g, 17 mmol), and HOAc (1.0 g, 17 mmol) in EtOH (50 mL) was stirred overnight at room temperature. After the reaction was completed, the insoluble material was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 143-3 (800 mg, approximately 90% yield) as a solid. MS Found: 263.2 [M+H] + It was.

[0696] 4-Bromo-N 3 -(2-chloroethyl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (143-4): [ka] A mixture of 143-3 (800 mg, 3.1 mmol), 2-chloroacetaldehyde (242 mg, 3.1 mmol, 40% in water), NaBHCN (1.3 g, 6.2 mmol) and HOAc (2 drops) in MeOH (50 mL) was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (EtOAc) to afford 143-4 (600 mg, approximately 60% yield) as a solid. MS Calcd: 324.0; MS Found: 325.0 [M+H] + It was.

[0697] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-N 1 Synthesis of -phenylbenzene-1,3-diamine (143-5): [ka] A mixture of 143-4 (600 mg, 1.85 mmol), 1H-1,2,4-triazole (192 mg, 2.78 mmol), and CsCO (1.2 g, 3.7 mmol) in acetone (20 mL) was stirred overnight at 80 °C. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (DCM / EtOH=20 / 1) to afford 143-5 (450 mg, approximately 68% yield) as a solid. MS Calcd: 357.1; MS Found: 358.3 [M+H] + was

[0698] Example 73 [ka]

[0699] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (SS20308-190-01): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44 mg, 0.21 mmol), Pd(dba) (6 mg, 0.007 mmol), X-Phos (6 mg, 0.02 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by prep-HPLC to afford SS20308-190-01 (14.9 mg, approximately 30% yield) as a solid. MS Calcd:359.4;MS Found:360.3[M+H] + It was.

[0700] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H), 8.20(s,1H), 7.93(s,1H), 7.45(d,J=1.6Hz,1H), 7.25(t,J=8.8Hz,2H), 7.13(d,J=7.6Hz,2H) ), 6.86~6.83(m,2H), 6.45~6.40(m,2H), 6·10(s,1H), 4.70(t,J=5.6Hz,1H), 4.35(t,J=6.0Hz,2H), 3.52(s,3H), 3.46~3.42(m,2H)

[0701] Example 74 [ka]

[0702] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1-methyl-1H-pyrazol-4-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (SS20308-191-01): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44 mg, 0.21 mmol), Pd(dba) (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated, and the crude product was purified by prep-HPLC to afford SS20308-191-01 (15 mg, approximately 30% yield) as a solid. MS Calcd:359.4;MS Found:360.3[M+H] + It was.

[0703] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H), 8.04(s,1H), 7.93(s,1H), 7.68(s,1H), 7.45(s,1H), (t,J=8.4Hz,2H), 7.07(d,J=7.6Hz,2H), 6.96 (d,J=8.0Hz,1H), 6.78(t,J=7.2Hz,1H), 6.44~6.39(m,2H), 4.84(t,J=6.4Hz,1H), 4.42(t,J=6.0Hz,2H), 3.86(s,3H), 3.46~3.41(m,2H)

[0704] Example 75 [ka]

[0705] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(3,5-dimethylisoxazol-4-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (SS20308-192-01): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 3,5-dimethylisoxazole-4-boronic acid (24 mg, 0.17 mmol), Pd(dba) (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated, and the crude product was purified by Prep-HPLC to afford SS20308-192-01 (14.6 mg, approximately 29% yield) as a solid. MS Calcd: 374.4; MS Found: 375.3 [M+H] + It was.

[0706] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H), 8.11(s,1H), 7.93(s,1H), 7.24(t,J=8.4Hz,1H), 7.13~7.10(m,2H), 6.82(t,J=7.2Hz,1H), 6.77(d,J=8.4Hz, 1H), 6.42(dd,J=8.0, 2.0Hz,1H), 6.39(d,J=1.6Hz,1H), 4.80(t,J=6.0Hz ,1H), 4.34(t,J=6.0Hz,2H), 3.45~3.41(m,2H), 2.10(s,3H), 1.93(s,3H)

[0707] Example 76 [ka]

[0708] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 1 Synthesis of -phenyl-4-(thiophen-2-yl)benzene-1,3-diamine (SS20308-193-01): [ka] A mixture of 143-5 (50 mg, 0.14 mmol), 2-thiopheneboronic acid (22 mg, 0.17 mmol), Pd(dba) (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated, and the crude product was purified by Prep-HPLC to afford SS20308-193-01 (5.6 mg, approximately 11% yield) as a solid. MS Calcd: 361.5; MS Found: 362.1 [M+H] + It was.

