# Patent

## Title
EBI2 modulators

## Abstract

Provided herein are small molecule Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) modulator compounds, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds. EBI2 is a therapeutic target for the treatment of a variety of diseases or conditions. In some embodiments, EBI2 is a therapeutic target for the treatment of diseases or conditions such as, but not limited to, autoimmune diseases or conditions, cancer, and cardiovascular disease.

## Background
CROSS-REFERENCE
This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Application No. PCT/US2014/057897 entitled “EBI2 MODULATORS,” filed Sep. 26, 2014, which claims the benefit of U.S, Application Ser. No. 61/883,092, filed Sep. 26, 2013, and U.S. Application Ser. No. 61/883,100, filed Sep. 26, 2013, each of which are incorporated herein by reference in their entirety.


SUMMARY OF THE INVENTION
Described herein are compounds that modulate the activity of Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2), also known as G-protein coupled receptor 183. EBI2 is a therapeutic target for the treatment of a variety of diseases or conditions. In some embodiments, EBI2 is a therapeutic target for the treatment of diseases or conditions such as, but not limited to, autoimmune diseases or conditions, cancer, and cardiovascular disease.
In one aspect, provided herein is a compound having the structure of Formula (I):




wherein:

    
    
        each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
        each R2 is independently F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl;
        R3 is F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, —OC1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, or PO3H;
        each R4 is independently H or C1-C6alkyl;
        each R5 is independently H or C1-C6alkyl;
        m is an integer selected from 0-3; and
        n is an integer selected from 1-3;

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

    
    


In another aspect, provided herein is a compound having the structure of Formula (II):




wherein:

    
    
        each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl;
        each R2 is independently F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl;
        R3 is F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, —OC1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, or PO3H;
        each R4 is independently H or C1-C6alkyl;
        each R5 is independently H or C1-C6alkyl;
        m is an integer selected from 0-2; and
        n is an integer selected from 1-3;

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

    
    


In one embodiment is a compound of Formula (I) or Formula (II) wherein R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (I) or Formula (II) wherein R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (I) or Formula (II) wherein R2 is F, Cl, Br, —CF3, —CH3, or —OCH3. In another embodiment is a compound of Formula (I) or Formula (II) wherein n is 1 and m is 0. In another embodiment is a compound of Formula (I) or Formula (II) wherein n is 2 and m is 0. In another embodiment is a compound of Formula (I) or Formula (II) wherein n is 1 and m is 1. In another embodiment is a compound of Formula (I) or Formula (II) wherein n is 2 and m is 1. In another embodiment is a compound of Formula (I) or Formula (II) wherein n is 1 and m is 2.
In another aspect, provided herein is a compound having the structure of Formula (III):




wherein:

each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R3 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3;
n is an integer selected from 0-3; and
p is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a compound of Formula (III) wherein p is 0. In another embodiment is a compound of Formula (III) wherein p is 1 and R3 is F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment is a compound of Formula (III) wherein p is 1 and R3 is F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl.
In another aspect, provided herein is a compound having the structure of Formula (IV):




wherein:

each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;

    
    
        each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
    
    


each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In another aspect, provided herein is a compound having the structure of Formula (V):




wherein:

each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, aryl, or heteroaryl;
R3 is H, C1-C6alkyl, or aryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In another aspect, provided herein is a compound having the structure of Formula (VI):




wherein:

X is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, aryl, or heteroaryl;
R3 is H, C1-C6alkyl, or aryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a compound of Formula (VI) wherein X is —CH2—. In another embodiment is a compound of Formula (VI) wherein X is —C(═O)—. In another embodiment is a compound of Formula (V) or (VI) wherein R3 is H. In another embodiment is a compound of Formula (V) or (VI) wherein R3 is —CH3. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment is a compound of Formula (I) or Formula (II) wherein R2 is F, Cl, Br, —CF3, —CH3, or —OCH3. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein n is 1 and m is 0. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein n is 1 and m is 1. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein n is 1 and m is 2. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein n is 2 and m is 1. In another embodiment is a compound of Formula (III), (IV), (V), or (VI) wherein n is 0 and m is 0.
Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, prodrug and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprising the compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof, is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.
In another aspect is a method of treating an autoimmune disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the autoimmune disease is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In another embodiment is a method or treating type-1-diabetes comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In another embodiment is a method of treating multiple sclerosis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In another embodiment is a method of treating rheumatoid arthritis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In another embodiment is a method of treating lupus comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In another aspect is a method of treating a cardiovascular disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In one embodiment, the cardiovascular disease is atherosclerosis.
In another aspect is a method of treating a viral infection comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the viral infection is an Epstein-Barr viral infection.
In another aspect is a method of treating cancer comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In another aspect, described herein is a method of treating a disease, disorder or condition mediated by EBI2 in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof. In another aspect, described herein is a method of treating a disease in a subject mediated by EBI2, which method comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder or condition is an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In some embodiments, the disease, disorder or condition is a cardiovascular disease or condition. In some embodiments, the cardiovascular disease or condition is atherosclerosis. In some embodiments, the disease, disorder or condition is a viral infection. In some embodiments, the viral infection is an Epstein-Barr viral infection. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the treatment of an Epstein-Barr viral infection in a human.
Further provided is the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of cancer in a human. In some embodiments is the use of a compound of Formula ((I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer in a human. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the manufacture of a medicament for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the manufacture of a medicament for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the manufacture of a medicament for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof for the manufacture of a medicament for the treatment of an Epstein-Barr viral infection in a human.
Further provided is the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of cancer in a human. In some embodiments is the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer in a human. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound of Formula (I), (II), (III), (IV), (V), or (VI), is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal; and/or (j) the effective amount is adminstered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
In any of the aforementioned aspects involving the administration of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, to a subject are further embodiments comprising administering at least one additional agent in addition to the administration of a compound having the structure of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof. In various embodiments, the compound of Formula (I), (II), (III), (IV), (V), or (VI), and the additional agent are administered in any order, including simultaneously. In some embodiments, the compound of Formula (I), (II), (III), (IV), (V), or (VI), and the additional agent are administered to the subject in the same pharmaceutical composition or in separate pharmaceutical compositions.
In another aspect, provided herein is a method of treating an autoimmune disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) having the structure:




wherein:

X is a bond, —CH2—, —C(H)(Ph)-, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a method of treating an autoimmune disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) wherein X is a bond. In another embodiment, X is —CH2—. In another embodiment, X is —C(H)(Ph)-. In another embodiment, X is —S(═O)2—. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, n is 1 and m is 0. In another embodiment, n is 1 and m is 1. In another embodiment, n is 1 and m is 2. In another embodiment, n is 2 and m is 1. In another embodiment, n is 0 and m is 0. In another embodiment, the autoimmune disease is type-1-diabetes. In another embodiment, the autoimmune disease is multiple sclerosis. In another embodiment, the autoimmune disease is rheumatoid arthritis. In another embodiment, the autoimmune disease is lupus.
In another aspect, provided herein is a method of treating a cardiovascular disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) having the structure:




wherein:

X is a bond, —CH2—, —C(H)(Ph)-, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a method of treating a cardiovascular disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) wherein X is a bond. In another embodiment, X is —CH2—. In another embodiment, X is —C(H)(Ph)-. In another embodiment, X is —S(═O)2—. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, n is 1 and m is 0. In another embodiment, n is 1 and m is 1. In another embodiment, n is 1 and m is 2. In another embodiment, n is 2 and m is 1. In another embodiment, n is 0 and m is 0. In another embodiment, the cardiovascular disease is atherosclerosis.
In another aspect, provided herein is a method of treating a viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) having the structure:




wherein:

X is a bond, —CH2—, —C(H)(Ph)-, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a method of treating a viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) wherein X is a bond. In another embodiment, X is —CH2—. In another embodiment, X is —C(H)(Ph)-. In another embodiment, X is —S(═O)2—. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, n is 1 and m is 0. In another embodiment, n is 1 and m is 1. In another embodiment, n is 1 and m is 2. In another embodiment, n is 2 and m is 1. In another embodiment, n is 0 and m is 0. In another embodiment, the viral infection is an Epstein-Barr viral infection.
In another aspect, provided herein is a method of treating an autoimmune disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VIII) having the structure:




wherein:

X is —N(H)—, —N(R3)—, —O—, or —S—;
Y is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
R3 is C1-C6alkyl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a method of treating an autoimmune disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VIII) wherein Y is a bond. In another embodiment, Y is —CH2—. In another embodiment, Y is —C(H)(Ph)-. In another embodiment, Y is —S(═O)2—. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, n is 1 and m is 0. In another embodiment, n is 1 and m is 1. In another embodiment, n is 1 and m is 2. In another embodiment, n is 2 and m is 1. In another embodiment, n is 0 and m is 0. In another embodiment, the autoimmune disease is type-1-diabetes. In another embodiment, the autoimmune disease is multiple sclerosis. In another embodiment, the autoimmune disease is rheumatoid arthritis. In another embodiment, the autoimmune disease is lupus.
In another aspect, provided herein is a method of treating a cardiovascular disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VIII) having the structure:




wherein:

X is —N(H)—, —N(R3)—, —O—, or —S—;
Y is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
R3 is C1-C6alkyl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a method of treating a cardiovascular disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) wherein X is a bond. In another embodiment, X is —CH2—. In another embodiment, X is —C(H)(Ph)-. In another embodiment, X is —S(═O)2—. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, n is 1 and m is 0. In another embodiment, n is 1 and m is 1. In another embodiment, n is 1 and m is 2. In another embodiment, n is 2 and m is 1. In another embodiment, n is 0 and m is 0. In another embodiment, the cardiovascular disease is atherosclerosis.
In another aspect, provided herein is a method of treating a viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VIII) having the structure:




wherein:

X is —N(H)—, —N(R3)—, —O—, or —S—;
Y is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
R3 is C1-C6alkyl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In one embodiment is a method of treating a viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (VII) wherein X is a bond. In another embodiment, X is —CH2—. In another embodiment, X is —C(H)(Ph)-. In another embodiment, X is —S(═O)2—. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl. In another embodiment, each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R1 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, each R2 is independently F, Cl, Br, —CF3, —OC1-C6alkyl, or C1-C6alkyl. In another embodiment, n is 1 and m is 0. In another embodiment, n is 1 and m is 1. In another embodiment, n is 1 and m is 2. In another embodiment, n is 2 and m is 1. In another embodiment, n is 0 and m is 0. In another embodiment, the viral infection is an Epstein-Barr viral infection.
In any of the embodiments disclosed herein, the subject is a human.
In some embodiments, compounds and compositions provided herein are administered to a human.
In some embodiments, compounds and compositions provided herein are orally administered.
In other embodiments, compounds provided herein are used for the formulation of a medicament for the modulation of the activity of EBI2 in a subject.
Articles of manufacture, which include packaging material, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for the treatment of diseases or conditions that would benefit from modulation of EBI2, are provided.
Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.


DETAILED DESCRIPTION OF THE INVENTION
A robust antibody response is essential for efficient identification and eradication of pathogenic microbes and toxins, whereas dysregulation of the antibody response can lead to autoimmune disease. Specific antigen encounter by B lymphocytes induces clonal expansion that encompasses several distinct stages of differentiation. During this differentiation process, a critical cell fate decision is made wherein some B cells will undergo terminal differentiation into antibody-producing cells, while a separate cohort will assume a distinct pathway of differentiation to become long-lived memory B cells.
EBI2 is expressed on B cells and is highly induced upon activation. EBI2 was cloned in 1993 as one out of nine up-regulated genes in Epstein-Barr virus (EBV)-infected Burkitt lymphoma cells. These nine genes were up-regulated from 4- to 100-fold upon EBV infection, and two 7TM receptors were identified among the up-regulated genes (Epstein-Barr-induced receptors 1 and 2, EBI1 and -2). EBI2 displayed the highest up-regulation (200-fold) among the nine EBV-induced genes. Initial expression analyses of the nine genes uncovered an expression of EBI2 in peripheral blood mononuclear cells (PBMCs), tonsils, spleen, and lung tissue.
EBI2 has been characterized in terms of signaling activities at the level of G-proteins as well as at the level of the transcriptional activity. Recent gene targeting experiments revealed that EBI2−/− B cells exhibited defective migration, resulting in strongly impaired T cell-dependent antibody responses.
The role of EBI2 in diseases involving an immune system dysregulation or diseases involving EBV infection is compelling. Many of these diseases overlap, as, in addition to EBI2, EBV regulates many different proteins related to the immune system, such as chemokines and their receptors. There are many disorders in which immune dysregulation have been implicated. Autoimmune and autoinflammatory disorders, such as type-1-diabetes, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, have been connected to an aberrant activation of the immune system.
Inflammation substantially contributes to the pathophysiology of cardiovascular disease, and especially of atherosclerosis. As high levels of oxysterols (physiologic ligands for EBI2) are present in an atherosclerotic plaque and EBI2 is expressed on monocytes, which have a central role in atherosclerosis, the oxysterol-EBI2 pathway may be involved in the recruitment of immune cells to atherosclerotic lesions. Thus, EBI2 blockade might provide a therapeutic benefit in atherosclerosis.
In some embodiments, the compounds described herein are EBI2 antagonists.
In some embodiments, the compounds described herein are EBI2 inverse agonists.
Compounds
In one aspect, provided herein is a compound having the structure of Formula (I):




wherein:

    
    
        each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
        each R2 is independently F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl;
        R3 is F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, —OC1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, or PO3H;
        each R4 is independently H or C1-C6alkyl;
        each R5 is independently H or C1-C6alkyl;
        m is an integer selected from 0-3; and
        n is an integer selected from 1-3;

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

    
    


In some embodiments is a compound of Formula (I) wherein R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (I) wherein R3 is F. In some embodiments is a compound of Formula (I) wherein R3 is Cl. In some embodiments is a compound of Formula (I) wherein R3 is Br. In some embodiments is a compound of Formula (I) wherein R3 is —CF3. In some embodiments is a compound of Formula (I) wherein R3 is —CH3. In some embodiments is a compound of Formula (I) wherein R3 is —OCF3. In some embodiments is a compound of Formula (I) wherein R3 is —OCH3.
In some embodiments is a compound of Formula (I) wherein R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (I) wherein R1 is F. In some embodiments is a compound of Formula (I) wherein R1 is Cl. In some embodiments is a compound of Formula (I) wherein R1 is Br. In some embodiments is a compound of Formula (I) wherein R1 is —CF3. In some embodiments is a compound of Formula (I) wherein R1 is —CH3. In some embodiments is a compound of Formula (I) wherein R1 is —OCF3. In some embodiments is a compound of Formula (I) wherein R1 is —OCH3.
In some embodiments is a compound of Formula (I) wherein R2 is independently F, Cl, Br, —CF3, —CH3, or —OCH3. In some embodiments is a compound of Formula (I) wherein R2 is F. In some embodiments is a compound of Formula (I) wherein R2 is Cl. In some embodiments is a compound of Formula (I) wherein R2 is Br. In some embodiments is a compound of Formula (I) wherein R1 is —CF3. In some embodiments is a compound of Formula (I) wherein R2 is —CH3. In some embodiments is a compound of Formula (I) wherein R2 is —OCF3. In some embodiments is a compound of Formula (I) wherein R1 is —OCH3.
In another embodiment is a compound of Formula (I) wherein n is 1 and m is 0. In another embodiment is a compound of Formula (I) wherein n is 2 and m is 0. In another embodiment is a compound of Formula (I) wherein n is 1 and m is 1. In another embodiment is a compound of Formula (I) wherein n is 2 and m is 1. In another embodiment is a compound of Formula (I) wherein n is 1 and m is 2. In another embodiment is a compound of Formula (I) wherein n is 2 and m is 2. In another embodiment is a compound of Formula (I) wherein n is 3 and m is 1. In another embodiment is a compound of Formula (I) wherein n is 3 and m is 2.
In another embodiment is a compound of Formula (I) wherein n is 1, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (I) wherein n is 1, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (I) wherein n is 1, m is 0, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (I) wherein n is 2, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (I) wherein n is 2, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 independently is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (I) wherein n is 2, m is 0, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R1 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (I) wherein m is 1, n is 1, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 and R2 are independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (I) wherein m is 1, n is 1, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 and R2 are independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (I) wherein m is 1, n is 1, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R1 and R2 are independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (I) wherein m is 0, n is 2, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (I) wherein m is 0, n is 2, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (I) wherein m is 0, n is 2, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R1 is independently F, Cl, Br, or —CF3.
In some embodiments is a compound having the structure of Formula (II):




wherein:

    
    
        each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl;
        each R2 is independently F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl; R3 is F, Cl, Br, —CN, —CF3, —OCF3, —OH, —C1-C6alkyl, —OC1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, or PO3H;
        each R4 is independently H or C1-C6alkyl;
        each R5 is independently H or C1-C6alkyl;
        m is an integer selected from 0-2; and
        n is an integer selected from 1-3;

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

    
    


In some embodiments is a compound of Formula (II) wherein R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (II) wherein R3 is F. In some embodiments is a compound of Formula (II) wherein R3 is Cl. In some embodiments is a compound of Formula (II) wherein R3 is Br. In some embodiments is a compound of Formula (II) wherein R3 is —CF3. In some embodiments is a compound of Formula (II) wherein R3 is —CH3. In some embodiments is a compound of Formula (II) wherein R3 is —OCF3. In some embodiments is a compound of Formula (II) wherein R3 is —OCH3.
In some embodiments is a compound of Formula (II) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (II) wherein R1 is F. In some embodiments is a compound of Formula (II) wherein R1 is Cl. In some embodiments is a compound of Formula (II) wherein R1 is Br. In some embodiments is a compound of Formula (II) wherein R1 is —CF3. In some embodiments is a compound of Formula (II) wherein R1 is —CH3. In some embodiments is a compound of Formula (II) wherein R1 is —OCF3. In some embodiments is a compound of Formula (II) wherein R1 is —OCH3.
In some embodiments is a compound of Formula (II) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, or —OCH3. In some embodiments is a compound of Formula (II) wherein R2 is F. In some embodiments is a compound of Formula (II) wherein R2 is Cl. In some embodiments is a compound of Formula (II) wherein R2 is Br. In some embodiments is a compound of Formula (II) wherein R1 is —CF3. In some embodiments is a compound of Formula (II) wherein R2 is —CH3. In some embodiments is a compound of Formula (II) wherein R2 is —OCF3. In some embodiments is a compound of Formula (II) wherein R1 is —OCH3.
In another embodiment is a compound of Formula (II) wherein n is 1 and m is 0. In another embodiment is a compound of Formula (II) wherein n is 2 and m is 0. In another embodiment is a compound of Formula (II) wherein n is 1 and m is 1. In another embodiment is a compound of Formula (II) wherein n is 2 and m is 1. In another embodiment is a compound of Formula (II) wherein n is 1 and m is 2. In another embodiment is a compound of Formula (II) wherein n is 2 and m is 2. In another embodiment is a compound of Formula (II) wherein n is 3 and m is 1. In another embodiment is a compound of Formula (II) wherein n is 3 and m is 2.
In another embodiment is a compound of Formula (II) wherein n is 1, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (II) wherein n is 1, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (II) wherein n is 1, m is 0, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (II) wherein n is 2, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (II) wherein n is 2, m is 0, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (II) wherein n is 2, m is 0, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R1 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (II) wherein m is 1, n is 1, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 and R2 are independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (II) wherein m is 1, n is 1, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R1 and R2 are independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (II) wherein m is 1, n is 1, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R1 and R2 are independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (II) wherein m is 0, n is 2, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (II) wherein m is 0, n is 2, R3 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (II) wherein m is 0, n is 2, R3 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R1 is independently F, Cl, Br, or —CF3.
In some embodiments is a compound having the structure of Formula (III):




wherein:

each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R3 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3;
n is an integer selected from 0-3; and
p is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (III) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (III) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (III) wherein each R1 is F. In some embodiments is a compound of Formula (III) wherein each R1 is Cl. In some embodiments is a compound of Formula (III) wherein each R1 is Br. In some embodiments is a compound of Formula (III) wherein each R1 is —CF3. In some embodiments is a compound of Formula (III) wherein each R1 is —CH3. In some embodiments is a compound of Formula (III) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (III) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (III) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (III) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (III) wherein each R2 is F. In some embodiments is a compound of Formula (III) wherein each R2 is Cl. In some embodiments is a compound of Formula (III) wherein each R2 is Br. In some embodiments is a compound of Formula (III) wherein each R2 is —CF3. In some embodiments is a compound of Formula (III) wherein each R2 is —CH3. In some embodiments is a compound of Formula (III) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (III) wherein each R2 is —OCH3.
In some embodiments is a compound of Formula (III) wherein each R3 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (III) wherein each R3 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (III) wherein each R3 is F. In some embodiments is a compound of Formula (III) wherein each R3 is Cl. In some embodiments is a compound of Formula (III) wherein each R3 is Br. In some embodiments is a compound of Formula (III) wherein each R3 is —CF3. In some embodiments is a compound of Formula (III) wherein each R3 is —CH3. In some embodiments is a compound of Formula (III) wherein each R3 is —OCF3. In some embodiments is a compound of Formula (III) wherein each R3 is —OCH3.
In another embodiment is a compound of Formula (III) wherein m is 0, n is 0, and p is 0.
In another embodiment is a compound of Formula (III) wherein m is 0, n is 1, and p is 0. In another embodiment is a compound of Formula (III) wherein m is 0, n is 2, and p is 0. In another embodiment is a compound of Formula (III) wherein m is 1, n is 1, and p is 1. In another embodiment is a compound of Formula (III) wherein m is 1, n is 2, and p is 1.
In another embodiment is a compound of Formula (III) wherein m is 0, n is 1, p is 0, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (III) wherein m is 0, n is 1, p is 0, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (III) wherein m is 0, n is 1, p is 0, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (III) wherein m is 0, n is 2, p is 0, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (III) wherein m is 0, n is 2, p is 0, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (III) wherein m is 0, n is 2, p is 0, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (III) wherein m is 0, n is 2, p is 0, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (III) wherein m is 1, n is 2, p is 1, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 and R3 are independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (III) wherein m is 1, n is 2, p is 1, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 and R3 are independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (III) wherein m is 1, n is 2, p is 1, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 and R3 are independently F, Cl, Br, or —CF3.
In some embodiments is a compound having the structure of Formula (IV):




wherein:

each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (IV) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (IV) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (IV) wherein each R1 is F. In some embodiments is a compound of Formula (IV) wherein each R1 is Cl. In some embodiments is a compound of Formula (IV) wherein each R1 is Br. In some embodiments is a compound of Formula (IV) wherein each R1 is —CF3. In some embodiments is a compound of Formula (IV) wherein each R1 is —CH3. In some embodiments is a compound of Formula (IV) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (IV) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (IV) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (IV) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (IV) wherein each R2 is F. In some embodiments is a compound of Formula (IV) wherein each R2 is Cl. In some embodiments is a compound of Formula (IV) wherein each R2 is Br. In some embodiments is a compound of Formula (IV) wherein each R2 is —CF3. In some embodiments is a compound of Formula (IV) wherein each R2 is —CH3. In some embodiments is a compound of Formula (IV) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (IV) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (IV) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (IV) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (IV) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (IV) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (IV) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (IV) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (IV) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (IV) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (IV) wherein m is 0, n is 1, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IV) wherein m is 0, n is 1, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IV) wherein m is 0, n is 1, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (IV) wherein m is 0, n is 2, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IV) wherein m is 0, n is 2, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IV) wherein m is 0, n is 2, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (IV) wherein m is 0, n is 2, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (IV) wherein m is 1, n is 1, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IV) wherein m is 1, n is 1, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IV) wherein m is 1, n is 1, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (IV) wherein m is 1, n is 2, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IV) wherein m is 1, n is 2, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IV) wherein m is 1, n is 2, each R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (IV) wherein m is 2, n is 1, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IV) wherein m is 2, n is 1, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IV) wherein m is 2, n is 1, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In some embodiments is a compound having the structure of Formula (V):




wherein:

each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, aryl, or heteroaryl;
R3 is H, C1-C6alkyl, or aryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (V) wherein R3 is H. In some embodiments is a compound of Formula (V) wherein R3 is C1-C6alkyl. In some embodiments is a compound of Formula (V) wherein R3 is CH3. In some embodiments is a compound of Formula (V) wherein R3 is aryl. In some embodiments is a compound of Formula (V) wherein R3 is phenyl.
In some embodiments is a compound of Formula (V) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (V) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (V) wherein each R1 is F. In some embodiments is a compound of Formula (V) wherein each R1 is Cl. In some embodiments is a compound of Formula (V) wherein each R1 is Br. In some embodiments is a compound of Formula (V) wherein each R1 is —CF3. In some embodiments is a compound of Formula (V) wherein each R1 is —CH3. In some embodiments is a compound of Formula (V) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (V) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (V) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (V) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (V) wherein each R2 is F. In some embodiments is a compound of Formula (V) wherein each R2 is Cl. In some embodiments is a compound of Formula (V) wherein each R2 is Br. In some embodiments is a compound of Formula (V) wherein each R2 is —CF3. In some embodiments is a compound of Formula (V) wherein each R2 is —CH3. In some embodiments is a compound of Formula (V) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (V) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (V) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (V) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (V) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (V) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (V) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (V) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (V) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (V) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (V) wherein m is 0, n is 1, R3 is H, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 0, n is 1, R3 is H, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 0, n is 1, R3 is H, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is H, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is H, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is H, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is H, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (V) wherein m is 1, n is 1, R3 is H, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 1, n is 1, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 1, n is 1, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 1, n is 2, R3 is H, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 1, n is 2, R3 is H, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 1, n is 2, R3 is H, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 2, n is 1, R3 is H, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 2, n is 1, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 2, n is 1, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 0, n is 1, R3 is —CH3, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 0, n is 1, R3 is —CH3, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 0, n is 1, R3 is —CH3, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is —CH3, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is —CH3, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is —CH3, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (V) wherein m is 0, n is 2, R3 is —CH3, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (V) wherein m is 1, n is 1, R3 is —CH3, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 1, n is 1, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 1, n is 1, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 1, n is 2, R3 is —CH3, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 1, n is 2, R3 is —CH3, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 1, n is 2, R3 is —CH3, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (V) wherein m is 2, n is 1, R3 is —CH3, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (V) wherein m is 2, n is 1, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (V) wherein m is 2, n is 1, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In some embodiments is a compound having the structure of Formula (VI):




wherein:

