Lipoxygenase inhibitors

Abstract

Various embodiments of the present disclosure relate to compounds having Formula I, Formula II, Formula IIA, Formula III, Formula IIIA, Formula IIIB, and / or pharmaceutically acceptable salts thereof. The compounds may be useful in the inhibition of lipoxygenase and / or the treatment of related diseases. In some embodiments, the subject compounds are useful in the preparation of compositions effective in the treatment of neurodegenerative diseases.

Description

Background Technology

[0001] Lipoxygenases (LOXs) and their catalytic products, such as inflammatory leukotrienes (LTs) and hydroxyeicosatetraenoic acid (HETEs), are involved in the pathogenesis of a variety of human diseases, including inflammatory diseases, cancer, and neurodegenerative diseases. Lipoxygenase inhibitors are known to be used to treat various LOX-related inflammatory diseases, including neurodegenerative diseases such as Alzheimer's disease. Summary of the Invention

[0002] The present invention aims to overcome the above-mentioned challenges as well as other challenges related to compounds, such as compounds as LOX inhibitors.

[0003] Various embodiments of this 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, while when n=1 or 2, the carbons in these bonds are optionally substituted by 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 by 1-3 R1 groups; B is a 5-6-membered heterocycle, 5-6-membered aryl, or 5-6-membered cyclohexyl, wherein the 5-6-membered heterocycle, 5-6-membered aryl, or 5-6-membered cyclohexyl is unsubstituted or independently substituted by 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 group, -(CH2)3NR x R y -NH(CH2)2R x R y -NHCH2CR x R y R z 5-6 aryl, 5-10 heterocyclic, 5-10 heteroaryl, or 5-10 heterocyclic aryl, wherein 1-3 R1 groups are optionally further divided by R a and / or R bSubstitution, wherein the two R1 groups optionally together 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 R1 groups. a Substitution; each R2 independently includes: halogen, C 1-2 Methoxy group, or -C(O)OR x The two R2 groups on adjacent atoms optionally form a 5-6 aryl group, wherein the 5-6 aryl group is optionally further bonded by 1-3 R2 groups. a Base substitution; R3 includes: C 1-3 Halogenated alkyl, or oxoalkyl; 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 Halogenated alkyl, or -NR a R b , where R x R y or R z Any two of them may optionally be combined to form a 4-6 membered heterocycle, a 5-6 membered aryl group, wherein R x R y and R z Each can choose to be further R a and R b Replace; R a and R b Each of these elements independently includes: H, halogen, cyano, oxo, and C. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic, wherein R a and R b Each of them is optionally further replaced by R′; and R′ is C 1-3 Alkyl, C 1-3 Halogenated alkyl, or C 5-6 Metaheteroaryl.

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

[0007]

[0008]

[0009] -NH2,

[0010] In some implementations, each R2 is independently selected from: F, Cl and

[0011]

[0012] In some embodiments, the compound (the compound of formula I) is selected from:

[0013]

[0014]

[0015]

[0016]

[0017]

[0018] And its pharmaceutically acceptable salts.

[0019] Various embodiments of this disclosure relate to compounds having Formula II or pharmaceutically acceptable salts thereof:

[0020]

[0021] 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, 6-membered aryl, or 6-membered cyclohexyl, wherein the 6-membered heterocycle, 6-membered aryl, or 6-membered cyclohexyl is unsubstituted or independently substituted by at most 2 R2 groups; each X1, X2, X3, and X4 independently includes: 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 z5-6-membered aryl, 5-10-membered heterocyclic, 5-10-membered heteroaryl, or 5-10-membered heterocyclic aryl, wherein the two R1 groups optionally together form a 5-6-membered heteroaryl, [5-6-membered heterocyclic, 5-6-membered cycloalkyl, 5-6-membered aryl], wherein the 5-6-membered heteroaryl, [5-6-membered heterocyclic, 5-6-membered cycloalkyl, 5-6-membered aryl] is optionally further surrounded by 1-3 R1 groups. a Base substitution; wherein 1-3 R1 bases are each optionally and independently further substituted by R. a or R b Substitution; each R2 independently includes: halogen, C 1-2 Methoxy group, or -C(O)OR x Each R x R y and R z Independently includes: H, halogen, C 1-2 Alkyl, C 1-2 alcohol, C 1-2 Alkoxy, C 1-2 Halogenated alkyl, or -NR a R b , where R x R y or R z The two elements can optionally be combined to form a 4-6 membered heterocycle, a 5-6 membered aryl group, wherein R x R y and R z Each can choose to be further R a and R b Replace; R a and R b Each of these elements independently includes: H, halogen, cyano, oxo, and C. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic, wherein R a and R b Optionally and independently, it is further replaced by R′; and R′ is C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups, or 5-6-membered heteroaryl groups.

[0022] In some implementations, each R1 is independently selected from:

[0023]

[0024]

[0025] In some implementations, each R2 is independently selected from: In some embodiments, the compound (the compound of formula II) is selected from:

[0026]

[0027]

[0028]

[0029] And its pharmaceutically acceptable salts.

[0030] Various embodiments involve compounds having formula IIA and their pharmaceutically acceptable salts:

[0031]

[0032] Wherein: B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 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 5-6 aryl, wherein R1 is optionally further converted to R a or R b Substitution; R2 is H, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, or C 1-3 Haloalkoxy groups, wherein R1 and R2 optionally together form a 5-6 membered heterocycle, wherein the 5-6 membered heterocycle is optionally further formed by R a or R b Replaced, or by R a and R b Both can be substituted; R4 is a halogen, or C 1-3 Alkyl; R x and R y Each is C independently 5-6 Meta-heterocyclic rings, R a and R b Each is C independently 1-3 Alkyl or C 1-3 Haloalkyl, wherein R a and R b Optionally further substituted with an R′ group; the R′ group is a 5-membered heteroaryl or a 5-6-membered heterocycle.

[0033] In some implementations, R1 is selected from:

[0034]

[0035] In some implementations, each R2 is independently selected from:

[0036]

[0037] In some embodiments, the compound (of formula IIA) is selected from:

[0038]

[0039] And its pharmaceutically acceptable salts.

[0040] Various embodiments involve compounds having formula IIB and their pharmaceutically acceptable salts:

[0041]

[0042] Wherein: B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; each X is independently C, N, or O; R1 is H, C 1-3 Alkyl, 5-6 membered heterocyclic, 5-6 membered aryl, 5-6 membered heteroaryl, 5-10 membered cyclic 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 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 cyclic heteroaryl, or -NR x R y R′2 is H or a halogen; each R3 is H, a halogen, or C. 1-3Alkyl group, -O(CH2)2NR x R y -NR x (CH2)2R y -NR x R y , or -(CH2)3NR x R y R4 is a halogen; furthermore, R1 and R 2a Or R 2b Optionally, they are combined to form a 5-6 membered heterocycle, which is then optionally further reacted with R. a and / or R b Replace, and in which R1, R 2a R 2b R'2 and R3 are each optionally and independently defined by one or more R's. a Replace; R x and R y H and C are independent of each other. 1-4 Alkyl, 5-6 aryl, 5-6 heteroaryl, -NR a R b , where R x and R y Each can be chosen to form a 4-5 member heterocycle, and R in this case... x Or R y Optionally and independently further by R a and / or R b Replace; R a and R b Each of these groups is independently H, halogen, oxo, cyano, and 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.

[0043] In some implementations, R1 is selected from:

[0044] H,

[0045] In some implementations, R 2a and R 2b Each is selected independently from:

[0046]

[0047] In some implementations, each R3 is independently H.

[0048] In some embodiments, the compound (the compound of formula IIB) is selected from:

[0049]

[0050] And its pharmaceutically acceptable salts.

[0051] Various embodiments involve compounds having Formula III and their pharmaceutically acceptable salts:

[0052]

[0053] Where n is 1-2; B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; X1, X2, X3, X4, and X5 are each independently C, N, or O; R1 is a halogen, C 1-4 Alkyl, -NR x R y -O(CH2)2NR x R y 6-membered cyclohexyl, 6-membered heterocyclic, 6-membered aryl, 6-membered heteroaryl, or 5-10-membered cycloalkyl, wherein, when two R1 groups are present, the two R1 groups optionally together form a 6-membered heteroaryl; wherein each (one or more) R1 group is optionally and independently further bounded by one or more R1 groups. a Substitution; each R2 is a halogen or C 1-3 Alkyl group; each R3 is independently H, oxo, C. 1-3 Haloalkyl, or hydroxyalkyl, wherein when one or more R3s are hydroxyalkyl, one or more of R3s optionally form a 4-membered heterocycle together with the C of Formula III; R x and R y H and C are independent entities. 1-3 Alkyl, 6-membered aryl, or 6-membered heteroaryl, wherein R x and R y Each of them may, independently and alternatively, be further subjected to one or more R a Replace; R a It is halogen, oxo, cyano, C 1-3 Haloalkyl, -NR′R′, 5-6 aryl, 5-6 heteroaryl, or 5-6 heterocyclic, and one or more of the R groups. a They can be optionally combined to form 4-5 membered heterocycles; R′ is C 1-3 alkyl.

[0054] In some implementations, each R1 is independently selected from:

[0055]

[0056] In some implementations, each R2 is independently: H,

[0057] In some implementations, R3 is H, oxo, or

[0058] In some embodiments, the compound (the compound of formula III) is selected from:

[0059]

[0060] And its pharmaceutically acceptable salts.

[0061] Various embodiments involve compounds having formula IIIA and their pharmaceutically acceptable salts:

[0062]

[0063] Where n is 1-2; B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; X1, X2, and X3 are each independently C, N, or O; R1 is C. 1-3 Alkyl group, R2 is H, halogen, C 1-3 Haloalkyl, C 1-4 Alkyl, 5-6 aryl, 5-6 cycloalkyl, 5-6 heterocyclic, 5-10 heteroaryl, 5-10 cycloaryl; R3 is H or halogen; each R4 is independently H, oxo, C. 1-3 The alkyl or hydroxyalkyl group, wherein when one or more of R4 are hydroxyalkyl, one or more R4 optionally form a 4-membered heterocycle with the C of formula IIIA; R5 is a halogen, or a 4-5-membered heterocycle; R1, R2, R4 and R5 are each optionally and independently formed by a maximum of 2 R groups. a or R b Replace; R a and R b Each is independent of the other. 1-3 Alkyl, C 1-3 Haloalkyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl, -N / -NR′R′, where R a and R b Optionally, they can be combined to form 4-5 membered heterocycles, where R a and R b Optionally and independently further substituted with one or more R′ groups; R′ is a halogen or C 1-3 alkyl.

[0064] In some implementations, R1 is selected from:

[0065]

[0066] In some implementations, R2 is selected from:

[0067]

[0068] In some implementations, R3 is H or F.

[0069] In some implementations, R4 is H.

[0070] In some implementations, R5 is

[0071] In some embodiments, the compound (of formula IIIA) is selected from:

[0072]

[0073] And its pharmaceutically acceptable salts.

[0074] Various embodiments involve compounds having formula IIIB and their pharmaceutically acceptable salts:

[0075]

[0076] Where n is 1-2; B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; X1, X2, X3, and X4 are each independently C or N; R1 is H, C 1-3 Alkyl, or 5-6 aryl; wherein R1 is optionally surrounded by one or more R a or R b Replace; R 2a and R 2b Each is C independently 1-4 Alkyl, or 5-6-membered heteroaryl; R1 and R 2a or R 2b Optionally, they are combined to form a 5-6 aryl or a 5-6 heteroaryl group, which is optionally further reacted with R. a and R b Substitution; each R3 is independently H, halogen, or C. 1-3 Alkyl group; each R4 is independently H or oxo; each R5 is independently halogen or a 4-5 membered heterocycle; R1, R 2a R 2b R3 and R5 are each independently and optionally further modified by R a and R b Replace; R a and R b Each is independently H, halogen, oxo, cyano, or C. 1-3 Alkyl, 5-6 membered heteroaryl.

[0077] In some implementations, R1 is:

[0078] H,

[0079] In some implementations, R 2a and R 2b Each independently is: H,

[0080] In some implementations, each R3 is independently H or

[0081] In some implementations, R4 is: H or oxidase.

[0082] In some implementations, each R5 is independently:

[0083] In some embodiments, the compound (the compound of formula IIIB) is selected from:

[0084] And its pharmaceutically acceptable salts and / or hydrates.

[0085] Various embodiments relate to methods for processing lipoxygenases in cells, wherein the cells are determined to require the method, the method comprising contacting or administering to the cells a compound having the structure disclosed in any of the preceding claims (e.g., claim 1). In some embodiments, these cells are human cells in vivo or human cells isolated in vitro. In some embodiments, the cells are in situ as part of a person determined to require inhibition of lipoxygenases or suffering from a disease associated with pathogenic lipoxygenase activity, said disease being selected from acute or chronic inflammatory diseases or neurodegenerative diseases.

[0086] In some embodiments, the disease is: (i) an acute or chronic inflammatory disease, namely asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis or cardiovascular disease, or (ii) a neurodegenerative disease, namely age-related neurodegeneration, amyloid-β-related disease, Alzheimer's disease, ischemia-related disease, Creutzfeldt-Jakob disease / prion peptide toxicity, ALS, dementia or Parkinson's disease.

[0087] In some embodiments, the method further includes (i) measuring lipoxygenase activity in a human sample; (ii) determining the level of lipoxygenase metabolites in the human sample; or (iii) determining that the person has the disease.

[0088] Various embodiments relate to a pharmaceutical composition comprising the compound for inhibiting lipoxygenase activity as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0089] Various embodiments relate to a pharmaceutical composition comprising the compound for inhibiting lipoxygenase activity as described in claim 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0090] Various embodiments involve compositions comprising compounds of Formula I above and second anti-neurodegenerative disease drugs.

[0091] Various embodiments relate to methods for identifying lipoxygenase inhibitors, including steps for screening compounds of Formula I and / or claim 44 for lipoxygenase inhibitory activity.

[0092] The embodiments described herein include all combinations of the specific embodiments described. Other embodiments and the full scope of the invention will become apparent from the detailed description provided below. However, it should be understood that while the detailed description and specific embodiments indicate preferred embodiments of the invention, they are given by way of illustration only, as various changes and modifications within the spirit and scope of the 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 Implementation

[0093] The following description is given under the understanding that this disclosure is intended to be an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. Headings used in this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments described under any heading may be combined with embodiments described under any other heading.

[0094] The singular forms “a,” “an,” and “described” used herein and in the appended claims include the plural meaning unless the context clearly indicates otherwise. Thus, for example, reference to “compound” includes multiple such compounds, reference to “determination” includes reference to one or more determinations, and so on.

[0095] The prefix "Cx-y" indicates that the following group has x (e.g., 1) to y (e.g., 6) carbon atoms. In some groups (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.), one or more carbon atoms may be replaced by one or more heteroatom or heteroatom groups. For example, "C 1-6"Alkyl" indicates that an 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 heterocyclic group," refers to a ring containing xy atoms (e.g., 3-12 atoms), of which up to half can be heteroatoms such as N, O, S, P, and the remaining atoms are carbon. Furthermore, 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 correspondingly called "alkylene" groups or "alkylene" groups, or alkylyl groups, "arylene" or "aryl" groups, or arylyl groups.

[0096] “Alkyl” means any group derived from a straight-chain or branched saturated hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., propyl-1-yl, propyl-2-yl (isopropyl), butyl (e.g., butyl-1-yl, butyl-2-yl (sec-butyl), 2-methyl-propyl-1-yl (isobutyl), 2-methyl-propyl-2-yl (tert-butyl), pentyl, hexyl, octyl, decyl, etc. Unless otherwise specified, alkyl groups have 1 to 10 carbon atoms, for example 1 to 6 carbon atoms, for example 1 to 4 carbon atoms.

[0097] "Alkenyl" refers to any group derived from a straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, vinyl (ethenyl or vinyl), allyl (propenyl), 1-butenyl, 1,3-butadienyl, etc. Unless otherwise stated, alkenyl groups have 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms.

[0098] "Alynyl" means any group derived from a straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, and includes those groups having one triple bond and one double bond. Examples of alkynyl include, but are not limited to, ethynyl (-CH≡CH), propynyl (-CH₂C≡CH), (E)-pent-3-en-1-alkynyl, etc. Unless otherwise stated, alkynyl groups have 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, for example 2 to 4 carbon atoms.

[0099] "Amino" refers to -NH2. Amino groups can also be substituted as described herein, for example, by 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).

[0100] "Aryl" refers to any group derived from one or more aromatic rings, i.e., monocyclic, bicyclic, or polycyclic systems. Aryl groups include, but are not limited to, those derived from acenaphthene, anthracene, azurite, benzene, etc. Those groups such as cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indene, perylene, phenalene, phenanthrene, pyrene, etc.

[0101] "Arylalkyl" (also known as "arylalkyl") refers to any combination of aryl and alkyl groups. Arylalkyl groups include, but are not limited to, those derived from benzyl, tolyl, dimethylphenyl, 2-phenylethyl-1-yl, 2-naphthylmethyl, etc. Arylalkyl groups contain 6 to 30 carbon atoms; for example, alkyl groups may contain 1 to 10 carbon atoms, and aryl groups may contain 5 to 20 carbon atoms.

[0102] "Cycloaryl" refers to a combination of an aryl group and a ring. Some representative examples of cycloaryl groups include 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene, and 3a,5,6,7-tetrahydro-4H-indene.

[0103] "Heterocyclic aryl" refers to a combination of aryl and heterocyclic groups. Some representative examples of heterocyclic aryl groups include 1,2,3,4-tetrahydroisoquinoline, isochorane, 1,3-dihydroisobenzofuran, and isodihydroindole.

[0104] "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 bridging groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcyclopropyl (cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl, etc. Another example includes C5-7 cycloalkenyl groups.

[0105] "Halogenated" and "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0106] "Halogenated alkyl" 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, etc., as well as alkyl groups, such as perfluoroalkyl groups, in which all hydrogen atoms are replaced by fluorine atoms.

[0107] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups. Examples include, but are not limited to, -CH2OH, -CH2CH2OH, and -C(CH3)2OH.

[0108] "Halogenated 3-6 membered heterocyclic group" refers to a heterocyclic group in which at least one halogen atom is substituted on a carbon atom. It may include multiple halogen atoms, such as 3,3-difluoroazacyclobutane.

[0109] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are 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 groups include, but are not limited to, -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, -CH2NRCH3, -CH2OH, etc., where R is hydrogen, alkyl, aryl, aralkyl, heteroalkyl, or heteroaryl, each of which may optionally be substituted. Heteroalkyl groups contain 1 to 10 carbons and up to three heteroatoms, for example, 1 to 6 carbons and 1 to 2 heteroatoms.

[0110] "Heteroaryl" refers to a monocyclic or polycyclic aryl 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 systems are included in heteroaryl groups and can be attached to a ring via heteroatoms or aromatic rings. Heteroaryl groups include, but are not limited to, those derived from the following groups: acridine, benzimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, dihydroindole, indene, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthan, etc. Heteroaryl compounds can have prices of 5-14 yuan, 5-10 yuan, or 5-6 yuan.

[0111] "Heterocyclic," "heterocyclic," and "heterocyclic group" refer to saturated or partially unsaturated non-aromatic rings or partially non-aromatic polycyclic systems having at least one heteroatom or heteroatom group as defined above. Heterocycles include, but are not limited to, those derived from the following groups: aziridine, aziridine, imidazoline, morpholine, thiomorpholine, tetrahydro-2H-thiaran, 1-iminotetrahydro-2H-thiaran 1-oxide, ethylene oxide (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, N-bromopyrrolidine, N-chloropiperidine, etc. Heterocyclic groups also include 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; dihydroimidazole; tetrahydroimidazole; dihydroindole; isodihydroindole; isoindole ketones (e.g., isoindole-1-one); indigo; dihydrophthalazine; quinoline ketones; spiro[cyclopropane-1,1'-isoindole]-3'-one; etc. The heterocyclic group can be 3-12 quinones, 3-10 quinones, 3-7 quinones, or 5-6 quinones.

[0112] "Hydroxyl" and "hydroxyl" are used interchangeably and refer to -OH. "Oxy" refers to ═O, or an oxide containing N-oxide or S-oxide. When tautomerism exists in a compound, hydroxyl and oxo groups are interchangeable.

[0113] It should be understood that combinations of chemical groups can be used, and such combinations are those that will be recognized by those skilled in the art. For example, the group “hydroxyalkyl” refers to a hydroxyl group attached to an alkyl group. Many such combinations can be readily conceived. 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 heterocyclic-C1-6 alkyl (e.g., piperazine-CH2—), C1-6 alkylsulfonyl-5-7 membered heterocyclic (e.g., CH3S(O)2-morpholinyl-), 5-7 membered heterocyclic C1-6 alkoxy ( For example, pyrrolidinyl-O-), 5-7-membered heterocyclic groups, (4-7-membered heterocyclic)-4-7-membered heterocyclic groups (e.g., oxocyclic butyl-pyrrolidinyl-), C3-6 cycloalkylamino carbonyl groups (e.g., cyclopropyl-NH-C(O)-), 5-7-membered heterocyclic-C2-6 ynyl groups (e.g., N-piperazinyl-CH2C≡CCH2-), and C6-10 arylamino carbonyl groups (e.g., phenyl-NH-C(O)-).

[0114] A "pharmaceutically acceptable salt" is a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound (or can be converted into a form possessing 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, and phosphoric acid; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic 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, and trimethylacetic acid; and salts formed when an acidic proton present in the parent compound is replaced by any metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or salts formed by coordination with organic bases such as diethanolamine, triethanolamine, and N-methylglucosamine. This definition also includes ammonium salts and substituted ammonium salts or quaternary ammonium salts. A representative, non-restrictive list of pharmaceutically acceptable salts can be found in SMBerge, 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, Tables 38-5, both of which are incorporated herein by reference.

[0115] 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 interchangeably referred to as “ring A” or “A” and “ring B” or “B”, both referring to the specifically mentioned ring accordingly. Similarly, as used herein and in the claims, the various groups of compounds are sometimes interchangeably referred to by the presence or absence of an “atom” or “base / group” at the end, such as “R1” and “R1 base / group”, both referring to the specifically mentioned atom or chemical group accordingly.

[0116] "Objects" and "objects" refer to people, livestock (such as dogs and cats), farm animals (such as cows, horses, sheep, goats, and pigs), laboratory animals (such as mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys), etc.

[0117] The “management” and “treatment” of a disease include the following:

[0118] (1) To prevent or reduce the risk of developing the disease, even if the clinical symptoms of the disease do not develop in individuals who may be exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms of the disease.

[0119] (2) Suppressing the disease, that is, halting or slowing the development of the disease or its clinical symptoms, and / or

[0120] (3) To alleviate the disease, that is, to reduce the disease or its clinical symptoms.

[0121] "Effective amount" refers to the amount that effectively elicits the desired biological, clinical, or medical response, including the amount of a compound sufficient to achieve treatment when administered to a subject for a disease. Effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject. Effective amounts can include a range of amounts.

[0122] The compounds of the present invention include their solvates, hydrates, tautomers, stereoisomers and salt forms.

[0123] Pharmaceutical compositions of the disclosed general formulas can be administered in single or multiple doses via any acceptable route of administration of agents having similar efficacy, such as by means of those patents and patent applications incorporated herein by reference, including rectal, oral, intranasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhaler, or by means of impregnated or coated devices, such as stents, or arterial insertion cylindrical polymers. In one aspect, the compounds described herein can be administered orally. Oral administration can be, for example, via capsules or enteric-coated tablets.

[0124] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulations may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavorings.

[0125] In some embodiments, the compounds disclosed herein are compounds of formula I:

[0126]

[0127] Where n is 0, 1, or 2. When n is 0, this indicates a direct bond between B and the NH group attached to the A ring (as shown in the formula above), and R3 is absent. When n is 1 or 2, the R3 group can be substituted by any CH atom. For example, one or two CH groups can be independently unsubstituted or substituted by the R3 group.

[0128] In some embodiments, ring A is a 6-membered heteroaryl group. In some embodiments, ring A is a 6-membered heteroaryl group 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 group, X1, X2, and X3 are independently C, N, or O.

[0129] In some embodiments, ring B can be a 5-6 membered heterocycle, a 5-6 membered aryl group, or a 5-6 membered cyclohexyl group. In some embodiments, ring B can be a 5-6 membered heterocycle independently substituted by up to three R2 groups. In some embodiments, ring B can be a 5-6 membered aryl group independently substituted by up to three R2 groups. In some embodiments, ring B can be a 5-6 membered cyclohexyl group independently substituted by up to three R2 groups. In some embodiments, when ring B is a 5-6 membered aryl group, X4, X5, and X6 are all carbons. In some embodiments, when ring B is a 5-6 membered heterocycle or a 5-6 membered heteroaryl group, each X4, X5, and X6 can be independently C, N, or O.

[0130] In some implementations, R1 can be a 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 group, -(CH2)3NR x R y -NH(CH2)2R x R y -NHCH2CR x R y R z 5-6 aryl, 5-10 heterocyclic, 5-10 heteroaryl, or 5-10 heterocyclic aryl. As used herein, a heterocyclic aryl refers to two rings, such as a heterocycle fused with an aryl group. In some embodiments, R1 may be further independently surrounded by 1, 2, or 3 R groups. a Or R b Alkyl substitution. In some embodiments, the two R1 groups can together form a 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered cycloalkyl, or 5-6 membered aryl. In some embodiments, when the two R1 groups together form a 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered cycloalkyl, or 5-6 membered aryl, the resulting 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered cycloalkyl, or 5-6 membered aryl can be further substituted with one, two, or three R1 groups.a Base substitution.