[0709] 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H), 7.94(s,1H), 7.36~7.35(m,1H), 7.34~7.24(m,1H), 7.16~7.14(m,2H), 7.08~7.03(m,2H), 6.9 4~6.93(m,1H), 6.89(t,J=7.6Hz,1H), 6.49(dd,J=8.4,2.0Hz,1H), 6.45~6.44(m,1H), 4.44(t,J=6.0Hz,2H), 3.61(t,J=6.0Hz,2H)

[0710] Example 77 [ka]

[0711] Synthesis of 5-(2-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4-(phenylamino)phenyl)thiophene-2-carbonitrile (SS20308-194-01): [ka] A mixture of 143-5 (100 mg, 0.28 mmol), (5-cyanothiophen-2-yl)boronic acid (86 mg, 0.56 mmol), Pd(dba) (20 mg, 0.028 mmol), and CsF (85 mg, 0.5 mmol) in DMF (3 mL) was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by Prep-HPLC to afford SS20308-194-01 (5.65 mg, approximately 5% yield) as a solid. MS Calcd: 386.5; MS Found: 387.3 [M+H] + It was.

[0712] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H), 8.36(s,1H), 7.97(s,1H), 7.92(d,J=4.4Hz,1H), 7.29~7.25(m,2H), 7.19(d,J=3.6Hz,2 H), 7.16~6.13(m,3H), 6.90~6.87(m,1H), 6.49~6.44(m,2H), 5.48(t,J=6.0Hz,1H), 4.43(t,J=6.0Hz,2H), 3.46~3.42(m,2H)

[0713] Example 78 [ka]

[0714] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(2,5-dihydrofuran-2-yl)-N 1 Synthesis of -phenylbenzene-1,3-diamine (195-01-1): [ka] A mixture of 143-5 (100 mg, 0.28 mmol), 2,3-dihydrofuran (86 mg, 0.56 mmol), Pd(OAc) (6 mg, 0.028 mmol), PPh (15 mg, 0.056), and KCO (77 mg, 0.56 mmol) in DMF (3 mL) was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated. The crude product was used directly in the next step without further purification. MS Calcd: 347.2; MS Found: 348.4 [M+H] + It was.

[0715] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 1 Synthesis of -phenyl-4-(tetrahydrofuran-2-yl)benzene-1,3-diamine (SS20308-195-01): [ka] A mixture of 195-01-1 (crude product, 0.28 mmol) and Pd / C (10%, 100 mg) in EtOAc (2 mL) was stirred under H2 at room temperature overnight. After the reaction was complete, the insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by Prep-HPLC to afford SS20308-195-01 (5.74 mg, approximately 6% yield) as a solid. MS Calcd: 349.4; MS Found: 350.2 [M+H] + It was.

[0716] 1H NMR (400MHz, DMSO-d6) δ8.51(s,1H), 7.99(s,1H), 7.97(s,1H), 7.22~7.18(m,2H), 7.05(d, J=7.6Hz2H), 6.93(d,J=7.6Hz,1H), 6.77(t,J=7.6Hz,1H), 6.37~6.36(m,1H), 6.35~6.35(m, 1H), 5.13(t,J=5.6Hz,1H), 4.63~4.59(m,1H), 4.41(t,J=6.0Hz,2H), 3.94~3.89(m,1H), 3, 70~3.65(m,1H), 3.47~3.43(m,2H), 2.07~1.90(m,1H), 1.88~1.85(m,2H), 1.69~1.62(m,1H)

[0717] Example 79 [ka]

[0718] Example Route for Example 79 [ka]

[0719] Synthesis of methyl 2-(2-nitro-5-(phenylamino)phenyl)acetate (197-2): [ka] A mixture of 197-1 (2.00 g, 7.30 mmol), aniline (1.36 g, 14.60 mmol), Pd(dba) (668 mg, 0.73 mmol), Xantphos (854 mg, 1.46 mmol), and CsCO (4.74 g, 14.60 mmol) in toluene (60 mL) was stirred at 100 °C overnight under a N atmosphere. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford 197-2 (1.20 g, 57% yield) as a yellow oil. MS Calcd: 2.86.1; MS Found: 287.4 [M+H]+ It was.

[0720] Synthesis of 2-(2-nitro-5-(phenylamino)phenyl)acetic acid (197-3): [ka] A mixture of 197-2 (500 mg, 1.75 mmol) and LiOH (147 mg, 3.50 mmol) in THF (30 mL) was stirred overnight at room temperature. The reaction mixture was then basified with saturated aqueous NaHCO3 until the pH reached 10. The resulting mixture was extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na2CO3, and concentrated to afford 197-3 (400 mg, approximately 84% yield) as an oil. MS Calcd: 272.1; MS Found: 273.4 [M+H] + It was.

