Lipoxygenase inhibitors

Abstract

Various embodiments of the present disclosure relate to compounds of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA, Formula IIIB, and / or pharmaceutically acceptable salts thereof. The compounds may be useful for inhibiting lipoxygenase and / or treating related diseases. In some embodiments, the subject compounds are used to prepare compositions effective for treating neurodegenerative diseases.

Description

Background Art

[0001] Lipoxygenase (LOX) enzymes and their catalytic products, such as inflammatory leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), are implicated in the pathogenesis of a variety of human diseases, including inflammatory disorders, cancer, and neurodegenerative diseases. Lipoxygenase inhibitors are known to be useful in treating various LOX-related inflammatory diseases, including neurodegenerative diseases such as Alzheimer's disease. Summary of the Invention

[0002] The present invention is directed to overcoming the aforementioned challenges as well as other challenges associated with compounds, such as compounds that are LOX inhibitors.

[0003] Various embodiments of the present disclosure relate to compounds having Formula I and pharmaceutically acceptable salts thereof:

[0004]

[0005] wherein: n is 0-2, such that when n=0, there is a direct bond between B and the NH group and there is no R3, and when n=1 or 2, the carbons in these bonds are optionally substituted with one R3 group; A is a 6-membered heteroaryl or 6-membered aryl, wherein the 6-membered heteroaryl or 6-membered aryl is further independently substituted with 1-3 R1 groups; B is a 5-6-membered heterocycle, a 5-6-membered aryl, or a 5-6-membered cyclohexyl, wherein the 5-6-membered heterocycle, the 5-6-membered aryl, or the 5-6-membered cyclohexyl is unsubstituted or independently substituted with up to 3 R2 groups; X1, X2, X3, X4, X5, and X6 are each independently C, N, or O; each R1 independently includes: halogen, 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)2R x R y , -NHCH2CR x R y R z , 5-6 membered aryl, 5-10 membered heterocyclic, 5-10 membered heteroaryl, or 5-10 membered heterocyclic aryl, wherein 1-3 R1 groups are optionally further replaced by R a and / or R bsubstituted, wherein two R1 groups are optionally taken together to form a 5-6 membered heteroaryl, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl], wherein the 5-6 membered heteroaryl, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl] is optionally further substituted by 1-3 R a Each R2 independently includes: halogen, C 1-2 Methoxy, or -C(O)OR x wherein two R2 groups on adjacent atoms optionally together form a 5-6 membered aryl group, wherein the 5-6 membered aryl group is optionally further substituted by 1-3 R a R3 includes: C 1-3 Haloalkyl, or oxo; R x 、R y and R z Each independently includes: H, halogen, C 1-2 Alkyl, C 1-2 Alcohol, C 1-2 Alkoxy, C 1-2 Haloalkyl, or -NR a R b , where R x 、R y or R z Any two of which are optionally taken together to form a 4-6 membered heterocyclic ring, a 5-6 membered aryl group, wherein R x 、R y and R z Each optionally further represented by R a and R b Replacement; R a and R b Each independently includes: H, halogen, cyano, oxo, C 1-3 Alkyl, -C(O)OR′, C 1-3 haloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl, or 4-6 membered heterocycle, wherein R a and R b Each is optionally further substituted with R'; and R' is C 1-3 Alkyl, C 1-3 Haloalkyl, or C 5-6 Metaheteroaryl.

[0006] In some embodiments, each R1 is independently selected from:

[0007]

[0008]

[0009] In some embodiments, wherein each R2 is independently selected from: F, Cl and

[0010]

[0011] In some embodiments, the compound (compound of Formula I) is selected from:

[0012]

[0013]

[0014]

[0015]

[0016] and pharmaceutically acceptable salts thereof.

[0017] Various embodiments of the present disclosure relate to compounds having Formula II or pharmaceutically acceptable salts thereof:

[0018]

[0019] wherein A is a 6-membered heteroaryl or 6-membered aryl, wherein the 6-membered heteroaryl or 6-membered aryl is independently substituted by 1-3 R1 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 unsubstituted or independently substituted by up to 2 R2 groups; each X1, X2, X3, and X4 independently include: C, N, or O; each R1 independently includes: halogen, 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)2R 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, wherein two R1 groups are optionally taken together to form a 5-6 membered heteroaryl, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl], wherein the 5-6 membered heteroaryl, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl] is optionally further replaced by 1-3 R a wherein 1-3 R1 groups are each optionally and independently further substituted by Ra or R b Substituted; each R2 independently includes: halogen, C 1-2 Methoxy, or -C(O)OR x ; Each R x 、R y and R z independently include: H, halogen, C 1-2 Alkyl, C 1-2 Alcohol, C 1-2 Alkoxy, C 1-2 Haloalkyl, or -NR a R b , where R x 、R y or R z Two of the optionally together form a 4-6 membered heterocyclic ring, a 5-6 membered aryl group, wherein R x 、R y and R z Each optionally further represented by R a and R b Replacement; R a and R b Each independently includes: H, halogen, cyano, oxo, C 1-3 Alkyl, -C(O)OR′, C 1-3 haloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl, or 4-6 membered heterocycle, wherein R a and R b is optionally and independently further substituted with R'; and R' is C 1-3 Alkyl, C 1-3 a haloalkyl group, or a 5- to 6-membered heteroaryl group.

[0020] In some embodiments, each R1 is independently selected from:

[0021]

[0022]

[0023] In some embodiments, each R2 is independently selected from:

[0024] In some embodiments, the compound (compound of Formula II) is selected from:

[0025]

[0026]

[0027] and pharmaceutically acceptable salts thereof.

[0028] Various embodiments relate to compounds having Formula IIA and pharmaceutically acceptable salts thereof:

[0029]

[0030] Wherein: B is cyclohexyl, 6-membered heterocyclic ring, 6-membered aryl, or 6-membered heteroaryl; X1, X3 and X4 are each independently C, N, or O; 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 5-6 membered aryl group, wherein R1 is optionally further replaced by R a or R b Substituted; R2 is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 Haloalkoxy, wherein R1 and R2 optionally together form a 5-6 membered heterocyclic ring, wherein the 5-6 membered heterocyclic ring is optionally further replaced by R a or R b Replaced by, or replaced by R a and R b Both are substituted; R4 is halogen, or C 1-3 Alkyl; R x and R y Each is independently C 5-6 Heterocyclic ring, R a and R b Each is independently C 1-3 Alkyl or C 1-3 Haloalkyl, where R a and R b Optionally further substituted with an R' group; the R' group is a 5-membered heteroaryl group or a 5-6-membered heterocycle.

[0031] In some embodiments, R1 is selected from:

[0032]

[0033] In some embodiments, each R2 is independently selected from:

[0034]

[0035] In some embodiments, wherein the compound (compound of Formula IIA) is selected from:

[0036] and pharmaceutically acceptable salts thereof.

[0037] Various embodiments relate to compounds having Formula IIB and pharmaceutically acceptable salts thereof:

[0038]

[0039] Wherein: B is cyclohexyl, 6-membered heterocyclic ring, 6-membered aryl, or 6-membered heteroaryl; each X is independently C, N, or O; R1 is H, C 1-3 alkyl, 5-6 membered heterocyclic ring, 5-6 membered aryl, 5-6 membered heteroaryl, 5-10 membered heteroaryl, 5-10 membered heteroaryl, or -C(O)R x ; R 2a and R 2b Each independently is: H, C 1-3 Alkyl, 5-6 membered aryl, -NR x (CH2)2R y , -NR x (CH2)3R y , -NR x C(O)(CH2)2R y , -NH(CH2)2NR 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 , 5-10 membered ring heteroaryl, or -NR x R y ; R'2 is H or halogen; each R3 is H, halogen, 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 halogen; further, wherein R1 and R 2a or R 2bOptionally together form a 5-6 membered heterocyclic ring, the 5-6 membered heterocyclic ring is optionally further R a and / or R b substituted, and wherein R1, R 2a 、R 2b , R′2 and R3 are each optionally and independently replaced by one or more R a Replacement; R x and R y Independently H, C 1-4 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, -NR a R b , where R x and R y Each optionally together form a 4-5 membered heterocyclic ring, and wherein R x or R y Optionally and independently further R a and / or R b Replacement; R a and R b are independently H, halogen, oxo, cyano, C 1-3 Alkyl, C 1-3 Alcohol, C 1-3 Alkoxy, phenyl, -(CH2)2R', 5-6 membered heteroaryl, or 5-6 membered heterocycle; R' is a 5 membered heteroaryl.

[0040] In some embodiments, R1 is selected from:

[0041]

[0042] In some embodiments, R 2a and R 2b Each independently selected from:

[0043]

[0044] In some embodiments, each R3 is independently H,

[0045] In some embodiments, the compound (compound of Formula IIB) is selected from:

[0046] and pharmaceutically acceptable salts thereof.

[0047] Various embodiments relate to compounds having Formula III and pharmaceutically acceptable salts thereof:

[0048]

[0049] wherein n is 1-2; B is cyclohexyl, 6-membered heterocyclic ring, 6-membered aryl, or 6-membered heteroaryl; X1, X2, X3, X4, and X5 are each independently C, N, or O; R1 is halogen, C 1-4 Alkyl, -NR x 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, wherein, when there are two R1 groups, the two R1 groups are optionally taken together to form a 6-membered heteroaryl group; wherein each (one or more) R1 is optionally and independently further replaced by one or more R a Substituted; each R2 is halogen or C 1-3 Alkoxy; each R3 is independently H, oxo, C 1-3 Haloalkyl, or hydroxyalkyl, wherein when one or more R3 is hydroxyalkyl, one or more of R3 optionally together with C of formula III form a 4-membered heterocyclic ring; R x and R y Each independently is H, C 1-3 Alkyl, 6-membered aryl, or 6-membered heteroaryl, wherein R x and R y Each optionally and independently further represented by one or more R a Replacement; R a is halogen, oxo, cyano, C 1-3 haloalkyl, -NR'R', 5-6 membered aryl, 5-6 membered heteroaryl, or 5-6 membered heterocycle, and one or more R a Optionally together form a 4-5 membered heterocyclic ring; R' is C 1-3 alkyl.

[0050] In some embodiments, each R1 is independently selected from:

[0051]

[0052] In some embodiments, each R2 is independently: H,

[0053] In some embodiments, R3 is H, oxo, or

[0054] In some embodiments, the compound (compound of Formula III) is selected from:

[0055] and pharmaceutically acceptable salts thereof.

[0056] Various embodiments relate to compounds having Formula IIIA and pharmaceutically acceptable salts thereof:

[0057]

[0058] wherein n is 1-2; B is cyclohexyl, 6-membered heterocyclic ring, 6-membered aryl, or 6-membered heteroaryl; X1, X2, and X3 are each independently C, N, or O; R1 is C 1-3 Alkyl, R2 is H, halogen, C 1-3 Haloalkyl, C 1-4 alkyl, 5-6 membered aryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclic, 5-10 membered heteroaryl, 5-10 membered cycloaryl; R3 is H or halogen; each R4 is independently H, oxo, C 1-3 haloalkyl, or hydroxyalkyl, wherein when one or more of R4 is hydroxyalkyl, one or more R4 optionally together with C of formula IIIA form a 4-membered heterocyclic ring; R5 is halogen, or a 4-5 membered heterocyclic ring; R1, R2, R4 and R5 are each optionally and independently replaced by up to 2 R a or R b Replacement; R a and R b Each is independent of C 1-3 Alkyl, C 1-3 Halogenated alkyl, 5-6 membered heterocyclic ring, 5-6 membered heteroaryl, -N / -NR'R', wherein R a and R b Optionally, together they form a 4-5 membered heterocyclic ring, wherein R a and R b Optionally and independently further substituted with one or more R' groups; R' is halogen or C 1-3 alkyl.

[0059] In some embodiments, R1 is selected from:

[0060]

[0061] In some embodiments, R2 is selected from:

[0062]

[0063] In some embodiments, R3 is H or F.

[0064] In some embodiments, R4 is H,

[0065] In some embodiments, R5 is

[0066] In some embodiments, the compound (compound of Formula IIIA) is selected from:

[0067] and pharmaceutically acceptable salts thereof.

[0068] Various embodiments relate to compounds having Formula IIIB and pharmaceutically acceptable salts thereof:

[0069]

[0070] wherein n is 1-2; B is cyclohexyl, 6-membered heterocyclic, 6-membered aryl, or 6-membered heteroaryl; X1, X2, X3, and X4 are each independently C or N; R1 is H, C 1-3 Alkyl, or 5-6 membered aryl; wherein R1 is optionally replaced by one or more R a or R b Replacement; R 2a and R 2b Each is independently C 1-4 Alkyl, or 5-6 membered heteroaryl; R1 and R 2a or R 2b Optionally together form a 5-6 membered aryl or 5-6 membered heteroaryl, the optional 5-6 membered aryl or 5-6 membered heteroaryl optionally further substituted by R a and R b Substituted; each R3 is independently H, halogen, or C 1-3 Alkoxy; each R4 is independently H or oxo; each R5 is independently halogen or 4-5 membered heterocycle; R1, R 2a 、R 2b , R3 and R5 are each independently and optionally further R a and R b Replacement; R a and R b are each independently H, halogen, oxo, cyano, or C 1-3 Alkyl, 5-6 membered heteroaryl.

[0071] In some embodiments, R1 is:

[0072]

[0073] In some embodiments, R 2a and R 2b Each independently is: H,

[0074] In some embodiments, each R3 is independently H or

[0075] In some embodiments, R4 is: H or oxo.

[0076] In some embodiments, each R5 is independently:

[0077] In some embodiments, the compound (compound of Formula IIIB) is selected from:

[0078] and pharmaceutically acceptable salts and / or hydrates thereof.

[0079] Various embodiments relate to methods for inhibiting lipoxygenase in a cell identified as being in need of such methods, comprising contacting or administering to the cell a compound having a structure disclosed in any of the above claims (e.g., claim 1). In some embodiments, the cells are human cells in vivo or isolated human cells in vitro. In some embodiments, the cells are in situ as part of a human identified as being in need of lipoxygenase inhibition or having a disease associated with pathogenic lipoxygenase activity, wherein the disease is selected from an acute or chronic inflammatory disease or a neurodegenerative disease.

[0080] In some embodiments, the disease is: (i) an acute or chronic inflammatory disease, i.e., asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, or cardiovascular disease, or (ii) a neurodegenerative disease, i.e., age-related neurodegeneration, amyloid beta-related disease, Alzheimer's disease, ischemia-related disease, Creutzfeldt-Jakob disease / prion peptide toxicity, ALS, dementia, or Parkinson's disease.

[0081] In some embodiments, the method further comprises (i) measuring lipoxygenase activity in a sample from the human; (ii) determining the level of a lipoxygenase metabolite in the sample from the human; or (iii) determining that the human has the disease.

[0082] Various embodiments relate to a pharmaceutical composition comprising the compound for inhibiting lipoxygenase activity according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0083] Various embodiments relate to a pharmaceutical composition comprising the compound for inhibiting lipoxygenase activity according to claim 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0084] Various embodiments relate to compositions comprising a compound of Formula I described above and a second anti-neurodegenerative disease agent.

[0085] Various embodiments relate to methods of identifying lipoxygenase inhibitors comprising the step of screening compounds of formula I and / or claim 44 for lipoxygenase inhibitory activity.

[0086] Embodiments according to the present disclosure include all combinations of the specific embodiments described. From the detailed description provided below, other embodiments of the present invention and the entire scope of application will become apparent. However, it should be understood that the detailed description and specific embodiments, although indicating preferred embodiments of the present invention, are provided only by way of illustration, because various changes and modifications within the spirit and scope of the present invention will be apparent to those skilled in the art. All publications, patents, and patent applications cited herein, including citations therein, are incorporated herein by reference in their entirety for all purposes. DETAILED DESCRIPTION

[0087] The following description is made with the understanding that this disclosure is to be considered as an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. The headings used in this disclosure are provided for convenience and should not be construed as limiting the claims in any way. The embodiments described under any heading may be combined with the embodiments described under any other heading.

[0088] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, reference to "an assay" includes reference to one or more assays, and so forth.

[0089] The prefix "Cx-y" indicates that the following group has x (e.g., 1) to y (e.g., 6) carbon atoms. In certain groups (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.), one or more carbon atoms may be replaced by one or more heteroatoms or heteroatom groups. For example, "C 1-6 "alkyl" means that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "xy-membered" ring, where x and y are numerical ranges, such as "3-12 membered heterocyclyl", refers to a ring containing xy atoms (e.g., 3-12 atoms), up to half of which may be heteroatoms such as N, O, S, P, and the remaining atoms are carbon. In addition, 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 also be referred to as "alkylene" groups or "alkylene" groups, or alkylene groups, "arylene" or "arylene" groups or aryl groups, respectively.

[0090] "Alkyl" refers to any group derived from a straight-chain or branched saturated hydrocarbon. Alkyl includes, but is not limited to, methyl, ethyl, propyl, such as prop-1-yl, prop-2-yl (isopropyl), butyl, such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), pentyl, hexyl, octyl, decyl, etc. Unless otherwise specified, an alkyl group has 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 4 carbon atoms.

[0091] "Alkenyl" refers to any group derived from a straight or branched hydrocarbon having at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl or vinyl, propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless otherwise indicated, alkenyl groups have 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms.

[0092] "Alkynyl" refers to any group derived from a straight or branched hydrocarbon having at least one carbon-carbon triple bond, and includes groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-CH≡CH), propargyl (-CH2C≡CH), (E)-pent-3-ene-1-ynyl, and the like. Unless otherwise specified, alkynyl groups have 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms.

[0093] "Amino" refers to -NH2. Amino groups may also be substituted as described herein, for example, with alkyl, carbonyl, or other amino groups. The term "alkylamino" refers to an amino group substituted with one or two alkyl substituents (e.g., dimethylamino or propylamino).

[0094] "Aryl" refers to any group derived from one or more aromatic rings, i.e., a single aromatic ring, a bicyclic ring, or a polycyclic ring system. Aryl groups include, but are not limited to, groups derived from acenaphthene, anthracene, azulene, benzene, , cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, pyrene and the like.

[0095] "Arylalkyl" (also referred to as "aralkyl") refers to any combination of aryl and alkyl groups. Arylalkyl groups include, but are not limited to, those derived from benzyl, tolyl, dimethylphenyl, 2-phenyleth-1-yl, 2-naphthylmethyl, and the like. Arylalkyl groups contain from 6 to 30 carbon atoms, e.g., alkyl groups can contain from 1 to 10 carbon atoms and aryl groups can contain from 5 to 20 carbon atoms.

[0096] "Cycloaryl" refers to the combination of an aryl group and a ring. Some representative examples of cycloaryl include 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene, 3a,5,6,7-tetrahydro-4H-indene, and the like.

[0097] "Heterocyclic aryl" refers to a combination of aryl and heterocyclic groups. Some representative examples of heterocyclic aryl include 1,2,3,4-tetrahydroisoquinoline, isochromane, 1,3-dihydroisobenzofuran, isoindoline, and the like.

[0098] "Cycloalkyl" refers to cyclic alkyl and alkenyl groups. Cycloalkyl groups can have one or more rings and include fully saturated or partially unsaturated 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 includes C5-7 cycloalkenyl.

[0099] "Halo" and "halogen" refer to fluoro, chloro, bromo and iodo.

[0100] "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH2Cl, -CH2F, -CH2Br, -CFClBr, -CH2CH2Cl, -CH2CH2F, -CF3, -CH2CF3, -CH2CCl3, and the like, as well as alkyl groups, such as perfluoroalkyl groups, in which all hydrogen atoms are replaced by fluorine atoms.

[0101] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are each replaced by a hydroxy group. Examples include, but are not limited to, -CH2OH, -CH2CH2OH, -C(CH3)2OH, and the like.

[0102] "Halogenated 3-6 membered heterocyclic group" refers to a heterocyclic group substituted by at least one halogen atom on a carbon atom, and may include multiple halogen atoms, for example, 3,3-difluoroazetidinyl.

[0103] " heteroalkyl " refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatoms or heteroatom groups. 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)2-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. Heteroalkyl includes but is not limited to -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, -CH2NRCH3, -CH2OH, etc., where R is hydrogen, alkyl, aryl, aralkyl, heteroalkyl or heteroaryl, each of which can be optionally substituted. Heteroalkyl comprises 1 to 10 carbon atoms and up to three heteroatoms, for example 1 to 6 carbon atoms and 1 to 2 heteroatoms.

[0104] "Heteroaryl" refers to a monocyclic or polycyclic aromatic group in which one or more aromatic carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms or heteroatom groups, as defined above. Polycyclic ring systems are encompassed by heteroaryl and may be attached to the ring via a heteroatom or aromatic 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, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. The heteroaryl group can have 5-14 members, 5-10 members, or 5-6 members.

[0105] "Heterocycle," "heterocyclic," and "heterocyclyl" refer to a saturated or partially unsaturated non-aromatic ring or partially non-aromatic polycyclic ring system having 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-iminotetarahydro-2H-thiopyran 1-oxide, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocyclyl also includes partially unsaturated ring systems containing one or more double bonds, including fused ring systems having one aromatic ring and one non-aromatic ring, but excluding fully aromatic ring systems. Examples include dihydroquinolines such as 3,4-dihydroquinoline, dihydroisoquinolines such as 1,2-dihydroisoquinoline, dihydroimidazoles, tetrahydroimidazoles, etc., dihydroindoline, isoindoline, isoindolinone (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindoline]-3'-one, etc. The heterocyclic group may have 3-12 members, or 3-10 members, or 3-7 members, or 5-6 members.

[0106] "Hydroxy" and "hydroxy" are used interchangeably to refer to -OH. "Oxo" refers to ═O, or an oxide where an N-oxide or S-oxide exists. When tautomeric forms of a compound exist, hydroxy and oxo are interchangeable.

[0107] It will be understood that combinations of chemical groups can be used and that such combinations will be recognized by one of ordinary skill in the art. For example, the group "hydroxyalkyl" refers to a hydroxyl group attached to an alkyl group. Many such combinations can be readily envisioned. Other examples of substituent combinations used herein include: C1-6 alkylaminocarbonyl (e.g., CH3CH2NHC(O)—), C1-6 alkoxycarbonyl (e.g., CH3O—C(O)—), 5-7 membered heterocyclyl-C1-6 alkyl (e.g., piperazinyl-CH2—), C1-6 alkylsulfonyl-5-7 membered heterocyclyl (e.g., CH3S(O)2-morpholinyl-), 5-7 membered heterocyclyl C1-6 alkoxy ( For example, pyrrolidinyl-O—), 5-7 membered heterocyclyl, (4-7 membered heterocyclyl)-4-7 membered heterocyclyl (for example, oxetanyl-pyrrolidinyl-), C3-6 cycloalkylaminocarbonyl (for example, cyclopropyl-NH—C(O)—), 5-7 membered heterocyclyl-C2-6 alkynyl (for example, N-piperazinyl-CH2C≡CCH2—), and C6-10 arylaminocarbonyl (for example, phenyl-NH—C(O)—).

[0108] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound (or can be converted into a form having the desired pharmacological activity of the parent compound). These 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, p-toluenesulfonic acid, trimethylacetic acid, etc., as well as salts formed when the acidic proton present in the parent compound is replaced by any metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or salts formed by coordination with an organic base such as diethanolamine, triethanolamine, N-methylglucamine, etc. This definition also includes ammonium salts and substituted ammonium salts or quaternary ammonium salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, both of which are incorporated herein by reference.

[0109] As used herein and in the claims, "hydrogen" and "H," "oxygen" and "O," "carbon" and "C," and "nitrogen" and "N" are used interchangeably and each refers to a hydrogen atom, an oxygen atom, a carbon atom, and / or a nitrogen atom, respectively. As used herein and in the claims, the rings of various compounds are sometimes referred to interchangeably as "Ring A" or "A" and "Ring B" or "B," both of which refer to the specifically mentioned rings, respectively. Similarly, as used herein and in the claims, the various groups of the compounds are sometimes referred to interchangeably, with or without an "atom" or "radical" at the end, for example, "R1" and "R1 radical," both of which refer to the specifically mentioned atom or chemical group, respectively.

[0110] "Subject" and "subjects" refer to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cows, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys), etc.

[0111] "Management" and "treatment" of a disease include the following:

[0112] (1) prevent or reduce the risk of developing the disease, even if clinical symptoms of the disease do not develop in a subject who may be exposed to or susceptible to the disease but who has not yet experienced or displayed symptoms of the disease,

[0113] (2) inhibiting the disease, i.e., arresting or slowing the progression of the disease or its clinical symptoms, and / or

[0114] (3) Alleviate the disease, that is, reduce the disease or its clinical symptoms.

[0115] An "effective amount" refers to an amount effective to elicit a desired biological, clinical, or medical response, and includes an amount of a compound that, when administered to a subject to treat a disease, is sufficient to achieve such treatment. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. An effective amount may encompass a range of amounts.

[0116] The compounds of the present invention include solvates, hydrates, tautomers, stereoisomers and salt forms thereof.

[0117] The pharmaceutical compositions of the compounds of the disclosed formula can be administered in single or multiple doses by any acceptable mode of administration for similarly effective pharmaceuticals, such as those described in the patents and patent applications incorporated by reference, including rectal, oral, intranasal and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or by impregnation or coating devices, such as stents, or arterial insertion cylindrical polymers. In one aspect, the compounds described herein can be administered orally. Oral administration can be carried out, for example, by capsules or enteric-coated tablets.

[0118] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may also include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0119] In some embodiments, the compounds of the present disclosure are compounds of Formula I:

[0120]

[0121] wherein n is 0, 1, or 2. When n is 0, this indicates that there is a direct bond between B and the NH group attached to ring A (as shown above), and R3 is absent. When n is 1 or 2, the R3 group may be substituted by any CH atom. For example, one or two CH groups may each independently be unsubstituted or substituted by an R3 group.

[0122] 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 one, two, or three R1 groups, wherein the R1 groups may be the same or different. In some embodiments, Ring A is a 6-membered aryl substituted with one, two, or three R1 groups, wherein the R1 groups may be the same or different. In some embodiments where Ring A is a heteroaryl, X1, X2, and X3 are independently C, N, or O.

[0123] In some embodiments, Ring B can be a 5-6 membered heterocyclic ring, a 5-6 membered aryl group, or a 5-6 membered cyclohexyl group. In some embodiments, Ring B can be a 5-6 membered heterocyclic ring independently substituted with up to three R2 groups. In some embodiments, Ring B can be a 5-6 membered aryl group independently substituted with up to three R2 groups. In some embodiments, Ring B can be a 5-6 membered cyclohexyl group independently substituted with up to three R2 groups. In some embodiments, when Ring B is a 5-6 membered aryl group, X4, X5, and X6 are all carbon. In some embodiments, when Ring B is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaryl group, each of X4, X5, and X6 can independently be C, N, or O.

[0124] In some embodiments, R1 can be halogen, 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)2R x R y , -NHCH2CR x R y R z , 5-6 membered aryl, 5-10 membered heterocyclic, 5-10 membered heteroaryl, or 5-10 membered heterocyclic aryl. As used herein, heterocyclic aryl refers to two rings, such as a heterocyclic ring fused to an aryl. In some embodiments, R1 can be further independently replaced by 1, 2 or 3 R a or R b In some embodiments, two R1 groups can be combined to 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, when two R1 groups are combined to form a 5-6 membered heteroaryl, a 5-6 membered heterocycle, a 5-6 membered cycloalkyl, or a 5-6 membered aryl, the resulting 5-6 membered heteroaryl, 5-6 membered heterocycle, 5-6 membered cycloalkyl, or 5-6 membered aryl can be further replaced by one, two, or three R a Base substitution.

[0125] In some embodiments, R1 is:

[0126]

[0127]

[0128] In some embodiments, each R2 can independently be a halogen atom, C 1-2 Methoxy, or -C(O)OR x In some embodiments, two R2 groups on adjacent atoms can form a 5-6 membered aromatic ring. In some embodiments, two R2 groups on adjacent atoms can form a 5-6 membered aromatic ring. The 5-6 membered aromatic ring can be independently replaced by one, two or three R a The group may be substituted or unsubstituted.

[0129] In some embodiments, R2 is F, Cl or H.

[0130] In some embodiments, R3 is C 1-3 Haloalkyl or oxo.

[0131] In some embodiments, R x 、R y and R z can be independently hydrogen, halogen, C 1-2 Alkyl, C 1-2 Alcohol, C1-2 Alkoxy, C 1-2 Haloalkyl, or -NR a R b In some embodiments, R x 、R y and R z may be independently cyano, oxygen or oxo, C 1-3 Alkyl, -C(O)OR′, C 1-3 In some embodiments, R x 、R y and R z Any two of can together form a 4-6 membered heterocyclic ring or a 5-6 membered aryl group. x 、R y and R z Can be further R a and / or R b replace.