X is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, aryl, or heteroaryl;
R3 is H, C1-C6alkyl, or aryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (VI) wherein R3 is H. In some embodiments is a compound of Formula (VI) wherein R3 is C1-C6alkyl. In some embodiments is a compound of Formula (VI) wherein R3 is CH3. In some embodiments is a compound of Formula (VI) wherein R3 is aryl. In some embodiments is a compound of Formula (VI) wherein R3 is phenyl.
In some embodiments is a compound of Formula (VI) wherein X is a bond. In another embodiment is a compound of Formula (VI) wherein X is —CH2—. In another embodiment is a compound of Formula (VI) wherein X is —C(H)(Ph)-. In another embodiment is a compound of Formula (VI) wherein X is —C(═O)—. In another embodiment is a compound of Formula (VI) wherein X is —S(═O)2—.
In some embodiments is a compound of Formula (VI) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (VI) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (VI) wherein each R1 is F. In some embodiments is a compound of Formula (VI) wherein each R1 is Cl. In some embodiments is a compound of Formula (VI) wherein each R1 is Br. In some embodiments is a compound of Formula (VI) wherein each R1 is —CF3. In some embodiments is a compound of Formula (VI) wherein each R1 is —CH3. In some embodiments is a compound of Formula (VI) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (VI) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (VI) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (VI) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (VI) wherein each R2 is F. In some embodiments is a compound of Formula (VI) wherein each R2 is Cl. In some embodiments is a compound of Formula (VI) wherein each R2 is Br. In some embodiments is a compound of Formula (VI) wherein each R2 is —CF3. In some embodiments is a compound of Formula (VI) wherein each R2 is —CH3. In some embodiments is a compound of Formula (VI) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (VI) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (VI) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (VI) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (VI) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (VI) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (VI) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (VI) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (VI) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (VI) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —CH2—, R3 is H, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —CH2—, R3 is H, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —CH2—, R3 is H, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is H, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is H, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is H, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is H, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —CH2—, R3 is H, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —CH2—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —CH2—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —CH2—, R3 is H, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —CH2—, R3 is H, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —CH2—, R3 is H, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —CH2—, R3 is H, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —CH2—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —CH2—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —C(═O)—, R3 is H, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —C(═O)—, R3 is H, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —C(═O)—, R3 is H, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is H, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is H, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is H, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is H, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —C(═O)—, R3 is H, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —C(═O)—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —C(═O)—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —C(═O)—, R3 is H, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —C(═O)—, R3 is H, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —C(═O)—, R3 is H, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —C(═O)—, R3 is H, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —C(═O)—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —C(═O)—, R3 is H, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —CH2—, R3 is —CH3, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —CH2—, R3 is —CH3, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —CH2—, R3 is —CH3, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is —CH3, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is —CH3, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is —CH3, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —CH2—, R3 is —CH3, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —CH2—, R3 is —CH3, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —CH2—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —CH2—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —CH2—, R3 is —CH3, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —CH2—, R3 is —CH3, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —CH2—, R3 is —CH3, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —CH2—, R3 is —CH3, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —CH2—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —CH2—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —C(═O)—, R3 is —CH3, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —C(═O)—, R3 is —CH3, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 1, X is —C(═O)—, R3 is —CH3, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is —CH3, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is —CH3, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is —CH3, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VI) wherein m is 0, n is 2, X is —C(═O)—, R3 is —CH3, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —C(═O)—, R3 is —CH3, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —C(═O)—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 1, X is —C(═O)—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —C(═O)—, R3 is —CH3, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —C(═O)—, R3 is —CH3, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 1, n is 2, X is —C(═O)—, R3 is —CH3, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —C(═O)—, R3 is —CH3, R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —C(═O)—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VI) wherein m is 2, n is 1, X is —C(═O)—, R3 is —CH3, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In some embodiments is a compound having the structure of Formula (VII):




wherein:

X is a bond, —CH2—, —C(H)(Ph)-, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (VII) wherein X is a bond. In another embodiment is a compound of Formula (VII) wherein X is —CH2—. In another embodiment is a compound of Formula (VII) wherein X is —C(H)(Ph)-. In another embodiment is a compound of Formula (VII) wherein X is —S(═O)2—.
In some embodiments is a compound of Formula (VII) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (VII) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (VII) wherein each R1 is F. In some embodiments is a compound of Formula (VII) wherein each R1 is Cl. In some embodiments is a compound of Formula (VII) wherein each R1 is Br. In some embodiments is a compound of Formula (VII) wherein each R1 is —CF3. In some embodiments is a compound of Formula (VII) wherein each R1 is —CH3. In some embodiments is a compound of Formula (VII) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (VII) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (VII) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (VII) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (VII) wherein each R2 is F. In some embodiments is a compound of Formula (VII) wherein each R2 is Cl. In some embodiments is a compound of Formula (VII) wherein each R2 is Br. In some embodiments is a compound of Formula (VII) wherein each R2 is —CF3. In some embodiments is a compound of Formula (VII) wherein each R2 is —CH3. In some embodiments is a compound of Formula (VII) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (VII) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (VII) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (VII) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (VII) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (VII) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (VII) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (VII) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (VII) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (VII) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is a bond, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is a bond, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is a bond, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is a bond, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is a bond, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is a bond, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is a bond, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is a bond, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is a bond, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is a bond, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —CH2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —CH2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —CH2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —CH2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —CH2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —CH2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —CH2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —CH2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —C(H)(Ph)-, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —C(H)(Ph)-, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —C(H)(Ph)-, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —C(H)(Ph)-, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —S(═O)2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —S(═O)2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 1, X is —S(═O)2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —S(═O)2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —S(═O)2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —S(═O)2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VII) wherein m is 0, n is 2, X is —S(═O)2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 1, X is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —S(═O)2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 1, n is 2, X is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VII) wherein m is 2, n is 1, X is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof, and a pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprising the compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof, is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.
In another aspect is a method for treating an autoimmune disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the autoimmune disease is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In another embodiment is a method for treating type-1-diabetes comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating multiple sclerosis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating rheumatoid arthritis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating lupus comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof.
In another aspect is a method for treating a cardiovascular disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cardiovascular disease is atherosclerosis.
In another aspect is a method of treating a viral infection comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the viral infection is an Epstein-Barr viral infection.
In another aspect is a method of treating cancer comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VII) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In another aspect, described herein is a method of treating a disease, disorder or condition mediated by EBI2 in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (VII), or a pharmaceutically acceptable salt thereof. In another aspect, described herein is a method of treating a disease in a subject mediated by EBI2, which method comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (VII), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder or condition is an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In some embodiments, the disease, disorder or condition is a cardiovascular disease or condition. In some embodiments, the cardiovascular disease or condition is atherosclerosis. In some embodiments, the disease, disorder or condition is a viral infection. In some embodiments, the viral infection is an Epstein-Barr viral infection. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an Epstein-Barr viral infection in a human.
Further provided is the use of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of cancer in a human. In some embodiments is the use of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer in a human. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an Epstein-Barr viral infection in a human.
Further provided is the use of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of cancer in a human. In some embodiments is the use of a compound of Formula (VII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer in a human. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound of Formula (VII), is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal; and/or (j) the effective amount is adminstered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
In any of the aforementioned aspects involving the administration of a compound of Formula (VII), or a pharmaceutically acceptable salt thereof, to a subject are further embodiments comprising administering at least one additional agent in addition to the administration of a compound having the structure of Formula (VII), or a pharmaceutically acceptable salt thereof. In various embodiments, the compound of Formula (VII), and the additional agent are administered in any order, including simultaneously. In some embodiments, the compound of Formula (VII), and the additional agent are administered to the subject in the same pharmaceutical composition or in separate pharmaceutical compositions.
In some embodiments is a compound having the structure of Formula (VIII):




wherein:

X is —N(H)—, —N(R3)—, —O—, or —S—;
Y is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
R3 is C1-C6alkyl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (VIII) wherein X is —N(H)—. In another embodiment is a compound of Formula (VIII) wherein X is —N(R3)—. In another embodiment is a compound of Formula (VIII) wherein X is —N(CH3)—. In another embodiment is a compound of Formula (VIII) wherein X is —O—. In another embodiment is a compound of Formula (VIII) wherein X is —S—.
In some embodiments is a compound of Formula (VIII) wherein Y is a bond. In another embodiment is a compound of Formula (VIII) wherein Y is —CH2—. In another embodiment is a compound of Formula (VIII) wherein Y is —C(H)(Ph)-. In another embodiment is a compound of Formula (VIII) wherein Y is —C(═O)—. In another embodiment is a compound of Formula (VIII) wherein Y is —S(═O)2—.
In some embodiments is a compound of Formula (VIII) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (VIII) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (VIII) wherein each R1 is F. In some embodiments is a compound of Formula (VIII) wherein each R1 is Cl. In some embodiments is a compound of Formula (VIII) wherein each R1 is Br. In some embodiments is a compound of Formula (VIII) wherein each R1 is —CF3. In some embodiments is a compound of Formula (VIII) wherein each R1 is —CH3. In some embodiments is a compound of Formula (VIII) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (VIII) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (VIII) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (VIII) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (VIII) wherein each R2 is F. In some embodiments is a compound of Formula (VIII) wherein each R2 is Cl. In some embodiments is a compound of Formula (VIII) wherein each R2 is Br. In some embodiments is a compound of Formula (VIII) wherein each R2 is —CF3. In some embodiments is a compound of Formula (VIII) wherein each R2 is —CH3. In some embodiments is a compound of Formula (VIII) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (VIII) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (VIII) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (VIII) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (VIII) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (VIII) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (VIII) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (VIII) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (VIII) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (VIII) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is a bond, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, Y is a bond, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, Y is a bond, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is a bond, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is a bond, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is a bond, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is a bond, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is a bond, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —CH2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —CH2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —CH2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —CH2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —CH2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —CH2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —CH2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —CH2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —C(═O)—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —C(═O)—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —C(═O)—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —C(═O)—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —S(═O)2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —S(═O)2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —N(H)—, Y is —S(═O)2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —N(H)—, Y is —S(═O)2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —N(H)—, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —N(H)—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —N(H)—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is a bond, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is a bond, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is a bond, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is a bond, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is a bond, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is a bond, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is a bond, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is a bond, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —CH2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —CH2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —CH2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —CH2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —CH2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —CH2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —CH2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —CH2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(H)(Ph)-, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —C(═O)—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —C(═O)—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —C(═O)—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —C(═O)—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —S(═O)2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —S(═O)2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —O—, Y is —S(═O)2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —O—, Y is —S(═O)2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —O—, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —O—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —O—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is a bond, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is a bond, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is a bond, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is a bond, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is a bond, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is a bond, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is a bond, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is a bond, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —CH2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —CH2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —CH2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —CH2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —CH2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —CH2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —CH2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —CH2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(H)(Ph)-, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —C(═O)—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —C(═O)—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —C(═O)—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(═O)—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —C(═O)—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —S(═O)2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —S(═O)2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 1, X is —S—, Y is —S(═O)2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (VIII) wherein m is 0, n is 2, X is —S—, Y is —S(═O)2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 1, X is —S—, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 1, n is 2, X is —S—, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (VIII) wherein m is 2, n is 1, X is —S—, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof, and a pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprising the compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof, is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.
In another aspect is a method for treating an autoimmune disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the autoimmune disease is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In another embodiment is a method for treating type-1-diabetes comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating multiple sclerosis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating rheumatoid arthritis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating lupus comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof.
In another aspect is a method for treating a cardiovascular disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cardiovascular disease is atherosclerosis.
In another aspect is a method of treating a viral infection comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the viral infection is an Epstein-Barr viral infection.
In another aspect is a method of treating cancer comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In another aspect, described herein is a method of treating a disease, disorder or condition mediated by EBI2 in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof. In another aspect, described herein is a method of treating a disease in a subject mediated by EBI2, which method comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder or condition is an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In some embodiments, the disease, disorder or condition is a cardiovascular disease or condition. In some embodiments, the cardiovascular disease or condition is atherosclerosis. In some embodiments, the disease, disorder or condition is a viral infection. In some embodiments, the viral infection is an Epstein-Barr viral infection. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an Epstein-Barr viral infection in a human.
Further provided is the use of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of cancer in a human. In some embodiments is the use of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer in a human. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an Epstein-Barr viral infection in a human.
Further provided is the use of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of cancer in a human. In some embodiments is the use of a compound of Formula (VIII), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer in a human. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound of Formula (VIII), is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal; and/or (j) the effective amount is adminstered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
In any of the aforementioned aspects involving the administration of a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, to a subject are further embodiments comprising administering at least one additional agent in addition to the administration of a compound having the structure of Formula (VIII), or a pharmaceutically acceptable salt thereof. In various embodiments, the compound of Formula (VIII), and the additional agent are administered in any order, including simultaneously. In some embodiments, the compound of Formula (VIII), and the additional agent are administered to the subject in the same pharmaceutical composition or in separate pharmaceutical compositions.
In some embodiments is a compound having the structure of Formula (IX):




wherein:

X is —C(═O)—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (IX) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (IX) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (IX) wherein each R1 is F. In some embodiments is a compound of Formula (IX) wherein each R1 is Cl. In some embodiments is a compound of Formula (IX) wherein each R1 is Br. In some embodiments is a compound of Formula (IX) wherein each R1 is —CF3. In some embodiments is a compound of Formula (IX) wherein each R1 is —CH3. In some embodiments is a compound of Formula (IX) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (IX) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (IX) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (IX) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (IX) wherein each R2 is F. In some embodiments is a compound of Formula (IX) wherein each R2 is Cl. In some embodiments is a compound of Formula (IX) wherein each R2 is Br. In some embodiments is a compound of Formula (IX) wherein each R2 is —CF3. In some embodiments is a compound of Formula (IX) wherein each R2 is —CH3. In some embodiments is a compound of Formula (IX) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (IX) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (IX) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (IX) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (IX) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (IX) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (IX) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (IX) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (IX) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (IX) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (IX) wherein m is 0, n is 1, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IX) wherein m is 0, n is 1, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IX) wherein m is 0, n is 1, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (IX) wherein m is 0, n is 2, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IX) wherein m is 0, n is 2, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IX) wherein m is 0, n is 2, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (IX) wherein m is 0, n is 2, X is a bond, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (IX) wherein m is 1, n is 1, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IX) wherein m is 1, n is 1, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IX) wherein m is 1, n is 1, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (IX) wherein m is 1, n is 2, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IX) wherein m is 1, n is 2, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IX) wherein m is 1, n is 2, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (IX) wherein m is 2, n is 1, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (IX) wherein m is 2, n is 1, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (IX) wherein m is 2, n is 1, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof, and a pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprising the compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof, is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.
In another aspect is a method for treating an autoimmune disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the autoimmune disease is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In another embodiment is a method for treating type-1-diabetes comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating multiple sclerosis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating rheumatoid arthritis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating lupus comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof.
In another aspect is a method for treating a cardiovascular disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cardiovascular disease is atherosclerosis.
In another aspect is a method of treating a viral infection comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the viral infection is an Epstein-Barr viral infection.
In another aspect is a method of treating cancer comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In another aspect, described herein is a method of treating a disease, disorder or condition mediated by EBI2 in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt thereof. In another aspect, described herein is a method of treating a disease in a subject mediated by EBI2, which method comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (IX), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder or condition is an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In some embodiments, the disease, disorder or condition is a cardiovascular disease or condition. In some embodiments, the cardiovascular disease or condition is atherosclerosis. In some embodiments, the disease, disorder or condition is a viral infection. In some embodiments, the viral infection is an Epstein-Barr viral infection. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an Epstein-Barr viral infection in a human.
Also provided is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (IX), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an Epstein-Barr viral infection in a human.
In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound of Formula (IX), is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal; and/or (j) the effective amount is adminstered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
In any of the aforementioned aspects involving the administration of a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, to a subject are further embodiments comprising administering at least one additional agent in addition to the administration of a compound having the structure of Formula (IX), or a pharmaceutically acceptable salt thereof. In various embodiments, the compound of Formula (IX), and the additional agent are administered in any order, including simultaneously. In some embodiments, the compound of Formula (IX), and the additional agent are administered to the subject in the same pharmaceutical composition or in separate pharmaceutical compositions.
In some embodiments is a compound having the structure of Formula (X):




wherein:

A is a bicyclic heteroaryl;
Y is a bond, —CH2—, —C(H)(Ph)-, —C(═O)—, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
R3 is C1-C6alkyl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
In some embodiments is a compound of Formula (X) wherein Y is a bond. In another embodiment is a compound of Formula (X) wherein Y is —CH2—. In another embodiment is a compound of Formula (X) wherein Y is —C(H)(Ph)-. In another embodiment is a compound of Formula (X) wherein Y is —C(═O)—. In another embodiment is a compound of Formula (X) wherein Y is —S(═O)2—.
In some embodiments is a compound of Formula (X) wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (X) wherein each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (X) wherein each R1 is F. In some embodiments is a compound of Formula (X) wherein each R1 is Cl. In some embodiments is a compound of Formula (X) wherein each R1 is Br. In some embodiments is a compound of Formula (X) wherein each R1 is —CF3. In some embodiments is a compound of Formula (X) wherein each R1 is —CH3. In some embodiments is a compound of Formula (X) wherein each R1 is —OCF3. In some embodiments is a compound of Formula (X) wherein each R1 is —OCH3.
In some embodiments is a compound of Formula (X) wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, aryl, or heteroaryl. In some embodiments is a compound of Formula (X) wherein each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In some embodiments is a compound of Formula (X) wherein each R2 is F. In some embodiments is a compound of Formula (X) wherein each R2 is Cl. In some embodiments is a compound of Formula (X) wherein each R2 is Br. In some embodiments is a compound of Formula (X) wherein each R2 is —CF3. In some embodiments is a compound of Formula (X) wherein each R2 is —CH3. In some embodiments is a compound of Formula (X) wherein each R2 is —OCF3. In some embodiments is a compound of Formula (X) wherein each R2 is —OCH3.
In another embodiment is a compound of Formula (X) wherein m is 0 and n is 0.
In another embodiment is a compound of Formula (X) wherein m is 0 and n is 1. In another embodiment is a compound of Formula (X) wherein m is 1 and n is 0. In another embodiment is a compound of Formula (X) wherein m is 0 and n is 2. In another embodiment is a compound of Formula (X) wherein m is 2 and n is 0. In another embodiment is a compound of Formula (X) wherein m is 1 and n is 1. In another embodiment is a compound of Formula (X) wherein m is 1 and n is 2. In another embodiment is a compound of Formula (X) wherein m is 2 and n is 2.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is a bond, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is a bond, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is a bond, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is a bond, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is a bond, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is a bond, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is a bond, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is a bond, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is a bond, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is a bond, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is a bond, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, X is —N(H)—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, X is —N(H)—, Y is a bond, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —CH2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —CH2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —CH2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —CH2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —CH2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —CH2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —CH2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —CH2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —CH2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —CH2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —CH2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —CH2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —C(H)(Ph)-, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(H)(Ph)-, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(H)(Ph)-, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —C(H)(Ph)-, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —C(H)(Ph)-, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —C(H)(Ph)-, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —C(═O)—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —C(═O)—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —C(═O)—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(═O)—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(═O)—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —C(═O)—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —C(═O)—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —C(═O)—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —C(═O)—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —C(═O)—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —S(═O)2—, and R1 is F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —S(═O)2—, and R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 1, Y is —S(═O)2—, and R1 is F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —S(═O)2—, and each R1 is independently F, Cl, Br, or —CF3. In another embodiment is a compound of Formula (X) wherein m is 0, n is 2, Y is —S(═O)2—, and two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 1, Y is —S(═O)2—, R1 is F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 1, n is 2, Y is —S(═O)2—, each R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and R2 is independently F, Cl, Br, or —CF3.
In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl, and each R2 is independently F, Cl, Br, —CN, —NR4R5, —NO2, —CF3, —OCF3, —OH, —C1-C6alkyl, or —OC1-C6alkyl. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3, and each R2 is independently F, Cl, Br, —CF3, —CH3, —OCF3, or —OCH3. In another embodiment is a compound of Formula (X) wherein m is 2, n is 1, Y is —S(═O)2—, R1 is independently F, Cl, Br, —CF3, —CH3, or —OCH3, and each R2 is independently F, Cl, Br, or —CF3.
In another embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof, and a pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprising the compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof, is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.
In another aspect is a method for treating an autoimmune disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the autoimmune disease is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In another embodiment is a method for treating type-1-diabetes comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating multiple sclerosis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating rheumatoid arthritis comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In another embodiment is a method for treating lupus comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof.
In another aspect is a method for treating a cardiovascular disease or condition comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cardiovascular disease is atherosclerosis.
In another aspect is a method of treating a viral infection comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In some embodiments, the viral infection is an Epstein-Barr viral infection.
In another aspect is a method of treating cancer comprising administering to an individual in need a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof. In one embodiment, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
In another aspect, described herein is a method of treating a disease, disorder or condition mediated by EBI2 in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof. In another aspect, described herein is a method of treating a disease in a subject mediated by EBI2, which method comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder or condition is an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus. In some embodiments, the disease, disorder or condition is a cardiovascular disease or condition. In some embodiments, the cardiovascular disease or condition is atherosclerosis. In some embodiments, the disease, disorder or condition is a viral infection. In some embodiments, the viral infection is an Epstein-Barr viral infection. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is blood, brain, breast, colorectal, gastrointestinal, liver, lung, ovarian, pancreatic, prostate, skin or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) mediated signaling. In some embodiments, the molecules are EBI2 receptor. In some embodiments, the cancer is associated with EBV or other herpes virus infections. In some embodiments, the cancer is a hematopoietic tumor. In some embodiments, the hematopoietic tumor is a tumor of myeloid or lymphoid tissues. In some embodiments, the cancer is a brain cancer. In some embodiments, the EBI2 receptor is mutated or its expression level altered. In some embodiments, the molecules are oxysterols. In some embodiments, the oxysterol is an EBI2 ligand. In some embodiments, the oxysterol level is altered. In some embodiments, the molecule is an enzyme involved in metabolism of oxysterols. In some embodiments, the enzyme is mutated or its expression level altered.
Also provided is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the treatment of an Epstein-Barr viral infection in a human.
Also provided is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human. In some embodiments is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an autoimmune disease or condition in a human, wherein the autoimmune disease or condition is selected from type-1-diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
Further provided is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a cardiovascular disease or condition in a human. In some embodiments is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of atherosclerosis in a human.
Further provided is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of a viral infection in a human. In some embodiments is the use a compound of Formula (X), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug, or N-oxide thereof for the manufacture of a medicament for the treatment of an Epstein-Barr viral infection in a human.
In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound of Formula (X), is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal; and/or (j) the effective amount is adminstered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
In any of the aforementioned aspects involving the administration of a compound of Formula (X), or a pharmaceutically acceptable salt thereof, to a subject are further embodiments comprising administering at least one additional agent in addition to the administration of a compound having the structure of Formula (X), or a pharmaceutically acceptable salt thereof. In various embodiments, the compound of Formula (X), and the additional agent are administered in any order, including simultaneously. In some embodiments, the compound of Formula (X), and the additional agent are administered to the subject in the same pharmaceutical composition or in separate pharmaceutical compositions.
In another embodiment is a compound having the structure of Formula (XI):




wherein:

    
    
        R1 and R2 are independently selected from the group consisting of optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted cycloalkyl;
        Y and Z are independently a bond, O, —C(O)—N(R3)—, —C(O)—O—, —N(R4)—, —C(R5)(R6)—, SO2, S, C(O)═CH—, C(O)═CR7—, spiroalkyl, spiroheteroalkyl;
        X is CH— or N—;
        R3-R7 are independently selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
        R10 and R11 are independently selected from the group consisting of hydrogen, halogen, —CN, —S(O)R12—C(O)—N(R13)—R14, —C(O)—O—R15, —SO2N(R16)(R17) optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof.

    
    


In another embodiment is a compound of Formula (XI) wherein the compound is a selective EBI2 antagonist or inverse agonist.
In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (XI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect is a method of treating a disease in a subject mediated by EBI2 comprising administering to a subject a pharmaceutical composition comprising a compound of Formula (XI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another embodiment is a compound having the structure of Formula (XII):




wherein:

    
    
        R1 and R2 are independently selected from the group consisting of optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted cycloalkyl;
        Y and Z are independently a bond, O, —C(O)—N(R3)—, —C(O)—O—, —N(R4)—, —C(R5)(R6)—, SO2, S, C(O)═CH—, C(O)═CR7—, spiroalkyl, spiroheteroalkyl;
        Z is independently CR8 or N;
        X is CH— or N—;
        A, B and C are independently N, O, S, CR9;
        R3-R9 are independently selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof.