[0721] Synthesis of 2-(2-nitro-5-(phenylamino)phenyl)acetic acid (197-4): [ka] A mixture of 197-3 (400 mg, 1.47 mmol), dimethylamine hydrochloride (132 mg, 2.92 mmol), HOBT (397 mg, 2.94 mmol), EDCI (564 mg, 2.94 mmol), and DIPEA (379 mg, 2.94 mmol) in DMF (20 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water (100 mL). The resulting mixture was extracted with EtOAc (80 mL × 3). The organic layer was washed with brine, dried over Na2CO3, and concentrated to afford 197-4 (405 mg, approximately 92% yield) as an oil. MS Calcd: 299.1; MS Found: 300.1 [M+H] + It was.

[0722] Synthesis of 3-(2-(dimethylamino)ethyl)-4-nitro-N-phenylaniline (197-5): [ka] 197-4 (405 mg, 1.35 mmol) and BH3·S(Me)2 (2.7 mL, 2.7 mmol) in THF (5 mL) were stirred overnight at room temperature. The reaction mixture was then concentrated and added dropwise to MeOH. The resulting mixture was acidified with 1N HCl until the pH reached 1 and stirred at 80 °C overnight. The mixture was then extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2CO3, and concentrated to afford 197-5 (340 mg, approximately 88% yield) as an oil. MS Calcd: 285.1; MS Found: 286.2 [M+H] + It was.

[0723] 3-(2-(dimethylamino)ethyl)-N 1 Synthesis of -phenylbenzene-1,4-diamine (197-6): [ka] A mixture of 197-5 (340 mg, 1.19 mmol) and 10% Pd / C (34 mg) in MeOH (5 mL) was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then filtered and concentrated to afford 297-6 (280 mg, approximately 92% yield) as a solid. MS Calcd: 255.2; MS Found: 256.2 [M+H] + It was.

[0724] N 2 -(2-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N 4 Synthesis of -phenylbenzene-1,4-diamine (SS20308-0197-01): [ka] A mixture of 197-6 (130 mg, 0.51 mmol), 2-chloro-1-bromobenzene (195 mg, 1.02 mmol), Pd(dba) (46 mg, 0.05 mmol), Xantphos (57.8 mg, 0.10 mmol), and CsCO (332 mg, 1.02 mmol) in toluene (4 mL) was stirred overnight at 100 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated. The filtrate was diluted with water (20 mL) and then extracted with EtOAc (10 mL × 3). The residue was purified by prep-HPLC (petroleum ether / EtOAc = 1 / 2) to afford SS20308-0197-01 (6 mg, approximately 3% yield) as an oil. MS Calcd:365.2;MS Found:366.3[M+H] + It was.

[0725] 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H), 7.57(s,1H), 7.32(dd,J=8.0Hz,1.2Hz,1H), 7.23(t,J=8.0Hz,2H), 7.06~7.02(m,5H), 6.96~6 .94(m,1H), 6.80(t,J=7.2Hz,1H), 6.67~6.63(m,1H), 6.56(dd,J=8.0Hz,1H), 2.60(t,J=6.8Hz,2H), 2.44~2.43(m,2H), 2.13(s,6H)

[0726] Example 80 [ka]

[0727] Example Route for Example 80 [ka]

[0728] Synthesis of 4-(3-(dimethylamino)prop-1-ynyl)-2-nitroaniline (198-2): [ka] A solution of 0155-1 (1.0 g, 4.61 mmol), N,N-dimethylprop-2-yn-1-amine (1.92 g, 23.04 mmol), X-phos (110 mg, 9.22 mmol), Pd(CHCN)Cl (48 mg, 0.019 mmol), and potassium carbonate (1.27 g, 9.22 mmol) was suspended in CHCN (20 mL). The reaction mixture was stirred at reflux under N overnight, then filtered and rinsed with EtOAc. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, 3 / 1, 1 / 1) to afford 198-2 (0.83 g, approximately 92% yield) as a solid. MS Calcd: 219.1; MS Found: 219.6 [M+H] + It was.

[0729] Synthesis of 4-(3-(dimethylamino)propyl)benzene-1,2-diamine (198-3): [ka] A mixture of 198-2 (830 mg, 2.79 mmol) and 10% Pd / C (83 mg) in MeOH (20 mL) was stirred at room temperature overnight under an atmosphere of H2(g). The reaction mixture was then filtered through celite. The filtrate was concentrated to afford 198-3 (700 mg, approximately 96% yield) as a brown oil. MS Calcd: 193.2; MS Found: 194.4 [M+H] + It was.

