SMALL MOLECULE FURIN INHIBITORS FOR TREATING INFECTIOUS DISEASES

Abstract

Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutical composition comprising Formula (I). Further provided herein are methods for inhibiting the replication of a virus (e.g., a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburg virus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumo virus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus (e.g., a henipavims (e.g., Nipah virus), a morbillivims (e.g., measles morbillivirus))) in a subject in need thereof. Also provided herein are methods for treating and/or preventing a disorder due to a microbial toxin (e.g., due to P. aeruginosa exotoxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein. Also provided are pharmaceutical compositions and kits including a compound of Formula (I) for use in the treatment and/or prevention of a viral infection in a subject in need thereof.

##STR00001##

Claims

1. A method of treating a viral infection in a subject in need thereof comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is of the formula: ##STR00499## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

2. A method of inhibiting the replication of a virus in a subject in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), wherein the compound of Formula (I) is of the formula: ##STR00500## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

3. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating and/or preventing a viral infection in a subject in need thereof, wherein the compound of Formula (I) is of the formula: ##STR00501## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

4. Use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and/or prevention of a viral infection in a subject in need thereof, wherein the compound of Formula (I) is of the formula: ##STR00502## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

5. A pharmaceutical composition comprising a compound of Formula (I), for use in the methods or uses of any one of the preceding claims, wherein the compound of Formula (I) is of the formula: ##STR00503## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

6. The method or use of any one of claims 1 to 5, wherein the virus is a togaviridae family virus.

7. The method or use of claim 6, wherein the togaviridae family virus is an alphavirus.

8. The method or use of claim 7, wherein the alphavirus is Chikungunya virus, Eastern equine encephalitis virus, Mayaro virus, Onyong-nyong virus, Ross River virus, Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, or Western equine encephalitis virus.

9. The method or use of any one of claims 6 to 8, wherein the virus is Chikungunya virus.

10. The method or use of any one of claims 1 to 5, wherein the virus is a flavivirus.

11. The method or use of any one of claim 10, wherein the virus is dengue virus.

12. The method or use of any one of claim 10, wherein the virus is Usutu virus.

13. The method or use of any one of claims 1 to 5, wherein the virus is a filoviradae family virus.

14. The method or use of claim 13, wherein the filoviradae family virus is a Marburgvirus.

15. The method or use of claim 14, wherein the virus is Marburg virus.

16. The method or use of any one of claims 1 to 5, wherein the virus is human respiratory syncytial virus.

17. The method or use of any one of claims 1 to 5, wherein the virus is an orthoparamyxovirinae virus.

18. The method or use of any one of claims 1 to 5, or 17 wherein the virus is Measles morbillivirus.

19. The method or use of any one of claims 1 to 5, or 17 wherein the virus is Nipah virus.

20. A method of treating and/or preventing a disorder due to a microbial toxin in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the compound of Formula (I) is of the formula: ##STR00504## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

21. A method of preventing the activation of a toxin in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the compound of Formula (I) is of the formula: ##STR00505## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

22. A compound of Formula (I) for use in treating and/or preventing a disorder due to a microbial toxin in a subject in need thereof, wherein the compound of Formula (I) is of the formula: ##STR00506## A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═; X is —O— or —N(R.sup.8)—; R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7; each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl; R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl; optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9; each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy; each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9); each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and n is 1, 2, 3, or 4.

23. The method or use of any one of claims 20 to 22, wherein the toxin is P. aeruginosa toxin A.

24. The method or use of any one of claims 20 to 22 wherein the toxin is Clostridium septicum alpha-toxin.

25. The method or use of any one of claims 20 to 22 wherein the toxin is diphtheria toxin.

26. The method or use of any one of claims 20 to 22 wherein the toxin is a shiga toxin.

27. The method or use of any one of claims 1 to 26, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, is of the formula: ##STR00507## ##STR00508##

28. The method or use of claim 27, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, is of the Formula (I-4): ##STR00509##

29. The method or use of claim 27, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, is of the Formula (I-7): ##STR00510##

30. The method or use of any one of claims 1 to 29, wherein R.sup.3 is halogen.

31. The method or use of any one of claims 1 to 30, wherein R.sup.3 is —Cl.

32. The method or use of any one of claims 1 to 31, wherein n is 2.

33. The method or use of any one of claims 1 to 32, wherein X is —O—.

34. The method or use of any one of claims 1 to 31, wherein R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered heterocyclic ring, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7.

35. The method or use of any one of claims 1 to 33, wherein R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, or morpholine ring.

36. The method or use of claim 35, wherein R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula: ##STR00511##

37. The method or use of claim 35, wherein R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula: ##STR00512##

38. The method or use of any one of claims 1 to 37, wherein R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered heterocyclic ring, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9.

39. The method or use of any one of claims 1 to 38, wherein R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, or morpholine ring.

40. The method or use of any one of claims 1 to 39, wherein R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a heterocyclic ring of the formula: ##STR00513##

41. The method or use of any one of claims 1 to 40, wherein the compound, or pharmaceutically acceptable salt thereof, is: 2-(4-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperazin-1-yl)-N-methylacetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)-4-hydroxypiperidin-4-yl)methyl)acetamide; 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)-4-hydroxypiperidin-4-yl)methyl)-3-methylurea; methyl ((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)-4-hydroxypiperidin-4-yl)methyl)carbamate; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethanesulfonic acid; (1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methanesulfonic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)acetic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanamide; N-((1-((2-((6-(4-(2-(1H-tetrazol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-(methylsulfinyl)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(4-(methylsulfonyl)butan-2-yl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfinyl)butyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-(methylsulfonyl)butan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-(methylsulfonyl)butan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-hydroxybutan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(1-hydroxypropan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-hydroxycyclobutyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-((1r,3r)-3-hydroxy-3-methylcyclobutyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-((trans)-3-(methylsulfonamido)cyclobutyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-((cis)-3-(methylsulfonamido)cyclobutyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-((6-(4-(2-aminoethyl)piperazin-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2,4-dihydroxybutyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; (2-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)phosphonic acid; 2-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl carbamate; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-(N-methylmethylsulfonamido)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)-4-oxobutanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-((1-(hydroxymethyl)cyclopropyl)methyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-((1-hydroxycyclopropyl)methyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-N-ethylacetamide; 1-(2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)-N-methylmethanamine; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(sulfamoylmethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((methylsulfonyl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; N-((1-((5-(4-aminophenoxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((5-((5-aminopyrimidin-2-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(methylsulfonamidomethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; N-((1-((5-((5-aminopyridin-2-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((5-((6-amino-5-fluoropyridin-3-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propane-1-sulfonamide; methyl ((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((methylamino)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-fluoro-4-(((methoxycarbonyl)amino)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethanol; 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)acetic acid; 3-(4-(5-((4-((4-(2-(carbamoyloxy)ethyl)piperazin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((4-((4-(2-(carbamoyloxy)ethyl)piperazin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(3-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methoxycarbonyl)amino)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propanoic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(2-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 3-(4-(5-((4-((4-(cyclopropanecarboxamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(propionamidomethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)butan-2-ol; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3-chloro-5-(difluoromethyl)phenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methoxycarbonyl)amino)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; methyl ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; methyl ((1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; (1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; (1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; N-((1-((3′,5′-dichloro-5-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 5-((4-((4-((1H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidine; (1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; (1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; methyl ((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methylcarbamoyl)oxy)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((4-((4-(3-amino-3-oxopropyl)piperazin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((4-((4-(2-amino-2-oxoethyl)piperazin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-(((1R,7S,8r)-8-(methylsulfonamido)-4-azabicyclo[5.1.0]octan-4-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-(((1R,7S,8r)-8-(methylsulfonamido)-4-azabicyclo[5.1.0]octan-4-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 4-(4-(5-((4-(((1R,7S,8r)-8-acetamido-4-azabicyclo[5.1.0]octan-4-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 3-(4-(5-((4-((4-(cyclopropanecarboxamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((dimethylphosphoryl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetamide; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethanesulfonamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyrimidin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((6-(3,5-dichlorophenyl)-2-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyrimidin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)-4-hydroxypiperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-N-methylpropanamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)butanamide; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)butanamide; 1-(5-((3′,5′-dichloro-5-(((2-methoxyethyl)amino)methyl)-[1,1′-biphenyl]-3-yl)oxy)pyridin-2-yl)-N-methylpiperidin-4-amine; 1-(3′,5′-dichloro-5-((6-(piperazin-1-yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-methylmethanamine; N.sub.1-(5-((3′,5′-dichloro-5-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)oxy)pyridin-2-yl)ethane-1,2-diamine; 1-(5-((3′,5′-dichloro-5-((methylamino)methyl)-[1,1′-biphenyl]-3-yl)oxy)pyridin-2-yl)piperidin-4-amine; N.sub.1-(5-((3′,5′-dichloro-5-((methylamino)methyl)-[1,1′-biphenyl]-3-yl)oxy)pyridin-2-yl)propane-1,3-diamine; 1-(3′,5′-dichloro-5-((6-(3,3-dimethylpiperazin-1-yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-methylmethanamine; 1-(5-((6-(1,4-diazepan-1-yl)pyridin-3-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)-N-methylmethanamine; 1-(3′,5′-dichloro-5-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-methylmethanamine; N-((1-((5-((6-((2-amino-2-methylpropyl)amino)pyridin-3-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((5-((6-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)pyridin-3-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((3′,5′-dichloro-5-((6-(3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-(5-((6-(3-chloro-5-methylphenyl)-4-((methylamino)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperidin-4-amine; N-((1-((2-(3,5-dichlorophenyl)-6-((5-(piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)propanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((3′,5′-dichloro-5-((2-(4-(3-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(1-((3′,5′-dichloro-5-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)propanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3-chloro-5-fluorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3-bromo-5-fluorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 2-(1-((3′,5′-dichloro-5-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-((2-(1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-((2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-N,N-dimethylethanamine oxide; N-((1-((2-(3,5-dichlorophenyl)-6-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-hydroxy-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; ((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)dimethylphosphine oxide; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)azetidin-3-yl)butanoic acid; 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)acetic acid; 2-(2-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)acetic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propanoic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; 2-(1-((2-((2-(1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; (S)-3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; 1-(7-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-hydroxyethanone; (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octane-8-carboxylic acid; (R)-3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; 1-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propan-2-ol; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-hydroxypropanoic acid; 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)acetic acid; 9-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)-2-oxa-4,9-diazaspiro[5.5]undecan-3-one; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)cyclopropanecarboxylic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-methoxy-4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(6-fluoro-4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-hydroxy-4,6-dimethyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-fluoro-4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((4-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-(4-(4-methylpiperazin-1-yl)phenoxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; (S)-2-(4-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-1,4-oxazepan-7-yl)ethanol; N-((1R,5S,6r)-3-((2-(3,5-dichlorophenyl)-6-((2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetamide; 1-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propan-2-one; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(1-((2-((2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; (S)-2-(1-((2-(3,5-dichlorophenyl)-6-((2-(3-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((6-(1,4-diazepan-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((3′,5′-dichloro-5-((2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((5-((4-(acetamidomethyl)piperidin-1-yl)methyl)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(6-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridazin-3-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((5-((4-(acetamidomethyl)piperidin-1-yl)methyl)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; methyl (3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoyl)carbamate; 1-(2-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)ethyl)cyclopropanecarboxylic acid; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; methyl (3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoyl)carbamate; methyl (3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoyl)carbamate; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2,3-dihydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-1-methylpiperazine 1-oxide; 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-1,1-bis(2-hydroxyethyl)piperazin-1-ium; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-1,1-dimethylpiperazin-1-ium; N-((1-((2-((6-(4-amino-3-fluoropiperidin-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-((1S,4S)-5-(2-(methylsulfonyl)ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-((6-((3S,4R)-3-(aminomethyl)-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-((1R,5S)-3-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propanoic acid; (S)-3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)propanoic acid; 2-(1-((2-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)-2-ethylbutanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-1,4-diazepan-1-yl)propanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)-2,2-dimethylpiperazin-1-yl)propanoic acid; N-((1-((2-((6-(1,4-diazepan-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(3-(hydroxymethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-((6-(4-aminopiperidin-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(3,3-dimethylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-((6-(4-amino-3,3-dimethylpiperidin-1-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-((6-(2,7-diazaspiro[4.4]nonan-2-yl)pyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-(3′,5′-dichloro-5-((6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-methylmethanamine; 1-(5-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)-N-methylmethanamine; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfinyl)butyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)butyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methylcarbamoyl)oxy)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)pentanoic acid; (1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-hydroxybutan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; (1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methylcarbamoyl)oxy)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)cyclobutanecarboxylic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)butyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)pentanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)cyclobutanecarboxylic acid; methyl ((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)butyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)butyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)butyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)cyclobutanecarboxylic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methoxycarbonyl)amino)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)pentanoic acid; methyl ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; 2-((1R,7S,8r)-4-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octan-8-yl)acetic acid; 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)-2-methylpropanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-hydroxy-4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(dimethylamino)piperidin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-((1-hydroxycyclopropyl)methyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-ethyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(4-cyclopropylpiperazin-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-isopropylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-fluoroethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-hydroxybutyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-hydroxybutan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-(methylamino)butan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4-(dimethylamino)butan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-((methylcarbamoyl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-sulfamoylpropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methylcarbamoyl)oxy)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)butanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-sulfamoylpropyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-sulfamoylpropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((5-((4-(acetamidomethyl)piperidin-1-yl)methyl)-3′,5′-dichloro-[1,1′-biphenyl]-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propane-1-sulfonamide; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetamide; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-hydroxy-4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)-3-fluoropyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((ethoxycarbonyl)amino)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(2-(ethylamino)-2-oxoethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)-3-fluoropyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propanoic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3-chloro-4,5-difluorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanamide; 1-((1-((2-(3-chloro-5-fluorophenyl)-6-((2-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; methyl ((1-((2-(3-chloro-5-fluorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(2-(methylsulfonyl)ethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(2-sulfamoylethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-(1-hydroxycyclopropyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-hydroxy-3-methylbutyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-hydroxy-2,2-dimethylpropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)butanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)butanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropanoic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropanamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-sulfamoylethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 2-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)ethanesulfonic acid; 2-((4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)butanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-sulfamoylethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropanamide; 3-(4-(5-((3′,5′-dichloro-5-((4-((3-methylureido)methyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropanoic acid; N-((1-((3′,5′-dichloro-5-((6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)acetamide; (S)-3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(((methoxycarbonyl)amino)methyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)-2-methylpiperazin-1-yl)propanoic acid; 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-hydroxybutyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(3-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propanoic acid; methyl 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoate; (R)-2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; (R)-2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-((R)-2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; (R)-N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3-fluoro-2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; (R)-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; (1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; (R)-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl methylcarbamate; (R)-1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; (R)-1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; methyl ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; (R)-methyl ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; 1-((1-((3′,5′-dichloro-5-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)propanoic acid; N-((1-((2-(3-chloro-5-fluorophenyl)-6-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-hydroxypropanoic acid; (R)-2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-(2-hydroxypropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)acetic acid; ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)boronic acid; (2-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)ethyl)boronic acid; ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)dimethylphosphine oxide; (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octane-8-carboxylic acid; ((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)boronic acid; (2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethyl)boronic acid; (1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl acetylcarbamate; N-1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-N′-methoxylcarbonylurea; N-(((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamoyl)methanesulfonamide; N-(((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamoyl)acetamide; N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)carbamoyl)methanesulfonamide; 1-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)urea; (S)-(4-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-1,4-oxazepan-7-yl)methanol; (1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)dimethylphosphine oxide; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-methyl-2-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-((2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; methyl ((1-((2-((2-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; (1R,7S,8r)-4-((2-((2-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octane-8-carboxylic acid; 4-(5-((6-(3,5-dichlorophenyl)-4-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)-1,4-diazabicyclo[3.2.1]octane; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(2-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethanol; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((6-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyridazin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-ethyl-1,4-diazepan-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((5-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyrazin-2-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-(3-hydroxybutyl)piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethanol; 3-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 1-((1-((2-(3,5-dichlorophenyl)-6-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)oxy)cyclopropanecarboxylic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-ethyl-1,4-diazepan-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methyl-1,4-diazepan-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-ethylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)ethanol; (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octane-8-carboxylic acid; (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)-6-((6-(4-methyl-1,4-diazepan-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octane-8-carboxylic acid; 3-(4-(6-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridazin-3-yl)piperazin-1-yl)-2-methylpropanoic acid; (R)-3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; (S)-3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)-2-methylpropanoic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((6-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(4-(5-((4-(((1R,7S,8r)-8-acetamido-4-azabicyclo[5.1.0]octan-4-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid; methyl 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoate; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2,2-dimethylbutanoic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-methyl-2-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; N-((1-((2-(3-chloro-5-fluorophenyl)-6-((2-(4-(4-(methylsulfonyl)butan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3-chloro-5-fluorophenyl)-6-((2-(4-(4-(methylsulfonyl)butan-2-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; 2-(1-((2-(3-chloro-5-fluorophenyl)-6-((2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-(isopropyl(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((3′,5′-dichloro-4-fluoro-5-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((4-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)-3-fluoropyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; 2-(1-((2-((2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)-3-fluoropyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; methyl 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoate; 2-(1-((6-(3,5-dichlorophenyl)-3-methyl-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-((2-(4-((1H-1,2,3-triazol-5-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-(methyl(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-(ethyl(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro-2-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)propanamide; 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4-(propionamidomethyl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; N-((1-((2-(3,5-dichlorophenyl)-6-((5-(4-(1-hydroxypropan-2-yl)piperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide; 1-((1-((2-(3,5-dichlorophenyl)-6-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)-3-methylurea; methyl ((1-((2-(3,5-dichlorophenyl)-6-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)carbamate; 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)-2-methylbutanoic acid; (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)-6-((2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)-4-azabicyclo[5.1.0]octane-8-carboxylic acid; 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; or 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6-fluoro-1,4-diazepan-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)acetic acid; or a pharmaceutically acceptable salt thereof.