    
    


In another embodiment is a compound of Formula (XII) wherein the compound is a selective EBI2 antagonist or inverse agonist.
In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (XII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect is a method of treating a disease in a subject mediated by EBI2 comprising administering to a subject a pharmaceutical composition comprising a compound of Formula (XII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another embodiment is a compound selected from:












(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-


en-1-one


(E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-


carbonyl)phenyl)phosphonic acid


(2E)-3-(4-bromophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-1-one


(2E)-3-(3,4-dichlorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-1-one


3-(4-chlorophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}-3-(4-methylphenyl)prop-2-yn-1-


one


1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}-3-[4-


(trifluoromethyl)phenyl]prop-2-yn-1-one


3-(4-bromophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


3-(3,4-dichlorophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-


en-1-one


3-(3,4-dichlorophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-


yn-1-one


(2E)-3-(4-bromophenyl)-1-[4-(phenylamino)piperidyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-[4-(phenylcarbonyl)piperazinyl]prop-2-en-1-one


(2E)-1-{4-[(3,5-difluorophenyl)amino]piperidyl}-3-(4-bromophenyl)prop-2-en-


1-one


3-(4-chlorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-methoxyphenyl)prop-2-en-1-one


3-(2,3-dichlorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


1-{4-[(4-bromophenyl)carbonyl]piperazinyl}-3-(4-chlorophenyl)prop-2-yn-1-


one


(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-


en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-ethoxyphenyl)prop-2-en-1-one


(2E)-1-[4-(2-3,4-dihydronaphthylsulfonyl)piperazinyl]-3-(4-fluorophenyl)prop-


2-en-1-one


(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-


en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromo-2-fluorophenyl)prop-2-en-1-one


3-(2,3-dichlorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)amino]piperidyl}prop-2-en-1-


one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromophenyl)prop-2-en-1-one


3-(4-chlorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[4-(trifluoromethyl)phenyl]prop-2-en-


1-one


3-(2,3-dichlorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


(2E)-1-{4-[(3,5-difluorophenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-fluoro-3-


methylphenyl)methyl]piperazinyl}prop-2-en-1-one


1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-(4-methylphenyl)prop-2-yn-1-


one


3-(3-chlorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


3-(3-chlorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl 5-chlorobenzo[b]thiophen-2-yl ketone


(2E)-3-(4-bromophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-en-


1-one


1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-(4-methylphenyl)prop-2-yn-1-


one


(2E)-1-{4-[(3,4-dichlorophenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-


en-1-one


2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-chloro-2-fluorophenyl)prop-2-en-1-


one


(2E)-3-(4-bromophenyl)-1-{4-[(4-methylphenyl)methyl]piperazinyl}prop-2-en-


1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-phenylprop-2-en-1-one


4-(diphenylmethyl)piperazinyl 5-bromoindol-2-yl ketone


(2E)-3-(4-bromophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 6-chlorobenzo[b]thiophen-2-yl ketone


(2E)-1-{4-[(2,4-difluorophenyl)carbonyl]piperazinyl}-3-(4-bromophenyl)prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-[4-({[(4-


fluorophenyl)methyl]amino}methyl)piperidyl]prop-2-en-1-one


4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl 5-methylindol-2-yl ketone


(2E)-3-(4-bromophenyl)-1-(4-butylpiperazinyl)prop-2-en-1-one


1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromophenyl)prop-2-yn-1-one


3-(3,4-dichlorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-[4-(methylpropyl)piperazinyl]prop-2-en-1-one


3-(4-methylphenyl)-1-(4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-


2-yn-1-one


(2E)-1-[4-({[(3,5-difluorophenyl)methyl]amino}methyl)piperidyl]-3-(4-


bromophenyl)prop-2-en-1-one


3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


4-(diphenylmethyl)piperazinyl 5-chloroindol-2-yl ketone


5-methylindol-2-yl 4-[(2-phenylethyl)sulfonyl]piperazinyl ketone


1-[4-(diphenylmethyl)piperazinyl]-3-(4-methylphenyl)prop-2-yn-1-one


3-(3-chlorophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-[4-(trifluoromethyl)phenyl]prop-


2-yn-1-one


3-(4-bromophenyl)-1-{4-[(4-bromophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


methyl 4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoate


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-nitrophenyl)prop-2-en-1-one


4-[(4-chlorophenyl)carbonyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


1-{4-[(4-bromophenyl)carbonyl]piperazinyl}-3-phenylprop-2-yn-1-one


1-[4-(diphenylmethyl)piperazinyl]-3-[4-(trifluoromethyl)phenyl]prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-


one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-fluorophenyl)prop-2-en-1-one


1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-yn-1-one


3-(4-bromophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl indol-2-yl ketone


(2E)-1-{4-[(3,5-dimethoxyphenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-


2-en-1-one


3-(4-chlorophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-


2-yn-1-one


(2E)-3-(4-bromophenyl)-1-[4-({[(4-


chlorophenyl)methyl]amino}methyl)piperidyl]prop-2-en-1-one


3-(4-fluorophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-[4-(trifluoromethyl)phenyl]prop-2-


yn-1-one


3-(3,4-dichlorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-[4-(2-methylbutanoyl)piperazinyl]prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


(2E)-3-(4-bromophenyl)-1-(4-heptanoylpiperazinyl)prop-2-en-1-one


methyl 4-({4-[(5-bromoindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoate


(2E)-3-(4-bromophenyl)-1-[4-(cyclopentylcarbonyl)piperazinyl]prop-2-en-1-


one


potassium (E)-5-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-


carbonyl)phenyl)tetrazol-1-ide


3-[4-(trifluoromethyl)phenyl]-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


5-bromoindol-2-yl 4-[(4-chlorophenyl)carbonyl]piperazinyl ketone


4-(diphenylmethyl)piperazinyl 7-fluoro(3-quinolyl) ketone


benzo[d]furan-2-yl 4-(diphenylmethyl)piperazinyl ketone


5-chloroindol-2-yl 4-[(2-phenylethyl)sulfonyl]piperazinyl ketone


5-chloroindol-2-yl 4-[(4-chlorophenyl)carbonyl]piperazinyl ketone


3-(2,3-dichlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-(4-{[4-chloro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one


1-[4-(diphenylmethyl)piperazinyl]-3-(3-chlorophenyl)prop-2-yn-1-one


3-(3,4-dichlorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


4-(diphenylmethyl)piperazinyl 5-fluorobenzo[b]thiophen-2-yl ketone


(2E)-1-{4-[(((1E)-2-phenylvinyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-


en-1-one


(2E)-1-{4-[(4-chlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-


1-one


4-(diphenylmethyl)piperazinyl 5-methoxyindol-2-yl ketone


(2E)-3-(4-bromophenyl)-1-(4-pentanoylpiperazinyl)prop-2-en-1-one


(2E)-1-[4-((2E)-3-phenylprop-2-enoyl)piperazinyl]-3-phenylprop-2-en-1-one


(2E)-1-{4-[(2-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 2-naphthyl ketone


4-[(4-{[5-(trifluoromethyl)indol-2-


yl]carbonyl}piperazinyl)carbonyl]benzenecarbonitrile


(2E)-3-(4-bromophenyl)-1-(4-{[4-(methylethyl)phenyl]methyl}piperazinyl)prop-


2-en-1-one


4-(diphenylmethyl)piperazinyl 6-chloroindol-2-yl ketone


1,5-dimethylindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


(2E)-3-(3,4-difluorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromo-2-fluorophenyl)prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl 6-bromoindol-2-yl ketone


(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-


en-1-one


4-(diphenylmethyl)piperazinyl 6-quinolyl ketone


4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl 5-methylindol-2-yl ketone


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{1-[(4-fluorophenyl)carbonyl](4-


piperidyl)}prop-2-yn-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-fluorophenyl)prop-2-en-1-one


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-


chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


5-chloroindol-2-yl 4-[(4-iodophenyl)carbonyl]piperazinyl ketone


1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-phenylprop-2-yn-1-one


3-(3-chlorophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-


2-yn-1-one


(2E)-3-(4-bromophenyl)-1-[4-(3-methylbutanoyl)piperazinyl]prop-2-en-1-one


5-chloroindol-2-yl 4-[(4-fluorophenyl)carbonyl]piperazinyl ketone


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-


bromophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-{4-[({[3-fluoro-4-


(trifluoromethyl)phenyl]methyl}amino)methyl]piperidyl}prop-2-en-1-one


1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-(4-methylphenyl)prop-2-yn-1-one


benzo[b]thiophen-2-yl 4-(diphenylmethyl)piperazinyl ketone


(2E)-3-(4-fluorophenyl)-1-{4-[(4-methylphenyl)sulfonyl]piperazinyl}prop-2-en-


1-one


4-(diphenylmethyl)piperazinyl 3-quinolyl ketone


4-(diphenylmethyl)piperazinyl 5-fluoroindol-2-yl ketone


4-[(3-chlorophenyl)carbonyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


3-(4-fluorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


3-(3-chlorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chloro-2-


fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one


3-(2,3-dichlorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


5-(trifluoromethyl)indol-2-yl 4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl


ketone


piperazinyl 5-nitroindol-2-yl ketone


5-bromoindol-2-yl 4-[(4-fluorophenyl)carbonyl]piperazinyl ketone


N-({1-[(2E)-3-(4-bromophenyl)prop-2-enoyl](4-piperidyl)}methyl)(4-


fluorophenyl)carboxamide


1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-[4-(trifluoromethyl)phenyl]prop-2-


yn-1-one


(2E)-1-{4-[(3-chlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-


1-one


1-[4-(diphenylmethyl)piperazinyl]-3-phenylprop-2-yn-1-one


5-bromoindol-2-yl 4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


3-(2,3-dichlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl 5-(trifluoromethyl)benzo[b]thiophen-2-yl ketone


4-[(4-bromophenyl)sulfonyl]piperazinyl 5-methylindol-2-yl ketone


(2E)-1-(4-{[4-(tert-butyl)phenyl]methyl}piperazinyl)-3-(4-bromophenyl)prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-(4-propanoylpiperazinyl)prop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-methoxyphenyl)prop-2-


en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(3,4,5-trifluorophenyl)prop-2-en-1-one


5-methylindol-2-yl 4-(phenylethyl)piperazinyl ketone


3-(4-bromophenyl)-1-{4-[(4-(5H-1,2,3,4-tetraazol-5-


yl)phenyl)carbonyl]piperazinyl}prop-2-yn-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-bromophenyl)prop-2-


en-1-one


6-chloroindol-2-yl 4-[(4-methoxyphenyl)carbonyl]piperazinyl ketone


(2E)-3-(4-bromophenyl)-1-{4-[(4-(1H-1,2,3,4-tetraazol-5-


yl)phenyl)carbonyl]piperazinyl}prop-2-en-1-one


(E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-carbonyl)phenyl)boronic


acid


(2E)-3-(4-bromophenyl)-1-{4-[({[4-


(trifluoromethyl)phenyl]methyl}amino)methyl]piperidyl}prop-2-en-1-one


1-[4-(diphenylmethyl)piperazinyl]-3-bromo-3-(4-bromophenyl)prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 5-fluorobenzo[b]thiophen-2-yl ketone


3-(3-chlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


[4-(diphenylmethyl)piperazinyl](5-methylindol-2-yl)methane-1-thione


1-[4-(diphenylmethyl)piperazinyl]-3-(4-fluorophenyl)prop-2-yn-1-one


4-(4-(3-(4-bromophenyl)propioloyl)piperazine-1-carbonyl)phenylboronic acid


(2E)-1-{4-[(4-nitrophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


N-[1-(diphenylmethyl)(4-piperidyl)](5-methylindol-2-yl)carboxamide


5-chloroindol-2-yl 4-(pyrrol-3-ylcarbonyl)piperazinyl ketone


4-bromophenyl 4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl


ketone


4-bromophenyl 4-[(4-fluorophenyl)methyl]piperazinyl ketone


3-(2,4-difluorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one


benzothiazol-2-yl 4-(diphenylmethyl)piperazinyl ketone


3-[2-(trifluoromethyl)phenyl]-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


4-[(4-chlorophenyl)methyl]piperazinyl 2-(trifluoromethyl)benzimidazol-5-yl


ketone


3-(3,4-dichlorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


5-chloroindol-2-yl 4-{[4-(4-chlorophenyl)phenyl]sulfonyl}piperazinyl ketone


4-(diphenylmethyl)piperazinyl 6-methylthiopheno[3,2-d]pyrrol-5-yl ketone


(2E)-3-(5-bromo-2-fluorophenyl)-1-{4-[(4-


bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


4-[(4-chlorophenyl)methyl]piperazinyl 3-quinolyl ketone


4-bromophenyl 4-{[4-(methylethyl)phenyl]methyl}piperazinyl ketone


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoic acid


4-(diphenylmethyl)piperazinyl 7-nitroindol-2-yl ketone


3-(4-fluorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


6-bromoindol-2-yl 4-[(4-bromophenyl)methyl]piperazinyl ketone


[4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)phenyl]-N-(4-


fluorophenyl)carboxamide


5-chloroindol-2-yl 4-(2-pyridyl)piperazinyl ketone


5-chloroindol-2-yl 4-{[2-(trifluoromethyl)benzimidazol-5-yl]carbonyl}piperazinyl


ketone


N-{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}(4-chlorophenyl)carboxamide


4-(diphenylmethyl)piperazinyl 3-methylbenzo[b]thiophen-2-yl ketone


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one


[3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)phenyl]-N-(4-


fluorophenyl)carboxamide


3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoic acid


6-fluoroindol-2-yl 4-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}piperazinyl


ketone


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(2-fluorophenyl)prop-2-


en-1-one


(2E)-3-phenyl-1-[4-(2-pyridylmethyl)piperazinyl]prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)(1,4-diazaperhydroepinyl)]-3-(4-fluorophenyl)prop-


2-en-1-one


4-(diphenylmethyl)piperazinyl pyrrolo[4,5-b]pyridin-2-yl ketone


5-chloroindol-2-yl 4-[(4-phosphonophenyl)carbonyl]piperazinyl ketone


3-(3,5-difluorophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-


2-yn-1-one


(2E)-3-(2-methylphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


3-(3,5-difluorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl](1,4-diazaperhydroepinyl)}-3-(4-


fluorophenyl)prop-2-en-1-one


5-chloroindol-2-yl 4-morpholin-4-ylpiperidyl ketone


4-{[3-fluoro-4-(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-


(trifluoromethyl)indol-2-yl ketone


(2E)-1-{4-[(3-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-fluorophenyl)prop-2-


en-1-one


(2E)-1-{4-[(4-bromophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


5-chloroindol-2-yl 4-[(4-(1H-1,2,3,4-tetraazol-5-yl)phenyl)carbonyl]piperazinyl


ketone


(2E)-3-(4-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-nitrophenyl)sulfonyl]piperazinyl}prop-2-en-1-


one


4-(diphenylmethyl)piperazinyl 5-bromobenzo[b]thiophen-2-yl ketone


5-bromoindol-2-yl 4-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}piperazinyl


ketone


(2E)-1-{4-[(3-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-


1-one


(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-


en-1-one


4-[(4-fluorophenyl)methyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


(2E)-3-(4-fluorophenyl)-1-{4-[(3-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-


one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-ethoxyphenyl)prop-2-en-


1-one


(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-


en-1-one


4-(diphenylmethyl)piperazinyl 6-fluoroindol-2-yl ketone


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-


fluorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 5-phenylindol-2-yl ketone


(2E)-1-{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-3-[4-


(trifluoromethyl)phenyl]prop-2-en-1-one


4-[(4-fluorophenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-(4-methoxyphenyl)indol-2-yl ketone


(2E)-3-(4-fluorophenyl)-1-[4-(2-naphthylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-ethylpiperazinyl)prop-2-en-1-one


6-amino(2-naphthyl) 4-(diphenylmethyl)piperazinyl ketone


1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}piperazinyl)-3-(4-


methylphenyl)prop-2-yn-1-one


(2E)-1-{4-[(2,5-dichlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-


en-1-one


5-chloroindol-2-yl 4-[(4-fluorophenyl)amino]piperidyl ketone


4-(diphenylmethyl)piperazinyl 6-fluoro(3-quinolyl) ketone


4-(diphenylmethyl)piperazinyl 2-methylthiopheno[2,3-d]pyrrol-5-yl ketone


5-chloroindol-2-yl 4-(phenylcarbonyl)piperidyl ketone


(2E)-3-(3,4-dichlorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-[4-(trifluoromethyl)phenyl]prop-2-


yn-1-one


4-{[4-(diethylamino)phenyl]carbonyl}piperazinyl 5-chloroindol-2-yl ketone


(2E)-3-[4-(dimethylamino)phenyl]-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-


1-one


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-


bromophenyl)carbonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-


one


1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-(4-methylphenyl)prop-2-yn-1-


one


(2E)-3-(4-fluorophenyl)-1-{4-[(2-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-


one


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-


chlorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


6-bromoindol-2-yl 4-[(4-chlorophenyl)carbonyl]piperazinyl ketone


(2E)-1-{4-[(3-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-methylphenyl)prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 1-methylindol-2-yl ketone


5-chloroindol-2-yl 4-(phenylcarbonyl)piperazinyl ketone


4-{[4-(tert-butyl)phenyl]methyl}piperazinyl 5-methylindol-2-yl ketone


1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-(4-methylphenyl)prop-2-yn-1-one


4-[(2,4-dichlorophenyl)carbonyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


benzo[b]thiophen-5-yl 4-(diphenylmethyl)piperazinyl ketone


(2E)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


3-(3,4-dichlorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


4,6-dichloroindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


4-[(3,5-difluorophenyl)methyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


5-chloroindol-2-yl 4-[(3-fluorophenyl)amino]piperidyl ketone


3-(4-fluorophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-


2-yn-1-one


5-chloroindol-2-yl 4-[(4-(3-pyridyl)phenyl)carbonyl]piperazinyl ketone


6-chloroindol-2-yl 4-[(4-chlorophenyl)carbonyl]piperazinyl ketone


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-


methoxyphenyl)carbonyl]piperazinyl}prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 6-chloro(3-quinolyl) ketone


4-[(2,4-difluorophenyl)amino]piperidyl 5-chloroindol-2-yl ketone


(2E)-3-(4-fluorophenyl)-1-{4-[(4-propylphenyl)sulfonyl]piperazinyl}prop-2-en-


1-one


2E)-1-{4-[(4-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-(4-{[4-(methylethyl)phenyl]sulfonyl}piperazinyl)prop-


2-en-1-one


3-(2,3-dichlorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


4,6-difluoroindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


6-bromoindol-2-yl 4-[(4-bromophenyl)carbonyl]piperazinyl ketone


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-


1-one


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


(E)-(3-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-carbonyl)phenyl)boronic


acid


6-chloroindol-2-yl 4-[(4-fluorophenyl)carbonyl]piperazinyl ketone


(2E)-3-(4-bromophenyl)-1-{4-[(2-fluorophenyl)methyl]piperazinyl}prop-2-en-1-


one


(2E)-1-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}-3-phenylprop-2-en-1-one


5-(trifluoromethyl)indol-2-yl 4-{[3-(trifluoromethyl)phenyl]carbonyl}piperazinyl


ketone


5-chloroindol-2-yl 4-(3-chlorophenoxy)piperidyl ketone


4-[(3,5-difluorophenyl)amino]piperidyl 5-chloroindol-2-yl ketone


3-(4-bromophenyl)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}prop-2-yn-1-


one


3-(2,3-dichlorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-yn-1 -


one


4-(diphenylmethyl)piperazinyl quinoxalin-2-yl ketone


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-[2-


(trifluoromethyl)phenyl]prop-2-en-1-one


5-chloroindol-2-yl 4-(8-hydropyrazolo[1,5-a]pyridin-2-ylcarbonyl)piperazinyl


ketone


5-chloroindol-2-yl 4-(4-hydroimidazo[1,2-a]pyridin-2-ylcarbonyl)piperazinyl


ketone


5,6-dimethoxyindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


3-(2,3-dichlorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzamide


2-(difluoromethyl)benzimidazol-5-yl 4-(diphenylmethyl)piperazinyl ketone


3-(3,4-dichlorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-


one


4-[(2-chloro(3-pyridyl))carbonyl]piperazinyl 5-chloroindol-2-yl ketone


tert-butyl 4-[(1-methylindol-2-yl)carbonyl]piperazinecarboxylate


3-(4-fluorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


4-(benzimidazol-2-ylcarbonyl)piperazinyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-(2-pyridyloxy)piperidyl ketone


benzo[b]thiophen-3-yl 4-(diphenylmethyl)piperazinyl ketone


3-(3,4-dichlorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-yn-1-


one


6-fluoroindol-2-yl 4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


6-bromoindol-2-yl 4-[(4-fluorophenyl)methyl]piperazinyl ketone


3-(3,5-difluorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


5-chloroindol-2-yl 4-ethylpiperazinyl ketone


benzimidazol-5-yl 4-(diphenylmethyl)piperazinyl ketone


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-


chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-


bromophenyl)methyl]piperazinyl}prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 2-(trifluoromethyl)benzimidazol-5-yl ketone


(2E)-3-(4-chloro-2-fluorophenyl)-1-{4-[(5-chloroindol-2-


yl)carbonyl]piperazinyl}prop-2-en-1-one


2-anthryl 4-(diphenylmethyl)piperazinyl ketone


3-(3-chlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


5-bromoindol-2-yl 4-[(4-chlorophenyl)methyl]piperazinyl ketone


4-(diphenylmethyl)piperazinyl 6-methoxyindol-2-yl ketone


(2E)-3-(4-aminophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


4-{[(4-bromophenyl)sulfonyl]amino}piperidyl 5-chloroindol-2-yl ketone


4-({4-[(2E)-3-(4-ethoxyphenyl)prop-2-enoyl]piperazinyl}sulfonyl)-1-


acetylbenzene


(2E)-1-[4-(naphthylmethyl)piperazinyl]-3-phenylprop-2-en-1-one


1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-[2-(trifluoromethyl)phenyl]prop-


2-yn-1-one


6-bromoindol-2-yl 4-[(4-(1H-1,2,3,4-tetraazol-5-yl)phenyl)carbonyl]piperazinyl


ketone


[4-(diphenylmethyl)piperazinyl]-3-quinolylmethane-1-thione


(2E)-1-(4-butylpiperazinyl)-3-phenylprop-2-en-1-one


(2E)-3-(4-ethoxyphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(3-methoxyphenyl)sulfonyl]piperazinyl}prop-2-


en-1-one


5-chloroindol-2-yl 4-(4-fluorophenoxy)piperidyl ketone


3-(3-chlorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


5-chloroindol-2-yl 4-(4-chlorophenoxy)piperidyl ketone


(2E)-1-{4-[(2,5-dimethoxyphenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-


2-en-1-one


5-chloroindol-2-yl 4-[(4-fluorophenyl)methyl]piperazinyl ketone


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-chlorophenyl)prop-2-en-1-one


1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}piperazinyl)-3-phenylprop-2-


yn-1-one


4-[(3,4-dimethylphenyl)amino]piperidyl 5-chloroindol-2-yl ketone


(2E)-3-(4-fluorophenyl)-1-{4-[benzylsulfonyl]piperazinyl}prop-2-en-1-one


methyl 4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoate


1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}piperazinyl)-3-[4-


(trifluoromethyl)phenyl]prop-2-yn-1-one


4-{3-[4-(diphenylmethyl)piperazinyl]-3-oxoprop-1-ynyl}benzenecarbonitrile


5-chloroindol-2-yl 4-[(4-phenylphenyl)methyl]piperazinyl ketone


4-[(3,4-dichlorophenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


6-bromoindol-2-yl 4-{[3-fluoro-4-(trifluoromethyl)phenyl]carbonyl}piperazinyl


ketone


4-{[3,5-bis(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-(trifluoromethyl)indol-


2-yl ketone


5-chloroindol-2-yl 4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


(2E)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


4-[(4-bromophenyl)sulfonyl]piperazinyl 5-chloroindol-2-yl ketone


(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-(tert-


butyl)phenyl]sulfonyl}piperazinyl)prop-2-en-1-one


4-{[4-((2E)-3-phenylprop-2-enoyl)piperazinyl]methyl}benzenecarbonitrile


3-(4-bromophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


(2E)-3-phenyl-1-[4-benzylpiperazinyl]prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 5-(methylethyl)indol-2-yl ketone


4-[(4-chlorophenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


2-({4-[(2E)-3-(4-fluorophenyl)prop-2-


enoyl]piperazinyl}sulfonyl)benzenecarbonitrile


3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


3-(3,5-difluorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


(2E)-1-{4-[(2-bromophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-[4-(naphthylsulfonyl)piperazinyl]prop-2-en-1-one


3-(4-methylphenyl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-


yn-1-one


indol-2-yl 4-(phenylethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 5-hydroxyindol-2-yl ketone


3-(2,4-difluorophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


(2E)-1-{4-[(2,5-difluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


4-(diphenylmethyl)piperazinyl 2-quinolyl ketone


1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-[4-(trifluoromethyl)phenyl]prop-


2-yn-1-one


3-(3-chlorophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-


yn-1-one


(2E)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl](1,4-diazaperhydroepinyl)}-3-(4-


bromophenyl)prop-2-en-1-one


3-(4-chlorophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-


yn-1-one


5-chloroindol-2-yl 4-(4-fluoro-2-methylphenoxy)piperidyl ketone


methyl 3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoate


4-[(3,5-dimethylphenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


4-{[2-fluoro-4-(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-


(trifluoromethyl)indol-2-yl ketone


(2E)-1-{4-[2-(2-fluorophenyl)ethyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-[4-(2-(1,3-dihydroisobenzofuran-5-yl)ethyl)piperazinyl]-3-phenylprop-2-


en-1-one


methyl 3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoate


3-(4-bromophenyl)-1-{4-[(4-bromophenyl)methyl]piperazinyl}prop-2-yn-1-one


(2E)-1-{4-[(3-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


4-[(4-chlorophenyl)carbonyl]piperazinyl 6-fluoroindol-2-yl ketone


(2E)-3-(4-fluorophenyl)-1-[4-(2-thienylsulfonyl)piperazinyl]prop-2-en-1-one


4-butylpiperazinyl 5-chloroindol-2-yl ketone


3-(4-chlorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl indol-6-yl ketone