[0730] N 1 ,N 2 Synthesis of -bis(2-chlorophenyl)-4-(3-(dimethylamino)propyl)benzene-1,2-diamine (SS20308-0198-01): [ka] A solution of 198-3 (520 mg, 2.69 mmol), 1-bromo-2-chlorobenzene (3.09 mg, 16.14 mmol), Xantphos (312 mg, 0.54 mmol), Pd(dba) (247 mg, 0.27 mmol), and anhydrous cesium carbonate (2.63 g, 8.07 mmol) was suspended in toluene (20 mL). The reaction mixture was stirred overnight at 120 °C under N, then filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 5, 1 / 1, 100% EtOAc, DCM / MeOH = 20 / 1) to afford an oil. MS Calcd: 413.1; MS Found: 414.2 [M+H] + It was.

[0731] 1 H NMR (400MHz, DMSO-d6) δ7.37~7.28(m,2H), 7.20~7.00(m,6H), 6.96~6.88(m,2H), 6.81~6 .69(m,3H), 2.55(t,J=7.6Hz,2H), 2.20(t,J=7.0Hz,2H), 2.11(s,6H), 1.73~1.63(m,2H)

[0732] Example 81 [ka]

[0733] Example Route for Example 81 [ka]

[0734] Synthesis of 2-bromo-5-fluorobenzene-1,4-diamine (199-2): [ka] To a solution of 199-1 (300 mg, 1.28 mmol) in acetone (30 mL), Zn powder (417 mg, 6.38 mmol) and NH₄Cl (341 mg, 6.38 mmol) were added, and the mixture was stirred at 70 °C for 16 h. After the reaction was complete, the insoluble material was removed by filtration. The filtrate was poured into water (50 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO₄, concentrated in vacuo, and used in the next step without further purification.

[0735] Synthesis of 2-(3-(dimethylamino)prop-1-ynyl)-5-fluorobenzene-1,4-diamine (199-3): [ka] A mixture of 199-2 (500 mg, 2.44 mmol), N,N-dimethylprop-2-yn-1-amine (2.03 g, 24.39 mmol), Pd(CHCN)Cl (63 mg, 0.24 mmol), CsCO (1.59 g, 4.88 mmol), and X-phos (232 mg, 0.49 mmol) in CHCN (20 mL) was stirred at 80 °C overnight under a nitrogen atmosphere and then filtered. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to afford 163-01-3 (450 mg, approximately 89% yield) as a yellow oil. MS Calcd:207.1;MS Found:208.1[M+H] + It was.

[0736] Synthesis of 2-(3-(dimethylamino)propyl)-5-fluorobenzene-1,4-diamine (199-4): [ka] To a solution of 199-3 (250 mg, 1.21 mmol) in MeOH (30 mL) was added 10% Pd / C (50 mg), and the mixture was stirred overnight at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the insoluble material was removed by filtration. The filtrate was poured into water (50 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO4, concentrated in vacuo, and used in the next step without further purification.

[0737] N 1 ,N 4 Synthesis of -bis(2-chloro-4-fluorophenyl)-2-(3-(dimethylamino)propyl)-5-fluorobenzene-1,4-diamine (SS20308-0199-01): [ka] A mixture of 199-4 (120 mg, 0.57 mmol), 1-bromo-2-chloro-4-fluorobenzene (357 mg, 1.70 mmol), Pd(dba) (52 mg, 0.06 mmol), CsCO (555 mg, 1.70 mmol), and X-Phos (54 mg, 0.11 mmol) in toluene (10 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, the insoluble material was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO, and concentrated in vacuo. The crude product was purified by prep-HPLC to afford SS20308-0199-01 (6 mg, approximately 2% yield) as a yellow oil. MS Calcd:467.1;MS Found:467.9[M+H] + It was.

[0738] 1H NMR (400MHz, CDCl3) δ7.11~6.97(m,5H), 6.93~6·88(m,1H), 6.82~6.79(m,1H), 6 .77~6.73(m,2H), 5.73(s,1H), 2.66~2.60(m,4H), 2.56(s,6H), 2.00~1.97(m,2H)

[0739] Example 82 [ka]

[0740] Example Route for Example 82 [ka]

[0741] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -cyclohexyl-2,4-diamine (SS20308-200-01): [ka] A mixture of 95-5 (60 mg, 0.18 mmol), cyclohexylamine (36 mg, 0.36 mmol), Pd(OAc) (9 mg, 0.036 mmol), X-Phos (52 mg, 0.072 mmol), and t-BuONa (36 mg, 0.36 mmol) in toluene (2 mL) was stirred at 150 °C for 8 h in a microwave reactor. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated to a crude oil and purified by Prep-HPLC to afford SS20308-200-01 (4.3 mg, approximately 7% yield) as an oil. MS Calcd: 361.2; MS Found: 362.3 [M+H] + It was.