[0132] In some embodiments, R a and R b are independently a hydrogen atom, a halogen atom, a cyano group, an oxygen atom, C 1-3 Alkyl, -C(O)OR′, C 1-3 In some embodiments, R a and / or R b may be further independently substituted with R' groups.

[0133] In some embodiments, R' can be C 1-3 Alkyl, C 1-3 a haloalkyl group, or a 5- to 6-membered heteroaryl group.

[0134] In some embodiments, the disclosed compounds are pharmaceutically acceptable salts or pharmaceutically acceptable hydrates of Formula I.

[0135] In some embodiments, the compound having the structure of Formula (I) is selected from:

[0136]

[0137]

[0138]

[0139]

[0140] and pharmaceutically acceptable salts or hydrates thereof.

[0141] In some embodiments, the disclosed compounds have a structure corresponding to Formula II:

[0142]

[0143] In some embodiments of Formula II, Ring A is a 6-membered heteroaryl or 6-membered aryl group. In some embodiments of Formula II, Ring A is a 6-membered heteroaryl or 6-membered aryl ring, wherein Ring A is independently substituted with one, two, or three R1 groups. In some embodiments of Formula II, Ring A is an unsubstituted 6-membered heteroaryl or unsubstituted 6-membered aryl group. In embodiments of Ring A, when Ring A is a 6-membered heteroaryl group, X1, X2, and X3 are independently C, N, or O.

[0144] In some embodiments of Formula II, Ring B is a 6-membered heterocyclic ring, a 6-membered aryl ring, or a 6-membered cyclohexyl ring. In some embodiments of Formula II, Ring B is a 6-membered heterocyclic ring, a 6-membered aryl ring, or a 6-membered cyclohexyl ring, wherein Ring B is unsubstituted. In some embodiments of Formula II, Ring B is a 6-membered heterocyclic ring, a 6-membered aryl ring, or a 6-membered cyclohexyl ring, wherein Ring B is independently substituted with up to two R2 groups. Additionally, in embodiments of Ring B, when Ring B is a 6-membered heterocyclic ring, X4 can be C, N, or O.

[0145] In some embodiments of Formula II, R1 can be 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)2R 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 can be combined to 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 can be combined to form a 5-6 membered heteroaryl, a 5-6 membered heterocycle, a 5-6 membered cycloalkyl, or a 5-6 membered aryl, wherein the 5-6 membered heteroaryl, the 5-6 membered heterocycle, the 5-6 membered cycloalkyl, or the 5-6 membered aryl can be further replaced by 1 to 3 R aIn some embodiments, each of the 1 to 3 R1 groups can be independently further replaced by 1 to 3 R a and / or 1 to 3 R b Base substitution.

[0146] In some embodiments of Formula II, R1 is:

[0147]

[0148] In some embodiments of Formula II, each R2 can independently be a halogen atom, C 1-2 Methoxy, or -C(O)OR x .

[0149] In some embodiments of Formula II, each R2 is independently

[0150] In some embodiments of Formula II, R1 and / or R2 may contain one or more R x 、R y and / or R z Base, where each R x 、R y and R z The groups can each independently be a hydrogen atom, a halogen atom, a 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 II, when two R x 、R y or R z When present, R x 、R y or R z Any two of can together form a 4-6 membered heterocyclic ring or a 5-6 membered aromatic ring. In some embodiments of Formula II, R x 、R y and R z Each can be further R a Base or R a and R b Base substitution.

[0151] In some embodiments of Formula II, R a and R b can be independently a hydrogen atom, a halogen atom, a cyano group, an oxygen atom, C 1-3 Alkyl, -C(O)OR′, C 1-3 haloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some embodiments of Formula II, when Ra and / or R b Each is independently C 1-3 Alkyl, -C(O)OR′, C 1-3 When R is a halogenated alkyl, a 5-6 membered aryl, a 5-6 membered heteroaryl, or a 4-6 membered heterocycle, a and / or R b It may be further substituted with an R' group. In some embodiments of Formula II, R' may be C 1-3 Alkyl, C 1-3 In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of Formula II.

[0152] In some embodiments, exemplary compounds of Formula II have the following structure:

[0153]

[0154]

[0155] and pharmaceutically acceptable salts or hydrates thereof.

[0156] In some embodiments, the disclosed compounds have a structure corresponding to Formula IIA:

[0157]

[0158] In some embodiments, Ring B can be a cyclohexyl group, a 6-membered heterocycle, a 6-membered aryl group, or a 6-membered heteroaryl group. In some embodiments of Formula IIA, when Ring B is a cyclohexyl group, a 6-membered heterocycle, or a 6-membered heteroaryl group, X4 can be C, N, or O. In some embodiments of Formula IIA, when Ring B is a cyclohexyl group, a 6-membered heterocycle, or a 6-membered heteroaryl group, Ring B can be independently substituted with up to two R4 groups.

[0159] In some embodiments, X1 and X3 of Ring A can independently be C, N or O.

[0160] In some embodiments, R1 can be -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 5-6 membered aromatic ring. In some embodiments, when R1 is substituted, R1 may be replaced by R a and / or R b In some embodiments, R2 can be a hydrogen atom, a halogen atom, a C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 In some embodiments, R x and R y Can be C independently 5-6 In some embodiments, R1 and R2 can form a 5-6 membered heterocyclic ring. In some embodiments, when the corresponding R1 and the corresponding R2 form a 5-6 membered heterocyclic ring, and / or the 5-6 membered heterocyclic ring can be further replaced by R a and / or R b In some embodiments, R3 is a hydrogen atom or a halogen atom. In some embodiments, R4 can be a halogen atom or a C 1-3 In some embodiments, R1, R2, R3 and / or R4 can be further independently replaced by one or more R a and / or R b In some embodiments, R a and R b Can be C independently 1-3 Alkyl or C 1-3 In some embodiments, R a and R b It may be further substituted by an R' group. 1-3 Alkyl and C 1-3 In some embodiments, R' can be a 5-membered heteroaryl or a 5-6-membered heterocycle. In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of Formula IIA.

[0161] In some embodiments of Formula IIA, R1 is selected from:

[0162]

[0163] In some embodiments of Formula IIA, R2 is selected from:

[0164]

[0165] In some embodiments, the compound of Formula IIA has the following structure:

[0166] and pharmaceutically acceptable salts or hydrates thereof.

[0167] In some embodiments, the disclosed compounds have a structure corresponding to Formula IIB:

[0168]

[0169] Wherein, in some embodiments, Ring B is cyclohexyl, 6-membered heterocycle, 6-membered aryl, or 6-membered heteroaryl. In some embodiments, Ring B is cyclohexyl, 6-membered heterocycle, 6-membered aryl, or 6-membered heteroaryl, wherein the cyclohexyl, 6-membered heterocycle, 6-membered aryl, or 6-membered heteroaryl can be further independently substituted with up to two R4 groups.

[0170] In some embodiments, when Ring B is a 6-membered heterocycle or a 6-membered heteroaryl, X is N or O.

[0171] In some embodiments, each X of Ring A and / or Ring B can independently be C, N, or O. In some embodiments, Ring A can be independently substituted with R1, R'2, and / or one or two R3.

[0172] In some embodiments, R1 can be a hydrogen atom, C 1-3 alkyl, 5-6 membered heterocyclic ring, 5-6 membered aryl, 5-6 membered heteroaryl, 5-10 membered heteroaryl, 5-10 membered heteroaryl, or -C(O)R x .

[0173] In some embodiments, R 2a and R 2b can be 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 y , -NH(CH2)2NR 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 , 5-10 membered ring heteroaryl, or -NR x R y .

[0174] In some embodiments, R'2 can be a hydrogen atom or a halogen atom.

[0175] In some embodiments, each R3 can be independently a hydrogen atom, a halogen atom, a 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 .

[0176] In some embodiments, R4 is a halogen atom.

[0177] In some embodiments, R1 and R 2a or R 2b They can form a 5-6 membered heterocyclic ring.

[0178] In some embodiments, R1 and R 2a or R 2b can form a 5-6 membered heterocyclic ring, which can be further replaced by one or more R a and / or R b Base substitution.

[0179] In some embodiments, R1, R'2, R 2a 、R 2b and / or R3 may each be further independently replaced by one or more R a Base substitution.

[0180] In some embodiments, R x and R y can be independently a hydrogen atom, C 1-4 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, or -NR a R b In some embodiments, R x and R y can form a 4-5 membered heterocyclic ring and / or wherein R x and R y The resulting 4-5 membered heterocyclic ring can be a or R b replace.

[0181] In some embodiments, R a and R b are independently a hydrogen atom, a halogen atom, an oxygen atom, a cyano group, a C 1-3 Alkyl, C 1-3 Alcohol, C 1-3Alkoxy, phenyl, -(CH2)2R', 5-6 membered heteroaryl, or 5-6 membered heterocyclic ring.

[0182] In some embodiments, R' is a 5-membered heteroaryl.

[0183] In some embodiments, the disclosed compounds are pharmaceutically acceptable salts or hydrates of Formula IIB.

[0184] In some embodiments of Formula IIB, R1 is:

[0185]

[0186] In some embodiments of Formula IIB, R 2a and R 2b Each independently selected from:

[0187]

[0188] In some embodiments of Formula IIB, R3 is H,

[0189] In some embodiments of Formula IIB, the compound has the structure:

[0190]

[0191] and pharmaceutically acceptable salts or hydrates thereof.

[0192] In some embodiments, the disclosed compounds have a structure corresponding to Formula III:

[0193]

[0194] In some embodiments, n is 1-2.

[0195] In some embodiments, X1, X2, X3, and X4 of Ring A can each independently be C, N, or O.

[0196] In some embodiments, Ring A can be independently substituted with one, two, or three R1 groups.

[0197] In some embodiments, Ring B can be cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl.

[0198] In some embodiments, when Ring B is a 6-membered heterocycle or a 6-membered heteroaryl, X5 can be N or O. In some embodiments, X5 can be C.

[0199] In some embodiments, R1 can be a halogen atom, C 1-4 Alkyl, -NR x 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.

[0200] In some embodiments, when there are two R1 groups, the two R1 groups can be combined to form a 6-membered heteroaryl group. In some embodiments, when there are two R1 groups, the two R1 groups can be combined to form a 6-membered heteroaryl group, and either of the two R1 groups can be further replaced by one or more R a Base substitution.

[0201] In some embodiments, each R2 is a halogen atom or C 1-3 Alkoxy.

[0202] In some embodiments, R3 is or each R3 is independently a hydrogen atom, an oxygen atom, C 1-3 In some embodiments, when one or more R3 is a hydroxyalkyl group, one or more of R3 are optionally taken together with C of formula III to form a 4-membered heterocyclic ring.

[0203] In some embodiments, R x and R y can be independently a hydrogen atom, C 1-3 In some embodiments, when R x or R y It is C 1-3 When R is an alkyl group, a 6-membered aryl group, or a 6-membered heteroaryl group, x and / or R y Can be further replaced by one or more R a replace.

[0204] In some embodiments, R a It is a halogen atom, an oxygen atom, a cyano group, a C 1-3 In some embodiments, one or more R a They can form a 4-5 membered heterocyclic ring.

[0205] In some embodiments, R' is C 1-3 In some embodiments, the disclosed compounds are pharmaceutically acceptable salts or hydrates of Formula III.

[0206] In some embodiments, Formula III is:

[0207]

[0208] In some embodiments of Formula III, R1 is:

[0209]

[0210]

[0211] In some embodiments of Formula III, R2 is: H,

[0212] In some embodiments of Formula III, R3 is: H, oxo, or

[0213] In some embodiments of Formula III, the compound has the structure:

[0214]

[0215] and pharmaceutically acceptable salts or hydrates thereof.

[0216] In some embodiments, the compound of the present disclosure is a compound of Formula IIIA:

[0217]

[0218] In some embodiments, n is 1-2.

[0219] In some embodiments, Ring B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl.

[0220] In some embodiments, X1, X2, and X3 can each independently be C, N, or O.

[0221] In some embodiments, R1 is C 1-3 In some embodiments, R1 is further replaced by one or more R a or R b Substituted C 1-3 alkyl.

[0222] In some embodiments, R2 can be a hydrogen atom, a halogen atom, a C 1-3 Haloalkyl, C 1-4 In some embodiments, R3 is a hydrogen atom or a halogen atom. In some embodiments, R4 can be or each R4 can independently be a hydrogen atom, an oxygen atom, a C 1-3In some embodiments, when one or more of R4 is hydroxyalkyl, one or more R4 optionally forms a 4-membered heterocyclic ring together with C of formula IIIA. In some embodiments, R5 can be a halogen atom or a 4-5 membered heterocyclic ring. In some embodiments, R1, R2, R4 and / or R5 can be replaced by up to two R a and / or R b substituted with R a and / or R b The base is C 1-3 Alkyl, C 1-3 In some embodiments, when R1, R2, R4 and / or R5 are replaced by R a and / or R b When the group is substituted, R a and R b Can form a 4-5 membered heterocyclic ring together. a and R b Each of the R' groups may be further independently substituted with one or more R' groups, wherein if there is more than one R' group, the R' groups may be the same or different. In some embodiments, R' may be a halogen atom or a C 1-3 In some embodiments, the disclosed compounds are pharmaceutically acceptable salts or hydrates of Formula IIIA.

[0223] In some embodiments of Formula IIIA, R1 is:

[0224]

[0225] In some embodiments of Formula IIIA, R2 is:

[0226]

[0227] In some embodiments of Formula IIIA, R3 and R5 are independently H or F atoms. In some embodiments, R5 is a F atom. In some embodiments of Formula IIIA, R4 is H,

[0228] In some embodiments, Formula IIIA is:

[0229]

[0230] In some embodiments of Formula IIIA, the compound has the structure:

[0231] and pharmaceutically acceptable salts or hydrates thereof.

[0232] In some embodiments, the compound of the present disclosure is a compound of Formula IIIB:

[0233]

[0234] In some embodiments, n is 1-2.

[0235] In some embodiments, ring B can be cyclohexyl, 6-membered heterocyclic ring, 6-membered aryl, or 6-membered heteroaryl. In some embodiments, ring B can be cyclohexyl, 6-membered heterocyclic ring, 6-membered aryl, or 6-membered heteroaryl, wherein ring B can be further substituted with up to two R5 groups.

[0236] In some embodiments, X1, X2, X3, and X4 can each independently be C or N.

[0237] In some embodiments, R1 is a hydrogen atom, C 1-3 In some embodiments, R1 is a hydrogen atom, C 1-3 alkyl, or 5-6 membered aryl, and wherein when R1 is C 1-3 When the group is an alkyl or 5-6 membered aryl group, R1 may be replaced by one or more R a and / or R b replace.

[0238] In some embodiments, R 2a and R 2b Can be C independently 1-4 In some embodiments, R1 and R 2a or R 2b can optionally be taken together to form a 5-6 membered aryl or 5-6 membered heteroaryl group, the optional 5-6 membered aryl or 5-6 membered heteroaryl group being optionally further substituted by R a and R b replace.

[0239] In some embodiments, R3 is a hydrogen atom, a halogen atom, or C 1-3 Alkoxy.

[0240] In some embodiments, R4 is or each R4 is independently a hydrogen atom or an oxygen atom. In some embodiments, R5 is a halogen atom or a 4-5 membered heterocyclic ring. 2a 、R 2b , R3 and R5 can each be independently replaced by up to two R a or R b Substituted, where R a and R bIt can be a halogen atom, oxygen atom, cyano group, C 1-3 In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of Formula IIIB.

[0241] In some embodiments of Formula IIIB, R1 is H,

[0242] In some embodiments of Formula IIIB, R 2a and R 2b Each independently is H,

[0243] In some embodiments of Formula IIIB, each R3 is H or

[0244] In some embodiments of Formula IIIB, R4 is hydrogen or oxygen. In some embodiments of Formula IIIB, R5 is H, In some embodiments of Formula IIIB, R5 is

[0245] In some embodiments, Formula IIIB is:

[0246]

[0247] In some embodiments of Formula IIIB, the compound has the structure:

[0248] and pharmaceutically acceptable salts and / or hydrates thereof.

[0249] Some embodiments are methods of inhibiting lipoxygenase in a cell identified as being in need thereof, comprising contacting the cell with a compound having a structure disclosed in any of the compounds described above (or administering it to the cell), wherein the cell is a human cell, either in vivo or isolated in vitro. In some embodiments, the cell is in situ as part of a human identified as being in need of lipoxygenase inhibition or having a disease associated with pathogenic lipoxygenase activity, wherein the disease is selected from an acute or chronic inflammatory disease or a neurodegenerative disease. Some methods further comprise: (i) measuring lipoxygenase activity in a sample from the human; (ii) determining the level of a lipoxygenase metabolite in a sample from the human; or (iii) determining that the human has the disease. In some methods, the disease is: (i) an acute or chronic inflammatory disease, i.e., asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, or cardiovascular disease, or (ii) a neurodegenerative disease, i.e., age-related neurodegeneration, amyloid beta-related disease, Alzheimer's disease, ischemia-related disease, Creutzfeldt-Jakob disease / prion peptide toxicity, ALS, dementia, or Parkinson's disease.

[0250] Further contemplated are pharmaceutical compositions comprising a compound described above for inhibiting lipoxygenase activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further contemplated are pharmaceutical compositions comprising multiple compounds described above for inhibiting lipoxygenase activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further contemplated are compositions comprising a compound of Formula I described above and a second anti-neurodegenerative disease agent. Further contemplated are methods for identifying lipoxygenase inhibitors comprising the step of screening one or more of the above-described compounds for lipoxygenase inhibitory activity.

[0251] As described in more detail herein, the subject compounds can be used in pharmaceutically acceptable alternative forms, such as pharmaceutically acceptable salts, prodrugs (e.g., sulfamates, phosphates, esters, ethers, amides, etc.). Unless otherwise indicated, all references herein to compounds of formula (I) are intended to include such alternative forms. Pharmaceutically acceptable and pharmaceutically active combinations of these forms, such as salts of prodrugs, are possible and also within the scope of this disclosure. Some examples of salts and prodrugs are provided herein.

[0252] In some embodiments, the subject compounds are used to prepare compositions effective for treating neurodegenerative diseases (also referred to herein as "neurodegenerative disorders"). Examples of neurodegenerative diseases include neuroinflammatory-related neurodegenerative diseases, Alzheimer's disease, ischemia-related diseases, Creutzfeldt-Jakob disease / prion peptide toxicity, ALS, dementia, and Parkinson's disease. In some embodiments, the treatment of neurodegenerative diseases comprises administering a preparation containing the subject compounds. As described in more detail herein, the composition may comprise one or more active agents and one or more pharmaceutically acceptable additives. In addition, the composition may be formulated into any suitable dosage form.

[0253] In some embodiments, the subject compositions comprise a compound according to formula (I) as the sole active agent; such formulations may include pharmaceutically inactive components, such as carriers and the like.

[0254] In some embodiments, the subject compound is administered in combination with one or more additional anti-neurodegenerative disease drugs. Additional drugs may be present in a single formulation together with the subject compound and are therefore administered simultaneously. Alternatively, additional drugs may be in a separate formulation and may be administered according to a different regimen from that of the formulation containing the subject compound. In such an embodiment, the two regimens may be related; for example, the second formulation is administered together with the first formulation, or the second formulation is administered just before the first formulation is administered, or the second formulation is administered immediately after the first formulation is administered. Examples of other anti-neurodegenerative disease drugs include acetylcholinesterase inhibitors (e.g., tacrine, rivastigmine, galantamine, donepezil, etc.), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), hyperzine A, latrepirdine, hypothalamic proline-rich peptide 1 (PRP-1), etc.

[0255] The subject compound can be administered as a free base, or in the form of a salt, ester, amide, prodrug, active metabolite, analogue, etc., provided that the salt, prodrug, active metabolite or analogue is pharmaceutically acceptable and, in the case of this invention, pharmacologically active. Salts, esters, amides, prodrugs, active metabolites, analogues and other derivatives of activating agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry, and are, for example, described in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th edition (New York: Wiley-Interscience, 2001) and Green, Protective Groups in Organic Synthesis, 3rd edition (New York: Wiley-Interscience, 1999).

[0256] Pharmaceutically acceptable salts can be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or a combination thereof.

[0257] Suitable organic acids for preparing acid addition salts include, for example, C1-C6 alkyl and C6-C6 12 Aryl carboxylic acids, dicarboxylic acids, and tricarboxylic acids, such as 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 and terephthalic acid, and aryl and alkyl sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid and 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 and phosphoric acid, etc. Acid addition salts can be converted back to the free base by treatment with a suitable base.

[0258] Suitable organic bases for preparing base addition salts include, for example, primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, N,N-dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucosamine, glucosamine, histidine and polyamine resins, cyclic amines, such as caffeine, N-ethylmorpholine, N-ethylpiperidine and purines, and amine salts such as betaine, choline and procaine. Suitable inorganic bases for preparing base addition salts include, for example, salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium or zinc, such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate and potassium carbonate. The base addition salts can be converted back into the free acids by treatment with a suitable acid.

[0259] Prodrugs and active metabolites can also be prepared using technology known to those skilled in the art or described in the relevant literature. Prodrugs are usually prepared by covalently linking a portion that causes the compound to be therapeutically inactive before being modified by individual metabolic systems. For example, according to the compound of Formula I, it can be a pharmaceutically acceptable prodrug form, for example a sulfamate prodrug.

[0260] Other derivatives and analogs of the active agents can be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry or can be deduced by reference to the relevant literature.

[0261] Any compound of the present disclosure can be the active agent in the subject formulation. The formulation containing the disclosed compound can include 1, 2, 3 or more subject compounds, and can also include one or more additional active agents, 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 a free base) and its salts, prodrugs, etc.

[0262] Based on the gross weight of the preparation, the amount of the active agent in the preparation is generally in the range of about 0.05 wt % to about 95 wt %. For example, the amount of the active agent can be about 0.05 wt % to about 50 wt %, or about 0.1 wt % to about 25 wt %. Alternatively, the amount of the active agent in the preparation can be measured to achieve the desired dosage.

[0263] Formulations containing the subject compounds may be presented in unit-dose form or in multi-dose containers, with an optional preservative to increase shelf life.

[0264] The compositions of the present disclosure can be applied to the patient by any suitable method. In general, both systemic and local administration methods are acceptable. It will be apparent to those skilled in the art that the selection of administration method will be affected by many factors, such as the condition being treated, the frequency of administration, the dosage level, and the patient's needs. For example, certain methods may be more suitable for rapidly delivering a high dose of an active agent, while other methods may be more suitable for slowly and stably delivering an active agent. Examples of administration methods suitable for delivering the disclosed compounds include parenteral and transmembrane absorption (including delivery by the digestive tract and respiratory tract). Preparations suitable for delivery by these methods are well known in the art.

[0265] For example, formulations containing the disclosed compounds can be administered parenterally, for example, by intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and / or continuous infusion. Typically, liquid formulations are employed for parenteral administration.

[0266] The composition can also be administered through the digestive tract, including oral and rectal administration. Examples of formulations suitable for administration through the digestive tract include tablets, capsules, lozenges, chewing gums, aqueous solutions and suppositories.

[0267] Preparations can also be administered through mucosal administration. Transmucosal delivery includes delivery through the oral cavity (including buccal and sublingual), nasal, vaginal and rectal mucosa. Preparations suitable for transmucosal delivery are well known in the art and include tablets, chewing gums, mouthwashes, lozenges, suppositories, gels, creams, liquids and pastes.

[0268] The formulations can also be administered transdermally. Transdermal delivery can be accomplished using, for example, topical creams, liquids, pastes, gels, and the like, as well as pharmaceutical preparations commonly known as transdermal "patches."

[0269] The formulation can also be administered through the respiratory tract. Pulmonary delivery can be accomplished by oral or nasal inhalation using aerosols, dry powders, liquid formulations, etc. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms.

[0270] Liquid preparations include solutions, suspensions and emulsions. For example, a solution can be an aqueous solution of an active agent and can include one or more of propylene glycol, polyethylene glycol, etc. An aqueous suspension can be prepared by dispersing the finely divided active agent in water with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other suspending agents known. Also included are preparations of the solid form intended to be converted into a liquid form shortly before use.

[0271] Tablets and lozenges may contain, for example, a flavored base such as compressed lactose, sucrose and acacia or tragacanth, and an effective amount of the active agent. Troches typically contain the active agent in an inert base such as gelatin and glycerin or sucrose and acacia.

[0272] The subject compounds can inhibit one or more lipoxygenase enzymes, for example, by at least 50%, or at least 75%, or at least 85%, or at least 95%, or at least 98%. In some embodiments, the compounds are selective inhibitors and are inhibitors of a subset of the LOX enzyme family. In some embodiments, the subject compounds can inhibit 5-LOX, 12-LOX, or 15-LOX. In some embodiments, the subject compounds can inhibit various combinations of 5-LOX, 12-LOX, and 15-LOX, for example, 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.

[0273] The subject compounds are useful in the treatment of diseases associated with pathogenic lipoxygenase activity, particularly acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, cardiovascular disease, neurodegenerative diseases, such as age-related neurodegeneration, neuroinflammatory-related diseases, Alzheimer's disease, ischemia-related diseases, Creutzfeldt-Jakob disease / prion peptide toxicity, ALS, dementia, and Parkinson's disease.

[0274] For example, the method may include administering the subject compound to a patient in need thereof (e.g., a patient suffering from a neurodegenerative disease such as Alzheimer's disease, or a patient at risk of suffering from such a disease, or a patient exhibiting symptoms of such a disease, etc.). In some embodiments, the subject compound is used in a method for reducing or eliminating the severity of symptoms associated with the subject disease. For example, the method may involve contacting a nervous system cell or a cell located in the nervous system, or contacting a tissue associated with the nervous system, and such contact results in one or more of the following: inhibiting further neurodegeneration; inhibiting abnormal cell growth and development; inhibiting the growth of non-cellular objects in the nervous system; reducing neuroinflammation; reducing the severity of symptoms associated with a neurodegenerative disease, etc.

[0275] In some embodiments, the subject compound is used to prepare a composition effective for treating a subject disease. As described in more detail herein, the composition may comprise one or more active agents and one or more pharmaceutically acceptable additives. In addition, the composition may be formulated into any suitable dosage form.

[0276] In some embodiments, treatment of the subject disease comprises administering a formulation containing the subject compound. As described in more detail herein, such formulations may include any of a variety of additives and / or additional active agents, and such formulations may be prepared in any of a variety of dosage forms. In some embodiments, treatment of the subject disease with the compound involves determining that the subject has the subject disease associated with pathogenic lipoxygenase activity. This determination may be made by any means appropriate to the particular circumstances, including blood tests and imaging tests.

[0277] In some embodiments, the methods comprise measuring lipoxygenase activity (e.g., 5-LOX, 12-LOX, or 15-LOX, and / or various combinations thereof) in a patient before treatment with a subject compound, after treatment with a subject compound, or before and after treatment. In some embodiments, the methods involve measuring the level of a lipoxygenase metabolite in a patient. An exemplary metabolite is 5-HETE. In these methods, measuring enzyme activity or measuring metabolite levels can be performed using any suitable sample from a human, such as a body fluid (e.g., blood, urine, etc.).

[0278] Various embodiments are implemented according to the basic provisional application (serial number 62 / 953,023) entitled "Lipoxygenase Inhibitors" filed on December 23, 2019, the rights and interests of which are claimed herein, and the general and specific teachings thereof are fully incorporated herein by reference. For example, the embodiments herein and / or in the provisional application may be combined to varying degrees (including all). Reference may also be made to the experimental teachings and basic reference materials provided in the basic provisional application. Unless otherwise specified, the embodiments discussed in the provisional application are not intended to limit in any way any part of the entire technical disclosure or the claimed disclosure.

[0279] All patents, patent applications, and publications mentioned herein are incorporated herein by reference in their entirety. However, when a patent, patent application, or publication containing specific definitions is incorporated by reference, it should be understood that these specific definitions apply to the incorporated patent, patent application, or publication in which they appear, and not to the remainder of this application, and in particular not to the claims of this application.

[0280] It should be understood that although the present invention has been described in conjunction with preferred specific embodiments, the foregoing description and the following examples are intended to illustrate rather than limit the scope of the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the present invention, and that other aspects, advantages and modifications will be apparent to those skilled in the art to which the present invention pertains.

[0281] Experimental Implementation

[0282] The compounds disclosed herein were found to inhibit Akt and ERK activation by inhibiting 12-LOX-mediated arachidonic acid metabolism.