[0131] In some implementations, R1 is:

[0132]

[0133]

[0134] -NH2,

[0135] In some implementations, each R2 can be an independent halogen atom, C 1-2 Methoxy group, or -C(O)OR x In some embodiments, two R2 groups on adjacent atoms can together form a 5-6 membered aromatic ring. The 5-6 membered aromatic ring can be independently formed by one, two, or three R groups. a The radical can be substituted or unsubstituted.

[0136] In some implementations, R2 is F, Cl, or H.

[0137] In some implementations, R3 is C 1-3 Halogenated alkyl or oxoalkyl.

[0138] In some implementations, R x R y and R z Each of these atoms can be an independent hydrogen atom, a halogen atom, or a carbon atom. 1-2 Alkyl, C 1-2 alcohol, C 1-2 Alkoxy, C 1-2 Halogenated alkyl, or -NR a R b In some implementations, R x R y and R z Each group can be independently a cyano group, an oxygen group, or an oxo group, C. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic. In some embodiments, R x R y and R z Any two of them can together form a 4-6 membered heterocycle or a 5-6 membered aryl group. In some embodiments, R x R y and R z It can be further R a and / or Rb replace.

[0139] In some implementations, R a and R b Each atom is independently a hydrogen atom, a halogen atom, a cyano group, an oxygen atom, and a carbon atom. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic. In some embodiments, R a and / or R b It can be further independently replaced by the R′ base.

[0140] In some implementations, R′ can be C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, or 5-6-membered heteroaryl groups.

[0141] In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate of Formula I.

[0142] In some embodiments, compounds having the structure of formula (I) are selected from:

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] And its pharmaceutically acceptable salts or hydrates.

[0149] In some embodiments, the disclosed compound has a structure corresponding to Formula II:

[0150]

[0151] In some embodiments of Formula II, ring A is a 6-membered heteroaryl or 6-membered aryl. In some embodiments of Formula II, ring A is a 6-membered heteroaryl or 6-membered aryl ring, wherein ring A is independently substituted by 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. In embodiments of ring A, when ring A is a 6-membered heteroaryl, X1, X2, and X3 are independently C, N, or O.

[0152] 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 by at most two R2 groups. Furthermore, in embodiments of ring B, when ring B is a 6-membered heterocyclic ring, X4 can be C, N, or O.

[0153] 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 heterocyclic, 5-10-membered heteroaryl, or 5-10-membered heterocyclic aryl. In some embodiments, the two R1 groups can together form a 5-6-membered heteroaryl, 5-6-membered heterocyclic, 5-6-membered cycloalkyl, or 5-6-membered aryl. In some embodiments, the two R1 groups can together form a 5-6-membered heteroaryl, 5-6-membered heterocyclic, 5-6-membered cycloalkyl, or 5-6-membered aryl, wherein the 5-6-membered heteroaryl, 5-6-membered heterocyclic, 5-6-membered cycloalkyl, or 5-6-membered aryl can be further surrounded by 1 to 3 R1 groups. a Base substitution. In some embodiments, each of the 1 to 3 R1 bases may be independently further replaced by 1 to 3 R1 bases. a Base and / or 1 to 3 R b Base substitution.

[0154] In some embodiments of Equation II, R1 is:

[0155]

[0156] In some embodiments of Formula II, each R2 can be an independent halogen atom, C 1-2 Methoxy group, or -C(O)OR x .

[0157] In some embodiments of Equation II, each R2 is independently

[0158] In some embodiments of Formula II, R1 and / or R2 may contain one or more R x R y and / or R z Basis, where each R x R y and R z The radicals can be hydrogen atoms, halogen atoms, or carbon atoms, each independently. 1-2 Alkyl, C 1-2 alcohol, C 1-2 Alkoxy, C 1-2 Halogenated alkyl or -NR a R b In some embodiments of Equation II, when two R x R y Or R z When it exists, R x R y Or R z Any two of them 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.

[0159] In some embodiments of Formula II, R a and R b Each of these can be an independent hydrogen atom, halogen atom, cyano group, oxygen atom, or carbon atom. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic. In some embodiments of Formula II, when R a and / or R b Each is C independently 1-3 Alkyl group, -C(O)OR′, C 1-3 When R is a haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic ring, a and / or R b It can be further substituted with the R′ base. In some embodiments of formula II, R′ can be C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, or 5-6 membered heteroaryl rings. In some embodiments, the disclosed compounds are pharmaceutically acceptable salts or hydrates of Formula II.

[0160] In some embodiments, the exemplary compound of Formula II has the following structure:

[0161]

[0162]

[0163]

[0164] And its pharmaceutically acceptable salts or hydrates.

[0165] In some embodiments, the disclosed compounds have a structure corresponding to formula IIA:

[0166]

[0167] In some embodiments, ring B can be cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl. In some embodiments of Formula IIA, when ring B is cyclohexyl, a 6-membered heterocyclic ring, or a 6-membered heteroaryl, X4 can be C, N, or O. In some embodiments of Formula IIA, when ring B is cyclohexyl, a 6-membered heterocyclic ring, or a 6-membered heteroaryl, ring B can be independently substituted by up to two R4 groups.

[0168] In some implementations, X1 and X3 of ring A can be independently C, N, or O.

[0169] In some implementations, 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 quinone aromatic ring. In some embodiments, when R1 is substituted, R1 can be replaced by R a and / or R b Substitution. In some embodiments, R2 can be a hydrogen atom, a halogen atom, or a carbon atom. 1-3 Alkyl, C 1-3 Halogenated alkyl, or C 1-3 Halogenated alkoxy groups. In some embodiments, R x and R y Each can be C independently 5-6 5-6 member heterocyclic rings. In some embodiments, R1 and R2 can together form a 5-6 member heterocyclic ring. In some embodiments, when the respective R1 and the respective R2 together form a 5-6 member heterocyclic ring, and / or the 5-6 member heterocyclic ring can be further modified by R... a and / or R bRadical substitution. In some embodiments, R3 is a hydrogen atom or a halogen atom. In some embodiments, R4 can be a halogen atom or a carbon atom. 1- 3. Alkyl group. In some embodiments, R1, R2, R3 and / or R4 may be further independently substituted by one or more R groups. a and / or R b Base substitution. In some implementations, R a and R b Each can be C independently 1-3 Alkyl or C 1-3 Halogenated alkyl groups. In some embodiments, R a and R b It can be C that is further substituted by the R′ base. 1-3 Alkyl and C 1-3 Halogenated alkyl group. In some embodiments, R′ may be a 5-membered heteroaryl group or a 5-6-membered heterocyclic group. In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of formula IIA.

[0170] In some embodiments of Formula IIA, R1 is selected from:

[0171]

[0172] In some embodiments of Formula IIA, R2 is selected from:

[0173]

[0174] In some embodiments, the compound of formula IIA has the following structure:

[0175]

[0176] And its pharmaceutically acceptable salts or hydrates.

[0177] In some embodiments, the disclosed compounds have a structure corresponding to formula IIB:

[0178]

[0179] In some embodiments, ring B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl. In some embodiments, ring B is cyclohexyl, a 6-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, wherein the cyclohexyl, 6-membered heterocycle, 6-membered aryl, or 6-membered heteroaryl may be further independently substituted by up to two R4 groups.

[0180] In some implementations, when ring B is a 6-membered heterocyclic ring or a 6-membered heteroaryl ring, X is N or O.

[0181] In some embodiments, each X of ring A and / or ring B can be independently C, N, or O. In some embodiments, ring A can be independently replaced by R1, R′2, and / or one or both R3.

[0182] In some implementations, R1 can be a hydrogen atom, C 1-3 Alkyl, 5-6 membered heterocyclic, 5-6 membered aryl, 5-6 membered heteroaryl, 5-10 membered cyclic heteroaryl, 5-10 membered heteroaryl, or -C(O)R x .

[0183] In some implementations, R 2a and R 2b Each of the atoms can be a hydrogen atom independently, C 1-3 Alkyl, 5-6 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 cyclic heteroaryl, or -NR x R y .

[0184] In some implementations, R'2 can be a hydrogen atom or a halogen atom.

[0185] In some implementations, each R3 can be independently a hydrogen atom, a halogen atom, or a carbon atom. 1-3 Alkyl group, -O(CH2)2NR x R y -NR x (CH2)2R y -NR x R y , or -(CH2)3NR x R y .

[0186] In some implementations, R4 is a halogen atom.

[0187] In some implementations, R1 and R 2a or R 2b They can form 5-6 membered heterocycles together.

[0188] In some implementations, R1 and R 2a or R 2b They can together form a 5-6 membered heterocycle, which can be further reacted with one or more R... a and / or R b Base substitution.

[0189] In some implementations, R1, R′2, R 2a R 2b And / or R3 can each be further independently determined by one or more R a Base substitution.

[0190] In some implementations, R x and R y Each of the atoms can be a hydrogen atom independently, C 1-4 Alkyl, 5-6 aryl, 5-6 heteroaryl, or -NR a R b In some implementations, R x and R y They can together form 4-5 membered heterocycles and / or contain R x and R y The formed 4-5 member heterocycles can be R a or R b replace.

[0191] In some implementations, R a and R b Each atom is independently a hydrogen atom, a halogen atom, an oxygen atom, a cyano group, and a carbon atom. 1-3 Alkyl, C 1-3 alcohol, C 1-3 Alkoxy, phenyl, -(CH2)2R′, 5-6 membered heteroaryl, or 5-6 membered heterocyclic.

[0192] In some implementations, R′ is a 5-membered heteroaryl group.

[0193] In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of formula IIB.

[0194] In some embodiments of formula IIB, R1 is:

[0195] In some embodiments of formula IIB, R 2a and R 2b Each is independently selected from: H, In some embodiments of formula IIB, R3 is H. In some embodiments of Formula IIB, the compound has the following structure:

[0196]

[0197]

[0198] And its pharmaceutically acceptable salts or hydrates.

[0199] In some embodiments, the disclosed compounds have a structure corresponding to Formula III:

[0200]

[0201] In some implementations, n is 1-2.

[0202] In some implementations, X1, X2, X3, and X4 of ring A can each be independently C, N, or O.

[0203] In some implementations, ring A can be independently replaced by one, two, or three R1 bases.

[0204] In some implementations, ring B can be cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl.

[0205] In some embodiments, when ring B is a 6-membered heterocyclic ring or a 6-membered heteroaryl group, X5 can be N or O. In some embodiments, X5 can be C.

[0206] In some implementations, 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 heterocyclic, 6-membered aryl, 6-membered heteroaryl, or 5-10-membered cycloalkyl.

[0207] In some embodiments, when two R1 groups are present, the two R1 groups can together form a 6-membered heteroaryl group. In some embodiments, when two R1 groups are present, the two R1 groups can together form a 6-membered heteroaryl group, and either of the two R1 groups can be further reacted with one or more R... a Base substitution.

[0208] In some implementations, each R2 is a halogen atom or a carbon atom. 1-3 Alkyl group.

[0209] In some implementations, R3 is, or each R3 independently is, a hydrogen atom, an oxygen atom, or a carbon atom. 1-3 Halogenated alkyl, or hydroxyalkyl. In some embodiments, when one or more R3s are hydroxyalkyl, one or more of R3s optionally form a 4-membered heterocycle together with the C of Formula III.

[0210] In some implementations, R x and R y Each of the atoms can be a hydrogen atom independently, C 1-3 Alkyl, 6-membered aryl, or 6-membered heteroaryl. In some embodiments, when R x or R y It is C 1-3 When R is alkyl, 6-membered aryl, or 6-membered heteroaryl, x and / or R y It can be further used by one or more R a replace.

[0211] In some implementations, R a It consists of a halogen atom, an oxygen atom, a cyano group, and a carbon atom. 1-3 Haloalkyl, -NR′R′, 5-6 aryl, 5-6 heteroaryl, or 5-6 heterocyclic. In some embodiments, one or more R a They can form 4-5 membered heterocyclic rings together.

[0212] In some implementations, R′ is C 1-3 Alkyl group. In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of formula III.

[0213] In some implementations, Formula III is:

[0214]

[0215] In some embodiments of Equation III, R1 is:

[0216]

[0217]

[0218] In some embodiments of Equation III, R2 is: H, In some embodiments of Formula III, R3 is: H, oxidized, or In some embodiments of Formula III, the compound has the following structure:

[0219]

[0220]

[0221] And its pharmaceutically acceptable salts or hydrates.

[0222] In some embodiments, the compounds disclosed herein are compounds of formula IIIA:

[0223]

[0224] In some implementations, n is 1-2.

[0225] In some embodiments, ring B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl.

[0226] In some implementations, X1, X2, and X3 can each be independently C, N, or O.

[0227] In some implementations, R1 is C 1-3 Alkyl group. In some embodiments, R1 is further reacted with one or more R groups. a or R b Replacement C 1-3 alkyl.

[0228] In some implementations, R2 can be a hydrogen atom, a halogen atom, or a carbon atom. 1-3 Haloalkyl, C 1-4 Alkyl, 5-6 aryl, 5-6 cycloalkyl, 5-6 heterocyclic, 5-10 heteroaryl, or 5-10 cycloaryl. 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, or a carbon atom. 1-3 Haloalkyl, or hydroxyalkyl. In some embodiments, when one or more of R4 are hydroxyalkyl, one or more R4 optionally form a 4-membered heterocycle together with the C of formula IIIA. In some embodiments, R5 can be a halogen atom or a 4-5 membered heterocycle. In some embodiments, R1, R2, R4 and / or R5 can be up to two R... a and / or R b Base substitution, where R a and / or R b The base is C 1-3 Alkyl, C 1-3 Haloalkyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl, -NR′R′. In some embodiments, when R1, R2, R4 and / or R5 are replaced by R a and / or R b When the base is substituted, R a and R b They can together form 4-5 membered heterocyclic rings. In some implementations, R a and R bEach can be independently substituted with one or more R′ groups, wherein if there is more than one R′ group, the R′ groups can be the same or different. In some embodiments, R′ can be a halogen atom or a C atom. 1-3 Alkyl group. In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of formula IIIA.

[0229] In some embodiments of Formula IIIA, R1 is:

[0230]

[0231]

[0232] In some implementations of Formula IIIA, R2 is:

[0233]

[0234] In some embodiments of Formula IIIA, R3 and R5 are independently H or F atoms. In some embodiments, R5 is an F atom. In some embodiments of Formula IIIA, R4 is H.

[0235] In some implementations, formula IIIA is:

[0236]

[0237] In some embodiments of Formula IIIA, the compound has the following structure:

[0238] And its pharmaceutically acceptable salts or hydrates.

[0239] In some embodiments, the compounds disclosed herein are compounds of formula IIIB:

[0240]

[0241] In some implementations, n is 1-2.

[0242] In some embodiments, ring B may be cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl. In some embodiments, ring B may be cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl, wherein ring B may be further substituted by up to two R5 groups.

[0243] In some implementations, X1, X2, X3, and X4 can each be C or N independently.

[0244] In some implementations, R1 is a hydrogen atom, C 1-3 Alkyl, or 5-6 aryl. In some embodiments, R1 is a hydrogen atom, C 1-3 Alkyl, or 5-6 aryl, wherein when R1 is C 1-3 When R1 is alkyl or 5-6 aryl, R1 can be replaced by one or more R1s. a and / or R b replace.

[0245] In some implementations, R 2a and R 2b Each can be C independently 1-4 Alkyl or 5-6-membered heteroaryl. In some embodiments, R1 and R 2a or R 2b Optionally, they can be combined to form a 5-6 aryl or a 5-6 heteroaryl group, which may be further optionally subjected to R a and R b replace.

[0246] In some implementations, R3 is a hydrogen atom, a halogen atom, or a carbon atom. 1-3 Alkyl group.

[0247] In some embodiments, R4 is, or each R4 independently is, a hydrogen atom or an oxygen atom. In some embodiments, R5 is a halogen atom or a 4-5 membered heterocycle. In some embodiments, R1, R... 2a R 2b R3 and R5 can each be independently controlled by a maximum of two Rs. a or R b Replace, where R a and R b It can be a halogen atom, an oxygen atom, a cyano group, or a carbon atom. 1-3 Alkyl, or 5-6 membered heteroaryl. In some embodiments, the disclosed compound is a pharmaceutically acceptable salt or hydrate of formula IIIB.

[0248] In some embodiments of formula IIIB, R1 is H.

[0249] In some embodiments of formula IIIB, R 2a and R 2b Each is H independently.

[0250] In some embodiments of formula IIIB, each R3 is H or

[0251] In some embodiments of Formula IIIB, R4 is a hydrogen or oxygen atom. In some embodiments of Formula IIIB, R5 is H. In some embodiments of formula IIIB, R5 is

[0252] In some implementations, formula IIIB is:

[0253]

[0254] In some embodiments of Formula IIIB, the compound has the following structure:

[0255]

[0256] And its pharmaceutically acceptable salts and / or hydrates.

[0257] Some embodiments are methods for identifying cells in which lipoxygenase inhibition is desired, including contacting (or administering) cells with a compound having the structure disclosed in any of the compounds described above, wherein the cells are human cells, either in vivo or isolated in vitro. In some embodiments, in situ cell inhibition is performed as part of identifying a person who requires lipoxygenase inhibition or suffers from a disease associated with pathogenic lipoxygenase activity, said disease being selected from acute or chronic inflammatory diseases or neurodegenerative diseases. Some methods further include: (i) measuring lipoxygenase activity in a human sample; (ii) determining the level of lipoxygenase metabolites in the human sample; or (iii) determining that the person suffers from the disease. In some methods, the disease is: (i) an acute or chronic inflammatory disease, namely asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis or cardiovascular disease, or (ii) a neurodegenerative disease, namely age-related neurodegeneration, amyloid-β-related disease, Alzheimer's disease, ischemia-related disease, Creutzfeldt-Jakob disease / prion peptide toxicity, ALS, dementia or Parkinson's disease.

[0258] Further contemplated are pharmaceutical compositions comprising a compound, as 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, as described above, for inhibiting lipoxygenase activity, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. Further contemplated are compositions comprising compounds of Formula I above and a second anti-neurodegenerative disease drug. Further contemplated are methods for identifying lipoxygenase inhibitors, including a step of screening one or more of the above compounds for lipoxygenase inhibitory activity.

[0259] As described in more detail herein, the subject compounds may be used in pharmaceutically acceptable alternative forms, such as pharmaceutically acceptable salts, prodrugs (e.g., aminosulfonates, phosphates, esters, ethers, amides, etc.). Unless otherwise stated, 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.

[0260] In some embodiments, the subject compound is 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, treatment of neurodegenerative diseases comprises administration of a formulation containing the subject compound. As described in more detail herein, the composition may comprise one or more active agents and one or more pharmaceutically acceptable additives. Furthermore, the composition may be formulated into any suitable dosage form.

[0261] In some embodiments, the subject composition comprises a compound according to formula (I) as the sole active agent; such formulations may include pharmaceutically inactive components, such as carriers, etc.

[0262] In some embodiments, the subject compound is administered in combination with one or more other anti-neurodegenerative drugs. The other drugs may be present in a single formulation along with the subject compound, thus allowing for simultaneous administration. Alternatively, the other drugs may be in a separate formulation and may be administered according to a different dosing regimen than the formulation containing the subject compound. In such embodiments, the two regimens may be related; for example, the second formulation may be administered with the first formulation, or the second formulation may be administered just before the first formulation, or the second formulation may be administered immediately after the first formulation. Examples of other anti-neurodegenerative drugs include acetylcholinesterase inhibitors (e.g., tacrine, rivastigmine, galantamine, donepezil, etc.), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), hyperzine A, latrepirdine, and hypothalamic proline-rich peptide 1 (PRP-1), etc.

[0263] The subject compound may be administered as a free base or as 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 article, is pharmacologically active. Salts, esters, amides, prodrugs, active metabolites, analogues, and other derivatives of the active agent may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry, and described, for example, in the following literature: 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).

[0264] 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.

[0265] Suitable organic acids for preparing acid addition salts include, for example, C1-C6 alkyl and C6-C6 alkyl acids. 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, as well as 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. Acid addition salts can be converted back to free bases by treatment with a suitable base.

[0266] 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 salts of amines such as betaine, choline, and procaine. Suitable inorganic bases for preparing base addition salts include, for example, salts derived from sodium, potassium, ammonium, calcium, iron, ferrous, aluminum, lithium, magnesium, or zinc, such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, and potassium carbonate. Base addition salts can be converted back to free acids by treatment with a suitable acid.

[0267] Prodrugs and active metabolites can also be prepared using techniques known to those skilled in the art or described in relevant literature. Prodrugs are typically prepared by covalently linking a moiety that results in the compound being non-therapeutic before being modified by an individual's metabolic system. For example, compounds according to Formula I can be pharmaceutically acceptable prodrug forms, such as aminosulfonate prodrugs.

[0268] Other derivatives and analogs of the surfactant can be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or can be inferred by referring to relevant literature.

[0269] Any compound disclosed herein may be an active agent in a subject formulation. Formulations containing compounds of this disclosure may include one, two, three, or more subject compounds, and may also include one or more additional active agents, such as analgesics and other antibiotics. "Any compound disclosed herein" refers to any compound selected from the subject compound itself (i.e., as a free base) and its salts, prodrugs, etc.

[0270] Based on the total weight of the formulation, the amount of active agent in the formulation typically ranges from about 0.05% by weight to about 95% by weight. For example, the amount of active agent may be from about 0.05% by weight to about 50% by weight, or from about 0.1% by weight to about 25% by weight. Alternatively, the amount of active agent in the formulation may be measured to achieve the desired dosage.

[0271] Formulations containing the subject compound may be provided in single-dose or multi-dose containers, and may contain optional preservatives to extend shelf life.

[0272] The compositions of this disclosure can be administered to a patient by any suitable method. Generally, both systemic and local administration methods are acceptable. It will be apparent to those skilled in the art that the choice of administration method will be influenced by many factors, such as the condition being treated, the frequency of administration, the dose level, and the patient's needs. For example, some methods may be more suitable for the rapid delivery of high doses of the active agent, while others may be more suitable for the slow, stable delivery of the active agent. Examples of administration methods suitable for delivering the compounds of this disclosure include parenteral and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery by these methods are well known in the art.

[0273] For example, formulations containing the compounds disclosed herein can be administered parenterally, such as by intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and / or continuous infusion. Typically, parenterally administration is in the form of liquid formulations.

[0274] The composition can also be administered via the digestive tract, including oral and rectal administration. Examples of formulations suitable for administration via the digestive tract include tablets, capsules, lozenges, chewing gum, aqueous solutions, and suppositories.

[0275] Formulations can also be administered via mucosal delivery. Mucosal delivery includes delivery through the mucosa of the mouth (including the buccal and sublingual), nose, vagina, and rectum. Formulations suitable for mucosal delivery are well known in the art and include tablets, chewing gum, mouthwash, lozenges, suppositories, gels, creams, liquids, and pastes.

[0276] The formulation can also be administered transdermally. Transdermal delivery can be achieved using, for example, creams, liquids, pastes, gels, and other topical medications, as well as medications commonly referred to as transdermal "patches".

[0277] Formulations can also be administered via the respiratory tract. Lung delivery can be achieved through inhalation via the mouth or nose, using aerosols, dry powders, liquid formulations, etc. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms.

[0278] Liquid formulations include solutions, suspensions, and emulsions. For example, a solution may be an aqueous solution of an active agent and may include one or more of propylene glycol, polyethylene glycol, etc. Aqueous suspensions can be prepared by dispersing finely chopped active agents in water using a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Formulations in solid form that are intended to be converted into a liquid form shortly before use are also included.

[0279] Tablets and lozenges may contain, for example, a flavoring base such as compressed lactose, sucrose, and gum arabic or tragacanth, as well as an effective amount of active agent. Lozenges typically contain an active agent in an inert base such as gelatin and glycerin or sucrose and gum arabic.

[0280] The subject compound can inhibit one or more lipoxygenases, 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 compound is a selective inhibitor and an inhibitor of a sub-region of the LOX enzyme family. In some embodiments, the subject compound can inhibit 5-LOX, 12-LOX, or 15-LOX. In some embodiments, the subject compound can inhibit various combinations of 5-LOX, 12-LOX, and 15-LOX, such as inhibiting 5-LOX and 12-LOX, inhibiting 5-LOX and 15-LOX, inhibiting 12-LOX and 15-LOX, and / or inhibiting 5-LOX, 12-LOX, and 15-LOX.

[0281] The subject compounds can be used in therapies for 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, and 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.

[0282] For example, the method may include administering the subject compound to a patient in need (e.g., a patient with a neurodegenerative disease such as Alzheimer's disease, or a patient at risk of developing such a disease, or a patient exhibiting symptoms of such a disease, etc.). In some embodiments, the subject compound is used in methods to reduce or eliminate the severity of symptoms associated with the subject disease. For example, the method may involve contact with nerve cells or cells located in the nervous system, or contact with tissues associated with the nervous system, and such contact results in one or more of the following: inhibition of further neurodegeneration; inhibition of abnormal cell growth and development; inhibition of the growth of noncellular objects in the nervous system; reduction of neuroinflammation; reduction of the severity of symptoms associated with neurodegenerative diseases, etc.