[0742] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H), 7.34(t,J=7.6Hz,2H), 7.24~7.14(m,3H), 6 .72~7.70(m,1H), 5.97~5.95(m,2H), 5.28(d,J=8.4Hz,1H), 4.56(t,J=6.0Hz,1H ), 4.35(t,J=6.0Hz,2H), 3.44(q,J=6.0Hz,2H), 3.22~3.15(m,1H), 1.95~1.92(m , 2H), 1.73~1.70(m,2H), 1.61~1.58(m,1H), 1.39~1.29(m,2H), 1.22~1.09(m,3H)

[0743] Example 83 [ka]

[0744] Example Route for Example 83 [ka]

[0745] Synthesis of 1-(2-chloroethyl)-6-nitroindoline (201-2): [ka] To a solution of 201-1 (1.64 g, 10.0 mmol) in EtOH (50 mL), 2-chloroacetaldehyde (4.71 g, 60.0 mmol), NaBHCN (2.51 g, 40.0 mmol), and AcOH (10 mL) were added and then stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine and concentrated to dryness to afford the crude product, which was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 1 / 1) to afford 201-2 (2.10 g, approximately 93% yield) as a solid. MS Calcd: 226.1; MS Found: 227.4 [M+H] + It was.

[0746] Synthesis of 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-nitroindoline (201-3): [ka] To a mixture of 201-2 (1.20 g, 5.29 mmol) and CsCO (5.17 g, 15.88 mmol) in CHCN (60 mL) was added 1H-1,2,4-triazole (0.55 g, 7.94 mmol) and stirred at 80 °C for 7 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine and concentrated to dryness to afford the crude product, which was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 1 / 1) to afford 201-3 (1.10 g, approximately 80% yield) as a solid. MS Calcd: 259.1; MS Found: 260.1 [M+H] + It was.

[0747] Synthesis of 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)indoline-6-amine (201-4): [ka] To a solution of 201-2 (390 mg, 1.51 mmol) in EtOAc (15 mL) was added Pd / C (10%). The mixture was stirred overnight at room temperature. The mixture was then filtered through a pad of celite, washed with EtOAc, concentrated, and purified by Prep-TLC to afford 201-3 (260 mg, approximately 75% yield) as a solid. MS Calcd: 229.1; MS Found: 230.2 [M+H] + It was.

[0748] Synthesis of 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N-(4-fluorophenyl)indoline-6-amine (SS20308-0201-01): [ka] To a solution of 201-4 (187 mg, 0.82 mmol) in dioxane / t-BuOH (16 mL / 8 mL), CsCO (531 mg, 1.63 mmol), Pd(dba) (73 mg, 0.08 mmol), and 1-fluoro-4-indobenzene (272 mg, 1.22 mmol) were added and stirred overnight at 100 °C. The residue was purified by prep-THPLC to afford SS20308-0201-01 (14 mg, approximately 5% yield) as a solid. MS Calcd: 323.2; MS Found: 324.0 [M+H] + It was.

[0749] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H), 7.97(s,1H), 7.81(s,1H), 7.05~7.01(m,2H), 6.98~6.94(m,2H), 6.84(d,J=8.0Hz,1H), 6.24(dd, J=7.6Hz,2·0Hz,1H), 6.06(d,J=1.69Hz,1H), 4.39(t,J=6.4Hz,2H), 3.41(t,J=6.4Hz,2H), 3.29(t,J=8.0Hz, 2H), 2.78(t,J=8.0Hz,2H)

[0750] Example 84 [ka]

[0751] Example Route for Example 84 [ka]

[0752] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-01-1): [ka] A mixture of 143-01-0 (1.0 g, 4.6 mmol), phenylboronic acid (1.1 g, 9.2 mmol), Cu(OAc) (833 mg, 4.6 mmol), and EtN (2.3 g, 23 mmol) in CHCl (100 mL) was stirred at room temperature for 2 days. After the reaction was complete, the insoluble material was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined layers were dried over NaSO and concentrated in vacuo. The residue was purified by column chromatography to afford 143-01-1 (1.0 mg, approximately 74% yield) as a solid.

[0753] Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 2.0mL / min; mobile phase: 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 1.6 minutes to 0% [water + 10mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 minutes, and finally under these conditions for 0.1 minutes to 95% [water + 10mM NH4HCO3] and 5% [CH3CN], and under these conditions for 0.7 minutes. The purity was approximately 83.1%. Rt=2.314 min; MS Calcd.:292.0;

[0754] 4-Bromo-N 1 Synthesis of -phenylbenzene-1,3-diamine (143-01-2): [ka] A mixture of 143-01-1 (1.0 g, 3.4 mmol), Zn (1.1 g, 17 mmol), and HOAc (1.0 g, 17 mmol) in EtOH (50 mL) was stirred overnight at room temperature. After the reaction was completed, the insoluble material was removed by filtration. The filtrate was poured into water (100 mL) ...