42. The method or use of any one of claims 1 to 41, wherein the compound, or pharmaceutically acceptable salt thereof, is of the formula: ##STR00514##

43. The method or use of any one of claims 1 to 41, wherein the compound, or pharmaceutically acceptable salt thereof, is of the formula: ##STR00515##

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0083] The present disclosure provides methods for the treatment and/or prevention of a range of viral infections including, but not limited to, infections caused by togaviridae family viruses (e.g., alphaviruses (e.g., Chikungunya virus, Eastern equine encephalitis virus, Mayaro virus, Onyong-nyong virus, Ross River virus, Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus)), flaviviridae family viruses (e.g., flaviviruses (e.g., dengue virus, Japanese encephalitis virus, Kyasanur Forest disease virus, Murray Valley encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus, Rocio encephalitis virus, Saint Louis encephalitis virus, Tick-borne encephalitis virus, West Nile virus, Yellow fever virus, Usutu virus)), paramyxoviridae family viruses (e.g., orthoparamyxovirinae viruses (e.g., respiroviruses (e.g., human respirovirus 1, human respirovirus 3, murine respirovirus), henipaviruses (e.g., Cedar virus, Kumasi virus, Hendra virus, Mojiang virus, Nipah virus), morbilliviruses (e.g., Canine morbillivirus; Cetacean morbillivirus; Feline morbillivirus; Feline morbillivirus 2; Measles morbillivirus; Phocine morbillivirus; Rinderpest morbillivirus; Small ruminant morbillivirus)), filoviradae family viruses (e.g., Marburgviruses (e.g., Marburg Virus, Ravn Virus)), human respiratory syncytial virus (i.e., Human orthopneumovirus)), comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein.

[0084] Further provided herein are methods for inhibiting the replication of a virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein.

[0085] In certain embodiments, the present disclosure provides methods for the treatment and/or prevention of viral infections caused by togaviridae family viruses, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein. In certain embodiments, the provided methods are for the treatment and/or prevention of viral infections caused by togaviridae family viruses. In certain embodiments, the provided methods are for the treatment and/or prevention of viral infections caused by alphaviruses. In certain embodiments, the provided methods are for the treatment and/or prevention of viral infections caused by Chikungunya virus, Eastern equine encephalitis virus, Mayaro virus, Onyong-nyong virus, Ross River virus, Semliki Forest virus, sindbis virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus. In certain embodiments, the present disclosure provides methods for the treatment and/or prevention of viral infections caused by Chikungunya virus.

[0086] In certain embodiments, the provided methods are for the treatment and/or prevention of flaviviruses. In certain embodiments, the provided methods are for the treatment and/or prevention of dengue virus, Japanese encephalitis virus, Kyasanur Forest disease virus, Murray Valley encephalitis virus, omsk hemorrhagic fever virus, Powassan virus, Rocio encephalitis virus, Saint Louis encephalitis virus, Tick-borne encephalitis virus, West Nile virus, and/or yellow fever virus. In certain embodiments, the provided methods are for the treatment and/or prevention of dengue virus. In certain embodiments, the provided methods are for the treatment and/or prevention of Usutu virus. In certain embodiments, the provided methods are for the treatment and/or prevention of Japanese encephalitis virus. In certain embodiments, the provided methods are for the treatment and/or prevention of Powassan virus. In certain embodiments, the provided methods are for the treatment and/or prevention of yellow fever.

[0087] In certain embodiments, the present disclosure provides methods for the treatment and/or prevention of viral infections caused by filoviradae family viruses, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein. In certain embodiments, the provided methods are for the treatment and/or prevention of Marburgviruses. In certain embodiments, the provided methods are for the treatment and/or prevention of Marburg Virus and Ravn Virus. In certain embodiments, the provided methods for the treatment and/or prevention of Marburg virus.

[0088] In certain embodiments, the present disclosure provides methods for the treatment and/or prevention of viral infections caused by paramyxoviridae family viruses, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein. In certain embodiments, the provided methods are for the treatment and/or prevention of an orthoparamyxovirinae virus. In certain embodiments, the provided methods are for the treatment and/or prevention of a respirovirus. In certain embodiments, the provided methods are for the treatment and/or prevention of human respirovirus 1 (i.e., human parainfluenza virus type 1). In certain embodiments, the provided methods are for the treatment and/or prevention of human respirovirus 3 (i.e., human parainfluenza virus type 3). In certain embodiments, the provided methods are for the treatment and/or prevention of murine respirovirus (i.e., murine parainfluenza virus type 1). In certain embodiments, the provided methods are for the treatment and/or prevention of a henipavirus. In certain embodiments, the provided methods are for the treatment and/or prevention of Cedar virus (i.e., Cedar henipavirus). In certain embodiments, the provided methods are for the treatment and/or prevention of Kumasi virus (i.e., Ghanaian bat henipavirus). In certain embodiments, the provided methods are for the treatment and/or prevention of Hendra virus (i.e., Hendra henipavirus). In certain embodiments, the provided methods are for the treatment and/or prevention of Mojiang virus (i.e., Mojiang henipavirus). In certain embodiments, the provided methods are for the treatment and/or prevention of Nipah virus (i.e., Nipah henipavirus). In certain embodiments, the provided methods are for the treatment and/or prevention of morbilliviruses. In certain embodiments, the provided methods are for the treatment and/or prevention of Canine morbillivirus, Cetacean morbillivirus, Feline morbillivirus, Feline morbillivirus 2, Measles morbillivirus, Phocine morbillivirus, Rinderpest morbillivirus, and/or Small ruminant morbillivirus. In certain embodiments, the provided methods are for the treatment and/or prevention of Measles morbillivirus.

[0089] In another aspect, the present disclosure provides methods of treating a viral infection (e.g., infections resulting from togaviridae family viruses (e.g., alphaviruses (e.g., Chikungunya virus)), filoviradae family viruses (e.g., Marburgviruses (e.g., Marburg Virus, Ravn Virus)), human respiratory syncytial virus (i.e., Human orthopneumovirus), a flavivirus (e.g., dengue virus)) in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein. In certain embodiments, provided herein are methods of treating viral infections resulting from Chikungunya virus. In certain embodiments, provided herein are methods of treating viral infections resulting from dengue virus. In certain embodiments, provided herein are methods of treating viral infections resulting from Chikungunya virus. In certain embodiments, provided herein are methods of treating viral infections resulting from Eastern equine encephalitis. In certain embodiments, provided herein are methods of treating viral infections resulting from Mayaro virus. In certain embodiments, provided herein are methods of treating viral infections resulting from Venezuelan equine encephalitis virus. In certain embodiments, provided herein are methods of treating a viral infections resulting from Western equine encephalitis.

[0090] In another aspect, the present disclosure provides methods of preventing a viral infection in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., a prophylactically effective amount) of a compound of Formula (I), or a pharmaceutical composition comprising Formula (I) as described herein. In certain embodiments, provided herein are methods of preventing viral infections resulting from Chikungunya virus. In certain embodiments, provided herein are methods of preventing viral infections resulting from dengue virus. In certain embodiments, provided herein are methods of preventing viral infections resulting from Chikungunya virus.

[0091] In another aspect, the present disclosure provides methods of inhibiting the replication of a virus (e.g., a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus, (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutical composition described herein. In certain embodiments, the provided methods are for inhibiting the replication of Chikungunya virus in a subject in need thereof. In certain embodiments, the provided methods are for inhibiting the replication of Marburg virus in a subject in need thereof. In certain embodiments, the provided methods are for inhibiting the replication of dengue virus in a subject in need thereof.

[0092] Provided herein are methods of inhibiting the replication of a virus (e.g., a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus, (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are methods of inhibiting the replication of a virus in a subject by at least 1%, at least 3%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In certain embodiments, the replication of a virus in a subject is inhibited by at least 1%, at least 3%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In certain embodiments, provided herein are methods of inhibiting the replication of a virus in a subject by at least 30%. In certain embodiments, provided herein are methods of inhibiting the replication of a virus in a subject by at least 50%. In certain embodiments, provided herein are methods of inhibiting the replication of a virus in a subject by at least 75%.

[0093] In another aspect, the present disclosure provides methods of decreasing viral infectivity (e.g., infectivity of a virus (e.g., a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus, (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical composition comprising Formula (I) as described herein. In certain embodiments, the present disclosure provides methods of decreasing viral infectivity of Chikungunya virus in a subject. In certain embodiments, the present disclosure provides methods of decreasing viral infectivity of dengue virus in a subject. In certain embodiments, the present disclosure provides methods of decreasing viral infectivity of Marburg virus in a subject.

[0094] In another aspect, the present disclosure provides compounds of Formula (I) and pharmaceutical compositions described herein for use in treating and/or preventing a viral infection including, but not limited to, infections caused by togaviridae family viruses (e.g., alphaviruses (e.g., Chikungunya virus, Eastern equine encephalitis virus, Mayaro virus, Onyong-nyong virus, Ross River virus, Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus)), flaviviridae family viruses (e.g., flaviviruses (e.g., dengue virus, Japanese encephalitis virus, Kyasanur Forest disease virus, Murray Valley encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus, Rocio encephalitis virus, Saint Louis encephalitis virus, Tick-borne encephalitis virus, West Nile virus, Yellow fever virus, Usutu virus)), filoviradae family viruses (e.g., Marburgviruses (e.g., Marburg Virus, Ravn Virus)) human respiratory syncytial virus (i.e., Human orthopneumovirus)), comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I) as described herein.

[0095] In another aspect, the present disclosure provides compounds of Formula (I) and pharmaceutical compositions described herein for use in treating and/or preventing a viral infection including, but not limited to, infections caused by a virus (e.g., a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus, (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject in need thereof. In certain embodiments, the present disclosure provides compounds of Formula (I) and pharmaceutical compositions described herein for use in treating and/or preventing a viral infection caused by Chikungunya virus in a subject in need thereof. In certain embodiments, the present disclosure provides compounds of Formula (I) and pharmaceutical compositions described herein for use in treating and/or preventing a viral infection caused by Marburg virus in a subject in need thereof. In certain embodiments, the present disclosure provides compounds of Formula (I) and pharmaceutical compositions described herein for use in treating and/or preventing a viral infection caused by dengue virus in a subject in need thereof.

[0096] In another aspect, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for treating a viral infection (e.g., viral infections resulting from a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus, (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject in need thereof. In certain embodiments, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for treating viral infections resulting from Chikungunya virus in a subject in need thereof. In certain embodiments, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for treating a viral infection resulting from dengue virus in a subject in need thereof. In certain embodiments, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for treating Marburg virus in a subject in need thereof.

[0097] In another aspect, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for preventing a viral infection (e.g., infection resulting from a togaviridae family virus (e.g., an alphavirus (e.g., Chikungunya virus, Eastern equine encephalitis, Mayaro virus, Venezuelan equine encephalitis virus, Western equine encephalitis)), a filoviradae family virus (e.g., a Marburgvirus (e.g., Marburg virus, Ravn virus)), human respiratory syncytial virus (i.e., human orthopneumovirus), a flavivirus (e.g., dengue virus, Usutu virus, Japanese encephalitis virus, Powassan virus, yellow fever), a paramyxoviridae family virus (e.g., an orthoparamyxovirinae virus, (e.g., a henipavirus (e.g., Nipah virus), a morbillivirus (e.g., measles morbillivirus))) in a subject in need thereof. In another aspect, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for preventing Chikungunya virus in a subject in need thereof. In another aspect, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for preventing Marburg virus in a subject in need thereof. In another aspect, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for preventing a viral infection caused by dengue virus in a subject in need thereof.

[0098] In certain embodiments, the virus is a togaviridae family virus. In certain embodiments, the togaviridae family virus is an alphavirus. In certain embodiments, the alphavirus is Chikungunya virus, Eastern equine encephalitis virus, Mayaro virus, Onyong-nyong virus, Ross River virus, Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, or Western equine encephalitis virus. In certain embodiments, the alphavirus is dengue virus.

[0099] In certain embodiments, the virus is a paramyxoviridae family virus. In certain embodiments, the paramyxoviridae family virus is an orthoparamyxovirinae virus. In certain embodiments, the orthoparamyxovirinae virus is a henipavirus. In certain embodiments, the henipavirus is Nipah virus (i.e., Nipah henipavirus). In certain embodiments, the henipavirus is Cedar virus (i.e., Cedar henipavirus). In certain embodiments, the henipavirus is Kumasi virus (i.e., Ghanaian bat henipavirus. In certain embodiments, the henipavirus Hendra virus (i.e., Hendra henipavirus). In certain embodiments, the henipavirus is Mojiang virus (i.e., Mojiang henipavirus). In certain embodiments, the orthoparamyxovirinae virus is a respirovirus. In certain embodiments, the respirovirus is human respirovirus 1 (i.e., human parainfluenza virus type 1). In certain embodiments, the respirovirus is human respirovirus 3 (i.e., Human parainfluenza virus type 3). In certain embodiments, the respirovirus is murine respirovirus (i.e, Murine parainfluenza virus type 1). In certain embodiments, the paramyxoviridae family virus is a morbillivirus. In certain embodiments, the morbillivirus is a Canine morbillivirus, Cetacean morbillivirus, Feline morbillivirus, Feline morbillivirus 2, Measles morbillivirus, Phocine morbillivirus, Rinderpest morbillivirus, or Small ruminant morbillivirus. In certain embodiments, the morbillivirus is Measles morbillivirus (i.e., measles).

[0100] In certain embodiments, the virus is a flaviviridae family virus. In certain embodiments, the flaviviridae family virus is a flavivirus. In certain embodiments, the flavivirus is dengue virus, Japanese encephalitis virus, Kyasanur Forest disease virus, Murray Valley encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus, Rocio encephalitis virus, Saint Louis encephalitis virus, Tick-borne encephalitis virus, West Nile virus, or Yellow fever virus. In certain embodiments, the flavivirus is dengue virus.

[0101] In certain embodiments, the virus us a filoviradae family virus. In certain embodiments, the filoviradae family virus is a Marburgvirus. In certain embodiments, the Marburgvirus is Marburg Virus, or Ravn Virus. In certain embodiments, the Marburgvirus is Marburg virus. Virus. In certain embodiments, the Marburgvirus is Ravn virus.

[0102] Without wishing to be bound by any theory, in certain embodiments the compounds of Formula (I) useful in the methods and uses of this disclosure prevents or inhibits the furin-mediated processing of viral precursor protein E3E2, which prevents or inhibits viral fusion and infection.

[0103] Without wishing to be bound by any theory, in certain embodiments the compounds of Formula (I) useful in the methods and uses of this disclosure prevents or inhibits the furin-mediated cleavage of the virion premembrane (prM). Cleavage of prM is the defining event in flavivirus maturation and is a required step in the virus infection cycle. Thus, inhibition of prM cleavage prevents or inhibits viral infectivity.

[0104] Without wishing to be bound by any theory, in certain embodiments the compounds of Formula (I) useful in the methods and uses of this disclosure inhibits viral fusion by cleaving the glycoproteins of a virus.

[0105] Also provided herein are methods for treating and/or preventing a disorder due to a microbial toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I).

[0106] Further provided herein are methods for preventing the activation of a toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I).

[0107] In certain embodiments, provided are methods of decreasing the activity of a toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject by at least 1%, at least 3%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In certain embodiments, the activity of a toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject is decreased by at least 1%, at least 3%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some embodiments, the activity of a toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject is selectively decreased by a compound of Formula (I) or pharmaceutical composition described herein.

[0108] In another aspect, the present disclosure provides compounds of Formula (I) and pharmaceutical compositions described herein for use in treating and/or preventing a disorder due to a microbial toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject in need thereof.

[0109] In another aspect, the present disclosure provides uses of compounds of Formula (I) and pharmaceutical compositions described herein in the manufacture of a medicament for treating and/or preventing a disorder due to a microbial toxin (e.g., P. aeruginosa toxin A, Clostridium septicum alpha-toxin, diphtheria toxin(s), shiga toxin(s)) in a subject in need thereof.

[0110] Without wishing to be bound by any theory, in certain embodiments the compounds of Formula (I) useful in the methods and uses of this disclosure prevents or inhibits the processing of Pseudomonas aeruginosa exotoxin A by furin to prevent active forms of Pseudomonas aeruginosa exotoxin A from forming.

[0111] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00006##

or a pharmaceutically acceptable salt thereof, wherein:

[0112] A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═ or —C(R.sup.6)═;

[0113] X is —O— or —N(R.sup.8)—.

[0114] R.sup.1 and R.sup.2 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl;

[0115] optionally, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7;

[0116] each R.sup.3 is independently halogen, —CN, —O(C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.1-C.sub.4)alkyl;

[0117] R.sup.4 and R.sup.5 are each independently H or optionally substituted (C.sub.1-C.sub.4)alkyl;

[0118] optionally, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9;

[0119] each R.sup.6 is independently H, halogen, optionally substituted (C.sub.1-C.sub.4)alkyl, —OH, or optionally substituted (C.sub.1-C.sub.4)alkoxy;

[0120] each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or (C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, hydroxyl, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9);

[0121] each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl; and

[0122] n is 1, 2, 3, or 4.