[0283] In some embodiments, the subject compound is used to prepare a composition that effectively treats the subject disease. As described in more detail herein, the composition may comprise one or more active agents and one or more pharmaceutically acceptable additives. Furthermore, the composition may be formulated into any suitable dosage form.

[0284] In some embodiments, treatment of the subject disease involves 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, treating the subject disease with the compound involves determining that the person suffers from the subject disease associated with pathogenic lipoxygenase activity. This determination can be made in any manner suitable for specific conditions, including blood tests and imaging tests.

[0285] In some embodiments, the method includes measuring a patient's lipoxygenase activity (e.g., 5-LOX, 12-LOX, or 15-LOX, and / or various combinations thereof) before, after, or before and after treatment with the subject compound. In some embodiments, the method involves measuring the level of a patient's lipoxygenase metabolite. 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 person, such as bodily fluids (e.g., blood, urine, etc.).

[0286] Various embodiments are implemented based on the basic provisional application (serial number 62 / 953,023) entitled "Lipooxygenase Inhibitor," filed on December 23, 2019, which claims the benefit of this application, and its general and specific teachings are fully incorporated herein by reference. For example, embodiments described 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 references provided in the basic provisional application. Unless specifically indicated, the embodiments discussed in the provisional application are not intended to limit the entire technical disclosure or any part of the claimed disclosure in any way.

[0287] All patents, patent applications, and publications mentioned herein are incorporated in their entirety by reference. However, when a patent, patent application, or publication containing a specific definition is included by reference, it should be understood that such specific definition applies to the included patent, patent application, or publication in which it is contained, and not to the remainder of this application, and in particular not to the claims of this application.

[0288] It should be understood that although the invention has been described in conjunction with preferred embodiments, the foregoing description and the following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art will understand that various changes can be made and equivalents can be substituted without departing from the scope of the invention, and that other aspects, advantages, and modifications will be apparent to those skilled in the art.

[0289] Experimental Implementation Methods

[0290] The compounds disclosed in this paper were found to inhibit Akt and ERK activation by suppressing 12-LOX-mediated arachidonic acid metabolism.

[0291] 5-LOX FI fluorescence assay

[0292] 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 spread at 1 μL into 96-well microplates, followed by the addition of 40 μL of a solution containing the 5-LOX enzyme. The enzyme and compound were pre-incubated for 15 min. The assay was initiated by adding 40 μL of a substrate solution containing AA and ATP and 20 μL of a solution containing DHR123. The enzymatic reaction was allowed to proceed for 30 min, and kinetic readings were obtained at 500 nm excitation and 536 nm emission in a SpectraMax Paradigm (Molecular Device). The percentage of inhibition for each compound dose was calculated using a 4-parameter logistic model or a sigmoidal dose-response model for IC50 analysis. 50 Curve fitting.

[0293] 12-LOX / 15-LOX fluorescence assay

[0294] 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. 1 μL of the inhibitor (dissolved in DMSO) was spread onto a 96-well microplate, followed by the addition of 40 μL of a solution containing 12-LOX / 15-LOX enzyme. The enzyme and compounds were pre-incubated for 15 min. The assay was initiated by adding 40 μL of substrate solution containing AA / LA and 20 μL of solution containing DHR123. The enzymatic reaction proceeded for 30 min, and kinetic readings were obtained at 500 nm excitation and 536 nm emission in a SpectraMax Paradigm (Molecular Device). The percentage of inhibition per compound dose was calculated using a 4-parameter logic model or a sigmoid dose-response curve for IC50 analysis. 50 Curve fitting.

[0295] Inhibitory activity against a group of lipoxygenases was demonstrated in cell-based assays; for example, for 5-LOX, a fluorescence-based human 5-LOX enzyme assay was used (Anal. Biochem., 364:204.), and for 12-LOX, platelet 12-LOX activity was determined colorimetrically (Anal. Biochem., 231:354). Table 1 provides results for exemplary compounds on 5-LOX, 12-LOX, and 15-LOX.

[0296] Table 1: IC50 (μM) values ​​of lipoxygenase inhibition in vitro

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315] General information about the embodiments:All evaporations were performed in vacuum 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, with spots observed under UV light (214 and 254 nm). Purification was performed using silica gel (200–300 mesh) via column chromatography and rapid 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 used as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiply), coupling constant (Hz), and integral.

[0316] Example 1

[0317]

[0318] Example route of Implementation Example 1:

[0319]

[0320] Synthesis of 2-(2-bromo-6-nitrophenoxy)-N,N-dimethylethylamine (25-1):

[0321]

[0322] 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 h. The mixture was diluted with EtOAc (150 mL). The organic layer was washed successively with water (100 mL), saturated bicarbonate solution (100 mL), and brine (100 mL). 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 an oily 25-2 (2.3 g, 43% yield). MS calculated value: 288.0; MS measured value: 289.1 [M+H] + .

[0323] Synthesis of 2-(2-(dimethylamino)ethoxy)-N-(4-methoxybenzyl)-3-nitroaniline (25-3)

[0324]

[0325] 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 for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (50 mL). The organic phase was washed successively with water (50 mL) and brine (50 mL). 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 in solid form (230 mg, approximately 32% yield). MS calculated value: 345.2; MS measured value: 346.3 [M+H] + .

[0326] Synthesis of 2-(2-(dimethylamino)ethoxy)-N1-(4-methoxybenzyl)phenyl-1,3-diamine (SS20308-0025-01):

[0327]

[0328] A mixture of 25-3 (200 mg, 0.6 mmol), Zn powder (195 mg, 3.0 mmol), and HOAc (0.1 mL) and MeOH (10 mL) was stirred at 60 °C for 3 hours. The reaction mixture was cooled to room temperature, filtered, and washed with MeOH (20 mL). The organic phase was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give SS20308-0025-01 (62 mg, approximately 34% yield) in solid form.

[0329] 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).

[0330] Example 2

[0331]

[0332] Example route of Example 2:

[0333]

[0334] Synthesis of 2-(2-(dimethylamino)ethoxy)-3-nitro-N-phenylaniline (52-2):

[0335]

[0336] 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) in solid form. MS calculated value: 301.1; MS measured value: 302.4 [M+H] + .

[0337] 2-(2-(dimethylamino)ethoxy)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (52-3):

[0338]

[0339] Pd / C (10%, 50 mg) was added to a solution of 52-2 (500 mg, 1.66 mmol) in MeOH (20 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction mixture was then filtered. The filtrate was concentrated to give an oily 52-3 (370 mg, approximately 82% yield). MS calculated value: 271.2; MS measured value: 272.4 [M+H] + .

[0340] 2-(2-(dimethylamino)ethoxy)-N 1 -(4-Methoxybenzyl)-N 3 Synthesis of 1,3-phenylphenyl-1,3-diamine (SS20308-0052-01):

[0341]

[0342] A mixture of 52-3 (290 mg, 1.07 mmol) and p-methoxybenzaldehyde (146 mg, 1.07 mmol) in HOAc (1 mL) and MeOH (20 mL) was stirred at 70 °C for 2 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 alkalized 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 with Na2SO4, and concentrated. The residue was purified by preparative HPLC to give SS2308-0052-01 (60 mg, approximately 14% yield) in solid form. MS calculated value: 391.2; MS measured value: 392.2 [M+H] + .

[0343] 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).

[0344] Example 3

[0345]

[0346] Example route of Example 3:

[0347]

[0348] Synthesis of 3-bromo-2-(2-(dimethylamino)ethoxy)aniline (53-1):

[0349]

[0350] 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 diatomaceous earth. The filtrate was alkalized 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 53-1 in solid form (0.7 g, approximately 78% yield). MS calculated value: 258.0; MS measured value: 259.2 [M+H] + .

[0351] Synthesis of N-(3-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-3-oxo-3-phenylpropionamide (53-2):

[0352]

[0353] A mixture of 53-1 (410 mg, 1.58 mmol) and ethyl benzoyl (760 mg, 3.95 mmol) was stirred and heated to 140 °C for 0.5 h under microwave irradiation and a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1, 5 / 1, 3 / 1, 1 / 1, CH2Cl2 / MeOH = 20 / 1) to give 53-2 in solid form (400 mg, approximately 62% yield). MS calculated value: 404.1; MS measured value: 405.3 [M+H] + .

[0354] Synthesis of 7-bromo-8-(2-(dimethylamino)ethoxy)-4-phenylquinoline-2(1H)-one (53-3):

[0355]

[0356] The 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 onto ice, alkalized 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 an oily 53-3 (70 mg, approximately 15% yield). MS calculated value: 386.1; MS measured value: 387.2 [M+H] + .

[0357] Synthesis of 8-(2-(dimethylamino)ethoxy)-7-(4-methoxybenzylamino)-4-phenylquinoline-2(1H)-one (SS20308-0053-01):

[0358]

[0359] A solution of 53-3 (85 mg, 0.22 mmol), (4-methoxyphenyl)methylamine (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 under reflux overnight under a nitrogen atmosphere, then filtered and washed 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) in solid form. MS calculated value: 443.2; MS measured value: 444.3 [M+H] + .

[0360] 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).

[0361] Example 4

[0362]

[0363] Example route of Example 4:

[0364]

[0365] Synthesis of 2-(2-bromo-6-nitrophenoxy)-N,N-dimethylethylamine (71-1):

[0366]

[0367] 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 diatomaceous earth. 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 an oily 71-2 (1.1 g, approximately 28% yield). MS calculated value: 288.0; MS measured value: 289.1 [M+H] + .

[0368] Synthesis of N-benzyl-2-(2-(dimethylamino)ethoxy)-3-nitroaniline (71-3):

[0369]

[0370] To a solution of 71-2 (300 mg, 1.0 mmol) in toluene (3 mL), benzylamine (111 mg, 1.0 mmol), Cs₂CO₃ (696 mg, 2.0 mmol), Xantphos (62 mg, 0.1 mmol), and Pd₂(dba)₃ (98 mg, 0.1 mmol) were added, and the reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth, then diluted with EtOAc (20 mL). The organic layer was washed with brine and concentrated to dryness. The residue was purified by column chromatography (EtOAc / petroleum ether = 1 / 1 to 1 / 0) to give an oily 71-3 (200 mg, approximately 59% yield). MS calculated value: 315.2; MS measured value: 316.3 [M+H] + .

[0371] N 1 Synthesis of β-benzyl-2-(2-(dimethylamino)ethoxy)benzene-1,3-diamine (71-4):

[0372]

[0373] To a solution of 71-3 (200 mg, 0.63 mmol) in MeOH (6 mL), Zn powder (166 mg, 2.5 mmol) and HOAc (152 mg, 2.5 mmol) were added, 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 an oily 71-4 (200 mg, crude). MS calculated value: 285.2; MS measured value: 286.2 [M+H] + .

[0374] N 1 -Benzyl-N 3 Synthesis of 1,3-(3-chloropyridin-2-yl)-2-(2-(dimethylamino)ethoxy)benzene-1,3-diamine (SS20308-0071-01):

[0375]

[0376] To a solution of 71-4 (380 mg, 1.33 mmol) in 15 mL of toluene, 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) were added. The reaction mixture was then stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and concentrated to dryness. The residue was purified by preparative TLC (EtOAc) to give an oily SS₂0308-0071-01 (420 mg, approximately 80% yield). MS calculated value: 396.2; MS measured value: 397.3 [M+H] + .

[0377] 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).

[0378] Example 5

[0379]

[0380] Example route of Example 5:

[0381]

[0382] Synthesis of 4-bromo-2-nitrobenzene (95-2):

[0383]

[0384] A mixture of 95-1 (6.00 g, 21.36 mmol), phenylboronic acid (2.60 g, 21.36 mmol), Pd(PPh3)4 (1.23 g, 1.07 mmol), and Na2CO3 (7.90 g, 74.76 mmol) in toluene / H2O (60 mL, 5 / 1) was stirred overnight at 90 °C under a nitrogen 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) to give an oily 95-2 (3.70 g, approximately 62% yield).

[0385] 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).

[0386] Synthesis of 4-bromobiphenyl-2-amine (95-3):

[0387]

[0388] A mixture of 95-2 (3.70 g, 13.30 mmol), Zn powder (8.70 g, 133.00 mmol), and HOAc (3.5 mL) in EtOH (35 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water. The mixture was alkalized with 40% NaOH to pH 10. The resulting mixture was filtered through diatomaceous earth 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 an oily 95-3 (1.90 g, approximately 58% yield). MS calculated value: 247.0; MS measured value: 248.1 [M+H] + .

[0389] Synthesis of 4-bromo-N-(2-chloroethyl)biphenyl-2-amine (95-4):

[0390]

[0391] To a solution of 95-3 (1.75 g, 7.05 mmol) in 20 mL of MeOH, 2-chloroacetaldehyde (2.77 g, 14.11 mmol, 40%), AcOH (846 mg, 14.11 mmol), and NaBH3CN (887 mg, 14.11 mmol) were added, and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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 an oily 95-4 (2.00 g, approximately 91% yield). MS calculated value: 309.0; MS measured value: 309.8 [M+H] + .

[0392] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromobiphenyl-2-amine (95-5):

[0393]

[0394] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to give an oily 95-5 (2.10 g, approximately 95% yield). MS calculated value: 342.1; MS measured value: 342.8 [M+H] + .

[0395] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of 2,4-benzylbiphenyl-2,4-diamine (SS20308-0096-01):

[0396]

[0397] A mixture of 95-5 (200 mg, 0.58 mmol), benzylamine (75 mg, 0.70 mmol), Pd2dba3 (53 mg, 0.06 mmol), Xantphos (67 mg, 0.12 mmol), and Cs2CO3 (378 mg, 1.16 mmol) in toluene (20 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC to give SS20308-0096-01 (25 mg, approximately 12% yield) in solid form. MS calculated value: 369.2; MS measured value: 370.1 [M+H] + .

[0398] 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).

[0399] Example 6

[0400]

[0401] Example route of Example 6:

[0402]

[0403] Synthesis of N-(4-bromo-3-nitrophenyl)benzamide (135-2):

[0404]

[0405] Benzoyl chloride (420 mg, 3 mmol) was added to a solution of 135-1 (432 mg, 2 mmol) in 50 mL of DCM. 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) in solid form. MS calculated value: 320.0; MS measured value: 321.2 [M+H] + .

[0406] Synthesis of N-(2-nitro-[1,1'-biphenyl]-4-yl)benzamide (135-3):

[0407]

[0408] Cs₂CO₃ (652 mg, 2 mmol) and xphos Pd G₂ (20 mg) were added 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). The mixture was heated under 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 an oily 135-3 (230 mg, approximately 72% yield). MS calculated value: 318.1; MS measured value: 319.2 [M+H] + .

[0409] Synthesis of N-(2-amino-[1,1'-biphenyl]-4-yl)benzamide (135-4):

[0410]

[0411] To a mixture of 135-3 (230 mg, 0.72 mmol) in DCM (50 mL), HOAc (5 mL) and Zn powder (150 mg) were added 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 an oily 135-4 (140 mg, approximately 68% yield). MS calculated value: 288.1; MS measured value: 288.2 [M+H] + .

[0412] Synthesis of N-(2-((2-chloroethyl)amino)-[1,1'-biphenyl]-4-yl)benzamide (135-5):

[0413]

[0414] To a mixture of 135-4 (144 mg, 0.5 mmol) in EtOH (30 mL), 1 mL of 2-chloroacetaldehyde and 1 mL of HOAc were added, followed by 0.3 g of NaBH3CN. 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 an oily 135-5 (85 mg, approximately 48% yield). MS calculated value: 350.1; MS measured value: 350.2 [M+H] + .

[0415] Synthesis of N-(2-((2-(1H-1,2,4-triazol-1-yl)ethyl)amino)-[1,1'-biphenyl]-4-yl)benzamide (SS20308-0135):

[0416]

[0417] To a mixture of 135-5 (85 mg, 0.24 mmol) in DMF (15 mL), 1H-1,2,4-triazole (69 mg, 1 mmol) and Cs₂CO₃ (326 g, 1 mmol) were added 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, approximately 27% yield) in solid form. MS calculated value: 383.5; MS measured value: 384.2 [M+H] + .

[0418] 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).

[0419] Example 7

[0420]

[0421] Example route of Example 7:

[0422]

[0423] Synthesis of "5-bromobiphenyl-2-amine (145-2)"

[0424]

[0425] A mixture of 145-1 (6.40 g, 37.82 mmol) and NBS (6.70 g, 37.82 mmol) in DMF (10 mL) was stirred overnight at 0 °C. 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 an oily 145-2 (5.7 g, approximately 57.6% yield). MS calculated value: 247.0; MS measured value: 248.2 [M+H] + .

[0426] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (145-3):

[0427]

[0428] 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 overnight at room temperature. The resulting mixture was 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 = 10 / 1) to give 145-3 (6.0 g, approximately 84% yield) in solid form. MS calculated value: 309.0; MS measured value: 310.0 [M+H] + .

[0429] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (145-4):

[0430]

[0431] 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 (3 x 30 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 in solid form (3.8 g, approximately 70% yield). MS calculated value: 342.1; MS measured value: 343.9 [M+H] + .

[0432] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2,5-benzylbiphenyl-2,5-diamine (SS20308-0145-01):

[0433]

[0434] 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 overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1 / 2) to give an oily SS20308-0145-01 (100 mg, approximately 21% yield). MS calculated value: 369.2; MS measured value: 370.3 [M+H] + .

[0435] 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).

[0436] Example 8

[0437]

[0438] Example route of Example 8:

[0439] Synthesis of 5-bromobiphenyl-2-amine (146-2):

[0440]

[0441] A mixture of 146-1 (6.40 g, 37.82 mmol) and NBS (6.70 g, 37.82 mmol) in DMF (10 mL) was stirred overnight at 0 °C. 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 an oily 146-2 (5.7 g, approximately 57.6% yield). MS calculated value: 247.0; MS measured value: 248.2 [M+H] + .

[0442] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (146-3):

[0443]

[0444] 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 overnight at room temperature. The resulting mixture was 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 = 10 / 1) to give 146-3 (6.0 g, approximately 84% yield) in solid form. MS calculated value: 309.0; MS measured value: 310.0 [M+H] + .

[0445] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (146-4):

[0446]

[0447] 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 (3 x 30 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 in solid form (3.8 g, approximately 70% yield). MS calculated value: 342.1; MS measured value: 343.9 [M+H] + .

[0448] Synthesis of N-(6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)biphenyl-3-yl)benzamide (SS20308-0146-01):

[0449]

[0450] 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 h 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 an oily SS20308-0146-01 (50 mg, approximately 13% yield). MS calculated value: 384.2; MS measured value: 384.2 [M+H] +1 .

[0451] 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).

[0452] Example 9

[0453]

[0454] Example routes for Example 9 (SS20308-0211-01 & SS20308-0225-01):

[0455]

[0456] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-4-nitroaniline (211-2):

[0457]

[0458] 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 overnight at room temperature. 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) in solid form. MS calculated value: 311.0; MS measured value: 312.0 [M+H] + .

[0459] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)-4-nitroaniline (211-3):

[0460]

[0461] A mixture of 211-2 (2.00 g, 6.41 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 for 2 hours under N2 atmosphere. The resulting mixture was 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 211-3 (1.80 g, approximately 81% yield) in solid form. MS calculated value: 348.1; MS measured value: 349.4 [M+H] + .

[0462] N 1Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)phenyl-1,4-diamine (211-4)

[0463]

[0464] 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 for 3 hours at room temperature under a H2 atmosphere. The reaction mixture was then cooled to room temperature and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 221-4 in solid form (0.78 g, approximately 86% yield). MS calculated value: 318.2; MS measured value: 319.0 [M+H] + .

[0465] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(1H-indol-7-yl)phenyl-1,4-diamine (SS20308-0225-01):

[0466]

[0467] 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 overnight at room temperature. The mixture was then poured into water and extracted with CH2Cl2 (3 x 30 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) in solid form. MS calculated value: 426.2; MS measured value: 427.0 [M+H] + .

[0468] 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).

[0469] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(indoline-7-yl)phenyl-1,4-diamine (SS20308-0211-01):

[0470]

[0471] A mixture of SS20308-0225-01 (50 mg, 0.117 mmol) and NaBH3CN (8 mg, 0.117 mmol) in AcOH (2 mL) was stirred overnight at 0 °C. The residue was purified by preparative HPLC to give SS20308-0211-01 (20 mg, approximately 40% yield) in solid form. MS calculated value: 428.2; MS measured value: 429.0 [M+H] + .

[0472] 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).

[0473] Example 10

[0474]

[0475] Example route of Example 10:

[0476]

[0477] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-bromo-5-chloropyridin-2-amine (212-2):

[0478]

[0479] To a solution of 212-1 (500 mg, 2.38 mmol) in 6 mL of DMF, K₂CO₃ (1.31 g, 9.50 mmol) and 1H-1,2,4-triazol-1-ethylamine hydrochloride (1:2) (355 g, 2.38 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (2 × 50 mL), dried over MgSO₄, and concentrated under vacuum to give 212-2, which was used for the next step without further purification.

[0480] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-3-phenylpyridin-2-amine (212-3):

[0481]

[0482] 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 overnight at 90 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, filtered to remove insoluble matter, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO4, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give an oily 212-3 (170 mg, approximately 57% yield). MS calculated value: 299.1; MS measured value: 300.1 [M+H] + .

[0483] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of β-benzyl-3-phenylpyridine-2,5-diamine (SS20308-0212-01):

[0484]

[0485] 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 overnight at 110 °C under nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, filtered to remove insoluble matter, and the filtrate was extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO4, and concentrated under vacuum. The residue was purified by preparative HPLC to give an oily SS20308-0212-01 (7 mg, 6% yield). MS calculated value: 370.2; MS measured value: 371.0 [M+H] + .

[0486] 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).

[0487] Example 11

[0488]

[0489] Example route of Example 11:

[0490]

[0491] Synthesis of 5-nitro-4-phenylpyridine-2(1H)-one (213-2)

[0492]

[0493] 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 hours. After the reaction was complete, 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 under vacuum, and then purified by CC (petroleum ether / EtOAc = 5 / 1) to give 213-2 in solid form (800 mg, approximately 51% yield). MS calculated value: 216.1; MS measured value: 217.4 [M+H] + .

[0494] Synthesis of 2-chloro-5-nitro-4-phenylpyridine (213-3):

[0495]

[0496] A solution of 213-2 (800 mg, 3.7 mmol) in POCl3 (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), then extracted with EtOAc (20 mL x 3). The combined layers were dried over Na2SO4 and concentrated under vacuum, then purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to give 213-3 in solid form (700 mg, approximately 81% yield). MS calculated value: 234.0; MS measured value: 235.3 [M+H] + .

[0497] Synthesis of N-benzyl-5-nitro-4-phenylpyridine-2-amine (213-4):

[0498]

[0499] A mixture of benzylamine (385 mg, 3.6 mmol), 213-3 (700 mg, 3 mmol), and K2CO3 (828 mg, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 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 Na2SO4 and concentrated under vacuum, and then purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give 213-4 in solid form (600 mg, approximately 66% yield). MS calculated value: 305.1; MS measured value: 306.4 [M+H] + .

[0500] N 2Synthesis of β-benzyl-4-phenylpyridine-2,5-diamine (213-5):

[0501]

[0502] 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 complete, 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 under vacuum. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to give 213-5 in solid form (500 mg, approximately 70% yield). MS calculated value: 275.1; MS measured value: 276.4 [M+H] + .

[0503] N 2 -Benzyl-N 5 Synthesis of (2-chloroethyl)-4-phenylpyridine-2,5-diamine (213-6):

[0504]

[0505] A mixture of 213-5 (250 mg, 0.91 mmol), 2-chloroacetaldehyde (213 mg, 2.73 mmol), AcOH (2 drops), and NaBH3CN (118 mg, 1.82 mmol) in EtOH (10 mL) was stirred overnight at room temperature. 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 Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to give 213-6 (180 mg, approximately 53% yield) in solid form. MS calculated value: 337.1; MS measured value: 338.4 [M+H] + .

[0506] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of β-benzyl-4-phenylpyridine-2,5-diamine (SS20308-0213-01):

[0507]

[0508] 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 complete, 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 under vacuum. The crude product was purified by preparative HPLC to give SS20308-0213-01 (14 mg, approximately 13% yield) in solid form. MS calculated value: 370.5; MS measured value: 371.3 [M+H] + .

[0509] 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).

[0510] Example 12

[0511]

[0512] Example route of Example 12:

[0513]

[0514] Synthesis of 6-chloro-2-phenylpyridin-3-amine (214-2):

[0515]

[0516] 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 washed 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) in solid form. MS calculated value: 204.1; MS measured value: 205.1 [M+H]+ .

[0517] Synthesis of 6-chloro-N-(2-chloroethyl)-2-phenylpyridine-3-amine (214-3):

[0518]

[0519] A solution of 214-2 (1.0 g, 4.89 mmol), 2-chloroacetaldehyde (3.84 g, 19.55 mmol, in water, 40% concentration), NaBH3CN (461 mg, 7.34 mmol), and AcOH (2 mL) in EtOH (20 mL) was stirred overnight at room temperature. The reaction mixture was alkalized 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 for the next step without further purification. MS calculated value: 266.0; MS measured value: 267.0 [M+H] + .

[0520] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-chloro-2-phenylpyridin-3-amine (214-4):

[0521]

[0522] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (EtOAc / petroleum ether = 1 / 1, EtOAc) to give 214-4 in solid form (1.2 g, approximately 82% yield in two steps). MS calculated value: 299.1; MS measured value: 300.4 [M+H] + .