Claims

1. Compounds having formula 1 and pharmaceutically acceptable salts thereof: 【Chemistry 1】 n is 0 to 2. When n is 0, B and the NH group are directly bonded, and R 3 is absent, and when n is 1 or 2, the carbon at the bond may optionally be joined by one R 3 substituted by a group, A is a 6-membered heteroaryl or a 6-membered aryl, and the 6-membered heteroaryl or the 6-membered aryl is independently selected from 1 to 3 R 1 is further substituted by a group, B is a 5- to 6-membered heterocycle, a 5- to 6-membered aryl, or a 5- to 6-membered cyclohexyl, and the 5- to 6-membered heterocycle, the 5- to 6-membered aryl, or the 5- to 6-membered cyclohexyl is unsubstituted or independently has up to three R 2 substituted by a group, each X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently C, N, or O; Each R 1 are independently halo, C 1~4 Alkyl, —NR x R y , -O(CH 2 ) 2 R x , -O(CH 2 ) 2 NR x R y , -NHC(O)-C 2~4 Alkyl, -(CH 2 ) 3 NR x R y , -NH(CH 2 ) 2 R x R y , -NHCH 2 CR x R y R z , a 5- to 6-membered aryl, a 5- to 10-membered heterocycle, a 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl; 1 to 3 R 1 The group is optionally R a and / or R b and two R 1 The groups optionally together form a 5- to 6-membered heteroaryl, [5- to 6-membered heterocycle, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl], and the 5- to 6-membered heteroaryl, [5- to 6-membered heterocycle, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl] is optionally joined by one to three R a is further substituted by a group, Each R 2 are independently halo, C 1~2 Methoxy, or C(O)OR x and two R on adjacent atoms 2 The groups optionally together form a 5-6 membered aryl ring, and the 5-6 membered heteroaryl ring optionally comprises 1 to 3 R a is further substituted by a group, R 3 is C 1~3 haloalkyl or oxo, Each R x , R y , R z are independently H, halo, C 1~2 Alkyl, C 1~2 Alcohol, C 1~2 Alkoxy, C 1~2 haloalkyl, or NR a R b and R x , R y , R z Any two of R optionally together form a 4- to 6-membered heterocycle, a 5- to 6-membered aryl ring, and each R x , R y , R z optionally, R a and R b is further substituted by Each R a and R b are independently H, halo, cyano, oxo, C 1~3 alkyl, —C(O)OR′, C 1~3 haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle; R a and R b are each further substituted by R'; R' is C 1~3 Alkyl, C 1~3 Alkyl haloalkyl, or C 5~6 is heteroaryl, compound.

2. Each R 1 is, independently, 【Chemistry 2-1】 【Chemistry 2-2】 2. The compound of claim 1 selected from:

3. Each R 2 is, independently, 【Transformation 3】 2. The compound of claim 1 selected from:

4. The compound is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] and pharmaceutically acceptable salts thereof.

5. Compounds having formula 2 and pharmaceutically acceptable salts thereof: 【Transformation 5】 A is a 6-membered heteroaryl or a 6-membered aryl, and the 6-membered heteroaryl or the 6-membered aryl is independently selected from 1 to 3 R 1 is further substituted by a group, B is a 6-membered heterocycle, a 6-membered aryl, or a 6-membered cyclohexyl, and the 6-membered heterocycle, the 6-membered aryl, or the 6-membered cyclohexyl is unsubstituted or each has up to two R 2 substituted by a group; each X 1 , X 2 , X 3 , and X 4 are each C, N, or O, Each R 1 are independently halo, C 1~4 Alkyl, —NR x R y , -O(CH 2 ) 2 R x R y , -O(CH 2 ) 2 NR x R y , —NHC(O)-alkyl 2~4 , -(CH 2 ) 3 NR x R y , -NH(CH 2 ) 2 R x R y , -NHCH 2 CR x R y R z , a 5- to 6-membered aryl, a 5- to 10-membered heterocycle, a 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl; Two R's 1 groups optionally together form a 5- to 6-membered heteroaryl, [5- to 6-membered heterocycle, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl], and said 5- to 6-membered heteroaryl, [5- to 6-membered heterocycle, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl] optionally comprises one to three R a is further substituted by a group, 1 to 3 R 1 Each of the groups independently optionally comprises R a and R b is further substituted by Each R 2 are independently halo, C 1~2 Methoxy, or C(O)OR x Including, Each R x , R y , R z are independently H, halo, C 1~2 Alkyl, C 1~2 Alcohol, C 1~2 Alkoxy, C 1~2 haloalkyl, or NR a R b Including, R x , R y , R z Any two of R together form a 4- to 6-membered heterocycle or a 5- or 6-membered aryl ring, x , R y , R z optionally, R a and R b is further substituted by Each R a and R b are independently H, halo, cyano, oxo, C 1~3 alkyl, —C(O)OR′, C 1~3 haloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycle; R a and R b is independently optionally further substituted by R′; R' is C 1~3 Alkyl, C 1~3 haloalkyl, or C 5~6 is heteroaryl, compound.