5-bromoindol-2-yl 4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


3-(4-chlorophenyl)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}prop-2-yn-1-


one


1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}-3-[2-


(trifluoromethyl)phenyl]prop-2-yn-1-one


(2E)-1-{4-[(2-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


6-bromoindol-2-yl 4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


5-methylindol-2-yl 4-benzylpiperazinyl ketone


(2E)-3-(4-bromo-2-fluorophenyl)-1-{4-[(4-


bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


4-[(2,4-difluorophenyl)carbonyl]piperazinyl 5-chloroindol-2-yl ketone


(2E)-1-{4-[(3-methoxyphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


4-(diphenylmethyl)piperazinyl thiopheno[2,3-d]pyrrol-5-yl ketone


4-bromophenyl 4-(2-naphthylcarbonyl)piperazinyl ketone


4-(4-(6-bromo-1H-indole-2-carbonyl)piperazine-1-carbonyl)phenylboronic


acid


1-{4-[(4-bromophenyl)methyl]piperazinyl}-3-(4-chlorophenyl)prop-2-yn-1-one


3-(4-chlorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-methoxyphenyl)prop-


2-en-1-one


4-(diphenylmethyl)piperazinyl 8-fluoro(3-quinolyl) ketone


(2E)-1-{4-[(3-nitrophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-chloro-2-


fluorophenyl)prop-2-en-1-one


4-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}piperazinyl 5-


(trifluoromethyl)indol-2-yl ketone


5-chloroindol-2-yl 4-[4-(trifluoromethyl)phenoxy]piperidyl ketone


6-chloroindol-2-yl 4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


(2E)-1-[4-(methylpropyl)piperazinyl]-3-phenylprop-2-en-1-one


1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-[2-(trifluoromethyl)phenyl]prop-2-


yn-1-one


(2E)-1-{4-[(2-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzenecarbonitrile


{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}-N-(3-chlorophenyl)carboxamide


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzaldehyde


3-(3,5-difluorophenyl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


3-(4-chlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


4-(2,3-dimethylphenyl)piperazinyl 5-chloroindol-2-yl ketone


3-(4-bromophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


5-chloroindol-2-yl 4-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}piperazinyl


ketone


5-chloroindol-2-yl 4-[(3-phenylphenyl)methyl]piperazinyl ketone


(2E)-3-(4-bromo-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


benzo[d]furan-2-yl 4-(phenylethyl)piperazinyl ketone


1-{4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)propan-1-one


(2E)-1-{4-[2-(2,4-dichlorophenoxy)ethyl]piperazinyl}-3-phenylprop-2-en-1-one


3-(4-bromophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-


yn-1-one


4-(4-(5-chloro-1H-indole-2-carbonyl)piperazine-1-carbonyl)phenylboronic acid


3-(3,5-difluorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


3-[4-(trifluoromethyl)phenyl]-1-(4-{[4-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


4-[(2,4-difluorophenyl)methyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


5-chloroindol-2-yl 4-phenoxypiperidyl ketone


tert-butyl 4-(indol-2-ylcarbonyl)piperazinecarboxylate


4-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}piperazinyl 5-


(trifluoromethyl)indol-2-yl ketone


phenyl 4-[(5-chloroindol-2-yl)carbonyl]piperazinecarboxylate


{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}-N-(3-fluorophenyl)carboxamide


4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl 5-


(trifluoromethyl)indol-2-yl ketone


3-(3,5-difluorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-yn-1-one


5-chloroindol-2-yl 4-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}piperazinyl


ketone


5-chloroindol-2-yl 4-{[4-(4-methoxyphenyl)phenyl]sulfonyl}piperazinyl ketone


3-(3,5-difluorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


4-{[3,5-bis(trifluoromethyl)phenyl]methyl}piperazinyl 5-chloroindol-2-yl ketone


3-(2,4-difluorophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-


one


6-fluoroindol-2-yl 4-[(4-fluorophenyl)carbonyl]piperazinyl ketone


5-chloroindol-2-yl 4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl


ketone


4-[(2,4-difluorophenyl)methyl]piperazinyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}piperazinyl


ketone


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(4-chlorophenyl)carboxamide


3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-(4-{[4-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-1-one


4-(diphenylmethyl)piperazinyl pyrrolo[2,3-c]pyridin-2-yl ketone


1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl)-3-[4-


(trifluoromethyl)phenyl]prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl 1-methylindol-5-yl ketone


4-(2,4-difluorophenyl)piperazinyl 5-chloroindol-2-yl ketone


3-(4-chlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


4-(diphenylmethyl)piperazinyl 4-bromopyrrol-2-yl ketone


3-(3,4-dichlorophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-1-one


1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-[2-(trifluoromethyl)phenyl]prop-2-


yn-1-one


(2E)-3-(4-chloro-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-


one


3-(4-(5-chloro-1H-indole-2-carbonyl)piperazine-1-carbonyl)phenylboronic acid


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(5-bromo-2-fluorophenyl)prop-2-en-


1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-methylphenyl)prop-2-en-


1-one


1-[4-(diphenylmethyl)piperazinyl]-3-[2-(trifluoromethyl)phenyl]prop-2-yn-1-one


(2E)-3-phenyl-1-piperazinylprop-2-en-1-one


N-(4-bromophenyl){4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carboxamide


3-(4-fluorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


6-chloroindol-2-yl 4-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}piperazinyl


ketone


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-chloro-2-


fluorophenyl)prop-2-en-1-one


5-chloroindol-2-yl 4-(cyclopentylamino)piperidyl ketone


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-[4-fluoro-3-


(trifluoromethyl)phenyl]carboxamide


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(3-fluorophenyl)carboxamide


4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl benzo[d]furan-2-yl ketone


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-methylphenyl)prop-2-en-1-one


5-chloroindol-2-yl 4-[(4-phenylphenyl)sulfonyl]piperazinyl ketone


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-fluorophenyl)prop-2-en-


1-one


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-[4-


(trifluoromethyl)phenyl]carboxamide


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-(1H-1,2,3,4-tetraazol-5-


yl)phenyl)carbonyl]piperazinyl}prop-2-en-1-one


5-methylindol-2-yl 4-(3-pyridylmethyl)piperazinyl ketone


1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl)-3-(4-


methylphenyl)prop-2-yn-1-one


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoic acid


1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-(4-fluorophenyl)prop-2-yn-1-one


{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}(4-chlorophenyl)


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-


fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


4-[(4-chlorophenyl)methyl]piperazinyl 3-quinolyl ketone


4-(diphenylmethyl)piperazinyl 2-methylbenzimidazol-5-yl ketone


(2E)-3-phenyl-1-[4-(4-pyridylmethyl)piperazinyl]prop-2-en-1-one


3-(3,5-difluorophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-


1-one


4-(diphenylmethyl)piperazinyl 3-isoquinolyl ketone


1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-[2-(trifluoromethyl)phenyl]prop-2-


yn-1-one


5-chloroindol-2-yl 4-(4-fluorophenyl)piperazinyl ketone


6-bromoindol-2-yl 4-[(4-chlorophenyl)methyl]piperazinyl ketone


4-bromophenyl 4-[(4-chlorophenyl)methyl]piperazinyl ketone


3-(3-chlorophenyl)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}prop-2-yn-1-one


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(3-iodophenyl)carboxamide


3-[2-(trifluoromethyl)phenyl]-1-(4-{[4-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-one


5-chloroindol-2-yl 4-(2-fluorophenyl)piperazinyl ketone


N-(2,4-difluorophenyl){4-[(5-chloroindol-2-


yl)carbonyl]piperazinyl}carboxamide


4-(diphenylmethyl)piperazinyl 8-hydropyrazolo[1,5-a]pyridin-2-yl ketone


3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(2-methylphenyl)prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-


1-one


(E)-1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-phenylprop-2-en-1-one


(E)-3-(3,4-dichlorophenyl)-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)prop-


2-en-1-one


(E)-3-(4-bromophenyl)-1-(4-(mesitylsulfonyl)piperazin-1-yl)prop-2-en-1-one


(E)-1-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-


en-1-one


(E)-3-(4-fluorophenyl)-1-(4-(phenethylsulfonyl)piperazin-1-yl)prop-2-en-1-one


(E)-3-(4-methoxyphenyl)-1-(4-(phenylsulfonyl)piperazin-1-yl)prop-2-en-1-one


(E)-1-(4-((4-acetylphenyl)sulfonyl)piperazin-1-yl)-3-(4-bromo-2-


fluorophenyl)prop-2-en-1-one


(E)-3-(4-bromophenyl)-1-(4-(((4-


(trifluoromethyl)benzyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one


(E)-N-((1-(3-(4-bromophenyl)acryloyl)piperidin-4-yl)methyl)-4-


(trifluoromethyl)benzamide









In another embodiment is a compound selected from:










Name















(2E)-1-{4-[(2-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(3-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(3-methoxyphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(2-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(3-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(3-nitrophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(4-nitrophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(2-bromophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(4-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(3-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[(2-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


4-{[4-((2E)-3-phenylprop-2-enoyl)piperazinyl]methyl}benzenecarbonitrile


(2E)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-[4-((2E)-3-phenylprop-2-enoyl)piperazinyl]-3-phenylprop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-phenylprop-2-en-1-one


(2E)-3-phenyl-1-piperazinylprop-2-en-1-one


(2E)-3-phenyl-1-[4-benzylpiperazinyl]prop-2-en-1-one


(2E)-1-[4-(naphthylmethyl)piperazinyl]-3-phenylprop-2-en-1-one


(2E)-3-phenyl-1-[4-(2-pyridylmethyl)piperazinyl]prop-2-en-1-one


(2E)-1-{4-[(2,5-difluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-3-phenyl-1-[4-(4-pyridylmethyl)piperazinyl]prop-2-en-1-one


(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[2-(2-fluorophenyl)ethyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-{4-[2-(2,4-dichlorophenoxy)ethyl]piperazinyl}-3-phenylprop-2-en-1-one


(2E)-1-[4-(methylpropyl)piperazinyl]-3-phenylprop-2-en-1-one


(2E)-1-(4-butylpiperazinyl)-3-phenylprop-2-en-1-one


(2E)-1-[4-(2-(1,3-dihydroisobenzofuran-5-yl)ethyl)piperazinyl]-3-phenylprop-2-en-1-


one


(2E)-3-(4-fluorophenyl)-1-{4-[benzylsulfonyl]piperazinyl}prop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one


(2E)-1-{4-[(4-chlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-methylphenyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-nitrophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-fluorophenyl)prop-2-en-1-


one


(2E)-3-(4-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


1-[((1E)-2-phenylvinyl)sulfonyl]-4-(diphenylmethyl)piperazine


(2E)-1-[4-(2-3,4-dihydronaphthylsulfonyl)piperazinyl]-3-(4-fluorophenyl)prop-2-en-1-


one


(2E)-3-(4-fluorophenyl)-1-{4-[(2-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-methoxyphenyl)sulfonyl]piperazinyl}prop-2-en-1-


one


(2E)-3-(4-fluorophenyl)-1-{4-[(3-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-1-{4-[(3-chlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one


(2E)-1-{4-[(2-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(3-methoxyphenyl)sulfonyl]piperazinyl}prop-2-en-1-


one


(2E)-3-(4-fluorophenyl)-1-{4-[(4-propylphenyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-1-{4-[(2,5-dimethoxyphenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-


1-one


(2E)-3-(4-fluorophenyl)-1-(4-{[4-(methylethyl)phenyl]sulfonyl}piperazinyl)prop-2-en-


1-one


(2E)-1-{4-[(2,5-dichlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-


one


(2E)-1-{4-[(3-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one


2-({4-[(2E)-3-(4-fluorophenyl)prop-2-enoyl]piperazinyl}sulfonyl)benzenecarbonitrile


(2E)-3-(4-fluorophenyl)-1-[4-(2-naphthylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-[4-(naphthylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-fluorophenyl)-1-[4-(2-thienylsulfonyl)piperazinyl]prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 5-methyl(3-pyridyl) ketone


4-(diphenylmethyl)piperazinyl 3-bromophenyl ketone


4-(diphenylmethyl)piperazinyl 5-chloro(3-pyridyl) ketone


4-(diphenylmethyl)piperazinyl 5-bromo(3-pyridyl) ketone


4-(diphenylmethyl)piperazinyl 3-methylphenyl ketone


1-{4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)propan-1-one


(2E)-3-(4-fluorophenyl)-1-{4-[(2-phenylethyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(2,4,6-trimethylphenyl)sulfonyl]piperazinyl}prop-2-en-


1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-nitrophenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-chlorophenyl)prop-2-en-1-one


3-(4-aminophenyl)-1-[4-(diphenylmethyl)piperazinyl]propan-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(3-fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-methylphenyl)methyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-{[4-(methylethyl)phenyl]methyl}piperazinyl)prop-2-en-


1-one


(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-1-{4-[(3,4-dichlorophenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-1-{4-[(3,5-dimethoxyphenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-1-(4-{[4-(tert-butyl)phenyl]methyl}piperazinyl)-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-1-{4-[(3,5-difluorophenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-3-(4-bromophenyl)-1-{4-[(4-fluoro-3-methylphenyl)methyl]piperazinyl}prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chloro-2-fluorophenyl)methyl]piperazinyl}prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one


(2E)-3-(4-aminophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-{[4-chloro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(2-fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-methylphenyl)prop-2-en-1-one


(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl](1,4-diazaperhydroepinyl)}-3-(4-


bromophenyl)prop-2-en-1-one


(2E)—N-(2-{[((1E)-2-phenylvinyl)sulfonyl]amino}ethyl)-3-(4-bromophenyl)prop-2-


enamide


(2E)—N-(3-{[((1E)-2-phenylvinyl)sulfonyl]amino}propyl)-3-(4-bromophenyl)prop-2-


enamide


(2E)—N-(2-{[((1E)-2-phenylvinyl)sulfonyl]amino}ethyl)-3-(4-bromophenyl)-N-


methylprop-2-enamide


(2E)—N-(2-{[((1E)-2-phenylvinyl)sulfonyl]amino}ethyl)-3-(4-fluorophenyl)-N-


methylprop-2-enamide


(2E)—N-(2-{[((1E)-2-phenylvinyl)sulfonyl]amino}ethyl)-3-(4-fluorophenyl)prop-2-


enamide


(2E)—N-(3-{[((1E)-2-phenylvinyl)sulfonyl]amino}propyl)-3-(4-fluorophenyl)prop-2-


enamide


(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl](1,4-diazaperhydroepinyl)}-3-(4-


fluorophenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)(1,4-diazaperhydroepinyl)]-3-(4-fluorophenyl)prop-2-en-1-


one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromophenyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-ethylpiperazinyl)prop-2-en-1-one


4-(diphenylmethyl)piperazinyl 1-methylindol-5-yl ketone


(2E)-3-(4-bromophenyl)-1-(4-butylpiperazinyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-[4-(methylpropyl)piperazinyl]prop-2-en-1-one


(2E)-1-(4,4-dimethylpiperazinyl)-3-(4-bromophenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(3,4,5-trifluorophenyl)prop-2-en-1-one


(2E)-3-(3,4-dichlorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-methoxyphenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-ethoxyphenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-fluorophenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-methylphenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(5-bromo-2-fluorophenyl)prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromo-2-fluorophenyl)prop-2-en-1-one


(2E)-3-(2,4-difluorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


(2E)-3-(3,4-difluorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[2,4-bis(trifluoromethyl)phenyl]prop-2-en-1-


one


(2E)-3-(2,5-dichlorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one


(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(6-chloro-2-fluorophenyl)prop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-fluorophenyl)prop-2-en-1-one


(2E)-3-(2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(2-fluorophenyl)prop-2-en-1-


one


(2E)-3-(3,4-dichlorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)prop-2-


en-1-one


(2E)-3-(4-chloro-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-chloro-2-fluorophenyl)prop-2-


en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-chloro-2-fluorophenyl)prop-


2-en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-methoxyphenyl)prop-2-en-


1-one


(2E)-3-(4-methoxyphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-methoxyphenyl)prop-2-en-1-


one


(2E)-3-(2-methylphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(2-methylphenyl)prop-2-en-1-


one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-methylphenyl)prop-2-en-1-one


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-[2-(trifluoromethyl)phenyl]prop-2-


en-1-one


(2E)-1-[4-(phenylsulfonyl)piperazinyl]-3-[2-(trifluoromethyl)phenyl]prop-2-en-1-one


(2E)-3-(4-bromo-2-fluorophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-


en-1-one


(2E)-3-(4-bromo-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


4-({4-[(2E)-3-(4-bromo-2-fluorophenyl)prop-2-enoyl]piperazinyl}sulfonyl)-1-


acetylbenzene


4-({4-[(2E)-3-(4-ethoxyphenyl)prop-2-enoyl]piperazinyl}sulfonyl)-1-acetylbenzene


(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-ethoxyphenyl)prop-2-en-1-one


(2E)-3-(4-ethoxyphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


4-({4-[(2E)-3-(5-bromo-2-fluorophenyl)prop-2-enoyl]piperazinyl}sulfonyl)-1-


acetylbenzene


(2E)-3-(5-bromo-2-fluorophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-


en-1-one


(2E)-3-(5-bromo-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}prop-2-en-1-


one


(2E)-3-(4-bromophenyl)-1-[4-(phenylcarbonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-


en-1-one


(2E)-3-(4-bromophenyl)-1-[4-(cyclopentylcarbonyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-pentanoylpiperazinyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-[4-(3-methylbutanoyl)piperazinyl]prop-2-en-1-one


4-({4-[(2E)-3-(4-bromophenyl)prop-2-enoyl]piperazinyl}carbonyl)benzenecarbonitrile


(2E)-3-(4-bromophenyl)-1-[4-(2-methylbutanoyl)piperazinyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-(4-heptanoylpiperazinyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-methylphenyl)carbonyl]piperazinyl}prop-2-en-1-one


(2E)-1-{4-[(2,4-difluorophenyl)carbonyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-


one


(2E)-3-(4-bromophenyl)-1-(4-propanoylpiperazinyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-fluorophenyl)amino]piperidyl}prop-2-en-1-one


(2E)-1-{4-[(3,5-difluorophenyl)amino]piperidyl}-3-(4-bromophenyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-[4-(phenylamino)piperidyl]prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)amino]piperidyl}prop-2-en-1-one


N-({1-[(2E)-3-(4-bromophenyl)prop-2-enoyl](4-piperidyl)}methyl)(4-


fluorophenyl)carboxamide


(E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-carbonyl)phenyl)boronic acid


(2E)-3-(4-bromophenyl)-1-{4-[(4-(1H-1,2,3,4-tetraazol-5-


yl)phenyl)carbonyl]piperazinyl}prop-2-en-1-one


potassium (E)-5-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-


carbonyl)phenyl)tetrazol-1-ide


(2E)-3-(4-bromophenyl)-1-{4-[({[4-


(trifluoromethyl)phenyl]methyl}amino)methyl]piperidyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-[4-({[(4-fluorophenyl)methyl]amino}methyl)piperidyl]prop-


2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[({[3-fluoro-4-


(trifluoromethyl)phenyl]methyl}amino)methyl]piperidyl}prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-[4-({[(4-chlorophenyl)methyl]amino}methyl)piperidyl]prop-


2-en-1-one


N-({1-[(2E)-3-(4-bromophenyl)prop-2-enoyl](4-piperidyl)}methyl)[4-


(trifluoromethyl)phenyl]carboxamide


(2E)-1-[4-({[(3,5-difluorophenyl)methyl]amino}methyl)piperidyl]-3-(4-


bromophenyl)prop-2-en-1-one


(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


2-(4-bromophenyl)-1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}ethan-1-one


2-(4-bromophenyl)-1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}ethan-1-one


2-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one


2-(4-bromophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}ethan-1-one


2-(4-bromophenyl)-1-(4-{[4-fluoro-2-


(trifluoromethyl)phenyl]methyl}piperazinyl)ethan-1-one


1-{4-[(3,4-dichlorophenyl)methyl]piperazinyl}-2-(4-bromophenyl)ethan-1-one


2-(4-bromophenyl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)ethan-1-one


2-(4-bromophenyl)-1-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one


2-(4-bromophenyl)-1-(4-{[4-(methylethyl)phenyl]methyl}piperazinyl)ethan-1-one









In another embodiment is a compound selected from:










Name















4-(diphenylmethyl)piperazinyl 3-quinolyl ketone


indol-3-yl 4-methyl-4-(phenylethyl)piperazinyl ketone


tert-butyl 4-(indol-3-ylcarbonyl)piperazinecarboxylate


tert-butyl 4-(indol-2-ylcarbonyl)piperazinecarboxylate


4-(diphenylmethyl)piperazinyl indol-3-yl ketone


4-(diphenylmethyl)piperazinyl indol-2-yl ketone


1,5-dimethylindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 1-methylindol-2-yl ketone


indol-2-yl 4-(phenylethyl)piperazinyl ketone


indol-3-yl 4-(phenylethyl)piperazinyl ketone


tert-butyl 4-[(1-methylindol-3-yl)carbonyl]piperazinecarboxylate


tert-butyl 4-[(1-methylindol-2-yl)carbonyl]piperazinecarboxylate


benzo[d]furan-2-yl 4-(phenylethyl)piperazinyl ketone


4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl benzo[d]furan-2-yl ketone


4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl indol-3-yl ketone


4-(phenylethyl)piperazinyl 3-quinolyl ketone


5-methylindol-2-yl 4-(phenylethyl)piperazinyl ketone


[4-(diphenylmethyl)piperazinyl]-3-quinolylmethane-1-thione


4-(diphenylmethyl)piperazinyl 2-quinolyl ketone


4-(2H-benzo[3,4-d]1,3-dioxolen-5-ylmethyl)piperazinyl 2-quinolyl ketone


1-methylindol-3-yl 4-(phenylethyl)piperazinyl ketone


4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl 3-quinolyl ketone


4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl 5-methylindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-chloroindol-2-yl ketone


[4-(diphenylmethyl)piperazinyl](5-methylindol-2-yl)methane-1-thione


4-(diphenylmethyl)piperazinyl 5-phenylindol-2-yl ketone


benzimidazol-2-yl 4-(diphenylmethyl)piperazinyl ketone


5-methylindol-2-yl 4-benzylpiperazinyl ketone


4-(diphenylmethyl)piperazinyl 5-(4-methoxyphenyl)indol-2-yl ketone


4-(diphenylmethyl)piperazinyl 4-bromopyrrol-2-yl ketone


4-{[4-(tert-butyl)phenyl]methyl}piperazinyl 5-methylindol-2-yl ketone


4-[(4-fluorophenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 2-naphthyl ketone


4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl 5-methylindol-2-yl ketone


4-[(4-bromophenyl)sulfonyl]piperazinyl 5-methylindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-methyl(3-pyridyl) ketone


4-(diphenylmethyl)piperazinyl 3-bromophenyl ketone


4-(diphenylmethyl)piperazinyl 5-chloro(3-pyridyl) ketone


4-(diphenylmethyl)piperazinyl 5-bromo(3-pyridyl) ketone


benzo[b]thiophen-2-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 3-methylphenyl ketone


N-[1-(diphenylmethyl)(4-piperidyl)](5-methylindol-2-yl)carboxamide


4-(diphenylmethyl)piperazinyl indol-7-yl ketone


4-(diphenylmethyl)piperazinyl 5-bromoindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 4-quinolyl ketone


4-(diphenylmethyl)piperazinyl 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-fluoroindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 6-bromoindol-2-yl ketone


4-(diphenylmethyl)piperazinyl quinoxalin-2-yl ketone


4-(diphenylmethyl)piperazinyl 6-chloroindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-nitroindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-hydroxyindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 8-hydropyrazolo[1,5-a]pyridin-2-yl ketone


4-(diphenylmethyl)piperazinyl 6-fluoroindol-2-yl ketone


1H-indazol-3-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl pyrrolo[4,5-b]pyridin-2-yl ketone


5-methylindol-2-yl 4-[(2-phenylethyl)sulfonyl]piperazinyl ketone


4-(diphenylmethyl)piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


5-methylindol-2-yl 4-benzylpiperazinyl ketone


4-(diphenylmethyl)piperazinyl indol-4-yl ketone


benzo[b]thiophen-3-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 3-methylbenzo[b]thiophen-2-yl ketone


4-(diphenylmethyl)piperazinyl 3-isoquinolyl ketone


4,6-difluoroindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


4,6-dichloroindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 5-methoxyindol-2-yl ketone


5-methylindol-2-yl 4-(phenylamino)piperidyl ketone


5,6-dimethoxyindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 6-fluoro(2-naphthyl) ketone


4-(diphenylmethyl)piperazinyl 7-nitroindol-2-yl ketone


4-[(4-chlorophenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


4-[(3,5-dimethylphenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


4-[(3,4-dichlorophenyl)methyl]piperazinyl 5-methylindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 4-hydroimidazo[1,2-a]pyridin-2-yl ketone


5-methylindol-2-yl 4-(2-pyridylmethyl)piperazinyl ketone


5-methylindol-2-yl 4-(3-pyridylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl pyrrolo[2,3-c]pyridin-2-yl ketone