[0523] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of β-benzyl-6-phenylpyridine-2,5-diamine (SS20308-0214-01):

[0524]

[0525] 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 overnight under N2, then filtered and washed with EtOAc. The filtrate was concentrated and purified by preparative HPLC to give SS20308-0214-01 (6 mg, approximately 10% yield) in a semi-solid form. MS calculated value: 370.2; MS measured value: 371.0 [M+H] + .

[0526] 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).

[0527] Example 13

[0528]

[0529] Example route of Example 13:

[0530]

[0531] Synthesis of N-benzyl-3-bromo-4-nitroaniline (215-2):

[0532]

[0533] To a solution of 214-1 (5.00 g, 22.73 mmol) and benzylamine (2.43 g, 22.73 mmol) in DMSO (50 mL), K₂CO₃ (6.27 g, 45.46 mmol) was added. The reaction mixture was stirred overnight at room temperature. 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 give compound 0215-2 (6.2 g, approximately 89% yield) in solid form. MS calculated value: 306.0; MS measured value: 307.0 [M+H] + .

[0534] Synthesis of benzyl (3-bromo-4-nitrophenyl)carbamate tert-butyl ester (215-3):

[0535]

[0536] To a solution of 215-2 (5.00 g, 16.29 mmol) in 50 mL of DCM, TEA (3.29 g, 32.57 mmol) and DMAP (1.99 g, 16.29 mmol) were added, and the solution was cooled to 0 °C. Then, (Boc)₂O (5.33 g, 24.44 mmol) was added dropwise over 10 minutes. The solution was then stirred overnight at room temperature. Water was added to the solution, and the solution was extracted with DCM (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1, 10 / 1) to give 215-3 in solid form (6.0 g, approximately 91% yield). MS calculated value: 406.0; MS measured value: 351.0 [M-55] + .

[0537] Synthesis of tert-butyl 4-amino-3-bromophenyl(benzyl)carbamate (215-4):

[0538]

[0539] To a solution of 214-3 (6.00 g, 14.74 mmol) in 60 mL of EtOH, 6 mL of AcOH and 9.58 g of Zn powder (147.40 mmol) were added. 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 in solid form (4.2 g, approximately 75% yield). MS calculated value: 376.0; MS measured value: 377.0 [M+H] + .

[0540] Synthesis of benzyl (3-bromo-4-(2-chloroethylamino)phenyl)carbamate tert-butyl ester (215-5):

[0541]

[0542] To a solution of 215-4 (4.00 g, 14.44 mmol) in 50 mL of EtOH, 2-chloroacetaldehyde (40 wt% aqueous solution, 5.66 g, 28.88 mmol), NaBH3CN (1.81 g, 28.88 mmol), and AcOH (5 mL) were added. The reaction mixture was stirred overnight at room temperature. The solvent was removed by concentration. The residue was dissolved in EtOAc and water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. Purification was performed by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1, 10 / 1) to give compound 215-3 (3.6 g, approximately 78% yield) in solid form. MS calculated value: 438.0; MS measured value: 439.0 [M+H] + .

[0543] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-bromophenyl(benzyl)carbamate (215-6):

[0544]

[0545] To a solution of 215-5 (3.60 g, 8.22 mmol) in CH3CN (50 mL), 1H-1,2,4-triazole (40 wt% aqueous solution, 0.68 g, 9.86 mmol) and Cs2CO3 (5.36 g, 16.44 mmol) were added. The mixture was stirred at 80 °C for 4 hours. After cooling to room temperature and filtering, 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, approximately 90% yield) in solid form.

[0546] 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).

[0547] Synthesis of 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-4-yl)phenyl(benzyl)-tert-butyl carbamate (215-7):

[0548]

[0549] To a solution of 215-6 (200 mg, 0.42 mmol) in 1,4-dioxane / H₂O (5 mL / 0.5 mL), pyridin-4-ylboronic acid (104 mg, 0.84 mmol), K₂CO₃ (116 mg, 0.84 mmol), and Pd(dppf)Cl₂ (30 mg, 0.04 mmol) were added. The mixture was stirred in a microwave at 120 °C 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 in solid form (120 mg, approximately 60% yield). MS calculated value: 470.0; MS measured value: 471.0 [M+H] + .

[0550] Synthesis of N1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N4-benzyl-2-(pyridin-4-yl)phenyl-1,4-diamine (SS20308-0215-01);

[0551]

[0552] TFA (1 mL) was added to a 5 mL solution of DCM (120 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The solution was alkalized with NaHCO3 solution and extracted with DCM (10 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated, and purified by preparative HPLC to give SS20308-0215-01 (50 mg, approximately 52% yield) in solid form. MS calculated value: 370.0; MS measured value: 371.0 [M+H] + .

[0553] 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).

[0554] Example 14

[0555]

[0556] Example route of Example 14:

[0557]

[0558] Synthesis of 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-3-yl)phenyl(benzyl)carbamate tert-butyl ester (SS20308-0216-2):

[0559]

[0560] 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 overnight at 90 °C under a nitrogen atmosphere. 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 preparative TLC to give an oily 216-2 (200 mg, approximately 66.8% yield). MS calculated value: 470.2; MS measured value: 471.0 [M+H] + .

[0561] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of β-benzyl-2-(pyridin-3-yl)phenyl-1,4-diamine (SS20308-0216-01):

[0562]

[0563] 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 (3 x 30 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) in solid form. MS calculated value: 370.2; MS measured value: 371.0 [M+H] + .

[0564] 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).

[0565] Example 15

[0566]

[0567] Example route of Example 15:

[0568]

[0569] Synthesis of 3-bromo-N-(cyclohexylmethyl)-4-nitroaniline (217-1):

[0570]

[0571] Cyclohexylmethylamine (1.7 g, 15.0 mmol) and K₂CO₃ (3.6 g, 27.0 mmol) were added to a solution of 215⁻¹ (3.0 g, 12.4 mmol) in DMSO (20.0 mL). The mixture was then stirred for 4 hours. After the reaction was complete, 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 give an oily 217⁻¹ (3.5 g, approximately 83% yield). MS calculated value: 312.0; MS measured value: 313.0 [M+H] + .

[0572] Synthesis of tert-butyl 3-bromo-4-nitrophenyl (cyclohexylmethyl)carbamate (217-2):

[0573]

[0574] 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 overnight at room temperature. After the reaction was complete, 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 give an oily 217-2 (3.8 g, approximately 89% yield).

[0575] Synthesis of tert-butyl 4-amino-3-bromophenyl (cyclohexylmethyl)carbamate (217-3):

[0576]

[0577] A mixture of 217-2 (3.8 g, 9.2 mmol), Zn powder (2.9 mg, 45.0 mmol), and HOAc (2.8 g, 45.0 mmol) in EtOH (20.0 mL) was stirred overnight at room temperature. After the reaction was 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 give 217-3 (2.2 g, approximately 63% yield) in solid form. MS calculated value: 382.0; MS measured value: 328.0 [M+H] + .

[0578] Synthesis of tert-butyl 3-bromo-4-(2-chloroethylamino)phenyl(cyclohexylmethyl)carbamate (217-4):

[0579]

[0580] 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), NaBH3CN (372.0 mg, 6.0 mmol) and AcOH (2.0 mL) were added. The mixture was then stirred overnight. After the reaction was complete, the reaction was purified by column chromatography to give an oily 217-4 (770.0 mg, approximately 59% yield). MS calculated value: 444.0; MS measured value: 445.0 [M+H] + .

[0581] Synthesis of 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-bromophenyl(cyclohexylmethyl)carbamate tert-butyl ester (217-5):

[0582]

[0583] Cs₂CO₃ (1.1 g, 3.5 mmol) was added 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), and the mixture was stirred overnight at 80 °C. 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 an oily 217-5 (420.0 mg, approximately 51% yield). MS calculated value: 477.0; MS measured value: 478.0 [M+H] + .

[0584] Synthesis of 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(pyridin-4-yl)phenyl(cyclohexylmethyl)carbamate tert-butyl ester (217-6):

[0585]

[0586] 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 at MW. After the reaction was complete, the mixture was quenched with water and then extracted with EtOAc (5.0 mL x 3). The organic layer was separated, dried over MgSO4, concentrated, and purified by column chromatography to give 217-6 (80 mg, approximately 27%) in solid form. MS calculated value: 477.0; MS measured value: 478.0 [M+H] + .

[0587] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(cyclohexylmethyl)-2-(pyridin-4-yl)phenyl-1,4-diamine (217-01):

[0588]

[0589] A solution of 217-6 (50.0 mg, 0.1 mmol) in HCl / EA (10.0 mL, 1 M) was prepared. 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 an oily 217 (20.0 mg, approximately 51% yield). MS calculated value: 376.0; MS measured value: 377.0 [M+H] + .

[0590] 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).

[0591] Example 16

[0592]

[0593] Example route of Example 16:

[0594]

[0595] Synthesis of tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-3-(thiophen-2-yl)phenyl(benzyl)carbamate (218-1):

[0596]

[0597] 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 in a microwave reactor at 120 °C for 2 hours. The reaction mixture was then cooled to room temperature, filtered through diatomaceous earth, 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 an oily 218-1 (450 mg, approximately 84% yield). MS calculated value: 475.2; MS measured value: 476.4 [M+H] + .

[0598] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of β-benzyl-2-(thiophen-2-yl)phenyl-1,4-diamine (SS20308-0218-01):

[0599]

[0600] 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 overnight at room temperature. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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 an oily SS20308-218-01 (31.15 mg, approximately 9% yield). MS calculated value: 375.1; MS measured value: 376.0 [M+H] + .

[0601] 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)

[0602] Example 17

[0603]

[0604] Example routes for Implementation 17 (SS20308-0173-01 and 0219-01):

[0605]

[0606] Synthesis of 5-chloro-2-phenylpyridine-3-amine (173-2):

[0607]

[0608] A mixture of 173-1 (500 mg, 2.42 mmol), phenylboronic acid (590 mg, 4.84 mmol), Pd(PPh3)4 (277 mg, 0.24 mmol), and K2CO3 (668 mg, 4.84 mmol) in DME (10 mL) and water (1 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc = 10 / 1) to give an oily 173-2 (440 mg, approximately 91% yield). MS calculated value: 204.0; MS measured value: 205.1 [M+H] + .

[0609] Synthesis of 5-chloro-N-(2-chloroethyl)-2-phenylpyridine-3-amine (173-3):

[0610]

[0611] To a solution of 173-2 (450 mg, 2.20 mmol) in 10 mL of MeOH, 2-chloroacetaldehyde (432 mg, 4.40 mmol, in water, 40% concentration), AcOH (264 mg, 4.40 mmol), and NaBH3CN (275 mg, 4.40 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and alkalized with 1N NaOH until 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 in solid form (100 mg, approximately 17% yield). MS calculated value: 266.0; MS measured value: 237.1 [M+H] + .

[0612] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-2-phenylpyridine-3-amine (173-4):

[0613]

[0614] 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 overnight at 80 °C. 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 in solid form (77 mg, approximately 68% yield). MS calculated value: 299.1; MS measured value: 300.2 [M+H] + .

[0615] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2-diphenylpyridine-3,5-diamine (SS20308-0219-01):

[0616]

[0617] 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 in a microwave reactor at 150 °C for two hours. 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, approximately 6% yield) in solid form. MS calculated value: 370.2; MS measured value: 371.3 [M+H] + .

[0618] 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).

[0619] Example 18

[0620]

[0621] Example route of Example 18:

[0622]

[0623] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of β-benzyl-3-phenylpyridine-2,6-diamine (SS20308-0221-01):

[0624]

[0625] 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 overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, 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 under vacuum, and purified twice by preparative HPLC to give SS20308-0221-01 (8 mg, approximately 5% yield) in solid form. MS calculated value: 370.2; MS measured value: 371.3 [M+H] + .

[0626] 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).

[0627] Example 19

[0628]

[0629] Example route of Example 19:

[0630]

[0631] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-4-nitroaniline (211-2):

[0632]

[0633] 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 overnight at room temperature. 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) in solid form. MS calculated value: 311.0; MS measured value: 312.0 [M+H] + .

[0634] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)-4-nitroaniline (211-3):

[0635]

[0636] A mixture of 211-2 (2.00 g, 6.41 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 for 2 hours under N2 atmosphere. The resulting mixture was 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 211-3 (1.80 g, approximately 81% yield) in solid form. MS calculated value: 348.1; MS measured value: 349.4 [M+H] + .

[0637] N 1 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-(1H-indol-7-yl)phenyl-1,4-diamine (211-4):

[0638]

[0639] 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 for 3 hours at room temperature under a H2 atmosphere. The reaction mixture was then cooled to room temperature and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 221-4 in solid form (0.78 g, approximately 86% yield). MS calculated value: 318.2; MS measured value: 319.0 [M+H] + .

[0640] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(4-fluorobenzyl)-2-(1H-indol-7-yl)phenyl-1,4-diamine (SS20308-0225-01):

[0641]

[0642] 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 overnight at room temperature. The mixture was then poured into water and extracted with CH2Cl2 (3 x 30 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) in solid form. MS calculated value: 426.2; MS measured value: 427.0 [M+H] + .

[0643] 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).

[0644] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4Synthesis of -(4-fluorobenzyl)-2-(indoline-7-yl)phenyl-1,4-diamine (SS20308-0211-01):

[0645]

[0646] A mixture of SS20308-0225-01 (50 mg, 0.117 mmol) and NaBH3CN (8 mg, 0.117 mmol) in AcOH (2 mL) was stirred overnight at 0 °C. The residue was purified by preparative HPLC to give SS20308-0211-01 (20 mg, approximately 40% yield) in solid form. MS calculated value: 428.2; MS measured value: 429.0 [M+H] + .

[0647] 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).

[0648] Example 20

[0649]

[0650] Example route of Example 20:

[0651]

[0652] Synthesis of 5-bromobiphenyl-2-amine (226-2):

[0653]

[0654] The mixture of 226-1 (5.0 g, 29.6 mmol) in DMF (30 mL) was stirred at 0 °C, and NBS (5.3 g, 29.6 mmol) was added. The mixture was then stirred overnight at room temperature. After being poured into water (60 mL), the mixture was extracted with ethyl acetate (30 mL × 4). The organic layer was washed with brine and concentrated to dryness to give an oily 226-2 (5.0 g, approximately 68% yield). MS calculated value: 247.0; MS measured value: 250.1 [M+H] + .

[0655] Synthesis of 5-bromo-N-(2-chloroethyl)biphenyl-2-amine (226-3):

[0656]

[0657] To a solution of 226-2 (2.0 g, 8.1 mmol) in 20 mL of EtOH, 2-chloroacetaldehyde (950 mg, 12.1 mmol, 40% concentration in water), AcOH (970 mg, 16.1 mmol), and NaBH3CN (507 mg, 8.1 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into cold water (50 mL), alkalized to pH 9 with saturated Na2CO3 solution, and then extracted with ethyl acetate (150 mL). The organic layer was washed with brine and concentrated to dryness to give an oily 226-3 (1.7 g, approximately 68% yield). MS calculated value: 309.0; MS measured value: 310.0 [M+H] + .

[0658] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-bromobiphenyl-2-amine (226-4):

[0659]

[0660] To a solution of 226-3 (1.7 g, 5.5 mmol) in 10 mL of CH3CN, 1,2,4-triazole (756 mg, 11.0 mmol) and Cs2CO3 (3.6 g, 11.0 mmol) were added, and the reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give an oily 226-4 (1.0 g, approximately 53% yield). MS calculated value: 343.2; MS measured value: 345.2 [M+H] + .

[0661] 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):

[0662]

[0663] To a solution of 226-4 (180.0 mg, 0.5 mmol) in 10.0 mL of toluene, 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), and NaOBut (100.0 mg, 1.0 mmol) were added. The mixture was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine, dried over MgSO₄, and concentrated. The residue was purified twice by preparative HPLC to give SS₂0308-0226-01 (20.0 mg, approximately 9% yield) in solid form. MS calculated value: 437.0; MS measured value: 438.0 [M+H] + .

[0664] 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).

[0665] Example 21

[0666]

[0667] Example route of Example 21:

[0668]

[0669] Synthesis of 4-bromo-2,3-difluoro-6-nitroaniline (227-2):

[0670]

[0671] NBS (204 mg, 1.15 mmol) was added to a DMF (5 mL) solution of 227-1 (200 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 x 3). The organic layer was washed with brine (2 x 50 mL), dried over MgSO4, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give 227-2 in solid form (180 mg, approximately 62% yield). MS calculated value: 251.9; MS measured value: 252.9 [M+H] + .

[0672] Synthesis of 1-bromo-2,3-difluoro-5-nitrobenzene (227-3):

[0673]

[0674] Amyl nitrite (2.78 g, 23.72 mmol) was added to a THF (20 mL) solution of 227-2 (3 g, 11.86 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (2 x 50 mL), dried over MgSO4, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give 227-3 in solid form (2.3 g, approximately 82% yield).

[0675] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-6-fluoro-4-nitroaniline (227-4):

[0676]

[0677] 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 complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO₄, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 227-4 in solid form (2 g, approximately 72% yield). MS calculated value: 329.0; MS measured value: 330.0 [M+H] + .

[0678] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-5-nitrobiphenyl-2-amine (227-5):

[0679]

[0680] 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 overnight at 80 °C under a nitrogen atmosphere. After the reaction was complete, 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 under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 227-5 in solid form (850 mg, approximately 86% yield). MS calculated value: 327.1; MS measured value: 328.2 [M+H] + .

[0681] N 2 Synthesis of -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluorobiphenyl-2,5-diamine (227-6):

[0682]

[0683] Pd / C (10%, 50 mg) was added to a 20 mL solution of 227-5 (200 mg, 0.61 mmol) in MeOH. The mixture was stirred overnight at room temperature under a H2 atmosphere. After the reaction was complete, insoluble matter was removed by filtration. The organic layer was concentrated under vacuum and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give 227-6 in solid form (150 mg, approximately 83% yield). MS calculated value: 297.1; MS measured value: 298.2 [M+H] + .

[0684] 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):

[0685]

[0686] To a mixture of 227-6 (150 mg, 0.50 mmol) and 4-fluorobenzaldehyde (75 mg, 0.61 mmol) in MeOH (10 mL), NaBH3CN (95 mg, 1.51 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, 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 under vacuum, and purified by preparative HPLC to give an oily SS20308-0277-01 (33 mg, approximately 16% yield). MS calculated value: 405.2; MS measured value: 406.0 [M+H] + .

[0687] 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).

[0688] Example 22

[0689]

[0690] Example route of Example 22:

[0691]

[0692] Synthesis of 3-bromo-2-fluoro-N-(4-fluorobenzyl)-4-nitroaniline (228-2):

[0693]

[0694] A mixture of 228-1 (2.00 g, 8.40 mmol), 4-fluorobenzylamine (2.10 g, 16.8 mmol), and K₂CO₃ (3.48 g, 25.2 mmol) in DMSO (40 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (160 mL). The resulting solid was collected by filtration and concentrated to give 228-2 (2.88 g, approximately 100% yield) in solid form. MS calculated value: 342.0; MS measured value: 343.2 [M+H] + .

[0695] Synthesis of 2-fluoro-N-(4-fluorobenzyl)-6-nitrobiphenyl-3-amine (228-3):

[0696]

[0697] A mixture of 228-2 (2 g, 5.8 mmol), phenylboronic acid (1.42 g, 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 overnight at 80 °C under a nitrogen 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 in solid form (1.70 g, approximately 86% yield). MS calculated value: 340.1; MS measured value: 341.4 [M+H] + .

[0698] Synthesis of 2-fluoro-6-nitrobiphenyl-3-yl(4-fluorobenzyl)carbamate tert-butyl ester (228-4):

[0699]

[0700] To a solution of 228-3 (1.6 g, 4.70 mmol) in 20 mL of DCM, (Boc)₂O (1.54 g, 7.05 mmol), DMAP (575 mg, 4.71 mmol), and Et₃N (952 mg, 9.41 mmol) were added. 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 an oily 228-4 (2.07 g, approximately 100% yield). MS calculated value: 440.2; MS measured value: 385.3 [M-55] + .

[0701] Synthesis of tert-butyl 6-amino-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (228-5):

[0702]

[0703] A mixture of 228-4 (2.07 g, 4.70 mmol) and Zn powder (3.07 g, 47.00 mmol) in EtOH / AcOH (41 mL, 40 / 1) was stirred overnight at room temperature. The reaction mixture was then filtered through diatomaceous earth and concentrated to give 228-5 in solid form (1.93 g, approximately 100% yield). MS calculated value: 410.2; MS measured value: 355.3 [M-55] + .

[0704] Synthesis of 6-(2-chloroethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate tert-butyl ester (228-6):

[0705]

[0706] To a solution of 228-5 (500 mg, 1.22 mmol) in 5 mL of DCM, 2-chloroacetaldehyde (957 mg, 4.88 mmol, in water, 40% concentration), NaBH3CN (115 mg, 1.83 mmol), and AcOH (0.5 mL) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and alkalized with NaHCO3 solution until pH 8 was reached. The mixture was extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give an oily 228-6 (576 mg, approximately 100% yield). MS calculated value: 472.2; MS measured value: 417.3 [M-56] + .

[0707] Synthesis of 6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-2-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate tert-butyl ester (228-7):

[0708]

[0709] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give an oily 228-7 (200 mg, approximately 32% yield). MS calculated value: 505.2; MS measured value: 506.4 [M+H] + .

[0710] 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):

[0711]

[0712] 228-7 (400 mg, 1.27 mmol) was dissolved in HCl / dioxane (10 mL, 1 N) and stirred overnight at room temperature. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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 give an oily SS20308-0228-01 (40 mg, approximately 12% yield). MS calculated value: 405.2; MS measured value: 406.0 [M+H] + .

[0713] 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).

[0714] Example 23

[0715]

[0716] Example route of Example 23:

[0717]

[0718] Synthesis of 5-bromo-2-fluoro-N-(4-fluorobenzyl)-4-nitroaniline (229-2):

[0719]

[0720] A mixture of 229-1 (2.00 g, 8.40 mmol), 4-fluorobenzylamine (2.10 g, 16.8 mmol), and K₂CO₃ (3.48 g, 25.2 mmol) in DMSO (50 mL) was stirred overnight at room temperature. Water (150 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (150 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give 229-2 (2.64 g, approximately 91% yield) in solid form. MS calculated value: 342.0; MS measured value: 341.9 [M+H] + .

[0721] Synthesis of 4-fluoro-N-(4-fluorobenzyl)-6-nitrobiphenyl-3-amine (229-3):

[0722]

[0723] A mixture of 229-2 (2 g, 7.29 mmol), phenylboronic acid (1.78 g, 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 overnight at 80 °C under a nitrogen 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, approximately 91% yield) in solid form. MS calculated value: 292.2; MS measured value: 293.3 [M+H] + .

[0724] Synthesis of 4-fluoro-6-nitrobiphenyl-3-yl(4-fluorobenzyl)carbamate tert-butyl ester (229-4):

[0725]

[0726] To a solution of 229-3 (2.25 g, 6.61 mmol) in DCM (50 mL), (Boc)₂O (2.88 g, 13.2 mmol), DMAP (168 mg, 1.32 mmol), and Et₃N (1.34 g, 13.2 mmol) were added, and the reaction mixture was stirred overnight at room temperature. 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 in solid form (2.81 g, approximately 96% yield). MS calculated value: 440.2; MS measured value: 385.1 [M+H] + .

[0727] Synthesis of tert-butyl 6-amino-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate (229-5):

[0728]

[0729] A mixture of 229-4 (2.81 g, 6.38 mmol) and Zn powder (4.15 g, 63.8 mmol) in EtOH / AcOH (60 mL, 15 / 1) was stirred overnight at room temperature. The reaction mixture was then filtered through diatomaceous earth and concentrated to give 229-5 (2.50 g, approximately 95% yield) in solid form. MS calculated value: 410.2; MS measured value: 355.1 [M+H] + .

[0730] Synthesis of 6-(2-chloroethylamino)-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate tert-butyl ester (229-6):

[0731]

[0732] To a solution of 229-5 (2.50 g, 6.09 mmol) in 40 mL of EtOH, 2-chloroacetaldehyde (2.39 g, 12.2 mmol, 40% concentration in water), NaBH3CN (768 mg, 12.2 mmol), and AcOH (732 mg, 12.2 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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) in solid form. MS calculated value: 472.2; MS measured value: 317.3 [M+H] + .

[0733] Synthesis of 6-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4-fluorobiphenyl-3-yl(4-fluorobenzyl)carbamate tert-butyl ester (229-7):

[0734]

[0735] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give 229-7 (400 mg, approximately 62% yield) in solid form. MS calculated value: 505.2; MS measured value: 506.2 [M+H] + .

[0736] 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):

[0737]

[0738] 229-7 (400 mg, 1.27 mmol) was dissolved in HCl / dioxane (10 mL, 1 N) and stirred overnight at room temperature. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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 give an oily SS20308-0229-01 (39 mg, approximately 12% yield). MS calculated value: 405.2; MS measured value: 406.0 [M+H] + .

[0739] 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).

[0740] Example 24

[0741]

[0742] Example routes for Example 24 (SS20308-0232-01, SS20308-0275-01):

[0743]

[0744] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)phenyl-1,4-diamine (SS20308-0232-01):

[0745]

[0746] AlMe3 (0.89 mL, 1.78 mmol, 2N in THF) was added to a solution of 239-1 (180 mg, 0.89 mmol) and 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ketone (204 mg, 1.06 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After cooling, BH3-DMS (0.89 mL, 1.78 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried with MgSO4, concentrated under vacuum, and purified by preparative HPLC to obtain an oily SS20308-0232-01 (23 mg, approximately 7% yield). MS calculated value: 379.1; MS measured value: 380.0 [M+H] + .