[0123] Formula (I) contains the substituents A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 A.sup.6, and A.sup.7, wherein each of A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 A.sup.6, and A.sup.7 are independently ═N— or CR.sup.6; wherein each R.sup.6 is independently —H, halogen, —(C.sub.1-C.sub.4)alkyl, -halo(C.sub.1-C.sub.4)alkyl, —OH, or —(C.sub.1-C.sub.4)alkoxy. In certain embodiments, A.sup.1 is —N═. In certain embodiments, A.sup.1 is —CR.sup.6═. In certain embodiments, A.sup.1 is —CH═. In certain embodiments, A.sup.2 is —N═. In certain embodiments, A.sup.2 is —CR.sup.6═. In certain embodiments, A.sup.2 is —CH═. In certain embodiments, A.sup.3 is —N═. In certain embodiments, A.sup.3 is —CR.sup.6═. In certain embodiments, A.sup.3 is —CH═. In certain embodiments, A.sup.4 is —N═. In certain embodiments, A.sup.4 is —CR.sup.6═. In certain embodiments, A.sup.4 is —CH═. In certain embodiments, A.sup.5 is —N═. In certain embodiments, A.sup.5 is —CR.sup.6═. In certain embodiments, A.sup.5 is —CH═. In certain embodiments, A.sup.6 is —N═. In certain embodiments, A.sup.6 is —CR.sup.6═. In certain embodiments, A.sup.6 is —CH═. In certain embodiments, A.sup.7 is —N═. In certain embodiments, A.sup.7 is —CR.sup.6═. In certain embodiments, A.sup.7 is —CH═. In one embodiment, A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═, —CH═, or CR.sup.6, wherein zero, one, two, or three of A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are —N═. In another embodiment, A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are each independently —N═, CH, or CR.sup.6, wherein two or three of A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, and A.sup.7 are —N═. In another embodiment, A.sup.1, A.sup.2, A.sup.3, A.sup.4, and A.sup.5 are each independently —N═ or CH, wherein two or three of A.sup.1, A.sup.2, A.sup.3, A.sup.4, and A.sup.5 are —N═. In another embodiment, A.sup.1, A.sup.2, A.sup.3, A.sup.4, and A.sup.5 are each independently —N═ or CH, wherein three of A.sup.1, A.sup.2, A.sup.3, A.sup.4, and A.sup.5 are —N═. In another embodiment, A.sup.1, A.sup.2, A.sup.3, A.sup.4, and A.sup.5 are each independently —N═ or CH, wherein two of A.sup.1, A.sup.2, A.sup.3, A.sup.4, and A.sup.5 are —N═. In another embodiment, A.sup.1, A.sup.2, and A.sup.3 are each independently —N═ or —CH═, wherein two of A.sup.1, A.sup.2, and A.sup.3 are —N═. In another embodiment, A.sup.1, A.sup.2, and A.sup.3 are each independently —N═ or CH, wherein one of A.sup.1, A.sup.2, and A.sup.3 is —N═. In another embodiment, one of A.sup.1 and A.sup.2 is —N═ and the other is CH. In another embodiment, A.sup.1 and A.sup.2 are each CH. In another embodiment, A.sup.1 and A.sup.2 are each —N═. In another embodiment, A.sup.1 and A.sup.3 are each —N═. In another embodiment, A.sup.2 and A.sup.3 are each —N═. In another embodiment, A.sup.1 and A.sup.4 are each —N═. In another embodiment, A.sup.3 and A.sup.5 are each —N═. In another embodiment, A.sup.3 and A.sup.5 are each —N═, and each of A.sup.1, A.sup.2, A.sup.4, A.sup.6, and A.sup.7 are CH. In another embodiment, A.sup.4 and A.sup.6 are each CH. In another embodiment, A.sup.2, A.sup.3 and A.sup.5 are each —N═. In another embodiment, A.sup.2, A.sup.3 and A.sup.5 are each —N═, and each of A.sup.1, A.sup.4, A.sup.6, and A.sup.7 are CH.

[0124] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-1):

##STR00007##

[0125] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-2):

##STR00008##

[0126] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-3):

##STR00009##

[0127] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-4):

##STR00010##

[0128] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-5):

##STR00011##

[0129] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-6):

##STR00012##

[0130] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-7):

##STR00013##

[0131] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-8):

##STR00014##

[0132] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-9):

##STR00015##

[0133] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-10):

##STR00016##

[0134] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-11):

##STR00017##

[0135] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the Formula (I-12):

##STR00018##

[0136] In one embodiment, X is O or NR.sup.8, wherein R.sup.8 is (C.sub.1-C.sub.4)alkyl. In another embodiment, X is —NR.sup.8, wherein R.sup.8 is (C.sub.1-C.sub.4)alkyl. In certain embodiments, X is O.

[0137] In certain embodiments, R.sup.3 is optionally substituted —O(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.3 is optionally substituted —OCF.sub.3. In certain embodiments, R.sup.3 is optionally substituted (C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.3 is -Me. In certain embodiments, R.sup.3 is —CF.sub.3. In certain embodiments, R.sup.3 is —CHF.sub.2. In certain embodiments, R.sup.3 is —CH.sub.2F. In certain embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.3 is —F. In certain embodiments, R.sup.3 is —Cl. In certain embodiments, R.sup.3 is —Br. In certain embodiments, R.sup.3 is —I. In certain embodiments, R.sup.3 is -Me. In certain embodiments, each R.sup.3 is independently halogen, methyl, or difluoromethyl. In another embodiment, each R.sup.3 is independently fluoro, chloro, bromo, methyl, or difluoromethyl. In one embodiment, each R.sup.3 is independently halogen. In another embodiment, each R.sup.3 is independently fluoro, chloro, or bromo. In another embodiment, each R.sup.3 is independently fluoro or chloro. In certain embodiments, each R.sup.3 is chloro. In certain embodiments, R.sup.3 is —CN.

[0138] In certain embodiments, R.sup.1 and R.sup.2 are each independently H, (C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkylNH.sub.2. In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7. In one embodiment, R.sup.1 and R.sup.2 are each independently H, (C.sub.1-C.sub.4)alkyl, or —(C.sub.1-C.sub.4)alkylNH.sub.2. In another embodiment, R.sup.1 and R.sup.2 are each independently H or —(C.sub.1-C.sub.4)alkylNH.sub.2. R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7. In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, or morpholine ring.

[0139] In another embodiment, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached represent a 6- or 7-membered monocyclic ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —SO.sub.2R.sup.7. In another embodiment, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached represent a 6- or 7-membered monocyclic ring, optionally containing one or two additional nitrogen heteroatoms, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen, hydroxyl, oxo, R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, and —C(O)R.sup.7. In another embodiment, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached represent a 6- or 7-membered monocyclic ring, optionally containing one additional nitrogen heteroatom, wherein said ring is optionally substituted by one substituent which is R.sup.7. In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached represent an optionally substituted piperazine ring.

[0140] In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form an optionally substituted piperazine ring. In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00019##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00020##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00021##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00022##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00023##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00024##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00025##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00026##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00027##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00028##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperidine ring of the formula:

##STR00029##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a piperidine ring of the formula:

##STR00030##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00031##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00032##

In certain embodiments, R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a pyrrolidine ring of the formula:

##STR00033##

[0141] In certain embodiments, R.sup.4 and R.sup.5 are each independently H, or optionally substituted (C.sub.1-C.sub.4)alkyl. In certain embodiment, R.sup.4 and R.sup.5 are the same. In certain embodiments, R.sup.4 and R.sup.5 are different. In certain embodiments, R.sup.4 is H. In certain embodiments, R.sup.5 is H. In one embodiment, R.sup.4 and R.sup.5 are each independently H, (C.sub.1-C.sub.4)alkyl, or (C.sub.2-C.sub.4)alkyl(C.sub.1-C.sub.4)alkoxy. In certain embodiments, R.sup.4 is -Me. In certain embodiments, R.sup.4 is —C(O)R.sup.7. In certain embodiments, R.sup.4 is —C(O)Me. In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a 4-11 membered monocyclic, fused bicyclic, bridged, or spiro-bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, or three of halogen, hydroxyl, oxo, —OCONR.sup.8R.sup.9, —CO.sub.2R.sup.8, —C(O)CO.sub.2R.sup.8, —SO.sub.2(C.sub.1 C.sub.4)alkyl, —R.sup.7, —OR.sup.7, —NHR.sup.8, —NR.sup.7R.sup.8, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —C(O)R.sup.7, —CONHR.sup.8, —CONR.sup.7R.sup.8, or —P(O)R.sup.8R.sup.9. In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a piperidine ring of the formula:

##STR00034##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a piperidine ring of the formula:

##STR00035##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a piperidine ring of the formula:

##STR00036##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00037##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00038##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a piperazine ring of the formula:

##STR00039##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form ring of the formula

##STR00040##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a pyrrolidine ring of the formula:

##STR00041##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a pyrrolidine ring of the formula:

##STR00042##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a pyrrolidine ring of the formula:

##STR00043##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00044##

In another embodiment, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they are attached form a ring of the formula:

##STR00045##

[0142] In one embodiment, each R.sup.6 is independently halogen or (C.sub.1-C.sub.4)alkyl. In another embodiment, each R.sup.6 is independently halogen. In another embodiment, each R.sup.6 is independently selected from the group consisting of fluoro, chloro, bromo, and methyl. In another embodiment, each R.sup.6 is independently selected from the group consisting of fluoro, chloro, and bromo. In another embodiment, each R.sup.6 is independently fluoro or chloro. In certain embodiments, each R.sup.6 is fluoro. In another embodiment, each R.sup.6 is chloro. In another embodiment, each R.sup.6 is independently (C.sub.1-C.sub.4)alkyl. In another embodiment, each R.sup.6 is methyl.

[0143] In one embodiment, each R.sup.7 is independently (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or —(C.sub.1-C.sub.4)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted by one or two of triazolyl, tetrazolyl, —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —OH, (C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —OCON(R.sup.8)C(O)R.sup.9, (C.sub.1-C.sub.4)alkyl, —(C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(O)R.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)CON(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CON(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)SO.sub.2R.sup.9, —N(R.sup.8)CON(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, —B(OH).sub.2, —P(O)R.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9). In another embodiment, each R.sup.7 is independently (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, halo(C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or —(C.sub.1-C.sub.2)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted with —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —OH, oxo, —(C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —(C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CH.sub.2CO.sub.2R.sup.9, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9). In another embodiment, each R.sup.7 is independently (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, halo(C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or —(C.sub.1-C.sub.2)alkyl(C.sub.3-C.sub.6)cycloalkyl, each of which is optionally substituted by one or two substituents —CO.sub.2R.sup.8, —CONR.sup.8R.sup.9, —OH, (C.sub.1-C.sub.4)alkoxy, —OCONR.sup.8R.sup.9, —(C.sub.1-C.sub.4)alkylOH, —NR.sup.8R.sup.9, —N(R.sup.8)C(O)R.sup.9, —N(R.sup.8)CO.sub.2(C.sub.1-C.sub.4)alkyl, —N(R.sup.8)CONR.sup.8R.sup.9, —N(R.sup.8)SO.sub.2R.sup.9, —SO(C.sub.1-C.sub.4)alkyl, —SO.sub.2(C.sub.1-C.sub.4)alkyl, —SO.sub.3R.sup.8, —SO.sub.2NR.sup.8R.sup.9, or —P(O)(OR.sup.8)(OR.sup.9). In another embodiment, each R.sup.7 is (C.sub.1-C.sub.6)alkyl which is optionally substituted by one substituent which is —CO.sub.2H, —OH, —N(R.sup.8)C(O)R.sup.9, or —SO(C.sub.1-C.sub.4)alkyl. In another embodiment, each R.sup.7 is (C.sub.1-C.sub.4)alkyl which is optionally substituted by one substituent which is —CO.sub.2H, —OH, —N(R.sup.8)C(O)R.sup.9, or —SO(C.sub.1-C.sub.4)alkyl.

[0144] In certain embodiments, each of R.sup.8 and R.sup.9 is independently H, optionally substituted (C.sub.1-C.sub.4)alkyl, or optionally substituted (C.sub.3-C.sub.6)cycloalkyl. In one embodiment, each R.sup.8 and R.sup.9 is independently H or (C.sub.1-C.sub.4)alkyl. In another embodiment, each R.sup.8 and R.sup.9 is independently (C.sub.1-C.sub.4)alkyl. In another embodiment, R.sup.8 and R.sup.9 are each methyl. In another embodiment, each R.sup.8 and R.sup.9 is H. In another embodiment, R.sup.8 is H; and R.sup.9 is (C.sub.1-C.sub.4)alkyl. In another embodiment, R.sup.8 is H; and R.sup.9 is -Me. In another embodiment, R.sup.8 is (C.sub.1-C.sub.4)alkyl. In another embodiment, R.sup.8 is -Me. In another embodiment, R.sup.8 is —H. In another embodiment, R.sup.9 is (C.sub.1-C.sub.4)alkyl. In another embodiment, R.sup.9 is -Me. In another embodiment, R.sup.9 is —H.

[0145] In one embodiment, n is 1, 2, or 3. In another embodiment, n is 2 or 3. In another embodiment, n is 2.

[0146] In certain embodiments, the disclosed methods comprise administering to the subject in need thereof a therapeutically effective amount of any one of the compounds found in Table 1.

[0147] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, useful in the present disclosure is of the formula:

##STR00046##

[0148] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, useful in the present disclosure is of the formula:

##STR00047##

[0149] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, useful in the present disclosure is of the formula:

##STR00048##

[0150] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, useful in the present disclosure is of the formula:

##STR00049##

[0151] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, useful in the present disclosure is of the formula:

##STR00050##

[0152] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula thereof, useful in the present disclosure is of the formula:

##STR00051##

[0153] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00052##

[0154] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00053##

[0155] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00054##

[0156] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00055##

[0157] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00056##

[0158] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##

or a pharmaceutically acceptable salt thereof.

[0159] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00067##

or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments, the compound of Formula (I) useful in the present disclosure is of the formula:

##STR00068##

or a pharmaceutically acceptable salt thereof.

[0161] The synthesis and characterization of all compounds in Table 1 can be found in U.S. Provisional Application, U.S. Ser. No. 62/670,050, filed on May 11, 2018, and the corresponding international PCT application, Application No.: PCT/EP2019/062098, filed on May 10, 2019, the contents of both are incorporated herein by reference.