3-{[4-(diphenylmethyl)piperazinyl]carbonyl}-8-fluorohydroquinolin-4-one


4-(diphenylmethyl)piperazinyl 6-quinolyl ketone


4-(diphenylmethyl)piperazinyl 2-methylbenzimidazol-5-yl ketone


benzimidazol-5-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 6-methylthiopheno[3,2-d]pyrrol-5-yl ketone


4-(diphenylmethyl)piperazinyl indol-6-yl ketone


4-(diphenylmethyl)piperazinyl 6-ethylthiopheno[3,2-d]pyrrol-5-yl ketone


4-(diphenylmethyl)piperazinyl 5-fluorobenzo[b]thiophen-2-yl ketone


6-amino(2-naphthyl) 4-(diphenylmethyl)piperazinyl ketone


benzo[b]thiophen-5-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 1-methylindol-5-yl ketone


4-(diphenylmethyl)piperazinyl 4-methoxyindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 6-methoxyindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-(phenylmethoxy)indol-2-yl ketone


4-(diphenylmethyl)piperazinyl 2-chloro(3-quinolyl) ketone


5-(tert-butyl)-3-methylindol-2-yl 4-(diphenylmethyl)piperazinyl ketone


5-chloroindol-2-yl 4-[(4-fluorophenyl)methyl]piperazinyl ketone


5-chloroindol-2-yl 4-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


5-chloroindol-2-yl 4-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


5-chloroindol-2-yl 4-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


5-chloroindol-2-yl 4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


4-[(2,4-difluorophenyl)methyl]piperazinyl 5-chloroindol-2-yl ketone


4-{[3,5-bis(trifluoromethyl)phenyl]methyl}piperazinyl 5-chloroindol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-(methylethyl)indol-2-yl ketone


4-(diphenylmethyl)piperazinyl 7-chloro-2-methyl(3-quinolyl) ketone


benzothiazol-2-yl 4-(diphenylmethyl)piperazinyl ketone


5-(tert-butyl)indol-2-yl 4-(diphenylmethyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 5-bromobenzo[b]thiophen-2-yl ketone


4-(diphenylmethyl)piperazinyl thiopheno[2,3-d]pyrrol-5-yl ketone


4-(diphenylmethyl)piperazinyl 5-(trifluoromethyl)benzo[b]thiophen-2-yl ketone


4-(diphenylmethyl)piperazinyl 6-chlorobenzo[b]thiophen-2-yl ketone


4-[(4-fluorophenyl)methyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


4-(diphenylmethyl)piperazinyl 8-fluoro(3-quinolyl) ketone


3-{[4-(diphenylmethyl)piperazinyl]carbonyl}chromen-2-one


5-chloroindol-2-yl 2-1,2,3,4-tetrahydroisoquinolyl ketone


5-chloroindol-2-yl 3-phenylimidazo[2,1-c]piperazin-7-yl ketone


5-chloroindol-2-yl 4,5,6,7-tetrahydroimidazo[5,4-c]pyridin-5-yl ketone


5-chloroindol-2-yl 3-phenyl(1,2,4-triazolo[3,4-c]piperazin-7-yl) ketone


4-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}piperazinyl 5-(trifluoromethyl)indol-2-yl


ketone


4-[(2,4-difluorophenyl)methyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


4-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}piperazinyl 5-(trifluoromethyl)indol-2-yl


ketone


4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl 5-(trifluoromethyl)indol-2-yl


ketone


4-[(3,5-difluorophenyl)methyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-chlorobenzo[b]thiophen-2-yl ketone


4-(diphenylmethyl)piperazinyl 5-fluorobenzo[b]thiophen-2-yl ketone


2,8-diazabicyclo[4.3.0]non-8-yl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 2-ethyl-2,8-diazabicyclo[4.3.0]non-8-yl ketone


5-chloroindol-2-yl 4-morpholin-4-ylpiperidyl ketone


5-chloroindol-2-yl 4-phenoxypiperidyl ketone


4-[(2,4-difluorophenyl)amino]piperidyl 5-chloroindol-2-yl ketone


4-[(3,5-difluorophenyl)amino]piperidyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-[(3-fluorophenyl)amino]piperidyl ketone


4-[(3,4-dimethylphenyl)amino]piperidyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-[(4-fluorophenyl)amino]piperidyl ketone


5-chloroindol-2-yl 4-pyrrolidinylpiperidyl ketone


5-chloroindol-2-yl 4-(cyclopentylamino)piperidyl ketone


5-chloroindol-2-yl 4-ethylpiperazinyl ketone


4-butylpiperazinyl 5-chloroindol-2-yl ketone


5-methylindol-2-yl piperazinyl ketone


3-azabicyclo[4.4.0]dec-3-yl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 2-[(4-fluorophenyl)methyl]-2,8-diazabicyclo[4.3.0]non-8-yl ketone


4-(diphenylmethyl)piperazinyl 2-methylthiopheno[2,3-d]pyrrol-5-yl ketone


5-chloroindol-2-yl 3-methyl-4-(phenylcarbonyl)piperazinyl ketone


4-(diphenylmethyl)piperazinyl 2-(trifluoromethyl)benzimidazol-5-yl ketone


5-chloroindol-2-yl 4-(phenylcarbonyl)piperazinyl ketone


5-chloroindol-2-yl 4-[(4-fluorophenyl)carbonyl]piperazinyl ketone


5-chloroindol-2-yl 4-[(4-iodophenyl)carbonyl]piperazinyl ketone


4-{[4-(diethylamino)phenyl]carbonyl}piperazinyl 5-chloroindol-2-yl ketone


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzaldehyde


4-(2,3-dimethylphenyl)piperazinyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-(2-fluorophenyl)piperazinyl ketone


4-(2,4-difluorophenyl)piperazinyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-(2-pyridyl)piperazinyl ketone


5-chloroindol-2-yl 4-[(5-chloroindol-2-yl)carbonyl]piperazinyl ketone


5-chloroindol-2-yl 4-(4-pyridyl)piperazinyl ketone


5-chloroindol-2-yl 4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl ketone


4-[(4-chlorophenyl)methyl]piperazinyl 2-(trifluoromethyl)benzimidazol-5-yl ketone


5-chloroindol-2-yl 4-(4-fluorophenyl)piperazinyl ketone


5-chloroindol-2-yl 1,2,3,4-tetrahydropyridino[4,3-b]indol-2-yl ketone


5-chloroindol-2-yl 4-[4-(trifluoromethyl)phenoxy]piperidyl ketone


5-chloroindol-2-yl 4-(4-fluorophenoxy)piperidyl ketone


3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzenecarbonitrile


5-chloroindol-2-yl 4-[(3-phenylphenyl)methyl]piperazinyl ketone


5-chloroindol-2-yl 4-[(4-phenylphenyl)methyl]piperazinyl ketone


5-chloroindol-2-yl 4-(3-chlorophenoxy)piperidyl ketone


5-chloroindol-2-yl 4-(4-fluoro-2-methylphenoxy)piperidyl ketone


5-chloroindol-2-yl 4-(4-chlorophenoxy)piperidyl ketone


5-(trifluoromethyl)indol-2-yl 4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


5-(trifluoromethyl)indol-2-yl 4-{[3-(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


4-{[3,5-bis(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-(trifluoromethyl)indol-2-yl


ketone


4-[(2,4-dichlorophenyl)carbonyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


4-[(3-chlorophenyl)carbonyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


4-[(4-{[5-(trifluoromethyl)indol-2-


yl]carbonyl}piperazinyl)carbonyl]benzenecarbonitrile


4-[(4-chlorophenyl)carbonyl]piperazinyl 5-(trifluoromethyl)indol-2-yl ketone


2-(difluoromethyl)benzimidazol-5-yl 4-(diphenylmethyl)piperazinyl ketone


2-anthryl 4-(diphenylmethyl)piperazinyl ketone


1-[4-(diphenylmethyl)piperazinyl]-2-(5-chlorobenzimidazol-2-yl)ethan-1-one


4-{[3-fluoro-4-(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-(trifluoromethyl)indol-2-


yl ketone


4-{[2-fluoro-4-(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-(trifluoromethyl)indol-2-


yl ketone


5-chloroindol-2-yl 4-[(4-(1H-1,2,3,4-tetraazol-5-yl)phenyl)carbonyl]piperazinyl


ketone


5-chloroindol-2-yl 4-[(4-chlorophenyl)carbonyl]piperazinyl ketone


4-[(2,4-difluorophenyl)carbonyl]piperazinyl 5-chloroindol-2-yl ketone


N-({1-[(2E)-3-(4-bromophenyl)prop-2-enoyl](4-piperidyl)}methyl)(4-


fluorophenyl)carboxamide


(E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-carbonyl)phenyl)boronic acid


(2E)-3-(4-bromophenyl)-1-{4-[(4-(1H-1,2,3,4-tetraazol-5-


yl)phenyl)carbonyl]piperazinyl}prop-2-en-1-one


potassium (E)-5-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-


carbonyl)phenyl)tetrazol-1-ide


methyl 4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoate


methyl 4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoate


methyl 3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoate


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoic acid


4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoic acid


5-chloroindol-2-yl 4-[(4-(3-pyridyl)phenyl)carbonyl]piperazinyl ketone


methyl 3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carbonyl)benzoate


3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)benzoic acid


N-(2,4-difluorophenyl){4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carboxamide


5-chloroindol-2-yl 4-{[4-(4-chlorophenyl)phenyl]sulfonyl}piperazinyl ketone


5-chloroindol-2-yl 4-{[4-(4-methoxyphenyl)phenyl]sulfonyl}piperazinyl ketone


[4-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)phenyl]-N-(4-


fluorophenyl)carboxamide


[3-({4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}methyl)phenyl]-N-(4-


fluorophenyl)carboxamide


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-[4-fluoro-3-


(trifluoromethyl)phenyl]carboxamide


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(3-fluorophenyl)carboxamide


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(4-chlorophenyl)carboxamide


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-[4-


(trifluoromethyl)phenyl]carboxamide


N-(4-bromophenyl){4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}carboxamide


{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(3-iodophenyl)carboxamide


4-[(4-bromophenyl)sulfonyl]piperazinyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-[(2-phenylethyl)sulfonyl]piperazinyl ketone


N-{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}(4-chlorophenyl)carboxamide


{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}(4-chlorophenyl)


4-{[(4-bromophenyl)sulfonyl]amino}piperidyl 5-chloroindol-2-yl ketone


5-chloroindol-2-yl 4-(2-pyridyloxy)piperidyl ketone









In another embodiment is a compound having the structure:










































































































In another embodiment is a compound having the structure:


































































































































Further Forms of Compounds

In one aspect, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.
In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
In one aspect, prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacokinetic, pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is known, the design prodrugs of the compound is possible. (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).
In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
In some embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.
In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
“Pharmaceutically acceptable” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) with a base to form a salt.
Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Synthesis of Compounds
In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.
In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FisherScientific (Fisher Chemicals), and AcrosOrganics.
In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.
In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, which are incorporated herein by reference for such disclosure).
In some embodiments, compounds described herein are prepared as shown in Scheme 1.




The synthesis of compound VII, IX and X can be accomplished by the reactions illustrated in Scheme 1. Activation of the carboxylic acid of formula I with a coupling reagent such as 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and Hydroxybenzotriazole (HOBt) in a solvent such as DMF or acetonitrile containing an amine base such as N,N-Diisopropylethylamine, triethylamine or other organic bases followed by treatment of this mixture with compound II gives rise to compounds of formula III. For compound II any other suitable amino protecting group, such as 9-fluorenylmethoxycarbonyl (FMOC) or benzyloxycarbonyl (Z), can be alternatively used instead of the BOC group. Substitution of the coupling reagent EDC by carbonyliimidazole, BOP reagent, dicyclohexylcarbodimide (DCC), or HATU produces compound III. The deprotection of compound III can be carried out by treatment of compound III with trifluoracetic acid (TFA) in an inert solvent such as methylene chloride (DCM), to yield compounds of formula IV. The reaction is preferably carried out at temperatures between 0° C. and 50° C. Activation of the carboxylic acid of formula VIII with 1-Propanephosphonic anhydride solution, 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) in a solvent such as ethyl acetate or acetonitrile containing an amine base such as N,N-Diisopropylethylamine, triethylamine or other organic bases followed by treatment with compound V gives rise to compounds of formula VII. Alkylation of compound IV with an alkylhalide VII, benzylhalide VII, or benzyltosylate in an inert organic solvent such as DMF with an inorganic base such as potassium carbonate or an organic base such as triethylamine produces compounds of formula IX. The reaction is preferably carried out at temperatures between 0° C. and 100° C. Treatment of compound IV with cinnamic acid VII in an inert organic solvent such as DMF or THF containing N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl) uronium hexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and an organic base such as N,N-Diisopropylethylamine produces compounds of formula X. Finally, treatment compound VI in an inert organic solvent such as THF containing an organic base such as triethylamine with a sulphonyl chloride XI produces compounds of formula XII. The reaction is preferably carried out at temperatures between 0° C. and 25° C.
In some embodiments, compounds described herein are prepared as shown in Scheme 2.




The synthesis of compound XV and XVI can be accomplished by the reactions illustrated in Scheme 2. Compound XII and Compound XIV can be prepared by the reactions described in General Procedure A and B. Activation of the carboxylic acid of formula V with a coupling reagent such as 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and Hydroxybenzotriazole (HOBt) in a solvent such as DMF or acetonitrile containing an amine base such as N,N-Diisopropylethylamine, triethylamine or other organic bases followed by treatment of this mixture with compound XIV gives rise to compounds of formula XV. Substitution of the coupling reagent EDC by carbonyliimidazole, BOP reagent, dicyclohexylcarbodimide (DCC), or HATU produces compound XV. Compound XVII when treated with sodium triacetoxy-borohydride in dichloroethane (DCE) containing acetic acid Compound XIV produces Compound XVI. The reaction is preferably carried out at temperatures between 0° C. and 100° C.
It will be understood that the reactions shown above are illustrative.
In one aspect, compounds are synthesized as described in the Examples section.
Definitions
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise:
“Amino” refers to the —NH2 radical.
“Cyano” refers to the —CN radical.
“Hydroxy” or “hydroxyl” refers to the —OH radical.
“Nitro” refers to the —NO2 radical.
“Oxo” refers to the ═O substituent.
“Thioxo” refers to the ═S substituent.
“Alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to thirty carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 10 are included. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10 alkyl, C1-C9 alkyl, C1-C3 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below. “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group.
“Alkoxy” refers to a radical of the formula —OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below.
“Heteroalkylene” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to —OCH2CH2OMe, —OCH2CH2OCH2CH2NH2, or —OCH2CH2OCH2CH2OCH2CH2N(Me)2. Representative heteroalkylene groups include, but are not limited to —OCH2CH2O—, —OCH2CH2OCH2CH2O—, or —OCH2CH2OCH2CH2OCH2CH2O—.
“Alkylamino” refers to a radical of the formula —NHR or —NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of benzene, indane, indene, and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.
“Carboxy” refers to —CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,




and the like.

“Cycloalkyl” refers to a stable, non-aromatic, monocyclic or polycyclic carbocyclic ring, which may include fused or bridged ring systems, which is saturated or unsaturated, and attached to the rest of the molecule by a single bond. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms, from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, from three to five carbon atoms, or three to four carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:




and the like.

“Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
“Perhalo” or “perfluoro” refers to a moiety in which each hydrogen atom has been replaced by a halo atom or fluorine atom, respectively.
“Heterocyclyl” or “heterocyclic ring” or “heterocycloalkyl” refers to a stable 3- to 14-membered non-aromatic ring radical comprising 2 to 13 carbon atoms and from one to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, or bicyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:







and the like. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.
All the above groups may be either substituted or unsubstituted. The term “substituted” as used herein means any of the above groups may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent. Unless stated specifically in the specification, a substituted group may include one or more substituents selected from: oxo, —CO2H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, perfluoroalkyl or perfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with —NRgC(═O)NRgRh, —NRgC(═O)ORh, —NRgSO2Rh, —OC(═O)NRgRh, —ORg, —SRg, —SORg, —SO2Rg, —OSO2Rg, —SO2ORg, ═NSO2Rg, and —SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with —C(═O)Rg, —C(═O)ORg, —CH2SO2Rg, —CH2SO2NRgRh, —SH, —SRg or —SSRg. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents. In some embodiments, optional substituents are independently selected from hydrogen, halogen, —CN, —OH, —NO2, —N(R12)—R13, —C(═O)—N(R12)—R13, —NR12C(═O)R11, —C(═O)—O—R11, —O—C(═O)—R11, —SR12, —S(═O)R11, —S(═O)2R11, —N(R12)S(═O)2R11, —S(═O)2—N(R12)—R13, —C(═O)R11, —B(OH)2, —PO3H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; each of R12 and R13 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl; R15 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl. In some embodiments, optional substituents are independently selected from hydrogen, halogen, —CN, —OH, —NO2, —N(R12)—R13, —C(═O)—N(R12)—R13, —NR12C(═O)R11, —C(═O)—O—R11, —O—C(═O)—R11, —SR12, —S(═O)R11, —S(═O)2R11, —N(R12)S(═O)2R11, —S(═O)2—N(R12)—R13, —C(═O)R13, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl; each of R12 and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl; or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl; R15 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl.
The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
The term “individual”, “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.
The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:




Administration and Pharmaceutical Composition

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.
A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism.
Pharmaceutical formulations described herein are administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are administered orally.
In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are administered topically. In such embodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. In one aspect, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are administered topically to the skin.
In another aspect, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are administered by inhalation.
In another aspect, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.
In another aspect, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are formulated as eye drops.
In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) adminstered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
In certain embodiments, a compound as described herein is administered in a local rather than systemic manner.
In some embodiments, the compound described herein is administered topically. In some embodiments, the compound described herein is administered systemically.
In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are in the form of a capsule.
In one aspect, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.
For administration by inhalation, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) is formulated for use as an aerosol, a mist or a powder.
For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.
In some embodiments, compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are prepared as transdermal dosage forms.
In one aspect, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.
In some embodiments, the compounds described herein may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.
Methods of Dosing and Treatment Regimens
In one embodiment, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are used in the preparation of medicaments for the treatment of diseases or conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said subject.
In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.
In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
Doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.
Combination Treatments
In certain instances, it is appropriate to administer at least one compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) in combination with another therapeutic agent.
In one specific embodiment, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) is co-administered with a second therapeutic agent, wherein the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.
EXAMPLES
The following examples are intended to illustrate but not limit the disclosed embodiments. All reactions involving air and moisture-sensitive reagents and solvents were performed under a nitrogen atmosphere using standard chemical techniques. Anhydrous solvents were purchased and freshly used from Sigma-Aldrich or EMD Biosciences. All organic reagents were used as purchased. Analytical thin-layer chromatography was performed on Partisil K6F silica gel 60 Å, 250 μm. Microwave-assisted reactions were performed using a CEM Discover system. 1H and 13C chemical shifts are reported in δ values in ppm in the corresponding solvent. All solvents used for chromatography on the synthetic materials were Fisher Scientific HPLC grade, and the water was Millipore Milli-Q PP filtered. LCMS analysis of synthetic materials was completed on a Waters Autopurification system, which consists of a 2767 sample manager, a 2545 binary gradient module, a system fluidics organizer, a 2489 UV/vis detector, and a 3100 mass detector, all controlled with MassLynx software. A Sunfire Analytical C18 5 μm column (4.6×50 mm) and stepwise gradient {10% [(MeCN+0.1% TFA) in (water+0.1% TFA)] to 98% [(MeCN+0.1% TFA) in (water+0.1% TFA)] for 9 min.} was used for analytical LCMS of final compounds. The final compounds were purified by silica gel flash chromatography with ethyl acetate/hexanes as the eluant. All NMR spectra for the synthetic materials were recorded on a Bruker Avance II 400 or DRX-500 MHz instrument. The MestReNova 7 program was used to process and interpret NMR spectra. High Resolution Mass Spectrometry (HRMS) spectra were carried out on an Agilent 6224A Accurate-Mass Time-of-Flight (TOF) LC/MS system with electron spray ionization (ESI).
Example A1
Preparation of tert-butyl (E)-tert-butyl 4-(3-(4-bromophenyl)acryloyl) piperazine-1-carboxylate (General Procedure A)




4-Bromocinnamic acid (200 mg, 0.880 mmol) was dissolved in 10 mL of THF and after the addition of CDI (213.9 mg, 1.3 mmol), the mixture was stirred at room temperature for 30 minutes. Boc-Piperazine (196.6 mg, 1.055 mmol) was added to the resulting mixture and the reaction mixture was stirred for 2 hours at room temperature. When the reaction was determined to be complete by HPLC, the reaction mixture was concentrated under reduced pressure and the resulting solid was dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl, and dried over Na2SO4. The resulting organic layer was concentrated under reduced pressure afforded the title compound as a white solid which was used directly into the next step without purification. MS (EI) m/z 397 [(M+H)+].
Example A2
Preparation of tert-butyl 4-cinnamoylpiperazine-1-carboxylate




The title compound was prepared from the reaction of cinnamic acid with Boc-Piperazine according to the procedure given in Example A1 obtained as a white solid. MS (EI) m/z 317 [(M+H)+].
Example A3
Preparation of (E)-tert-butyl 4-(3-(3, 4-dichloro phenyl) acryloyl)piperazine-1-carboxylate




The title compound was prepared from the reaction of 3,4-dichloro cinnamic acid with Boc-Piperazine according to the procedure given in Example A1 obtained as a white solid. MS (EI) m/z 386 [(M+H)+].
Example B1
Preparation of (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl)piprazin-1-yl) prop-2-en-1one (General Procedure B)




(E)-tert-butyl-4-(3-(4-bromophenyl) acryloyl) piperazine-1-carboxylate (200 mg, 0.505 mmol) obtained from Example A1 was dissolved in dichloromethane (3 mL) and cooled to 0° C. Trifluoroacetic acid (1.2 mL) was slowly added to the resulting mixture and the reaction was stirred for one hour at room temperature. When the reaction was determined to be complete by HPLC, the reaction mixture was concentrated under reduced pressure. The resulting mixture was washed with toluene twice to remove excess of TFA and the organic layer was concentrated under reduced pressure to yield (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1one (379 mg). MS (EI) m/z 297 [(M+H)+].
Example B2
Preparation of (E)-1-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one




The title compound was prepared from the reaction of (E)-1-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one according to the procedure given in Example B1 obtained as a white solid. MS (EI) m/z 381 [(M+H)+].
Example B3
Preparation of (E)-3-(3, 4-dichlorophenyl)-1-(4-(2, 2, 2-trifluoroacetyl) piperazin-1-yl) prop-2-en-1-one




The title compound was prepared from the reaction of (E)-tert-butyl 4-(3-(3, 4-dichloro phenyl) acryloyl) piperazine-1-carboxylate according to the procedure given in Example B1 obtained as a white solid. MS (EI) m/z 381 [(M+H)+].
Example C1
Preparation of (E)-3-(4-bromophenyl)-1-(4-(4-chlorobenzoyl)piperazin-1-yl) prop-2-en-1-one




4-Chlorobenzoic acid (60.73 mg), EDC (80.97 mg), and HOBT (57.09 mg) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 30 minutes. N-methyl morpholine (196.53 uL) and (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one (148.2 mg) obtained from Example B1 were added to the reaction mixture and the reaction was stirred overnight at room temperature. When the reaction was determined to be complete by HPLC, the reaction mixture was concentrated under reduced pressure and the resulting solid was dissolved in DCM. The solution was washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl and dried over Na2SO4 and the solvent was evaporated to give crude product which was purified using C-18 HPLC with acetonitrile and water (20:100 gradient) to yield the desired product as white solid. MS (EI) m/z 435 [(M+H)+].
Example C2
Preparation of (2E)-3-(4-bromophenyl)-1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl} prop-2-en-1-one




The title compound was prepared from the reaction of (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1one with 4-methoxybenzoic acid according to the procedure given in Example C1 and was obtained as a white solid. MS (EI) m/z 430 [(M+H)+].
Example C3
Preparation of (E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-carbonyl)phenyl)phosphonic acid




The title compound was prepared from the reaction of (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1one with 4-phosphonobenzoic acid according to the procedure given in Example C1 and was obtained as a white solid. MS (EI) m/z 480 [(M+H)+].
Example C4
Preparation of (2E)-3-(4-bromophenyl)-1-{4-[(4-methylphenyl)carbonyl]piperazinyl} prop-2-en-1-one




The title compound was prepared from the reaction of (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1one with 4-methyl benzoic acid according to the procedure given in Example C1 and was obtained as a white solid. MS (EI) m/z 414 [(M+H)+].
Example C5
Preparation of (2E)-3-(3, 4-dichlorophenyl)-1-[4-(diphenylmethyl) piperazinyl] prop-2-en-1-one




The title compound was prepared from the reaction of 3,4-dichloro cinnamic acid with diphenyl methyl piperazine according to the procedure given in Example C1 and was obtained as a white solid. MS (EI) m/z 452 [(M+H)+].
Example C6
Preparation of (2E)-3-(3, 4-dichlorophenyl)-1-(4-{[4-(trifluoromethyl) phenyl] carbonyl} piperazinyl) prop-2-en-1-one




The title compound was prepared from the reaction of (E)-3-(3, 4-dichlorophenyl)-1-(4-(2, 2, 2-trifluoroacetyl) piperazin-1-yl) prop-2-en-1one with 4-trifluoromethyl benzoic acid according to the procedure given in Example C1 and was obtained as a white solid. MS (EI) m/z 458 [(M+H)+].
Example D1
Preparation of (E)-3-(4-bromophenyl)-1-(4-(4-chlorobenzyl)piperazin-1-yl) prop-2-en-1-one (General Procedure D)