[0283] 5-LOX FI assay fluorescence assay

[0284] The enzyme assay (100 μL) contained 50 mM Tris, pH 7.5, 0.1 mM 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). The inhibitor (dissolved in DMSO) was applied to a 96-well assay microplate at 1 μL, and then 40 μL of a solution containing 5-LOX enzyme was added. The enzyme was pre-incubated with the compound for 15 minutes. The assay was started by adding 40 μL of a substrate solution containing AA and ATP and 20 μL of a solution containing DHR123. The enzymatic reaction was carried out for 30 minutes, and kinetic readings were obtained in a SpectraMax Paradigm (Molecular Device) at 500 nm excitation and 536 nm emission. The percentage inhibition of each compound dose was calculated using a 4-parameter logistic model or a sigmoidal dose-response model to determine the IC 50 Curve fitting.

[0285] 12-LOX / 15-LOX fluorescence assay

[0286] The enzyme assay (100 μL) contained 50 mM Tris, pH 7.5, 0.05% Tween-20, 20 μM AA / LA, 1 μM DHR123, and 100 nM recombinant 12-LOX enzyme / 50 nM recombinant 15-LOX enzyme. The inhibitor (dissolved in DMSO) was applied to a 96-well assay microplate at 1 μL, and then 40 μL of a solution containing 12-LOX / 15-LOX enzyme was added. The enzyme was pre-incubated with the compound for 15 minutes. The assay was started by adding 40 μL of a substrate solution containing AA / LA and 20 μL of a solution containing DHR123. The enzymatic reaction was carried out for 30 minutes, and kinetic readings were obtained in a SpectraMax Paradigm (Molecular Device) at 500 nm excitation and 536 nm emission. The percentage inhibition of each compound dose was calculated using a 4-parameter logistic model or a sigmoidal dose-response curve to perform IC 50 Curve fitting.

[0287] Inhibitory activity against a panel of lipoxygenases was demonstrated in cell-based assays, e.g., for 5-LOX, using a fluorescence-based human 5-LOX enzyme assay (Anal. Biochem., 364:204.) and for 12-LOX, using a colorimetric assay for platelet 12-LOX activity (Anal. Biochem., 231:354). Table 1 provides the results for exemplary compounds on 5-LOX, 12-LOX, and 15-LOX.

[0288] Table 1: IC50 (μM) values ​​for in vitro lipoxygenase inhibition

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] General information about the examples:All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried under vacuum (1-5 mmHg) at room temperature (rt). Thin layer chromatography (TLC) was performed on silica gel plates and spots were observed by UV light (214 and 254 nm). Purification was performed using silica gel (200-300 mesh) by column and flash chromatography. Solvent systems were reported by volume as mixtures. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts were reported as δ values ​​in ppm with deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration.

[0308] Example 1

[0309]

[0310] Example route for Example 1:

[0311]

[0312] Synthesis of 2-(2-bromo-6-nitrophenoxy)-N,N-dimethylethylamine (25-1):

[0313]

[0314] A mixture of 25-1 (4.0 g, 18.4 mmol), 2-chloro-N,N-dimethylethylamine 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 hours (h). The mixture was diluted with EtOAc (150 mL). The organic layer was washed with water (100 mL), saturated bicarbonate solution (100 mL) and brine (100 mL) in sequence. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 4) to give 25-2 as an oil (2.3 g, 43% yield). MS calculated value: 288.0; MS found value: 289.1 [M+H] + .

[0315] Synthesis of 2-(2-(dimethylamino)ethoxy)-N-(4-methoxybenzyl)-3-nitroaniline (25-3)

[0316]

[0317] A mixture of 25-2 (600 mg, 2.1 mmol), (4-methoxyphenyl)methylamine (288 mg, 2.1 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), X-phos (173 mg, 0.3 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) in dioxane (20 mL) was stirred at 95 ° C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and then the mixture was filtered and washed with EtOAc (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL) in sequence. The ethyl acetate layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 5) to give 25-3 (230 mg, about 32% yield) as a solid. MS calculated value: 345.2; MS found value: 346.3 [M+H] + .

[0318] Synthesis of 2-(2-(dimethylamino)ethoxy)-N1-(4-methoxybenzyl)benzene-1,3-diamine (SS20308-0025-01):

[0319]

[0320] A mixture 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 hours. 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 preparative HPLC to afford SS20308-0025-01 (62 mg, approximately 34% yield) as a solid.

[0321] 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=8.0,1.2 Hz, 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).

[0322] Example 2

[0323]

[0324] Example route for Example 2:

[0325]

[0326] Synthesis of 2-(2-(dimethylamino)ethoxy)-3-nitro-N-phenylaniline (52-2):

[0327]

[0328] 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 a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc=8 / 1) to give 52-2 (500 mg, 96% yield) as a solid. MS calculated value: 301.1; MS found value: 302.4 [M+H] + .

[0329] 2-(2-(dimethylamino)ethoxy)-N 1 -Synthesis of phenylbenzene-1,3-diamine (52-3):

[0330]

[0331] 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 nitrogen for 4 hours. The reaction mixture was then filtered. The filtrate was concentrated to afford 52-3 as an oil (370 mg, approximately 82% yield). MS calculated: 271.2; MS found: 272.4 [M+H] + .

[0332] 2-(2-(dimethylamino)ethoxy)-N 1 -(4-methoxybenzyl)-N 3 -Synthesis of phenylbenzene-1,3-diamine (SS20308-0052-01):

[0333]

[0334] A mixture of 52-3 (290 mg, 1.07 mmol) and p-anisaldehyde (146 mg, 1.07 mmol) in HOAc (1 mL) and MeOH (20 mL) was stirred at 70°C for 2 hours. After cooling to room temperature, NaBH4 (40 mg, 1.07 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was then poured into water and basified with 1N 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 Na2SO4, and concentrated. The residue was purified by preparative HPLC to give SS2308-0052-01 (60 mg, approximately 14% yield) as a solid. MS calculated: 391.2; MS found: 392.2 [M+H] + .

[0335] 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(d,J=8.8Hz,2H),6.74(dd,J=7.6,7 .2Hz,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, 2H), 3.70 (s, 3H), 2.14 (s, 6H).

[0336] Example 3

[0337]

[0338] Example route for Example 3:

[0339]

[0340] Synthesis of 3-bromo-2-(2-(dimethylamino)ethoxy)aniline (53-1):

[0341]

[0342] 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 hours. The reaction mixture was then filtered through celite. The filtrate was basified with NaOH solution to a pH of 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 as a solid (0.7 g, approximately 78% yield). MS calculated: 258.0; MS found: 259.2 [M+H] + .

[0343] Synthesis of N-(3-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-3-oxo-3-phenylpropionamide (53-2):

[0344]

[0345] A mixture of 53-1 (410 mg, 1.58 mmol) and ethyl benzoyl acetate (760 mg, 3.95 mmol) was stirred and heated to 140° C. under microwave irradiation and a nitrogen atmosphere for 0.5 h. The reaction mixture was purified by silica gel column chromatography (petroleum ether / EtOAc=10 / 1, 5 / 1, 3 / 1, 1 / 1, CH 2 Cl 2 / MeOH=20 / 1) to give 53-2 as a solid (400 mg, approximately 62% yield). MS calculated value: 404.1; MS found value: 405.3 [M+H] + .

[0346] Synthesis of 7-bromo-8-(2-(dimethylamino)ethoxy)-4-phenylquinolin-2(1H)-one (53-3):

[0347]

[0348] A mixture of 53-2 (500 mg, 1.23 mmol) in H2SO4 (5 mL) was stirred and heated to 80°C for 4 hours. The reaction mixture was cooled to room temperature and poured into ice, basified with NaOH (40%) solution until the pH reached 9.0-10.0 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (CH2Cl2 / MeOH=20 / 1) to give 53-3 (70 mg, approximately 15% yield) as an oil. MS calculated value: 386.1; MS found value: 387.2 [M+H] + .

[0349] Synthesis of 8-(2-(dimethylamino)ethoxy)-7-(4-methoxybenzylamino)-4-phenylquinolin-2(1H)-one (SS20308-0053-01):

[0350]

[0351] A solution of 53-3 (85 mg, 0.22 mmol), (4-methoxyphenyl)methanamine (151 mg, 1.1 mmol), Xantphos (13 mg, 0.022 mmol), Pd2(dba)3 (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 overnight under a nitrogen atmosphere and then filtered and rinsed with EtOAc. The filtrate was concentrated and purified by preparative TLC (CH2Cl2 / MeOH=20 / 1) to give SS20308-0053-01 (61 mg, approximately 63% yield) as a solid. MS calculated value: 443.2; MS found value: 444.3 [M+H] + .

[0352] 1 H 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,1 H), 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).

[0353] Example 4

[0354]

[0355] Example route for Example 4:

[0356]

[0357] Synthesis of 2-(2-bromo-6-nitrophenoxy)-N,N-dimethylethylamine (71-1):

[0358]

[0359] A mixture of 71-1 (3.0 g, 13.6 mmol), 2-chloro-N,N-dimethylethylamine 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 hours. 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 give 71-2 (1.1 g, about 28% yield) as an oil. MS calculated value: 288.0; MS found value: 289.1 [M+H] + .

[0360] Synthesis of N-benzyl-2-(2-(dimethylamino)ethoxy)-3-nitroaniline (71-3):

[0361]

[0362] To a toluene (3 mL) solution of 71-2 (300 mg, 1.0 mmol), benzylamine (111 mg, 1.0 mmol), Cs2CO3 (696 mg, 2.0 mmol), Xantphos (62 mg, 0.1 mmol) and Pd2(dba)3 (98 mg, 0.1 mmol) were added, and the reaction mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite, 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 / 1~1 / 0) to give 71-3 (200 mg, about 59% yield) as an oil. MS calculated value: 315.2; MS found value: 316.3 [M+H] + .

[0363] N 1 -Synthesis of benzyl-2-(2-(dimethylamino)ethoxy)benzene-1,3-diamine (71-4):

[0364]

[0365] To a solution of 71-3 (200 mg, 0.63 mmol) in MeOH (6 mL) were added Zn powder (166 mg, 2.5 mmol) and HOAc (152 mg, 2.5 mmol), and the reaction mixture was stirred at 60°C for 4 hours. The mixture was diluted with water and extracted with EtOAc (150 mL). The organic layer was washed with brine and concentrated to dryness to give 71-4 (200 mg, crude) as an oil. MS calculated value: 285.2; MS found value: 286.2 [M+H] + .

[0366] N 1 -Benzyl-N 3 Synthesis of -(3-chloropyridin-2-yl)-2-(2-(dimethylamino)ethoxy)benzene-1,3-diamine (SS20308-0071-01):

[0367]

[0368] To a solution of 71-4 (380 mg, 1.33 mmol) in toluene (15 mL) were added 2,3-dichloropyridine (237 mg, 1.60 mmol), Cs2CO3 (868 mg, 2.66 mmol), Xantphos (77 mg, 0.1 mmol) and Pd2(dba)3 (61 mg, 0.13 mmol), and the reaction mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by preparative TLC (EtOAc) to give SS20308-0071-01 (420 mg, about 80% yield) as an oil. MS calculated value: 396.2; MS found value: 397.3 [M+H] + .

[0369] 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).

[0370] Example 5

[0371]

[0372] Example route for Example 5:

[0373]

[0374] Synthesis of 4-bromo-2-nitrobiphenyl (95-2):

[0375]

[0376] By 95-1 (6.00g, 21.36 mmol), phenylboronic acid (2.60g, 21.36 mmol), Pd(PPh 3 ) 4 (1.23g, 1.07 mmol) and Na CO 3 (7.90g, 74.76 mmol) in toluene / H 2 O (60mL, 5 / 1) mixture in N 2 atmosphere at 90 ℃ and stir overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (60mL x 3). The organic layer was washed with salt water, used Na 2 SO 4 dried, and concentrated. Residue was purified by column chromatography (petroleum ether) to obtain oily 95-2 (3.70g, about 62% yield).

[0377] 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).

[0378] Synthesis of 4-bromobiphenyl-2-amine (95-3):

[0379]

[0380] 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 at room temperature overnight. 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 x 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 give 95-3 (1.90 g, approximately 58% yield) as an oil. MS calculated value: 247.0; MS found value: 248.1 [M+H] + .

[0381] Synthesis of 4-bromo-N-(2-chloroethyl)biphenyl-2-amine (95-4):

[0382]

[0383] To a solution of 95-3 (1.75 g, 7.05 mmol) in MeOH (20 mL) were added 2-chloroacetaldehyde (2.77 g, 14.11 mmol, 40%), AcOH (846 mg, 14.11 mmol) and NaBH3CN (887 mg, 14.11 mmol), and the reaction mixture was stirred at 40°C overnight. 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=20 / 1) to give 95-4 (2.00 g, approximately 91% yield) as an oil. MS calculated value: 309.0; MS found value: 309.8 [M+H] + .

[0384] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromobiphenyl-2-amine (95-5):

[0385]

[0386] A mixture of 95-4 (2.00 g, 6.44 mmol), 1H-1,2,4-triazole (677 mg, 9.66 mmol) and Cs2CO3 (4.20 g, 12.88 mmol) in CH3CN (40 mL) was stirred at 80°C overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=2 / 1) to give 95-5 (2.10 g, approximately 95% yield) as an oil. MS calculated value: 342.1; MS found value: 342.8 [M+H] + .

[0387] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 -Synthesis of benzylbiphenyl-2,4-diamine (SS20308-0096-01):

[0388]

[0389] 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 at 110 ° C. under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative HPLC to give SS20308-0096-01 (25 mg, approximately 12% yield) as a solid. MS calculated value: 369.2; MS found value: 370.1 [M+H] + .

[0390] 1 H 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,1H),4.09(t,J=6.0Hz,1H),3.55-3.48(m,2H).

[0391] Example 6

[0392]

[0393] Example route for Example 6:

[0394]

[0395] Synthesis of N-(4-bromo-3-nitrophenyl)benzamide (135-2):

[0396]

[0397] 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 (rt) for 2 hours, and the solution 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 by silica gel column chromatography (hexane / EtOAc=5 / 1 to 1 / 1) to give 135-2 (350 mg, approximately 54% yield) as a solid. MS calculated value: 320.0; MS found value: 321.2 [M+H] + .

[0398] Synthesis of N-(2-nitro-[1,1'-biphenyl]-4-yl)benzamide (135-3):

[0399]

[0400] To a mixture of 135-2 (320 mg, 1 mmol) and phenylboronic acid (146 mg, 1.2 mmol) in toluene / H2O (30 mL / 3 mL) were added Cs2CO3 (652 mg, 2 mmol) and xphosPdG2 (20 mg). The mixture was heated at reflux for 6 hours. 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 MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=3 / 1) to give 135-3 (230 mg, approximately 72% yield) as an oil. MS calculated value: 318.1; MS found value: 319.2 [M+H] + .

[0401] Synthesis of N-(2-amino-[1,1'-biphenyl]-4-yl)benzamide (135-4):

[0402]

[0403] 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 hours, filtered, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc = 1 / 1) to give 135-4 as an oil (140 mg, approximately 68% yield). MS calculated value: 288.1; MS found value: 288.2 [M+H] + .

[0404] Synthesis of N-(2-((2-chloroethyl)amino)-[1,1'-biphenyl]-4-yl)benzamide (135-5):

[0405]

[0406] To a mixture of 135-4 (144 mg, 0.5 mmol) in EtOH (30 mL) was added 2-chloroacetaldehyde (1 mL) and HOAc (1 mL), and NaBH3CN (0.3 g) was added at room temperature. The mixture was stirred at room temperature for 6 hours, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (hexane / EtOAc=2 / 1) to give 135-5 as an oil (85 mg, approximately 48% yield). MS calculated value: 350.1; MS found value: 350.2 [M+H] + .

[0407] Synthesis of N-(2-((2-(1H-1,2,4-triazol-1-yl)ethyl)amino)-[1,1'-biphenyl]-4-yl)benzamide (SS20308-0135):

[0408]

[0409] To a mixture of 135-5 (85 mg, 0.24 mmol) in DMF (15 mL) was added 1H-1,2,4-triazole (69 mg, 1 mmol) and Cs2CO3 (326 g, 1 mmol) at room temperature. The mixture was stirred at 80°C for 8 hours, filtered and the solid was washed with DCM (50 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to give SS20308-0135 (25 mg, yield approximately 27%) as a solid. MS calculated value: 383.5; MS found value: 384.2 [M+H] + .

[0410] 1 H NMR(400MHz,DMSO-d6)δ3.50(br d,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),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,1H).

[0411] Example 7

[0412]

[0413] Example route for Example 7:

[0414]

[0415] Synthesis of 5-bromobiphenyl-2-amine (145-2)

[0416]

[0417] 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 at 0°C overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 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 give 145-2 (5.7 g, approximately 57.6% yield) as an oil. MS calculated value: 247.0; MS found value: 248.2 [M+H] + .

[0418] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (145-3):

[0419]

[0420] A mixture of 145-2 (5.70 g, 22.97 mmol), 2-chloroacetaldehyde (2.1 g, 27.56 mmol) and NaBH3CN (1.44 g, 22.97 mmol) in EtOH / AcOH (60 mL, 5 / 1) was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (30 mL x 3), and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=10 / 1) to give 145-3 (6.0 g, approximately 84% yield) as a solid. MS calculated value: 309.0; MS found value: 310.0 [M+H] + .

[0421] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (145-4):

[0422]

[0423] A mixture of 145-3 (5.00 g, 16.10 mmol), 1H-1,2,4-triazole (1.33 g, 19.32 mmol) and Cs2CO3 (15.73 g, 48.30 mmol) in CH3CN (15 mL) was stirred at 80°C for 4 hours. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give 145-4 (3.8 g, about 70% yield) as a solid. MS calculated value: 342.1; MS found value: 343.9 [M+H] + .

[0424] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 -Synthesis of benzylbiphenyl-2,5-diamine (SS20308-0145-01):

[0425]

[0426] A mixture of 145-4 (450 mg, 1.31 mmol), benzylamine (420 mg, 3.93 mmol), Pd(OAc)2 (29 mg, 0.13 mmol), P(tBu)3HBF4 (76 mg, 0.26 mmol) and NaOtBu (378 mg, 3.93 mmol) in toluene (5 mL) was stirred at 110°C overnight under a N2 atmosphere. The reaction mixture was then filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1 / 2) to give SS20308-0145-01 (100 mg, approximately 21% yield) as an oil. MS calculated: 369.2; MS found: 370.3 [M+H] + .

[0427] 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),7.2 5-7.28(m,1H),6.64(d,J=2Hz,2H),6.56-6.7(m,1H),4.30(t,J=5.6Hz,4H),3.66(brs,1H),3.55(t,J=5.2Hz 2H).

[0428] Example 8

[0429]

[0430] Example route for Example 8:

[0431] Synthesis of 5-bromobiphenyl-2-amine (146-2):

[0432]

[0433] 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 at 0°C overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 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 give 146-2 (5.7 g, approximately 57.6% yield) as an oil. MS calculated value: 247.0; MS found value: 248.2 [M+H] + .

[0434] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (146-3):

[0435]

[0436] A mixture of 146-2 (5.70 g, 22.97 mmol), 2-chloroacetaldehyde (2.1 g, 27.56 mmol) and NaBH3CN (1.44 g, 22.97 mmol) in EtOH / AcOH (60 mL, 5 / 1) was stirred at room temperature overnight. The resulting mixture was extracted with ethyl acetate (30 mL x 3), and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=10 / 1) to give 146-3 (6.0 g, approximately 84% yield) as a solid. MS calculated value: 309.0; MS found value: 310.0 [M+H] + 。

[0437] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (146-4):

[0438]

[0439] A mixture of 146-3 (5.00 g, 16.10 mmol), 1H-1,2,4-triazole (1.33 g, 19.32 mmol) and Cs2CO3 (15.73 g, 48.30 mmol) in CH3CN (15 mL) was stirred at 80°C for 4 hours. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give 146-4 (3.8 g, about 70% yield) as a solid. MS calculated value: 342.1; MS found value: 343.9 [M+H] + .

[0440] Synthesis of N-(6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)biphenyl-3-yl)benzamide (SS20308-0146-01):

[0441]

[0442] A mixture of 146-4 (350 mg, 1.02 mmol), benzamide (372 mg, 3.06 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), t-Bu-Bretphos (97 mg, 0.20 mmol) and Cs2CO3 (997 mg, 3.06 mmol) in t-BuOH (5 mL) was stirred at 130°C and MW for 1 hour under N2 atmosphere. The reaction mixture was then filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 2) to give SS20308-0146-01 (50 mg, approximately 13% yield) as an oil. MS calculated value: 384.2; MS found value: 384.2 [M+H] +1 .

[0443] 1 H 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).

[0444] Example 9

[0445]

[0446] Example route of Example 9 (SS20308-0211-01 & SS20308-0225-01):

[0447]

[0448] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-4-nitroaniline (211-2):

[0449]

[0450] A mixture of 211-1 (2.20 g, 10.00 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine hydrochloride (1.78 g, 12.00 mmol) and K2CO3 (4.15 g, 30.00 mmol) in DMSO (10 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with EtOAc (30 mL x 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 give 211-2 (2.00 g, approximately 64% yield) as a solid. MS calculated value: 311.0; MS found value: 312.0 [M+H] + .

[0451] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)-4-nitroaniline (211-3):

[0452]

[0453] 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)Cl2 (469 mg, 0.64 mmol) and K2CO3 (2.66 g, 19.23 mmol) in DME / H2O (10 mL, 5 / 1) was stirred at 80°C under N2 atmosphere for 2 hours. The resulting mixture was extracted with ethyl acetate (30 mL x 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 give 211-3 (1.80 g, about 81% yield) as a solid. MS calculated value: 348.1; MS found value: 349.4 [M+H] + .

[0454] N 1Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)benzene-1,4-diamine (211-4)

[0455]

[0456] 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 H2 atmosphere for 3 hours. The reaction mixture was then cooled to room temperature and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 221-4 (0.78 g, approximately 86% yield) as a solid. MS calculated value: 318.2; MS found value: 319.0 [M+H] + .

[0457] 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):

[0458]

[0459] A mixture of 211-4 (600 mg, 1.88 mmol), 4-fluorobenzaldehyde (281 mg, 2.26 mmol) and NaBH(CH3COO)3 (479 mg, 2.26 mmol) in DCM (10 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give SS20308-0225-01 (360 mg, approximately 45% yield) as a solid. MS calculated value: 426.2; MS found value: 427.0 [M+H] + .

[0460] 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).

[0461] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(indolin-7-yl)benzene-1,4-diamine (SS20308-0211-01):

[0462]

[0463] A mixture of SS20308-0225-01 (50 mg, 0.117 mmol) and NaBH3CN (8 mg, 0.117 mmol) in AcOH (2 mL) was stirred at 0°C overnight. The residue was purified by preparative HPLC to give SS20308-0211-01 (20 mg, approximately 40% yield) as a solid. MS calculated: 428.2; MS found: 429.0 [M+H] + .

[0464] 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.94(s,1H),7.36-7.40(m,2H),7.11-7.15(t, 2H),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,1H),4.28-4.30(m, 2H), 4.17 (d, J = 5.6Hz, 2H), 4.08-4.11 (m, 1H), 3.24-3.29 (m, 4H), 2.92-2.94 (m, 2H).

[0465] Example 10

[0466]

[0467] Example route for Example 10:

[0468]

[0469] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-bromo-5-chloropyridin-2-amine (212-2):

[0470]

[0471] To a solution of 212-1 (500 mg, 2.38 mmol) in DMF (6 mL) was added K2CO3 (1.31 g, 9.50 mmol) and 1H-1,2,4-triazole-1-ethylamine hydrochloride (1:2) (355 g, 2.38 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, 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 MgSO4, and concentrated in vacuo to give 212-2, which was used in the next step without further purification.

[0472] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-3-phenylpyridin-2-amine (212-3):

[0473]

[0474] A mixture of 212-2 (300 mg, 0.99 mmol), phenylboronic acid (121 mg, 0.99 mmol), Pd(PPh3)4 (115 mg, 0.10 mmol), and K2CO3 (274 mg, 1.98 mmol) in DME (20 ml) was stirred at 90°C overnight 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 give 212-3 (170 mg, approximately 57% yield) as an oil. MS calculated value: 299.1; MS found value: 300.1 [M+H] + .

[0475] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 -Synthesis of benzyl-3-phenylpyridine-2,5-diamine (SS20308-0212-01):

[0476]

[0477] A mixture of 212-3 (100 mg, 0.33 mmol), benzylamine (71 mg, 0.67 mmol), Pd2(dba)3 (31 mg, 0.03 mmol), X-Phos (32 mg, 0.07 mmol) and Cs2CO3 (217 mg, 0.67 mmol) in toluene (Tol) (10 ml) was stirred at 110 ° C overnight 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 (50 mL x 3). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative HPLC to obtain SS20308-0212-01 (7 mg, 6% yield) as an oil. MS calculated value: 370.2; MS found value: 371.0 [M+H] + .

[0478] 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).

[0479] Example 11

[0480]

[0481] Example route for Example 11:

[0482]

[0483] Synthesis of 5-nitro-4-phenylpyridin-2(1H)-one (213-2)

[0484]

[0485] A mixture of phenylboronic acid (1.3 g, 11.0 mmol), 213-1 (2.0 g, 7.3 mmol), Pd(dppf)Cl2 (534 mg, 0.73 mmol) and K2CO3 (3.0 g, 21.9 mmol) in DME (50 mL) and water (5 mL) was stirred at 100°C for 18 h. After completion of the reaction, 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, then purified by CC (petroleum ether / EtOAc=5 / 1) to give 213-2 (800 mg, approximately 51% yield) as a solid. MS calculated value: 216.1; MS found value: 217.4 [M+H] + .

[0486] Synthesis of 2-chloro-5-nitro-4-phenylpyridine (213-3):

[0487]

[0488] A solution of 213-2 (800 mg, 3.7 mmol) in POCl (10 mL) was stirred at 80° C. for 18 hours. After the reaction was complete, 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 Na SO and concentrated in vacuo, then purified by column chromatography (petroleum ether / EtOAc=10 / 1) to give 213-3 (700 mg, approximately 81% yield) as a solid. MS calculated value: 234.0; MS found value: 235.3 [M+H] + .

[0489] Synthesis of N-benzyl-5-nitro-4-phenylpyridin-2-amine (213-4):

[0490]

[0491] A mixture of benzylamine (385 mg, 3.6 mmoles), 213-3 (700 mg, 3 mmoles) and K CO (828 mg, 6 mmoles) in DMF (10 mL) was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was concentrated and quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined layers were dried and concentrated in vacuo, then purified by column chromatography (petroleum ether / EtOAc=5 / 1) to give 213-4 (600 mg, approximately 66% yield) in solid form. MS calculated: 305.1; MS found: 306.4 [M+H] + .

[0492] N 2-Synthesis of benzyl-4-phenylpyridine-2,5-diamine (213-5):

[0493]

[0494] A mixture of 213-4 (800 mg, 2.6 mmol), Fe (728 mg, 13 mol) and NH4Cl (aqueous solution (aq), 2 mL) in EtOH (20 mL) was stirred at 70 ° C for 18 hours. After the reaction was completed, the reaction mixture was concentrated and quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH=20 / 1) to give 213-5 (500 mg, about 70% yield) as a solid. MS calculated value: 275.1; MS found value: 276.4 [M+H] + .

[0495] N 2 -Benzyl-N 5 Synthesis of -(2-chloroethyl)-4-phenylpyridine-2,5-diamine (213-6):

[0496]

[0497] A mixture of 213-5 (250 mg, 0.91 mmol), 2-chloroacetaldehyde (213 mg, 2.73 mol), AcOH (2 drops) and NaBH3CN (118 mg, 1.82 mmol) in EtOH (10 mL) was stirred at room temperature overnight. 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 and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc=2 / 1) to obtain 213-6 (180 mg, approximately 53% yield) as a solid. MS calculated value: 337.1; MS found value: 338.4 [M+H] + .

[0498] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 -Synthesis of benzyl-4-phenylpyridine-2,5-diamine (SS20308-0213-01):

[0499]

[0500] A mixture of 1H-1,2,4-triazole (40 mg, 0.6 mmol), 213-6 (100 mg, 0.3 mmol) and K2CO3 (120 mg, 0.9 mmol) in CH3CN (5 mL) was stirred at 80 ° C for 2 days (d). After the reaction was completed, the reaction mixture was concentrated, quenched with water (10 mL), and extracted with EtOAc (10 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give SS20308-0213-01 (14 mg, approximately 13% yield) as a solid. MS calculated value: 370.5; MS found value: 371.3 [M+H] + .

[0501] 1 H 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).