[0747] 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).

[0748] 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)phenyl-1,4-diamine (SS20308-0275-01):

[0749]

[0750] AlMe3 (0.89 mL, 1.78 mmol, 2N in THF) was added to a solution of 239-1 (180 mg, 0.89 mmol) and 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (170 mg, 1.06 mmol) in CH2Cl2 (10 mL). The reaction was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After cooling, BH3-DMS (0.89 mL, 1.78 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried with MgSO4, concentrated under vacuum, and purified by preparative HPLC to obtain an oily SS20308-0275-01 (26 mg, approximately 8% yield). MS calculated value: 347.2; MS measured value: 348.2 [M+H] + .

[0751] 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).

[0752] Example 25

[0753]

[0754] Example route of Example 25:

[0755]

[0756] Synthesis of tert-butyl 3-(1H-1,2,4-triazol-1-yl)propylcarbamate (236-2):

[0757]

[0758] A mixture of (3-bromopropyl)carbamate tert-butyl ester (236-1) (5.0 g, 21.0 mmol), 1H-1,2,4-triazole (1.74 g, 25.2 mmol), and potassium carbonate (4.35 g, 31.5 mmol) in acetone (150 mL) was stirred overnight at 60 °C. The reaction mixture was then filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated and the residue purified by column chromatography (petroleum ether / EtOAc = 1 / 1, dichloromethane / methanol = 50 / 1, 20 / 1) to give an oily 236-2 (4.75 g, approximately 100% yield). MS calculated value: 226.1; MS measured value: 227.2 [M+H] + .

[0759] 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).

[0760] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-6-nitrobiphenyl-3-amine dihydrochloride (262-3):

[0761]

[0762] The mixture of 236-2 (4.75 g, 21.0 mmol) in THF (80 mL) and 6N HCl (20 mL) was stirred overnight at 60 °C. The mixture was concentrated under vacuum. Ethanol was added to the residue and the mixture was concentrated again to give 236-3 (3.8 g, about 92% yield) in solid form.

[0763] 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).

[0764] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-4-nitroaniline (236-4):

[0765]

[0766] 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 give 236-4 in solid form (157 mg, approximately 94% yield). MS calculated value: 265.1; MS measured value: 266.4 [M+H] + .

[0767] N 1 Synthesis of 3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (236-5):

[0768]

[0769] A solution of 236-4 (157 mg, 0.59 mmol) and Pd / C (30 mg, 10%) in MeOH (5 mL) was stirred for 2 hours at room temperature and H₂. The reaction mixture was then filtered through diatomaceous earth. The filtrate was concentrated to give an oily 236-5 (140 mg), which was used directly in the next step. MS calculated value: 235.1; MS measured value: 236.4 [M+H] + .

[0770] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-N 4 Synthesis of 1,4-(4-fluorobenzyl)phenyl-1,4-diamine (SS20308-0236-01):

[0771]

[0772] 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 overnight at room temperature. The reaction mixture was alkalized 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, approximately 40% yield in two steps) in solid form. MS calculated value: 343.2; MS measured value: 344.0 [M+H] + .

[0773] 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).

[0774] Example 26

[0775]

[0776] Example route of Implementation Example 26:

[0777]

[0778] Synthesis of 3-bromo-N-(4-fluorobenzyl)-4-methylaniline (237-2):

[0779]

[0780] A mixture of 237-1 (200 mg, 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 overnight at 80 °C. The reaction mixture was cooled to room temperature and poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine and evaporated to give an oily 237-2 (150 mg, approximately 39% yield). MS calculated value: 216.1; MS measured value: 294.3 [M+H] + .

[0781] N 3 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 1 Synthesis of 1,3-(4-fluorobenzyl)-4-methylphenyl-1,3-diamine (SS20308-0237-01):

[0782]

[0783] A mixture of 237-2 (130 mg, 0.44 mmol), 1H-1,2,4-triazol-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 overnight under reflux. 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. The residual crude product was purified by preparative HPLC to give an oily SS20308-0237-01 (13.5 mg, approximately 9% yield). MS calculated value: 339.2; MS measured value: 340.0 [M+H] + .

[0784] 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).

[0785] Example 27

[0786]

[0787] Example route of Example 27:

[0788]

[0789] Synthesis of 1,3-dibromo-5-fluoro-2-nitrobenzene (239-2):

[0790]

[0791] 3-Chloroperoxybenzoic acid (18.4 g, 90.63 mmol, 85 wt%) was added to a solution of 2,6-dibromo-4-fluoroaniline (5.0 g, 18.59 mmol) in dichloromethane (100 mL). 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-methyl OH (3 x 75 mL), and the organic layer was concentrated under vacuum to give a brown solid. The solid was dissolved in 50 mL of glacial acetic acid. 25 mL of 30% H₂O₂ solution and 4 mL of concentrated nitric acid were added to this solution. The mixture was heated to reflux and stirred for 3 hours, then poured into 250 mL of ice water. The suspension was filtered, and the solid was washed with water and then dried on a filter under air to give solid form 239-2 (4.4 g, approximately 79% yield). MS calculated value: 296.8; MS measured value: 298.2 [M+H] + .

[0792] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-3,5-dibromo-4-nitroaniline (239-3):

[0793]

[0794] A mixture of compounds 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 in solid form (2.3 g, approximately 85% yield). MS calculated value: 402.9; MS measured value: 403.9 [M+H] + .

[0795] N 1 Synthesis of 3-(1H-1,2,4-triazol-1-yl)propyl)phenyl-1,4-diamine (239-4):

[0796]

[0797] Pd / C (10%, 250 mg) was added to a solution of 239-3 (1.00 g, 2.47 mmol) in MeOH (5 mL) and EtOAc (5 mL). The resulting mixture was stirred overnight at room temperature under H2 atmosphere. The mixture was filtered and concentrated to give crude oily 239-4 (700 mg). MS calculated value: 217.1; MS measured value: 218.1 [M+H] + .

[0798] N 1-(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of cyclohexylphenyl-1,4-diamine (SS20308-0239-01):

[0799]

[0800] Cyclohexanone (361.37 mg, 3.68 mmol) and NaBH3CN (173.54 mg, 2.76 mmol) were added to a solution of 239-4 (200.00 mg, 0.92 mmol) in EtOH (3 mL) and AcOH (3 mL). The resulting mixture was stirred overnight at room temperature. The mixture was then alkalized with Na2CO3 (aqueous solution) until the pH reached 7–8, and extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give SS20308-0239-01 (15 mg, approximately 5% yield) in solid form. MS calculated value: 299.2; MS measured value: 300.2 [M+H] + .

[0801] 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).

[0802] Example 28

[0803]

[0804] Example route of Example 28:

[0805]

[0806] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4 Synthesis of 1,4-(cyclohexylmethyl)phenyl-1,4-diamine (SS20308-0240-01):

[0807]

[0808] To a solution of 239-4 (250.00 mg, 1.15 mmol) in EtOH (3 mL) and AcOH (3 mL), cyclohexaneformin (516.27 mg, 4.60 mmol) and NaBH3CN (216.93 mg, 3.45 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was then alkalized with Na2CO3 (aqueous solution) until pH reached 7–8, and extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give SS20308-0240-01 (40 mg, approximately 11% yield) in solid form. MS calculated value: 313.4; MS measured value: 314.2 [M+H] + .

[0809] 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).

[0810] Example 29

[0811]

[0812] Example route of Example 29:

[0813]

[0814] Synthesis of N-(cyclohexylmethyl)-4-nitroaniline (242-2):

[0815]

[0816] To a solution of 242-1 (2.00 g, 14.48 mmol) and cyclohexaneformaldehyde (1.95 g, 17.38 mmol) in MeOH (25 mL), NaBH3CN (2.73 g, 43.44 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (2 x 50 mL), dried over MgSO4, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give 242-2 in solid form (1.5 g, approximately 44% yield).

[0817] N 1 Synthesis of 1,4-(cyclohexylmethyl)phenyl-1,4-diamine (242-3):

[0818]

[0819] Pd / C (10%, 100 mg) was added to a 20 mL solution of 242-2 (1.00 g, 4.27 mmol) in MeOH. The mixture was stirred overnight at room temperature under a H2 atmosphere. After the reaction was complete, insoluble matter was removed by filtration. The organic layer was concentrated under vacuum and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give 242-3 in solid form (800 mg, approximately 92% yield). MS calculated value: 204.2; MS measured value: 205.4 [M+H] + .

[0820] N 1 -((3-(bromomethyl)oxetane-3-yl)methyl)-N 4 Synthesis of 1,4-(cyclohexylmethyl)phenyl-1,4-diamine (242-4):

[0821]

[0822] 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), NaBH3CN (138 mg, 2.20 mmol) was added, and the mixture was stirred overnight at room temperature. 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 (2 x 30 mL), dried over MgSO4, and concentrated under vacuum. A simple work-up was performed to give an oily 242-4 (160 mg, approximately 59% yield). MS calculated value: 366.1; MS measured value: 367.0 [M+H] + .

[0823] N1 -((3-((1H-1,2,4-triazol-1-yl)methyl)oxetane-3-yl)methyl)-N 4 Synthesis of 1,4-(cyclohexylmethyl)phenyl-1,4-diamine (SS20308-0242-01):

[0824]

[0825] 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 complete, the mixture was quenched with water and extracted with EtOAc (20 mL x 3). The organic layer was separated, dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC to give an oily SS20308-0242-01 (13 mg, approximately 8% yield). MS calculated value: 355.2; MS measured value: 356.1 [M+H] + .

[0826] 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).

[0827] Example 30

[0828]

[0829] Example route of Example 30:

[0830]

[0831] Synthesis of 5-nitro-N-(2,2,2-trifluoro-1-phenylethyl)pyridine-2-amine (0245-2):

[0832]

[0833] 2,2,2-trifluoro-1-phenyl-ethylamine (863 mg, 4.93 mmol) was added to 2-bromo-5-nitropyridine (245-1) (1.0 g, 4.93 mmol) in toluene (10 mL), followed by the addition of palladium(II) acetate (55 mg, 0.25 mmol), tritert-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 washed with ethyl acetate. The filtrate was concentrated and the residue purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1, 50 / 1, 20 / 1) to give compound 245-2 in solid form (0.3 g, approximately 20% yield). MS calculated value: 297.1; MS measured value: 298.1 [M+H] + .

[0834] Synthesis of tert-butyl 5-nitropyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-3):

[0835]

[0836] To a solution of 245-2 (300 mg, 1.01 mmol) in 5 mL of DCM, TEA (102 mg, 1.01 mmol), (Boc)₂O (440 mg, 2.02 mmol), and DMAP (62 mg, 0.50 mmol) were added. After stirring overnight at room temperature, the reaction mixture was concentrated and purified by preparative TLC (petroleum ether / EtOAc = 10 / 1) to give an oily 245-3 (171 mg, approximately 43% yield). MS calculated value: 397.1; MS measured value: 342.1 [M-55] + .

[0837] Synthesis of tert-butyl 5-aminopyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-4):

[0838]

[0839] 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 for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give crude product 245-4 (153 mg, approximately 100% yield) in solid form. MS calculated value: 367.2; MS measured value: 368.1 [M+H] + .

[0840] Synthesis of tert-butyl 5-nitropyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate (245-5):

[0841]

[0842] 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), NaBH3CN (55 mg, 0.87 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was alkalized 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 an oily compound 245-5 (162 mg, approximately 87% yield). MS calculated value: 429.1; MS measured value: 430.3 [M+H] + .

[0843] Synthesis of 5-(2-(1H-1,2,4-triazol-1-yl)ethylamino)pyridin-2-yl(2,2,2-trifluoro-1-phenylethyl)carbamate tert-butyl ester (245-6):

[0844]

[0845] A mixture of 245-5 (162 mg, 0.38 mmol), 1H-1,2,4-triazole (52 mg, 0.75 mmol), and potassium carbonate (104 mg, 0.75 mmol) in DMF (5 mL) was stirred at room temperature for 3 days. The reaction mixture was then poured into cold water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1 / 2, ethyl acetate, dichloromethane / methanol = 20 / 1) to give an oily compound 245-6 (77 mg, approximately 44% yield). MS calculated value: 462.2; MS measured value: 463.3 [M+H] + .

[0846] 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):

[0847]

[0848] 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 under vacuum 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 an oily compound SS20308-0245-01 (38 mg, approximately 63% yield). MS calculated value: 362.2; MS measured value: 363.3 [M+H] + .

[0849] 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).

[0850] Example 31

[0851]

[0852] Example route of Example 31:

[0853]

[0854] Synthesis of 5-bromo-N-(4-fluorobenzyl)pyridine-2-amine (246-2):

[0855]

[0856] A mixture of 246-1 (2.00 g, 11.4 mmol), (4-fluorophenyl)methylamine (2.85 g, 22.8 mmol), and K₂CO₃ (3.15 g, 22.8 mmol) in DMSO (50 mL) was stirred overnight at room temperature. Water (150 mL) was added to the reaction mixture, and the mixture was then 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) in solid form. MS calculated value: 280.0; MS measured value: 281.2 [M+H] + .

[0857] N 5 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 2 Synthesis of -(4-fluorobenzyl)pyridine-2,5-diamine (SS20308-0246-01):

[0858]

[0859] A mixture of 246-2 (250 mg, 0.89 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine (199 mg, 1.78 mmol), Brett Phos Palladacycle (71 mg, 0.089 mmol), and t-BuOK (199 mg, 1.78 mmol) in toluene (5 mL) was stirred in a microwave reactor at 140 °C for 1 h. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC to give SS20308-0246-01 (26 mg, approximately 9% yield) in solid form. MS calculated value: 312.2; MS measured value: 313.1 [M+H] + .

[0860] 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).

[0861] Example 32

[0862]

[0863] Example route of Example 32:

[0864]

[0865] Synthesis of 5-bromo-N-((4,4-difluorocyclohexyl)methyl)pyridine-2-amine (247-2):

[0866]

[0867] A mixture of 247-1 (50 mg, 0.28 mmol), (4,4-difluorocyclohexyl)methylamine (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 extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give an oily 247-2 (80 mg, approximately 92% yield). MS calculated value: 304.0; MS measured value: 305.2 [M+H] + .

[0868] 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):

[0869]

[0870] A mixture of 247-2 (80 mg, 0.26 mmol), 2-(1H-1,2,4-triazol-1-yl)ethylamine (58 mg, 0.52 mmol), Brett Phos Palladacycle (21 mg, 0.026 mmol), and t-BuOK (58 mg, 0.52 mmol) in toluene (3 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC to give an oily SS20308-0247-01 (7 mg, approximately 8% yield). MS calculated value: 336.2; MS measured value: 337.3 [M+H] + .

[0871] 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),5.8 1(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).

[0872] Example 33

[0873]

[0874] Example route of Example 33:

[0875]

[0876] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-bromopyridin-2-amine (249-2):

[0877]

[0878] 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 overnight at 120 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO₄, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 249-2 in solid form (300 mg, approximately 33% yield). MS calculated value: 267.0; MS measured value: 268.0 [M+H] + .

[0879] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of -(4-fluorobenzyl)pyridine-2,6-diamine (SS20308-0249-01):

[0880]

[0881] A mixture of 249-2 (100 mg, 0.37 mmol), (4-fluorophenyl)methylamine (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 overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, 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 under vacuum, and purified by preparative HPLC to give an oily SS20308-0249-01 (20 mg, approximately 17% yield). MS calculated value: 312.2; MS measured value: 313.0 [M+H] + .

[0882] 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).

[0883] Example 34

[0884]

[0885] Example route of Example 34:

[0886]

[0887] 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):

[0888]

[0889] A mixture of 249-2 (100 mg, 0.37 mmol), (4,4-difluorocyclohexyl)methylamine (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 overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water. Insoluble matter was removed by filtration, and the filtrate was extracted with EtOAc (30 mL × 3). The organic layer was separated, dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC to give an oily SS20308-0250-01 (6 mg, approximately 5% yield). MS calculated value: 336.2; MS measured value: 337.3 [M+H] + .

[0890] 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).

[0891] Example 35

[0892]

[0893] Example route of Example 35:

[0894]

[0895] Synthesis of 3-(2-(4-fluorobenzylamino)-6-(1H-indol-7-yl)phenyl)-N,N-dimethylpropionamide (253-1):

[0896]

[0897] 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 crude product. Purification by column chromatography (EtOAc / petroleum ether = 5 / 1) gave an oily 253-1 (50 mg, approximately 17% yield). MS calculated value: 415.2; MS measured value: 416.4 [M+H] + .

[0898] Synthesis of 2-(3-(dimethylamino)propyl)-N-(4-fluorobenzyl)-3-(indoline-7-yl)aniline (SS20308-0253-01):

[0899]

[0900] A mixture of 253-1 (40 mg, 100 μmol) 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 the mixture was stirred at 70 °C for 6 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined layers were dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was then purified by preparative HPLC to give SS20308-0253-01 (1.84 mg, approximately 5% yield) as a light-colored solid. MS calculated value: 403.5; MS measured value: 404.3 [M+H] + .

[0901] 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).

[0902] Example 36

[0903]

[0904] Example route of Example 36:

[0905]

[0906] Synthesis of N-(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-4-nitroaniline (265-01):

[0907]

[0908] A mixture of 3,4-difluoronitrobenzene (1.60 g, 10.06 mmol), 236-3 (2.40 g, 12.07 mmol), and K₂CO₃ (6.55 g, 20.11 mmol) in DMSO (10 mL) was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO₄, concentrated under vacuum, and purified by column chromatography (PE / EtOAc = 1 / 1) to give 265-1 in solid form (2.20 g, approximately 82% yield). MS calculated value: 265.1; MS measured value: 266.1 [M+H] + .

[0909] N 1 Synthesis of 3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (265-2):

[0910]

[0911] Pd / C (10%, 50 mg) was added to a 20 mL solution of 265-1 (1.00 g, 3.77 mmol) in MeOH. The mixture was stirred overnight at room temperature under a H2 atmosphere. After the reaction was complete, insoluble matter was removed by filtration. The organic layer was concentrated under vacuum and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give an oily 265-01-3 (700 mg, approximately 79% yield). MS calculated value: 235.1; MS measured value: 236.0 [M+H] + .

[0912] N 1 -(3-(1H-1,2,4-triazol-1-yl)propyl)-2-fluoro-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)phenyl-1,4-diamine (SS20308-0265-01):

[0913]

[0914] AlMe3 (1.06 mL, 2.12 mmol, 2N in THF) was added to a solution of 265-2 (250 mg, 1.28 mmol) in CH2Cl2 (10 mL), and the reaction was stirred at 40 °C for 2 h under a nitrogen atmosphere. After cooling, BH3-DMS (1.06 mL, 2.12 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried with MgSO4, concentrated under vacuum, and purified by preparative HPLC to obtain an oily SS20308-0265-01 (33 mg, approximately 8% yield). MS calculated value: 393.2; MS measured value: 394.1 [M+H] + .

[0915] 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).

[0916] Example 37

[0917]

[0918] Example route of Example 37:

[0919]

[0920] N 1 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of 1,4-diamine (SS20308-0275-01): -(3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)phenyl-1,4-diamine

[0921]

[0922] AlMe3 (0.89 mL, 1.78 mmol, 2N in THF) was added to a solution of 239-1 (180 mg, 0.89 mmol) and 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (170 mg, 1.06 mmol) in CH2Cl2 (10 mL). The reaction was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After cooling, BH3-DMS (0.89 mL, 1.78 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried with MgSO4, concentrated under vacuum, and purified by preparative HPLC to obtain an oily SS20308-0275-01 (26 mg, approximately 8% yield). MS calculated value: 347.2; MS measured value: 348.2 [M+H] + .

[0923] 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).

[0924] Example 38

[0925]

[0926] Example route of Example 38:

[0927]

[0928] Synthesis of 3-(2-fluoro-4-nitrophenylamino)prop-1-ol (302-2):

[0929]

[0930] A mixture of 3,4-difluoronitrobenzene (1.60 g, 10.06 mmol), 3-aminoprop-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 complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO₄, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give an oily 302-2 (2.00 g, approximately 93% yield). MS calculated value: 214.1; MS measured value: 215.2 [M+H] + .

[0931] Synthesis of 3-(4-amino-2-fluorophenylamino)prop-1-ol (302-3):

[0932]

[0933] Pd / C (10%, 150 mg) was added to a solution of 302-2 (1.90 g, 8.87 mmol) in 20 mL of EtOAc. The mixture was stirred at room temperature under a H2 atmosphere for 4 hours. After the reaction was complete, insoluble matter was removed by filtration. The organic layer was concentrated under vacuum and purified by column chromatography (petroleum ether / EtOAc = 1 / 2) to give an oily 302-3 (1.5 g, approximately 92% yield). MS calculated value: 184.1; MS measured value: 185.2 [M+H] + .

[0934] Synthesis of 3-(2-fluoro-4-(2,2,2-trifluoro-1-phenylethylamino)phenylamino)prop-1-ol (302-4):

[0935]

[0936] AlMe3 (2.71 ml, 5.42 mmol, 2N in THF) was added to a solution of 302-3 (500 mg, 2.71 mmol) and 2,2,2-trifluoro-1-acetophenone (614 mg, 353 mmol) in CH2Cl2 (10 ml). The reaction was stirred at 40 °C for 2 h under a nitrogen atmosphere. After cooling, BH3-DMS (2.71 ml, 5.42 mmol, 2N in THF) was added to the mixture, and the mixture was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC to obtain an oily 302-4 (400 mg, approximately 43% yield). MS calculated value: 342.1; MS measured value: 343.0 [M+H]+ .

[0937] Synthesis of 3-(2-fluoro-4-(2,2,2-trifluoro-1-phenylethylamino)phenylamino)propyl methanesulfonate (302-5):

[0938]

[0939] Ms₂O (153 mg, 0.88 mmol) and DIPEA (189 mg, 1.46 mmol) were added to a CH₂Cl₂ (20 mL) solution of 302-4 (250 mg, 0.73 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water and extracted with CH₂Cl₂ (50 mL x 3). The organic layer was separated, dried over MgSO₄, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give an oily 302-5 (160 mg, approximately 52% yield). MS calculated value: 327.1; MS measured value: 328.2 [M+H] + .

[0940] N 1 -(3-(dimethylamino)propyl)-2-fluoro-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)phenyl-1,4-diamine (SS20308-0302-01):

[0941]

[0942] To a 20 mL solution of CH3CN (160 mg, 0.38 mmol), dimethylamine hydrochloride (47 mg, 0.57 mmol) and K2CO3 (210 mg, 1.52 mmol) were added, and the mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC to obtain an oily SS20308-0302-01 (24 mg, approximately 17% yield). MS calculated value: 369.2; MS measured value: 370.2 [M+H] + .

[0943] 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).

[0944] Example 39

[0945]

[0946] Example route of Example 39:

[0947]

[0948] Synthesis of 2-bromo-N-(3-morpholinopropyl)-4-nitroaniline (315-2):

[0949]

[0950] A mixture of 3-morpholinopropyl-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 in solid form (1.4 g, approximately 89% yield). MS calculated value: 343.1; MS measured value: 344.0 [M+H] + .

[0951] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(3-morpholinopropyl)-4-nitroaniline (315-3):

[0952]

[0953] To a mixture of 315-2 (1 g, 2.91 mmol), palladium(II) acetate (33 mg, 0.15 mmol), S-phos (120 mg, 0.29 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxane-1,2-dioxane-1,2-dioxane-3,2-dioxane (672 mg, 3.20 mmol), and potassium phosphate (2.16 g, 10.17 mmol) in toluene (40 mL), water (2 mL) was added and the mixture was stirred at 110 °C for 16 h under N2. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, 100% EtOAc, DCM / methanol = 50 / 1) to give compound 0315-3 in solid form (700 mg, approximately 69% yield). MS calculated value: 347.2; MS measured value: 348.3 [M+H] + .

[0954] N 1 Synthesis of -(3-morpholinopropyl)-2-(tetrahydro-2H-pyran-4-yl)phenyl-1,4-diamine (315-4):

[0955]

[0956] A suspension of 315-3 (650 mg, 1.87 mmol) and palladium / activated carbon (10%, 130 mg) in EtOAc (20 mL) was vigorously stirred at room temperature for 16 hours under hydrogen (balloon) atmosphere. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give an oily crude product 315-4 (597 mg, approximately 100% yield). MS calculated value: 319.2; MS measured value: 320.3 [M+H] + .

[0957] N 1 -(3-morpholinopropyl)-2-(tetrahydro-2H-pyran-4-yl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)phenyl-1,4-diamine (SS20308-0315-01):

[0958]

[0959] 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 a 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 NaHCO3 solution and extracted with EtOAc (10 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 (DCM / methanol = 20 / 1) to give compound SS20308-0315-01 (33.8 mg, approximately 23% yield) in solid form. MS calculated value: 477.3; MS measured value: 478.3 [M+H] + .

[0960] 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).