6. Each R 1 is, independently, 【Transformation 6】 6. The compound of claim 5 selected from:

7. Each R 2 is, independently, 【Transformation 7】 6. The compound of claim 5 selected from:

8. The compound is 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 and pharmaceutically acceptable salts thereof.

9. Compounds having formula 2A and pharmaceutically acceptable salts thereof: 【Chemistry 9】 B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each X 1 , X 3 , and X 4 are independently C, N, or O; R 1 Ha-C 1~3 Alkyl-R x , -(CH 2 ) 2 NR x R y , -CH 2 C ( R x R y ) R a , -CH 2 C ( R x R y ) NR a R b or a 5- to 6-membered aryl, and R 1 optionally, R a or R b and R 2 is H, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 further substituted with haloalkoxy; R 1 and R 2 The groups optionally together form a 5- to 6-membered heterocyclic ring, which may optionally be joined by R a Or R b , or R a and R b and further replaced by both R 3 is H or halo, R 4 is halo or C 1~3 is alkyl, Each R x and R y are independently a 5- or 6-membered heterocycle, Each R a and R b are independently 1~3 Alkyl or C 1~3 is haloalkyl, R a and R b is optionally further substituted with an R' group, wherein the R' group is a 5-membered heteroaryl or a 5-6 membered heterocycle; compound.

10. R 1 teeth, 【Chemistry 10】 10. The compound of claim 9 selected from:

11. Each R 2 is, independently, 【Chemistry 11】 10. The compound of claim 9 selected from:

12. The compound is 【Chemistry 12-1】 【Chemistry 12-2】 and pharmaceutically acceptable salts thereof.

13. Compounds having formula 2B and pharmaceutically acceptable salts thereof: 【Chemistry 13】 B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; Each X is independently C, N, or O; R 1 is H, C 1~3 alkyl, a 5- to 6-membered heterocycle, a 5- to 6-membered aryl, a 5- to 6-membered heteroaryl, a 5- to 10-membered cycloheteroaryl, a 5- to 10-membered heteroaryl, or —C(O)R x , Each R 2a and R 2b are independently H, C 1~3 Alkyl, 5- to 6-membered aryl, —NR x (CH 2 ) 2 R y , -NR x (CH 2 ) 3 R y , -NR x C(O)(CH 2 ) 2 R y , -O(CH 2 ) 2 R x , -NH(CH 2 )CR x R y CH 2 R a , -NH(CH 2 )CR x R y CH 2 NR a R b , -(CH 2 ) 3 NR x R y , 5- to 10-membered cycloheteroaryl, or —NR x R y , R' 2 is H or halo, Each R 3 are independently H, halo, C 1~3 Alkyl, —O(CH 2 ) 2 NR x R y , -NR x (CH 2 ) 2 R y , -NR x R y , or -(CH 2 ) 3 NR x R y and R 4 is the halo, Furthermore, R 1 optionally, R 2a or R 2b and R a or R b is further substituted by Each R 1 , R 2a , R 2b , R' 2 , and R 3 optionally, independently, one or more R a is replaced by R x and R y are independently H, C 1~4 Alkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, —NR a R b and Each R x and R y is optionally a 4- to 5-membered heterocycle; R x and R y optionally, independently, R a and / or R b is further substituted by Each R a and R b are independently H, halo, oxo, cyano, C 1~3 Alkyl, C 1~3 Alcohol, C 1~3 Alkoxy, phenyl, -(CH 2 ) 2 R' is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocycle; R' is a 5-membered heteroaryl; compound.