[0502] Example 12

[0503]

[0504] Example route for Example 12:

[0505]

[0506] Synthesis of 6-chloro-2-phenylpyridin-3-amine (214-2):

[0507]

[0508] A solution of 214-1 (2.0 g, 9.64 mmol), phenylboronic acid (1.18 g, 9.64 mmol), Pd(dppf)Cl2 (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 to 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 give compound 214-2 (1.4 g, approximately 71% yield) as a solid. MS calculated value: 204.1; MS found value: 205.1 [M+H]+ .

[0509] Synthesis of 6-chloro-N-(2-chloroethyl)-2-phenylpyridin-3-amine (214-3):

[0510]

[0511] A solution of 214-2 (1.0 g, 4.89 mmol), 2-chloroacetaldehyde (3.84 g, 19.55 mmol, 40% in water), NaBH3CN (461 mg, 7.34 mmol) and AcOH (2 mL) in EtOH (20 mL) was stirred at room temperature overnight. The reaction mixture was basified with NaHCO3 solution and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was used in the next step without further purification. MS calculated value: 266.0; MS found value: 267.0 [M+H] + .

[0512] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-chloro-2-phenylpyridin-3-amine (214-4):

[0513]

[0514] A mixture of 214-3 (1.31 g, 4.9 mmol), 1H-1,2,4-triazole (508 mg, 7.36 mmol) and K2CO3 (1.02 g, 7.36 mmol) in CH3CN (40 mL) was stirred at 80°C overnight. 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 give 214-4 (1.2 g, two-step yield approximately 82%) as a solid. MS calculated value: 299.1; MS found value: 300.4 [M+H] + .

[0515] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 -Synthesis of benzyl-6-phenylpyridine-2,5-diamine (SS20308-0214-01):

[0516]

[0517] A solution of 214-4 (50 mg, 0.17 mmol), benzylamine (36 mg, 0.34 mmol), Xantphos (20 mg, 0.035 mmol), Pd2(dba)3 (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 to 110°C under N2 overnight, then filtered and rinsed with EtOAc. The filtrate was concentrated and purified by preparative HPLC to give SS20308-0214-01 (6 mg, approximately 10% yield) as a semisolid. MS calculated: 370.2; MS found: 371.0 [M+H] + .

[0518] 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(t,J=5.8Hz,2H),3.48(t,J=5.6Hz,2H).

[0519] Example 13

[0520]

[0521] Example route for Example 13:

[0522]

[0523] Synthesis of N-benzyl-3-bromo-4-nitroaniline (215-2):

[0524]

[0525] To a DMSO (50 mL) solution of 214-1 (5.00 g, 22.73 mmol) and benzylamine (2.43 g, 22.73 mmol) was added K2CO3 (6.27 g, 45.46 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc (50 mL x 3). The combined organic layers were 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 obtain compound 0215-2 (6.2 g, approximately 89% yield) in solid form. MS calculated value: 306.0; MS found value: 307.0 [M+H] + .

[0526] Synthesis of tert-butyl benzyl (3-bromo-4-nitrophenyl) carbamate (215-3)

[0527]

[0528] To a solution of 215-2 (5.00 g, 16.29 mmol) in DCM (50 mL) was added TEA (3.29 g, 32.57 mmol) and DMAP (1.99 g, 16.29 mmol), cooled to 0°C, and then (Boc)2O (5.33 g, 24.44 mmol) was added dropwise over 10 minutes. The solution was then stirred at room temperature overnight. Water was added to the solution and extracted with DCM (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc=30 / 1, 10 / 1) to give 215-3 (6.0 g, approximately 91% yield) as a solid. MS calculated value: 406.0; MS found value: 351.0 [M-55] + .

[0529] Synthesis of tert-butyl 4-amino-3-bromophenyl(benzyl)carbamate (215-4):

[0530]

[0531] To a solution of 214-3 (6.00 g, 14.74 mmol) in EtOH (60 mL) were 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 give 215-4 as a solid (4.2 g, approximately 75% yield). MS calculated value: 376.0; MS found value: 377.0 [M+H] + .

[0532] Synthesis of tert-butyl benzyl (3-bromo-4-(2-chloroethylamino)phenyl)carbamate (215-5):

[0533]

[0534] To a solution of 215-4 (4.00 g, 14.44 mmol) in EtOH (50 mL) was added 2-chloroacetaldehyde (40 wt% aqueous solution, 5.66 g, 28.88 mmol), NaBH3CN (1.81 g, 28.88 mmol) and AcOH (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was concentrated to remove the residue. The residue was dissolved in EtOAc and water and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc=20 / 1, 10 / 1) to obtain compound 215-3 (3.6 g, about 78% yield) in solid form. MS calculated value: 438.0; MS found value: 439.0 [M+H] + .

[0535] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-bromophenyl(benzyl)carbamate (215-6):

[0536]

[0537] To a solution of 215-5 (3.60 g, 8.22 mmol) in CH 3 CN (50 mL) were added 1H-1,2,4-triazole (40 wt % aqueous solution, 0.68 g, 9.86 mmol) and Cs 2 CO 3 (5.36 g, 16.44 mmol). The mixture was stirred at 80 ° C for 4 hours. Cooled to room temperature and filtered, the filtrate was concentrated, and then purified by silica gel column chromatography (petroleum ether / EtOAc=3 / 1 to 1 / 1) to give 215-6 (3.5 g, about 90% yield) as a solid.

[0538] 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.97(s,1H),7.33-7.29(m,2H),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).

[0539] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-4-yl)phenyl(benzyl)carbamate (215-7):

[0540]

[0541] To a solution of 215-6 (200 mg, 0.42 mmol) in 1,4-dioxane / H2O (5 mL / 0.5 mL) was added pyridin-4-ylboronic acid (104 mg, 0.84 mmol), K2CO3 (116 mg, 0.84 mmol) and Pd(dppf)Cl2 (30 mg, 0.04 mmol). The mixture was stirred at 120 ° C. under microwave for 1 hour. The filtrate was filtered and concentrated, and then purified by silica gel column chromatography (petroleum ether / EtOAc=3 / 1, 1 / 1) to give 215-7 (120 mg, about 60% yield) as a solid. MS calculated value: 470.0; MS found value: 471.0 [M+H] + .

[0542] 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);

[0543]

[0544] To a solution of 215-7 (120 mg, 0.25 mmol) in DCM (5 mL) was added TFA (1 mL). The solution was stirred at room temperature overnight. The solution was basified with NaHCO 3 solution and extracted with DCM (10 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated, and purified by preparative HPLC to give SS20308-0215-01 (50 mg, approximately 52% yield) as a solid. MS calculated value: 370.0; MS found value: 371.0 [M+H] + .

[0545] 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,3 H), 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).

[0546] Example 14

[0547]

[0548] Example route for Example 14:

[0549]

[0550] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-3-yl)phenyl(benzyl)carbamate (SS20308-0216-2):

[0551]

[0552] A mixture of 215-6 (300 mg, 0.64 mmol), pyridin-3-ylboronic acid (117 mg, 0.95 mmol), Pd(dppf)Cl2 (47 mg, 0.064 mmol) and Na2CO3 (203 mg, 1.92 mmol) in DMF / H2O (10 mL, 5 / 1) was stirred at 90°C overnight under N2 atmosphere. The mixture was then poured into water and extracted with EtOAc (30 mL x 3), and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by preparative TLC to give 216-2 (200 mg, approximately 66.8% yield) as an oil. MS calculated value: 470.2; MS found value: 471.0 [M+H] + .

[0553] 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):

[0554]

[0555] A mixture of 216-2 (200 mg, 0.43 mmol) and TFA (0.1 mL, 1.26 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC to give SS20308-0216-01 (126 g, approximately 80% yield) as a solid. MS calculated: 370.2; MS found: 371.0 [M+H] + .

[0556] 1H 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,1H),5.67-5.70(m,1H),4.20-4.29(m,4H),3.28-3.30(m,2H).

[0557] Example 15

[0558]

[0559] Example route for Example 15:

[0560]

[0561] Synthesis of 3-bromo-N-(cyclohexylmethyl)-4-nitroaniline (217-1):

[0562]

[0563] To a solution of 215-1 (3.0 g, 12.4 mmol) in DMSO (20.0 mL) was added cyclohexylmethylamine (1.7 g, 15.0 mmol) and K2CO3 (3.6 g, 27.0 mmol). The mixture was then stirred for 4 hours. After completion of the reaction, 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 MgSO4 and concentrated to afford 217-1 (3.5 g, approximately 83% yield) as an oil. MS calculated: 312.0; MS found: 313.0 [M+H] + .

[0564] Synthesis of tert-butyl 3-bromo-4-nitrophenyl (cyclohexylmethyl)carbamate (217-2):

[0565]

[0566] A mixture of 217-1 (3.5 g, 11.2 mmol), (Boc)2O (3.2 g, 15.0 mmol), DMAP (600.0 mg, 5.0 mmol), and TEA (2.0 g, 20.0 mmol) in DCM (20.0 ml) was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with water and then extracted with EtOAc (20.0 mL x 3). The organic layer was separated, dried over MgSO4, and concentrated to afford 217-2 (3.8 g, approximately 89% yield) as an oil.

[0567] Synthesis of tert-butyl 4-amino-3-bromophenyl(cyclohexylmethyl)carbamate (217-3):

[0568]

[0569] 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 at room temperature overnight. After the reaction was complete, the mixture was quenched with water and NaHCO3 and then extracted with EtOAc (20.0 mL x 3). The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=10 / 1) to obtain 217-3 (2.2 g, approximately 63% yield) as a solid. MS calculated value: 382.0; MS found value: 328.0 [M+H] + .

[0570] Synthesis of tert-butyl 3-bromo-4-(2-chloroethylamino)phenyl(cyclohexylmethyl)carbamate (217-4):

[0571]

[0572] 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) were added NaBH3CN (372.0 mg, 6.0 mmol) and AcOH (2.0 ml). The mixture was then stirred overnight. After completion of the reaction, the reaction was purified by column chromatography to afford 217-4 as an oil (770.0 mg, approximately 59% yield). MS calculated: 444.0; MS found: 445.0 [M+H] + .

[0573] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-bromophenyl(cyclohexylmethyl)carbamate (217-5):

[0574]

[0575] To a mixture of 217-4 (770.0 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), followed by stirring 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 MgSO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 217-5 (420.0 mg, approximately 51% yield) as an oil. MS calculated value: 477.0; MS found value: 478.0 [M+H] + .

[0576] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-4-yl)phenyl(cyclohexylmethyl)carbamate (217-6):

[0577]

[0578] A mixture of 217-5 (300.0 mg, 0.6 mmol), pyridin-4-ylboronic acid (200.0 mg, 1.6 mmol), pd(dppf)Cl2 (10.0 mg, 0.1 mmol), and K2CO3 (150.0 mg, 1.1 mmol) in dioxane (3.0 mL) was stirred at 120°C for 1 hour under MW. After completion of the reaction, the mixture was quenched with water and then extracted with EtOAc (5.0 mL x 3). The organic layer was separated, dried over MgSO4, and concentrated. The reaction was purified by column chromatography to afford 217-6 (80 mg, approximately 27%) as a solid. MS Calcd: 477.0; MS Found: 478.0 [M+H] + .

[0579] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(cyclohexylmethyl)-2-(pyridin-4-yl)benzene-1,4-diamine (217-01):

[0580]

[0581] A solution of 217-6 (50.0 mg, 0.1 mmol) in HCl / EA (10.0 ml, 1 M) was added. The mixture was stirred overnight. The reaction mixture was then quenched with H2O and extracted with EtOAc (5 mL x 3). The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give 217 (20.0 mg, approximately 51% yield) as an oil. MS calculated value: 376.0; MS found value: 377.0 [M+H] + .

[0582] 1 H 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,1H ),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).

[0583] Example 16

[0584]

[0585] Example route for Example 16:

[0586]

[0587] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(thiophen-2-yl)phenyl(benzyl)carbamate (218-1):

[0588]

[0589] A mixture of 215-6 (500 mg, 1.06 mmol), 2-thiopheneboronic acid (271 mg, 2.12 mmol), Pd(dppf)Cl2 (78 mg, 0.11 mmol) and K2CO3 (293 mg, 2.12 mmol) in DMSO (5 mL) and water (0.5 mL) was stirred at 120 ° C for 2 hours in a microwave reactor. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The reaction mixture was then poured into water (20 mL). The mixture was extracted with EtOAc (30 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 / 1) to give 218-1 (450 mg, approximately 84% yield) as an oil. MS calculated value: 475.2; MS found value: 476.4 [M+H] + .

[0590] N 1 -(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):

[0591]

[0592] A mixture of 218-1 (450 mg, 0.94 mmol) and HCl (2 mL, 2 mmol, 1 N in dioxane) in dioxane (5 mL) was stirred at room temperature overnight. 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 preparative HPLC to give SS20308-218-01 (31.15 mg, approximately 9% yield) as an oil. MS calculated value: 375.1; MS found value: 376.0 [M+H] + .

[0593] 1H 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,2H),4.20(d,J=5.6Hz,2H),3.(t,J=5.8Hz,2H)

[0594] Example 17

[0595]

[0596] Example route for Example 17 (SS20308-0173-01 and 0219-01):

[0597]

[0598] Synthesis of 5-chloro-2-phenylpyridin-3-amine (173-2):

[0599]

[0600] 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), K2CO3 (668 mg, 4.84 mmol) in DME (10 mL) and water (1 mL) was stirred overnight at 80 ° C under N2 atmosphere. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=10 / 1) to give 173-2 (440 mg, about 91% yield) as an oil. MS calculated value: 204.0; MS found value: 205.1 [M+H] + .

[0601] Synthesis of 5-chloro-N-(2-chloroethyl)-2-phenylpyridin-3-amine (173-3):

[0602]

[0603] To a solution of 173-2 (450 mg, 2.20 mmol) in MeOH (10 mL) were added 2-chloroacetaldehyde (432 mg, 4.40 mmol in water, 40% concentration), AcOH (264 mg, 4.40 mmol) and NaBH3CN (275 mg, 4.40 mmol), and the reaction mixture was stirred at room temperature overnight. 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 x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 173-3 (100 mg, approximately 17% yield) as a solid. MS calculated value: 266.0; MS found value: 237.1 [M+H] + .

[0604] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-2-phenylpyridin-3-amine (173-4):

[0605]

[0606] A mixture of 173-3 (100 ng, 0.37 mmol), 1H-1,2,4-triazole (52 mg, 0.74 mmol) and Cs2CO3 (240 mg, 0.74 mmol) in CH3CN (10 mL) was stirred at 80 ° C overnight. The reaction mixture was then cooled to room temperature and filtered through diatomite and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 173-4 (77 mg, about 68% yield) as a solid. MS calculated value: 299.1; MS found value: 300.2 [M+H] + .

[0607] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 , Synthesis of 2-diphenylpyridine-3,5-diamine (SS20308-0219-01):

[0608]

[0609] A mixture of 173-4 (300 mg, 1.00 mmol), benzylamine (214 mg, 2.00 mmol), Pd(OAc)2 (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 two hours in a microwave reactor. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 3) and preparative HPLC to give SS20308-0219-01 (21 mg, about 6% yield) as a solid. MS calculated value: 370.2; MS found value: 371.3 [M+H] + .

[0610] 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=6.0 Hz, 1H), 6.25 (d, J = 2.0Hz, 1H), 4.97 (t, J = 6.0Hz, 1H), 4.32-7.28 (m, 4H), 3.40 (dd, J = 12.0, 6.0Hz, 2H).

[0611] Example 18

[0612]

[0613] Example route for Example 18:

[0614]

[0615] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 -Synthesis of benzyl-3-phenylpyridine-2,6-diamine (SS20308-0221-01):

[0616]

[0617] A mixture of 175-3 (130 mg, 0.43 mmol), benzylamine (93 mg, 0.87 mmol), Pd2(dba)3 (40 mg, 0.04 mmol), Cs2CO3 (282 mg, 0.87 mmol) and X-Phos (41 mg, 0.09 mmol) in toluene (10 ml) was stirred at 110 ° C overnight 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 x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified twice by preparative HPLC to give SS20308-0221-01 (8 mg, approximately 5% yield) as a solid. MS calculated value: 370.2; MS found value: 371.3 [M+H] + .

[0618] 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).

[0619] Example 19

[0620]

[0621] Example route for Example 19:

[0622]

[0623] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-4-nitroaniline (211-2):

[0624]

[0625] A mixture of 211-1 (2.20 g, 10.00 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine hydrochloride (1.78 g, 12.00 mmol) and K2CO3 (4.15 g, 30.00 mmol) in DMSO (10 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 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 give 211-2 (2.00 g, approximately 64% yield) as a solid. MS calculated value: 311.0; MS found value: 312.0 [M+H] + .

[0626] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)-4-nitroaniline (211-3):

[0627]

[0628] 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)Cl2 (469 mg, 0.64 mmol) and K2CO3 (2.66 g, 19.23 mmol) in DME / H2O (10 mL, 5 / 1) was stirred at 80°C under N2 atmosphere for 2 hours. The resulting mixture was extracted with ethyl acetate (30 mL x 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 give 211-3 (1.80 g, about 81% yield) as a solid. MS calculated value: 348.1; MS found value: 349.4 [M+H] + .

[0629] N 1 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)benzene-1,4-diamine (211-4):

[0630]

[0631] 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 H2 atmosphere for 3 hours. The reaction mixture was then cooled to room temperature and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 221-4 (0.78 g, approximately 86% yield) as a solid. MS calculated value: 318.2; MS found value: 319.0 [M+H] + .

[0632] 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):

[0633]

[0634] A mixture of 211-4 (600 mg, 1.88 mmol), 4-fluorobenzaldehyde (281 mg, 2.26 mmol) and NaBH(CH3COO)3 (479 mg, 2.26 mmol) in DCM (10 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give SS20308-0225-01 (360 mg, approximately 45% yield) as a solid. MS calculated value: 426.2; MS found value: 427.0 [M+H] + .

[0635] 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).

[0636] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4Synthesis of -(4-fluorobenzyl)-2-(indolin-7-yl)benzene-1,4-diamine (SS20308-0211-01):

[0637]

[0638] A mixture of SS20308-0225-01 (50 mg, 0.117 mmol) and NaBH3CN (8 mg, 0.117 mmol) in AcOH (2 mL) was stirred at 0°C overnight. The residue was purified by preparative HPLC to give SS20308-0211-01 (20 mg, approximately 40% yield) as a solid. MS calculated: 428.2; MS found: 429.0 [M+H] + .

[0639] 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.94(s,1H),7.36-7.40(m,2H),7.11-7.15(t, 2H),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,1H),4.28-4.30(m, 2H), 4.17 (d, J = 5.6Hz, 2H), 4.08-4.11 (m, 1H), 3.24-3.29 (m, 4H), 2.92-2.94 (m, 2H).

[0640] Example 20

[0641]

[0642] Example route for Example 20:

[0643]

[0644] Synthesis of 5-bromobiphenyl-2-amine (226-2):

[0645]

[0646] 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, and the mixture was stirred at room temperature overnight. After pouring into water (60 mL), the mixture was extracted with ethyl acetate (30 mL x 4). The organic layer was washed with brine and concentrated to dryness to give 226-2 as an oil (5.0 g, approximately 68% yield). MS calculated value: 247.0; MS found value: 250.1 [M+H] + .

[0647] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (226-3):

[0648]

[0649] To a solution of 226-2 (2.0 g, 8.1 mmol) in EtOH (20 mL) were added 2-chloroacetaldehyde (950 mg, 12.1 mmol in water, 40% concentration), AcOH (970 mg, 16.1 mmol) and NaBH3CN (507 mg, 8.1 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold water (50 mL), basified with saturated Na2CO3 solution to pH 9, and then extracted with ethyl acetate (150 mL). The organic layer was washed with brine and concentrated to dryness to give 226-3 as an oil (1.7 g, approximately 68% yield). MS calculated value: 309.0; MS found value: 310.0 [M+H] + .

[0650] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (226-4):

[0651]

[0652] To a solution of 226-3 (1.7 g, 5.5 mmol) in CH3CN (10 mL) were added 1,2,4-triazole (756 mg, 11.0 mmol) and Cs2CO3 (3.6 g, 11.0 mmol), and the reaction mixture was stirred at 80 ° C for 4 hours. 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 give 226-4 (1.0 g, about 53% yield) as an oil. MS calculated value: 343.2; MS found value: 345.2 [M+H] + .

[0653] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N5 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)biphenyl-2,5-diamine (SS20308-0226-01):

[0654]

[0655] To a toluene (10.0 mL) solution of 226-4 (180.0 mg, 0.5 mmol), 2,2,2-trifluoro-1-phenylethylamine (262.0 mg, 1.5 mmol), Pd(OAc)2 (10.0 mg, 0.1 mmol), S-Phos (20.0 mg, 0.1 mmol), NaOBut (100.0 mg, 1.0 mmol) were added. The mixture was stirred at 110 ° C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified twice by preparative HPLC to obtain SS20308-0226-01 (20.0 mg, about 9% yield) as a solid. MS calculated value: 437.0; MS found value: 438.0 [M+H] + .

[0656] 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(d,J=10.8Hz,1H),5.37 -5.42(m,1H),4.27(t,J=6.0Hz,2H),4.11(t,J=6.0Hz,1H),3.36(s,2H).

[0657] Example 21

[0658]

[0659] Example route for Example 21:

[0660]

[0661] Synthesis of 4-bromo-2,3-difluoro-6-nitroaniline (227-2):

[0662]

[0663] 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 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL x3). The organic layer was washed with brine (2x50 mL), dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc=5 / 1) to give 227-2 (180 mg, approximately 62% yield) as a solid. MS calculated value: 251.9; MS found value: 252.9 [M+H] + .

[0664] Synthesis of 1-bromo-2,3-difluoro-5-nitrobenzene (227-3):

[0665]

[0666] To THF (20mL) solution of 227-2 (3g, 11.86 mmoles), isoamyl nitrite (2.78g, 23.72 mmoles) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was poured into water (50mL) and extracted with EtOAc (40mL x 3). The organic layer was washed with salt water (2x50mL), dried over MgSO4, and concentrated in vacuo. Purified by column chromatography (petroleum ether / EtOAc=5 / 1) to obtain 227-3 (2.3g, approximately 82% yield) as a solid.

[0667] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-6-fluoro-4-nitroaniline (227-4):

[0668]

[0669] A mixture of 227-3 (2.00 g, 8.40 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine dihydrochloride (1.56 g, 8.40 mmol) and K2CO3 (4.65 g, 33.62 mmol) in CH3CN (30 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 (50 mL x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 227-4 (2 g, about 72% yield) in solid form. MS calculated value: 329.0; MS found value: 330.0 [M+H] + .

[0670] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-5-nitrobiphenyl-2-amine (227-5):

[0671]

[0672] 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 toluene (20 ml) and water (2 ml) was stirred at 80°C overnight 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 x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 227-5 (850 mg, about 86% yield) as a solid. MS calculated value: 327.1; MS found value: 328.2 [M+H] + .

[0673] N 2 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluorobiphenyl-2,5-diamine (227-6):

[0674]

[0675] 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 at room temperature under a H2 atmosphere overnight. 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 give 227-6 (150 mg, approximately 83% yield) as a solid. MS calculated value: 297.1; MS found value: 298.2 [M+H] + .

[0676] 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):

[0677]

[0678] 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 NaBH3CN (95 mg, 1.51 mmol) and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was quenched with water, filtered to remove insoluble material, and the filtrate was extracted with EtOAc (30 mL x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by preparative HPLC to give SS20308-0277-01 (33 mg, approximately 16% yield) as an oil. MS calculated value: 405.2; MS found value: 406.0 [M+H] + .

[0679] 1 H 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,2H),4.08(t,J=6.0Hz,2H),3.67-3.63(m,1H),3.06-3.02(m,2H).

[0680] Example 22

[0681]

[0682] Example route for Example 22:

[0683]

[0684] Synthesis of 3-bromo-2-fluoro-N-(4-fluorobenzyl)-4-nitroaniline (228-2):

[0685]

[0686] 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 at room temperature overnight. The reaction mixture was diluted with water (160 mL). The resulting solid was collected by filtration and concentrated to afford 228-2 as a solid (2.88 g, approximately 100% yield). MS calculated: 342.0; MS found: 343.2 [M+H] + .

[0687] Synthesis of 2-fluoro-N-(4-fluorobenzyl)-6-nitrobiphenyl-3-amine (228-3):

[0688]

[0689] A mixture of 228-2 (2.g, 5.8 mmol), phenylboronic acid (1.42g, 11.7 mmol), Pd(dppf)Cl2 (238 mg, 0.3 mmol) and K2CO3 (2.01 g, 14.6 mmol) in DME / H2O (48 mL, 5 / 1) was stirred at 80°C overnight under N2 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 give 228-3 (1.70 g, about 86% yield) as a solid. MS calculated value: 340.1; MS found value: 341.4 [M+H] + .

[0690] Synthesis of tert-butyl 2-fluoro-6-nitrobiphenyl-3-yl (4-fluorobenzyl)carbamate (228-4):

[0691]

[0692] To a solution of 228-3 (1.6 g, 4.70 mmol) in DCM (20 mL) were added (Boc)2O (1.54 g, 7.05 mmol), DMAP (575 mg, 4.71 mmol) and Et3N (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 give 228-4 as an oil (2.07 g, approximately 100% yield). MS calculated value: 440.2; MS found value: 385.3 [M-55] + .

[0693] Synthesis of tert-butyl 6-amino-2-fluorobiphenyl-3-yl (4-fluorobenzyl)carbamate (228-5):

[0694]

[0695] 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 at room temperature overnight. The reaction mixture was then filtered through Celite and concentrated to afford 228-5 as a solid (1.93 g, approximately 100% yield). MS calculated: 410.2; MS found: 355.3 [M-55] + .

[0696] Synthesis of tert-butyl 6-(2-chloroethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-6):

[0697]

[0698] To a solution of 228-5 (500 mg, 1.22 mmol) in DCM (5 mL) were added 2-chloroacetaldehyde (957 mg, 4.88 mmol in water, 40% concentration), NaBH3CN (115 mg, 1.83 mmol) and AcOH (0.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and basified with NaHCO3 solution until the pH reached 8. The mixture was extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 228-6 (576 mg, approximately 100% yield) as an oil. MS calculated value: 472.2; MS found value: 417.3 [M-56] + .

[0699] Synthesis of tert-butyl 6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-7):

[0700]

[0701] A mixture of 228-6 (576 mg, 1.22 mmol), 1H-1,2,4-triazole (126 mg, 1.83 mmol) and Cs2CO3 (595 mg, 1.83 mmol) in DMF (10 mL) was stirred at 80 ° C overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give 228-7 (200 mg, about 32% yield) as an oil. MS calculated value: 505.2; MS found value: 506.4 [M+H] + .

[0702] 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):

[0703]

[0704] 228-7 (400 mg, 1.27 mmol) was dissolved in HCl / dioxane (10 mL, 1 N) and stirred at room temperature overnight. 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 x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to obtain SS20308-0228-01 (40 mg, approximately 12% yield) as an oil. MS calculated value: 405.2; MS found value: 406.0 [M+H] + .

[0705] 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,1H ), 6.34 (d, J = 8.8Hz, 1H), 5.45 (t, J = 5.8Hz, 1H), 4.26-4.23 (m, 4H), 3.87 (t, J = 6.2Hz, 1H), 3.32-3.29 (m, 2H).

[0706] Example 23

[0707]

[0708] Example route for Example 23:

[0709]

[0710] Synthesis of 5-bromo-2-fluoro-N-(4-fluorobenzyl)-4-nitroaniline (229-2):

[0711]

[0712] 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 at room temperature overnight. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 229-2 as a solid (2.64 g, approximately 91% yield). MS calculated value: 342.0; MS found value: 341.9 [M+H] + .

[0713] Synthesis of 4-fluoro-N-(4-fluorobenzyl)-6-nitrobiphenyl-3-amine (229-3):

[0714]

[0715] A mixture of 229-2 (2.g, 7.29 mmol), phenylboronic acid (1.78g, 14.6 mmol), Pd(dppf)Cl2 (522 mg, 0.73 mmol) and K2CO3 (2.01 g, 14.6 mmol) in DME / H2O (60 mL, 5 / 1) was stirred at 80°C overnight under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (60 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=10 / 1) to give 229-3 (2.25 g, about 91% yield) as a solid. MS calculated value: 292.2; MS found value: 293.3 [M+H] + .

[0716] Synthesis of tert-butyl 4-fluoro-6-nitrobiphenyl-3-yl (4-fluorobenzyl)carbamate (229-4):

[0717]

[0718] To a solution of 229-3 (2.25 g, 6.61 mmol) in DCM (50 mL) were added (Boc)2O (2.88 g, 13.2 mmol), DMAP (168 mg, 1.32 mmol) and Et3N (1.34 g, 13.2 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was then poured into water and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 229-4 (2.81 g, approximately 96% yield) as a solid. MS calculated: 440.2; MS found: 385.1 [M+H] + .