[0961] Example 40

[0962]

[0963] Example 41

[0964]

[0965] Example route of Example 41:

[0966]

[0967] Synthesis of 2-cyclohexenyl-N-(3-morpholinopropyl)-4-nitroaniline (325-1):

[0968]

[0969] Water (1 mL) was added 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). After stirring at 100 °C under N2 (g) for 16 hours, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and the residue purified by column chromatography (petroleum ether / EtOAc = 1 / 1, 100% EtOAc) to give an oily compound 325-1 (548 mg, approximately 94% yield). MS calculated value: 345.2; MS measured value: 346.2 [M+H] + .

[0970] 2-Cyclohexyl-N 1 Synthesis of 3-(3-morpholinopropyl)phenyl-1,4-diamine (325-2):

[0971]

[0972] A suspension of 325-1 (550 mg, 1.59 mmol) and palladium / activated carbon (10%, 55 mg) in EtOAc (10 mL) was vigorously stirred at room temperature for 16 hours under hydrogen (balloon). The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give an oily crude product 325-2 (498 mg, approximately 99% yield). MS calculated value: 317.3; MS measured value: 318.3 [M+H] + .

[0973] 2-Cyclohexyl-N 1 -(3-morpholinopropyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)phenyl-1,4-diamine (SS20308-0325-01):

[0974]

[0975] A mixture of 325-2 (100 mg, 0.31 mmol) and trimethylaluminum (2 M in hexane) (0.24 mL, 0.48 mmol) in dichloromethane (10 mL) was heated to 40 °C and maintained for 2 hours. The reaction mixture was cooled to room temperature and a borane-methyl sulfide complex (2 M 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 layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM / methanol = 20 / 1) to give compound SS20308-0325-01 in solid form (85.4 mg, approximately 57% yield). MS calculated value: 475.3; MS measured value: 476.4 [M+H] + .

[0976] 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).

[0977] Example 42

[0978]

[0979] Example route of Example 42:

[0980]

[0981] Synthesis of 2-bromo-N-(3-morpholinopropyl)-4-nitroaniline (326-1):

[0982]

[0983] A mixture of compound 3-pyrrolidine-1-ylpropyl-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 in solid form (2.95 g, approximately 99% yield). MS calculated value: 327.1; MS measured value: 328.0 [M+H] + .

[0984] Synthesis of 2-cyclohexenyl-4-nitro-N-(3-(pyrrolidone-1-yl)propyl)aniline (326-2):

[0985]

[0986] Water (2 mL) was added 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). After stirring at 100 °C under N2 for 3 hours, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and the residue purified by CC (petroleum ether / EtOAc = 1 / 1, 100% EtOAc, DCM / methanol = 20 / 1) to give the oily compound 326-2 (1.0 g, approximately 100% yield). MS calculated value: 329.2; MS measured value: 330.3 [M+H] + .

[0987] 2-Cyclohexyl-N 1 Synthesis of 3-(pyrrolidone-1-yl)propyl)phenyl-1,4-diamine (0326-3):

[0988]

[0989] A suspension of 326-2 (1.00 g, 3.04 mmol) and palladium / activated carbon (10%, 110 mg) in EtOAc (15 mL) was vigorously stirred at room temperature for 16 hours under hydrogen (balloon). The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give an oily crude product 326-3 (915 mg, approximately 100% yield). MS calculated value: 301.3; MS measured value: 302.2 [M+H] + .

[0990] 2-Cyclohexyl-N1 -(3-(pyrrolid-1-yl)propyl)-N 4 Synthesis of -(2,2,2-trifluoro-1-phenylethyl)phenyl-1,4-diamine (SS20308-0326-01):

[0991]

[0992] 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 a 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 NaHCO3 solution and extracted with EtOAc (10 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 (DCM / methanol = 10 / 1) to give the oily compound SS20308-0326-01 (16.3 mg, approximately 11% yield). MS calculated value: 459.3; MS measured value: 460.3 [M+H] + .

[0993] 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).

[0994] Example 43

[0995]

[0996] Example route of Example 43:

[0997]

[0998] Synthesis of 1-(2-(2-nitrophenoxy)ethyl)-1H-1,2,4-triazole (33-2):

[0999]

[1000] 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 overnight at 70 °C. 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 to 30 / 1) to give 0016-01-3 (2.0 g, approximately 32% yield) in solid form. MS calculated value: 234.1; MS measured value: 235.2 [M+H] + .

[1001] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)aniline (33-3):

[1002]

[1003] Pd / C (200 mg, 10%) was added to a solution of 33-2 (2.0 g, 8.54 mmol) in 20 mL of MeOH, 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 an oily 33-3 (1.0 g, approximately 57% yield). MS calculated value: 204.1; MS measured value: 205.3 [M+H] + .

[1004] Synthesis of ethyl 4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenylamino)benzoate (SS20308-0033-01):

[1005]

[1006] A solution of 33-3 (1.0 g, 4.90 mmol), ethyl 4-bromobenzoate (1.4 g, 5.88 mmol), Pd(OAc)2 (110 mg, 0.49 mmol), BINAP (610 mg, 0.98 mmol), and Cs2CO3 (2.4 g, 7.34 mmol) in toluene (150 mL) was stirred overnight at 110 °C. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL). The organic layer was washed with water (300 mL) and brine (2 x 300 mL), and the solvent was evaporated to give a solid, which was purified by column chromatography (CH2Cl2 / MeOH = 100 / 1 to 20 / 1) and preparative HPLC to give SS20308-0033-01 in solid form (700 mg, approximately 40% yield). MS calculated value: 352.2; MS measured value: 353.3 [M+H] + .

[1007] 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).

[1008] Example 44

[1009]

[1010] Example route of Example 44:

[1011]

[1012] Synthesis of 1-(2-(2-bromo-6-nitrophenoxy)ethyl)-1H-1,2,4-triazole (55-2):

[1013]

[1014] A mixture of 55-1 (2.2 g, 10.09 mmol), 1-(2-bromoethyl)-1H-1,2,4-triazole (2.1 g, 12.11 mmol), and K₂CO₃ (2.1 g, 15.14 mmol) in DMF (50 mL) was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature 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 to 20 / 1) to give an oily 55-2 (2.2 g, approximately 70% yield). MS calculated value: 312.0; MS measured value: 313.0 [M+H] + .

[1015] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-3-nitro-N-phenylaniline (55-3):

[1016]

[1017] 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 overnight at 110 °C 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 an oily 55-3 (700 mg, approximately 83% yield). MS calculated value: 325.1; MS measured value: 326.2 [M+H] + .

[1018] 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (55-4):

[1019]

[1020] Pd / C (10%, 100 mg) was added to a 20 mL solution of 55-3 (550 mg, 1.69 mmol) in MeOH, and the mixture was stirred overnight at room temperature. 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 in solid form (400 mg, approximately 80% yield). MS calculated value: 295.1; MS measured value: 296.1 [M+H] + .

[1021] Synthesis of ethyl 4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-3-(phenylamino)phenylamino)benzoate (SS20308-0055-01):

[1022]

[1023] 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 overnight at 110 °C under 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 / 1–30 / 1) and preparative HPLC to give 55-3 in solid form (67 mg, approximately 18% yield). MS calculated value: 443.2; MS measured value: 444.2 [M+H] + .

[1024] 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).

[1025] Example 45

[1026]

[1027] Example route of Example 45:

[1028]

[1029] Synthesis of 3-bromo-2-(2-(dimethylamino)ethoxy)aniline (72-2):

[1030]

[1031] 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 diatomaceous earth. The filtrate was alkalized 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 in solid form (0.7 g, approximately 78% yield). MS calculated value: 258.0; MS measured value: 259.2 [M+H] + .

[1032] Synthesis of N-(3-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-3-oxo-3-phenylpropionamide (72-3):

[1033]

[1034] A mixture of 72-2 (410 mg, 1.58 mmol) and ethyl 3-oxo-3-phenylpropionate (760 mg, 3.95 mmol) was stirred and heated to 140 °C under microwave irradiation and a nitrogen atmosphere, and maintained 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, CH2Cl2 / MeOH = 20 / 1) to give 72-3 in solid form (400 mg, approximately 62% yield). MS calculated value: 404.1; MS measured value: 405.3 [M+H] + .

[1035] Synthesis of 7-bromo-8-(2-(dimethylamino)ethoxy)-4-phenylquinoline-2(1H)-one (72-4):

[1036]

[1037] The 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 onto ice, alkalized 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 an oily 72-4 (70 mg, approximately 15% yield). MS calculated value: 386.1; MS measured value: 387.2 [M+H] + .

[1038] Synthesis of 8-(2-(dimethylamino)ethoxy)-4-phenyl-7-(phenylamino)quinoline-2(1H)-one (SS20308-0072-01):

[1039]

[1040] 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 under reflux overnight under a nitrogen atmosphere, then filtered and washed 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) in solid form. MS calculated value: 399.2; MS measured value: 400.4 [M+H] + .

[1041] 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).

[1042] Example 46

[1043]

[1044] Example route of Example 46:

[1045]

[1046] Synthesis of 4-bromo-2-nitrobenzene (95-2):

[1047]

[1048] A mixture of 95-1 (6.00 g, 21.36 mmol), phenylboronic acid (2.60 g, 21.36 mmol), Pd(PPh3)4 (1.23 g, 1.07 mmol), and Na2CO3 (7.90 g, 74.76 mmol) in toluene / H2O (60 mL, 5 / 1) was stirred overnight at 90 °C under a nitrogen 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) to give an oily 95-2 (3.70 g, approximately 62% yield).

[1049] 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).

[1050] Synthesis of 4-bromobiphenyl-2-amine (95-3):

[1051]

[1052] A mixture of 95-2 (3.70 g, 13.30 mmol), Zn powder (8.70 g, 133.00 mmol), and HOAc (3.5 mL) in EtOH (35 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water. The mixture was alkalized with 40% NaOH to pH 10. The resulting mixture was filtered through diatomaceous earth 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 an oily 95-3 (1.90 g, approximately 58% yield). MS calculated value: 247.0; MS measured value: 248.1 [M+H] + .

[1053] Synthesis of 4-bromo-N-(2-chloroethyl)biphenyl-2-amine (95-4):

[1054]

[1055] To a solution of 95-3 (1.75 g, 7.05 mmol) in 20 mL of MeOH, 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) were added, and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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 an oily 95-4 (2.00 g, approximately 91% yield). MS calculated value: 309.0; MS measured value: 309.8 [M+H] + .

[1056] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromobiphenyl-2-amine (95-5):

[1057]

[1058] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to give an oily 95-5 (2.10 g, approximately 95% yield). MS calculated value: 342.1; MS measured value: 342.8 [M+H] + .

[1059] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of 2,4-phenylbiphenyl-2,4-diamine (SS20308-0095-01):

[1060]

[1061] A mixture of 95-5 (200 mg, 0.58 mmol), aniline (65 mg, 0.70 mmol), Pd2dba3 (53 mg, 0.06 mmol), Xantphos (67 mg, 0.12 mmol), and Cs2CO3 (378 mg, 1.16 mmol) in toluene (20 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC to give SS20308-0095-01 (45 mg, approximately 22% yield) in solid form. MS calculated value: 355.2; MS measured value: 356.1 [M+H] + .

[1062] 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).

[1063] Example 47

[1064]

[1065] Example route of Example 47:

[1066]

[1067] Synthesis of 4-chloro-2-nitro-1,1'-biphenyl (129-2):

[1068]

[1069] Cs₂CO₃ (6.52 g, 20 mmol) and Xphos Pd G₂ (200 mg) were added 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). The mixture was heated under reflux for 6 hours. The mixture was diluted with ethyl acetate (50 mL). The organic layer was washed successively 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 = 15 / 1) to give an oily 129-2 (1.2 g, approximately 51% yield). MS calculated value: 233.0; MS measured value: 234.2 [M+H] + .

[1070] Synthesis of 4-chloro-[1,1'-biphenyl]-2-amine (129-3):

[1071]

[1072] To a mixture of 129-2 (1.2 g, 4.3 mmol) in DCM (50 mL), HOAc (5 mL) and Zn powder (500 mg) were added 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 an oily 129-3 (800 mg, approximately 77% yield). MS calculated value: 203.1; MS measured value: 204.2 [M+H] + .

[1073] Synthesis of 4-chloro-N-(2-chloroethyl)-[1,1'-biphenyl]-2-amine (129-4):

[1074]

[1075] To a mixture of 129-3 (406 mg, 2 mmol) in EtOH (50 mL), 2-chloroacetaldehyde (5 mL, in water, 40% concentration) and HOAc (2 mL) were added at room temperature. NaBH3CN (0.5 g) was added to the mixture, 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 = 3 / 1) to give a colorless oily 129-4 (380 mg, approximately 71% yield). MS calculated value: 265.0; MS measured value: 266.2 [M+H] + .

[1076] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-[1,1'-biphenyl]-2-amine (129-5):

[1077]

[1078] To a mixture of 129-4 (380 mg, 1.4 mmol) in DMF (10 mL), 1H-1,2,4-triazole (193 mg, 2.8 mmol) and Cs₂CO₃ (913 mg, 2.8 mmol) were added 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 successively 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 / 5) to give 129-5 in solid form (260 mg, approximately 61% yield). MS calculated value: 298.1; MS measured value: 299.2 [M+H] + .

[1079] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0129):

[1080]

[1081] Aniline (74.4 mg, 0.8 mmol), Cs₂CO₃ (326 g, 1 mmol), and Xphos Pd G₂ (30 mg) were added to a mixture of 129-5 (130 mg, 0.4 mmol) in dioxane (5 mL) at room temperature. The mixture was heated under reflux in nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (80 mL). The filtrate was washed successively with water (100 mL) and brine (100 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 an oily SS₂0308-0129 (20 mg, approximately 13% yield). MS calculated value: 355.2; MS measured value: 356.2 [M+H] + .

[1082] 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).

[1083] Example 48

[1084]

[1085] Example route of Example 48:

[1086]

[1087] Synthesis of N1-(4-chloro-[1,1'-biphenyl]-2-yl)-N2,N2-dimethylethane-1,2-diamine (130-1):

[1088]

[1089] Dimethylamine (7 mL, 14 mmol) and Cs₂CO₃ (913 mg, 2.8 mmol) were added to a mixture of 129-4 (380 mg, 1.4 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred at 80 °C for 8 hours. The mixture was diluted with DCM (30 mL). The mixture was washed successively 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 / 5) to give an oily 130-1 (220 mg, approximately 56% yield). MS calculated value: 274.1; MS measured value: 275.2 [M+H] + .

[1090] Synthesis of N2-(2-(dimethylamino)ethyl)-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0130):

[1091]

[1092] Aniline (74.4 mg, 0.8 mmol), Cs₂CO₃ (326 g, 1 mmol), and xphos Pd G₂ (30 mg) were added to a mixture of 130⁻¹ (137 mg, 0.5 mmol) in dioxane (5 mL) at room temperature. The mixture was heated under reflux in nitrogen for 12 hours. The reaction mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc (40 mL). The filtrate was washed successively 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 (DCM / MeOH = 20 / 1 to 4 / 1) to give SS₂₀₃₀₈-0130 (10 mg, approximately 13% yield) in solid form. MS calculated value: 331.2; MS measured value: 332.2 [M+H] + .

[1093] 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).

[1094] Example 49

[1095]

[1096] Example route of Example 49:

[1097]

[1098] Synthesis of 4-chloro-N-(2-chloroethyl)-N-methyl-[1,1'-biphenyl]-2-amine (131-1):

[1099]

[1100] To a mixture of 129-4 (266 mg, 1 mmol) in EtOH (30 mL), HCHO (aqueous solution (aq)) (3 mL) and HOAc (2 mL) were added, followed by the addition of NaBH3CN (0.5 g). The mixture was stirred at room temperature for 6 hours. The mixture was then filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane / EtOAc = 1 / 1) to give an oily 131-1 (180 mg, approximately 64% yield). MS calculated value: 279.1; MS measured value: 280.2 [M+H] + .

[1101] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-N-methyl-[1,1'-biphenyl]-2-amine (131-2):

[1102]

[1103] To a mixture of 131-1 (180 mg, 0.6 mmol) in DMF (10 mL), 1H-1,2,4-triazole (138 mg, 2 mmol) and Cs₂CO₃ (652 mg, 2 mmol) were added at room temperature. The mixture was stirred at 80 °C for 8 hours. The mixture was diluted with DCM (30 mL) and 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 an oily 131-2 (120 mg, approximately 60% yield). MS calculated value: 312.1; MS measured value: 313.2 [M+H] + .

[1104] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N2-methyl-N4-phenyl-[1,1'-biphenyl]-2,4-diamine (SS20308-0131):

[1105]

[1106] Aniline (74.4 mg, 0.8 mmol), Cs₂CO₃ (326 g, 1 mmol), and xphos Pd G₂ (30 mg) were added to a mixture of 131-2 (120 mg, 0.4 mmol) in toluene (15 mL) at room temperature. The mixture was heated under reflux in 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) in solid form. MS calculated value: 369.2; MS measured value: 370.2 [M+H] + .

[1107] 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).

[1108] Example 50

[1109]

[1110] Example route of Implementation Example 50:

[1111]

[1112] Synthesis of 4-bromo-2-(2-bromoethoxy)-1-chlorobenzene (132-2):

[1113]

[1114] To a mixture of 132-1 (412 mg, 2 mmol) in acetone (50 mL), 1,2-dibromoethane (744 mg, 4 mmol) and Cs₂CO₃ (1.3 g, 4 mmol) were added 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 an oily 132-2 (380 mg, approximately 61% yield). MS calculated value: 311.9; MS measured value: 312.9 [M+H]+ .

[1115] Synthesis of 1-(2-(5-bromo-2-chlorophenoxy)ethyl)-1H-1,2,4-triazole (132-3):

[1116]

[1117] To a mixture of 132-2 (312 mg, 1.0 mmol) in DMF (10 mL), 1H-1,2,4-triazole (138 mg, 2.0 mmol) and Cs₂CO₃ (652 mg, 2.0 mmol) were added at room temperature. The mixture was stirred at 80 °C for 8 hours. The mixture was diluted with DCM (30 mL) and washed successively 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 an oily 132-3 (220 mg, approximately 73% yield). MS calculated value: 301.0; MS measured value: 302.2 [M+H] + .

[1118] Synthesis of 3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-4-chloro-N-phenylaniline (132-4):

[1119]

[1120] Aniline (65 mg, 0.7 mmol), Cs₂CO₃ (326 g, 1 mmol), and Xphos Pd G₂ (30 mg) were added to a mixture of 132-3 (220 mg, 0.7 mmol) in toluene (10 mL) at room temperature. The mixture was then heated under reflux in 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 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 an oily 132-4 (80 mg, approximately 35% yield). MS calculated value: 314.1; MS measured value: 315.1 [M+H] + .

[1121] Synthesis of 2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-N-phenyl-[1,1'-biphenyl]-4-amine (SS20308-0132):

[1122]

[1123] Cs₂CO₃ (326 mg, 1 mmol) and xphos Pd G₂ (15 mg) were added 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). The mixture was heated under reflux for 6 hours. The mixture was diluted with ethyl acetate (50 mL), 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) in solid form. MS calculated value: 356.2; MS measured value: 357.2 [M+H] + .

[1124] 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).

[1125] Example 51

[1126]

[1127] Example route of Example 51:

[1128]

[1129] Synthesis of 4-chloro-2',6'-dimethyl-2-nitro-1,1'-biphenyl (133-2):

[1130]

[1131] To a mixture of 133-1 (235 mg, 1 mmol) and (2,6-dimethylphenyl)boric acid (180 mg, 1.2 mmol) in toluene / H₂O (15 mL / 3 mL), Cs₂CO₃ (652 mg, 2 mmol) and Xphos Pd G₂ (20 mg) were added, and the mixture was heated under reflux for 6 hours. The solution was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). 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 an oily 133-2 (90 mg, approximately 35% yield). MS calculated value: 261.1; MS measured value: 262.2 [M+H] + .

[1132] Synthesis of 4-chloro-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-3):

[1133]

[1134] To a mixture of 133-2 (261 mg, 1 mmol) in DCM (50 mL), HOAc (5 mL) and Zn powder (150 mg) were added 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 an oily 133-3 (200 mg, approximately 86% yield). MS calculated value: 231.1; MS measured value: 232.2 [M+H] + .

[1135] Synthesis of 4-chloro-N-(2-chloroethyl)-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-4):

[1136]

[1137] To a mixture of 133-3 (200 mg, 2 mmol) in EtOH (30 mL), 2-chloroacetaldehyde (1 mL, in water, 40% concentration) and HOAc (1 mL) were added, followed by the addition of NaBH3CN (0.3 g). The mixture was stirred at room temperature for 6 hours. The solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (hexane / EtOAc = 1 / 1) to give a colorless oily 133-4 (160 mg, approximately 63% yield). MS calculated value: 293.1; MS measured value: 293.2 [M+H] + .

[1138] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-chloro-2',6'-dimethyl-[1,1'-biphenyl]-2-amine (133-5):

[1139]

[1140] To a mixture of 133-4 (160 mg, 0.5 mmol) in DMF (10 mL), 1H-1,2,4-triazole (69 mg, 1 mmol) and Cs₂CO₃ (326 mg, 1 mmol) were added at room temperature. The mixture was stirred at 80 °C for 8 hours, diluted with DCM (30 mL), and 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 in solid form (120 mg, approximately 67% yield). MS calculated value: 326.1; MS measured value: 327.2 [M+H] +

[1141] 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):

[1142]

[1143] Aniline (74.4 mg, 0.8 mmol), Cs₂CO₃ (326 g, 1 mmol), and Xphos Pd G₂ (20 mg) were added to a mixture of 133-5 (120 mg, 0.37 mmol) in dioxane (15 mL) at room temperature. The mixture was heated under reflux at 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) in solid form. MS calculated value: 383.2; MS measured value: 384.2 [M+H] +

[1144] 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).

[1145] Example 52

[1146]

[1147] Example route of Implementation Example 52:

[1148]

[1149] Synthesis of ethyl 3-(1H-1,2,4-triazol-1-yl)propionate (134-2):

[1150]

[1151] To a mixture of 134-1 (500 mg, 2.8 mmol) in CH3CN (50 mL), 1H-1,2,4-triazole (241 mg, 3.5 mmol) and Cs2CO3 (1.6 g, 5 mmol) were added 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 a colorless oil of 134-2 (300 mg, approximately 64% yield). MS calculated value: 169.1; MS measured value: 170.2 [M+H] +

[1152] Synthesis of 3-(1H-1,2,4-triazol-1-yl)propionic acid (134-3):

[1153]

[1154] LiOH (228 mg, 6 mmol) was added to a mixture of 134-2 (300 mg, 1.8 mmol) in MeOH (30 mL). The mixture was stirred at room temperature for 6 hours. HCl (2 M) was added to the solution to pH 3-4, and the mixture was concentrated under reduced pressure to give a colorless, oily crude product 134-2 (400 mg, yield approximately 80%), which was used for the next step without further purification. MS calculated value: 141.1; MS measured value: 142.2 [M+H] +

[1155] Synthesis of 4-bromo-3-nitro-N-phenylaniline (134-5):

[1156]

[1157] To a mixture of 134-4 (432 mg, 2 mmol) in DCM (50 mL), phenylboronic acid (268 mg, 2.2 mmol), Cu(OAc)₂ (362 g, 2 mmol), and TEA (300 mg, 3 mmol) were added at room temperature. The mixture was stirred under nitrogen at room temperature 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 an oily 134-5 (256 mg, approximately 44% yield). MS calculated value: 292.0; MS measured value: 293.2 [M+H] +

[1158] Synthesis of 2-nitro-N-phenyl-[1,1'-biphenyl]-4-amine (134-6):

[1159]

[1160] 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), K₂CO₃ (276 mg, 2 mmol) and Sphos Pd G₂ (40 mg) were added. The mixture was heated under 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 in solid form (220 mg, approximately 76% yield). MS calculated value: 290.1; MS measured value: 291.2 [M+H] +

[1161] Synthesis of N4-phenyl-[1,1'-biphenyl]-2,4-diamine (134-7):

[1162]

[1163] To a mixture of 134-6 (220 mg, 0.76 mmol) in DCM (50 mL), HOAc (5 mL) and Zn powder (150 mg) were added 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 an oily 134-7 (140 mg, approximately 71% yield). MS calculated value: 260.1; MS measured value: 261.2 [M+H] +

[1164] Synthesis of N-(4-(phenylamino)-[1,1'-biphenyl]-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (SS20308-0134):

[1165]

[1166] SOCl2 (3 mL) was added to a solution of 134-3 (140 mg, 1 mmol) in 50 mL of DCM. 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, approximately 21% yield) in solid form. MS calculated value: 383.5; MS measured value: 384.2 [M+H] +

[1167] 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).

[1168] Example 53

[1169]

[1170] Example route of Example 53:

[1171]

[1172] Synthesis of 4-chloro-2-fluoro-6-nitroaniline (141-2):

[1173]

[1174] Add NCS (4.5 g, 33.7 mmol) to a DMF (40 mL) solution of 141-1 (5.0 g, 32.1 mmol) at room temperature. Stir the mixture overnight at room temperature. Dilute the mixture with water (100 mL). Obtain the solid by filtration, wash with water and dry under vacuum to give 141-2 (4.5 g, about 74% yield) in solid form.

[1175] Synthesis of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (141-3):

[1176]

[1177] CuBr2 (2.1 g, 9.4 mmol) was added to a CH3CN (10 mL) solution of 141-2 (900 mg, 4.7 mmol) at room temperature. Then, t-BuONO (2.4 g, 23.5 mmol) was added dropwise at 60 °C. The mixture was stirred at 60 °C for 2 hours under nitrogen. The mixture was filtered and washed with EtOAc; the filtrate was concentrated into a crude oil, which was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 20) to give an oily 141-3 (620 mg, approximately 52% yield).