TABLE-US-00001 TABLE 1 Compounds useful in the disclosure # Structure Name 1 [00069] 2-(4-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperazin- 1-yl)-N-methylacetamide 2 [00070] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)-4-hydroxy- piperidin-4-yl)methyl)acetamide 3 [00071] 3-(1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl) propanoic acid 4 [00072] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl) acetic acid 5 [00073] 1-((1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)-4-hydroxy- piperidin-4- yl)methyl)-3-methylurea 6 [00074] methyl ((1-((2-(3,5-dichlorophenyl)-6- ((6-(piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)-4- hydroxypiperidin- 4-yl)methyl)carbamate 7 [00075] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl) ethanesulfonic acid 8 [00076] (1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methanesulfonic acid 9 [00077] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 10 [00078] 2-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)acetic acid 11 [00079] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)propanoic acid 12 [00080] N-((1-((2-(3,5-dischlorophenyl)-6-((6- (4-(2-(methylsulfonyl)ethyl)piperazin- 1-yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 13 [00081] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)propanamide 14 [00082] N-((1-((2-(((6-(4-(2-(1H-tetrazol-5- yl)ethyl)piperazin-1-yl)pyridin-3-yl) oxy)-6-(3,5-dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 15 [00083] (N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2-(methylsulfinyl)ethyl)piperazin- 1-yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 16 [00084] (N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-(4-(methylsulfonyl)butan-2-yl) piperazin- 1-yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 17 [00085] 1-((1-((2-(3,5-chlorophenyl)-6-((2-(4- (3-(methylsulfinyl)butyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 18 [00086] 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- (4-(methylsulfonyl)butan-2-yl)piperazin- 1-yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 19 [00087] N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- (4-(methylsulfonyl)butan-2-yl)piperazin- 1-yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 20 [00088] 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- (4-hydroxybutan-2-yl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 21 [00089] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (1-hydroxypropan-2-yl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 22 [00090] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-hydroxycyclobutyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 23 [00091] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (1,3-dihydroxypropan-2-yl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 24 [00092] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- ((1s,3s)-3-hydroxy-3- methylcyclobutyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 25 [00093] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- ((1r,3r)-3-hydroxy-3- methylcyclobutyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 26 [00094] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-((trans)-3- (methylsulfonamido)cyclobutyl) piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 27 [00095] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-((cis)-3- (methylsulfonamido)cyclobutyl) piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 28 [00096] N-((1-((2-((6-(4-(2-aminoethyl) piperazin-1-yl)pyridin-3-yl)oxy)-6-(3, 5-dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 29 [00097] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2,4-dihydroxybutyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 30 [00098] (2-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)ethyl)phosphonic acid 31 [00099] 2-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)ethylcarbamate 32 [00100] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (2-(N-methylmethylsulfonamido) ethyl)piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 33 [00101] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)-4-oxobutanoic acid 34 [00102] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-((1- (hydroxymethyl)cyclopropyl)methyl) piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 35 [00103] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-((1-hydroxycyclopropyl)methyl) piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 36 [00104] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)-N- ethylacetamide 37 [00105] 1-(2-(3,5-dichlorophenyl)-6-((2-(4-(3- (methylsulfonyl)propyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4-yl)-N- methylmethanamine 38 [00106] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (sulfamoylmethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyridin-2- yl)piperazin-1-yl)propanoic acid 39 [00107] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((methylsulfonyl)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyridin-2- yl)piperazin-1-yl)propanoic acid 40 [00108] 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (2-hydroxyethyl)piperazin-1-yl)pyridin- 3-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-3-methylurea 41 [00109] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyridin-2- yl)piperazin-1-yl)propanoic acid 42 [00110] N-((1-((5-(4-aminophenoxy)-3′,5′- dichloro-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 43 [00111] N-((1-((5-((5-aminopyrimidin-2-yl) oxy)-3′,5′-dichloro-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 44 [00112] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (methylsulfonamidomethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyridin-2- yl)piperazin-1-yl)propanoic acid 45 [00113] N-((1-((5-((5-aminopyridin-2-yl)oxy)- 3′,5′-dichloro-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 46 [00114] N-((1-((5-((6-amino-5-fluoropyridin-3- yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]- 3-yl)methyl)piperidin-4- yl)methyl)acetamide 47 [00115] 1-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-hydroxyethyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)methyl)-3-methylurea 48 [00116] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)propane-1- sulfonamide 49 [00117] methyl((1-((2-(3,5-dichlorophenyl)-6- ((2-(piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)carbamate 50 [00118] 3-(4-(5-((6-(3,5-dichlorophenyl)-4- ((methylamino)methyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1- yl)propanoic acid 51 [00119] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- fluoro-4- (((methoxycarbonyl)amino)methyl) piperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 52 [00120] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)ethanol 53 [00121] 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)oxy)acetic acid 54 [00122] 3-(4-(5-((4-((4-(2- (carbamoyloxy)ethyl)piperazin-1- yl)methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrimidin-2-yl) piperazin-1-yl)propanoic acid 55 [00123] 3-(4-(5-((4-((4-(2- (carbamoyloxy)ethyl)piperazin-1- yl)methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)propanoic acid 56 [00124] 3-(3-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methoxycarbonyl)amino)methyl) piperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl) propanoic acid 57 [00125] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (2-hydroxyethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)-2-methylbutanoic acid 58 [00126] 3-(4-(5-((4-((4- (cyclopropanecarboxamidomethyl) piperidin-1-yl)methyl)-6-(3,5- dichlorophenyl)pyridin-2-yl)oxy) pyridin-2-yl)piperazin-1-yl)propanoic acid 59 [00127] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (propionamidomethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)-2-methylbutanoic acid 60 [00128] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- fluoropiperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)butan-2-ol 61 [00129] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3-chloro-5- (difluoromethyl)phenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 62 [00130] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methoxycarbonyl)amino)methyl) piperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 63 [00131] methyl((1-((2-(3,5-dichlorophenyl)-6- ((2-(4-methylpiperazin-1-yl)pyrimidin- 5-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)carbamate 64 [00132] N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 65 [00133] methyl((1-((2-(3,5-dichlorophenyl)-6- ((6-(4-methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)carbamate 66 [00134] (1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methylmethylcarbamate 67 [00135] (1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methylmethylcarbamate 68 [00136] N-((1-((3′,5′-dichloro-5-((2-(4- methylpiperazin-1-yl)pyrimidin-5-yl) oxy)-[1,1′-biphenyl]-3-yl)methyl) piperidin-4-yl)methyl)acetamide 69 [00137] 1-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-3-methylurea 70 [00138] 1-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-3-methylurea 71 [00139] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (8-methyl-3,8-diazabicyclo[3.2.1] octan-3- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 72 [00140] 5-((4-((4-((1H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)-6- (3,5-dichlorophenyl)pyridin-2-yl) oxy)-2-(4- methylpiperazin-1-yl)pyrimidine 73 [00141] (1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methylmethylcarbamate 74 [00142] (1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methylmethylcarbamate 75 [00143] l-((1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-3-methylurea 76 [00144] methyl((1-((2-(3,5-dichlorophenyl)-6- ((6-(piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)carbamate 77 [00145] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methylcarbamoyl)oxy)methyl) piperidin-1-yl)methyl)pyridin-2-yl) oxy)pyridin-2-yl)piperazin-1-yl) propanoic acid 78 [00146] 3-(4-(5-((4-((4-(3-amino-3- oxopropyl)piperazin-1-yl)methyl)-6-(3, 5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 79 [00147] 3-(4-(5-((4-((4-(2-amino-2- oxoethyl)piperazin-1-yl)methyl)-6- (3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 80 [00148] 3-(4-(5-((6-(3,5-dichlorophenyl)-4- (((1R,7S,8r)-8-(methylsulfonamido)-4- azabicyclo[5.1.0]octan-4- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)propanoic acid 81 [00149] 4-(4-(5-((6-(3,5-dichlorophenyl)-4- (((1R,7S,8r)-8-(methylsulfonamido)-4- azabicyclo[5.1.0]octan-4- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)-2-methylbutanoic acid 82 [00150] 4-(4-(5-((4-(((1R,7S,8r)-8-acetamido-4- azabicyclo[5.1.0]octan-4-yl)methyl)-6- (3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1-yl)- 2-methylbutanoic acid 83 [00151] 4-(4-(5-((6-(3,5-dichlorophenyl)-4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1-yl)- 2-methylbutanoic acid 84 [00152] 3-(4-(5-((4-((4- (cyclopropanecarboxamidomethyl) piperidin-1-yl)methyl)-6-(3,5- dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 85 [00153] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((dimethylphosphoryl)methyl)piperidin- 1-yl)methyl)pyridin-2-yl)oxy)pyridin- 2-yl)piperazin-1-yl)propanoic acid 86 [00154] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetamide 87 [00155] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)ethanesulfonamide 88 [00156] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl)pyridin- 2-yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanamide 89 [00157] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3- yl)oxy)pyrimidin-4-yl)methyl) piperidin-4-yl)methyl)acetamide 90 [00158] N-((1-((6-(3,5-dichlorophenyl)-2-((6- (piperazin-1-yl)pyridin-3- yl)oxy)pyrimidin-4-yl)methyl) piperidin-4-yl)methyl)acetamide 91 [00159] N-((1-((2-(3,5-dichlorophenyl)-6-((5- fluoro-6-(piperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)-4- hydroxypiperidin-4-yl)methyl) acetamide 92 [00160] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 93 [00161] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-hydroxyethyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl) piperidin-4-yl)methyl)acetamide 94 [00162] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl)pyridin- 2-yl)oxy)pyrimidin-2-yl)piperazin-1- yl)-N-methylpropanamide 95 [00163] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrimidin-2-yl) piperazin-1-yl)butanamide 96 [00164] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrimidin-2-yl) piperazin-1-yl)butanamide 97 [00165] 1-(5-((3′,5′-dichloro-5-(((2- methoxyethyl)amino)methyl)-[1,1′- biphenyl]-3-yl)oxy)pyridin-2-yl)-N- methylpiperidin-4-amine 98 [00166] 1-(3′,5′-dichloro-5-((6-(piperazin-1- yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3- yl)-N-methylmethanamine 99 [00167] N1-(5-((3′,5′-dichloro-5- (morpholinomethyl)-[1,1′-biphenyl]-3- yl)oxy)pyridin-2-yl)ethane-1,2- diamine 100 [00168] 1-(5-((3′,5′-dichloro-5- ((methylamino)methyl)-[1,1′-biphenyl]- 3-yl)oxy)pyridin-2-yl)piperidin-4- amine 101 [00169] N1-(5-((3′,5′-dichloro-5- ((methylamino)methyl)-[1,1′-biphenyl]- 3-yl)oxy)pyridin-2-yl)propane-1,3- diamine 102 [00170] 1-(3′,5′-dichloro-5-((6-(3,3- dimethylpiperazin-1-yl)pyridin-3-yl) oxy)-[1,1′-biphenyl]-3-yl)-N- methylmethanamine 103 [00171] 1-(5-((6-(1,4-diazepan-1-yl)pyridin-3- yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]- 3-yl)-N-methylmethanamine 104 [00172] 1-(3′,5′-dichloro-5-((6-(4- methylpiperazin-l-yl)pyridin-3-yl) oxy)-[1,1′-biphenyl]-3- yl)-N-methylmethanamine 105 [00173] N-((1-((5-((6-((2-amino-2- methylpropyl)amino)pyridin-3-yl)oxy)- 3′,5′-dichloro-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 106 [00174] N-((1-((5-((6-((3S,4R)-4-amino-3- fluoropiperidin-1-yl)pyridin-3-yl)oxy)- 3′,5′-dichloro-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 107 [00175] N-((1-((3′,5′-dichloro-5-((6-(3- oxohexahydroimidazo[1,5-a]pyrazin- 7(1H)-yl)pyridin-3-yl)oxy)-[1,1′- biphenyl]-3-yl)methyl)piperidin-4- yl)methyl)acetamide 108 [00176] 1-(5-((6-(3-chloro-5-methylphenyl)-4- ((methylamino)methyl)pyridin-2- yl)oxy)pyridin-2-yl)piperidin-4-amine 109 [00177] N-((1-((2-(3,5-dichlorophenyl)-6-((5- (piperazin-1-yl)pyrazin-2-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 110 [00178] N-((1-((2-(3,5-dichlorophenyl)-6-((5- (4-methylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 111 [00179] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrazin-2-yl) piperazin-1-yl)propanoic acid 112 [00180] 2-(1-((2-(3,5-dichlorophenyl)-6-((5- (piperazin-1-yl)pyrazin-2-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl) acetic acid 113 [00181] N-((1-((3′,5′-dichloro-5-((2-(4-(3- hydroxypropyl)piperazin-1-yl) pyrimidin-5-yl)oxy)-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 114 [00182] 3-(1-((3′,5′-dichloro-5-((2-(4-(2- hydroxyethyl)piperazin-1-yl)pyrimidin- 5-yl)oxy)-[1,1′-biphenyl]-3- yl)methyl)piperidin-4-yl)propanoic acid 115 [00183] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3-chloro-5-fluorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)propanoic acid 116 [00184] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3-bromo-5-fluorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)propanoic acid 117 [00185] 2-(1-((3′,5′-dichloro-5-((2-(4- methylpiperazin-1-yl)pyrimidin-5-yl) oxy)-[1,1′-biphenyl]-3-yl)methyl) piperidin-4-yl)acetic acid 118 [00186] N-((1-((2-((2-(1,4-diazepan-1- yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 119 [00187] N-((1-((2-((2-(4-aminopiperidin-1- yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 120 [00188] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl)- N,N-dimethylethanamineoxide 121 [00189] N-((1-((2-(3,5-dichlorophenyl)-6-((5- fluoro-6-(piperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 122 [00190] 2-((1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)oxy)acetic acid 123 [00191] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- hydroxy-1,4-diazepan-1-yl)pyrimidin- 5-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 124 [00192] 2-(1-((2-((2-(4-amino-4-(2- hydroxyethyl)piperidin-1-yl)pyrimidin- 5-yl)oxy)-6-(3,5-dichlorophenyl) pyridin-4-yl)methyl)piperidin-4-yl) acetic acid 125 [00193] ((1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)dimethylphosphineoxide 126 [00194] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methyl-1,4-diazepan-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 127 [00195] 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)azetidin-3- yl)butanoic acid 128 [00196] 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)pyrrolidin-3- yl)oxy)acetic acid 129 [00197] 2-(2-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4- yl)methyl)octahydrocyclopenta[c] pyrrol-5-yl)acetic acid 130 [00198] 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)propanoic acid 131 [00199] 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)-2-methylpropanoic acid 132 [00200] 2-(1-((2-((2-(1,4-diazepan-1-yl) pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4-yl) acetic acid 133 [00201] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(5- methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 134 [00202] (S)-3-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)-2-methylpropanoic acid 135 [00203] 1-(7-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)-2- hydroxyethanone 136 [00204] (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)- 6-((6-(4-methylpiperazin-1-yl)pyridin- 3-yl)oxy)pyridin-4-yl)methyl)-4- azabicyclo[5.1.0]octane-8-carboxylic acid 137 [00205] (R)-3-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)-2-methylpropanoic acid 138 [00206] 1-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)propan-2-ol 139 [00207] 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)-2-hydroxypropanoic acid 140 [00208] 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methyl-1,4-diazepan-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)oxy)acetic acid 141 [00209] 9-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)-2-oxa-4,9- diazaspiro[5.5]undecan-3-one 142 [00210] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetamide 143 [00211] 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)oxy)cyclopropanecarboxylic acid 144 [00212] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- methoxy-4-methyl-1,4-diazepan-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 145 [00213] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (6-fluoro-4-methyl-1,4-diazepan-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 146 [00214] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- hydroxy-4,6-dimethyl-1,4-diazepan-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 147 [00215] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- fluoro-4-methyl-1,4-diazepan-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 148 [00216] 2-(1-((2-(3,5-dichlorophenyl)-6-((4- methyl-2-(4-methylpiperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 149 [00217] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- methyl-6-(4-methylpiperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 150 [00218] 2-(1-((2-(3,5-dichlorophenyl)-6-(4-(4- methylpiperazin-1-yl)phenoxy)pyridin- 4-yl)methyl)piperidin-4-yl)acetic acid 151 [00219] 2-(1-((2-(3,5-dichlorophenyl)-6-((5- fluoro-6-(4-methylpiperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 152 [00220] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(3- (methylamino)pyrrolidin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 153 [00221] (S)-2-(4-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)-1,4- oxazepan-7-yl)ethanol 154 [00222] N-((1R,5S,6r)-3-((2-(3,5-dichloro- phenyl)-6-((2-(4-methyl-1,4- diazepan-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)-3-azabicyclo [3.1.0]hexan-6-yl)acetamide 155 [00223] 1-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)propan-2-one 156 [00224] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- methyl-1,4-diazepan-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 157 [00225] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-methylpiperazin-1-yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 158 [00226] 2-(1-((2-((2-(4-aminopiperidin-1- yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 159 [00227] (S)-2-(1-((2-(3,5-dichlorophenyl)-6-((2- (3-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 160 [00228] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(3, 3-dimethylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 161 [00229] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 162 [00230] 2-(1-((2-((2-(3,6- diazabicyclo[3.1.1]heptan-3-yl) pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4-yl) acetic acid 163 [00231] 2-(1-((2-((2-(3,8-diazabicyclo[3.2.1] octan-3-yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 164 [00232] 2-(1-((2-((2-(4,7-diazaspiro[2.5]octan- 7-yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 165 [00233] 2-(1-((2-((2-(4-amino-4- (hydroxymethyl)piperidin-1-yl) pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4-yl) acetic acid 166 [00234] 2-(1-((2-((6-(1,4-diazepan-1-yl) pyridin-3-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl) acetic acid 167 [00235] N-((1-((3′,5′-dichloro-5-((2-(4-(2- (methylsulfonyl)ethyl)piperazin-1- yl)pyrimidin-5-yl)oxy)-[1,1′- biphenyl]-3-yl)methyl)piperidin-4- yl)methyl)acetamide 168 [00236] 3-(4-(5-((5-(4- (acetamidomethyl)piperidin-1-yl) methyl)-3′,5′-dichloro-[1,1′- biphenyl]-3-yl)oxy)pyrimidin-2- yl)piperazin-1- yl)propanoic acid 169 [00237] 3-(4-(6-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridazin-3-yl) piperazin-1-yl)propanoic acid 170 [00238] 3-(4-(5-((5-((4- (acetamidomethyl)piperidin-1-yl) methyl)-3′,5′-dichloro-[1,1′- biphenyl]-3-yl)oxy)pyrimidin-2- yl)piperazin-1-yl)propanamide 171 [00239] 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-hydroxypropyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)methyl)-3-methylurea 172 [00240] methyl(3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoyl)carbamate 173 [00241] 1-(2-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)ethyl)cyclopropanecarboxylic acid 174 [00242] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1-yl)-2- methylbutanoic acid 175 [00243] methyl(3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrimidin-2-yl) piperazin-1-yl)propanoyl)carbamate 176 [00244] methyl(3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1- yl)propanoyl)carbamate 177 [00245] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (2,3-dihydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 178 [00246] 4-(5-((4-((4-(acetamidomethyl) piperidin-1-yl)methyl)-6-(3,5- dichlorophenyl)pyridin-2-yl)oxy) pyridin-2-yl)-1- methylpiperazinel-oxide 179 [00247] 4-(5-((4-((4-(acetamidomethyl) piperidin-1-yl)methyl)-6-(3,5- dichlorophenyl)pyridin-2-yl)oxy) pyridin-2-yl)-1,1-bis(2-hydroxyethyl) piperazin-1-ium 180 [00248] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2-hydroxyethyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)methyl)acetamide 181 [00249] 4-(5-((4-((4-(acetamidomethyl) piperidin- 1-yl)methyl)-6-(3,5- dichlorophenyl)pyridin-2-yl)oxy) pyridin-2-yl)-1,1-dimethylpiperazin- 1-ium 182 [00250] N-((1-((2-((6-(4-amino-3- fluoropiperidin- 1-yl)pyridin-3-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 183 [00251] N-((1-((2-(3,5-dichlorophenyl)-6-((6- ((1S,4S)-5-(2-(methylsulfonyl)ethyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)methyl)acetamide 184 [00252] N-((1-((2-((6-((3S,4R)-3- (aminomethyl)- 4-hydroxypyrrolidin-1-yl)pyridin-3- yl)oxy)-6-(3,5-dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4- yl)methyl)acetamide 185 [00253] 3-((1R,5S)-3-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl) propanoic acid 186 [00254] (S)-3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)-2- methylpiperazin-1-yl)propanoic acid 187 [00255] 2-(1-((2-((6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin- 3-yl)oxy)-6-(3,5-dichlorophenyl) pyridin-4-yl)methyl)piperidin-4-yl) acetic acid 188 [00256] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1-yl)-2- ethylbutanoic acid 189 [00257] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1-yl)- 2,2-dimethylpropanoic acid 190 [00258] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)-1,4-diazepan-1- yl)propanoic acid 191 [00259] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)-2,2- dimethylpiperazin-1-yl)propanoic acid 192 [00260] N-((1-((2-((6-(1,4-diazepan-1-yl) pyridin-3-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4- yl)methyl)acetamide 193 [00261] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (methylamino)piperidin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 194 [00262] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 195 [00263] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(3- (hydroxymethyl)piperazin-1-yl)pyridin- 3-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 196 [00264] N-((1-((2-((6-(4-aminopiperidin-1- yl)pyridin-3-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 197 [00265] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (3,3-dimethylpiperidin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 198 [00266] N-((1-((2-((6-(4-amino-3,3- dimethylpiperidin-1-yl)pyridin-3-yl) oxy)-6-(3,5-dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 199 [00267] N-((1-((2-((6-(2,7-diazaspiro[4.4]- nonan2-yl)pyridin-3-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 200 [00268] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperidin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 201 [00269] 1-(3′,5′-dichloro-5-((6- (hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3- yl)-N-methylmethanamine 202 [00270] 1-(5-((6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin- 3-yl)oxy)-3′,5′-dichloro-[1,1′-biphenyl]- 3-yl)-N-methylmethanamine 203 [00271] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- ((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin- 3-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 204 [00272] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-(methylsulfonyl)butyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 205 [00273] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-(methylsulfonyl)butyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 206 [00274] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 207 [00275] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 208 [00276] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methylcarbamoyl)oxy)methyl) piperidin-1-yl)methyl)pyridin-2-yl) oxy)pyrimidin- 2-yl)piperazin-1-yl)pentanoic