[0719] Synthesis of tert-butyl 6-amino-4-fluorobiphenyl-3-yl (4-fluorobenzyl)carbamate (229-5):

[0720]

[0721] 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 at room temperature overnight. The reaction mixture was then filtered through Celite and concentrated to afford 229-5 as a solid (2.50 g, approximately 95% yield). MS Calcd: 410.2; MS Found: 355.1 [M+H] + .

[0722] Synthesis of tert-butyl 6-(2-chloroethylamino)-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-6):

[0723]

[0724] To a solution of 229-5 (2.50 g, 6.09 mmol) in EtOH (40 mL) were added 2-chloroacetaldehyde (2.39 g, 12.2 mmol in water, 40% concentration), NaBH3CN (768 mg, 12.2 mmol) and AcOH (732 mg, 12.2 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and basified with 1N NaOH until the pH reached 10. The mixture was extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 229-6 (2.50 g, approximately 87% yield) as a solid. MS calculated value: 472.2; MS found value: 317.3 [M+H] + .

[0725] Synthesis of tert-butyl 6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-7):

[0726]

[0727] A mixture of 229-6 (600 mg, 1.27 mmol), 1H-1,2,4-triazole (175 mg, 2.54 mmol) and Cs2CO3 (825 mg, 2.54 mmol) in DMF (15 mL) was stirred at 80 ° C overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give 229-7 (400 mg, about 62% yield) as a solid. MS calculated value: 505.2; MS found value: 506.2 [M+H] + .

[0728] 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):

[0729]

[0730] 229-7 (400 mg, 1.27 mmol) was dissolved in HCl / dioxane (10 mL, 1 N) and stirred at room temperature overnight. 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 x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to obtain SS20308-0229-01 (39 mg, approximately 12% yield) as an oil. MS calculated value: 405.2; MS found value: 406.0 [M+H] + .

[0731] 1 H 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).

[0732] Example 24

[0733]

[0734] Example route of Example 24 (SS20308-0232-01, SS20308-0275-01):

[0735]

[0736] 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):

[0737]

[0738] To a solution of 239-1 (180 mg, 0.89 mmol), 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (204 mg, 1.06 mmol) in CH2Cl2 (10 ml) was added AlMe3 (0.89 ml, 1.78 mmol, 2N in THF), and the reaction mixture was stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was cooled, BH3-DMS (0.89 ml, 1.78 mmol, 2N in THF) was added to the mixture and stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was completed, it 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 preparative HPLC to obtain SS20308-0232-01 (23 mg, about 7% yield) as an oil. MS calculated value: 379.1; MS found value: 380.0 [M+H] + .

[0739] 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 (t, J = 6.0Hz, 2H), 3.31 (t, J = 6.4Hz, 2H).

[0740] 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):

[0741]

[0742] To a solution of 239-1 (180 mg, 0.89 mmol), 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (170 mg, 1.06 mmol) in CH2Cl2 (10 ml) was added AlMe3 (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, BH3-DMS (0.89 ml, 1.78 mmol, 2N in THF) was added to the mixture and stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was completed, it was quenched with water and extracted with EtOAc (50 mL x3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by preparative HPLC to obtain SS20308-0275-01 (26 mg, about 8% yield) as an oil. MS calculated value: 347.2; MS found value: 348.2 [M+H] + .

[0743] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),7.98(s,1H),7.25-7.21(m,3H),7.17-7.13(m,1H),6.61(d,J=8.8Hz,2H),6.46(d,J=8.8Hz,2H),5.04(d ,J=8.8Hz,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).

[0744] Example 25

[0745]

[0746] Example route for Example 25:

[0747]

[0748] Synthesis of tert-butyl 3-(1H-1,2,4-triazol-1-yl)propylcarbamate (236-2):

[0749]

[0750] 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 at 60 ° C overnight. 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, 20 / 1) to give oily 236-2 (4.75 g, about 100% yield). MS calculated value: 226.1; MS found value: 227.2 [M+H] + .

[0751] 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).

[0752] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-6-nitrobiphenyl-3-amine dihydrochloride (262-3):

[0753]

[0754] A mixture of 236-2 (4.75 g, 21.0 mmol) in THF (80 mL) and 6N HCl (20 mL) was stirred at 60° C. overnight. The mixture was concentrated in vacuo. Ethanol was added to the residue and the mixture was concentrated again to give 236-3 (3.8 g, approximately 92% yield) as a solid.

[0755] 1 H 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).

[0756] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-4-nitroaniline (236-4):

[0757]

[0758] 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, dried, and concentrated to afford 236-4 as a solid (157 mg, approximately 94% yield). MS calculated: 265.1; MS found: 266.4 [M+H] + .

[0759] N 1 Synthesis of -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (236-5):

[0760]

[0761] A solution of 236-4 (157 mg, 0.59 mmol) and Pd / C (30 mg, 10%) in MeOH (5 mL) was stirred at room temperature under H2 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] + .

[0762] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-N 4 Synthesis of -(4-fluorobenzyl)benzene-1,4-diamine (SS20308-0236-01):

[0763]

[0764] A solution of 236-5 (140 mg, 0.6 mmol), 4-chlorobenzaldehyde (74 mg, 0.6 mmol), NaBH3CN (56 mg, 0.89 mmol) and AcOH (0.2 mL) in EtOH (20 mL) was stirred at room temperature overnight. The reaction mixture was basified with NaHCO3 solution and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (EtOAc) and preparative HPLC to give compound SS20308-0236-01 (82.3 mg, two-step yield approximately 40%) as a solid. MS calculated value: 343.2; MS found value: 344.0 [M+H] + .

[0765] 1H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.96(s,1H),7.37(dd,J=8.4,5.6Hz,2H),7.13(dd,J=8.8,8.8Hz,2H),6.47(dd,J=9.6,8.8Hz,1H),6.36(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).

[0766] Example 26

[0767]

[0768] Example route for Example 26:

[0769]

[0770] Synthesis of 3-bromo-N-(4-fluorobenzyl)-4-methylaniline (237-2):

[0771]

[0772] A mixture of 237-1 (200 mg g, 1.3 mmol), 4-fluorobenzaldehyde (190 mg, 1.6 mmol), AcOH (one drop) and NaCNBH3 (130 mg, 2.0 mmol) in CH2Cl2 (10 mL) was stirred at 80°C overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated to give 237-2 as an oil (150 mg, approximately 39% yield). MS calculated value: 216.1; MS found value: 294.3 [M+H] + .

[0773] N 3 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 1 Synthesis of -(4-fluorobenzyl)-4-methylbenzene-1,3-diamine (SS20308-0237-01):

[0774]

[0775] A mixture of 237-2 (130 mg, 0.44 mmol), 1H-1,2,4-triazole-1-propylamine (86 mg, 0.53 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), X-Phos (21 mg, 0.044 mmol) and Cs2CO3 (430 mg, 1.32 mmol) in toluene (3 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated, and the residual crude product was purified by preparative HPLC to give SS20308-0237-01 (13.5 mg, approximately 9% yield) as an oil. MS calculated value: 339.2; MS found value: 340.0 [M+H] + .

[0776] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),7.98(s,1H),7.96(dd,J=8.8,5.6Hz,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).

[0777] Example 27

[0778]

[0779] Example route for Example 27:

[0780]

[0781] Synthesis of 1,3-dibromo-5-fluoro-2-nitrobenzene (239-2):

[0782]

[0783] To a solution of 2,6-dibromo-4-fluoroaniline (5.0 g, 18.59 mmol) in dichloromethane (100 mL) was added 3-chloroperoxybenzoic 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 in vacuo to obtain a brown solid. The solid was dissolved in 50 mL of glacial acetic acid. To this solution were added 25 mL of a 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, then dried on the filter under air to obtain 239-2 (4.4 g, approximately 79% yield) as a solid. MS calculated value: 296.8; MS found value: 298.2 [M+H] + .

[0784] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-3,5-dibromo-4-nitroaniline (239-3):

[0785]

[0786] 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 give compound 239-3 (2.3 g, approximately 85% yield) as a solid. MS calculated value: 402.9; MS found value: 403.9 [M+H] + .

[0787] N 1 Synthesis of -(3-(1H-1,2,4-triazol-1-yl)propyl)benzene-1,4-diamine (239-4):

[0788]

[0789] 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 under H2 atmosphere at room temperature overnight. The mixture was filtered and concentrated to afford 239-4 (700 mg) as a crude oil. MS calculated: 217.1; MS found: 218.1 [M+H] + .

[0790] N 1-(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 -Synthesis of cyclohexylbenzene-1,4-diamine (SS20308-0239-01):

[0791]

[0792] To a solution of 239-4 (200.00 mg, 0.92 mmol) in EtOH (3 mL) and AcOH (3 mL) were added cyclohexanone (361.37 mg, 3.68 mmol) and NaBH3CN (173.54 mg, 2.76 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then basified with Na2CO3 (aq.) until the pH reached 7-8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give SS20308-0239-01 (15 mg, approximately 5% yield) as a solid. MS calculated: 299.2; MS found: 300.2 [M+H] + .

[0793] 1 H 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).

[0794] Example 28

[0795]

[0796] Example route for Example 28:

[0797]

[0798] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (SS20308-0240-01):

[0799]

[0800] To a solution of 239-4 (250.00 mg, 1.15 mmol) in EtOH (3 mL) and AcOH (3 mL) were added cyclohexanecarboxaldehyde (516.27 mg, 4.60 mmol) and NaBH3CN (216.93 mg, 3.45 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then basified with Na2CO3 (aq) until the pH reached 7-8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give SS20308-0240-01 (40 mg, approximately 11% yield) as a solid. MS calculated: 313.4; MS found: 314.2 [M+H] + .

[0801] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.97(s,1H),6.42-6.37(m,4H),4.76-4.69(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).

[0802] Example 29

[0803]

[0804] Example route for Example 29:

[0805]

[0806] Synthesis of N-(cyclohexylmethyl)-4-nitroaniline (242-2):

[0807]

[0808] To 242-1 (2.00g, 14.48 mmoles) and cyclohexanecarboxaldehyde (1.95g, 17.38 mmoles) in MeOH (25mL) is added NaBH CN (2.73g, 43.44 mmoles), the mixture is stirred at room temperature overnight. After the reaction is complete, the reaction mixture is poured into water (50mL) and extracted with EtOAc (40mL x 3). The organic layer is washed with salt water (2x50mL), dried with MgSO, and concentrated in vacuo, purified by column chromatography (petroleum ether / EtOAc=5 / 1) to obtain 242-2 (1.5g, about 44% yield) as a solid.

[0809] N 1 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (242-3):

[0810]

[0811] 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 at room temperature under a H2 atmosphere overnight. 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 give 242-3 (800 mg, approximately 92% yield) as a solid. MS calculated value: 204.2; MS found value: 205.4 [M+H] + .

[0812] N 1 -((3-(bromomethyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (242-4):

[0813]

[0814] To a solution of 242-3 (150 mg, 0.73 mmol) and 3-(bromomethyl)oxetane-3-carboxaldehyde (131 mg, 0.73 mmol) in MeOH (15 mL) was added NaBH CN (138 mg, 2.20 mmol) and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (2x30 mL), dried over MgSO and concentrated in vacuo to give oily 242-4 (160 mg, approximately 59% yield) by simple work-up. MS calculated value: 366.1; MS found value: 367.0 [M+H] + .

[0815] N 1 -((3-((1H-1,2,4-triazol-1-yl)methyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(cyclohexylmethyl)benzene-1,4-diamine (SS20308-0242-01):

[0816]

[0817] A mixture of 242-4 (160 mg, 0.44 mmol), 1H-1,2,4-triazole (60 mg, 0.87 mmol) and K2CO3 (180 mg, 1.31 mmol) in CH3CN (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 MgSO4, concentrated in vacuo, and purified by preparative HPLC to give SS20308-0242-01 (13 mg, approximately 8% yield) as an oil. MS calculated value: 355.2; MS found value: 356.1 [M+H] + .

[0818] 1 H 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,2H ),1.69-1.63(m,3H),1.51-1.45(m,1H),1.24-1.11(m,3H),0.94-0.86(m,2H).

[0819] Example 30

[0820]

[0821] Example route for Example 30:

[0822]

[0823] Synthesis of 5-nitro-N-(2,2,2-trifluoro-1-phenylethyl)pyridin-2-amine (0245-2):

[0824]

[0825] 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-ethylamine (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 hour under microwave irradiation. The reaction mixture was then filtered through diatomaceous earth and rinsed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc=100 / 1, 50 / 1, 20 / 1) to give compound 245-2 (0.3 g, about 20% yield) in solid form. MS calculated value: 297.1; MS found value: 298.1 [M+H] + .

[0826] Synthesis of tert-butyl 5-nitropyridin-2-yl (2,2,2-trifluoro-1-phenylethyl)carbamate (245-3):

[0827]

[0828] 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 preparative TLC (petroleum ether / EtOAc=10 / 1) to give 245-3 (171 mg, approximately 43% yield) as an oil. MS calculated value: 397.1; MS found value: 342.1 [M-55] + .

[0829] Synthesis of tert-butyl 5-aminopyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-4):

[0830]

[0831] A suspension of 245-3 (166 mg, 0.42 mmol) and palladium / carbon (166 mg, 10%) in EtOAc (20 mL) was vigorously stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to give the crude product 245-4 (153 mg, approximately 100% yield) as a solid. MS calculated: 367.2; MS found: 368.1 [M+H] + .

[0832] Synthesis of tert-butyl 5-nitropyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-5):

[0833]

[0834] To a solution of 245-4 (159 mg, 0.43 mmol), 2-chloroacetaldehyde (255 mg, 1.30 mmol, in water, 40% concentration) and glacial acetic acid (1 mL) in ethanol (10 mL) was added NaBH3CN (55 mg, 0.87 mmol). After stirring at room temperature for 16 hours, the reaction mixture was basified with NaHCO3 solution and extracted with EtOAc (10 mL x 3). The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=2 / 1) to give compound 245-5 (162 mg, approximately 87% yield) as an oil. MS calculated value: 429.1; MS found value: 430.3 [M+H] + .

[0835] 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):

[0836]

[0837] 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. Then, the reaction mixture was poured into cold water (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 2, ethyl acetate, dichloromethane / methanol=20 / 1) to give compound 245-6 (77 mg, about 44% yield) as an oil. MS calculated value: 462.2; MS found value: 463.3[M+H] + .

[0838] 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):

[0839]

[0840] A suspension of 245-6 (77 mg, 0.17 mmol) in HCl (4 M in dioxane, 10 mL) was stirred at room temperature for 16 hours. 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 x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (dichloromethane / methanol=15 / 1) to give compound SS20308-0245-01 (38 mg, approximately 63% yield) as an oil. MS calculated value: 362.2; MS found value: 363.3 [M+H] + .

[0841] 1 H 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,1H ), 6.87 (dd, J = 8.8, 2.8 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 5.97-5.86 (m, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.26 (t, J = 6.0 Hz, 2H), 3.37-3.30 (m, 2H).

[0842] Example 31

[0843]

[0844] Example route for Example 31:

[0845]

[0846] Synthesis of 5-bromo-N-(4-fluorobenzyl)pyridin-2-amine (246-2):

[0847]

[0848] A mixture of 246-1 (2.00 g, 11.4 mmol), (4-fluorophenyl)methanamine (2.85 g, 22.8 mmol) and K2CO3 (3.15 g, 22.8 mmol) in DMSO (50 mL) was stirred at room temperature overnight. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 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=10 / 1) to give 246-2 (500 mg, approximately 16% yield) as a solid. MS calculated value: 280.0; MS found value: 281.2 [M+H] + .

[0849] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -(4-fluorobenzyl)pyridine-2,5-diamine (SS20308-0246-01):

[0850]

[0851] 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 in a microwave reactor for 1 hour. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative HPLC to give SS20308-0246-01 (26 mg, approximately 9% yield) as a solid. MS calculated value: 312.2; MS found value: 313.1 [M+H] + .

[0852] 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 = 8.8Hz, 1H), 6.29 (t, J = 6.2Hz, 1H), 4.97 (t, J = 6.2Hz, 1H), 4.34 (d, J = 6.0Hz, 2H), 4.28 (t, J = 6.2Hz, 2H), 3.38-3.34 (m, 2H).

[0853] Example 32

[0854]

[0855] Example route for Example 32:

[0856]

[0857] Synthesis of 5-bromo-N-((4,4-difluorocyclohexyl)methyl)pyridin-2-amine (247-2):

[0858]

[0859] 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 hours. The reaction mixture was diluted with water (10 mL), and then the mixture was extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 247-2 (80 mg, about 92% yield) as an oil. MS calculated value: 304.0; MS found value: 305.2 [M+H] + .

[0860] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -((4,4-difluorocyclohexyl)methyl)pyridine-2,5-diamine (SS20308-0247-01):

[0861]

[0862] 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. under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative HPLC to give SS20308-0247-01 (7 mg, about 8% yield) as an oil. MS calculated value: 336.2; MS found value: 337.3 [M+H] + .

[0863] 1H 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,5H),1.23-1.10(m,2H).

[0864] Example 33

[0865]

[0866] Example route for Example 33:

[0867]

[0868] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-bromopyridin-2-amine (249-2):

[0869]

[0870] A mixture of 249-1 (600 mg, 3.41 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine dihydrochloride (757 mg, 4.09 mmol) and K2CO3 (1.18 g, 8.52 mmol) in DMF (10 ml) was stirred at 120 ° C overnight under a nitrogen atmosphere. After the reaction was completed, 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 column chromatography (petroleum ether / EtOAc=1 / 1) to give 249-2 (300 mg, about 33% yield) as a solid. MS calculated value: 267.0; MS found value: 268.0 [M+H] + .

[0871] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of -(4-fluorobenzyl)pyridine-2,6-diamine (SS20308-0249-01):

[0872]

[0873] A mixture of 249-2 (100 mg, 0.37 mmol), (4-fluorophenyl)methanamine (56 mg, 0.45 mmol), Pd2(dba)3 (17 mg, 0.02 mmol), X-Phos (18 mg, 0.04 mmol) and Cs2CO3 (243 mg, 0.75 mmol) in toluene (10 ml) was stirred at 110°C overnight under a nitrogen atmosphere. After completion of the reaction, 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 MgSO4, concentrated in vacuo, and purified by preparative HPLC to give SS20308-0249-01 (20 mg, approximately 17% yield) as an oil. MS calculated: 312.2; MS found: 313.0 [M+H] + .

[0874] 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).

[0875] Example 34

[0876]

[0877] Example route for Example 34:

[0878]

[0879] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of -((4,4-difluorocyclohexyl)methyl)pyridine-2,6-diamine (SS20308-0250-01):

[0880]

[0881] A mixture of 249-2 (100 mg, 0.37 mmol), (4,4-difluorocyclohexyl)methanamine (67 mg, 0.45 mmol), Pd2(dba)3 (17 mg, 0.02 mmol), X-Phos (18 mg, 0.04 mmol) and Cs2CO3 (243 mg, 0.75 mmol) in toluene (10 ml) was stirred at 110 ° C overnight 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 preparative HPLC to give SS20308-0250-01 (6 mg, about 5% yield) as an oil. MS calculated value: 336.2; MS found value: 337.3 [M+H] + .

[0882] 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, 1H), 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).

[0883] Example 35

[0884]

[0885] Example route for Example 35:

[0886]

[0887] Synthesis of 3-(2-(4-fluorobenzylamino)-6-(1H-indol-7-yl)phenyl)-N,N-dimethylpropionamide (253-1):

[0888]

[0889] A mixture of 171-6 (200 mg, 0.7 mmol), 1-(bromomethyl)-4-fluorobenzene (120 mg, 0.7 mmol) and Cs2CO3 (180 mg, 1.4 mmol) in DMF (5 mL) was stirred at 90 ° C for 18 hours. The reaction mixture was cooled to room temperature and poured into water (20 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated to a crude product. Purification by column chromatography (EtOAc / petroleum ether=5 / 1) gave 253-1 (50 mg, approximately 17% yield) as an oil. MS calculated value: 415.2; MS found value: 416.4 [M+H] + .

[0890] Synthesis of 2-(3-(dimethylamino)propyl)-N-(4-fluorobenzyl)-3-(indolin-7-yl)aniline (SS20308-0253-01):

[0891]

[0892] A mixture of 253-1 (40 mg, 100 micromoles (umol)) and BH3 (0.5 mL) in THF (1 mL) was stirred at room temperature for 18 hours. HCl (0.5 mL, 3N) and MeOH (1 mL) were added to the mixture and stirred at 70°C for 6 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo to give the crude product, which was then purified by preparative HPLC to give SS20308-0253-01 (1.84 mg, approximately 5% yield) as a light solid. MS calculated value: 403.5; MS found value: 404.3 [M+H] + .

[0893] 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,1H),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,1 H),2.34-2.32(m,1H),2.12-2.06(m,2H),2.02(s,6H),1.57-1.46(m,2H).

[0894] Example 36

[0895]

[0896] Example route for Example 36:

[0897]

[0898] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-4-nitroaniline (265-01):

[0899]

[0900] 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 completed, 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 column chromatography (PE / EtOAc=1 / 1) to give 265-1 (2.20 g, approximately 82% yield) as a solid. MS calculated value: 265.1; MS found value: 266.1 [M+H] + .

[0901] N 1 Synthesis of -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (265-2):

[0902]

[0903] 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 at room temperature under H2 atmosphere overnight. 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 give 265-01-3 (700 mg, approximately 79% yield) as an oil. MS calculated value: 235.1; MS found value: 236.0 [M+H] + .

[0904] 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):

[0905]

[0906] To a solution of 265-2 (250 mg, 1.06 mmol), 2,2,2-trifluoro-1-acetophenone (222 mg, 1.28 mmol) in CH2Cl2 (10 ml) was added AlMe3 (1.06 ml, 2.12 mmol, 2N in THF), and the reaction was stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was cooled, BH3-DMS (1.06 ml, 2.12 mmol, 2N in THF) was added to the mixture and stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was completed, it 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 preparative HPLC to give SS20308-0265-01 (33 mg, about 8% yield) as an oil. MS calculated value: 393.2; MS found value: 394.1 [M+H] + .

[0907] 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).

[0908] Example 37

[0909]

[0910] Example route of Example 37:

[0911]

[0912] 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):

[0913]

[0914] To a solution of 239-1 (180 mg, 0.89 mmol), 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (170 mg, 1.06 mmol) in CH2Cl2 (10 ml) was added AlMe3 (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, BH3-DMS (0.89 ml, 1.78 mmol, 2N in THF) was added to the mixture and stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was completed, it was quenched with water and extracted with EtOAc (50 mL x3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by preparative HPLC to obtain SS20308-0275-01 (26 mg, about 8% yield) as an oil. MS calculated value: 347.2; MS found value: 348.2 [M+H] + .

[0915] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),7.98(s,1H),7.25-7.21(m,3H),7.17-7.13(m,1H),6.61(d,J=8.8Hz,2H),6.46(d,J=8.8Hz,2H),5.04(d ,J=8.8Hz,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).

[0916] Example 38

[0917]

[0918] Example route for Example 38:

[0919]

[0920] Synthesis of 3-(2-fluoro-4-nitrophenylamino)propan-1-ol (302-2):

[0921]

[0922] 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 hours. After the reaction was completed, 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 column chromatography (petroleum ether / EtOAc=1 / 2) to give 302-2 (2.00 g, about 93% yield) as an oil. MS calculated value: 214.1; MS found value: 215.2 [M+H] + .

[0923] Synthesis of 3-(4-amino-2-fluorophenylamino)propan-1-ol (302-3):

[0924]

[0925] 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 under H2 atmosphere for 4 hours. 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 give 302-3 (1.5 g, about 92% yield) as an oil. MS calculated value: 184.1; MS found value: 185.2 [M+H] + .

[0926] Synthesis of 3-(2-fluoro-4-(2,2,2-trifluoro-1-phenylethylamino)phenylamino)propan-1-ol (302-4):

[0927]

[0928] To a solution of 302-3 (500 mg, 2.71 mmol), 2,2,2-trifluoro-1-acetophenone (614 mg, 353 mmol) in CH2Cl2 (10 ml) was added AlMe3 (2.71 ml, 5.42 mmol, 2N in THF), and the reaction was stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was cooled, BH3-DMS (2.71 ml, 5.42 mmol, 2N in THF) was added to the mixture and stirred at 40 ° C for 2 hours under a nitrogen atmosphere. After the reaction was completed, it 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 preparative HPLC to give 302-4 (400 mg, about 43% yield) as an oil. MS calculated value: 342.1; MS found value: 343.0 [M+H]+ .

[0929] Synthesis of 3-(2-fluoro-4-(2,2,2-trifluoro-1-phenylethylamino)phenylamino)propyl methanesulfonate (302-5):

[0930]

[0931] To a solution of 302-4 (250 mg, 0.73 mmol) in CH2Cl2 (20 mL) were added Ms2O (153 mg, 0.88 mmol) and DIPEA (189 mg, 1.46 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, it was quenched with water and extracted with CH2Cl2 (50 mL x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 302-5 (160 mg, approximately 52% yield) as an oil. MS calculated value: 327.1; MS found value: 328.2 [M+H] + .

[0932] N 1 -(3-(dimethylamino)propyl)-2-fluoro-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0302-01):

[0933]

[0934] To a solution of 302-5 (160 mg, 0.38 mmol) in CH3CN (20 mL) were added dimethylamine hydrochloride (47 mg, 0.57 mmol) and K2CO3 (210 mg, 1.52 mmol), and the mixture was stirred at 80°C for 4 hours. After completion of the reaction, it 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 preparative HPLC to give SS20308-0302-01 (24 mg, approximately 17% yield) as an oil. MS calculated value: 369.2; MS found value: 370.2 [M+H] + .

[0935] 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=10.8Hz ,1H),5.31-5.36(m,1H),4.63(t,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).

[0936] Example 39

[0937]

[0938] Example route of Example 39:

[0939]

[0940] Synthesis of 2-bromo-N-(3-morpholinopropyl)-4-nitroaniline (315-2):

[0941]

[0942] 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 give compound 0315-2 (1.4 g, approximately 89% yield) in solid form. MS calculated value: 343.1; MS found value: 344.0 [M+H] + .

[0943] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(3-morpholinopropyl)-4-nitroaniline (315-3):

[0944]

[0945] To 315-2 (1g, 2.91 mmol), palladium (II) acetate (33mg, 0.15 mmol), S-phos (120mg, 0.29 mmol), 2- (3,6- dihydro -2H- pyrans -4- bases) -4,4,5,5- tetramethyl -1,3,2- dioxaborolane (672mg, 3.20 mmol) and potassium phosphate (2.16g, 10.17 mmol) in toluene (40mL) is added water (2mL) and stirred at 110 DEG C for 16 hours under N2. The reaction mixture is filtered through diatomaceous earth and rinsed with EtOAc. The filtrate is concentrated and the residue is purified by column chromatography (petroleum ether / EtOAc = 1 / 1, 100% EtOAc, DCM / methanol = 50 / 1) to obtain compound 0315-3 (700mg, about 69% yield) as a solid. MS calculated value: 347.2; MS found value: 348.3 [M+H] + .

[0946] N 1 Synthesis of -(3-morpholinopropyl)-2-(tetrahydro-2H-pyran-4-yl)benzene-1,4-diamine (315-4):

[0947]

[0948] A suspension of 315-3 (650 mg, 1.87 mmol) and palladium / activated carbon (10%, 130 mg) in EtOAc (20 mL) was stirred vigorously under hydrogen (balloon) at room temperature for 16 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to give the crude product 315-4 (597 mg, approximately 100% yield) as an oil. MS calculated: 319.2; MS found: 320.3 [M+H] + .

[0949] 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):

[0950]

[0951] A mixture of 315-4 (100 mg, 0.31 mmol) and trimethylaluminum (2 M in hexane) (0.23 mL, 0.46 mmol) in dichloromethane (10 mL) was heated to 40 ° C and maintained for 2 hours. 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 hours, the reaction mixture was quenched with methanol at 0 ° C and then concentrated. The residue was alkalized with NaHCO solution and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with water and brine, dried over Na SO and concentrated. The residue was purified by preparative TLC (DCM / methanol=20 / 1) to obtain compound SS20308-0315-01 (33.8 mg, about 23% yield) in solid form. MS calculated value: 477.3; MS found value: 478.3 [M+H] + .

[0952] 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).

[0953] Example 40

[0954]

[0955] Example 41

[0956]

[0957] Example route of Example 41:

[0958]

[0959] Synthesis of 2-cyclohexenyl-N-(3-morpholinopropyl)-4-nitroaniline (325-1):

[0960]

[0961] To a mixture of 315-2 (580 mg, 1.69 mmol), cyclohexene-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 (g) 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 give compound 325-1 (548 mg, about 94% yield) as an oil. MS calculated value: 345.2; MS found value: 346.2 [M+H] + .