[1178] Synthesis of 4-chloro-2-fluoro-6-nitrobiphenyl (141-4):

[1179]

[1180] PdCl2 (dppf) (58 mg, 0.1 mmol) and K2CO3 (673 mg, 4.88 mmol) were added 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) at room temperature. The mixture was then heated to 80 °C under nitrogen and maintained 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 and purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 10) to give oily 141-4 (750 mg, approximately 60% yield).

[1181] Synthesis of 2-fluoro-6-nitro-N-phenylbiphenyl-4-amine (141-5):

[1182]

[1183] 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), and 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 and purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 8) to give an oily 141-5 (180 mg, approximately 25% yield). MS calculated value: 308.1; MS measured value: 309.3 [M+H] + .

[1184] Synthesis of 6-fluoro-N4-phenylbiphenyl-2,4-diamine (141-6):

[1185]

[1186] Pd / C (10%, 30 mg) was added to a 10 mL solution of 141-5 (240 mg, 0.79 mmol) in EtOAc at room temperature. The mixture was stirred overnight at room temperature under hydrogen (1 atm). The mixture was filtered and washed with EtOAc. The filtrate was concentrated to an oil to give an oily 141-6 (170 mg, approximately 78% yield). MS calculated value: 278.1; MS measured value: 279.1 [M+H] + .

[1187] Synthesis of 6-fluoro-N4-phenylbiphenyl-2,4-diamine (141-7):

[1188]

[1189] To a solution of 141-6 (170 mg, 0.61 mmol) and 2-chloroacetaldehyde (143 mg, 1.83 mmol, in water, 40% concentration) in EtOH (5 mL) and HOAc (0.2 mL), NaBH3CN (77 mg, 1.22 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water, extracted with DCM, and the DCM phase was dried over Na2SO4. The filtrate was filtered and concentrated to an oily substance, which was purified by preparative TLC to give an oily 141-7 (58 mg, approximately 28% yield). MS calculated value: 340.1; MS measured value: 341.0 [M+H]+ .

[1190] Synthesis of N2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-fluoro-N4-phenylbiphenyl-2,4-diamine (SS20308-0141-01):

[1191]

[1192] At room temperature, Cs₂CO₃ (91 mg, 0.28 mmol) was added 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). The mixture was then heated to 80 °C and maintained for 7 hours. The solution was diluted with water, extracted with EtOAc, and the EtOAc phase was dried over Na₂SO₄. The filtrate was filtered and concentrated to an oily state, which was then purified by preparative HPLC to give SS₂0308-0141-01 (12 mg, approximately 23% yield) in solid form. MS calculated value: 373.2; MS measured value: 374.3 [M+H] + .

[1193] 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).

[1194] Example 54

[1195]

[1196] Example route of Example 54:

[1197]

[1198] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 4 Synthesis of 2,4-(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0142-01):

[1199]

[1200] 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 overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth. 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) in solid form. MS calculated value: 373.2; MS measured value: 374.2 [M+H] + .

[1201] 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).

[1202] Example 55

[1203]

[1204] Example route of Implementation Example 55:

[1205]

[1206] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-2):

[1207]

[1208] 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 complete, insoluble matter 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 under vacuum. The residue was purified by column chromatography to give 143-2 (1.0 g, approximately 74% yield) in solid form.

[1209] 4-Bromo-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (143-3):

[1210]

[1211] A mixture of 143-2 (1.0 g, 3.4 mmol), Zn (1.1 g, 17 mmol), and HOAc (1.0 g, 17 mmol) in EtOH (50 mL) was stirred overnight at room temperature. After the reaction was complete, 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 over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give 143-3 in solid form (800 mg, approximately 90% yield). MS result: 263.2 [M+H] + .

[1212] 4-Bromo-N 3 -(2-Chloroethyl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (143-4):

[1213]

[1214] 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 overnight at 40 °C. After the reaction was complete, 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 under vacuum. The residue was purified by reversed-phase column chromatography (EtOAc) to give 143-4 in solid form (600 mg, approximately 60% yield). MS calculated value: 324.0; MS measured value: 325.0 [M+H] + .

[1215] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (143-01-4):

[1216]

[1217] 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 overnight at 80 °C. After the reaction was complete, 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 under vacuum. The residue was purified by reversed-phase (silica) column chromatography (DCM / EtOH = 20 / 1) to give 143-5 in solid form (450 mg, approximately 68% yield). MS calculated value: 357.1; MS measured value: 358.3 [M+H] + .

[1218] Synthesis of (2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)methanol (SS20308-143-01):

[1219]

[1220] 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 overnight under reflux. 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) in solid form. MS calculated value: 385.5; MS measured value: 386.2 [M+H] + .

[1221] 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).

[1222] Example 56

[1223]

[1224] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-2'-methoxy-N 4 Synthesis of 2,4-phenylbiphenyl-2,4-diamine (SS20308-144-01):

[1225]

[1226] 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 overnight under reflux. 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. The remaining 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) in solid form. MS calculated value: 385.2; MS measured value: 386.2 [M+H] + .

[1227] 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).

[1228] Example 57

[1229]

[1230] Example route of Implementation Example 57:

[1231]

[1232] Synthesis of 4-bromo-4'-chloro-2-nitrobenzene (147-2):

[1233]

[1234] A mixture of 147-1 (2.00 g, 7.12 mmol), 4-chloroboronic acid (1.11 g, 7.12 mmol), Pd(PPh3)4 (0.42 g, 0.36 mmol), and Na2CO3 (1.51 g, 14.24 mmol) in toluene / H2O (30 mL, 5 / 1) was stirred overnight at 90 °C under a nitrogen 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 Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether) to give 147-2 (1.70 g, approximately 76% yield) in solid form.

[1235] 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).

[1236] Synthesis of 4-bromo-4'-chlorobiphenyl-2-amine (147-3):

[1237]

[1238] A mixture of 147-2 (1.50 g, 4.80 mmol), Zn powder (3.14 g, 48.00 mmol), and HOAc (3 mL) in EtOH (30 mL) was stirred overnight at room temperature. The reaction mixture was then concentrated and poured into water. The mixture was alkalized with 40% NaOH to pH 10. The resulting mixture was filtered through diatomaceous earth 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) in solid form. MS calculated value: 280.96; MS measured value: 282.0 [M+H] + .

[1239] Synthesis of 4-bromo-4'-chloro-N-(2-chloroethyl)biphenyl-2-amine (147-4):

[1240]

[1241] To a solution of 147-3 (1.00 g, 3.54 mmol) in 20 mL of MeOH, 2-chloroacetaldehyde (1.11 g, 14.16 mmol, 40%), AcOH (844 mg, 14.16 mmol), and NaBH3CN (890 mg, 14.16 mmol) were added, and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was then poured into water and alkalized with 1 N NaOH until 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 an oily 147-4 (710 mg, approximately 59% yield). MS calculated value: 343.0; MS measured value: 344.0 [M+H] + .

[1242] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-4'-chlorobiphenyl-2-amine (147-5):

[1243]

[1244] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give an oily 147-5 (537 mg, approximately 73% yield). MS calculated value: 376.01; MS measured value: 379.0 [M+H] + .

[1245] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4'-chloro-N 4 Synthesis of 2,4-phenylbiphenyl-2,4-diamine (SS20308-0147-01):

[1246]

[1247] A mixture of 147-5 (150 mg, 0.40 mmol), aniline (45 mg, 0.48 mmol), Pd2dba3 (37 mg, 0.04 mmol), Xantphos (46 mg, 0.08 mmol), and Cs2CO3 (261 mg, 0.80 mmol) in toluene (30 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC to give an oily SS20308-0147-01 (15 mg, approximately 9% yield). MS calculated value: 389.1; MS measured value: 390.3 [M+H] + .

[1248] 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).

[1249] Example 58

[1250]

[1251] Example route of Example 58:

[1252]

[1253] Synthesis of 1,4-dibromo-2-fluoro-3-nitrobenzene (148-2):

[1254]

[1255] 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 min; tert-butyl nitrite (2.19 g, 21.28 mmol) was slowly added. The mixture was stirred at 60 °C for 0.5 h, 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 in solid form (820 mg, approximately 65% ​​yield).

[1256] Synthesis of 4-bromo-3-fluoro-2-nitrobenzene (148-3):

[1257]

[1258] A solution of 148-2 (810 mg, 2.71 mmol), phenylboronic acid (331 mg, 2.71 mmol), Pd(PPh3)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 washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1) to give an oily compound 148-3 (622 mg, approximately 78% yield).

[1259] Synthesis of 4-bromo-3-fluorobiphenyl-2-amine (148-4):

[1260]

[1261] A mixture of 148-3 (622 mg, 2.10 mmol) and zinc powder (825 mg, 12.61 mmol) in isopropanol (15 mL) and acetic acid (1.5 mL) was stirred overnight at room temperature. The reaction mixture was then filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1) to give an oily compound 148-4 (622 mg, approximately 93% yield). MS calculated value: 265.0; MS measured value: 266.2 [M+H] + .

[1262] Synthesis of N-(4-bromo-3-fluorobiphenyl-2-yl)-2-chloroacetamide (148-5):

[1263]

[1264] 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, washed with brine, dried over sodium sulfate, and concentrated to give 148-5 (428 mg, approximately 71% yield) in solid form. MS calculated value: 341.0; MS measured value: 342.2 [M+H] + .

[1265] Synthesis of N-(4-bromo-3-fluorobiphenyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (148-6):

[1266]

[1267] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (EtOAc / petroleum ether = 1 / 5, 1 / 1) to give 148-6 in oil (386 mg, approximately 82% yield). MS calculated value: 374.0; MS measured value: 375.0 [M+H] + .

[1268] Synthesis of N-(3-fluoro-4-(phenylamino)biphenyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (148-7):

[1269]

[1270] 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 overnight under N2, then filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, 1 / 1) to give an oily 148-7. MS calculated value: 387.2; MS measured value: 388.3 [M+H] + .

[1271] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-fluoro-N 4 Synthesis of 2,4-phenylbiphenyl-2,4-diamine (SS20308-0148-01):

[1272]

[1273] A borane-dimethyl sulfide complex (10 mL, 2 M in THF) was slowly added to a solution of 148-7 (44 mg, 0.26 mmol) in 5 mL of THF. The reaction mixture was stirred overnight at room temperature, then quenched with MeOH and acidified to pH ~1 with 1 N HCl. The reaction mixture was then heated to 60 °C and stirred overnight. After cooling to room temperature, the reaction mixture was alkalized 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) in solid form. MS calculated value: 373.2; MS measured value: 374.3 [M+H] + .

[1274] 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).

[1275] Example 59

[1276]

[1277] Example route of Example 59: Synthesis of methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)acetate (149-2):

[1278]

[1279] 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-dioxane), 368 mg, 1.45 mmol, Pd(dppf)Cl2 (48 mg, 0.07 mmol), and AcOK (259 mg, 2.64 mmol) in 1,4-dioxane (5 mL) was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature 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, approximately 49% yield) in solid form. MS calculated value: 276.2; MS measured value: 277.4 [M+H] + .

[1280] Synthesis of methyl 2-(2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)acetate (149-3):

[1281]

[1282] 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 overnight under reflux. 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 remaining crude product was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to give 149-3 (60 mg, approximately 64% yield) in solid form. MS calculated value: 427.2; MS measured value: 428.3 [M+H] +

[1283] Synthesis of 2-(2'-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4'-(phenylamino)biphenyl-2-yl)ethanol (SS20308-0149-01):

[1284]

[1285] A mixture of 149-3 (60 mg, 0.14 mmol) and LiAlH4 (27 mg, 0.7 mmol) in THF (3 mL) was stirred overnight at room temperature. After the reaction was complete, the crude reaction mixture was poured onto wet Na2SO4(s), filtered to remove insoluble matter, and washed with Et2O. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give SS20308-0149-01 in solid form (7.2 mg, approximately 13% yield). MS calculated value: 399.2; MS measured value: 400.3 [M+H] + .

[1286] 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).

[1287] Example 60

[1288]

[1289] Example route of Implementation Example 60:

[1290]

[1291] Synthesis of 5-bromobiphenyl-2-amine (151-2):

[1292]

[1293] A mixture of 151-1 (6.40 g, 37.82 mmol) and NBS (6.70 g, 37.82 mmol) in DMF (10 mL) was stirred overnight at 0 °C. 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 an oily 151-2 (5.7 g, approximately 57.6% yield). MS calculated value: 247.0; MS measured value: 248.2 [M+H] + .

[1294] Synthesis of N-(5-bromobiphenyl-2-yl)-3-chloropropionamide (151-3):

[1295]

[1296] 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), 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) in solid form. MS calculated value: 337.0; MS measured value: 3380.2 [M+H] + .

[1297] Synthesis of N-(5-bromobiphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (151-4):

[1298]

[1299] A mixture of 151-3 (5.00 g, 14.77 mmol), 1H-1,2,4-triazole (1.22 g, 17.72 mmol), 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 (3 x 30 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 in solid form (3.3 g, approximately 60% yield). MS calculated value: 370.0; MS measured value: 372.3 [M+H] + .

[1300] Synthesis of N-(5-(phenylamino)biphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (151-5):

[1301]

[1302] 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 overnight at 110 °C under a nitrogen atmosphere. 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 an oily 151-5 (810 mg, approximately 60% yield). MS calculated value: 383.2; MS measured value: 384.3 [M+H] + .

[1303] N 2 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 5 Synthesis of 2,5-phenylbiphenyl-2,5-diamine (SS20308-0151-01):

[1304]

[1305] A mixture of 151-5 (50 mg, 0.13 mmol) and BMS (2.5 M, in THF) (5 mL) was stirred overnight at room temperature. 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 preparative TLC (petroleum ether / EtOAc = 1 / 2) to give SS20308-0151-01 (30 mg, approximately 62% yield) in solid form. MS calculated value: 369.2; MS measured value: 370.3 [M+H] + .

[1306] 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).

[1307] Example 61

[1308]

[1309] Example route of Implementation Example 61:

[1310]

[1311] Synthesis of tert-butyl 2-(1H-1,2,4-triazol-1-yl)ethylcarbamate (153-2):

[1312]

[1313] To a mixture of 153-1 (2.2 g, 9.82 mmol) and K2CO3 (2.7 g, 19.63 mmol) in acetone (30 mL), 1H-1,2,4-triazole (1.0 g, 14.73 mmol) was added, and the mixture was stirred overnight at 60 °C. The reaction mixture was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to give an oily 153-2 (2.0 g, approximately 96% yield). MS calculated value: 212.1; MS measured value: 213.2 [M+H] + .

[1314] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-2-bromo-6-nitroaniline (153-4):

[1315]

[1316] To a solution of 153-2 (424 mg, 2.00 mmol) in 10 mL of THF, HCl (6N, 5 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness several times, then dissolved in 10 mL of DMSO, and 1-bromo-2-fluoro-3-nitrobenzene (440 mg, 2.00 mmol) and K₂CO₃ (552 mg, 4.00 mmol) were added on top. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (40 mL) and 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 an oily 153-4 (474 ​​mg, approximately 76% yield in two steps). MS calculated value: 311.0; MS measured value: 312.0 [M+H] + .

[1317] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-nitrobiphenyl-2-amine (153-5):

[1318]

[1319] To a solution of 153-4 (443 mg, 1.42 mmol) in DME / water (10 / 1, 15 mL), phenylboronic acid (260 mg, 2.13 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), and K2CO3 (392 mg, 2.84 mmol) were added, and the reaction mixture was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with water (30 mL) and 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, approximately 91% yield) in solid form. MS calculated value: 309.1; MS measured value: 310.0 [M+H] + .

[1320] N 2 Synthesis of 2-(1H-1,2,4-triazol-1-yl)ethyl)biphenyl-2,3-diamine (153-6):

[1321]

[1322] Pd / C (35 mg, 10%) was added to a 5 mL solution of 153-5 (350 mg, 1.13 mmol) in MeOH, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth. The filtrate was purified by preparative TLC (EtOAc) to give 153-6 (100 mg, approximately 32% yield) in solid form. MS calculated value: 279.1; MS measured value: 280.1 [M+H] + .

[1323] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 3 Synthesis of 2,3-phenylbiphenyl-2,3-diamine (SS20308-0153-01):

[1324]

[1325] To a solution of 10 mL of toluene (100 mg, 0.36 mmol) of 153-6, 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) were added, and the reaction mixture was stirred overnight at 110 °C. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with water (20 mL) 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 (petroleum ether / EtOAc = 1 / 1) to give an oily SS20308-0153-01 (31 mg, approximately 24% yield). MS calculated value: 355.2; MS measured value: 356.0 [M+H] + .

[1326] 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).

[1327] Example 62

[1328]

[1329] Example route of Implementation Example 62:

[1330] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2-(2-chloro-4-fluorophenyl)biphenyl-2,5-diamine (SS20308-0165-01):

[1331]

[1332] A solution of 0061-3 (1.0 g, 2.91 mmol), 2-chloro-4-fluoroaniline (637 mg, 4.38 mmol), t-Bu3PHBF4 (169 mg, 0.583 mmol), Pd(OAc)2 (66 mg, 0.294 mmol), and t-BuONa (840 mg, 8.74 mmol) was suspended in toluene (20 mL). The reaction mixture was heated under reflux at N2 overnight, then filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, 3 / 1, 1 / 1) to give an oily SS20308-0165-01 (440 mg, approximately 37% yield). MS calculated value: 407.1; MS measured value: 408.0 [M+H] + .

[1333] 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).

[1334] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1H-indol-7-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (166-1):

[1335]

[1336] A mixture of 143-5 (50 mg, 0.14 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 overnight under reflux. 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) in solid form. MS calculated value: 394.2; MS measured value: 395.2 [M+H] + .

[1337] Example 63

[1338]

[1339] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(indoline-7-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (SS20308-0166-01):

[1340]

[1341] 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 complete, 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 under vacuum. The residue was purified by preparative HPLC to give SS20308-0166-01 in solid form (10.3 mg, approximately 20% yield). MS calculated value: 396.5; MS measured value: 397.3 [M+H] + .

[1342] 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).

[1343] Example 64

[1344]

[1345] Synthesis of 2-(3-(dimethylamino)propyl)-3-(1H-indol-7-yl)-N-phenylaniline (SS20308-0171-01) - The synthesis of SS20308-0172-01 is described below:

[1346]

[1347] A mixture of SS20308-0172-01 (50 mg, 0.13 mmol) and DDQ (59 mg, 0.58 mmol) in dioxane (2 mL) was stirred overnight at room temperature. 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. The remaining crude product was purified by preparative HPLC to give SS20308-0171-01 (2.5 mg, approximately 5% yield) in solid form. MS calculated value: 369.5; MS measured value: 370.3 [M+H] + .

[1348] 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).

[1349] Example 65

[1350]

[1351] Example routes for Implementation 65 (SS20308-0172-01 and SS20308-0171-01):

[1352]

[1353] Synthesis of (E)-methyl 3-(2-bromo-6-nitrophenyl)acrylate (171-2):

[1354]

[1355] A mixture of 171-1 (1.0 g, 4.4 mmol) and methyl triphenylphosphazene acetate (2.2 g, 6.6 mmol) in THF (50 mL) was stirred overnight at room temperature. 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, approximately 95% yield) in solid form. MS calculated value: 285.0; MS measured value: 303.0 [M+18] + .

[1356] Synthesis of (E)-3-(2-bromo-6-nitrophenyl)acrylic acid (171-3):

[1357]

[1358] 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 overnight at room temperature. 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 in solid form (500 mg, approximately 88% yield). MS calculated value: 271.0; MS measured value: 289.0 [M+18] + .

[1359] Synthesis of (E)-3-(2-bromo-6-nitrophenyl)-N,N-dimethylacrylamide (171-4):

[1360]

[1361] 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 overnight at room temperature. 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 give 171-4 (500 mg, approximately 90% yield) in solid form. MS calculated value: 298.0; MS measured value: 299.0 [M+H] + .

[1362] Synthesis of (E)-3-(2-(1H-indol-7-yl)-6-nitrophenyl)-N,N-dimethylacrylamide (171-5):

[1363]

[1364] A mixture of 171-4 (500 mg, 0.14 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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 overnight under reflux. 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 171-5 (450 mg, approximately 48% yield) in solid form. MS calculated value: 335.1; MS measured value: 336.4 [M+H] + .

[1365] Synthesis of 3-(2-amino-6-(1H-indol-7-yl)phenyl)-N,N-dimethylpropionamide (171-5):

[1366]

[1367] A mixture of 171-4 (600 mg, 1.4 mmol) and Pd / C (10%; 100 mg) in MeOH (10 mL) was stirred overnight at room temperature and H2 (g). The reaction mixture was filtered and purified by column chromatography (EtOAc) to give 171-5 in solid form (450 mg, approximately 90% yield). MS calculated value: 307.2; MS measured value: 308.4 [M+H] + .

[1368] Synthesis of 3-(2-(1H-indol-7-yl)-6-(phenylamino)phenyl)-N,N-dimethylpropionamide (171-6)

[1369]

[1370] 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 overnight under reflux. 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) in solid form. MS calculated value: 383.2; MS measured value: 384.3 [M+H] + .

[1371] Synthesis of 2-(3-(dimethylamino)propyl)-3-(indoline-7-yl)-N-phenylaniline (SS20308-0172-01):

[1372]

[1373] A mixture of 171-6 (50 mg, 0.13 mmol), BH3 (0.5 mL, 1 M in THF), and THF (2 mL) was stirred overnight at room temperature. Then, HCl (1 N, 2 mL) and MeOH (2 mL) were added, and the final mixture was stirred overnight at room temperature. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL 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) in solid form. MS calculated value: 371.5; MS measured value: 372.4 [M+H] + .

[1374] 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).

[1375] Example 66

[1376]

[1377] Example routes for Implementation 66 (SS20308-0173-01 and SS20308-0219-01):

[1378]

[1379] Synthesis of 5-chloro-2-phenylpyridine-3-amine (173-2):

[1380]

[1381] A mixture of 173-1 (500 mg, 2.42 mmol), phenylboronic acid (590 mg, 4.84 mmol), Pd(PPh3)4 (277 mg, 0.24 mmol), and K2CO3 (668 mg, 4.84 mmol) in DME (10 mL) and water (1 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc = 10 / 1) to give an oily 173-2 (440 mg, approximately 91% yield). MS calculated value: 204.0; MS measured value: 205.1 [M+H] + .

[1382] Synthesis of 5-chloro-N-(2-chloroethyl)-2-phenylpyridine-3-amine (173-3):

[1383]

[1384] To a solution of 173-2 (450 mg, 2.20 mmol) in 10 mL of MeOH, 2-chloroacetaldehyde (432 mg, 4.40 mmol, in water, 40% concentration), AcOH (264 mg, 4.40 mmol), and NaBH3CN (275 mg, 4.40 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and alkalized with 1N NaOH until 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 in solid form (100 mg, approximately 17% yield). MS calculated value: 266.0; MS measured value: 237.1 [M+H] + .

[1385] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-2-phenylpyridine-3-amine (173-4):

[1386]

[1387] 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 overnight at 80 °C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 173-4 (77 mg, approximately 68% yield) in solid form. MS calculated value: 299.1; MS measured value: 300.2 [M+H] + .

[1388] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 5 Synthesis of 2-diphenylpyridine-3,5-diamine (SS20308-0173-01):

[1389]

[1390] 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 overnight at 110 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1 / 3) and preparative HPLC to give SS20308-0173-01 (13 mg, approximately 54% yield) in solid form. MS calculated value: 356.2; MS measured value: 357.3 [M+H] + .

[1391] 1 H 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).

[1392] Example 67

[1393]

[1394] Example route of Implementation Example 67:

[1395]

[1396] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-bromo-6-chloropyridin-2-amine (175-2):

[1397]

[1398] 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 overnight at room temperature. 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 175-2 (1.0 g, approximately 71% yield) in solid form. MS calculated value: 301.0; MS measured value: 302.0 [M+H] + .

[1399] Synthesis of N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-6-chloro-3-phenylpyridin-2-amine (175-3):

[1400]

[1401] 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 for 4 hours under a nitrogen atmosphere. The resulting mixture was 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 175-3 in solid form (250 mg, approximately 84% yield). MS calculated value: 299.1; MS measured value: 300.2 [M+H] + .

[1402] N 2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 6 Synthesis of 3-diphenylpyridine-2,6-diamine (SS20308-0175-01):

[1403]

[1404] 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 for 3 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and purified by preparative HPLC to give SS₂0308-0175-01 (44 mg, approximately 72% yield) in solid form. MS calculated value: 356.2; MS measured value: 357.3 [M+H] + .

[1405] 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).

[1406] Example 68

[1407]

[1408] Example route of Implementation Example 68:

[1409]

[1410] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1-methyl-1H-imidazol-5-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (SS20308-177-01):

[1411]

[1412] A mixture of 143-5 (70 mg, 0.20 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-imidazolium (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 overnight under reflux. 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) in solid form. MS calculated value: 359.4; MS measured value: 360.3 [M+H] + .

[1413] 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).

[1414] Example 69

[1415]

[1416] Example route of Example 69:

[1417]

[1418] Synthesis of 4-bromo-3-nitro-N-phenylaniline (178-2):

[1419]

[1420] 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 in solid form (500 mg, approximately 37% yield).