acid 209 [00277] (1-((2-(3,5-dichlorophenyl)-6-((2-(4-(4- hydroxybutan-2-yl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methylmethylcarbamate 210 [00278] (1-((2-(3,5-dichlorophenyl)-6-((2-(4-(3- (methylsulfonyl)propyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methylmethylcarbamate 211 [00279] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methylcarbamoyl)oxy)methyl) piperidin-1-yl)methyl)pyridin-2-yl) oxy)pyrimidin-2-yl)piperazin- 1-yl)cyclobutanecarboxylic acid 212 [00280] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 213 [00281] 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)-2-methylpropanoic acid 214 [00282] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-(methylsulfonyl)butyl)piperazin- 1-yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 215 [00283] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)pentanoic acid 216 [00284] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)cyclobutanecarboxylic acid 217 [00285] methyl((1-((2-(3,5-dichlorophenyl)-6- ((6-(4-(3-(methylsulfonyl)butyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)carbamate 218 [00286] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (3-(methylsulfonyl)butyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 219 [00287] 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (3-(methylsulfonyl)butyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 220 [00288] 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-(methylsulfonyl)butyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 221 [00289] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl) cyclobutanecarboxylic acid 222 [00290] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methoxycarbonyl)amino)methyl) piperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)pentanoic acid 223 [00291] methyl((1-((2-(3,5-dichlorophenyl)-6- ((2-(4-(3-(methylsulfonyl)propyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4- yl)methyl)piperidin-4- yl)methyl)carbamate 224 [00292] 2-((1R,7S,8r)-4-((2-(3,5-dichloro- phenyl)-6-((2-(4-methylpiperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)-4- azabicyclo[5.1.0]octan-8-yl)acetic acid 225 [00293] 2-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)oxy)-2-methylpropanoic acid 226 [00294] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- hydroxy-4-methyl-1,4-diazepan-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 227 [00295] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (dimethylamino)piperidin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 228 [00296] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- methyl-3,6-diazabicyclo[3.1.l]heptan-3- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 229 [00297] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- ((1-hydroxycyclopropyl)methyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 230 [00298] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- ethyl-1,4-diazepan-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 231 [00299] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- ((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 232 [00300] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- ((1S,4S)-5-ethyl-2,5- diazabicyclo[2.2.1]heptan-2-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 233 [00301] 2-(1-((2-((2-(4-cyclopropylpiperazin-1- yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 234 [00302] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- ethylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 235 [00303] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- isopropylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 236 [00304] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-fluoroethyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 237 [00305] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-hydroxybutyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 238 [00306] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(4-hydroxybutan-2-yl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 239 [00307] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(4-(methylamino)butan-2-yl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 240 [00308] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(4-(dimethylamino)butan-2-yl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 241 [00309] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-((methylcarbamoyl)oxy)ethyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 242 [00310] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-(methylsulfonyl)propyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 243 [00311] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (4-(3-(methylsulfonyl)propyl) piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 244 [00312] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2-methoxyethyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4- yl)acetic acid 245 [00313] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-methoxyethyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 246 [00314] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-sulfamoylpropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 247 [00315] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-methoxyethyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 248 [00316] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((methylcarbamoyl)oxy)methyl) piperidin-1-yl)methyl)pyridin-2-yl)oxy) pyrimidin-2-yl)piperazin-1-yl) propanoic acid 249 [00317] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1- yl)butanoic acid 250 [00318] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (2-methoxyethyl)piperazin-1-yl)pyridin- 3-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 251 [00319] N-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 252 [00320] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (4-(3-sulfamoylpropyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 253 [00321] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-sulfamoylpropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 254 [00322] 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (2-methoxyethyl)piperazin-1-yl)pyridin- 3-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-3-methylurea 255 [00323] 1-((1-((2-(3,5-dichlorophenyl)-6-((6-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 256 [00324] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)propanoic acid 257 [00325] 1-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 258 [00326] 3-(4-(5-((5-((4- (acetamidomethyl)piperidin-1-yl) methyl)-3′,5′-dichloro-[1,1′-biphenyl]- 3-yl)oxy)pyridin-2-yl)piperazin-1- yl)propanoic acid 259 [00327] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-(methylsulfonyl)propyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)methyl)acetamide 260 [00328] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyridin-2- yl)piperazin-1-yl)propane-1- sulfonamide 261 [00329] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy) pyrimidin-2-yl)piperazin-1-yl) propanamide 262 [00330] 1-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-methoxyethyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)methyl)-3-methylurea 263 [00331] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrimidin-2-yl) piperazin-1-yl)propanoic acid 264 [00332] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- (4-(3-(methylsulfonyl)propyl) piperazin-1-yl)pyridin-3-yl)oxy) pyridin-4-yl)methyl)piperidin-4- yl)acetamide 265 [00333] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- hydroxy-4-((3- methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy) pyrimidin-2-yl)piperazin-1-yl) propanamide 266 [00334] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)- 3-fluoropyridin-2-yl)piperazin-1- yl)propanoic acid 267 [00335] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (((ethoxycarbonyl)amino)methyl) piperidin-1-yl)methyl)pyridin-2-yl) oxy)pyrimidin-2-yl)piperazin-1-yl) propanoic acid 268 [00336] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (2-(ethylamino)-2-oxoethyl)piperidin- 1-yl)methyl)pyridin-2-yl)oxy) pyrimidin-2-yl)piperazin-1-yl) propanoic acid 269 [00337] 3-(1-((2-(3,5-dichlorophenyl)-6-((2- (piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)-2-methylpropanoic acid 270 [00338] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)-3- fluoropyridin-2-yl)piperazin-1- yl)propanoic acid 271 [00339] 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)propanoic acid 272 [00340] 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)propanoic acid 273 [00341] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3-chloro-4,5- difluorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanamide 274 [00342] 1-((1-((2-(3-chloro-5-fluorophenyl)-6- ((2-(4-(3-(methylsulfonyl)propyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl) methyl)-3-methylurea 275 [00343] methyl((1-((2-(3-chloro-5- fluorophenyl)-6-((2-(piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)methyl)carbamate 276 [00344] 3-(4-(5-((6-(3,5-dichlorophenyl)-4- ((4-(2-(methylsulfonyl)ethyl) piperidin-1-yl)methyl)pyridin-2-yl) oxy)pyridin-2- yl)piperazin-1-yl)propanoic acid 277 [00345] 3-(4-(5-((6-(3,5-dichlorophenyl)-4- ((4-(2-sulfamoylethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyridin-2- yl)piperazin-1-yl)propanoic acid 278 [00346] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-(1-hydroxycyclopropyl)ethyl) piperazin-1-yl)pyrimidin-5-yl)oxy) pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 279 [00347] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-hydroxy-3-methylbutyl) piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 280 [00348] 2-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-hydroxy-2,2-dimethylpropyl) piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 281 [00349] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)butanoic acid 282 [00350] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)butanoic acid 283 [00351] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)-2-methylpropanoic acid 284 [00352] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin- 1-yl)-2-methylpropan amide 285 [00353] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-(methylsulfonyl)ethyl)piperazin- 1-yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 286 [00354] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-sulfamoylethyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 287 [00355] 2-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1- yl)ethanesulfonic acid 288 [00356] 2-((4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyridin-2-yl)piperazin-1- yl)methyl)butanoic acid 289 [00357] N-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2-sulfamoylethyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)methyl)acetamide 290 [00358] 1-((1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2-(methylsulfonyl)ethyl)piperazin- 1-yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 291 [00359] 3-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- ((3-methylureido)methyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)-2-methyl- propanamide 292 [00360] 3-(4-(5-((3′,5′-dichloro-5-((4-((3- methylureido)methyl)piperidin-1- yl)methyl)-[1,1′-biphenyl]-3- yl)oxy)pyrimidin-2-yl)piperazin-1-yl)- 2-methylpropanoic acid 293 [00361] N-((1-((3′,5′-dichloro-5-((6-(4-(2- (methylsulfonyl)ethyl)piperazin-1- yl)pyridin-3-yl)oxy)-[1,1′-biphenyl]-3- yl)methyl)piperidin-4- yl)methyl)acetamide 294 [00362] (S)-3-(4-(5-((6-(3,5-dichlorophenyl)- 4-((4- (((methoxycarbonyl)amino)methyl) piperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)-2-methyl- piperazin-1-yl)propanoic acid 295 [00363] 1-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-hydroxybutyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl) piperidin-4-yl)methyl)-3-methylurea 296 [00364] 3-(3-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl) propanoic acid 297 [00365] methyl3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoate 298 [00366] (R)-2-(1-((2-(3,5-dichlorophenyl)-6- ((2-(4-(2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 299 [00367] (R)-2-(1-((2-(3,5-dichlorophenyl)-6- ((6-(4-(2-hydroxypropyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 300 [00368] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- (2-hydroxyethyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 301 [00369] 3-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- ((R)-2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)-2- methylpropanoic acid 302 [00370] (R)-N-((1-((2-(3,5-dichlorophenyl)-6- ((2-(4-(2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 303 [00371] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-hydroxy-2-methylpropyl) piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 304 [00372] N-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-(3-fluoro-2-hydroxypropyl) piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 305 [00373] (R)-(1-((2-(3,5-dichlorophenyl)-6-((6- (4-(2-hydroxypropyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)methylmethylcarbamate 306 [00374] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- (2-hydroxyethyl)piperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)acetic acid 307 [00375] (1-((2-(3,5-chlorophenyl)-6-((2-(4-(2- hydroxyethyl)piperazin-1-yl)pyrimidin- 5-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methylmethylcarbamate 308 [00376] (R)-(1-((2-(3,5-dichlorophenyl)-6-((2- (4-(2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methylmethylcarbamate 309 [00377] (R)-1-((1-((2-(3,5-dichlorophenyl)-6- ((6-(4-(2-hydroxypropyl)piperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 310 [00378] (R)-1-((1-((2-(3,5-dichlorophenyl)-6- ((2-(4-(2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 311 [00379] methyl((1-((2-(3,5-dichlorophenyl)-6- ((2-(4-(2-hydroxyethyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)carbamate 312 [00380] (R)-methyl((1-((2-(3,5-dichlorophenyl)- 6-((2-(4-(2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)carbamate 313 [00381] 1-((1-((3′,5′-dichloro-5-((2-(4-(2- hydroxyethyl)piperazin-1-yl)pyrimidin- 5-yl)oxy)-[1,1′-biphenyl]-3- yl)methyl)piperidin-4-yl)methyl)-3- methylurea 314 [00382] 3-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- (2-hydroxyethyl)piperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)propanoic acid 315 [00383] N-((1-((2-(3-chloro-5-fluorophenyl)-6- ((2-(4-(2-hydroxyethyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 316 [00384] 3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin- 1-yl)-2-hydroxypropanoic acid 317 [00385] (R)-2-((1-((2-(3,5-dichlorophenyl)-6- ((2-(4-(2-hydroxypropyl)piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)oxy)acetic acid 318 [00386] ((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)boronic acid 319 [00387] (2-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl)pyridin- 2-yl)oxy)pyrimidin-2-yl)piperazin-1- yl)ethyl)boronic acid 320 [00388] ((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)dimethylphosphineoxide 321 [00389] (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)- 6-((2-(4-methylpiperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)-4-azabicyclo[5.1.0]octane- 8-carboxylic acid 322 [00390] ((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methyl-1,4-diazepan-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)boronic acid 323 [00391] (2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)ethyl)boronic acid 324 [00392] (1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methylacetylcarbamate 325 [00393] N-1-((1-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-N′-methoxyl- carbonylurea 326 [00394] N-(((1-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)carbamoyl)methane- sulfonamide 327 [00395] N-(((1-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)carbamoyl)acetamide 328 [00396] N-((1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)carbamoyl)methanesulfonamide 329 [00397] 1-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)urea 330 [00398] (S)-(4-((2-(3,5-dichlorophenyl)-6-((2- (4-methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)-1,4- oxazepan-7-yl)methanol 331 [00399] (1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)dimethylphosphineoxide 332 [00400] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(4- methylpiperazin-1-yl)pyrimidin-5- yl)amino)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 333 [00401] 2-(1-((6-(3,5-dichlorophenyl)-3-methyl- 2-((5-(4-methylpiperazin-1-yl)pyrazin- 2-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 334 [00402] 2-(1-((2-((2-(1,4-diazabicyclo[3.2.1] octan-4-yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 335 [00403] N-((1-((2-((2-(3,8- diazabicyclo[3.2.1]octan-3-yl) pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4- yl)methyl)acetamide 336 [00404] methyl((1-((2-((2-(1,4- diazabicyclo[3.2.1]octan-4-yl) pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4- yl)methyl)carbamate 337 [00405] (1R,7S,8r)-4-((2-((2-(1,4- diazabicyclo[3.2.1]octan-4-yl) pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)pyridin- 4-yl)methyl)-4-azabicyclo[5.1.0] octane-8-carboxylic acid 338 [00406] 4-(5-((6-(3,5-dichlorophenyl)-4-((4- fluoropiperidin-1-yl)methyl)pyridin-2- yl)oxy)pyrimidin-2-yl)-1,4- diazabicyclo[3.2.1]octane 339 [00407] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- methylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 340 [00408] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- methyl-1,4-diazepan-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 341 [00409] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (2-hydroxyethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrazin- 2-yl)piperazin-1-yl)-2-methylbutanoic acid 342 [00410] 2-(1-((2-(3,5-dichlorophenyl)-6-((5- (piperazin-1-yl)pyrazin-2-yl)oxy) pyridin-4-yl)methyl)piperidin-4-yl) ethanol 343 [00411] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- (2-hydroxy-2-methylpropyl)piperazin- 1-yl)pyrazin-2-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 344 [00412] 2-(1-((2-((6-(1,4-diazabicyclo[3.2.1] octan-4-yl)pyridazin-3-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 345 [00413] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- ethyl-1,4-diazepan-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 346 [00414] 2-(1-((2-(3,5-dichlorophenyl)-6-((5- ((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl) pyrazin-2-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 347 [00415] 2-(1-((2-(3,5-dichlorophenyl)-6-((5- (4-isopropylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 348 [00416] 2-(1-((2-((5-(1,4-diazabicyclo[3.2.1] octan-4-yl)pyrazin-2-yl)oxy)-6-(3,5- dichlorophenyl)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 349 [00417] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- (3-hydroxybutyl)piperazin-1-yl) pyrazin-2-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 350 [00418] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- methylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)ethanol 351 [00419] 3-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- methyl-1,4-diazepan-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)-2-methylpropanoic acid 352 [00420] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(6- methyl-3,6-diazabicyclo[3.1.l]heptan-3- yl)pyrazin-2-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 353 [00421] 1-((1-((2-(3,5-dichlorophenyl)-6-((5-(4- methylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)oxy)cyclopropanecarboxylic acid 354 [00422] 2-(1-((2-(3,5-dichlorophenyl)-6-((5-(4- (3-(methylsulfonyl)propyl)piperazin-1- yl)pyrazin-2-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 355 [00423] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- ethyl-1,4-diazepan-1-yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 356 [00424] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- methyl-1,4-diazepan-1-yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid 357 [00425] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- ((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl) pyridazin-3-yl)oxy)pyridin-4-yl) methyl)piperidin-4-yl)acetic acid 358 [00426] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- ethylpiperazin-1-yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 359 [00427] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 360 [00428] 2-(1-((2-(3,5-dichlorophenyl)-6-((6-(4- methylpiperazin-1-yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)ethanol 361 [00429] (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)- 6-((6-(4-methylpiperazin-1-yl) pyridazin-3- yl)oxy)pyridin-4-yl)methyl)-4- azabicyclo[5.1.0]octane-8- carboxylic acid 362 [00430] (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)- 6-((6-(4-methyl-1,4-diazepan-1- yl)pyridazin-3-yl)oxy)pyridin-4- yl)methyl)-4-azabicyclo[5.1.0]octane- 8-carboxylic acid 363 [00431] 3-(4-(6-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridazin-3-yl) piperazin-1-yl)-2- methylpropanoic acid 364 [00432] (R)-3-(1-((2-(3,5-dichlorophenyl)-6- ((6-(4-methylpiperazin-1-yl)pyridazin- 3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)-2-methylpropanoic acid 365 [00433] (S)-3-(1-((2-(3,5-dichlorophenyl)-6- ((6-(4-methylpiperazin-1-yl) pyridazin-3-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)-2-methylpropanoic acid 366 [00434] 2-(1-((2-(3,5-dichlorophenyl)-6-((6- ((1S,4S)-5-ethyl-2,5- diazabicyclo[2.2.1]heptan-2-yl) pyridazin-3-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)acetic acid 367 [00435] 3-(4-(5-((4-(((1R,7S,8r)-8-acetamido- 4-azabicyclo[5.1.0]octan-4-yl)methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin-1- yl)propanoic acid 368 [00436] methyl4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin- 1-yl)-2-methylbutanoate 369 [00437] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin- 1-yl)-2-methylbutanoic acid 370 [00438] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)- 6-(3,5-dichlorophenyl)pyridin-2- yl)oxy)pyrimidin-2-yl)piperazin- 1-yl)-2,2-dimethylbutanoic acid 371 [00439] 2-(1-((6-(3,5-dichlorophenyl)-3- methyl-2-((6-(4-methylpiperazin- 1-yl)pyridazin-3-yl)oxy)pyridin- 4-yl)methyl)piperidin- 4-yl)acetic acid 372 [00440] N-((1-((2-(3-chloro-5-fluorophenyl)-6- ((2-(4-(4-(methylsulfonyl)butan-2- yl)piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)acetamide 373 [00441] 1-((1-((2-(3-chloro-5-fluorophenyl)-6- ((2-(4-(4-(methylsulfonyl)butan-2- yl)piperazin-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)-3-methylurea 374 [00442] 2-(1-((2-(3-chloro-5-fluorophenyl)-6- ((2-(4-methyl-1,4-diazepan-1-yl)p yrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin-4- yl)acetic acid 375 [00443] 2-(1-((2-(3,5-dichlorophenyl)-6- (isopropyl(2-(4-methylpiperazin-1- yl)pyrimidin-5-yl)amino)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 376 [00444] 2-(1-((3′,5′-dichloro-4-fluoro-5-((2-(4- methylpiperazin-1-yl)pyrimidin-5-yl) oxy)-[1,1′-biphenyl]-3-yl)methyl) piperidin-4-yl)acetic acid 377 [00445] 2-(1-((6-(3,5-dichlorophenyl)-3- fluoro-2-((6-(4-methylpiperazin-1-yl) pyridin-3-yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 378 [00446] 2-(1-((6-(3,5-dichlorophenyl)-3- fluoro-2-((2-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin- 4-yl)acetic acid 379 [00447] 2-(1-((6-(3,5-dichlorophenyl)-3- fluoro-2-((2-(4-methylpiperazin-1-yl) pyrimidin-5-yl)oxy)pyridin-4-yl) methyl)piperidin- 4-yl)acetic acid 380 [00448] 2-(1-((6-(3,5-dichlorophenyl)-3- fluoro-2-((4-methyl-2-(4-methyl- piperazin-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 381 [00449] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl)-3- fluoropyridin-2-yl)oxy)pyrimidin- 2-yl)piperazin-1-yl)-2- methylbutanoic acid 382 [00450] 2-(1-((2-((2-(3,8-diazabicyclo[3.2.1] octan-3-yl)pyrimidin-5-yl)oxy)-6-(3,5- dichlorophenyl)-3-fluoropyridin-4- yl)methyl)piperidin-4-yl)acetic acid 383 [00451] 2-(1-((6-(3,5-dichlorophenyl)-3- fluoro-2- ((2-methyl-6-(4-methylpiperazin-1- yl)pyridin-3-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 384 [00452] 2-(1-((6-(3,5-dichlorophenyl)-3- fluoro-2-((6-(4-methylpiperazin-1- yl)pyridazin-3- yl)oxy)pyridin-4-yl)methyl) piperidin-4- yl)acetic acid 385 [00453] methyl3-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyridin-2-yl) piperazin-1-yl)propanoate 386 [00454] 2-(1-((6-(3,5-dichlorophenyl)-3- methyl-2-((6-(4-methylpiperazin- 1-yl)pyridin-3- yl)oxy)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 387 [00455] 2-(1-((2-((2-(4-((1H-l,2,3-triazol-5- yl)methyl)piperazin-1-yl)pyrimidin-5- yl)oxy)-6-(3,5-dichlorophenyl)pyridin- 4-yl)methyl)piperidin-4-yl)acetic acid 388 [00456] 2-(1-((2-(3,5-dichlorophenyl)-6- (methyl(2-(4-methylpiperazin-1- yl)pyrimidin-5-yl)amino)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 389 [00457] 2-(1-((2-(3,5-dichlorophenyl)-6-(ethyl (2-(4-methylpiperazin-1-yl)pyrimidin- y5-l)amino)pyridin-4-yl)methyl) piperidin-4-yl)acetic acid 390 [00458] 2-(1-((6-(3,5-dichlorophenyl)-3-fluoro- 2-((5-(4-methylpiperazin-1-yl)pyrazin- 2-yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)acetic acid 391 [00459] 3-(4-(5-((4-(4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2-yl)oxy)pyrazin-2-yl) piperazin-1-yl)propanamide 392 [00460] 4-(4-(5-((6-(3,5-dichlorophenyl)-4-((4- (propionamidomethyl)piperidin-1- yl)methyl)pyridin-2-yl)oxy)pyrazin-2- yl)piperazin-1-yl)-2-methylbutanoic acid 393 [00461] N-((1-((2-(3,5-dichlorophenyl)-6-((5-(4- (1-hydroxypropan-2-yl)piperazin-1- yl)pyrazin-2-yl)oxy)pyridin-4- yl)methyl)piperidin-4- yl)methyl)acetamide 394 [00462] 1-((1-((2-(3,5-dichlorophenyl)-6-((5-(4- methylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)methyl)-3-methylurea 395 [00463] methyl((1-((2-(3,5-dichlorophenyl)-6- ((5-(4-methylpiperazin-1-yl)pyrazin-2- yl)oxy)pyridin-4-yl)methyl)piperidin- 4-yl)methyl)carbamate 396 [00464] 4-(4-(5-((4-((4- (acetamidomethyl)piperidin-1-yl) methyl)-6-(3,5-dichlorophenyl) pyridin-2- yl)oxy)pyrazin-2-yl)piperazin-1-yl)- 2-methylbutanoic acid 397 [00465] (1R,7S,8r)-4-((2-(3,5-dichlorophenyl)- 6-((2-(4-methyl-1,4-diazepan-1- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)-4-azabicyclo[5.1.0]octane- 8-carboxylic acid 398 [00466] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(8- methyl-3,8-diazabicyclo[3.2.1]octan-3- yl)pyrimidin-5-yl)oxy)pyridin-4- yl)methyl)piperidin-4-yl)acetic acid 399 [00467] 2-(1-((2-(3,5-dichlorophenyl)-6-((2-(6- fluoro-1,4-diazepan-1-yl)pyrimidin-5- yl)oxy)pyridin-4-yl)methyl)piperidin-4- yl)acetic acid [00468]