(E)-3-(4-bromophenyl)-1-(4-2,2,2-trifluroacetyl)piprazin-1-yl)prop-2-en-1-one (100 mg, 0.244 mmol) obtained from Example B1 was dissolved in acetone (5 mL), potassium carbonate (112 mg, 0.812 mmol) was added followed by 4-chlorobenzyl bromide (50 mg, 0.244 mmol). The resulting reaction mixture was stirred at 50° C. for about 2 hours. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting precipitate was dissolved in EtOAc (20 ml). Water (15 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (3×20 mL), the collected organic phases were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated to give crude product which was purified using C-18 HPLC with acetonitrile and water (20:100 gradient) to yield the desired product as white solid. MS (EI) m/z 420 [(M+H)+].
Example D2
Preparation of (2E)-3-(4-bromophenyl)-1-{4-[(3-fluorophenyl)methyl]piperazinyl} prop-2-en-1-one




The title compound was prepared from the reaction (E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one with 3-fluoro benzyl bromide according to the procedure given in Example D1 and obtained as a white solid. MS (EI) m/z 404 [(M+H)+].
Example D3
Preparation of (2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-(trifluoromethyl) phenyl]methyl}piperazinyl)prop-2-en-1-one




The title compound was prepared from the reaction of (E)-3-(3, 4-dichlorophenyl)-1-(4-(2, 2, 2-trifluroracetyl) piperazin-1-yl) prop-2-en-1-one with 4-trifluoro methyl benzyl bromide according to the procedure given in Example D1 was obtained as a white solid. MS (EI) m/z 444 [(M+H)+].
Example E1
Preparation of (2E)-3-(4-bromophenyl)-1-{4-[(2,4,6-trimethylphenyl) sulfonyl] piperazinyl} prop-2-en-1-one (General Procedure E)




(E)-3-(4-bromophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one (158 mg, 0.402 mmol) obtained from the procedures to prepare Example B1, was dissolved in Dichloromethane (2 mL) at 0° C. N, N-Diisopropylethylamine (200 uL) was added followed by 2, 4, 6-trimethylbenzene sulfonyl chloride (1.8 mg, 0.603 mmol). The resulting reaction mixture was stirred at 0° C. to room temperature for 2 hours. When the reaction was determined to be complete by HPLC, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was portioned between DCM (5 mL) and water (5 mL), the collected organic phases were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated to give crude product which was purified using C-18 HPLC with acetonitrile and water (20:100 gradient) to yield the desired product as white solid. MS (EI) m/z 479 [(M+H)+].
Example E2
Preparation of (2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl) prop-2-en-1-one




The title compound was prepared from the reaction (E)-3-(4-fluorophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one with 4-bromo benzene sulfonyl chloride according to the procedure given in Example E1 and obtained as a white solid MS (EI) m/z 454 [(M+H)+].
Example E3
Preparation of (2E)-3-(4-fluorophenyl)-1-{4-[(2-phenylethyl)sulfonyl]piperazinyl}prop-2-en-1-one




The title compound was prepared from the reaction (E)-3-(4-fluorophenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one with phenethyl benzene sulfonyl chloride according to the procedure given in Example E1 and obtained as a white solid. MS (EI) m/z 403 [(M+H)+].
Example E4
Preparation of (2E)-3-(4-methoxyphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one




The title compound was prepared from the reaction (E)-3-(4-methoxyphenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one with benzene sulfonyl chloride according to the procedure given in Example E1 was obtained as a white solid. MS (EI) m/z 387 [(M+H)+].
Example E5
Preparation of 4-({4-[(2E)-3-(4-bromo-2-fluorophenyl)prop-2-enoyl]piperazinyl}sulfonyl)-1-acetylbenzene




The title compound was prepared from the reaction (E)-3-(4-bromo-2-fluoro phenyl)-1-(4-2, 2, 2-trifluroacetyl) piprazin-1-yl) prop-2-en-1-one with 4-acetylbenzene-1-sulfonyl chloride according to the procedure given in Example E1 was obtained as a white solid. MS (EI) m/z 496 [(M+H)+].
Example F1
Preparation of (E)-3-(4-bromophenyl)-1-(4-(((2,2,2-trifluoroacetyl)-λ4-azanyl) methyl)piperidin-1-yl)prop-2-en-1-one




The title compound was prepared in two steps from the commercially available tert-butyl (piperidin-4-ylmethyl)carbamate by the reactions described in General Procedure A and B give (E)-3-(4-bromophenyl)-1-(4-(((2, 2, 2-trifluoroacetyl)-λ4-azanyl) methyl) piperidin-1-yl) prop-2-en-1-one as a white solid. MS (EI) m/z 421 [(M+H)+].
Example F2
Preparation of (E)-3-(4-bromophenyl)-1-(4-(((4-(trifluoromethyl)benzyl) amino)methyl)benzyl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (General Procedure F)




(E)-3-(4-bromophenyl)-1-(4-(((2,2,2-trifluoroacetyl)-λ4-azanyl) methyl piperidin-1-yl) prop-2-en-1-one obtained from example F1, 4-(trifluoromethyl) benzaldehyde (50.13 uL, sodium triacetoxy-borohydride (138.83 mg), acetic acid (51.35 uL) and dichloroethane (3 mL) were taken into a microwave safe bowl and subjected to heating for 30 minutes at 130° C. After the completion of the reaction the reaction mixture was cooled and extracted with Dichloromethane. The solution was washed with saturated aqueous NaHCO3, and dried over Na2SO4. The solvent was evaporated to give crude product which was purified using C-18 HPLC with acetonitrile and water (20:100 gradients) to yield the desired product (E)-3-(4-bromophenyl)-1-(4-(((4-(trifluoromethyl)benzyl)amino)methyl)benzyl)amino)methyl) piperidin-1-yl)prop-2-en-1-one as white solid. MS (EI) m/z 483 (M+1).
Example F3
Preparation of (E)-N-((1-(3-(4-bromophenyl)acryloyl)piperidin-4-yl)methyl)-4-(trifluoromethyl)benzamide




The title compound was prepared from the reaction of (E)-3-(4-bromophenyl)-1-(4-(((2,2,2-trifluoroacetyl)-λ4-azanyl)methyl)piperidin-1-yl)prop-2-en-1-one obtained in Example F1 with 4-trifluoromethylbenzoic acid according to Procedure 3. The crude product was purified using C-18 HPLC with acetonitrile and water (20:100 gradients) to yield the desired product (E)-N-((1-(3-(4-bromophenyl)acryloyl)piperidin-4-yl)methyl)-4-(trifluoromethyl)benzamide as a white solid. MS (EI) m/z 496 [(M+1)+].
Example G1
Preparation of 2,3-dibromo-3-(4-chlorophenyl)propanoic acid (General Procedure G)




4-Chlorocinnamic acid (3.6 g, 19.7 mmol) was dissolved in 60 mL of CCl4 and after the addition of 1 drop of aqueous HBr, the mixture was stirred at room temperature, and Br2 (1 mL 19.5 mmol) was added dropwise to the resulting mixture. The reaction mixture was stirred overnight at room temperature. When the reaction was determined to be complete by HPLC, the white precipitates were filtered and washed with hexane. The white solid precipitate of 2,3-dibromo-3-(4-chlorophenyl)propanoic acid was air dried and used directly into the next step without purification. MS (EI) m/z 397 [(M+1)+].
Example H1
Preparation of 3-(4-bromophenyl)propiolic acid (General Procedure H)




2,3-dibromo-3-(4-chlorophenyl)propanoic acid (2 g, 5.84 mmol) was dissolved in 16% KOH in EtOH (7.1 mL) and stirred with refluxing at 40° C. for about 3 hours. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature. The resulting precipitate was filtered off and saved. The reaction solution was acidified with concentrated HCl and concentrated in vacuum. The residue was combined with the previously extracted precipitate and dissolved in water (100 mL). The solution was acidified with 20% sulfuric acid and adjusted with cooling (ice bath) to pH=1. After stirring for 20 min at room temperature, the solution was filtered and washed with 2% sulfuric acid and dried. After crystallization from acetonitrile and re-crystallizing the residue from ethanol, 3-(4-bromophenyl)propiolic acid was isolated as a white solid. MS (EI) m/z 297 [(M+1)+].
Example H2
Preparation of 3-(benzo[d][1,3]dioxol-5-yl)propiolic acid




Propiolic acid (0.24 ml, 3.9 mmol), Pd(PPh3)2Cl2 (55 mg, 0.078 mmol) and DIPEA (1.7 ml, 9.8 mmol) were added in 20 ml of DMF. After the addition of CuI (30 mg, 0.16 mmol) and 5-iodobenzo[d][1,3]dioxole (0.5 ml, 3.9 mmol), the mixture was stirred for 2 hours under nitrogen atmosphere in an enclosed flask at room temperature. When the reaction was determined to be complete by HPLC, the resulting mixture was diluted with EtOAc and filtered through a bed of celite. The filtrate was washed with cold aqueous KOH solution and acidified with dilute sulfuric acid (10% solution) at 0° C. The solid obtained was extracted with dichloromethane and the extract was washed with water, brine solution and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to get the resulting title compound as a dark brown powder, which was used as isolated in the next reaction. MS (EI) m/z 397[(M+1)+].
Example H3
Preparation of 3-(4-bromophenyl)-1-(4-(4-methoxybenzyl)piperazin-1-yl)prop-2-yn-1-one




The title compound was prepared from the reaction 3-(4-bromophenyl)-1-(4-(2, 2, 2-trifluoroacetyl)piperazin-1-yl)prop-2-yn-1-one with 4-methoxybenzylbromide according to the procedure given in Example D1, to yield the desired product 3-(4-bromophenyl)-1-(4-(4-methoxybenzyl) piperazin-1-yl)prop-2-yn-1-one obtained as a white solid. MS (EI) m/z 413 [(M+1)+].
Example H4
Preparation of 1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(p-tolyl)prop-2-yn-1-one




The title compound was prepared from the 3-(p-tolyl)-1-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)prop-2-yn-1-one with 4-fluorobenzylbromide according to the procedure given in Example D1, to yield the desired product 1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(p-tolyl)prop-2-yn-1-one obtained as a yellow solid. MS (EI) m/z 337 [(M+1)+].
The following compounds were prepared using Procedures A-H described above:














MS (EI)


Compound
Name
[(M + H)+]







C1
(2E)-3-(4-bromophenyl)-1-{4-[(4-
434



chlorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


C2
(2E)-3-(4-bromophenyl)-1-{4-[(4-
430



methoxyphenyl)carbonyl]piperazinyl}prop-2-en-1-one


C3
(E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-
480



carbonyl)phenyl)phosphonic acid


C4
(2E)-3-(4-bromophenyl)-1-(4-{[4-
468



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-



1-one


C5
(2E)-3-(3,4-dichlorophenyl)-1-[4-
452



(diphenylmethyl)piperazinyl]prop-2-en-1-one


C6
(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-
458



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-



1-one


C7
3-(4-chlorophenyl)-1-{4-[(4-
384



methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C8
1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}-3-(4-
363



methylphenyl)prop-2-yn-1-one


C9
1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}-3-[4-
417



(trifluoromethyl)phenyl]prop-2-yn-1-one


C10
3-(4-bromophenyl)-1-{4-[(4-
428



methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C11
3-(3,4-dichlorophenyl)-1-{4-[(4-
420



methoxyphenyl)carbonyl]piperazinyl}prop-2-en-1-one


C12
3-(3,4-dichlorophenyl)-1-{4-[(4-
418



methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C13
(2E)-3-(4-bromophenyl)-1-[4-
386



(phenylamino)piperidyl]prop-2-en-1-one


C14
(2E)-3-(4-bromophenyl)-1-[4-
400



(phenylcarbonyl)piperazinyl]prop-2-en-1-one


C15
(2E)-1-{4-[(3,5-difluorophenyl)amino]piperidyl}-3-(4-
422



bromophenyl)prop-2-en-1-one


C16
3-(4-chlorophenyl)-1-{4-[(4-
388



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C17
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-
413



methoxyphenyl)prop-2-en-1-one


C18
3-(2,3-dichlorophenyl)-1-{4-[(4-
406



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C19
1-{4-[(4-bromophenyl)carbonyl]piperazinyl}-3-(4-
432



chlorophenyl)prop-2-yn-1-one


C20
(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-
408



fluorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


C21
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-
427



ethoxyphenyl)prop-2-en-1-one


C22
(2E)-1-[4-(2-3,4-dihydronaphthylsulfonyl)piperazinyl]-
427



3-(4-fluorophenyl)prop-2-en-1-one


C23
(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-
424



chlorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


C24
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromo-2-
480



fluorophenyl)prop-2-en-1-one


C25
3-(2,3-dichlorophenyl)-1-[4-
450



(diphenylmethyl)piperazinyl]prop-2-yn-1-one


C26
(2E)-3-(4-bromophenyl)-1-{4-[(4-
420



chlorophenyl)amino]piperidyl}prop-2-en-1-one


C27
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-
462



bromophenyl)prop-2-en-1-one


C28
3-(4-chlorophenyl)-1-{4-[(4-
372



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C29
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[4-
451



(trifluoromethyl)phenyl]prop-2-en-1-one


C30
3-(2,3-dichlorophenyl)-1-{4-[(4-
495



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C31
(2E)-1-{4-[(3,5-difluorophenyl)methyl]piperazinyl}-3-(4-
422



bromophenyl)prop-2-en-1-one


C32
(2E)-3-(4-bromophenyl)-1-{4-[(4-fluoro-3-
418



methylphenyl)methyl]piperazinyl}prop-2-en-1-one


C33
1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-(4-
367



methylphenyl)prop-2-yn-1-one


C34
3-(3-chlorophenyl)-1-{4-[(4-
388



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C35
3-(3-chlorophenyl)-1-{4-[(4-
371



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C36
4-(diphenylmethyl)piperazinyl 5-
447



chlorobenzo[b]thiophen-2-yl ketone


C37
(2E)-3-(4-bromophenyl)-1-{4-[(4-
515



bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C38
1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-(4-
351



methylphenyl)prop-2-yn-1-one


C39
(2E)-1-{4-[(3,4-dichlorophenyl)methyl]piperazinyl}-3-
455



(4-bromophenyl)prop-2-en-1-one


C40
2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-chloro-2-
435



fluorophenyl)prop-2-en-1-one


C41
(2E)-3-(4-bromophenyl)-1-{4-[(4-
400



methylphenyl)methyl]piperazinyl}prop-2-en-1-one


C42
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-phenylprop-2-
383



en-1-one


C43
4-(diphenylmethyl)piperazinyl 5-bromoindol-2-yl
475



ketone


C44
(2E)-3-(4-bromophenyl)-1-(4-{[4-
468



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-



1-one


C45
4-(diphenylmethyl)piperazinyl 6-
447



chlorobenzo[b]thiophen-2-yl ketone


C46
(2E)-1-{4-[(2,4-difluorophenyl)carbonyl]piperazinyl}-3-
434



(4-bromophenyl)prop-2-en-1-one


C47
(2E)-3-(4-bromophenyl)-1-[4-({[(4-
432



fluorophenyl)methyl]amino}methyl)piperidyl]prop-2-en-



1-one


C48
4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl 5-
410



methylindol-2-yl ketone


C49
(2E)-3-(4-bromophenyl)-1-(4-butylpiperazinyl)prop-2-
352



en-1-one


C50
1-[4-(diphenylmethyl)piperazinyl]-3-(4-
460



bromophenyl)prop-2-yn-1-one


C51
3-(3,4-dichlorophenyl)-1-{4-[(4-
422



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C52
(2E)-3-(4-bromophenyl)-1-[4-
352



(methylpropyl)piperazinyl]prop-2-en-1-one


C53
3-(4-methylphenyl)-1-(4-{[4-
401



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C54
(2E)-1-[4-({[(3,5-
450



difluorophenyl)methyl]amino}methyl)piperidyl]-3-(4-



bromophenyl)prop-2-en-1-one


C55
3-(4-bromophenyl)-1-{4-[(4-
432



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C56
4-(diphenylmethyl)piperazinyl 5-chloroindol-2-yl
430



ketone


C57
5-methylindol-2-yl 4-[(2-
412



phenylethyl)sulfonyl]piperazinyl ketone


C58
1-[4-(diphenylmethyl)piperazinyl]-3-(4-
395



methylphenyl)prop-2-yn-1-one


C59
3-(3-chlorophenyl)-1-{4-[(4-
383



methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C60
1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-[4-
421



(trifluoromethyl)phenyl]prop-2-yn-1-one


C61
3-(4-bromophenyl)-1-{4-[(4-
477



bromophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C62
methyl 4-({4-[(5-chloroindol-2-
426



yl)carbonyl]piperazinyl}carbonyl)benzoate


C63
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-
428



nitrophenyl)prop-2-en-1-one


C64
4-[(4-chlorophenyl)carbonyl]piperazinyl 5-
435



(trifluoromethyl)indol-2-yl ketone


C65
1-{4-[(4-bromophenyl)carbonyl]piperazinyl}-3-
398



phenylprop-2-yn-1-one


C66
1-[4-(diphenylmethyl)piperazinyl]-3-[4-
449



(trifluoromethyl)phenyl]prop-2-yn-1-one


C67
(2E)-3-(4-bromophenyl)-1-{4-[(4-
420



chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


C68
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-
401



fluorophenyl)prop-2-en-1-one


C69
1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-(4-
371



fluorophenyl)prop-2-yn-1-one


C70
3-(4-bromophenyl)-1-{4-[(4-
416



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C71
4-(diphenylmethyl)piperazinyl indol-2-yl ketone
396


C72
(2E)-1-{4-[(3,5-dimethoxyphenyl)methyl]piperazinyl}-3-
446



(4-bromophenyl)prop-2-en-1-one


C73
3-(4-chlorophenyl)-1-(4-{[4-
421



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C74
(2E)-3-(4-bromophenyl)-1-[4-({[(4-
448



chlorophenyl)methyl]amino}methyl)piperidyl]prop-2-



en-1-one


C75
3-(4-fluorophenyl)-1-{4-[(4-
367



methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C76
1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-[4-
405



(trifluoromethyl)phenyl]prop-2-yn-1-one


C77
3-(3,4-dichlorophenyl)-1-[4-
450



(diphenylmethyl)piperazinyl]prop-2-yn-1-one


C78
(2E)-3-(4-bromophenyl)-1-[4-(2-
380



methylbutanoyl)piperazinyl]prop-2-en-1-one


C79
4-(diphenylmethyl)piperazinyl 5-(trifluoromethyl)indol-
464



2-yl ketone


C80
(2E)-3-(4-bromophenyl)-1-(4-
408



heptanoylpiperazinyl)prop-2-en-1-one


C81
methyl 4-({4-[(5-bromoindol-2-
471



yl)carbonyl]piperazinyl}carbonyl)benzoate


C82
(2E)-3-(4-bromophenyl)-1-[4-
392



(cyclopentylcarbonyl)piperazinyl]prop-2-en-1-one


C83
potassium (E)-5-(4-(4-(3-(4-
505



bromophenyl)acryloyl)piperazine-1-



carbonyl)phenyl)tetrazol-1-ide


C84
3-[4-(trifluoromethyl)phenyl]-1-(4-{[4-
455



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C85
5-bromoindol-2-yl 4-[(4-
447



chlorophenyl)carbonyl]piperazinyl ketone


C86
4-(diphenylmethyl)piperazinyl 7-fluoro(3-quinolyl)
426



ketone


C87
benzo[d]furan-2-yl 4-(diphenylmethyl)piperazinyl
397



ketone


C88
5-chloroindol-2-yl 4-[(2-phenylethyl)sulfonyl]piperazinyl
432



ketone


C89
5-chloroindol-2-yl 4-[(4-
403



chlorophenyl)carbonyl]piperazinyl ketone


C90
3-(2,3-dichlorophenyl)-1-(4-{[4-fluoro-2-
474



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C91
(2E)-3-(4-bromophenyl)-1-(4-{[4-chloro-2-
488



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-



one


C92
1-[4-(diphenylmethyl)piperazinyl]-3-(3-
415



chlorophenyl)prop-2-yn-1-one


C93
3-(3,4-dichlorophenyl)-1-{4-[(4-
406



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C94
4-(diphenylmethyl)piperazinyl 5-
431



fluorobenzo[b]thiophen-2-yl ketone


C95
(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl}-3-
401



(4-fluorophenyl)prop-2-en-1-one


C96
(2E)-1-{4-[(4-chlorophenyl)sulfonyl]piperazinyl}-3-(4-
409



fluorophenyl)prop-2-en-1-one


C97
4-(diphenylmethyl)piperazinyl 5-methoxyindol-2-yl
426



ketone


C98
(2E)-3-(4-bromophenyl)-1-(4-
380



pentanoylpiperazinyl)prop-2-en-1-one


C99
(2E)-1-[4-((2E)-3-phenylprop-2-enoyl)piperazinyl]-3-
347



phenylprop-2-en-1-one


C100
(2E)-1-{4-[(2-bromophenyl)sulfonyl]piperazinyl}-3-(4-
454



fluorophenyl)prop-2-en-1-one


C101
4-(diphenylmethyl)piperazinyl 2-naphthyl ketone
406


C102
4-[(4-{[5-(trifluoromethyl)indol-2-
427



yl]carbonyl}piperazinyl)carbonyl]benzenecarbonitrile


C103
(2E)-3-(4-bromophenyl)-1-(4-{[4-
428



(methylethyl)phenyl]methyl}piperazinyl)prop-2-en-1-



one


C104
4-(diphenylmethyl)piperazinyl 6-chloroindol-2-yl
430



ketone


C105
1,5-dimethylindol-2-yl 4-(diphenylmethyl)piperazinyl
424



ketone


C106
(2E)-3-(3,4-difluorophenyl)-1-[4-
419



(diphenylmethyl)piperazinyl]prop-2-en-1-one


C107
1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromo-2-
478



fluorophenyl)prop-2-yn-1-one


C108
4-(diphenylmethyl)piperazinyl 6-bromoindol-2-yl
475



ketone


C109
(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-
414



(4-bromophenyl)prop-2-en-1-one


C110
4-(diphenylmethyl)piperazinyl 6-quinolyl ketone
408


C111
4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl 5-
378



methylindol-2-yl ketone


C112
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{1-[(4-
380



fluorophenyl)carbonyl](4-piperidyl)}prop-2-yn-1-one


C113
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-
401



fluorophenyl)prop-2-en-1-one


C114
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-
397



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C115
5-chloroindol-2-yl 4-[(4-
494



iodophenyl)carbonyl]piperazinyl ketone


C116
1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-
337



phenylprop-2-yn-1-one


C117
3-(3-chlorophenyl)-1-(4-{[4-
421



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C118
(2E)-3-(4-bromophenyl)-1-[4-(3-
380



methylbutanoyl)piperazinyl]prop-2-en-1-one


C119
5-chloroindol-2-yl 4-[(4-
386



fluorophenyl)carbonyl]piperazinyl ketone


C120
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-
442



bromophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C121
(2E)-3-(4-bromophenyl)-1-{4-[({[3-fluoro-4-
500



(trifluoromethyl)phenyl]methyl}amino)methyl]piperidyl}



prop-2-en-1-one


C122
1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-(4-
337



methylphenyl)prop-2-yn-1-one


C123
benzo[b]thiophen-2-yl 4-(diphenylmethyl)piperazinyl
413



ketone


C124
(2E)-3-(4-fluorophenyl)-1-{4-[(4-
389



methylphenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C125
4-(diphenylmethyl)piperazinyl 3-quinolyl ketone
408


C126
4-(diphenylmethyl)piperazinyl 5-fluoroindol-2-yl ketone
414


C127
4-[(3-chlorophenyl)carbonyl]piperazinyl 5-
436



(trifluoromethyl)indol-2-yl ketone


C128
3-(4-fluorophenyl)-1-{4-[(4-
355



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C129
3-(3-chlorophenyl)-1-{4-[(4-
357



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C130
(2E)-3-(4-bromophenyl)-1-{4-[(4-chloro-2-
438



fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


C131
(2E)-3-(4-bromophenyl)-1-(4-{[4-fluoro-2-
472



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-



one


C132
3-(2,3-dichlorophenyl)-1-(4-{[4-
456



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C133
5-(trifluoromethyl)indol-2-yl 4-{[4-
470



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C134
piperazinyl 5-nitroindol-2-yl ketone
441


C135
5-bromoindol-2-yl 4-[(4-
431



fluorophenyl)carbonyl]piperazinyl ketone


C136
N-({1-[(2E)-3-(4-bromophenyl)prop-2-enoyl](4-
446



piperidyl)}methyl)(4-fluorophenyl)carboxamide


C137
1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-[4-
407



(trifluoromethyl)phenyl]prop-2-yn-1-one


C138
(2E)-1-{4-[(3-chlorophenyl)sulfonyl]piperazinyl}-3-(4-
409



fluorophenyl)prop-2-en-1-one


C139
1-[4-(diphenylmethyl)piperazinyl]-3-phenylprop-2-yn-1-
381



one


C140
5-bromoindol-2-yl 4-{[4-
481



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C141
3-(2,3-dichlorophenyl)-1-(4-{[4-fluoro-2-
460



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C142
4-(diphenylmethyl)piperazinyl 5-
481