[0962] 2-cyclohexyl-N 1 Synthesis of -(3-morpholinopropyl)benzene-1,4-diamine (325-2):

[0963]

[0964] A suspension of 325-1 (550 mg, 1.59 mmol) and palladium / activated carbon (10%, 55 mg) in EtOAc (10 mL) was vigorously stirred under hydrogen (balloon) at room temperature for 16 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to give the crude product 325-2 (498 mg, approximately 99% yield) as an oil. MS calculated: 317.3; MS found: 318.3 [M+H] + .

[0965] 2-cyclohexyl-N 1 -(3-morpholinopropyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0325-01):

[0966]

[0967] A mixture of 325-2 (100 mg, 0.31 mmol) and trimethylaluminum (2M in hexane) (0.24 mL, 0.48 mmol) in dichloromethane (10 mL) was heated to 40 ° C for 2 hours. The reaction mixture was cooled to room temperature and borane-methyl sulfide complex (2M in THF) (0.8 mL, 1.6 mmol) was added. After stirring at 40 ° C for 2 hours, the reaction mixture was quenched with methanol at 0 ° C and then concentrated. The residue was alkalized with NaHCO3 solution and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM / methanol=20 / 1) to obtain compound SS20308-0325-01 (85.4 mg, about 57% yield) in solid form. MS calculated value: 475.3; MS found value: 476.4 [M+H] + .

[0968] 1 H NMR (400MHz, DMSO-d6) δ7.59 (d, J = 6.8 Hz, 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).

[0969] Example 42

[0970]

[0971] Example route for Example 42:

[0972]

[0973] Synthesis of 2-bromo-N-(3-morpholinopropyl)-4-nitroaniline (326-1):

[0974]

[0975] A mixture of compound 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 give compound 326-1 (2.95 g, approximately 99% yield) as a solid. MS calculated value: 327.1; MS found value: 328.0 [M+H] + .

[0976] Synthesis of 2-cyclohexenyl-4-nitro-N-(3-(pyrrolidin-1-yl)propyl)aniline (326-2):

[0977]

[0978] To a mixture of 326-1 (1.00 g, 3.05 mmol), cyclohexene-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 hours 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, DCM / methanol=20 / 1) to give compound 326-2 (1.0 g, about 100% yield) as an oil. MS calculated value: 329.2; MS found value: 330.3 [M+H] + .

[0979] 2-cyclohexyl-N 1 Synthesis of -(3-(pyrrolidin-1-yl)propyl)benzene-1,4-diamine (0326-3):

[0980]

[0981] A suspension of 326-2 (1.00 g, 3.04 mmol) and palladium / activated carbon (10%, 110 mg) in EtOAc (15 mL) was stirred vigorously at room temperature under hydrogen (balloon) for 16 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to give the crude product 326-3 (915 mg, approximately 100% yield) as an oil. MS calculated: 301.3; MS found: 302.2 [M+H] + .

[0982] 2-cyclohexyl-N1 -(3-(Pyrrolidin-1-yl)propyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)benzene-1,4-diamine (SS20308-0326-01):

[0983]

[0984] A mixture of 326-3 (100 mg, 0.33 mmol) and trimethylaluminum (2 M in hexane) (0.25 mL, 0.50 mmol) in dichloromethane (10 mL) was heated to 40 ° C and maintained for 2 hours. 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 hours, the reaction mixture was quenched with methanol at 0 ° C and then concentrated. The residue was alkalized with NaHCO solution and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with water and brine, dried with Na SO and concentrated. The residue was purified by preparative TLC (DCM / methanol=10 / 1) to obtain oily compound SS20308-0326-01 (16.3 mg, about 11% yield). MS calculated value: 459.3; MS found value: 460.3 [M+H] + .

[0985] 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(d,J=8.4Hz,1H),6.51(dd,J=8.8,2.8H z,1H),4.99(q,J=8.0Hz,1H),3.10(t,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).

[0986] Example 43

[0987]

[0988] Example route for Example 43:

[0989]

[0990] Synthesis of 1-(2-(2-nitrophenoxy)ethyl)-1H-1,2,4-triazole (33-2):

[0991]

[0992] A mixture of 33-1 (3.7 g, 26.60 mmol), 1-(2-bromoethyl)-1H-1,2,4-triazole (7.0 g, 39.90 mmol) and K2CO3 (7.4 g, 53.20 mmol) in DMF (70 mL) was stirred at 70 ° C overnight. The reaction mixture was cooled to room temperature and poured into water (150 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (CH2Cl2 / MeOH=100 / 1~30 / 1) to give 0016-01-3 (2.0 g, about 32% yield) as a solid. MS calculated value: 234.1; MS found value: 235.2 [M+H] + .

[0993] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)aniline (33-3):

[0994]

[0995] 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 at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove the solvent. The residue was purified by column chromatography (CH2Cl2 / MeOH = 100 / 1 to 20 / 1) to give 33-3 as an oil (1.0 g, approximately 57% yield). MS calculated value: 204.1; MS found value: 205.3 [M+H] + .

[0996] Synthesis of ethyl 4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenylamino)benzoate (SS20308-0033-01):

[0997]

[0998] 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 at 110° C. overnight. 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 give a solid, which was purified by column chromatography (CHCl / MeOH=100 / 1 to 20 / 1) and preparative HPLC to give SS20308-0033-01 (700 mg, approximately 40% yield) as a solid. MS calculated value: 352.2; MS found value: 353.3 [M+H] + .

[0999] 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=5.0Hz,2H),4.57(q,J=7.2Hz,2H),1.38(t,J=7.0Hz,3H).

[1000] Example 44

[1001]

[1002] Example route for Example 44:

[1003]

[1004] Synthesis of 1-(2-(2-bromo-6-nitrophenoxy)ethyl)-1H-1,2,4-triazole (55-2):

[1005]

[1006] 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 at 60 ° C overnight. The reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with EtOAc (70 mL x 3). The organic layer was washed with brine and concentrated. The residue was purified by column chromatography (CH2Cl2 / MeOH=100 / 1~20 / 1) to give 55-2 (2.2 g, about 70% yield) as an oil. MS calculated value: 312.0; MS found value: 313.0 [M+H] + .

[1007] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-3-nitro-N-phenylaniline (55-3):

[1008]

[1009] A solution of 55-2 (1.1 g, 3.51 mmol), aniline (393 mg, 4.22 mmol), Pd2(dba)3 (321 mg, 0.35 mmol), Xant-Phos (203 mg, 0.35 mmol) and Cs2CO3 (1.7 g, 5.27 mmol) in toluene (30 ml) was stirred at 110° C. overnight under a nitrogen atmosphere. The reaction mixture was then poured into water (100 mL) and extracted with EtOAc (40 mL x 4). The organic layer was washed with water (50 mL) and brine (2 x 50 mL), and the solvent was evaporated to give a solid, which was purified by column chromatography (CH2Cl2 / MeOH=100 / 1 to 20 / 1) to give 55-3 (700 mg, approximately 83% yield) as an oil. MS calculated value: 325.1; MS found value: 326.2 [M+H] + .

[1010] 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-N 1 -Synthesis of phenylbenzene-1,3-diamine (55-4):

[1011]

[1012] To a solution of 55-3 (550 mg, 1.69 mmol) in MeOH (20 mL) was added Pd / C (10%, 100 mg) and stirred at room temperature overnight. The reaction mixture was filtered and washed with methanol (10 mL x 4). The solvent was concentrated and purified by column chromatography (CH2Cl2 / MeOH = 100 / 1 to 20 / 1) to give 55-4 as a solid (400 mg, approximately 80% yield). MS calculated value: 295.1; MS found value: 296.1 [M+H] + .

[1013] Synthesis of ethyl 4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-3-(phenylamino)phenylamino)benzoate (SS20308-0055-01):

[1014]

[1015] A solution of 55-4 (250 mg, 0.85 mmol), ethyl 4-bromobenzoate (291 mg, 1.27 mmol), Pd2(dba)3 (78 mg, 0.085 mmol), Xant-Phos (49 mg, 0.085 mmol) and Cs2CO3 (552 mg, 1.69 mmol) in toluene (6 ml) was stirred at 110°C overnight under a nitrogen atmosphere. The reaction mixture was then poured into water (15 mL) and extracted with EtOAc (10 mL x 5). The organic layer was washed with water (10 mL) and brine (2 x 10 mL), and the solvent was evaporated to give a solid, which was purified by column chromatography (CH2Cl2 / MeOH=80 / 1 to 30 / 1) and preparative HPLC to give 55-3 (67 mg, approximately 18% yield) as a solid. MS calculated value: 443.2; MS found value: 444.2 [M+H] + .

[1016] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.16(s,1H),7.99(s,1H),7.78(d,J=8.8H z,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,1H),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).

[1017] Example 45

[1018]

[1019] Example route for Example 45:

[1020]

[1021] Synthesis of 3-bromo-2-(2-(dimethylamino)ethoxy)aniline (72-2):

[1022]

[1023] A mixture of 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) was stirred at 85°C for 2 hours. The reaction mixture was then filtered through celite. The filtrate was basified with NaOH solution to a pH of 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 give 72-2 as a solid (0.7 g, approximately 78% yield). MS calculated: 258.0; MS found: 259.2 [M+H] + .

[1024] Synthesis of N-(3-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-3-oxo-3-phenylpropionamide (72-3):

[1025]

[1026] 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 to 140° C. under microwave irradiation and a nitrogen atmosphere for 0.5 hours. The reaction mixture was purified by silica gel column chromatography (petroleum ether / EtOAc=10 / 1, 5 / 1, 3 / 1, 1 / 1, CH 2 Cl 2 / MeOH=20 / 1) to give 72-3 (400 mg, approximately 62% yield) as a solid. MS calculated value: 404.1; MS found value: 405.3 [M+H] + .

[1027] Synthesis of 7-bromo-8-(2-(dimethylamino)ethoxy)-4-phenylquinolin-2(1H)-one (72-4):

[1028]

[1029] A mixture of 72-3 (500 mg, 1.23 mmol) in H2SO4 (5 mL) was stirred and heated to 80°C for 4 hours. The reaction mixture was cooled to room temperature and poured into ice, basified with NaOH (40%) solution until the pH reached 9.0-10.0 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (CH2Cl2 / MeOH=20 / 1) to give 72-4 (70 mg, approximately 15% yield) as an oil. MS calculated value: 386.1; MS found value: 387.2 [M+H] + .

[1030] Synthesis of 8-(2-(dimethylamino)ethoxy)-4-phenyl-7-(phenylamino)quinolin-2(1H)-one (SS20308-0072-01):

[1031]

[1032] A solution of 72-4 (60 mg, 0.15 mmol), aniline (73 mg, 0.78 mmol), Xantphos (9 mg, 0.016 mmol), Pd2(dba)3 (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 overnight under a nitrogen atmosphere and then filtered and rinsed with EtOAc. The filtrate was concentrated and purified by preparative TLC (CH2Cl2 / MeOH=20 / 1) to give SS20308-0072-01 (35 mg, approximately 57% yield) as a solid. MS calculated value: 399.2; MS found value: 400.4 [M+H] + .

[1033] 1 H 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,2H ),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).

[1034] Example 46

[1035]

[1036] Example route for Example 46:

[1037]

[1038] Synthesis of 4-bromo-2-nitrobiphenyl (95-2):

[1039]

[1040] By 95-1 (6.00g, 21.36 mmol), phenylboronic acid (2.60g, 21.36 mmol), Pd(PPh 3 ) 4 (1.23g, 1.07 mmol) and Na CO 3 (7.90g, 74.76 mmol) in toluene / H 2 O (60mL, 5 / 1) mixture in N 2 atmosphere at 90 ℃ and stir overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (60mL x 3). The organic layer was washed with salt water, used Na 2 SO 4 dried, and concentrated. Residue was purified by column chromatography (petroleum ether) to obtain oily 95-2 (3.70g, about 62% yield).

[1041] 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).

[1042] Synthesis of 4-bromobiphenyl-2-amine (95-3):

[1043]

[1044] 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 at room temperature overnight. 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 x 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 give 95-3 (1.90 g, approximately 58% yield) as an oil. MS calculated value: 247.0; MS found value: 248.1 [M+H] + .

[1045] Synthesis of 4-bromo-N-(2-chloroethyl)biphenyl-2-amine (95-4):

[1046]

[1047] To a solution of 95-3 (1.75 g, 7.05 mmol) in MeOH (20 mL) were added 2-chloroacetaldehyde (2.77 g, 14.11 mmol in water, 40% concentration), AcOH (846 mg, 14.11 mmol) and NaBH3CN (887 mg, 14.11 mmol), and the reaction mixture was stirred at 40°C overnight. 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=20 / 1) to give 95-4 (2.00 g, approximately 91% yield) as an oil. MS calculated value: 309.0; MS found value: 309.8 [M+H] + .

[1048] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromobiphenyl-2-amine (95-5):

[1049]

[1050] A mixture of 95-4 (2.00 g, 6.44 mmol), 1H-1,2,4-triazole (677 mg, 9.66 mmol) and Cs2CO3 (4.20 g, 12.88 mmol) in CH3CN (40 mL) was stirred at 80°C overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=2 / 1) to give 95-5 (2.10 g, approximately 95% yield) as an oil. MS calculated value: 342.1; MS found value: 342.8 [M+H] + .

[1051] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of phenylbiphenyl-2,4-diamine (SS20308-0095-01):

[1052]

[1053] 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 at 110 ° C. under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative HPLC to give SS20308-0095-01 (45 mg, approximately 22% yield) as a solid. MS calculated value: 355.2; MS found value: 356.1 [M+H] + .

[1054] 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, 2H) ), 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).

[1055] Example 47

[1056]

[1057] Example route of Example 47:

[1058]

[1059] Synthesis of 4-chloro-2-nitro-1,1'-biphenyl (129-2):

[1060]

[1061] To a mixture of 129-1 (2.36 g, 10 mmol) and phenylboronic acid (1.22 g, 10 mmol) in toluene / H2O (50 mL / 5 mL) was added Cs2CO3 (6.52 g, 20 mmol) and Xphos Pd G2 (200 mg). The mixture was heated at reflux for 6 hours. The mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL) in sequence. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=15 / 1) to give 129-2 (1.2 g, approximately 51% yield) as an oil. MS calculated value: 233.0; MS found value: 234.2 [M+H] + .

[1062] Synthesis of 4-chloro-[1,1'-biphenyl]-2-amine (129-3):

[1063]

[1064] 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 at room temperature for 4 hours. The reaction mixture was filtered and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=5 / 1) to give 129-3 (800 mg, approximately 77% yield) as an oil. MS calculated value: 203.1; MS found value: 204.2 [M+H] + .

[1065] Synthesis of 4-chloro-N-(2-chloroethyl)-[1,1'-biphenyl]-2-amine (129-4):

[1066]

[1067] 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. To this mixture was added NaBH3CN (0.5 g) and the resultant was stirred at room temperature for 6 hours. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane / EtOAc=3 / 1) to give 129-4 (380 mg, approximately 71% yield) as a colorless oil. MS calculated value: 265.0; MS found value: 266.2 [M+H] + .

[1068] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-[1,1'-biphenyl]-2-amine (129-5):

[1069]

[1070] 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 Cs2CO3 (913 mg, 2.8 mmol) at room temperature. The mixture was stirred at 80°C for 8 hours. The mixture was diluted with DCM (30 mL). The mixture was washed with H2O (40 mL) and brine (40 mL) in sequence. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=1 / 5) to give 129-5 (260 mg, approximately 61% yield) as a solid. MS calculated value: 298.1; MS found value: 299.2 [M+H] + .

[1071] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0129):

[1072]

[1073] To a mixture 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 at reflux under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (80 mL). The filtrate was washed with water (100 mL) and brine (100 mL) in sequence. The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=5 / 1 to 1 / 5) to give SS20308-0129 (20 mg, approximately 13% yield) as an oil. MS calculated value: 355.2; MS found value: 356.2 [M+H] + .

[1074] 1H NMR (400MHz, DMSO-d6) δ3.36-3.44(m,2H),4.30(t,J=6.02Hz,2H),4.34-4.38(m,1H),4.71(br t,J=5.77Hz,1H),6.24(t,J=2.01Hz,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).

[1075] Example 48

[1076]

[1077] Example route of Example 48:

[1078]

[1079] Synthesis of N1-(4-chloro-[1,1'-biphenyl]-2-yl)-N2,N2-dimethylethane-1,2-diamine (130-1):

[1080]

[1081] To a mixture of 129-4 (380 mg, 1.4 mmol) in DMF (10 mL) was added dimethylamine (7 mL, 14 mmol) and Cs2CO3 (913 mg, 2.8 mmol) at room temperature, and the mixture was then stirred at 80°C for 8 hours. The mixture was diluted with DCM (30 mL). The mixture was washed with H2O (40 mL) and brine (40 mL) in sequence. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=1 / 5) to give 130-1 (220 mg, approximately 56% yield) as an oil. MS calculated value: 274.1; MS found value: 275.2 [M+H] + .

[1082] Synthesis of N2-(2-(dimethylamino)ethyl)-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0130):

[1083]

[1084] To a mixture of 130-1 (137 mg, 0.5 mmol) in dioxane (5 mL) was added aniline (74.4 mg, 0.8 mmol), Cs2CO3 (326 g, 1 mmol) and xphosPdG2 (30 mg) at room temperature. The mixture was heated under reflux for 12 hours under nitrogen. 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) in sequence. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=20 / 1 to 4 / 1) to give SS20308-0130 (10 mg, approximately 13% yield) as a solid. MS calculated value: 331.2; MS found value: 332.2 [M+H] + .

[1085] 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).

[1086] Example 49

[1087]

[1088] Example route of Example 49:

[1089]

[1090] Synthesis of 4-chloro-N-(2-chloroethyl)-N-methyl-[1,1'-biphenyl]-2-amine (131-1):

[1091]

[1092] To a mixture of 129-4 (266 mg, 1 mmol) in EtOH (30 mL) was added HCHO (aq. (aq.)) (3 mL) and HOAc (2 mL) at room temperature, followed by NaBH3CN (0.5 g), and the mixture was stirred at room temperature for 6 hours. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane / EtOAc = 1 / 1) to give 131-1 (180 mg, approximately 64% yield) as an oil. MS calculated value: 279.1; MS found value: 280.2 [M+H] + .

[1093] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-N-methyl-[1,1'-biphenyl]-2-amine (131-2):

[1094]

[1095] 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 Cs2CO3 (652 mg, 2 mmol) at room temperature. The mixture was stirred at 80°C for 8 hours. The mixture was diluted with DCM (30 mL), washed with saturated H2O (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 by silica gel column chromatography (hexane / EtOAc=1 / 6) to give 131-2 (120 mg, approximately 60% yield) as an oil. MS calculated value: 312.1; MS found value: 313.2 [M+H] + .

[1096] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N2-methyl-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0131):

[1097]

[1098] 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 xphosPdG2 (30 mg) at room temperature. The mixture was heated at reflux under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, 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 by silica gel column chromatography (hexane / EtOAc=5 / 1 to 1 / 4) to give SS20308-0131 (28 mg, approximately 20% yield) as a solid. MS calculated value: 369.2; MS found value: 370.2 [M+H] + .

[1099] 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).

[1100] Example 50

[1101]

[1102] Example route of Example 50:

[1103]

[1104] Synthesis of 4-bromo-2-(2-bromoethoxy)-1-chlorobenzene (132-2):

[1105]

[1106] To a mixture of 132-1 (412 mg, 2 mmol) in acetone (50 mL) was added 1,2-dibromoethane (744 mg, 4 mmol) and Cs2CO3 (1.3 g, 4 mmol) at room temperature. The mixture was stirred at 70°C for 8 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=20 / 1) to give 132-2 (380 mg, approximately 61% yield) as an oil. MS calculated value: 311.9; MS found value: 312.9 [M+H]+ .

[1107] Synthesis of 1-(2-(5-bromo-2-chlorophenoxy)ethyl)-1H-1,2,4-triazole (132-3):

[1108]

[1109] To a mixture of 132-2 (312 mg, 1.0 mmol) in DMF (10 mL) was added 1H-1,2,4-triazole (138 mg, 2.0 mmol) and Cs2CO3 (652 mg, 2.0 mmol) at room temperature. The mixture was stirred at 80°C for 8 hours. The mixture was diluted with DCM (30 mL) and washed sequentially with H2O (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 by silica gel column chromatography (hexane / EtOAc=1 / 3) to give 132-3 (220 mg, approximately 73% yield) as an oil. MS calculated value: 301.0; MS found value: 302.2 [M+H] + .

[1110] Synthesis of 3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-4-chloro-N-phenylaniline (132-4):

[1111]

[1112] 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 G2 (30 mg) at room temperature, and the mixture was heated under reflux for 12 hours under nitrogen. The reaction mixture was cooled to room temperature, 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 by silica gel column chromatography (hexane / EtOAc=5 / 1 to 1 / 5) to give 132-4 (80 mg, approximately 35% yield) as an oil. MS calculated value: 314.1; MS found value: 315.1 [M+H] + .

[1113] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-N-phenyl-[1,1'-biphenyl]-4-amine (SS20308-0132):

[1114]

[1115] To a mixture of 132-4 (80 mg, 0.25 mmol) and phenylboronic acid (61 mg, 0.5 mmol) in toluene / H2O (15 mL / 3 mL) were added Cs2CO3 (326 mg, 1 mmol) and xphosPdG2 (15 mg). The mixture was heated at reflux for 6 hours. The mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give SS20308-0132 (15 mg, approximately 16% yield) as a solid. MS calculated value: 356.2; MS found value: 357.2 [M+H] + .

[1116] 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).

[1117] Example 51

[1118]

[1119] Example route of Example 51:

[1120]

[1121] Synthesis of 4-chloro-2',6'-dimethyl-2-nitro-1,1'-biphenyl (133-2):

[1122]

[1123] To a mixture of 133-1 (235 mg, 1 mmol) and (2,6-dimethylphenyl)boronic acid (180 mg, 1.2 mmol) in toluene / H2O (15 mL / 3 mL) were added Cs2CO3 (652 mg, 2 mmol) and Xphos Pd G2 (20 mg), and the mixture was heated at reflux for 6 hours. The solution was cooled to room temperature and diluted with ethyl acetate (30 mL), and the organic layer was washed with water (30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=15 / 1) to give 133-2 (90 mg, approximately 35% yield) as an oil. MS calculated value: 261.1; MS found value: 262.2 [M+H] + .

[1124] Synthesis of 4-chloro-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-3):

[1125]

[1126] 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 at room temperature for 4 hours, filtered, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc = 4 / 1) to give 133-3 as an oil (200 mg, approximately 86% yield). MS calculated value: 231.1; MS found value: 232.2 [M+H] + .

[1127] Synthesis of 4-chloro-N-(2-chloroethyl)-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-4):

[1128]

[1129] 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 the addition of NaBH3CN (0.3 g), and the mixture was stirred at room temperature for 6 hours. The solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (hexane / EtOAc=1 / 1) to give 133-4 (160 mg, approximately 63% yield) as a colorless oil. MS calculated value: 293.1; MS found value: 293.2 [M+H] + .

[1130] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-5):

[1131]

[1132] 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 Cs2CO3 (326 mg, 1 mmol) at room temperature. The mixture was stirred at 80°C for 8 hours, diluted with DCM (30 mL), 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 by silica gel column chromatography (hexane / EtOAc=1 / 3) to give 133-5 (120 mg, approximately 67% yield) as a solid. MS calculated value: 326.1; MS found value: 327.2 [M+H] +

[1133] 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):

[1134]

[1135] 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 at reflux under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (40 mL). The filtrate was washed 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 by silica gel column chromatography (DCM / MeOH=10 / 1) to give SS20308-0133 (37 mg, approximately 26% yield) as a solid. MS calculated value: 383.2; MS found value: 384.2 [M+H] +

[1136] 1H 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,1H),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).

[1137] Example 52

[1138]

[1139] Example route for Example 52:

[1140]

[1141] Synthesis of ethyl 3-(1H-1,2,4-triazol-1-yl)propionate (134-2):

[1142]

[1143] To a mixture of 134-1 (500 mg, 2.8 mmol) in CH3CN (50 mL) was added 1H-1,2,4-triazole (241 mg, 3.5 mmol) and Cs2CO3 (1.6 g, 5 mmol) at room temperature. The mixture was stirred at 80°C for 8 hours. The solution was filtered and the solid was washed with DCM (50 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=1 / 5) to give 134-2 (300 mg, about 64% yield) as a colorless oil. MS calculated value: 169.1; MS found value: 170.2 [M+H] +

[1144] Synthesis of 3-(1H-1,2,4-triazol-1-yl)propionic acid (134-3):

[1145]

[1146] To a mixture of 134-2 (300 mg, 1.8 mmol) in MeOH (30 mL) was added LiOH (228 mg, 6 mmol). The mixture was stirred at room temperature for 6 hours. HCl (2 M) was added to the solution until the pH was 3-4, and the mixture was concentrated under reduced pressure to give the crude product 134-2 (400 mg, approximately 80% yield) as a colorless oil, which was used in the next step without further purification. MS calculated value: 141.1; MS found value: 142.2 [M+H] +

[1147] Synthesis of 4-bromo-3-nitro-N-phenylaniline (134-5):

[1148]

[1149] 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)2 (362 g, 2 mmol) and TEA (300 mg, 3 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (hexane / EtOAc=15 / 1 to 3 / 1) to give 134-5 (256 mg, approximately 44% yield) as an oil. MS calculated value: 292.0; MS found value: 293.2 [M+H] +

[1150] Synthesis of 2-nitro-N-phenyl-[1,1'-biphenyl]-4-amine (134-6):

[1151]

[1152] To a mixture of 134-5 (292 mg, 1 mmol) and phenylboronic acid (146 mg, 1.2 mmol) in toluene / H2O (25 mL / 5 mL) were added K2CO3 (276 mg, 2 mmol) and Sphos Pd G2 (40 mg). The mixture was heated at reflux for 6 hours. The mixture was diluted with EtOAc (30 mL), and the organic layer was washed with water (30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=2 / 1) to give 134-6 (220 mg, approximately 76% yield) as a solid. MS calculated value: 290.1; MS found value: 291.2 [M+H] +

[1153] Synthesis of N4-phenyl-[1,1'-biphenyl]-2,4-diamine (134-7):

[1154]

[1155] 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 at room temperature for 4 hours. The reaction mixture was filtered and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc=1 / 2) to give 134-7 (140 mg, approximately 71% yield) as an oil. MS calculated value: 260.1; MS found value: 261.2 [M+H] +

[1156] Synthesis of N-(4-(phenylamino)-[1,1'-biphenyl]-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (SS20308-0134):

[1157]

[1158] 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 hours. 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 hours, 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 by silica gel column chromatography (hexane / EtOAc=5 / 1 to 1 / 5) to give SS20308-0134 (40 mg, about 21% yield) as a solid. MS calculated value: 383.5; MS found value: 384.2 [M+H] +

[1159] 1 H 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),7.1 2(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).

[1160] Example 53

[1161]

[1162] Example route for Example 53:

[1163]

[1164] Synthesis of 4-chloro-2-fluoro-6-nitroaniline (141-2):

[1165]

[1166] 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. The mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL). The solid was obtained by filtration, washed with water and dried in vacuo to give 141-2 (4.5 g, approximately 74% yield) as a solid.

[1167] Synthesis of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (141-3):

[1168]

[1169] To a solution of 141-2 (900 mg, 4.7 mmol) in CH 3 CN (10 mL) was added CuBr 2 (2.1 g, 9.4 mmol) at room temperature. t-BuONO (2.4 g, 23.5 mmol) was then added dropwise at 60° C. The mixture was stirred at 60° C. under nitrogen for 2 hours. The mixture was filtered and washed with EtOAc. The filtrate was concentrated to a crude oil, which was purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 20) to give 141-3 (620 mg, approximately 52% yield) as an oil.

[1170] Synthesis of 4-chloro-2-fluoro-6-nitrobiphenyl (141-4):

[1171]

[1172] 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 PdCl2(dppf) (58 mg, 0.1 mmol), K2CO3 (673 mg, 4.88 mmol) at room temperature, and the mixture was heated to 80°C under nitrogen for 5 hours. The reaction mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc. The filtrate was concentrated to an oil, which was purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 10) to give oily 141-4 (750 mg, approximately 60% yield).