[0162] Typically, but not absolutely, the salts of the present disclosure are pharmaceutically acceptable salts. Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and naphthalene-2-sulfonates.

[0163] Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases, such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.

[0164] Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this disclosure and these should be considered to form a further aspect of this disclosure. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of this disclosure and their pharmaceutically acceptable salts.

[0165] This disclosure further provides a pharmaceutical composition useful in the present disclosure (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

[0166] Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of this disclosure once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

[0167] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0168] Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s). The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0169] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0170] A therapeutically effective amount of a compound of the present disclosure will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication. However, an effective amount of a compound of Formula (I) for the treatment of a viral infection (e.g., resulting from a virus (e.g., dengue, Marburg, Chikungunya viruses) will generally be in the range of 0.001 to 100 mg/kg body weight of recipient per day, suitably in the range of 0.01 to 10 mg/kg body weight per day. For a 70 kg adult mammal, the actual amount per day would suitably be from 7 to 700 mg and this amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. Inhaled daily dosages range from 10 μg-10 mg/day, with preferred 10 μg-2 mg/day, and more preferred 50 μg-500 μg/day. An effective amount of a salt or solvate, etc., may be determined as a proportion of the effective amount of the compound of Formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.

[0171] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, the kit comprises a compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition). In certain embodiments, each of the first or second containers are independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.

[0172] In certain embodiments, a kit described herein includes a first container comprising a compound of Formula (I) or a pharmaceutical composition as described herein. In certain embodiments, a kit described herein is useful in treating and/or preventing a viral infection, such as a viral infection resulting from Marburg virus. In certain embodiments, a kit described herein is useful in treating and/or preventing a viral infection, such as a viral infection resulting from dengue virus. In certain embodiments, a kit described herein is useful in treating and/or preventing a viral infection, such as a viral infection resulting from Chikungunya virus.

[0173] In certain embodiments, the kit comprises a compound of Formula (I), or a pharmaceutical composition thereof; and instructions for using the compound or pharmaceutical composition.

[0174] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a viral infection (e.g., an infection resulting from Marburg virus, dengue virus, Chikungunya virus).

[0175] In certain embodiments, the instructions are for administering the compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information.

EXAMPLES

Example 1. Percent Inhibition of Different Viruses Using the Compounds of Formula (I)

Cell Preparation

[0176] Each compound was tested at 1 μM dilution. One day before cell infection, Vero cells were seeded in a 96-well plate at 1.00E+04 μM per well. One day later, the cell medium was aspirated and 99 μL of medium was added to wells testing 1 μM compound. Next, 1 μL of compound was added to bring the total volume to 200 μM, and the medium was incubated for 1 hour.

Virus Dilutions and Incubation

[0177] Virus dilutions were prepared with infection medium in a 15 or 50 mL conical tube. The virus dilution was poured into a sterile reservoir. 100 μL of the virus dilutions was added to the wells in the 96-well plate and the plates incubated at 37° C. for 2-5 days: 2 days for Chikungunya virus (CHIKV), 3 days for Marburg virus (MARV), and 5 days for dengue virus (DENV).

[0178] 50 μL crystal violet solution was added to each well, and fixed/stained for 30-60 minutes at room temperature. The crystal violet stain was removed over the sink and the wells rinsed with tap water. The plates were tapped on absorbent paper and read on a plate reader at 570 nM.

[0179] The data in Table 2 represents the percentage of inhibition detected for each tested compound (from 2 technical replicates) at the dilution 1 μM with CHIKV, DENV, and MARV.

TABLE-US-00002 TABLE 2 Percent viral inhibition of selected compounds of Formula (1) Example CHKV DENY MARV 1 6.99 0.00 0.00 2 33.78 34.28 60.40 4 18.38 16.63 70.75 6 0.00 0.00 0.00 7 9.36 12.89 51.94 8 1.77 14.65 10.94 10 13.11 8.50 34.76 11 17.90 30.16 41.64 12 24.68 58.29 44.53 13 15.92 26.52 25.45 14 3.02 0.00 17.31 16 4.14 41.66 28.57 17 7.16 57.38 52.85 19 21.61 35.51 79.75 21 26.19 8.18 46.43 22 26.75 64.39 52.49 23 21.57 10.96 52.53 24 34.56 25.78 63.07 25 26.32 13.69 65.55 27 26.83 51.12 50.27 30 10.09 44.33 15.46 31 18.68 38.93 61.39 32 49.44 34.22 63.47 33 36.54 49.41 67.27 34 1.42 46.79 30.29 36 5.78 38.02 52.49 37 32.92 100.00 56.56 38 39.09 14.17 50.05 39 23.73 54.71 60.13 40 3.24 0.00 0.00 41 30.07 68.72 42.99 42 7.42 23.96 0.00 44 35.50 69.04 49.05 45 0.00 0.00 18.40 48 15.23 26.04 15.73 50 4.75 32.73 35.62 51 21.14 56.68 43.58 52 26.27 45.56 29.88 53 29.98 42.51 53.53 54 36.80 70.53 62.70 55 16.82 3.58 40.19 56 31.28 57.11 60.85 57 21.14 37.65 54.43 59 35.12 53.74 57.50 60 38.78 78.98 53.57 61 22.04 65.40 29.20 62 35.25 19.09 19.85 63 0.00 2.35 14.74 64 6.90 36.95 37.79 66 7.64 57.86 60.67 70 0.00 0.00 5.52 72 33.69 11.18 55.79 77 42.02 20.59 57.19 80 25.02 0.00 64.60 81 26.14 50.53 73.73 82 18.42 19.79 53.21 83 33.39 28.88 53.80 87 16.91 30.16 30.29 88 10.87 54.65 58.63 89 0.00 35.51 0.00 90 44.18 54.92 75.45 91 41.54 48.29 55.11 93 0.00 56.68 10.44 94 31.28 41.50 66.00 95 46.64 58.07 59.04 98 0.00 0.00 0.00 99 0.00 15.4 0.00 105 0.00 19.95 0.00 108 16.39 0.00 65.69 109 7.33 0.00 32.87 110 9.88 13.58 59.45 111 22.30 48.82 29.79 114 26.62 38.07 74.19 115 4.53 2.30 59.18 116 10.4 6.7 4.3 117 17.99 28.56 43.58 118 0.00 15.61 0.00 120 0.00 47.01 22.33 122 35.46 33.69 23.55 123 19.24 39.89 50.59 124 21.18 1.28 63.83 126 23.64 8.34 38.52 127 25.97 0.00 52.12 128 3.67 7.97 51.40 129 23.64 38.50 29.75 130 28.43 32.99 33.27 131 3.11 20.70 52.44 132 35.16 32.83 46.75 133 43.36 47.81 54.02 134 0.00 43.16 45.12 135 12.81 56.20 51.27 136 39.82 17.97 57.78 138 21.70 54.92 32.37 140 32.73 14.06 51.54 141 20.92 27.71 66.64 142 15.36 51.55 49.10 143 34.43 34.49 40.46 144 32.61 35.03 56.65 145 23.25 32.83 30.83 146 23.12 41.82 66.18 147 31.71 42.83 44.21 150 17.00 59.95 56.92 152 16.31 18.98 44.12 153 14.06 41.55 56.78 155 14.54 8.98 42.04 156 38.35 43.90 13.16 157 25.28 53.42 77.53 158 2.85 19.30 17.99 159 22.91 17.49 49.77 160 21.74 49.47 35.13 161 28.52 32.99 44.94 162 30.80 41.44 72.78 163 22.04 32.46 34.40 164 34.60 45.51 36.12 165 18.64 36.90 50.86 166 35.33 21.28 45.03 167 0.00 41.28 0.00 168 29.64 38.88 60.26 169 0.00 0.00 16.37 170 7.29 57.59 10.31 171 0.00 41.71 0.00 174 19.76 28.56 46.88 177 14.28 24.01 37.03 178 30.41 71.07 57.69 179 5.87 42.09 27.40 180 0.00 10.37 25.41 181 11.73 49.09 12.52 183 16.39 21.02 74.77 185 22.86 0.00 64.15 186 19.93 53.90 30.65 187 22.43 83.96 24.10 190 2.11 41.82 44.80 191 14.15 71.18 50.63 195 18.12 39.36 38.20 199 21.57 49.04 18.54 200 31.67 37.11 41.59 203 23.64 7.17 55.20 204 9.15 37.33 50.81 205 23.68 57.59 77.62 206 34.43 29.30 50.77 207 26.27 47.86 42.22 208 46.29 68.61 55.24 210 3.75 21.02 32.64 211 44.69 13.26 62.52 213 26.53 27.97 49.28 214 3.02 18.13 18.13 215 32.53 24.44 56.69 216 21.40 8.34 38.52 217 3.19 34.87 8.18 218 0.00 5.51 0.00 220 27.91 62.46 46.88 221 44.39 25.94 63.25 222 25.02 17.65 60.04 224 33.09 71.98 52.26 225 24.25 33.26 52.31 226 26.66 58.93 41.37 227 40.55 53.96 54.48 228 17.26 31.87 36.17 229 43.18 54.81 23.73 230 35.16 4.22 49.41 231 25.84 44.17 66.64 232 37.06 19.52 43.40 233 16.26 55.72 57.14 234 26.66 36.90 49.10 235 27.44 0.00 69.76 236 39.82 64.49 68.49 237 36.97 52.14 37.70 238 35.76 66.10 56.83 240 28.52 36.79 67.41 241 32.44 43.37 73.10 242 31.92 16.42 55.47 243 14.62 37.91 46.79 244 6.34 14.01 61.44 245 24.07 53.32 53.89 246 24.59 50.80 39.87 247 31.10 50.05 49.68 248 34.81 81.23 49.64 249 32.48 48.56 51.40 250 25.93 55.03 0.00 251 0.00 45.45 38.88 252 33.18 23.26 53.53 253 36.15 27.33 52.08 254 5.74 56.95 40.37 255 16.13 10.32 40.14 256 30.41 47.17 49.32 257 10.27 46.52 26.54 258 24.50 48.18 59.63 259 14.97 46.95 67.18 261 0.69 53.58 56.78 262 18.98 10.27 39.29 263 28.86 39.73 48.46 264 19.20 46.84 32.46 266 22.61 48.72 56.28 267 34.56 37.01 65.01 268 18.38 57.70 68.08 269 24.46 39.47 35.04 270 30.72 61.60 53.62 271 22.52 0.00 59.67 272 30.28 42.41 45.48 273 23.43 25.35 58.54 274 44.43 56.15 49.01 275 0.00 0.00 0.00 276 31.84 27.27 51.81 277 11.73 21.71 61.80 278 45.60 45.51 81.74 279 37.83 27.49 18.76 281 31.62 55.99 38.79 282 8.20 21.82 63.74 283 29.77 43.80 49.59 285 35.29 22.89 80.38 286 0.00 0.00 19.17 287 7.89 29.41 56.69 288 28.17 52.19 49.14 289 28.95 43.48 40.64 290 0.00 18.88 50.59 292 15.92 25.99 54.25 293 0.00 0.00 0.00 294 28.73 57.70 54.25 298 20.66 57.01 55.11 300 18.25 0.00 45.03 301 28.82 56.15 68.40 302 39.04 26.58 56.87 303 33.39 34.44 49.64 304 0.00 41.76 12.43 306 13.59 7.27 51.08 308 0.00 0.00 23.73 310 2.85 19.30 17.99 311 8.41 0.00 17.54 314 32.05 7.86 52.12 315 26.19 41.28 89.15 316 30.59 55.94 54.43 317 14.75 20.21 53.62 318 15.31 44.60 31.65 320 17.47 15.29 52.49 321 23.81 27.27 43.44 323 5.87 0.00 30.74 325 0.00 5.08 0.00 326 22.74 45.45 63.92 327 0.00 0.00 63.79 328 37.53 55.83 49.50 329 22.17 19.25 42.31 330 24.59 26.42 58.68 331 22.61 56.47 69.30 334 29.55 20.75 41.41 337 15.92 0.00 37.57 338 19.33 55.35 12.21 339 23.60 0.00 52.08 340 21.66 40.32 41.73 341 29.25 31.18 50.50 343 35.72 28.61 50.95 344 26.62 77.91 43.49 345 22.13 44.01 56.96 346 9.36 54.60 56.83 347 24.85 56.84 57.73 348 35.81 55.78 46.65 349 26.19 57.59 64.51 350 0.00 22.83 29.93 351 22.74 42.78 60.44 352 31.02 13.10 47.92 353 16.61 51.34 35.44 354 17.17 40.80 45.16 355 22.04 30.16 52.35 356 30.80 49.30 54.29 357 38.61 61.23 100.00 358 20.36 67.11 48.96 359 28.90 45.29 62.03 360 0.00 2.83 3.44 361 26.57 12.09 42.00 362 14.93 50.16 50.90 363 0.00 0.00 2.80 364 31.36 40.05 47.60 365 0.00 32.41 17.45 366 6.17 48.45 23.06 367 27.39 14.97 54.70 368 32.48 65.83 65.37 369 32.92 33.26 47.15 370 24.63 41.66 56.96 372 18.25 81.82 45.34 373 28.82 53.42 67.77 374 17.64 38.50 48.60 376 13.46 0.00 12.70 379 41.50 35.24 51.18 385 14.88 48.50 56.74 387 36.32 39.89 41.41 391 14.02 51.44 35.44 392 15.75 34.87 60.58 395 0.00 88.24 37.25 396 21.48 46.26 26.67 397 25.06 38.72 46.16 399 21.83 76.15 61.39

Example 2. In-Vitro Antiviral Activity of Example 369

[0180] In vitro studies of the antiviral activity were also carried out for several viruses using Example 369. The results are summarized in Table 3.