(trifluoromethyl)benzo[b]thiophen-2-yl ketone


C143
4-[(4-bromophenyl)sulfonyl]piperazinyl 5-methylindol-
463



2-yl ketone


C144
(2E)-1-(4-{[4-(tert-butyl)phenyl]methyl}piperazinyl)-3-
442



(4-bromophenyl)prop-2-en-1-one


C145
(2E)-3-(4-bromophenyl)-1-(4-
352



propanoylpiperazinyl)prop-2-en-1-one


C146
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-
466



methoxyphenyl)prop-2-en-1-one


C147
(2E)-1[4-(diphenylmethyl)piperazinyl]-3-(3,4,5-
437



trifluorophenyl)prop-2-en-1-one


C148
5-methylindol-2-yl 4-(phenylethyl)piperazinyl ketone
348


C149
3-(4-bromophenyl)-1-{4-[(4-(5H-1,2,3,4-tetraazol-5-
466



yl)phenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C150
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-
492



(4-bromophenyl)prop-2-en-1-one


C151
6-chloroindol-2-yl 4-[(4-
398



methoxyphenyl)carbonyl]piperazinyl ketone


C152
(2E)-3-(4-bromophenyl)-1-{4-[(4-(1H-1,2,3,4-tetraazol-
468



5-yl)phenyl)carbonyl]piperazinyl}prop-2-en-1-one


C153
(E)-(4-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-
444



carbonyl)phenyl)boronic acid


C154
(2E)-3-(4-bromophenyl)-1-{4-[({[4-
482



(trifluoromethyl)phenyl]methyl}amino)methyl]piperidyl}



prop-2-en-1-one


C155
1-[4-(diphenylmethyl)piperazinyl]-3-bromo-3-(4-
541



bromophenyl)prop-2-en-1-one


C156
4-(diphenylmethyl)piperazinyl 5-
431



fluorobenzo[b]thiophen-2-yl ketone


C157
3-(3-chlorophenyl)-1-(4-{[4-fluoro-2-
439



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C158
[4-(diphenylmethyl)piperazinyl](5-methylindol-2-
426



yl)methane-1-thione


C159
1-[4-(diphenylmethyl)piperazinyl]-3-(4-
399



fluorophenyl)prop-2-yn-1-one


C160
4-(4-(3-(4-bromophenyl)propioloyl)piperazine-1-
442



carbonyl)phenylboronic acid


C161
(2E)-1-{4-[(4-nitrophenyl)methyl]piperazinyl}-3-
352



phenylprop-2-en-1-one


C162
N-[1-(diphenylmethyl)(4-piperidyl)](5-methylindol-2-
424



yl)carboxamide


C163
5-chloroindol-2-yl 4-(pyrrol-3-ylcarbonyl)piperazinyl
357



ketone


C164
4-bromophenyl 4-{[4-fluoro-2-
446



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C165
4-bromophenyl 4-[(4-fluorophenyl)methyl]piperazinyl
378



ketone


C166
3-(2,4-difluorophenyl)-1-(4-{[4-
423



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C167
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-
419



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-



one


C168
benzothiazol-2-yl 4-(diphenylmethyl)piperazinyl ketone
414


C169
3-[2-(trifluoromethyl)phenyl]-1-(4-{[4-
455



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C170
4-[(4-chlorophenyl)methyl]piperazinyl 2-
423



(trifluoromethyl)benzimidazol-5-yl ketone


C171
3-(3,4-dichlorophenyl)-1-(4-{[4-
442



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C172
5-chloroindol-2-yl 4-{[4-(4-
515



chlorophenyl)phenyl]sulfonyl}piperazinyl ketone


C173
4-(diphenylmethyl)piperazinyl 6-methylthiopheno[3,2-
416



d]pyrrol-5-yl ketone


C174
(2E)-3-(5-bromo-2-fluorophenyl)-1-{4-[(4-
533



bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C175
4-[(4-chlorophenyl)methyl]piperazinyl 3-quinolyl
366



ketone


C176
4-bromophenyl 4-{[4-
402



(methylethyl)phenyl]methyl}piperazinyl ketone


C177
4-({4-[(5-chloroindol-2-
398



yl)carbonyl]piperazinyl}methyl)benzoic acid


C178
4-(diphenylmethyl)piperazinyl 7-nitroindol-2-yl ketone
441


C179
3-(4-fluorophenyl)-1-(4-{[4-fluoro-2-
409



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C180
6-bromoindol-2-yl 4-[(4-
478



bromophenyl)methyl]piperazinyl ketone


C181
[4-({4-[(5-chloroindol-2-
491



yl)carbonyl]piperazinyl}methyl)phenyl]-N-(4-



fluorophenyl)carboxamide


C182
5-chloroindol-2-yl 4-(2-pyridyl)piperazinyl ketone
341


C183
5-chloroindol-2-yl 4-{[2-(trifluoromethyl)benzimidazol-
476



5-yl]carbonyl}piperazinyl ketone


C184
N-{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}(4-
417



chlorophenyl)carboxamide


C185
4-(diphenylmethyl)piperazinyl 3-
427



methylbenzo[b]thiophen-2-yl ketone


C186
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-fluoro-2-
437



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-



one


C187
[3-({4-[(5-chloroindol-2-
491



yl)carbonyl]piperazinyl}methyl)phenyl]-N-(4-



fluorophenyl)carboxamide


C188
3-({4-[(5-chloroindol-2-
398



yl)carbonyl]piperazinyl}methyl)benzoic acid


C189
6-fluoroindol-2-yl 4-{[4-fluoro-2-
438



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C190
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-
431



(2-fluorophenyl)prop-2-en-1-one


C191
(2E)-3-phenyl-1-[4-(2-pyridylmethyl)piperazinyl]prop-2-
308



en-1-one


C192
(2E)-1-[4-(diphenylmethyl)(1,4-diazaperhydroepinyl)]-
415



3-(4-fluorophenyl)prop-2-en-1-one


C193
4-(diphenylmethyl)piperazinyl pyrrolo[4,5-b]pyridin-2-yl
397



ketone


C194
5-chloroindol-2-yl 4-[(4-
448



phosphonophenyl)carbonyl]piperazinyl ketone


C195
3-(3,5-difluorophenyl)-1-(4-{[4-
409



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C196
(2E)-3-(2-methylphenyl)-1-[4-
371



(phenylsulfonyl)piperazinyl]prop-2-en-1-one


C197
3-(3,5-difluorophenyl)-1-{4-[(4-
359



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C198
(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl](1,4-
415



diazaperhydroepinyl)}-3-(4-fluorophenyl)prop-2-en-1-



one


C199
5-chloroindol-2-yl 4-morpholin-4-ylpiperidyl ketone
348


C200
4-{[3-fluoro-4-
488



(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-



(trifluoromethyl)indol-2-yl ketone


C201
(2E)-1-{4-[(3-methylphenyl)methyl]piperazinyl}-3-
321



phenylprop-2-en-1-one


C202
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-
431



(4-fluorophenyl)prop-2-en-1-one


C203
(2E)-1-{4-[(4-bromophenyl)methyl]piperazinyl}-3-
386



phenylprop-2-en-1-one


C204
5-chloroindol-2-yl 4-[(4-(1H-1,2,3,4-tetraazol-5-
436



yl)phenyl)carbonyl]piperazinyl ketone


C205
(2E)-3-(4-fluorophenyl)-1-[4-
375



(phenylsulfonyl)piperazinyl]prop-2-en-1-one


C206
(2E)-3-(4-fluorophenyl)-1-{4-[(4-
420



nitrophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C207
4-(diphenylmethyl)piperazinyl 5-
492



bromobenzo[b]thiophen-2-yl ketone


C208
5-bromoindol-2-yl 4-{[4-fluoro-2-
499



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C209
(2E)-1-{4-[(3-bromophenyl)sulfonyl]piperazinyl}-3-(4-
454



fluorophenyl)prop-2-en-1-one


C210
(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-
394



fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


C211
4-[(4-fluorophenyl)methyl]piperazinyl 5-
406



(trifluoromethyl)indol-2-yl ketone


C212
(2E)-3-(4-fluorophenyl)-1-{4-[(3-
393



fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C213
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-
480



ethoxyphenyl)prop-2-en-1-one


C214
(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-
410



chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


C215
4-(diphenylmethyl)piperazinyl 6-fluoroindol-2-yl ketone
414


C216
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-
383



fluorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


C217
4-(diphenylmethyl)piperazinyl 5-phenylindol-2-yl
472



ketone


C218
(2E)-1-{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-3-
462



[4-(trifluoromethyl)phenyl]prop-2-en-1-one


C219
4-[(4-fluorophenyl)methyl]piperazinyl 5-methylindol-2-
352



yl ketone


C220
4-(diphenylmethyl)piperazinyl 5-(4-
502



methoxyphenyl)indol-2-yl ketone


C221
(2E)-3-(4-fluorophenyl)-1-[4-(2-
425



naphthylsulfonyl)piperazinyl]prop-2-en-1-one


C222
(2E)-3-(4-bromophenyl)-1-(4-ethylpiperazinyl)prop-2-
324



en-1-one


C223
6-amino(2-naphthyl) 4-(diphenylmethyl)piperazinyl
422



ketone


C224
1-(4-{[4-fluoro-2-
419



(trifluoromethyl)phenyl]carbonyl}piperazinyl)-3-(4-



methylphenyl)prop-2-yn-1-one


C225
(2E)-1-{4-[(2,5-dichlorophenyl)sulfonyl]piperazinyl}-3-
444



(4-fluorophenyl)prop-2-en-1-one


C226
5-chloroindol-2-yl 4-[(4-fluorophenyl)amino]piperidyl
372



ketone


C227
4-(diphenylmethyl)piperazinyl 6-fluoro(3-quinolyl)
425



ketone


C228
4-(diphenylmethyl)piperazinyl 2-methylthiopheno[2,3-
416



d]pyrrol-5-yl ketone


C229
5-chloroindol-2-yl 4-(phenylcarbonyl)piperidyl ketone
367


C230
(2E)-3-(3,4-dichlorophenyl)-1-[4-
426



(phenylsulfonyl)piperazinyl]prop-2-en-1-one


C231
1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-[4-
391



(trifluoromethyl)phenyl]prop-2-yn-1-one


C232
4-{[4-(diethylamino)phenyl]carbonyl}piperazinyl 5-
439



chloroindol-2-yl ketone


C233
(2E)-3-[4-(dimethylamino)phenyl]-1-[4-
426



(diphenylmethyl)piperazinyl]prop-2-en-1-one


C234
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-
444



bromophenyl)carbonyl]piperazinyl}prop-2-en-1-one


C235
(2E)-3-(4-fluorophenyl)-1-{4-[(4-
393



fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C236
1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-(4-
349



methylphenyl)prop-2-yn-1-one


C237
(2E)-3-(4-fluorophenyl)-1-{4-[(2-
393



fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C238
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-
399



chlorophenyl)carbonyl]piperazinyl}prop-2-en-1-one


C239
6-bromoindol-2-yl 4-[(4-
447



chlorophenyl)carbonyl]piperazinyl ketone


C240
(2E)-1-{4-[(3-fluorophenyl)methyl]piperazinyl}-3-
325



phenylprop-2-en-1-one


C241
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-
397



methylphenyl)prop-2-en-1-one


C242
4-(diphenylmethyl)piperazinyl 1-methylindol-2-yl
410



ketone


C243
5-chloroindol-2-yl 4-(phenylcarbonyl)piperazinyl
368



ketone


C244
4-{[4-(tert-butyl)phenyl]methyl}piperazinyl 5-
390



methylindol-2-yl ketone


C245
1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-(4-
353



methylphenyl)prop-2-yn-1-one


C246
4-[(2,4-dichlorophenyl)carbonyl]piperazinyl 5-
471



(trifluoromethyl)indol-2-yl ketone


C247
benzo[b]thiophen-5-yl 4-(diphenylmethyl)piperazinyl
413



ketone


C248
(2E)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-
325



phenylprop-2-en-1-one


C249
3-(3,4-dichlorophenyl)-1-(4-{[4-
456



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C250
4,6-dichloroindol-2-yl 4-(diphenylmethyl)piperazinyl
465



ketone


C251
4-[(3,5-difluorophenyl)methyl]piperazinyl 5-
424



(trifluoromethyl)indol-2-yl ketone


C252
5-chloroindol-2-yl 4-[(3-fluorophenyl)amino]piperidyl
372



ketone


C253
3-(4-fluorophenyl)-1-(4-{[4-
405



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C254
5-chloroindol-2-yl 4-[(4-(3-
445



pyridyl)phenyl)carbonyl]piperazinyl ketone


C255
6-chloroindol-2-yl 4-[(4-
403



chlorophenyl)carbonyl]piperazinyl ketone


C256
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-{4-[(4-
395



methoxyphenyl)carbonyl]piperazinyl}prop-2-en-1-one


C257
4-(diphenylmethyl)piperazinyl 6-chloro(3-quinolyl)
442



ketone


C258
4-[(2,4-difluorophenyl)amino]piperidyl 5-chloroindol-2-
390



yl ketone


C259
(2E)-3-(4-fluorophenyl)-1-{4-[(4-
417



propylphenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C260
2E)-1-{4-[(4-methylphenyl)methyl]piperazinyl}-3-
321



phenylprop-2-en-1-one


C261
(2E)-3-(4-fluorophenyl)-1-(4-{[4-
417



(methylethyl)phenyl]sulfonyl}piperazinyl)prop-2-en-1-



one


C262
3-(2,3-dichlorophenyl)-1-{4-[(4-
392



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C263
4,6-difluoroindol-2-yl 4-(diphenylmethyl)piperazinyl
432



ketone


C264
6-bromoindol-2-yl 4-[(4-
492



bromophenyl)carbonyl]piperazinyl ketone


C265
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[3-
451



(trifluoromethyl)phenyl]prop-2-en-1-one


C266
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-(4-{[4-
431



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C267
(E)-(3-(4-(3-(4-bromophenyl)acryloyl)piperazine-1-
444



carbonyl)phenyl)boronic acid


C268
6-chloroindol-2-yl 4-[(4-
386



fluorophenyl)carbonyl]piperazinyl ketone


C269
(2E)-3-(4-bromophenyl)-1-{4-[(2-
404



fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


C270
(2E)-1-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}-3-
355



phenylprop-2-en-1-one


C271
5-(trifluoromethyl)indol-2-yl 4-{[3-
470



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C272
5-chloroindol-2-yl 4-(3-chlorophenoxy)piperidyl ketone
390


C273
4-[(3,5-difluorophenyl)amino]piperidyl 5-chloroindol-2-
390



yl ketone


C274
3-(4-bromophenyl)-1-{4-[(4-
414



methoxyphenyl)methyl]piperazinyl}prop-2-yn-1-one


C275
3-(2,3-dichlorophenyl)-1-{4-[(4-
408



chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C276
4-(diphenylmethyl)piperazinyl quinoxalin-2-yl ketone
409


C277
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-[2-
503



(trifluoromethyl)phenyl]prop-2-en-1-one


C278
5-chloroindol-2-yl 4-(8-hydropyrazolo[1,5-a]pyridin-2-
408



ylcarbonyl)piperazinyl ketone


C279
5-chloroindol-2-yl 4-(4-hydroimidazo[1,2-a]pyridin-2-
408



ylcarbonyl)piperazinyl ketone


C280
5,6-dimethoxyindol-2-yl 4-(diphenylmethyl)piperazinyl
456



ketone


C281
3-(2,3-dichlorophenyl)-1-(4-{[4-
442



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C282
4-({4-[(5-chloroindol-2-
412



yl)carbonyl]piperazinyl}carbonyl)benzamide


C283
2-(difluoromethyl)benzimidazol-5-yl 4-
447



(diphenylmethyl)piperazinyl ketone


C284
3-(3,4-dichlorophenyl)-1-{4-[(4-
392



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C285
4-[(2-chloro(3-pyridyl))carbonyl]piperazinyl 5-
404



chloroindol-2-yl ketone


C286
tert-butyl 4-[(1-methylindol-2-
344



yl)carbonyl]piperazinecarboxylate


C287
3-(4-fluorophenyl)-1-(4-{[4-fluoro-2-
423



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C288
4-(benzimidazol-2-ylcarbonyl)piperazinyl 5-
408



chloroindol-2-yl ketone


C289
5-chloroindol-2-yl 4-(2-pyridyloxy)piperidyl ketone
356


C290
benzo[b]thiophen-3-yl 4-(diphenylmethyl)piperazinyl
413



ketone


C291
3-(3,4-dichlorophenyl)-1-{4-[(4-
408



chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C292
6-fluoroindol-2-yl 4-{[4-
420



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C293
6-bromoindol-2-yl 4-[(4-
417



fluorophenyl)methyl]piperazinyl ketone


C294
3-(3,5-difluorophenyl)-1-{4-[(4-
375



chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C295
5-chloroindol-2-yl 4-ethylpiperazinyl ketone
292


C296
benzimidazol-5-yl 4-(diphenylmethyl)piperazinyl
397



ketone


C297
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-
385



chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


C298
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-
430



bromophenyl)methyl]piperazinyl}prop-2-en-1-one


C299
4-(diphenylmethyl)piperazinyl 2-
465



(trifluoromethyl)benzimidazol-5-yl ketone


C300
(2E)-3-(4-chloro-2-fluorophenyl)-1-{4-[(5-chloroindol-2-
446



yl)carbonyl]piperazinyl}prop-2-en-1-one


C301
2-anthryl 4-(diphenylmethyl)piperazinyl ketone
457


C302
3-(3-chlorophenyl)-1-(4-{[4-fluoro-2-
425



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C303
5-bromoindol-2-yl 4-[(4-
433



chlorophenyl)methyl]piperazinyl ketone


C304
4-(diphenylmethyl)piperazinyl 6-methoxyindol-2-yl
426



ketone


C305
(2E)-3-(4-aminophenyl)-1-[4-
398



(diphenylmethyl)piperazinyl]prop-2-en-1-one


C306
4-{[(4-bromophenyl)sulfonyl]amino}piperidyl 5-
497



chloroindol-2-yl ketone


C307
4-({4-[(2E)-3-(4-ethoxyphenyl)prop-2-
443



enoyl]piperazinyl}sulfonyl)-1-acetylbenzene


C308
(2E)-1-[4-(naphthylmethyl)piperazinyl]-3-phenylprop-2-
356



en-1-one


C309
1-{4-[(4-chlorophenyl)carbonyl]piperazinyl}-3-[2-
421



(trifluoromethyl)phenyl]prop-2-yn-1-one


C310
6-bromoindol-2-yl 4-[(4-(1H-1,2,3,4-tetraazol-5-
480



yl)phenyl)carbonyl]piperazinyl ketone


C311
[4-(diphenylmethyl)piperazinyl]-3-quinolylmethane-1-
424



thione


C312
(2E)-1-(4-butylpiperazinyl)-3-phenylprop-2-en-1-one
272


C313
(2E)-3-(4-ethoxyphenyl)-1-[4-
400



(phenylsulfonyl)piperazinyl]prop-2-en-1-one


C314
(2E)-3-(4-fluorophenyl)-1-{4-[(3-
404



methoxyphenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C315
5-chloroindol-2-yl 4-(4-fluorophenoxy)piperidyl ketone
373


C316
3-(3-chlorophenyl)-1-{4-[(4-
373



chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C317
5-chloroindol-2-yl 4-(4-chlorophenoxy)piperidyl ketone
389


C318
(2E)-1-{4-[(2,5-dimethoxyphenyl)sulfonyl]piperazinyl}-
434



3-(4-fluorophenyl)prop-2-en-1-one


C319
5-chloroindol-2-yl 4-[(4-fluorophenyl)methyl]piperazinyl
372



ketone


C320
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-
417



chlorophenyl)prop-2-en-1-one


C321
1-(4-{[4-fluoro-2-
404



(trifluoromethyl)phenyl]carbonyl}piperazinyl)-3-



phenylprop-2-yn-1-one


C322
4-[(3,4-dimethylphenyl)amino]piperidyl 5-chloroindol-2-
382



yl ketone


C323
(2E)-3-(4-fluorophenyl)-1-{4-
388



[benzylsulfonyl]piperazinyl}prop-2-en-1-one


C324
methyl 4-({4-[(5-chloroindol-2-
412



yl)carbonyl]piperazinyl}methyl)benzoate


C325
1-(4-{[4-fluoro-2-
472



(trifluoromethyl)phenyl]carbonyl}piperazinyl)-3-[4-



(trifluoromethyl)phenyl]prop-2-yn-1-one


C326
4-{3-[4-(diphenylmethyl)piperazinyl]-3-oxoprop-1-
405



ynyl}benzenecarbonitrile


C327
5-chloroindol-2-yl 4-[(4-
430



phenylphenyl)methyl]piperazinyl ketone


C328
4-[(3,4-dichlorophenyl)methyl]piperazinyl 5-
402



methylindol-2-yl ketone


C329
6-bromoindol-2-yl 4-{[3-fluoro-4-
498



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C330
4-{[3,5-bis(trifluoromethyl)phenyl]carbonyl}piperazinyl
537



5-(trifluoromethyl)indol-2-yl ketone


C331
5-chloroindol-2-yl 4-{[4-
422



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C332
(2E)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-
336



phenylprop-2-en-1-one


C333
4-[(4-bromophenyl)sulfonyl]piperazinyl 5-chloroindol-2-
483



yl ketone


C334
(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-(tert-
481



butyl)phenyl]sulfonyl}piperazinyl)prop-2-en-1-one


C335
4-{[4-((2E)-3-phenylprop-2-
331



enoyl)piperazinyl]methyl}benzenecarbonitrile


C336
3-(4-bromophenyl)-1-(4-{[4-fluoro-2-
483



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C337
(2E)-3-phenyl-1-[4-benzylpiperazinyl]prop-2-en-1-one
306


C338
4-(diphenylmethyl)piperazinyl 5-(methylethyl)indol-2-yl
438



ketone


C339
4-[(4-chlorophenyl)methyl]piperazinyl 5-methylindol-2-
368



yl ketone


C340
(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-
334



phenylprop-2-en-1-one


C341
2-({4-[(2E)-3-(4-fluorophenyl)prop-2-
399



enoyl]piperazinyl}sulfonyl)benzenecarbonitrile


C342
3-(4-bromophenyl)-1-{4-[(4-
418



chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C343
3-(3,5-difluorophenyl)-1-{4-[(4-
389



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C344
(2E)-1-{4-[(2-bromophenyl)methyl]piperazinyl}-3-
385



phenylprop-2-en-1-one


C345
(2E)-3-(4-fluorophenyl)-1-[4-
424



(naphthylsulfonyl)piperazinyl]prop-2-en-1-one


C346
3-(4-methylphenyl)-1-(4-{[4-
386



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C347
indol-2-yl 4-(phenylethyl)piperazinyl ketone
333


C348
4-(diphenylmethyl)piperazinyl 5-hydroxyindol-2-yl
411



ketone


C349
3-(2,4-difluorophenyl)-1-{4-[(4-
389



chlorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C350
(2E)-1-{4-[(2,5-difluorophenyl)methyl]piperazinyl}-3-
342



phenylprop-2-en-1-one


C351
4-(diphenylmethyl)piperazinyl 2-quinolyl ketone
408


C352
1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-[4-
402



(trifluoromethyl)phenyl]prop-2-yn-1-one


C353
3-(3-chlorophenyl)-1-(4-{[4-
407



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C354
(2E)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-
341



phenylprop-2-en-1-one


C355
(2E)-1-{4-[((1E)-2-phenylvinyl)sulfonyl](1,4-
475



diazaperhydroepinyl)}-3-(4-bromophenyl)prop-2-en-1-



one


C356
3-(4-chlorophenyl)-1-(4-{[4-
407



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C357
5-chloroindol-2-yl 4-(4-fluoro-2-
387



methylphenoxy)piperidyl ketone


C358
methyl 3-({4-[(5-chloroindol-2-
412



yl)carbonyl]piperazinyl}methyl)benzoate


C359
4-[(3,5-dimethylphenyl)methyl]piperazinyl 5-
361



methylindol-2-yl ketone


C360
4-{[2-fluoro-4-
487



(trifluoromethyl)phenyl]carbonyl}piperazinyl 5-



(trifluoromethyl)indol-2-yl ketone


C361
(2E)-1-{4-[2-(2-fluorophenyl)ethyl]piperazinyl}-3-
338



phenylprop-2-en-1-one


C362
(2E)-1-[4-(2-(1,3-dihydroisobenzofuran-5-
362



yl)ethyl)piperazinyl]-3-phenylprop-2-en-1-one


C363
methyl 3-({4-[(5-chloroindol-2-
426



yl)carbonyl]piperazinyl}carbonyl)benzoate


C364
3-(4-bromophenyl)-1-{4-[(4-
462



bromophenyl)methyl]piperazinyl}prop-2-yn-1-one


C365
(2E)-1-{4-[(3-chlorophenyl)methyl]piperazinyl}-3-
341



phenylprop-2-en-1-one


C366
4-[(4-chlorophenyl)carbonyl]piperazinyl 6-fluoroindol-
386



2-yl ketone


C367
(2E)-3-(4-fluorophenyl)-1-[4-(2-
380



thienylsulfonyl)piperazinyl]prop-2-en-1-one


C368
4-butylpiperazinyl 5-chloroindol-2-yl ketone
320


C369
3-(4-chlorophenyl)-1-{4-[(4-
357



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C370
4-(diphenylmethyl)piperazinyl indol-6-yl ketone
395


C371
5-bromoindol-2-yl 4-{[4-
466



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C372
3-(4-chlorophenyl)-1-{4-[(4-
369



methoxyphenyl)methyl]piperazinyl}prop-2-yn-1-one


C373
1-{4-[(4-methoxyphenyl)carbonyl]piperazinyl}-3-[2-
416



(trifluoromethyl)phenyl]prop-2-yn-1-one


C374
(2E)-1-{4-[(2-chlorophenyl)methyl]piperazinyl}-3-
341



phenylprop-2-en-1-one


C375
6-bromoindol-2-yl 4-{[4-
480



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C376
5-methylindol-2-yl 4-benzylpiperazinyl ketone
333