[1173] Synthesis of 2-fluoro-6-nitro-N-phenylbiphenyl-4-amine (141-5):

[1174]

[1175] A mixture of 141-4 (590 mg, 2.35 mmol), aniline (230 mg, 2.47 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), tBu3PHBF4 (58 mg, 0.2 mmol), tBuONa (564 mg, 5.88 mmol) in toluene (15 mL) was heated to 110°C overnight under hydrogen. The mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated to an oil, which was purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 8) to give 141-5 (180 mg, approximately 25% yield) as an oil. MS calculated value: 308.1; MS found value: 309.3 [M+H] + .

[1176] Synthesis of 6-fluoro-N4-phenylbiphenyl-2,4-diamine (141-6):

[1177]

[1178] 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 under hydrogen (1 atm) at room temperature overnight. The mixture was filtered and washed with EtOAc. The filtrate was concentrated to an oil to give 141-6 (170 mg, approximately 78% yield) as an oil. MS calculated value: 278.1; MS found value: 279.1 [M+H] + .

[1179] Synthesis of 6-fluoro-N4-phenylbiphenyl-2,4-diamine (141-7):

[1180]

[1181] To a solution of 141-6 (170 mg, 0.61 mmol) and 2-chloroacetaldehyde (143 mg, 1.83 mmol in water, 40%) in EtOH (5 mL) and HOAc (0.2 mL) was added NaBH3CN (77 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with DCM, and the DCM phase was then dried over Na2SO4. The filtrate was filtered and concentrated to an oil, which was purified by preparative TLC to give 141-7 (58 mg, approximately 28% yield) as an oil. MS calculated value: 340.1; MS found value: 341.0 [M+H]+ .

[1182] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-fluoro-N4-phenylbiphenyl-2,4-diamine (SS20308-0141-01):

[1183]

[1184] To a solution of 141-7 (48 mg, 0.14 mmol) and 1H-1,2,4-triazole (10 mg, 0.14 mmol) in CH3CN (8 mL) was added Cs2CO3 (91 mg, 0.28 mmol) at room temperature, and the mixture was then heated to 80°C for 7 hours, diluted with water, extracted with EtOAc, and the EtOAc phase was dried over Na2SO4. The filtrate was filtered and concentrated to an oil, which was purified by preparative HPLC to give SS20308-0141-01 (12 mg, approximately 23% yield) as a solid. MS calculated: 373.2; MS found: 374.3 [M+H] + .

[1185] 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),7.30-7.24(m,2H), 7.17-7.11(m,4H),6.88(t,J=7.4Hz,1H),6.23-6.18(m,2H),4.64(t,J=6.0,1H),4.33(t,J=6.0,2H),3.44-3.38(m,2H).

[1186] Example 54

[1187]

[1188] Example route for Example 54:

[1189]

[1190] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0142-01):

[1191]

[1192] A mixture of 95-5 (100 mg, 0.29 mmol), 4-fluoroaniline (39 mg, 0.35 mmol), Pd2(dba)3 (26 mg, 0.029 mmol), Xantphos (34 mg, 0.058 mmol) and Cs2CO3 (189 mg, 0.58 mmol) in toluene (10 mL) was stirred at 110°C under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated to a crude oil, which was purified by preparative HPLC to give SS20308-0142-01 (14.3 mg, approximately 13% yield) as a solid. MS calculated: 373.2; MS found: 374.2 [M+H] + .

[1193] 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,1H),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=6.0Hz,2H),3.46-3.39(m,2H).

[1194] Example 55

[1195]

[1196] Example route for Example 55:

[1197]

[1198] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-2):

[1199]

[1200] A mixture of 143-1 (1.0 g, 4.6 mmol), phenylboronic acid (1.1 g, 9.2 mmol), Cu(OAc)2 (833 mg, 4.6 mmol), and Et3N (2.3 g, 23 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 2 days. 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 to obtain 143-2 (1.0 g, approximately 74% yield) as a solid.

[1201] 4-Bromo-N 1 -Synthesis of phenylbenzene-1,3-diamine (143-3):

[1202]

[1203] 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 at room temperature overnight. After the reaction was complete, the insoluble matter was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined layers were dried with Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc=5 / 1) to obtain 143-3 (800 mg, approximately 90% yield) as a solid. MS measured value: 263.2 [M+H] + .

[1204] 4-Bromo-N 3 -(2-chloroethyl)-N 1 -Synthesis of phenylbenzene-1,3-diamine (143-4):

[1205]

[1206] A mixture of 143-3 (800 mg, 3.1 mmol), 2-chloroacetaldehyde (242 mg, 3.1 mmol, in water, 40% concentration), NaBH3CN (1.3 g, 6.2 mmol) and HOAc (2 drops) in MeOH (50 mL) was stirred at 40°C overnight. After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase column chromatography (EtOAc) to give 143-4 (600 mg, approximately 60% yield) as a solid. MS calculated value: 324.0; MS found value: 325.0 [M+H] + .

[1207] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-N 1 -Synthesis of phenylbenzene-1,3-diamine (143-01-4):

[1208]

[1209] A mixture of 143-4 (600 mg, 1.85 mmol), 1H-1,2,4-triazole (192 mg, 2.78 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in acetone (20 mL) was stirred at 80 ° C overnight. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase (silica) column chromatography (DCM / EtOH=20 / 1) to give 143-5 (450 mg, about 68% yield) as a solid. MS calculated value: 357.1; MS found value: 358.3 [M+H] + .

[1210] Synthesis of (2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)methanol (SS20308-143-01):

[1211]

[1212] A mixture of 143-5 (100 mg, 0.28 mmol), 2-hydroxymethylphenylboronic acid (51 mg, 0.34 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), X-Phos (613 mg, 0.028 mmol) and Cs2CO3 (183 mg, 0.56 mmol) in toluene / water (3 / 0.3 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine and concentrated. The residual crude product was purified by preparative HPLC to give SS20308-143-01 (43.6 mg, approximately 40% yield) as a solid. MS calculated value: 385.5; MS found value: 386.2 [M+H] + .

[1213] 1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.06(s,1H),7.89(s,1H),7.56(d,J=7.2Hz,1H) ,7.36-7.33(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),6.41(s,1H),4.93(t,J=5.6Hz ,1H),4.31-4.26(m,2H),4.22-4.20(m,2H),4.17(t,J=6.0Hz,1H),3.42-3.38(m,2H).

[1214] Example 56

[1215]

[1216] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2'-methoxy-N 4 -Synthesis of phenylbiphenyl-2,4-diamine (SS20308-144-01):

[1217]

[1218] A mixture of 143-5 (50 mg, 0.14 mmol), 2-methoxyphenylboronic acid (32 mg, 0.21 mmol), Pd(PPh3)4 (6 mg, 0.007 mmol), X-Phos (7 mg, 0.014 mmol) and Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (2 / 0.2 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated, and the residual crude product was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to give SS20308-0144-01 (6.22 mg, approximately 11% yield) as a solid. MS calculated value: 385.2; MS found value: 386.2 [M+H] + .

[1219] 1H 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,2H),7.10(d,J=7.6Hz,2H), 7.05-7.02(m,2H),6.99-6.97(m,1H),6.81-6.75(m,2H),6.45-6.38(m,2H),4.33-4.25(m,3H),3.64(s,3H),3.44-3.41(m,2H).

[1220] Example 57

[1221]

[1222] Example route of Example 57:

[1223]

[1224] Synthesis of 4-bromo-4'-chloro-2-nitrobiphenyl (147-2):

[1225]

[1226] A mixture of 147-1 (2.00 g, 7.12 mmol), 4-chloroboric acid (1.11 g, 7.12 mmol), Pd(PPh 3 ) 4 (0.42 g, 0.36 mmol) and Na 2 CO 3 (1.51 g, 14.24 mmol) in toluene / H 2 O (30 mL, 5 / 1) was stirred at 90° C. overnight under N 2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated. The residue was purified by column chromatography (petroleum ether) to give 147-2 (1.70 g, approximately 76% yield) as a solid.

[1227] 1 H NMR (400MHz, CDCl3) δ7.96 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H).

[1228] Synthesis of 4-bromo-4'-chlorobiphenyl-2-amine (147-3):

[1229]

[1230] 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 at room temperature overnight. The reaction mixture was then concentrated and poured into water. The mixture was alkalized 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 x 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 give 147-3 (1.20 g, approximately 88% yield) as a solid. MS calculated value: 280.96; MS found value: 282.0 [M+H] + .

[1231] Synthesis of 4-bromo-4'-chloro-N-(2-chloroethyl)biphenyl-2-amine (147-4):

[1232]

[1233] To a solution of 147-3 (1.00 g, 3.54 mmol) in MeOH (20 mL) were added 2-chloroacetaldehyde (1.11 g, 14.16 mmol, 40%), AcOH (844 mg, 14.16 mmol) and NaBH3CN (890 mg, 14.16 mmol), and the reaction mixture was stirred at 40°C overnight. 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=20 / 1) to give 147-4 (710 mg, approximately 59% yield) as an oil. MS calculated value: 343.0; MS found value: 344.0 [M+H] + .

[1234] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-4'-chlorobiphenyl-2-amine (147-5):

[1235]

[1236] A mixture of 147-4 (670 mg, 1.94 mmol), 1H-1,2,4-triazole (201 mg, 2.91 mmol) and Cs2CO3 (1.26 g, 3.88 mmol) in CH3CN (10 mL) was stirred at 80°C overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 147-5 (537 mg, approximately 73% yield) as an oil. MS calculated value: 376.01; MS found value: 379.0 [M+H] + .

[1237] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4'-chloro-N 4 -Synthesis of phenylbiphenyl-2,4-diamine (SS20308-0147-01):

[1238]

[1239] 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 at 100 ° C. under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative HPLC to give SS20308-0147-01 (15 mg, about 9% yield) as an oil. MS calculated value: 389.1; MS found value: 390.3 [M+H] + .

[1240] 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 (d, J = 1.6Hz, 1H), 4.84 (t, J = 5.6Hz, 1H), 4.37 (t, J = 6.0Hz, 2H), 3.44-3.38 (m, 2H).

[1241] Example 58

[1242]

[1243] Example route of Example 58:

[1244]

[1245] Synthesis of 1,4-dibromo-2-fluoro-3-nitrobenzene (148-2):

[1246]

[1247] A mixture of 148-1 (1.0 g, 4.26 mmol) and copper bromide (1.43 g, 6.38 mmol) in CH3CN (20 mL) was stirred at 60°C for 10 minutes (min); tert-butyl nitrite (2.19 g, 21.28 mmol) was slowly added. The mixture was stirred at 60°C for 0.5 hours and then poured into water (100 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=20 / 1) to give 148-2 (820 mg, approximately 65% ​​yield) as a solid.

[1248] Synthesis of 4-bromo-3-fluoro-2-nitrobiphenyl (148-3):

[1249]

[1250] A solution of 148-2 (810 mg, 2.71 mmol), phenylboronic acid (331 mg, 2.71 mmol), Pd(PPh 3 ) 4 (157 mg, 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 filtered and rinsed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc=100 / 1) to give compound 148-3 (622 mg, approximately 78% yield) in an oily state.

[1251] Synthesis of 4-bromo-3-fluorobiphenyl-2-amine (148-4):

[1252]

[1253] 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 at room temperature overnight. 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 give compound 148-4 (622 mg, approximately 93% yield) as an oil. MS calculated value: 265.0; MS found value: 266.2 [M+H] + .

[1254] Synthesis of N-(4-bromo-3-fluorobiphenyl-2-yl)-2-chloroacetamide (148-5):

[1255]

[1256] 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 hour, then washed with brine, dried over sodium sulfate, and concentrated to afford 148-5 (428 mg, approximately 71% yield) as a solid. MS calculated: 341.0; MS found: 342.2 [M+H] + .

[1257] Synthesis of N-(4-bromo-3-fluorobiphenyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (148-6):

[1258]

[1259] A mixture of 148-5 (430 mg, 1.25 mmol), 1H-1,2,4-triazole (130 mg, 1.88 mmol) and Cs2CO3 (611 mg, 1.88 mmol) in CH3CN (20 mL) was stirred at 80 ° C overnight. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (EtOAc / petroleum ether=1 / 5, 1 / 1) to give 148-6 (386 mg, about 82% yield) as an oil. MS calculated value: 374.0; MS found value: 375.0 [M+H] + .

[1260] Synthesis of N-(3-fluoro-4-(phenylamino)biphenyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (148-7):

[1261]

[1262] A solution of 148-6 (386 mg, 1.03 mmol), aniline (288 mg, 3.09 mmol), Xantphos (119 mg, 0.21 mmol), Pd2(dba)3 (95 mg, 0.10 mmol) and anhydrous cesium carbonate (503 mg, 1.54 mmol) was suspended in toluene (10 mL). The reaction mixture was heated to 120° C. 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, 1 / 1) to give 148-7 as an oil. MS calculated value: 387.2; MS found value: 388.3 [M+H] + .

[1263] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-N 4 Synthesis of phenylbiphenyl-2,4-diamine (SS20308-0148-01):

[1264]

[1265] To a solution of 148-7 (44 mg, 0.26 mmol) in THF (5 mL) was slowly added borane-dimethyl sulfide complex (10 mL, 2 M in THF). The reaction mixture was stirred at room temperature overnight, 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 x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (EtOAc) to give SS20308-0148-01 (3.8 mg, approximately 9% yield) as a solid. MS calculated value: 373.2; MS found value: 374.3 [M+H] + .

[1266] 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).

[1267] Example 59

[1268]

[1269] Example 59 Illustrative Route: Synthesis of methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (149-2):

[1270]

[1271] A mixture of 149-1 (300 mg, 1.32 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(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 at 80 ° C overnight. The reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with EtOAc (60 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc=10 / 1) to give 149-2 (180 mg, about 49% yield) as a solid. MS calculated value: 276.2; MS found value: 277.4 [M+H] + .

[1272] Synthesis of methyl 2-(2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)acetate (149-3):

[1273]

[1274] A mixture of 143-5 (80 mg, 0.22 mmol), 149-2 (91 mg, 0.33 mmol), Pd(PPh3)4 (10 mg, 0.011 mmol), X-Phos (10 mg, 0.022 mmol) and Cs2CO3 (143 mg, 0.44 mmol) in toluene / water (2 / 0.2 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and evaporated, and the residual crude product was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to give 149-3 (60 mg, about 64% yield) as a solid. MS calculated value: 427.2; MS found value: 428.3 [M+H] +

[1275] Synthesis of 2-(2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)ethanol (SS20308-0149-01):

[1276]

[1277] A mixture of 149-3 (60 mg, 0.14 mmol) and LiAlH4 (27 mg, 0.7 mmol) in THF (3 mL) was stirred at room temperature overnight. After the reaction was complete, the crude reaction mixture was poured onto wet Na2SO4(s), filtered to remove insoluble material, and rinsed with Et2O. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give SS20308-0149-01 (7.2 mg, approximately 13% yield) as a solid. MS calculated: 399.2; MS found: 400.3 [M+H] + .

[1278] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.06(s,1H),7.88(s,1H),7.32-7.19(m,6H),7.11(d,J=7.6Hz,2H),6.98-6.96(m,1H),6.80(t,J=7.2Hz,1H ),6.73(d,J=8.0Hz,1H),6.48-6.42(m,1H),6.41(s,1H),4.48(t,J=5.2 Hz, 1H), 4.29 (t, J = 6.0 Hz, 2H), 4.12 (t, J = 5.6 Hz, 1H), 3.44-3.30 (m, 5H).

[1279] Example 60

[1280]

[1281] Example route of Example 60:

[1282]

[1283] Synthesis of 5-bromobiphenyl-2-amine (151-2):

[1284]

[1285] 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 at 0°C overnight. The mixture was then poured into water and extracted with EtOAc (30 mL x 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 give 151-2 (5.7 g, approximately 57.6% yield) as an oil. MS calculated value: 247.0; MS found value: 248.2 [M+H] + .

[1286] Synthesis of N-(5-bromobiphenyl-2-yl)-3-chloropropionamide (151-3):

[1287]

[1288] A mixture of 151-2 (5.70 g, 22.97 mmol), 3-chloropropionyl chloride (3.50 g, 27.56 mmol) and pyridine (0.181 g, 2.3 mmol) in DCM (10 mL) was stirred at room temperature for 4 hours. The resulting mixture was extracted with ethyl acetate (30 mL x 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 give 151-3 (5.0 g, approximately 64% yield) as a solid. MS calculated value: 337.0; MS found value: 3380.2 [M+H] + .

[1289] Synthesis of N-(5-bromobiphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (151-4):

[1290]

[1291] A mixture of 151-3 (5.00 g, 14.77 mmol), 1H-1,2,4-triazole (1.22 g, 17.72) and Cs2CO3 (14.43 g, 44.29 mmol) in CH3CN (15 mL) was stirred at 80°C for 4 hours. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) to give 151-4 (3.3 g, about 60% yield) as a solid. MS calculated value: 370.0; MS found value: 372.3 [M+H] + .

[1292] Synthesis of N-(5-(phenylamino)biphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (151-5):

[1293]

[1294] A mixture of 151-4 (1.00 g, 2.69 mmol), aniline (752 mg, 8.08 mmol), Pd2(dba)3 (247 mg, 0.27 mmol), Xantphos (312 mg, 0.54 mmol) and Cs2CO3 (378 mg, 8.07 mmol) in toluene (5 mL) was stirred at 110° C. under N2 atmosphere overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 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 give 151-5 (810 mg, approximately 60% yield) as an oil. MS calculated value: 383.2; MS found value: 384.3 [M+H] + .

[1295] N 2 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 5 Synthesis of phenylbiphenyl-2,5-diamine (SS20308-0151-01):

[1296]

[1297] A mixture of 151-5 (50 mg, 0.13 mmol) and BMS (2.5 M in THF) (5 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 3), and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 2) to give SS20308-0151-01 (30 mg, approximately 62% yield) as a solid. MS calculated value: 369.2; MS found value: 370.3 [M+H] + .

[1298] 1H NMR (400MHz, DMSO-d6) δ8.49(s,1H),7.93(s,1H),7.65(s,1H),7.40-7.48(m,4H),7.34-7.38(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).

[1299] Example 61

[1300]

[1301] Example route of Example 61:

[1302]

[1303] Synthesis of tert-butyl 2-(1H-1,2,4-triazol-1-yl)ethylcarbamate (153-2):

[1304]

[1305] To a mixture of 153-1 (2.2 g, 9.82 mmol) and K2CO3 (2.7 g, 19.63 mmol) in acetone (30 mL) was added 1H-1,2,4-triazole (1.0 g, 14.73 mmol), followed by stirring at 60°C overnight. The reaction mixture was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to afford 153-2 as an oil (2.0 g, approximately 96% yield). MS calculated: 212.1; MS found: 213.2 [M+H] + .

[1306] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-6-nitroaniline (153-4):

[1307]

[1308] To a solution of 153-2 (424 mg, 2.00 mmol) in THF (10 mL) was added HCl (6N, 5 mL), followed by stirring at room temperature overnight. 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 thereto. The mixture was stirred at room temperature overnight. 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 / 1-3 / 1) to give 153-4 (474 ​​mg, two-step yield approximately 76%) as an oil. MS calculated value: 311.0; MS found value: 312.0 [M+H] + .

[1309] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-nitrobiphenyl-2-amine (153-5):

[1310]

[1311] To a solution of 153-4 (443 mg, 1.42 mmol) in DME / water (10 / 1, 15 mL) was added phenylboronic acid (260 mg, 2.13 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol) and K2CO3 (392 mg, 2.84 mmol), and the reaction mixture was 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 x 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / EtOAc=10 / 1-4 / 1) to give 153-5 (400 mg, about 91% yield) as a solid. MS calculated value: 309.1; MS found value: 310.0 [M+H] + .

[1312] N 2 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)biphenyl-2,3-diamine (153-6):

[1313]

[1314] To a solution of 153-5 (350 mg, 1.13 mmol) in MeOH (5 mL) was added Pd / C (35 mg, 10%), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite. The filtrate was purified by preparative TLC (EtOAc) to give 153-6 as a solid (100 mg, approximately 32% yield). MS calculated: 279.1; MS found: 280.1 [M+H] + .

[1315] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 3 Synthesis of phenylbiphenyl-2,3-diamine (SS20308-0153-01):

[1316]

[1317] To a solution of 153-6 (100 mg, 0.36 mmol) in toluene (10 mL) were added bromobenzene (84 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (29 mg, 0.06 mmol) and Cs2CO3 (233 mg, 0.72 mmol), and the reaction mixture was 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 x 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 1) to give SS20308-0153-01 (31 mg, about 24% yield) as an oil. MS calculated value: 355.2; MS found value: 356.0 [M+H] + .

[1318] 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,3H),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).

[1319] Example 62

[1320]

[1321] Example route for Example 62:

[1322] 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):

[1323]

[1324] A solution of 0061-3 (1.0 g, 2.91 mmol), 2-chloro-4-fluoroaniline (637 mg, 4.38 mmol), t-Bu 3 PHBF 4 (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 under reflux overnight under N 2 , 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 give SS20308-0165-01 (440 mg, approximately 37% yield) as an oil. MS calculated value: 407.1; MS found value: 408.0 [M+H] + .

[1325] 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),7.0 3-6.93(m,3H),6.79(d,J=2.8Hz,1H),6.71(d,J=8.8Hz,1H),4.59(t,J=6.0Hz,1H),4.35(t,J=5.8Hz,2H),3.50-3.44(m,2H).

[1326] 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):

[1327]

[1328] 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), Pd2(dba)3 (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with EtOAc (60 mL x 3). The organic layer was washed with brine and concentrated, and the residual crude product was purified by column chromatography (petroleum ether / EtOAc=5 / 1) to give 166-1 (50 mg, approximately 91% yield) as a solid. MS calculated value: 394.2; MS found value: 395.2 [M+H] + .

[1329] Example 63

[1330]

[1331] 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):

[1332]

[1333] A mixture of 166-1 (50 mg, 0.13 mmol) and NaBH3CN (25 mg, 0.39 mmol) in AcOH (1 mL) was stirred at 0°C for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give SS20308-0166-01 (10.3 mg, approximately 20% yield) as a solid. MS calculated value: 396.5; MS found value: 397.3 [M+H] + .

[1334] 1H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.08(s,1H),7.96(s,1H),7.23(t,J=8.4Hz ,2H),7.10(d,J=7.6Hz,2H),7.00(d,J=6.8Hz,1H),6.90(d,J=8.0Hz,1H),6.82-6 .76(m,2H),6.61(t,J=7.2Hz,1H),6.50-6.45(m,2H),4.67(s,1H),4.62-4.61(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).

[1335] Example 64

[1336]

[1337] Synthesis of 2-(3-(dimethylamino)propyl)-3-(1H-indol-7-yl)-N-phenylaniline (SS20308-0171-01) – Synthesis of SS20308-0172-01 is shown below:

[1338]

[1339] A mixture of SS20308-0172-01 (50 mg, 0.13 mmol) and DDQ (59 mg, 0.58 mmol) in dioxane (2 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL x 3). The organic layer was washed with brine and evaporated, and the residual crude product was purified by preparative HPLC to give SS20308-0171-01 (2.5 mg, approximately 5% yield) as a solid. MS calculated: 369.5; MS found: 370.3 [M+H] + .

[1340] 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.19(s,1H),7.53(d,J=8.0Hz,1H),7.30 (d,J=7.2Hz,1H),7.29-7.17(m,4H),7.05(t,J=6.8Hz,1H),6.95(d,J=7.6Hz,2 H),6.90(d,J=7.2Hz,1H),6.86-6.85(m,1H),6.73(t,J=7.2Hz,1H),6.48-6.46 (m,1H),2.36-2.30(m,2H),1.93(s,6H),1.89-1.86(m,2H),1.29-1.23(m,2H).

[1341] Example 65

[1342]

[1343] Example route for Example 65 (SS20308-0172-01 and SS20308-0171-01):

[1344]

[1345] Synthesis of (E)-methyl 3-(2-bromo-6-nitrophenyl)acrylate (171-2):

[1346]

[1347] A mixture of 171-1 (1.0 g, 4.4 mmol) and methyl triphenylphosphane acetate (2.2 g, 6.6 mmol) in THF (50 mL) was stirred at room temperature overnight. The reaction mixture was cooled to room temperature and poured into water (100 mL), and extracted with EtOAc (60 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc=5 / 1) to give 171-2 (1.2 g, about 95% yield) as a solid. MS calculated value: 285.0; MS found value: 303.0 [M+18] + .

[1348] Synthesis of (E)-3-(2-bromo-6-nitrophenyl)acrylic acid (171-3):

[1349]

[1350] A mixture of 171-2 (600 mg, 2.1 mmol) and LiOH (100 mg, 4.2 mmol) in THF (5 mL) and H2O (2 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated to give 171-3 (500 mg, approximately 88% yield) as a solid. MS calculated value: 271.0; MS found value: 289.0 [M+18] + .

[1351] Synthesis of (E)-3-(2-bromo-6-nitrophenyl)-N,N-dimethylacrylamide (171-4):

[1352]

[1353] A mixture of 171-3 (500 mg, 1.85 mmol), dimethylamine (225 mg, 2.78 mmol), HOBt (300 mg, 2.22 mmol), EDCI (424 mg, 2.22 mmol) and DIPEA (525 mg, 4.07 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc=5 / 1) to obtain 171-4 (500 mg, about 90% yield) as a solid. MS calculated value: 298.0; MS found value: 299.0 [M+H] + .

[1354] Synthesis of (E)-3-(2-(1H-indol-7-yl)-6-nitrophenyl)-N,N-dimethylacrylamide (171-5):

[1355]

[1356] A mixture of 171-4 (500 mg, 0.14 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indole (610 mg, 1.7 mmol), Pd2(dba)3 (80 mg, 0.07 mmol), X-Phos (80 mg, 0.14 mmol) and Cs2CO3 (1.1 mg, 2.8 mmol) in toluene (10 mL) and H2O (1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (EtOAc) to obtain 171-5 (450 mg, approximately 48% yield) as a solid. MS calculated value: 335.1; MS found value: 336.4 [M+H] + .

[1357] Synthesis of 3-(2-amino-6-(1H-indol-7-yl)phenyl)-N,N-dimethylpropionamide (171-5):

[1358]

[1359] A mixture of 171-4 (600 mg, 1.4 mmol) and Pd / C (10%; 100 mg) in MeOH (10 mL) was stirred at room temperature under H2(g) overnight. The reaction mixture was filtered and purified by column chromatography (EtOAc) to give 171-5 (450 mg, approximately 90% yield) as a solid. MS calculated: 307.2; MS found: 308.4 [M+H] + .

[1360] Synthesis of 3-(2-(1H-indol-7-yl)-6-(phenylamino)phenyl)-N,N-dimethylpropionamide (171-6)

[1361]

[1362] A mixture of 171-5 (450 mg, 1.5 mmol), bromobenzene (281 mg, 1.8 mmol), Pd2(dba)3 (38.7 mg, 0.075 mmol), xant-Phos (72 mg, 0.15 mmol) and Cs2CO3 (978 mg, 3.0 mmol) in toluene (5 ml) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (EtOAc) to give 171-6 (320 mg, approximately 56% yield) as a solid. MS calculated value: 383.2; MS found value: 384.3 [M+H] + .

[1363] Synthesis of 2-(3-(dimethylamino)propyl)-3-(indolin-7-yl)-N-phenylaniline (SS20308-0172-01):

[1364]

[1365] A mixture of 171-6 (50 mg, 0.13 mmol), BH3 (0.5 mL, 1 M in THF) in THF (2 mL) was stirred at room temperature overnight. HCl (1 N, 2 mL) and MeOH (2 mL) were then added, and the final mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by preparative HPLC to give SS20308-0172-01 (5.1 mg, approximately 10% yield) as a solid. MS calculated value: 371.5; MS found value: 372.4 [M+H] + .

[1366] 1 H NMR (400MHz, CDCl3) δ10.64(brs,1H),7.37-7.34(m,1H),7.31-7.29(m,2H),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,2H),2.91-2.80(m,2H),2.76-2.68(m,2H),2.54(s,3H),2.45(s,3H),1.73-1.67(m,2H).

[1367] Example 66

[1368]

[1369] Example route for Example 66 (SS20308-0173-01 and SS20308-0219-01):

[1370]

[1371] Synthesis of 5-chloro-2-phenylpyridin-3-amine (173-2):

[1372]

[1373] 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), K2CO3 (668 mg, 4.84 mmol) in DME (10 mL) and water (1 mL) was stirred overnight at 80 ° C under N2 atmosphere. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=10 / 1) to give 173-2 (440 mg, about 91% yield) as an oil. MS calculated value: 204.0; MS found value: 205.1 [M+H] + .