[1421] 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).

[1422] Synthesis of 2-nitro-N-phenylbiphenyl-4-amine (178-3):

[1423]

[1424] A mixture of 178-2 (500 mg, 1.71 mmol), phenylboronic acid (250 mg, 2.05 mmol), Pd(PPh3)4 (196 mg, 0.17 mmol), and Na2CO3 (544 mg, 5.13 mmol) in DME / H2O (5 mL, 5 / 1) was stirred overnight at 90 °C under a nitrogen atmosphere. The resulting mixture was 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 = 2 / 1) to give 178-3 (400 mg, approximately 81% yield) in solid form. MS calculated value: 290.1; MS measured value: 291.1 [M+H] + .

[1425] N 4 Synthesis of 2,4-phenylbiphenyl-2,4-diamine (178-4):

[1426]

[1427] 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 for 1 hour at room temperature and H2 (g) (1 atm). The reaction mixture was then cooled to room temperature and purified by preparative TLC to give 178-4 in solid form (320 mg, approximately 89% yield). MS calculated value: 260.1; MS measured value: 261.4 [M+H] + .

[1428] Synthesis of 3-chloro-N-(4-(phenylamino)biphenyl-2-yl)propionamide (178-5):

[1429]

[1430] 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 (3 x 30 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) in solid form. MS calculated value: 350.1; MS measured value: 351.3 [M+H] + .

[1431] Synthesis of N-(4-(phenylamino)biphenyl-2-yl)-3-(1H-1,2,4-triazol-1-yl)propionamide (178-6):

[1432]

[1433] 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 overnight at 80 °C. 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 178-6 (300 mg, 78% yield) in solid form. MS calculated value: 383.2; MS measured value: 384.3 [M+H] + .

[1434] N 2 -(3-(1H-1,2,4-triazol-1-yl)propyl)-N 4Synthesis of 2,4-phenylbiphenyl-2,4-diamine (SS20308-0178-01):

[1435]

[1436] A mixture of 178-6 (50 mg, 0.13 mmol) and borane-methyl sulfide (2.5 M, in THF) (5 mL) was stirred overnight at room temperature. 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 preparative MPLC (petroleum ether / EtOAc = 1 / 2) to give SS20308-0178-01 (28 mg, approximately 59% yield) in solid form. MS calculated value: 369.2; MS measured value: 370.0 [M+H] + .

[1437] 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).

[1438] Example 70

[1439]

[1440] Example route of Implementation Example 70:

[1441]

[1442] N 2 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4'-chloro-N 4 Synthesis of 2,4-(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0181-01):

[1443]

[1444] A mixture of 147-5 (50 mg, 0.13 mmol), 4-fluoroaniline (22 mg, 0.20 mmol), Pd2dba3 (26 mg, 0.29 mmol), Xantphos (34 mg, 0.058 mmol), and Cs2CO3 (189 mg, 0.58 mmol) in toluene (2 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC to give SS20308-0181-01 in solid form (14.3 mg, approximately 13% yield). MS calculated value: 407.1; MS measured value: 408.2 [M+H] + .

[1445] 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).

[1446] Example 71

[1447]

[1448] Example route of Implementation Example 71:

[1449]

[1450] Synthesis of 4-bromo-N-(4-fluorophenyl)-3-nitroaniline (184-2):

[1451]

[1452] 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 complete, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (2 x 50 mL), dried over MgSO4, concentrated under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 184-2 in solid form (650 mg, approximately 91% yield). MS calculated value: 310.0; MS measured value: 311.0 [M+H] + .

[1453] Synthesis of N-(4-fluorophenyl)-2-nitrobiphenyl-4-amine (184-3):

[1454]

[1455] 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), and K2CO3 (578 mg, 4.18 mmol) in DME (20 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. After the reaction was complete, 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 under vacuum, and purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give 184-3 in solid form (450 mg, approximately 70% yield). MS calculated value: 308.1; MS measured value: 309.0 [M+H] + .

[1456] N 4 Synthesis of 184-(4-fluorophenyl)biphenyl-2,4-diamine (184-4):

[1457]

[1458] 10% Pd / C (6.09 g, 93.13 mmol) was added to a 50 mL solution of EtOAc (3.00 g, 9.31 mmol). The mixture was stirred overnight at room temperature and H2 (g) (1 atm). After the reaction was complete, insoluble matter was removed by filtration, and the filtrate was concentrated under vacuum. The crude product was used for the next step without further purification. MS calculated value: 278.1; MS measured value: 279.2 [M+H] + .

[1459] N 2 -((3-(bromomethyl)oxetane-3-yl)methyl)-N 4 Synthesis of 184-(4-fluorophenyl)biphenyl-2,4-diamine (184-7):

[1460]

[1461] Add Dess-Martin periodinane (937 mg, 2.21 mmol) to a solution of 184-5 (200 mg, 1.10 mmol) in 10 mL of CH2Cl2. Stir the mixture overnight at room temperature. After the reaction is complete, filter to remove insoluble matter, add 184-4 (307 mg, 1.10 mmol) and NaBH3CN (139 mg, 2.21 mmol) to the filtrate, and stir the mixture overnight at room temperature. After the reaction is complete, pour the reaction mixture into water (50 mL) and extract with EtOAc (50 mL x 3). Wash the organic layer with brine (2 x 50 mL), dry with MgSO4, and concentrate under vacuum. The crude product obtained is used for the next step without further purification.

[1462] N 2 -((3-((dimethylamino)methyl)oxetane-3-yl)methyl)-N 4 Synthesis of 2,4-(4-fluorophenyl)biphenyl-2,4-diamine (SS20308-0184-01):

[1463]

[1464] 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 overnight at 80 °C under a nitrogen atmosphere. After the reaction was complete, 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, and concentrated under vacuum. The crude product was purified by preparative HPLC to give SS₂0308-0184-01 (6 mg, approximately 13% yield) in solid form. MS calculated value: 405.2; MS measured value: 406.0 [M+H] + .

[1465] 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).

[1466] Example 72

[1467]

[1468] Example routes for Implementation Examples 72 (SS20308-0189-01 and SS20308-0223-01):

[1469]

[1470] A mixture of 143-5 (50 mg, 0.14 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 overnight under reflux. 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. The remaining crude product was purified by preparative HPLC to obtain SS20308-189-01 (7.04 mg, approximately 16% yield) in solid form. MS calculated value: 345.4; MS measured value: 346.3 [M+H] + ,

[1471] 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),

[1472] And in solid form SS20308-223-01 (8.59 mg, approximately 22% yield, MS calculated value: 279.3; MS measured value: 280.0 [M+H]). + ,

[1473] 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).

[1474] Examples 73 to 78 all follow the same initial synthesis steps as shown below, and will not be repeated for each individual example:

[1475]

[1476] Synthesis of 4-bromo-3-nitro-N-phenylaniline (143-2):

[1477]

[1478] 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 complete, 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 over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography to give 143-2 (1.0 g, approximately 74% yield) in solid form.

[1479] 4-Bromo-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (143-3):

[1480]

[1481] A mixture of 143-2 (1.0 g, 3.4 mmol), Zn powder (1.1 g, 17 mmol), and HOAc (1.0 g, 17 mmol) in EtOH (50 mL) was stirred overnight at room temperature. After the reaction was complete, 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 over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give 143-3 in solid form (800 mg, approximately 90% yield). MS result: 263.2 [M+H] + .

[1482] 4-Bromo-N 3 -(2-Chloroethyl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (143-4):

[1483]

[1484] 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 overnight at 40 °C. After the reaction was complete, 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 under vacuum. The residue was purified by reversed-phase column chromatography (EtOAc) to give 143-4 in solid form (600 mg, approximately 60% yield). MS calculated value: 324.0; MS measured value: 325.0 [M+H] + .

[1485] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-bromo-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (143-5):

[1486]

[1487] 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 overnight at 80 °C. After the reaction was complete, 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 under vacuum. The residue was purified by reversed-phase column chromatography (DCM / EtOH = 20 / 1) to give 143-5 in solid form (450 mg, approximately 68% yield). MS calculated value: 357.1; MS measured value: 358.3 [M+H] + .

[1488] Example 73

[1489]

[1490] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (SS20308-190-01):

[1491]

[1492] A mixture of 143-5 (50 mg, 0.14 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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 overnight under reflux. 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) in solid form. MS calculated value: 359.4; MS measured value: 360.3 [M+H] + .

[1493] 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).

[1494] Example 74

[1495]

[1496] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(1-methyl-1H-pyrazole-4-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (SS20308-191-01):

[1497]

[1498] A mixture of 143-5 (50 mg, 0.14 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 overnight under reflux. 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) in solid form. MS calculated value: 359.4; MS measured value: 360.3 [M+H] + .

[1499] 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).

[1500] Example 75

[1501]

[1502] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(3,5-dimethylisoxazol-4-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (SS20308-192-01):

[1503]

[1504] A mixture of 143-5 (50 mg, 0.14 mmol), 3,5-dimethylisoxazole-4-boric acid (24 mg, 0.17 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 overnight under reflux. 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) in solid form. MS calculated value: 374.4; MS measured value: 375.3 [M+H] + .

[1505] 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).

[1506] Example 76

[1507]

[1508] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 1 Synthesis of phenyl-4-(thiophen-2-yl)phenyl-1,3-diamine (SS20308-193-01):

[1509]

[1510] 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), X-Phos (6 mg, 0.014 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in toluene / water (1 / 0.1 mL) was stirred overnight under reflux. 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) in solid form. MS calculated value: 361.5; MS measured value: 362.1 [M+H] + .

[1511] 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).

[1512] Example 77

[1513]

[1514] Synthesis of 5-(2-(2-(1H-1,2,4-triazol-1-yl)ethylamino)-4-(phenylamino)phenyl)thiophene-2-nitrile (SS20308-194-01):

[1515]

[1516] A mixture of 143-5 (100 mg, 0.28 mmol), (5-cyanothiophene-2-yl)boric 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 overnight at 100 °C. 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) in solid form. MS calculated value: 386.5; MS measured value: 387.3 [M+H] + .

[1517] 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).

[1518] Example 78

[1519]

[1520] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(2,5-dihydrofuran-2-yl)-N 1 Synthesis of 1,3-phenylphenyl-1,3-diamine (195-01-1):

[1521]

[1522] 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 overnight at 110 °C. 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 for the next step without further purification. MS calculated value: 347.2; MS measured value: 348.4 [M+H] + .

[1523] N 3 -(2-(1H-1,2,4-triazol-1-yl)ethyl)-N 1 Synthesis of phenyl-4-(tetrahydrofuran-2-yl)phenyl-1,3-diamine (SS20308-0195-01):

[1524]

[1525] A mixture of 195-01-1 (crude product, 0.28 mmol) and Pd / C (10%, 100 mg) in EtOAc (2 mL) was stirred overnight at room temperature and H2. After the reaction was complete, insoluble matter was removed by filtration. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give SS20308-0195-01 (5.74 mg, approximately 6% yield) in solid form. MS calculated value: 349.4; MS measured value: 350.2 [M+H] + .

[1526] 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).

[1527] Example 79

[1528]

[1529] Example route of Implementation Example 79:

[1530]

[1531] Synthesis of methyl 2-(2-nitro-5-(phenylamino)phenyl)acetate (197-2):

[1532]

[1533] 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 overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 197-2 (1.20 g, 57% yield) as a yellow oil. MS calculated value: 286.1; MS measured value: 287.4.

[1534] Synthesis of 2-(2-nitro-5-(phenylamino)phenyl)acetic acid (197-3):

[1535]

[1536] A mixture of 197-2 (500 mg, 1.75 mmol) and LiOH (147 mg, 3.50 mmol) in THF (30 mL) was stirred overnight at room temperature. The reaction mixture was then alkalized with a saturated aqueous solution of NaHCO3 until 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 an oily 197-3 (400 mg, approximately 84% yield). MS calculated value: 272.1; MS measured value: 273.4 [M+H] + .

[1537] Synthesis of 2-(2-nitro-5-(phenylamino)phenyl)acetic acid (197-4):

[1538]

[1539] 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 overnight at room temperature. The reaction mixture was then concentrated and poured into water (100 mL). The resulting mixture was extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give an oily 197-4 (405 mg, approximately 92% yield). MS calculated value: 299.1; MS measured value: 300.1 [M+H] + .

[1540] Synthesis of 3-(2-(dimethylamino)ethyl)-4-nitro-N-phenylaniline (197-5)

[1541]

[1542] 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 overnight at room temperature. The reaction mixture was then concentrated and added dropwise to MeOH. The resulting mixture was acidified with 1N HCl until pH 1 was reached and stirred overnight at 80 °C. 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 an oily 197-5 (340 mg, approximately 88% yield). MS calculated value: 285.1; MS measured value: 286.2 [M+H] + .

[1543] 3-(2-(dimethylamino)ethyl)-N1 Synthesis of 1,4-phenylphenyl-1,4-diamine (197-6):

[1544]

[1545] A mixture of 197-5 (340 mg, 1.19 mmol) and 10% Pd / C (34 mg) in MeOH (5 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated to give an oily 197-6 (280 mg, approximately 92% yield). MS calculated value: 255.2; MS measured value: 256.2 [M+H] + .

[1546] N 1 -(2-Chlorophenyl)-2-(2-(dimethylamino)ethyl)-N 4 Synthesis of 1,4-phenylphenyl-1,4-diamine (SS20308-0197-01):

[1547]

[1548] 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 overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 2) and preparative HPLC to give an oily SS20308-0197-01 (6 mg, 3% yield). MS calculated value: 365.2; MS measured value: 366.3 [M+H] + .

[1549] 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).

[1550] Example 80

[1551]

[1552] Example route of Implementation Example 80:

[1553]

[1554] Synthesis of 4-(3-(dimethylamino)prop-1-ynyl)-2-nitroaniline (198-2):

[1555]

[1556] 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 at N2 overnight, then filtered and washed 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 in solid form (0.83 g, approximately 92% yield). MS calculated value: 219.1; MS measured value: 219.6 [M+H] + .

[1557] Synthesis of 4-(3-(dimethylamino)propyl)phenyl-1,2-diamine (198-3):

[1558]

[1559] 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 and with H2 (g). The reaction mixture was then filtered through diatomaceous earth. The filtrate was concentrated to give a brown oily 198-3 (700 mg, 96% yield). MS calculated value: 193.2; MS measured value: 194.4 [M+H] + .

[1560] N 1 N 2 Synthesis of bis(2-chlorophenyl)-4-(3-(dimethylamino)propyl)phenyl-1,2-diamine (SS20308-0198-01):

[1561]

[1562] 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 ...

Claims

1. A compound having formula I and a pharmaceutically acceptable salt thereof: in: n is 0-2, such that when n=0, there is a direct bond between B and NH groups and no R3, while when n=1 or 2, the carbons in these bonds are optionally replaced by an 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 by 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, 5-6 membered aryl, or 5-6 membered cyclohexyl is unsubstituted or independently substituted by a maximum of 3 R2 groups. X1, X2, X3, X4, X5, and X6 each independently include: 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 group, -(CH2)3NR x R y -NH(CH2)2R x R y -NHCH2CR x R y R z 5-6 aryl, 5-10 heterocyclic, 5-10 heteroaryl, or 5-10 heterocyclic aryl One to three of the R1 bases are optionally further modified by R a and / or R b replace, The two R1 groups optionally combine to form a 5-6 membered heteroaryl group, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl], wherein the 5-6 membered heteroaryl group, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl] is optionally further surrounded by 1-3 R1 groups. a Base substitution; Each R2 independently includes: halogen, C 1-2 Methoxy group, or -C(O)OR x ; The two R2 groups on adjacent atoms optionally form a 5-6 aryl group, wherein the 5-6 aryl group is optionally further bonded by 1-3 R groups. a Base substitution; R3 includes: C 1-3 Halogenated alkyl groups, or oxoalkyl groups; 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 Halogenated alkyl, or -NR a R b , where R x R y or R z Any two of them may optionally be combined to form a 4-6 membered heterocycle, a 5-6 membered aryl group, wherein R x R y and R z Each can choose to be further R a and R b replace; R a and R b Each of these elements independently includes: H, halogen, cyano, oxo, and C. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic. Where R a and R b Each of them may be further replaced by R′ at its own discretion; R′ is C 1-3 Alkyl, C 1-3 Halogenated alkyl, or C 5-6 Metaheteroaryl.

2. The compound of claim 1, wherein, Each R1 is selected independently from:

3. The compound of claim 1, wherein, Each R2 is selected independently from: F, Cl, and 4. The compound of claim 1, wherein, The compound is selected from: And its pharmaceutically acceptable salts.

5. A compound having formula II and a pharmaceutically acceptable salt thereof: in: 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 group, or a 6-membered cyclohexyl group, wherein the 6-membered heterocycle, 6-membered aryl group, or 6-membered cyclohexyl group is unsubstituted or independently substituted by a maximum of 2 R2 groups. X1, X2, X3, and X4 each 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 aryl, 5-10 heterocyclic, 5-10 heteroaryl, or 5-10 heterocyclic aryl The two R1 groups optionally combine to form a 5-6 membered heteroaryl group, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl], wherein the 5-6 membered heteroaryl group, [5-6 membered heterocycle, 5-6 membered cycloalkyl, 5-6 membered aryl] is optionally further surrounded by 1-3 R1 groups. a Base substitution; One to three R1 bases are each optionally and independently further modified by R... a or R b replace; Each R2 independently includes: halogen, C 1-2 Methoxy group, or -C(O)OR x ; 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 Halogenated alkyl, or -NR a R b , Where R x R y or R z The two elements can optionally be combined to form a 4-6 membered heterocycle, a 5-6 membered aryl group, wherein R x R y and R z Each can choose to be further R a and R b replace; R a and R b Each of these elements independently includes: H, halogen, cyano, oxo, and C. 1-3 Alkyl group, -C(O)OR′, C 1-3 Haloalkyl, 5-6 aryl, 5-6 heteroaryl, or 4-6 heterocyclic. Where R a and R b Optionally and independently, it can be further replaced by R′; R′ is C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, or 5-6-membered heteroaryl groups.

6. The compound of claim 5, wherein, Each R1 is selected independently from:

7. The compound of claim 5, wherein each R2 is independently selected from:

8. The compound of claim 5, wherein, The compound is selected from: And its pharmaceutically acceptable salts.

9. A compound having formula IIA and a pharmaceutically acceptable salt thereof: in: B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 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 5-6 aryl, wherein R1 is optionally further converted to R a or R b replace; R2 is H, a halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl, or C 1-3 Halogenated alkoxy groups, R1 and R2 can optionally be combined to form a 5-6 member heterocycle, which can optionally be further divided by R a R b or R a and R b Both can replace each other; R3 is H or a halogen; R4 is a halogen, or C 1-3 alkyl; R x and R y Each is C independently 5-6 Metacyclic rings R a and R b Each is C independently 1-3 Alkyl or C 1-3 Halogenated alkyl groups, Where R a and R b Optionally further replaced by the R′ base; The R′ group is a 5-membered heteroaryl group or a 5-6-membered heterocycle.

10. The compound of claim 9, wherein, R1 is selected from:

11. The compound of claim 9, wherein, Each R2 is selected independently from:

12. The compound of claim 9, wherein, The compound is selected from: And its pharmaceutically acceptable salts.

13. A compound having formula IIB and a pharmaceutically acceptable salt thereof: in: B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; Each X is independently C, N, or O; R1 is H, C 1-3 Alkyl, 5-6 membered heterocyclic, 5-6 membered aryl, 5-6 membered heteroaryl, 5-10 membered cyclic 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 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 cyclic heteroaryl, or -NR x R y ; R′2 is H or a halogen; Each R3 is independently H, halogen, C 1-3 Alkyl group, -O(CH2)2NR x R y -NR x (CH2)2R y -NR x R y , or -(CH2)3NR x R y ; R4 is a halogen; Furthermore, where R1 and R 2a or R 2b Optionally, they are combined to form a 5-6 membered heterocycle, which is then optionally further reacted with R. a and R b One or more substitutions in, and Among them, R1, R 2a R 2b R'2 and R3 are each optionally and independently defined by one or more R's. a replace; R x and R y H and C are independent entities. 1-4 Alkyl, 5-6 aryl, 5-6 heteroaryl, -NR a R b , Where R x and R y Each can choose to form a 4-5 member heterocycle together, and Where R x or R y Optionally and independently further by R a and / or R b replace; R a and R b Each of these groups is independently H, halogen, oxo, cyano, and 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 group.

14. The compound of claim 13, wherein, R1 is selected from:

15. The compound of claim 13, wherein, R 2a and R 2b Each is selected independently from:

16. The compound of claim 13, wherein, Each R3 is independently H.

17. The compound of claim 13, wherein, The compound is selected from: And its pharmaceutically acceptable salts.

18. A compound having formula III and a pharmaceutically acceptable salt thereof: in: n is 1-2; B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; X1, X2, X3, X4, and X5 are each independently C, N, or O; R1 is a halogen, C 1-4 Alkyl, -NR x R y -O(CH2)2NR x R y 6-membered cyclohexyl, 6-membered heterocyclic, 6-membered aryl, 6-membered heteroaryl, or 5-10-membered cycloalkyl. When two R1 groups are present, the two R1 groups may optionally be combined to form a 6-membered heteroaryl group. Each R1 is optionally and independently further divided by one or more R a replace; Each R2 is a halogen or C 1-3 Alkoxy; Each R3 is independently H, oxo, C 1-3 Halogenated alkyl, or hydroxyalkyl, When one or more R3s are hydroxyalkyl, one or more of R3s may optionally form a 4-membered heterocycle together with the C of Formula III; R x and R y H and C are independent entities. 1-3 Alkyl, 6-membered aryl, or 6-membered heteroaryl Where R x and R y Each of them may optionally and independently be further subjected to one or more R a replace; R a It is halogen, oxo, cyano, C 1-3 Haloalkyl, -NR′R′, 5-6 aryl, 5-6 heteroaryl, or 5-6 heterocyclic, and One or more of R a They can be selectively combined to form 4-5 membered heterocycles; R′ is C 1-3 alkyl.

19. The compound of claim 18, wherein, Each R1 is selected independently from:

20. The compound of claim 18, wherein, Each R2 is independently: H, 21. The compound of claim 18, wherein, R3 is: H, oxo, or 22. The compound of claim 18, wherein, The compound is selected from: And its pharmaceutically acceptable salts.

23. A compound having formula IIIA and a pharmaceutically acceptable salt thereof: in: n is 1-2; B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; X1, X2, and X3 are each independently C, N, or O; R1 is C 1-3 alkyl, Or R1 can be optionally divided by one or more R a or R b replace; R2 is H, a halogen, and C. 1-3 Haloalkyl, C 1-4 Alkyl, 5-6 aryl, 5-6 cycloalkyl, 5-6 heterocyclic, 5-10 heteroaryl, 5-10 cycloaryl; R3 is H or a halogen; Each R4 group is independently H, oxo, C. 1-3 Halogenated alkyl, or hydroxyalkyl, When one or more of R4 are hydroxyalkyl, one or more R4 optionally form a 4-membered heterocycle together with C of formula IIIA; R5 is a halogen or a 4-5 membered heterocyclic ring; R1, R2, R4, and R5 are each arbitrarily and independently determined by at most two Rs. a or R b replace; R a and R b Each is independent of the other. 1-3 Alkyl, C 1-3 Haloalkyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl, -N / -NR′R′ Where R a and R b They can be selectively combined to form 4-5 membered heterocycles; Where R a and R b Each can be optionally and independently further replaced by one or more R′ bases; R′ is a halogen or C 1-3 alkyl.

24. The compound of claim 23, wherein, R1 is selected from:

25. The compound of claim 23, wherein, R2 is selected from:

26. The compound of claim 23, wherein, R3 is H or F.

27. The compound of claim 23, wherein, R4 is: H.

28. The compound of claim 23, wherein R5 is 29. The compound of claim 23, wherein, The compound is selected from: And its pharmaceutically acceptable salts.

30. A compound having formula IIIB and a pharmaceutically acceptable salt thereof: in: n is 1-2; B is cyclohexyl, a 6-membered heterocyclic ring, a 6-membered aryl, or a 6-membered heteroaryl; X1, X2, X3, and X4 are each independently C or N; R1 is H, C 1-3 Alkyl groups, or 5-6 aryl groups; Or R1 can be optionally divided by one or more R a or R b replace; R 2a and R 2b Each is C independently 1-4 Alkyl groups, or 5-6-membered heteroaryl groups; R1 and R 2a or R 2b Optionally, they are combined to form a 5-6 aryl or a 5-6 heteroaryl group, which is optionally further reacted with R. a and R b replace; R3 is H, a halogen, or C. 1-3 Alkoxy; Each R4 is independently either H or oxidized; R5 is a halogen or a 4-5 membered heterocyclic ring; R1, R 2a R 2b R3 and R5 are each independently and optionally further modified by R a and R b replace; R a and R b Each is independently H, halogen, oxo, cyano, or C. 1-3 Alkyl, 5-6 membered heteroaryl.

31. The compound of claim 30, wherein, R1 is: H， 32. The compound of claim 30, wherein, R 2a and R 2b Each independently is: H, 33. The compound of claim 30, wherein, R3 is: H or 34. The compound of claim 30, wherein, R4 is: H or oxygen.

35. The compound of claim 30, wherein, Each R5 is independent of:

36. The compound of claim 30, wherein, The compound is selected from: And its pharmaceutically acceptable salts and / or hydrates.

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