TABLE-US-00003 TABLE 3 In vitro viral inhibition using Example 369 EC.sub.50 (ug/mL) EC.sub.50 (ug/mL) (Neutral Red (NR) Virus (strain; cell) (VIS Drug Assay) Assay) Chikungunya (S27; Vero 76) 0.12 0.18 Dengue Virus 2 (New Guinea <0.1 <0.1 C; Huh7) Eastern equine encephalitis <0.1 <0.1 (FL39-939; Vero 76) Japanese encephalitis virus 0.32 3.0 (SA-14; Vero 76) Mayaro virus (BE AR 505411; 0.32 0.28 Vero 76) Measles (CC; Vero 76) <0.1 <0.1 Powassan virus (LB; BHK-21) <0.1 <0.1 Respiratory syncytial virus (A.sub.2; 028 0.3 RD) Usutu virus (TC-508; Vero 76) 2.7 5.8 Venezuelan equine encephalitis 0.55 0.77 (TC-83; Vero 76) Western equine encephalitis <0.1 <0.1 (California; Vero 76) Yellow Fever (YFV 17D; 0.18 0.18 Huh7)

Example 3. Compound Preparation

[0181] The compounds of this disclosure may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below (e.g., see Schemes 1, 2, and 3). The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.

TABLE-US-00004 Abbreviations Ac.sub.2O acetic anhydride AcOH acetic acid AIBN azobisisobutyronitrile aq. aqueous BBr.sub.3 boron tribromide BF.sub.3•OEt.sub.2 boron trifluoride diethyl etherate BH.sub.3•DMS borane dimethyl sulfide complex (±)-BINAP racemic 2,2'-bis(diphenylphosphino)-1,1'- binaphthalene Bn benzyl BnOH benzyl alcohol Boc.sub.2O di-tert-butyl decarbonate BPin 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Br.sub.2 bromine CaCl.sub.2 calcium chloride CBr.sub.4 carbon tetrabromide CbzCl benzyl chloroformate CCl.sub.4 carbon tetrachloride CDI 1,1'-carbonyldiimidazole Cl.sub.2 chlorine gas Cs.sub.2CO.sub.3 cesium carbonate CuI copper(I) iodide CuSO.sub.4 copper(II) sulfate DAST diethylaminosulfur trifluoride DCE dichloroethane DCM or CH.sub.2Cl.sub.2 dichloromethane DEAD diethyl azodicarboxylate Dess-Martin 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol- 3-(1H)-one DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF N, N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EA or EtOAc ethyl acetate EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ES-LCMS electrospray liquid chromatography-mass spectrometry EtI ethyl iodide EtMgBr ethylmagnesium bromide Et.sub.3N triethylamine EtOH ethanol g gram(s) Grubbs I benzylidene-bis(tricyclohexylphosphine) dichlororuthenium h hour(s) H2 hydrogen gas HATU O-(7-azabenzotriazol-1-yl)-N, N, N’, N”- tetramethyluronium hexafluorophosphate HCl hydrochloric acid H.sub.2O water HOBt hydroxybenzotriazole HPLC high performance liquid chromatography in vacuo under vacuum i-PrOH isopropyl alcohol [Ir(COD)OMe].sub.2 di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) KCN potassium cyanide K.sub.2CO.sub.3 potassium carbonate KI potassium iodide KOAc potassium acetate K.sub.3PO.sub.4 potassium phosphate tribasic L liter(s) LAH or LiAlH.sub.4 lithium aluminium hydride LCMS liquid chromatography-mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide LiOH lithium hydroxide LiOH•H.sub.2O lithium hydroxide monohydrate M molar m-CPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeI methyl iodide MeMgBr methylmagnesium bromide MeNH.sub.2 methylamine MeOH methanol MgSO.sub.4 magnesium sulfate min minute(s) mL milliliter(s) mmol millimole(s) mol mole(s) MsCl methanesulfonyl chloride MTBE methyl tert-butyl ether N normal N.sub.2 nitrogen gas NaBH.sub.4 sodium borohydride NaBH.sub.3CN sodium cyanoborohydride NaBH(OAc).sub.3 sodium triacetoxyborohydride NaCN sodium cyanide NaH sodium hydride NaHCO.sub.3 sodium bicarbonate NaOH sodium hydroxide Na.sub.2SO.sub.4 sodium sulfate NBS N-bromosuccinimide n-BuLi n-butyllithium n-BuMgCl n-butylmagnesium chloride NH.sub.3 ammonia NH.sub.4Cl ammonium chloride NH.sub.4OAc ammonium acetate NH.sub.4OH ammonium hydroxide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance OTf trifluoromethanesulfonate Oxone ® potassium peroxymonosulfate Pd(OAc).sub.2 palladium(II) acetate Pd/C palladium on carbon PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) Pd(OH).sub.2 palladium(II) hydroxide Pd(PPh.sub.3).sub.2Cl.sub.2 bis(triphenylphosphine)palladium(II) dichloride PE petroleum ether POCl.sub.3 phosphoryl chloride PPh.sub.3 triphenylphosphine p-TsCl para-toluenesulfonyl chloride p-TsOH para-toluenesulfonic acid SFC supercritical fluid chromatography SOCl.sub.2 thionyl chloride TBAF tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl TBSCl tert-butyldimethylsilyl chloride t-BuOH tert-butyl alcohol t-BuOK potassium tert-butoxide t-BuONa sodium tert-butoxide TFA trifluoroacetic acid Tf.sub.2O trifluoromethanesulfonic anhydride THF tetrahydrofuran TLC thin layer chromotrography TMS-N.sub.3 trimethylsilyl azide TosMIC para-toluenesulfonylmethyl isocyanide Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Zn zinc metal

[0182] Certain compounds of Formula (I) can be prepared according to Schemes 1, 2, or 3, or analogous or other methods known in the art.

##STR00469##

##STR00470##

##STR00471##

Experimentals

[0183] These examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the compounds in the methods and uses of the disclosure. While particular embodiments of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the disclosure. Unless otherwise noted, reagents are commercially available or are prepared according to procedures in the literature. The symbols and conventions used in the descriptions of processes, schemes, and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0184] Preparative HPLC was performed on a Gilson UV/VIS-156 with UV detection at 220/254 nm Gilson 281 automatic collection. HPLC column commonly used ASB-C18 21.2×150 mm or Phenomenex 21.2×150 mm. HPLC Gradient (acidic condition, 0.01% HCl or 0.1% formic acid) used 0-100% acetonitrile with water and corresponding acid, the gradient shape was optimized for individual separations. Unless specially mentioned, compounds are isolated in HCl system and thus obtained as HCl salts. However, the compounds can also be isolated and used as the free base. HPLC Gradient (basic condition, 0.05% NH.sub.3—H.sub.2O or neutral condition, 0.01% NH.sub.4HCO.sub.3) was optimized for individual separation.

[0185] Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (single), d (double), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), and br (broad).

[0186] Flash column chromatography was performed using silica gel.

[0187] The naming programs used are ACDLABs 11.0 Namebatch, ACD IUPAC, or ChemDraw.

Intermediate 1: tert-Butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0188] ##STR00472##

[0189] Intermediate 1 was prepared according to the following steps.

Step 1: 5-(Benzyloxy)-2-chloropyrimidine

[0190] ##STR00473##

[0191] To a mixture of 2-chloropyrimidin-5-ol (45 g, 345 mmol) in DMF (1 L) was added Cs.sub.2CO.sub.3 (337 g, 1034 mmol) and (bromomethyl)benzene (49.1 mL, 414 mmol). The mixture was stirred at 15° C. for 8 h under N.sub.2 atmosphere. Then the mixture was concentrated and saturated aqueous NaHCO.sub.3 solution (150 mL) was added. The aqueous layer was extracted with EtOAc (500 mL×2), and the combined extracts were washed with brine (150 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated to yield a yellow oil of 5-(benzyloxy)-2-chloropyrimidine (78 g, 318 mmol, 92.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.45 (s, 2H), 7.52-7.29 (m, 5H), 5.23 (s, 2H); ES-LCMS m/z 221.2, 223.1 [M+H].sup.+.

Step 2: tert-Butyl 4-(5-(benzyloxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0192] ##STR00474##

[0193] To a mixture of 5-(benzyloxy)-2-chloropyrimidine (15 g, 61.2 mmol) and tert-butyl piperazine-1-carboxylate (17.09 g, 92 mmol) in DMF (200 mL) was added Cs.sub.2CO.sub.3 (59.8 g, 184 mmol). The mixture was stirred at 120° C. for 10 h. The reaction mixture was concentrated and purified by silica gel column chromatography (PE/EtOAc=5/1). All fractions found to contain product by TLC (PE/EA=3/1, R.sub.f=0.6) were combined and concentrated to yield a white solid of tert-butyl 4-(5-(benzyloxy)pyrimidin-2-yl)piperazine-1-carboxylate (10 g, 25.6 mmol, 41.9% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.13 (s, 2H), 7.43-7.31 (m, 5H), 5.03 (s, 2H), 3.75-3.65 (m, 4H), 3.56-3.43 (m, 4H), 1.49 (s, 9H); ES-LCMS m/z 371.3 [M+H].sup.+.

Step 3: tert-Butyl 4-(5-hydroxypyrimidin-2-yl)piperazine-1-carboxylate

[0194] ##STR00475##

[0195] To a solution of tert-butyl 4-(5-(benzyloxy)pyrimidin-2-yl)piperazine-1-carboxylate (10 g, 25.6 mmol) in MeOH (30 mL) was added Pd/C (10 wt %, 2.73 g, 2.56 mmol). The mixture was stirred under 1 atm H.sub.2 atmosphere at 15° C. for 0.5 h. The mixture was filtered and concentrated to yield a light yellow solid of tert-butyl 4-(5-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (7.5 g, 22.74 mmol, 89.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.03 (s, 2H), 3.70-3.59 (m, 4H), 3.50 (d, J=4.5 Hz, 4H), 1.50 (s, 9H); ES-LCMS m/z 225.2 [M-t-Bu+H].sup.+.

Step 4: tert-Butyl 4-(5-((6-chloro-4-(methoxycarbonyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0196] ##STR00476##

[0197] To a mixture of methyl 2,6-dichloroisonicotinate, hydrochloride (6.7 g, 27.4 mmol) and tert-butyl 4-(5-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (7.4 g, 22.44 mmol) in DMF (80 mL) was added K.sub.2CO.sub.3 (9.30 g, 67.3 mmol). The mixture was stirred at 50° C. for 10 h. Then the solution was concentrated and saturated aqueous NaHCO.sub.3 solution (150 mL) was added. The aqueous layer was extracted with DCM (500 mL×2), and the combined extracts were washed with brine (150 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude material was purified by silica gel column chromatography (PE/EtOAc=5/1). All fractions found to contain product by TLC (PE/EA=3/1, R.sub.f=0.5) were combined and concentrated to yield a yellow oil of tert-butyl 4-(5-((6-chloro-4-(methoxycarbonyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (8.4 g, 16.80 mmol, 74.9% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.31 (s, 2H), 7.62 (s, 1H), 7.51 (s, 1H), 3.99 (s, 3H), 3.90-3.80 (m, 4H), 3.55 (m, 4H), 1.51 (s, 9H); ES-LCMS m/z 394.2, 396.1 [M-t-Bu+H].sup.+.

Step 5: tert-Butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(methoxycarbonyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0198] ##STR00477##

[0199] To a mixture of tert-butyl 4-(5-((6-chloro-4-(methoxycarbonyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (8 g, 16.00 mmol) and (3,5-dichlorophenyl)boronic acid (7.63 g, 40.0 mmol) in DMF (100 mL) was added K.sub.2CO.sub.3 (6.64 g, 48.0 mmol) and PdCl.sub.2(dppf) (0.586 g, 0.800 mmol). The mixture was stirred at 80° C. for 2 h under N.sub.2 atmosphere. The mixture was concentrated and purified by silica gel column chromatography (PE/EtOAc=5/1). All fractions found to contain product by TLC (PE/EA=3/1, R.sub.f=0.4) were combined and concentrated to yield a colorless oil of tert-butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(methoxycarbonyl)pyridine-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (7.4 g, 11.22 mmol, 70.1% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.30 (s, 2H), 7.95 (s, 1H), 7.75 (d, J=1.3 Hz, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 4.00 (s, 3H), 3.89-3.75 (m, 4H), 3.60-3.45 (m, 4H), 1.49 (s, 9H); ES-LCMS m/z 504.1, 506.1 [M-t-Bu+H].sup.+.

Step 6: tert-Butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(hydroxymethyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0200] ##STR00478##

[0201] To a mixture of tert-butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(methoxycarbonyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (7.4 g, 11.22 mmol) in MeOH (150 mL) was added NaBH.sub.4 (2.123 g, 56.1 mmol). The mixture was stirred at 15° C. for 10 min under N.sub.2 atmosphere then concentrated and saturated aqueous NaHCO.sub.3 solution (150 mL) was added. The aqueous layer was extracted with DCM (500 mL×2) and the combined extracts were washed with brine (150 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated to yield a yellow oil of tert-butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(hydroxymethyl)pyridine-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (7.2 g, 10.82 mmol, 96.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.35 (s, 2H), 7.81 (s, 2H), 7.60 (s, 1H), 7.44 (s, 1H), 7.06 (s, 1H), 4.75 (s, 2H), 3.89-3.82 (m, 4H), 3.54 (m, 4H), 1.51 (s, 9H); ES-LCMS m/z 532.2, 534.2 [M+H].sup.+.

Step 7: tert-Butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0202] ##STR00479##

[0203] To a mixture of tert-butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(hydroxymethyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (4.5 g, 6.76 mmol) in DCM (150 mL) was added MsCl (0.79 mL, 10.14 mmol) and DIEA (3.54 mL, 20.28 mmol). The mixture was stirred at 15° C. for 10 min under N.sub.2 atmosphere. Then the solution was concentrated and saturated aqueous NaHCO.sub.3 solution (150 mL) was added. The aqueous layer was extracted with DCM (500 mL×2), and the combined extracts were washed with brine (150 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated to yield a yellow oil of tert-butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (5 g, 6.55 mmol, 97.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.37 (s, 2H), 7.85 (s, 2H), 7.48 (s, 1H), 7.41 (s, 1H), 7.16 (s, 1H), 3.86 (d, J=5.5 Hz, 6H), 3.55 (s, 4H), 3.25-3.23 (m, 3H), 1.51 (s, 9H); ES-LCMS m/z 554.2, 556.2 [M-t-Bu+H].sup.+.

Example 92: N-((1-((2-(3,5-Dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide

[0204] ##STR00480##

[0205] Example 92 was prepared according to the following steps.

Step 1: tert-Butyl 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[0206] ##STR00481##

[0207] To a mixture of tert-butyl 4-(5-((6-(3,5-dichlorophenyl)-4-(((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.328 mmol), N-(piperidin-4-ylmethyl)acetamide hydrochloride (127 mg, 0.655 mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (181 mg, 1.310 mmol). The reaction was stirred at 50° C. for 8 h under N.sub.2 atmosphere then concentrated. Saturated aqueous NaHCO.sub.3 solution (15 mL) was added and the aqueous layer was extracted with DCM (150 mL×2). The combined extracts were washed with brine (15 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated to yield a yellow oil of tert-butyl 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.18 mmol, 54.6% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.33-8.21 (m, 3H), 7.78-7.64 (m, 2H), 7.48-7.28 (m, 2H), 3.82 (br. s, 4H), 3.52 (br. s, 4H), 3.25-3.07 (m, 4H), 2.85-2.90 (m, 4H), 1.99 (d, J=2.5 Hz, 3H), 1.90-1.80 (m, 5H), 1.49-1.40 (m, 9H); ES-LCMS m/z 670.3, 672.3 [M+H].sup.+.