[1374] Synthesis of 5-chloro-N-(2-chloroethyl)-2-phenylpyridin-3-amine (173-3):

[1375]

[1376] To a solution of 173-2 (450 mg, 2.20 mmol) in MeOH (10 mL) were added 2-chloroacetaldehyde (432 mg, 4.40 mmol in water, 40% concentration), AcOH (264 mg, 4.40 mmol) and NaBH3CN (275 mg, 4.40 mmol), and the reaction mixture was stirred at room temperature overnight. 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 x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=10 / 1) to give 173-3 (100 mg, approximately 17% yield) as a solid. MS calculated value: 266.0; MS found value: 237.1 [M+H] + .

[1377] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-2-phenylpyridin-3-amine (173-4):

[1378]

[1379] A mixture of 173-3 (100 ng, 0.37 mmol), 1H-1,2,4-triazole (52 mg, 0.74 mmol) and Cs2CO3 (240 mg, 0.74 mmol) in CH3CN (10 mL) was stirred at 80 ° C overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 173-4 (77 mg, about 68% yield) as a solid. MS calculated value: 299.1; MS found value: 300.2 [M+H] + .

[1380] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2-diphenylpyridine-3,5-diamine (SS20308-0173-01):

[1381]

[1382] A mixture of 173-4 (20 mg, 0.67 mmol), aniline (13 mg, 0.14 mmol), Pd(OAc)2 (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. under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 3) and preparative HPLC to give SS20308-0173-01 (13 mg, about 54% yield) as a solid. MS calculated value: 356.2; MS found value: 357.3 [M+H] + .

[1383] 1H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.25(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 ), 7.14 (d, J = 7.6Hz, 2H), 4.36 (t, J = 7.2Hz, 1H), 7.14 (d, J = 2.0Hz, 1H), 5.17 (t, J = 6.0Hz, 1H), 4.36 (t, J = 6.0Hz, 2H), 3.46 (dd, J = 12.0, 6.0Hz, 2H).

[1384] Example 67

[1385]

[1386] Example route of Example 67:

[1387]

[1388] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-bromo-6-chloropyridin-2-amine (175-2):

[1389]

[1390] A mixture of 175-1 (1.00 g, 4.75 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine hydrochloride (847 mg, 5.70 mmol) and K2CO3 (1.97 g, 14.25 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with EtOAc (30 mL x 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 give 175-2 (1.0 g, approximately 71% yield) as a solid. MS calculated value: 301.0; MS found value: 302.0 [M+H] + .

[1391] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-chloro-3-phenylpyridin-2-amine (175-3):

[1392]

[1393] A mixture of 175-2 (300 mg, 0.99 mmol), phenylboronic acid (145 mg, 1.19 mmol), Pd(dppf)Cl2 (7.3 mg, 0.01 mmol) and K2CO3 (410 mg, 2.97 mmol) in DME (5 ml) was stirred at 80°C under N2 atmosphere for 4 hours. The resulting mixture was extracted with ethyl acetate (30 mL x 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 / 2) to give 175-3 (250 mg, about 84% yield) as a solid. MS calculated value: 299.1; MS found value: 300.2 [M+H] + .

[1394] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of 3-diphenylpyridine-2,6-diamine (SS20308-0175-01):

[1395]

[1396] A mixture of 175-3 (50 mg, 0.17 mmol), aniline (47 mg, 0.50 mmol), Cs2CO3 (162 mg, 0.50 mmol), Pd2(dba)3 (16 mg, 0.017 mmol), and Xantphos (20 mg, 0.034 mmol) in toluene (3 mL) was stirred at 110°C under N2 atmosphere for 3 hours. The reaction mixture was then cooled to room temperature and purified by preparative HPLC to give SS20308-0175-01 (44 mg, approximately 72% yield) as a solid. MS calculated: 356.2; MS found: 357.3 [M+H] + .

[1397] 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.43(s,1H),7.98(s,1H),7.68(d,J=8.8Hz,2H),7.38-7.42(m,2H),7.29-7.31(m,3H),7.22-7.26(m, 2H), 7.18 (d, J = 8.0Hz, 1H), 6.85 (t, J = 7.2Hz, 1H), 6.17 (d, J = 8.0Hz, 1H) 5.80 (t, J = 5.4Hz, 1H), 4.42 (t, J = 6.0Hz, 2H), 3.75 (q, J = 6.0Hz, 2H).

[1398] Example 68

[1399]

[1400] Example route of Example 68:

[1401]

[1402] 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):

[1403]

[1404] 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), Pd2(dba)3 (9 mg, 0.01 mmol), X-Phos (9 mg, 0.02 mmol) and Cs2CO3 (130 mg, 0.40 mmol) in toluene / water (2 / 0.2 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by preparative HPLC to give SS20308-177-01 (14 mg, 19% yield) as a solid. MS calculated value: 359.4; MS found value: 360.3 [M+H] + .

[1405] 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,2H),7.12(d,J=7.6Hz,2H),6.8 5-6.82(m,2H),6.74(s,1H),6.43-6.39(m,2H),4.74(t,J=5.6Hz,1H),4.35(t,J=6.0Hz,2H),3.45-3.41(m,2H),3.28(s,3H).

[1406] Example 69

[1407]

[1408] Example route of Example 69:

[1409]

[1410] Synthesis of 4-bromo-3-nitro-N-phenylaniline (178-2):

[1411]

[1412] A mixture of 178-1 (1.00 g, 4.61 mmol), phenylboronic acid (674 mg, 5.53 mmol), Et3N (560 mg, 5.53 mmol) and Cu(OAc)2 (837 mg, 4.61 mmol) in DCM (10 mL) was stirred at room temperature for 48 hours. The mixture was then poured into water and extracted with EtOAc (30 mL x 3), the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=5 / 1) to give 178-2 (500 mg, approximately 37% yield) as a solid.

[1413] 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).

[1414] Synthesis of 2-nitro-N-phenylbiphenyl-4-amine (178-3):

[1415]

[1416] A mixture of 178-2 (500 mg, 1.71 mmol), phenylboronic acid (250 mg, 2.05 mmol), Pd(PPh 3 ) 4 (196 mg, 0.17 mmol) and Na 2 CO 3 (544 mg, 5.13 mmol) in DME / H 2 O (5 mL, 5 / 1) was stirred at 90 ° C. under N 2 atmosphere overnight. The resulting mixture was extracted with ethyl acetate (30 mL x 3), and the organic layer was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to give 178-3 (400 mg, about 81% yield) as a solid. MS calculated value: 290.1; MS found value: 291.1 [M+H] + .

[1417] N 4 -Synthesis of phenylbiphenyl-2,4-diamine (178-4):

[1418]

[1419] 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 H2(g) (1 atm) for 1 hour. The reaction mixture was then cooled to room temperature and purified by preparative TLC to afford 178-4 (320 mg, approximately 89% yield) as a solid. MS calculated: 260.1; MS found: 261.4 [M+H] + .

[1420] Synthesis of 3-chloro-N-(4-(phenylamino)biphenyl-2-yl)propionamide (178-5):

[1421]

[1422] A mixture of 178-4 (330 mg, 1.27 mmol), 3-chloropropionyl chloride (161 mg, 1.27 mmol) and TEA (128 mg, 1.27 mmol) in DCM (10 mL) was stirred at room temperature for 1 hour. The mixture was then poured into water and extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 178-5 (350 mg, approximately 79% yield) as a solid. MS calculated value: 350.1; MS found value: 351.3 [M+H] + .

[1423] Synthesis of N-(4-(phenylamino)biphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (178-6):

[1424]

[1425] A mixture of 178-5 (350 mg, 1.00 mmol), 1H-1,2,4-triazole (207 mg, 3.00 mmol) and Cs2CO3 (975 mg, 3.00 mmol) in CH3CN (10 mL) was stirred at 80°C overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 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 / 2) to give 178-6 (300 mg, 78% yield) as a solid. MS calculated value: 383.2; MS found value: 384.3 [M+H] + .

[1426] N 2-(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of phenylbiphenyl-2,4-diamine (SS20308-0178-01):

[1427]

[1428] A mixture of 178-6 (50 mg, 0.13 mmol) and borane-methyl sulfide (2.5 M in THF) (5 mL) was stirred at room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 3), and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by preparative MPLC (petroleum ether / EtOAc=1 / 2) to give SS20308-0178-01 (28 mg, approximately 59% yield) as a solid. MS calculated value: 369.2; MS found value: 370.0 [M+H] + .

[1429] 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), 4.64 (t, J = 5.6Hz, 1H), 4.22 (t, J = 6.8Hz, 2H), 2.98-3.03 (m, 2H), 2.02-2.08 (m, 2H).

[1430] Example 70

[1431]

[1432] Example route of Example 70:

[1433]

[1434] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4'-chloro-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0181-01):

[1435]

[1436] 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 at 100 ° C. under N2 atmosphere overnight. The reaction mixture was then cooled to room temperature and filtered through celite and concentrated. The residue was purified by preparative HPLC to give SS20308-0181-01 (14.3 mg, approximately 13% yield) as a solid. MS calculated value: 407.1; MS found value: 408.2 [M+H] + .

[1437] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.07(s,1H),7.97(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).

[1438] Example 71

[1439]

[1440] Example route of Example 71:

[1441]

[1442] Synthesis of 4-bromo-N-(4-fluorophenyl)-3-nitroaniline (184-2):

[1443]

[1444] A mixture of 184-1 (500 mg, 2.30 mmol), 4-fluorophenylboronic acid (322 mg, 2.30 mmol), Et3N (466 mg, 4.61 mmol) and Cu(OAc)2 (418 mg, 2.30 mmol) in MeOH (20 ml) was stirred at room temperature for 48 hours. After the reaction was completed, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (2x50 mL), dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 184-2 (650 mg, approximately 91% yield) as a solid. MS calculated value: 310.0; MS found value: 311.0 [M+H] + .

[1445] Synthesis of N-(4-fluorophenyl)-2-nitrobiphenyl-4-amine (184-3):

[1446]

[1447] A mixture of 184-2 (650 mg, 2.09 mmol), phenylboronic acid (255 mg, 2.09 mmol), Pd(dppf)Cl2 (76 mg, 0.10 mmol), K2CO3 (578 mg, 4.18 mmol) in DME (20 ml) was stirred at 90°C overnight under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (4 mL x 3). The organic layer was washed with brine (2 x 50 mL), dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 184-3 (450 mg, approximately 70% yield) as a solid. MS calculated value: 308.1; MS found value: 309.0 [M+H] + .

[1448] N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (184-4):

[1449]

[1450] 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 at room temperature under H2(g) (1 atm) overnight. 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 calculated value: 278.1; MS found value: 279.2 [M+H] + .

[1451] N 2 -((3-(bromomethyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (184-7):

[1452]

[1453] To CH 2 Cl 2 (10mL) solution of 184-5 (200mg, 1.10 mmoles), Dess-Martin periodinane (937mg, 2.21 mmoles) was added. The mixture was stirred at room temperature overnight. After reaction was complete, insoluble matter was removed by filtration, 184-4 (307mg, 1.10 mmoles) and NaBH 3 CN (139mg, 2.21 mmoles) were added to the filtrate, and the mixture was stirred at room temperature overnight. After reaction was complete, the reaction mixture was poured into water (50mL) and extracted with EtOAc (50mLx 3). The organic layer was washed with salt water (2x50mL), used MgSO 4 drying, and concentrated under vacuum. The gained crude product was used for next step without further purification.

[1454] N 2 -((3-((dimethylamino)methyl)oxetan-3-yl)methyl)-N 4 Synthesis of -(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0184-01):

[1455]

[1456] A mixture of 184-7 (50 mg, 0.11 mmol), dimethylamine hydrochloride (18 mg, 0.23 mmol) and K2CO3 (63 mg, 0.45 mmol) in CH3CN (20 ml) was stirred at 80 ° C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (4 mL x 3). The organic layer was washed with brine (2x50 mL), dried over MgSO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain SS20308-0184-01 (6 mg, about 13% yield) as a solid. MS calculated value: 405.2; MS found value: 406.0 [M+H] + .

[1457] 1H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.43-7.40(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).

[1458] Example 72

[1459]

[1460] Example route for Example 72 (SS20308-0189-01 and SS20308-0223-01):

[1461]

[1462] 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), Pd2(dba)3 (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and evaporated, and the residual crude product was purified by preparative HPLC to give SS20308-189-01 (7.04 mg, approximately 16% yield) as a solid. MS calculated value: 345.4; MS found value: 346.3 [M+H] + ,

[1463] 1H 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,1H),6.43-6.41(m,2H),4.45(t,J=6.0Hz,2H),3.63-3.58(m,2H),

[1464] and SS20308-223-01 (8.59 mg, approximately 22% yield, MS calculated: 279.3; MS found: 280.0 [M+H]) as a solid + ,

[1465] 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H),7.97(s,1H),7.91(s,1H),7.19(t,J=8.4Hz,2H),7.03(d,J=7.6Hz,2H),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,1H),4.32(t,J=6.4Hz,2H),3.44-3.40(m,2H).

[1466] Examples 73 to 78 all follow the same initial synthetic steps as shown below, which are not repeated for each individual example:

[1467]

[1468] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-2):

[1469]

[1470] A mixture of 143-1 (1.0 g, 4.6 mmol), phenylboronic acid (1.1 g, 9.2 mmol) and 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 matter was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined layers were dried with NaSO and concentrated in vacuo. The residue was purified by column chromatography to obtain 143-2 (1.0 g, approximately 74% yield) as a solid.

[1471] 4-Bromo-N 1 -Synthesis of phenylbenzene-1,3-diamine (143-3):

[1472]

[1473] 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 at room temperature overnight. After the reaction was complete, the insoluble matter was removed by filtration. The filtrate was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined layers were dried with Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc=5 / 1) to obtain 143-3 (800 mg, approximately 90% yield) as a solid. MS measured value: 263.2 [M+H] + .

[1474] 4-Bromo-N 3 -(2-chloroethyl)-N 1 -Synthesis of phenylbenzene-1,3-diamine (143-4):

[1475]

[1476] A mixture of 143-3 (800 mg, 3.1 mmol), 2-chloroacetaldehyde (242 mg, 3.1 mmol, in water, 40% concentration), NaBH3CN (1.3 g, 6.2 mmol) and HOAc (2 drops) in MeOH (50 mL) was stirred at 40°C overnight. After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase column chromatography (EtOAc) to give 143-4 (600 mg, approximately 60% yield) as a solid. MS calculated value: 324.0; MS found value: 325.0 [M+H] + .

[1477] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-N 1 -Synthesis of phenylbenzene-1,3-diamine (143-5):

[1478]

[1479] A mixture of 143-4 (600 mg, 1.85 mmol), 1H-1,2,4-triazole (192 mg, 2.78 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in acetone (20 mL) was stirred at 80 ° C overnight. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase column chromatography (DCM / EtOH=20 / 1) to give 143-5 (450 mg, about 68% yield) as a solid. MS calculated value: 357.1; MS found value: 358.3 [M+H] + .

[1480] Example 73

[1481]

[1482] 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):

[1483]

[1484] 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), Pd2(dba)3 (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by preparative HPLC to give SS20308-190-01 (14.9 mg, approximately 30% yield) as a solid. MS calculated value: 359.4; MS found value: 360.3 [M+H] + .

[1485] 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).

[1486] Example 74

[1487]

[1488] 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):

[1489]

[1490] 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), Pd2(dba)3 (6 mg, 0.007 mmol), X-Phos (6 mg, 0.014 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated, and the residual crude product was purified by preparative HPLC to give SS20308-191-01 (15 mg, approximately 30% yield) as a solid. MS calculated value: 359.4; MS found value: 360.3 [M+H] + .

[1491] 1H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.04(s,1H),7.93(s,1H),7.68(s,1H),7.45(s,1H),7.21(t,J=8.4Hz,2H),7.07(d,J=7.6Hz,2H),6.9 6(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).

[1492] Example 75

[1493]

[1494] 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):

[1495]

[1496] A mixture of 143-5 (50 mg, 0.14 mmol), 3,5-dimethylisoxazole-4-boronic acid (24 mg, 0.17 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and X-Phos (6 mg, 0.014 mmol), Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated, and the residual crude product was purified by preparative HPLC to give SS20308-192-01 (14.6 mg, approximately 29% yield) as a solid. MS calculated value: 374.4; MS found value: 375.3 [M+H] + .

[1497] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.11(s,1H),7.93(s,1H),7.24(t,J=8.4Hz,2H),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).

[1498] Example 76

[1499]

[1500] 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):

[1501]

[1502] A mixture of 143-5 (50 mg, 0.14 mmol), 2-thiopheneboronic acid (22 mg, 0.17 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and X-Phos (6 mg, 0.014 mmol), Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred under reflux overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated, and the residual crude product was purified by preparative HPLC to give SS20308-193-01 (5.6 mg, approximately 11% yield) as a solid. MS calculated value: 361.5; MS found value: 362.1 [M+H] + .

[1503] 1H NMR(400MHz,MeOD-d4)δ8.36(s,1H),7.94(s,1H),7.36-7.35(m,1H),7.34-7.24(m,2H),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).

[1504] Example 77

[1505]

[1506] Synthesis of 5-(2-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4-(phenylamino)phenyl)thiophene-2-carbonitrile (SS20308-194-01):

[1507]

[1508] A mixture of 143-5 (100 mg, 0.28 mmol), (5-cyanothiophene-2-yl)boronic acid (86 mg, 0.56 mmol), PdCl2(dppf) (20 mg, 0.028 mmol) and CsF (85 mg, 0.5 mmol) in DMF (3 mL) was stirred at 100 ° C overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated. The crude product was purified by preparative HPLC to give SS20308-194-01 (5.65 mg, approximately 5% yield) as a solid. MS calculated value: 386.5; MS found value: 387.3 [M+H] + .

[1509] 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,1 H),7.16-7.13(m,3H),6.90-6.87(m,1H),6.49-6.44(m,2H),5.38(t,J=6.0Hz,1H),4.43(t,J=6.0Hz,2H),3.46-3.42(m,2H).

[1510] Example 78

[1511]

[1512] 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):

[1513]

[1514] A mixture of 143-5 (100 mg, 0.28 mmol), 2,3-dihydrofuran (59 mg, 0.84 mmol), Pd(OAc)2 (6 mg, 0.028 mmol), PPh3 (15 mg, 0.056 mmol) and K2CO3 (77 mg, 0.56 mmol) in DMF (3 mL) was stirred at 110 ° C overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine and concentrated. The crude product was used directly in the next step without further purification. MS calculated value: 347.2; MS found value: 348.4 [M+H] + .

[1515] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 1 Synthesis of phenyl-4-(tetrahydrofuran-2-yl)benzene-1,3-diamine (SS20308-0195-01):

[1516]

[1517] A mixture of 195-01-1 (crude, 0.28 mmol) and Pd / C (10%, 100 mg) in EtOAc (2 mL) was stirred at room temperature under H2 overnight. After the reaction was complete, the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give SS20308-0195-01 (5.74 mg, approximately 6% yield) as a solid. MS calculated: 349.4; MS found: 350.2 [M+H] + .

[1518] 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 =7.6Hz,2H),6.93(d,J=7.6Hz,1H),6.77(t,J=7.6Hz,1H),6.37-6.36(m,1H),6.35-6.34(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),3.7 0-3.65(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).

[1519] Example 79

[1520]

[1521] Example route of Example 79:

[1522]

[1523] Synthesis of methyl 2-(2-nitro-5-(phenylamino)phenyl)acetate (197-2):

[1524]

[1525] A mixture of 197-1 (2.00 g, 7.30 mmol), aniline (1.36 g, 14.60 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), Xantphos (854 mg, 1.46 mmol) and Cs2CO3 (4.74 g, 14.60 mmol) in toluene (60 mL) was stirred at 100°C overnight under a N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 197-2 (1.20 g, 57% yield) as a yellow oil. MS calculated value: 286.1; MS found value: 287.4.

[1526] Synthesis of 2-(2-nitro-5-(phenylamino)phenyl)acetic acid (197-3):

[1527]

[1528] A mixture of 197-2 (500 mg, 1.75 mmol) and LiOH (147 mg, 3.50 mmol) in THF (30 mL) was stirred at room temperature overnight. 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 Na2SO4 and concentrated to give 197-3 (400 mg, approximately 84% yield) as an oil. MS calculated value: 272.1; MS found value: 273.4 [M+H] + .

[1529] Synthesis of 2-(2-nitro-5-(phenylamino)phenyl)acetic acid (197-4):

[1530]

[1531] A mixture of 197-3 (400 mg, 1.47 mmol), dimethylamine hydrochloride (132 mg, 2.94 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 at room temperature overnight. The reaction mixture was then concentrated and poured into water (100 mL). The resulting mixture was extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 197-4 (405 mg, approximately 92% yield) as an oil. MS calculated value: 299.1; MS found value: 300.1 [M+H] + .

[1532] Synthesis of 3-(2-(dimethylamino)ethyl)-4-nitro-N-phenylaniline (197-5)

[1533]

[1534] A mixture of 197-4 (405 mg, 1.35 mmol) and BH3·S(Me)2 (2.7 mL, 2.7 mmol) in THF (5 mL) was stirred at room temperature overnight. 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 x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 197-5 (340 mg, approximately 88% yield) as an oil. MS calculated value: 285.1; MS found value: 286.2 [M+H] + .

[1535] 3-(2-(dimethylamino)ethyl)-N1 -Synthesis of phenylbenzene-1,4-diamine (197-6):

[1536]

[1537] A mixture of 197-5 (340 mg, 1.19 mmol) and 10% Pd / C (34 mg) in MeOH (5 mL) was stirred at room temperature under N2 atmosphere overnight. The reaction mixture was then filtered and concentrated to afford 197-6 as an oil (280 mg, approximately 92% yield). MS calculated: 255.2; MS found: 256.2 [M+H] + .

[1538] N 1 -(2-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N 4 -Synthesis of phenylbenzene-1,4-diamine (SS20308-0197-01):

[1539]

[1540] A mixture of 197-6 (130 mg, 0.51 mmol), 2-chloro-1-bromobenzene (195 mg, 1.02 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (57.8 mg, 0.10 mmol) and Cs2CO3 (332 mg, 1.02 mmol) in toluene (4 mL) was stirred at 100°C overnight under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc=1 / 2) and preparative HPLC to give SS20308-0197-01 (6 mg, 3% yield) as an oil. MS calculated value: 365.2; MS found value: 366.3 [M+H] + .

[1541] 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,1.2Hz,1H),2.60(t,J=6.8Hz,2H),2.44-2.43(m,2H),2.13(s,6H).

[1542] Example 80

[1543]

[1544] Example route of Example 80:

[1545]

[1546] Synthesis of 4-(3-(dimethylamino)prop-1-ynyl)-2-nitroaniline (198-2):

[1547]

[1548] 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, 0.23 mmol), Pd(CH3CN)2Cl2 (48 mg, 0.19 mmol) and potassium carbonate (1.27 g, 9.22 mmol) was suspended in CH3CN (20 mL). The reaction mixture was heated under reflux overnight under N2, 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 give compound 198-2 (0.83 g, approximately 92% yield) as a solid. MS calculated value: 219.1; MS found value: 219.6 [M+H] + .

[1549] Synthesis of 4-(3-(dimethylamino)propyl)benzene-1,2-diamine (198-3):

[1550]

[1551] A solution of 198-2 (830 mg, 3.79 mmol) and 10% Pd / C (83 mg) in MeOH (20 mL) was stirred overnight at room temperature under H2(g). The reaction mixture was then filtered through celite. The filtrate was concentrated to afford 198-3 (700 mg, 96% yield) as a brown oil. MS calculated: 193.2; MS found: 194.4 [M+H] + .

[1552] N 1 ,N 2 Synthesis of bis(2-chlorophenyl)-4-(3-(dimethylamino)propyl)benzene-1,2-diamine (SS20308-0198-01):

[1553]

[1554] A solution of 198-3 (520 mg, 2.69 mmol), 1-bromo-2-chlorobenzene (3.09 g, 16.14 mmol), Xantphos (312 mg, 0.54 mmol), Pd2(dba)3 (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 heated to 120 ° C. 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, 1 / 1, 100% EtOAc, DCM / MeOH=20 / 1) to give an oil. MS calculated value: 413.1; MS found value: 414.2 [M+H] + .

[1555] 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).

[1556] Example 81

[1557]

[1558] Example route of Example 81:

[1559]

[1560] Synthesis of 2-bromo-5-fluorobenzene-1,4-diamine (199-2):

[1561]

[1562] To a solution of 199-1 (300 mg, 1.28 mmol) in acetone (30 mL) was added Zn powder (417 mg, 6.38 mmol) and NH4Cl (341 mg, 6.38 mmol), and the mixture was stirred at 70 ° C for 16 hours. After the reaction was completed, the insoluble matter was removed by filtration. The filtrate was poured into water (50 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (2x50 mL), dried over MgSO4, and concentrated in vacuo, and used for the next step without purification.

[1563] Synthesis of 2-(3-(dimethylamino)prop-1-ynyl)-5-fluorobenzene-1,4-diamine (199-3):

[1564]

[1565] A mixture of 199-2 (500 mg, 2.44 mmol), N, N-dimethylprop-2-yn-1-amine (2.03 g, 24.39 mmol), Pd(CH3CN)2Cl2 (63 mg, 0.24 mmol), Cs2CO3 (1.59 g, 4.88 mmol) and X-Phos (232 mg, 0.49 mmol) in CH3CN (20 ml) was stirred at 80 ° C overnight under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water, filtered to remove insoluble matter, and the filtrate was extracted with EtOAc (30 mL x 3). The organic layer was separated, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (petroleum ether / EtOAc=1 / 1) to give 163-01-3 (450 mg, 89% yield) as a yellow oil. MS calculated value: 207.1; MS found value: 208.1 [M+H] + .

[1566] Synthesis of 2-(3-(dimethylamino)propyl)-5-fluorobenzene-1,4-diamine (199-4):

[1567]

[1568] To a MeOH (30 mL) solution of 199-3 (250 mg, 1.21 mmoles) was added 10% Pd / C (50 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete, the insoluble matter was removed by filtration. The filtrate was poured into water (50 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with salt water (2x50 mL), dried over MgSO4, and concentrated in vacuo, and used for the next step without further purification.

[1569] N 1 ,N 4 -Synthesis of bis(2-chloro-4-fluorophenyl)-2-(3-(dimethylamino)propyl)-5-fluorobenzene-1,4-diamine (SS20308-0199-01):

[1570]

[1571] A mixture of 199-4 (120 mg, 0.57 mmol), 1-bromo-2-chloro-4-fluorobenzene (357 mg, 1.70 mmol), Pd2(dba)3 (52 mg, 0.06 mmol), Cs2CO3 (555 mg, 1.70 mmol) and X-Phos (54 mg, 0.11 mmol) in toluene (10 ml) was stirred at 110 ° C overnight 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 x 3). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The crude product was purified by preparative HPLC to give SS20308-0199-01 (6 mg, 2% yield) as a yellow oil. MS calculated value: 467.1; MS found value: 467.9 [M+H] + .

[1572] 1 H 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).

[1573] Example 82

[1574]

[1575] Example route of Example 82:

[1576]

[1577] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 -Synthesis of cyclohexylbiphenyl-2,4-diamine (SS20308-0200-01):

[1578]

[1579] A mixture of 95-5 (60 mg, 0.18 mmol), cyclohexylamine (36 mg, 0.36 mmol), Pd(OAc)2 (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 in a microwave reactor for 8 hours. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated to a crude oil, which was purified by preparative HPLC to give SS20308-0200-01 (4.3 mg, approximately 7% yield) as an oil. MS calculated value: 361.2; MS found value: 362.3 [M+H] + .

[1580] 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 7.96 (s, 1H), 7.34 (t, J = 7.6Hz, 2H), 7.24-7.17 (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=6.0 Hz,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...

Claims

1. A lipoxygenase inhibitor having formula I: in, The lipoxygenase inhibitor is selected from: and pharmaceutically acceptable salts thereof.

2. The lipoxygenase inhibitor according to claim 1, wherein the lipoxygenase inhibitor exhibits inhibitory activity against multiple lipoxygenases (LOX).

3. The lipoxygenase inhibitor of claim 2, wherein the plurality of LOXs comprises 5-LOX, 12-LOX, 15-LOX, or a combination thereof.

4. The lipoxygenase inhibitor of claim 1, wherein the lipoxygenase inhibitor has Formula II: in, The lipoxygenase inhibitor is selected from: and pharmaceutically acceptable salts thereof.

5. The lipoxygenase inhibitor of claim 1, wherein the lipoxygenase inhibitor has Formula IIA: in, The lipoxygenase inhibitor is selected from: and pharmaceutically acceptable salts thereof.

6. The lipoxygenase inhibitor of claim 1, wherein the lipoxygenase inhibitor has Formula IIB: in, The lipoxygenase inhibitor is selected from: and pharmaceutically acceptable salts thereof.

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