14. R 1 is, independently, 【Chemistry 14】 14. The compound of claim 13 selected from:

15. Each R 2a and R 2b is, independently, 【Chemistry 15】 14. The compound of claim 13 selected from:

16. Each R 3 is, independently, 【Chemistry 16】 14. The compound of claim 13, wherein:

17. The compound is 【Chemistry 17-1】 【Chemistry 17-2】 and pharmaceutically acceptable salts thereof.

18. Compounds having formula 3 and pharmaceutically acceptable salts thereof: [Chemistry 18] n is 1 to 2; B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each X 1 , X 2 , X 3 , X 4 , and X 5 are independently C, N, or O; R 1 Halo, C 1~4 Alkyl, —NR x R y , -O(CH 2 ) 2 NR x R y , a 6-membered cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, a 6-membered heteroaryl, or a 5- to 10-membered cycloalkyl; R 1 When there are two groups, two of them have R 1 The groups optionally together form a 6-membered heteroaryl ring, and each (one or more) R 1 optionally, independently, one or more R a and each R 2 is halo or C 1~3 is an alkoxy, Each R 3 are independently H, oxo, C 1~3 haloalkyl, or hydroxyalkyl; One or more R 3 When is hydroxyalkyl, R 3 optionally, one or more of these together with C of formula 3 form a 4-membered heterocycle; Each R x and R y are independently H, C 1~3 alkyl, 6-membered aryl, or 6-membered heteroaryl; Each R x and R y optionally, independently, one or more R a is further substituted by R a is H, halo, oxo, cyano, C 1~3 haloalkyl, -NR'R', 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycle; One or more R a optionally, together form a 4- to 5-membered heterocycle, and R' is C 1~3 is alkyl, compound.

19. Each R 1 is, independently, 【Chemistry 19】 20. The compound of claim 18, selected from:

20. Each R 2 is, independently, 【Chemistry 20】 20. The compound of claim 18, selected from:

21. R 3 teeth, 【Chemistry 21】 20. The compound of claim 18, selected from:

22. The compound is 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 and pharmaceutically acceptable salts thereof.

23. Compounds having formula 3A and pharmaceutically acceptable salts thereof: 【Chemistry 23】 n is 1 to 2; B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each X 1 , X 2 , and X 3 are independently C, N, or O, and R 1 is C 1~3 is alkyl, R 1 optionally, one or more R a or R b is replaced by R 2 is H, halo, C 1~3 Haloalkyl, C 1~4 alkyl, 5- to 6-membered aryl, 5- to 6-membered cycloaryl, 5- to 6-membered heterocycle, 5- to 10-membered heteroaryl, 5- to 6-membered cycloalkyl; R 3 is H or halo, Each R 4 are independently H, oxo, C 1~3 haloalkyl, or hydroxyalkyl; R 4 When one or more of R is hydroxyalkyl, one or more of R 4 optionally forms a 4-membered heterocycle together with C of formula 3A; R 5 is halo or a 4- to 5-membered heterocycle; Each R 1 , R 2 , R 4 , and R 5 optionally, independently, up to two R a or R b is replaced by Each R a and R b are independently 1~3 Alkyl, C 1~3 haloalkyl, 5- to 6-membered heterocycle, 5- to 6-membered heteroaryl, -N / -NR'R'; R a and R b optionally, together form a 4- to 5-membered heterocycle; R a and R b is optionally further substituted independently by one or more R′ groups; R' is halo or C 1~3 is alkyl, compound.

24. R 1 teeth, 【Chemistry 24】 24. The compound of claim 23 selected from:

25. R 2 teeth, 【Chemistry 25】 24. The compound of claim 23 selected from:

26. R 3 is H or F.

27. R 4 teeth, 【Chemistry 26】 24. The compound of claim 23, wherein:

28. R 5 teeth, 【Chemistry 27】 24. The compound of claim 23, wherein:

29. The compound is 【Chemistry 28-1】 【Chemistry 28-2】 and pharmaceutically acceptable salts thereof.

30. Compounds having formula 3B and pharmaceutically acceptable salts thereof: 【Chemistry 29】 n is 1 to 2; B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl; each X 1 , X 2 , X 3 , and X 4 are independently C or N, R 1 is H, C 1~3 alkyl, or 5- to 6-membered aryl; R 1 optionally, one or more R a or R b is replaced by Each R 2a and R 2b are independently 1~4 alkyl or 5-6 membered heteroaryl; R 1 and R 2a or R 2b optionally, together form a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl, and any 5- to 6-membered aryl or 5- to 6-membered heteroaryl may optionally be joined by R a and R b is further substituted by Each R 3 are independently H, halo, or C 1~3 is an alkoxy, Each R 4 are independently H or oxo; Each R 5 are independently halo or a 4- to 5-membered heterocycle; Each R 1 , R 2a , R 2b , R 3 , and R 5 optionally, independently, R a and R b is further substituted by Each R a and R b are independently H, halo, oxo, cyano, or C 1~3 alkyl, 5- to 6-membered heteroaryl; compound.

31. R 1 teeth, 【Transformation 30】 31. The compound of claim 30, wherein:

32. Each R 2a and R 2b is, independently, 【Chemistry 31】 31. The compound of claim 30, wherein:

33. R 3 teeth, 【Chemistry 32】 31. The compound of claim 30, wherein:

34. R 4 is H or oxo.

35. Each R 5 is, independently, 【Transformation 33】 31. The compound of claim 30, wherein:

36. The compound is 【Transformation 34】 and pharmaceutically acceptable salts thereof.

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