Step 2: N-((1-((2-(3,5-Dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide, 4 hydrochloride

[0208] ##STR00482##

[0209] To a mixture of tert-butyl 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 0.149 mmol) in DCM (10 mL) was added TFA (0.287 mL, 3.73 mmol). The reaction was stirred at 15° C. for 10 min under N.sub.2 atmosphere then concentrated and purified by preparative HPLC (MeCN/H.sub.2O as eluents, acidic condition) to yield a yellow solid of N-((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridine-4-yl)methyl)piperidin-4-yl)methyl)acetamide, 4 hydrochloride (5.39 mg, 7.45 μmol, 5.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.45 (s, 2H), 7.91 (s, 1H), 7.87 (d, J=1.8 Hz, 2H), 7.51 (t, J=1.8 Hz, 1H), 7.34-7.27 (m, 1H), 4.43 (s, 2H), 4.15-4.10 (m, 4H), 3.60 (d, J=12.3 Hz, 2H), 3.34 (d, J=5.3 Hz, 4H), 3.14-3.05 (m, 4H), 2.02-1.94 (m, 5H), 1.85 (br. s, 1H), 1.62-1.51 (m, 2H); ES-LCMS m/z 570.3, 572.3 [M+H].sup.+.

Example 368: methyl4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoate

[0210] ##STR00483##

[0211] To a solution of N-((1-((2-(3,5-dichlorophenyl)-6-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide, 4 hydrochloride (3.3 g, 4.38 mmol) and methyl 4-bromo-2-methylbutanoate (2.85 g, 13.13 mmol) in DMF (50 mL) was added K.sub.2CO.sub.3 (4.84 g, 35.0 mmol). Then the reaction mixture was stirred at 80° C. for 12 h. The solid was filtered off and solvent was removed in vacuo to give the crude product which was purified by chromatography (from pure DCM to DCM/MeOH=10/1, TLC: DCM/MeOH=10/1, R.sub.f=0.45) to yield a yellow solid of methyl 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoate (2.3 g, 2.88 mmol, 65.9% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.31-8.22 (m, 2H), 7.73-7.64 (m, 2H), 7.43-7.36 (m, 1H), 7.34-7.27 (m, 1H), 6.85 (s, 1H), 5.62 (t, J=5.4 Hz, 1H), 3.80 (t, J=4.7 Hz, 4H), 3.66 (s, 3H), 3.48 (s, 2H), 3.13 (t, J=6.3 Hz, 2H), 2.85 (d, J=11.2 Hz, 2H), 2.60-2.43 (m, 5H), 2.37 (t, J=7.2 Hz, 2H), 2.09-1.89 (m, 7H), 1.66 (d, J=12.1 Hz, 2H), 1.54-1.46 (m, 1H), 1.36-1.25 (m, 2H), 1.19-1.13 (m, 3H); ES-LCMS m/z 684.4, 686.4 [M+H].sup.+.

Example 369: 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid

[0212] ##STR00484##

[0213] To a solution of methyl4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoate (1.7 g, 2.130 mmol) in MeOH (20 mL) and H.sub.2O (3 mL) was added LiOH (0.153 g, 6.39 mmol). Then the reaction mixture was stirred at 25° C. for 0.5 h. The solvent was removed in vacuo to give the crude product which was dissolved with MeCN (10 mL) and H.sub.2O (10 mL). 1 N HCl was added to adjust pH=6-7. The mixture was purified by preparative HPLC (MeCN/H.sub.2O as eluents, acidic condition) and lyophilized to yield 4-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylbutanoic acid, 4 hydrochloride (1186.17 mg, 1.447 mmol, 67.9% yield) as a pale yellow solid: .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.63 (s, 2H), 8.05 (s, 1H), 7.88 (d, J=1.8 Hz, 2H), 7.47 (s, 1H), 7.44-7.38 (m, 1H), 4.88 (d, J=14.6 Hz, 2H), 4.47 (s, 2H), 3.75 (d, J=12.1 Hz, 2H), 3.64-3.51 (m, 4H), 3.43-3.29 (m, 2H), 3.27-3.07 (m, 6H), 2.66-2.51 (m, 1H), 2.22-2.08 (m, 4H), 2.01-1.88 (m, 4H), 1.77-1.61 (m, 2H), 1.29-1.20 (m, 3H); ES-LCMS m/z 670.4, 672.4 [M+H].sup.+.

Intermediate 2. N-((1-((2-((6-Bromopyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide

[0214] ##STR00485##

[0215] Intermediate 2 was synthesized according to the following the steps.

Step 1: Methyl 2-(benzyloxy)-6-chloroisonicotinate

[0216] ##STR00486##

[0217] To a solution of phenylmethanol (15.75 g, 146 mmol) in DMF (500 mL) was added NaH (7.57 g, 189 mmol) at 25° C. After the mixture was stirred at 25° C. for 0.5 h, methyl 2,6-dichloroisonicotinate (30 g, 146 mmol) in DMF (100 mL) was added and the mixture was stirred at 25° C. for 12 h. The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by column chromatography to yield a colorless oil of methyl 2-(benzyloxy)-6-chloroisonicotinate (16 g, 57.6 mmol, 39.6% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.43-7.36 (m, 3H), 7.36-7.26 (m, 4H), 5.32 (s, 2H), 3.87 (s, 3H); ES-LCMS m/z 278.1 [M+H].sup.+.

Step 2: Methyl 2-(benzyloxy)-6-(3, 5-dichlorophenyl)isonicotinate

[0218] ##STR00487##

[0219] A mixture of methyl 2-(benzyloxy)-6-chloroisonicotinate (12 g, 43.2 mmol), (3,5-dichlorophenyl)boronic acid (12.37 g, 64.8 mmol), PdCl.sub.2(dppf) (6.32 g, 8.64 mmol) and K.sub.2CO.sub.3 (11.94 g, 86 mmol) in 1,4-dioxane (200 mL) was stirred at 80° C. for 12 h under N.sub.2 atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to yield a colorless oil of methyl 2-(benzyloxy)-6-(3,5-dichlorophenyl)isonicotinate (13 g, 33.5 mmol, 77.0% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.96-7.92 (m, 1H), 7.91-7.87 (m, 2H), 7.85-7.80 (m, 2H), 7.42-7.38 (m, 5H), 5.50 (s, 2H), 3.92 (d, J=2.0 Hz, 3H); ES-LCMS m/z 388.0, 389.9 [M+H].sup.+.

Step 3: (2-(Benzyloxy)-6-(3, 5-dichlorophenyl)pyridin-4-yl)methanol

[0220] ##STR00488##

[0221] To a solution of methyl 2-(benzyloxy)-6-(3,5-dichlorophenyl)isonicotinate (12 g, 30.9 mmol) in THF (300 mL) was added LiAlH.sub.4 (2.35 g, 61.8 mmol) at −78° C. The mixture was allowed to warm up to 25° C. for 12 h. The reaction was quenched by addition of aqueous NaOH (20%, 10 mL) at 0° C. then was filtered and concentrated. The residue was purified by column chromatography to yield a yellow oil of (2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methanol (10.7 g, 29.7 mmol, 96.0% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.83-7.78 (m, 1H), 7.46-7.41 (m, 1H), 7.40-7.36 (m, 1H), 7.30 (d, J=4.0 Hz, 4H), 7.23 (s, 3H), 5.29 (s, 2H), 4.68 (d, J=4.9 Hz, 2H); ES-LCMS m/z 359.9, 362.0 [M+H].sup.+.

Step 4: (2-(Benzyloxy)-6-(3, 5-dichlorophenyl)pyridin-4-yl)methyl methanesulfonate

[0222] ##STR00489##

[0223] To a solution of (2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methanol (3.0 g, 8.33 mmol) and DIEA (2.91 mL, 16.66 mmol) in DCM (40 mL) was added MsCl (0.779 mL, 9.99 mmol) at 0° C. The mixture was stirred at 25° C. for 3 h. DCM (100 mL) was added, washed with water (30 mL×3) and dried over Na.sub.2SO.sub.4. The organic phase was concentrated to yield a yellow oil of (2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl methanesulfonate (3.0 g, 6.84 mmol, 82.0% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.80-7.78 (m, 2H), 7.43-7.41 (m, 2H), 7.40-7.36 (m, 1H), 7.36-7.31 (m, 5H), 5.42 (s, 2H), 5.16 (s, 2H), 3.01 (s, 3H); ES-LCMS m/z 437.9, 439.9 [M+H].sup.+.

Step 5: N-((1-((2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide

[0224] ##STR00490##

[0225] To a solution of (2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl methanesulfonate (3.0 g, 6.84 mmol) and K.sub.2CO.sub.3 (1.892 g, 13.69 mmol) in DMF (30 mL) was added N-(piperidin-4-ylmethyl)acetamide (1.069 g, 6.84 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to yield a yellow oil of N-((1-((2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide (3.0 g, 6.02 mmol, 88.0% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.93-7.84 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.42 (m, 1H), 7.41-7.34 (m, 4H), 7.34-7.30 (m, 1H), 5.47-5.44 (m, 2H), 3.54-3.50 (m, 2H), 3.18-3.11 (m, 2H), 2.91-2.77 (m, 4H), 2.11-2.07 (m, 3H), 1.71-1.67 (m, 2H), 1.55-1.49 (m, 1H), 1.32-1.23 (m, 2H); ES-LCMS m/z 498.1, 500.1 [M+H].sup.+.

Step 6: N-((1-((2-(3,5-dichlorophenyl)-6-hydroxypyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide

[0226] ##STR00491##

[0227] To a solution of N-((1-((2-(benzyloxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide (2.0 g, 4.01 mmol) in THF (20 mL) was added concentrated HCl (15 mL, 180 mmol). The mixture was stirred at 80° C. for 4 h then concentrated. The residue was purified by column chromatography to yield a brown solid of N-((1-((2-(3,5-dichlorophenyl)-6-hydroxypyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide (1.0 g, 2.449 mmol, 61.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 7.74-7.66 (m, 2H), 7.61-7.54 (m, 1H), 6.81-6.72 (m, 1H), 6.57-6.48 (m, 1H), 3.44 (s, 2H), 3.09-3.02 (m, 2H), 2.95-2.86 (m, 2H), 2.12-2.00 (m, 2H), 1.92 (s, 3H), 1.76-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.38-1.21 (m, 2H); ES-LCMS m/z 408.2, 410.1 [M+H].sup.+.

Step 7: N-((1-((2-((6-Bromopyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide

[0228] ##STR00492##

[0229] A mixture of N-((1-((2-(3,5-dichlorophenyl)-6-hydroxypyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide (1 g, 2.449 mmol), 2-bromo-5-fluoropyridine (0.646 g, 3.67 mmol) and Cs.sub.2CO.sub.3 (3.99 g, 12.25 mmol) in NMP (15 mL) was stirred at 130° C. for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified twice by silica gel column chromatography (MeOH/DCM=1/10). All fractions found to contain product by TLC (MeOH/DCM=1/10) were combined and concentrated to yield a brown solid of N-((1-((2-((6-bromopyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4yl)methyl)acetamide (580 mg, 0.504 mmol, 20.6% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.36-8.30 (m, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.54-7.51 (m, 1H), 7.50-7.47 (m, 1H), 7.45 (s, 1H), 7.35-7.31 (m, 1H), 7.01-6.93 (m, 1H), 3.53 (s, 2H), 3.18-3.14 (m, 2H), 2.88 (d, J=10.8 Hz, 2H), 2.00-1.96 (m, 5H), 1.73-1.60 (m, 2H), 1.53 (d, J=4.2 Hz, 1H), 1.32 (d, J=7.6 Hz, 2H); ES-LCMS m/z 563.0, 564.9 [M+H].sup.+.

Example 9: N-((1-((2-(3,5-Dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide, 4 hydrochloride

[0230] ##STR00493##

[0231] Example 9 was synthesized according to the following steps.

Step 1: tert-Butyl 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate

[0232] ##STR00494##

[0233] A mixture of N-((1-((2-((6-bromopyridin-3-yl)oxy)-6-(3,5-dichlorophenyl)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide (580 mg, 1.028 mmol), tert-butyl piperazine-1-carboxylate (574 mg, 3.08 mmol), (±)-BINAP (12.80 mg, 0.021 mmol), 18-crown-6 (815 mg, 3.08 mmol), Pd.sub.2(dba).sub.3 (47.1 mg, 0.051 mmol) and sodium tert-butoxide (296 mg, 3.08 mmol) in THF (15 mL) was stirred at 65° C. under N.sub.2 atmosphere for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (50 mL) and washed with brine (50 mL), dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by silica gel column chromatography (MeOH/DCM=1/10) then further purified by preparative HPLC(MeCN/H.sub.2O as eluents, acidic condition) to yield a pale yellow solid of tert-butyl 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate (81 mg, 0.094 mmol, 9.1% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.24-8.17 (m, 1H), 8.00 (d, J=6.8 Hz, 1H), 7.94 (s, 1H), 7.91-7.86 (m, 2H), 7.54 (t, J=1.9 Hz, 1H), 7.44-7.39 (m, 1H), 7.36 (s, 1H), 4.49-4.43 (m, 2H), 4.01-3.94 (m, 4H), 3.62 (d, J=12.3 Hz, 2H), 3.50-3.44 (m, 4H), 3.18-3.07 (m, 4H), 2.06-1.96 (m, 6H), 1.87 (m, 1H), 1.67-1.50 (m, 10H); ES-LCMS m/z 669.3, 671.3 [M+H].sup.+.

Step 2: N-((1-((2-(3,5-Dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide, 4 hydrochloride

[0234] ##STR00495##

[0235] A mixture of tert-butyl 4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate (81 mg, 0.121 mmol) and TFA (2 mL, 26.0 mmol) in DCM (8 mL) was stirred at 25° C. for 0.5 h. Then the mixture was concentrated and purified by preparative HPLC (MeCN/H.sub.2O as eluents, acidic condition) and lyophilized to yield a white solid N-((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide, 4 hydrochloride (37.43 mg, 0.052 mmol, 43.1% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.19 (d, J=2.4 Hz, 1H), 8.06 (d, J=9.5 Hz, 1H), 7.92 (s, 1H), 7.86 (d, J=1.7 Hz, 2H), 7.51 (s, 1H), 7.45 (d, J=9.8 Hz, 1H), 7.35 (s, 1H), 4.43 (s, 2H), 4.01-3.93 (m, 4H), 3.59 (d, J=12.7 Hz, 2H), 3.49-3.41 (m, 4H), 3.15-3.03 (m, 4H), 2.03-1.91 (m, 5H), 1.83 (br. s, 1H), 1.63-1.50 (m, 2H); ES-LCMS m/z 569.0, 571.0 [M+H].sup.+.

Example 11: 3-(4-(5-((4-((4-(Acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid, 4 hydrochloride

[0236] ##STR00496##

[0237] Example 11 was synthesized according to the following steps.

Step 1: Ethyl 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoate

[0238] ##STR00497##

[0239] To a solution of N-((1-((2-(3,5-dichlorophenyl)-6-((6-(piperazin-1-yl)pyridin-3-yl)oxy)pyridin-4-yl)methyl)piperidin-4-yl)methyl)acetamide (20 g, 33.4 mmol) and ethyl 3-bromopropanoate (18.12 g, 100 mmol) in DMF (350 mL) was added K.sub.2CO.sub.3 (13.83 g, 100 mmol). Then the reaction mixture was stirred at 80° C. for 12 h. The solid was filtered off and solution was concentrated to yield a pale yellow solid of ethyl 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoate (17.6 g, 24.97 mmol, 74.8% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.10 (d, J=3.1 Hz, 1H), 7.74 (d, J=1.8 Hz, 2H), 7.43-7.35 (m, 2H), 7.31 (s, 1H), 6.78 (s, 1H), 6.70 (d, J=9.3 Hz, 1H), 5.55 (br s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.58-3.50 (m, 4H), 3.47 (s, 2H), 3.14 (t, J=6.4 Hz, 2H), 2.88-2.82 (m, 2H), 2.77-2.70 (m, 2H), 2.64-2.56 (m, 4H), 2.55-2.49 (m, 2H), 2.04-1.94 (m, 5H), 1.66 (d, J=12.8 Hz, 2H), 1.54-1.46 (m, 1H), 1.35-1.21 (m, 5H); ES-LCMS m/z 669.3, 671.3 [M+H].sup.+.

Step 2: 3-(4-(5-((4-((4-(Acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoic acid, 4 hydrochloride

[0240] ##STR00498##

[0241] To a solution of ethyl 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridin-2-yl)piperazin-1-yl)propanoate (17.6 g, 24.97 mmol) in THF (200 mL) was added LiOH.H.sub.2O (2.096 g, 49.9 mmol) and water (2 mL). Then the reaction mixture was stirred at 25° C. for 12 h. 1 N HCl was added to adjust pH to 6 then concentrated to yield the crude product, which was washed with EA/MeOH=10/1 (500 mL) and THF (500 mL). The solid was collected to yield the crude product which was purified by preparative HPLC (MeCN/H.sub.2O as eluents, acidic condition). Concentrated HCl was added to the combined purified fractions to adjust to pH to 2, and lyophilized to yield a pale yellow solid of 3-(4-(5-((4-((4-(acetamidomethyl)piperidin-1-yl)methyl)-6-(3,5-dichlorophenyl)pyridin-2-yl)oxy)pyridine-2-yl)piperazin-1-yl)propanoic acid, 4 hydrochloride (15 g, 23.09 mmol, 92.0% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 8.23 (s, 1H), 8.20-8.16 (m, 1H), 7.99 (s, 1H), 7.89 (s, 2H), 7.55 (d, J=12 Hz, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 4.46 (s, 2H), 3.80-3.40 (m, 10H), 3.30-3.20 (m, 2H), 3.15-3.07 (m, 4H), 2.96-2.94 (m, 2H), 2.00-1.92 (m, 5H), 1.90-1.79 (m, 1H), 1.62-1.53 (m, 2H); ES-LCMS m/z 641.3, 643.2 [M+H].sup.+.

EQUIVALENTS AND SCOPE

[0242] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0243] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0244] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0245] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.