C377
(2E)-3-(4-bromo-2-fluorophenyl)-1-{4-[(4-
532



bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one


C378
4-[(2,4-difluorophenyl)carbonyl]piperazinyl 5-
404



chloroindol-2-yl ketone


C379
(2E)-1-{4-[(3-methoxyphenyl)methyl]piperazinyl}-3-
336



phenylprop-2-en-1-one


C380
4-(diphenylmethyl)piperazinyl thiopheno[2,3-d]pyrrol-
402



5-yl ketone


C381
4-bromophenyl 4-(2-naphthylcarbonyl)piperazinyl
423



ketone


C382
4-(4-(6-bromo-1H-indole-2-carbonyl)piperazine-1-
456



carbonyl)phenylboronic acid


C383
1-{4-[(4-bromophenyl)methyl]piperazinyl}-3-(4-
418



chlorophenyl)prop-2-yn-1-one


C384
3-(4-chlorophenyl)-1-{4-[(4-
373



chlorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C385
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-
443



(4-methoxyphenyl)prop-2-en-1-one


C386
4-(diphenylmethyl)piperazinyl 8-fluoro(3-quinolyl)
425



ketone


C387
(2E)-1-{4-[(3-nitrophenyl)methyl]piperazinyl}-3-
351



phenylprop-2-en-1-one


C388
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-
488



chloro-2-fluorophenyl)prop-2-en-1-one


C389
4-{[3-fluoro-4-
473



(trifluoromethyl)phenyl]methyl}piperazinyl 5-



(trifluoromethyl)indol-2-yl ketone


C390
5-chloroindol-2-yl 4-[4-
423



(trifluoromethyl)phenoxy]piperidyl ketone


C391
6-chloroindol-2-yl 4-{[4-
436



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C392
(2E)-1-[4-(methylpropyl)piperzinyl]-3-phenylprop-2-
272



en-1-one


C393
1-{4-[(4-fluorophenyl)carbonyl]piperazinyl}-3-[2-
404



(trifluoromethyl)phenyl]prop-2-yn-1-one


C394
(2E)-1-{4-[(2-methylphenyl)methyl]piperazinyl}-3-
320



phenylprop-2-en-1-one


C395
3-({4-[(5-chloroindol-2-
393



yl)carbonyl]piperazinyl}carbonyl)benzenecarbonitrile


C396
{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}-N-(3-
416



chlorophenyl)carboxamide


C397
4-({4-[(5-chloroindol-2-
396



yl)carbonyl]piperazinyl}carbonyl)benzaldehyde


C398
3-(3,5-difluorophenyl)-1-(4-{[4-
422



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C399
3-(4-chlorophenyl)-1-(4-{[4-fluoro-2-
439



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C400
4-(2,3-dimethylphenyl)piperazinyl 5-chloroindol-2-yl
368



ketone


C401
3-(4-bromophenyl)-1-{4-[(4-
401



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C402
5-chloroindol-2-yl 4-{[3-fluoro-4-
440



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C403
5-chloroindol-2-yl 4-[(3-
430



phenylphenyl)methyl]piperazinyl ketone


C404
(2E)-3-(4-bromo-2-fluorophenyl)-1-[4-
453



(phenylsulfonyl)piperazinyl]prop-2-en-1-one


C405
benzo[d]furan-2-yl 4-(phenylethyl)piperazinyl ketone
334


C406
1-{4-[((1E)-2-phenylvinyl)sulfonyl]piperazinyl}-3-(4-
402



fluorophenyl)propan-1-one


C407
(2E)-1-{4-[2-(2,4-dichlorophenoxy)ethyl]piperazinyl}-3-
405



phenylprop-2-en-1-one


C408
3-(4-bromophenyl)-1-(4-{[4-
451



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C409
4-(4-(5-chloro-1H-indole-2-carbonyl)piperazine-1-
412



carbonyl)phenylboronic acid


C410
3-(3,5-difluorophenyl)-1-{4-[(4-
372



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C411
3-[4-(trifluoromethyl)phenyl]-1-(4-{[4-
440



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C412
4-[(2,4-difluorophenyl)methyl]piperazinyl 5-
423



(trifluoromethyl)indol-2-yl ketone


C413
5-chloroindol-2-yl 4-phenoxypiperidyl ketone
355


C414
tert-butyl 4-(indol-2-ylcarbonyl)piperazinecarboxylate
329


C415
4-{[4-fluoro-3-
473



(trifluoromethyl)phenyl]methyl}piperazinyl 5-



(trifluoromethyl)indol-2-yl ketone


C416
phenyl 4-[(5-chloroindol-2-
384



yl)carbonyl]piperazinecarboxylate


C417
{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}-N-(3-
400



fluorophenyl)carboxamide


C418
4-{[4-fluoro-2-
473



(trifluoromethyl)phenyl]methyl}piperazinyl 5-



(trifluoromethyl)indol-2-yl ketone


C419
3-(3,5-difluorophenyl)-1-[4-
416



(diphenylmethyl)piperazinyl]prop-2-yn-1-one


C420
5-chloroindol-2-yl 4-{[4-fluoro-3-
440



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C421
5-chloroindol-2-yl 4-{[4-(4-
510



methoxyphenyl)phenyl]sulfonyl}piperazinyl ketone


C422
3-(3,5-difluorophenyl)-1-(4-{[4-fluoro-2-
426



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C423
4-{[3,5-bis(trifluoromethyl)phenyl]methyl}piperazinyl 5-
490



chloroindol-2-yl ketone


C424
3-(2,4-difluorophenyl)-1-{4-[(4-
372



fluorophenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C425
6-fluoroindol-2-yl 4-[(4-
369



fluorophenyl)carbonyl]piperazinyl ketone


C426
5-chloroindol-2-yl 4-{[4-fluoro-2-
440



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C427
4-[(2,4-difluorophenyl)methyl]piperazinyl 5-chloroindol-
390



2-yl ketone


C428
5-chloroindol-2-yl 4-{[4-chloro-2-
456



(trifluoromethyl)phenyl]methyl}piperazinyl ketone


C429
{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(4-
417



chlorophenyl)carboxamide


C430
3-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-1-(4-{[4-
432



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-



1-one


C431
4-(diphenylmethyl)piperazinyl pyrrolo[2,3-c]pyridin-2-yl
396



ketone


C432
1-(4-{[4-fluoro-2-
458



(trifluoromethyl)phenyl]methyl}piperazinyl)-3-[4-



(trifluoromethyl)phenyl]prop-2-yn-1-one


C433
4-(diphenylmethyl)piperazinyl 1-methylindol-5-yl
410



ketone


C434
4-(2,4-difluorophenyl)piperazinyl 5-chloroindol-2-yl
376



ketone


C435
3-(4-chlorophenyl)-1-(4-{[4-fluoro-2-
425



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C436
4-(diphenylmethyl)piperazinyl 4-bromopyrrol-2-yl
424



ketone


C437
3-(3,4-dichlorophenyl)-1-(4-{[4-fluoro-2-
473



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-yn-



1-one


C438
1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-[2-
390



(trifluoromethyl)phenyl]prop-2-yn-1-one


C439
(2E)-3-(4-chloro-2-fluorophenyl)-1-[4-
409



(phenylsulfonyl)piperazinyl]prop-2-en-1-one


C440
3-(4-(5-chloro-1H-indole-2-carbonyl)piperazine-1-
412



carbonyl)phenylboronic acid


C441
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(5-bromo-2-
479



fluorophenyl)prop-2-en-1-one


C442
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-
449



methylphenyl)prop-2-en-1-one


C443
1-[4-(diphenylmethyl)piperazinyl]-3-[2-
448



(trifluoromethyl)phenyl]prop-2-yn-1-one


C444
(2E)-3-phenyl-1-piperazinylprop-2-en-1-one
216


C445
N-(4-bromophenyl){4-[(5-chloroindol-2-
462



yl)carbonyl]piperazinyl}carboxamide


C446
3-(4-fluorophenyl)-1-{4-[(4-
340



fluorophenyl)methyl]piperazinyl}prop-2-yn-1-one


C447
6-chloroindol-2-yl 4-{[4-fluoro-2-
454



(trifluoromethyl)phenyl]carbonyl}piperazinyl ketone


C448
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-
465



(4-chloro-2-fluorophenyl)prop-2-en-1-one


C449
5-chloroindol-2-yl 4-(cyclopentylamino)piperidyl ketone
346


C450
{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-[4-
469



fluoro-3-(trifluoromethyl)phenyl]carboxamide


C451
{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(3-
401



fluorophenyl)carboxamide


C452
4-(2H-benzo[d]1,3-dioxolan-5-ylmethyl)piperazinyl
364



benzo[d]furan-2-yl ketone


C453
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-
397



methylphenyl)prop-2-en-1-one


C454
5-chloroindol-2-yl 4-[(4-
480



phenylphenyl)sulfonyl]piperazinyl ketone


C455
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-
453



fluorophenyl)prop-2-en-1-one


C456
{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-[4-
451



(trifluoromethyl)phenyl]carboxamide


C457
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-(1H-
432



1,2,3,4-tetraazol-5-



yl)phenyl)carbonyl]piperazinyl}prop-2-en-1-one


C458
5-methylindol-2-yl 4-(3-pyridylmethyl)piperazinyl
334



ketone


C459
1-(4-{[4-fluoro-2-
404



(trifluoromethyl)phenyl]methyl}piperazinyl)-3-(4-



methylphenyl)prop-2-yn-1-one


C460
4-({4-[(5-chloroindol-2-
412



yl)carbonyl]piperazinyl}carbonyl)benzoic acid


C461
1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-(4-
357



fluorophenyl)prop-2-yn-1-one


C462
{1-[(5-chloroindol-2-yl)carbonyl](4-piperidyl)}(4-
431



chlorophenyl)


C463
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-
368



fluorophenyl)methyl]piperazinyl}prop-2-en-1-one


C464
4-[(4-chlorophenyl)methyl]piperazinyl 3-quinolyl
388



ketone


C465
4-(diphenylmethyl)piperazinyl 2-methylbenzimidazol-5-
411



yl ketone


C466
(2E)-3-phenyl-1-[4-(4-pyridylmethyl)piperazinyl]prop-2-
307



en-1-one


C467
3-(3,5-difluorophenyl)-1-{4-[(4-
384



methoxyphenyl)carbonyl]piperazinyl}prop-2-yn-1-one


C468
4-(diphenylmethyl)piperazinyl 3-isoquinolyl ketone
408


C469
1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-[2-
407



(trifluoromethyl)phenyl]prop-2-yn-1-one


C470
5-chloroindol-2-yl 4-(4-fluorophenyl)piperazinyl ketone
358


C471
6-bromoindol-2-yl 4-[(4-
433



chlorophenyl)methyl]piperazinyl ketone


C472
4-bromophenyl 4-[(4-chlorophenyl)methyl]piperazinyl
394



ketone


C473
3-(3-chlorophenyl)-1-{4-[(4-
369



methoxyphenyl)methyl]piperazinyl}prop-2-yn-1-one


C474
{4-[(5-chloroindol-2-yl)carbonyl]piperazinyl}-N-(3-
509



iodophenyl)carboxamide


C475
3-[2-(trifluoromethyl)phenyl]-1-(4-{[4-
441



(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-yn-1-



one


C476
5-chloroindol-2-yl 4-(2-fluorophenyl)piperazinyl ketone
358


C477
N-(2,4-difluorophenyl){4-[(5-chloroindol-2-
419



yl)carbonyl]piperazinyl}carboxamide


C478
4-(diphenylmethyl)piperazinyl 8-hydropyrazolo[1,5-
397



a]pyridin-2-yl ketone


C479
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-fluoro-2-
451



(trifluoromethyl)phenyl]carbonyl}piperazinyl)prop-2-en-



1-one


C480
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-
427



(2-methylphenyl)prop-2-en-1-one


D1
(2E)-3-(4-bromophenyl)-1-{4-[(4-
420



chlorophenyl)methyl]piperazinyl}prop-2-en-1-one


D2
(E)-1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-phenylprop-
404



2-en-1-one


D3
(E)-3-(3,4-dichlorophenyl)-1-(4-(4-
444



(trifluoromethyl)benzyl)piperazin-1-yl)prop-2-en-1-one


E1
(E)-3-(4-bromophenyl)-1-(4-(mesitylsulfonyl)piperazin-
479



1-yl)prop-2-en-1-one


E2
(E)-1-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-3-(4-
454



fluorophenyl)prop-2-en-1-one


E3
(E)-3-(4-fluorophenyl)-1-(4-
403



(phenethylsulfonyl)piperazin-1-yl)prop-2-en-1-one


E4
(E)-3-(4-methoxyphenyl)-1-(4-
387



(phenylsulfonyl)piperazin-1-yl)prop-2-en-1-one


E5
(E)-1-(4-((4-acetylphenyl)sulfonyl)piperazin-1-yl)-3-(4-
496



bromo-2-fluorophenyl)prop-2-en-1-one


F2
(E)-3-(4-bromophenyl)-1-(4-(((4-
483



(trifluoromethyl)benzyl)amino)methyl)piperidin-1-



yl)prop-2-en-1-one


F3
(E)—N-((1-(3-(4-bromophenyl)acryloyl)piperidin-4-
496



yl)methyl)-4-(trifluoromethyl)benzamide









Example PC
Parenteral Composition
To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, is dissolved in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL. The mixture is incorporated into a dosage unit form suitable for administration by injection.
Example OC
Oral Composition
To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
Example BA
Cell-Based Luminescent Assay
To assess EBI2 modulation, the compounds described herein were assayed in the following cell-based luminescent assay:
Protocol
Day 1 Cell Seeding
1) Plated 600 cells/well in 4 uL of assay media into columns 1-48 of a 1536-well assay plate, using a liquid dispenser.
2) Centrifuged plates at 1000 rpm for 1 minute and covered with lids.
3) Incubated overnight at 37° C., 100% relative humidity, 5% CO2.
Day 2 Compound Addition
1) Centrifuged compound plates containing compounds described herein at 500 rpm for 1 minute.
2) Added compounds into assay plate col 5-48 to final concentration 4-5 uM. Added matching amount of DMSO to positive and negative control wells in columns 1-4.
3) Dispensed 2 ul/well of assay media to columns 1-2 for the positive control wells.
4) Added 2 ul/well of 400 nM 7a,25-OHC (final assay concentration=80 nM) in assay media to columns 3-48 for the negative control and test compound wells.
5) Centrifuged plates at 1000 rpm for 1 minute and re-lid plates.
6) Incubated plates at 37° C., 100% relative humidity, 5% CO2 for 60 minutes.
7) Following 60 minute incubation, delivered 2.5 uL of Detection Reagent solution to each assay plate (Columns 1-48) using a liquid handler.
8) Centrifuged plates at 2000 rpm for 2 minutes and re-lid plates.
9) Incubated plates for 60 minutes at 25 degrees in the dark.
10) Read plates using the Viewlux, Envision or other suitable plate reader using a luminescence detection.
The test compounds that demonstrated a corrected % activity of >=50% were defined as inhibitors of the reaction. The experimental values were normalized by the difference between values from neutral and stimulator control wells in each plate. Then normalized data was corrected to remove systematic plate patterns due to artifacts such as dispensing tip issues etc. IC50 data for the assay is shown in Table 1.







TABLE 1







IC50: IC50: A <100 nM; 100 nM ≦ B ≦ 500 nM; C 500 nM < C < 5 μM










Compound
IC50 nM







CI
A



C2
A



C3
A



C4
A



C5
A



C6
A



C7
A



C8
A



C9
A



C10
A



C11
A



C12
A



C13
A



C14
A



C15
A



C16
A



C17
A



C18
A



C19
A



C20
A



C21
A



C22
A



C23
A



C24
A



C25
A



C26
A



C27
A



C28
A



C29
A



C30
A



C31
A



C32
A



C33
A



C34
A



C35
A



C36
A



C37
A



C38
A



C39
A



C40
A



C41
A



C42
A



C43
A



C44
A



C45
A



C46
A



C47
A



C48
A



C49
A



C50
A



C51
A



C52
A



C53
A



C54
A



C55
A



C56
A



C57
A



C58
A



C59
A



C60
A



C61
A



C62
A



C63
A



C64
A



C65
A



C66
A



C67
A



C68
A



C69
A



C70
A



C71
A



C72
A



C73
A



C74
A



C75
A



C76
A



C77
A



C78
A



C79
A



C80
A



C81
A



C82
A



C83
A



C84
A



C85
A



C86
A



C87
A



C88
A



C89
A



C90
A



C91
A



C92
A



C93
A



C94
A



C95
A



C96
A



C97
A



C98
A



C99
A



C100
A



C101
A



C102
A



C103
A



C104
A



C105
A



C106
A



C107
A



C108
A



C109
A



C110
A



C111
A



C112
A



C113
A



C114
A



C115
A



C116
A



C117
A



C118
A



C119
A



C120
A



C121
A



C122
A



C123
A



C124
A



C125
A



C126
A



C127
A



C128
A



C129
A



C130
A



C131
A



C132
A



C133
A



C134
A



C135
A



C136
A



C137
A



C138
A



C139
A



C140
A



C141
A



C142
A



C143
A



C144
A



C145
A



C146
A



C147
A



C148
A



C149
A



C150
A



C151
A



C152
A



C153
A



C154
A



C155
A



C156
A



C157
A



C158
A



C159
A



C160
A



C161
A



C162
C



C163
C



C164
C



C165
C



C166
C



C167
C



C168
C



C169
C



C170
C



C171
C



C172
C



C173
C



C174
C



C175
C



C176
C



C177
C



C178
C



C179
C



C180
C



C181
C



C182
C



C183
C



C184
C



C185
C



C186
C



C187
C



C188
C



C189
C



C190
C



C191
C



C192
C



C193
C



C194
C



C195
C



C196
C



C197
C



C198
C



C199
C



C200
A



C201
A



C202
A



C203
A



C204
A



C205
A



C206
A



C207
A



C208
A



C209
A



C210
A



C211
A



C212
A



C213
A



C214
A



C215
A



C216
A



C217
A



C218
A



C219
A



C220
A



C221
A



C222
A



C223
A



C224
A



C225
A



C226
A



C227
A



C228
A



C229
A



C230
A



C231
A



C232
A



C233
A



C234
A



C235
A



C236
A



C237
A



C238
A



C239
A



C240
A



C241
A



C242
A



C243
A



C244
A



C245
A



C246
A



C247
A



C248
A



C249
A



C250
A



C251
A



C252
A



C253
A



C254
A



C255
A



C256
A



C257
A



C258
A



C259
A



C260
A



C261
A



C262
A



C263
A



C264
A



C265
A



C266
A



C267
A



C268
A



C269
A



C270
A



C271
A



C272
A



C273
A



C274
A



C275
A



C276
B



C277
B



C278
B



C279
B



C280
B



C281
B



C282
B



C283
B



C284
B



C285
B



C286
B



C287
B



C288
B



C289
B



C290
B



C291
B



C292
B



C293
B



C294
B



C295
B



C296
B



C297
B



C298
B



C299
B



C300
A



C301
A



C302
A



C303
A



C304
A



C305
A



C306
A



C307
A



C308
A



C309
A



C310
A



C311
A



C312
A



C313
A



C314
A



C315
A



C316
A



C317
A



C318
A



C319
A



C320
A



C321
A



C322
A



C323
A



C324
A



C325
A



C326
A



C327
A



C328
A



C329
A



C330
A



C331
A



C332
A



C333
A



C334
A



C335
A



C336
A



C337
A



C338
A



C339
A



C340
A



C341
A



C342
A



C343
A



C344
A



C345
A



C346
A



C347
A



C348
A



C349
A



C350
A



C351
A



C352
A



C353
A



C354
A



C355
A



C356
A



C357
A



C358
A



C359
B



C360
A



C361
A



C362
A



C363
B



C364
A



C365
A



C366
B



C367
A



C368
A



C369
A



C370
A



C371
A



C372
A



C373
A



C374
A



C375
B



C376
A



C377
A



C378
A



C379
A



C380
A



C381
A



C382
A



C383
A



C384
A



C385
A



C386
A



C387
A



C388
A



C389
A



C390
B



C391
A



C392
A



C393
A



C394
B



C395
A



C396
A



C397
A



C398
B



C399
A



C400
A



C401
A



C402
A



C403
A



C404
A



C405
B



C406
B



C407
B



C408
B



C409
B



C410
B



C411
B



C412
B



C413
B



C414
B



C415
B



C416
B



C417
B



C418
B



C419
B



C420
B



C421
B



C422
B



C423
B



C424
B



C425
B



C426
B



C427
B



C428
B



C429
B



C430
B



C431
B



C432
B



C433
B



C434
B



C435
B



C436
B



C437
B



C438
B



C439
B



C440
B



C441
B



C442
B



C443
B



C444
B



C445
B



C446
B



C447
B



C448
B



C449
B



C450
B



C451
B



C452
B



C453
B



C454
B



C455
B



C456
B



C457
B



C458
B



C459
B



C460
B



C461
B



C462
B



C463
B



C464
B



C465
B



C466
B



C467
B



C468
B



C469
B



C470
B



C471
B



C472
B



C473
B



C474
B



C475
B



C476
B



C477
B



C478
B



C479
B



C480
B



D1
A



D2
A



D3
A



E1
A



E2
A



E3
A



E4
A



E5
A



F2
A



F3
A



H3
A



H4
A










While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

## Claims

1. A method of modulating the activity of Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) in an individual with an autoimmune disease, cardiovascular disease, cancer, or a viral infection comprising administering to an individual in need thereof a therapeutically effective amount of a EBI2 modulator compound having the structure of Formula (VII):




wherein:
X is a bond, —CH2—, —C(H)(Ph)-, or —S(═O)2—;
each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; or two R1 on adjacent carbon atoms are combined with the adjacent carbon atoms to form a —OCH2O— ring;
each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, —C(═O)C1-C6alkyl, CO2H, B(OH)2, PO3H, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently H or C1-C6alkyl;
each R5 is independently H or C1-C6alkyl;
m is an integer selected from 0-3; and
n is an integer selected from 0-3;
or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.

2. The method of claim 1, wherein each R1 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl.

3. The method of claim 1, wherein each R2 is independently F, Cl, Br, I, —CN, —NR4R5, —NO2, —OH, —CF3, —OCF3, —OC1-C6alkyl, or C1-C6alkyl.

4. The method of claim 1, wherein n is 1 and m is 0; or n is 1 and m is 1; or n is 1 and m is 2; or n is 2 and m is 1; or n is 0 and m is 0.

5. The method of claim 1, wherein the compound is:
(2E)-3-(3, 4-dichlorophenyl)-1-[4-(diphenylmethyl) piperazinyl] prop-2-en-1-one;
(E)-3-(4-bromophenyl)-1-(4-(4-chlorobenzyl)piperazin-1-yl) prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(3-fluorophenyl)methyl] piperazinyl} prop-2-en-1-one;
(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-(trifluoromethyl) phenyl]methyl}piperazinyl)prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4[(2,4,6-trimethylphenyl) sulfonyl] piperazinyl} prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl) prop-2-en-1-one;
(2E)-3-(4-methoxyphenyl)-1-[4-(phenylsulfonyl)piperazinyl] prop-2-en-1-one;
4-({4-[(2E)-3-(4-bromo-2-fluorophenyl)prop-2-enoyl]piperazinyl}sulfonyl)-1-acetylbenzene;
(2E)-3-(3,4-dichlorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-methoxyphenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-ethoxyphenyl)prop-2-en-1-one;
(2E)-1-[4-(2-(3,4-dihydronaphthyl)sulfonyl)piperazinyl]-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromo-2-fluorophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one;
(2E)-1-{4-[(3,5-difluorophenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(4-fluoro-3-methylphenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(3,4-dichlorophenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(4-methylphenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-phenylprop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-1-{4-[(3,5-dimethoxyphenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-(4-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one;
(2E)-1-{4-[(4-chlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-1-{4-[(2-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-(4-{[4-(methylethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one;
(2E)-3-(3,4-difluorophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one;
(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-fluorophenyl)prop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(4-methylphenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(4-chloro-2-fluorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one;
(2E)-1-{4-[(3-chlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]methyl}piperazinyl)-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-methoxyphenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(3,4,5-trifluorophenyl)prop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-bromophenyl)prop-2-en-1-one;
1-[4-(diphenylmethyl)piperazinyl]-3-bromo-3-(4-bromophenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-nitrophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one;
(2E)-3-(5-bromo-2-fluorophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}piperazinyl)prop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(2-fluorophenyl)prop-2-en-1-one;
(2E)-3-(2-methylphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one;
(2E)-1-{4-[(3-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(4-nitrophenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(3-bromophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(3-fluorophenyl) sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-ethoxyphenyl)prop-2-en-1-one;
(2E)-3-(3,4-dichlorophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(2,5-dichlorophenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-3-(3,4-dichlorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one;
(2E)-3-[4-(dimethylamino)phenyl]-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(4-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(2-fluorophenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(3-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-methylphenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(4-propylphenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(4-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-(4-{[4-(methylethyl)phenyl]sulfonyl}piperazinyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(2-fluorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-[2-(trifluoromethyl)phenyl]prop-2-en-1-one;
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-one;
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-bromophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-3-(4-aminophenyl)-1-[4-(diphenylmethyl)piperazinyl]prop-2-en-1-one;
(2E)-1-(4-butylpiperazinyl)-3-phenylprop-2-en-1-one;
(2E)-3-(4-ethoxyphenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one;
(2E)-3-(4-fluorophenyl)-1-{4-[(3-methoxyphenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(2,5-dimethoxyphenyl)sulfonyl]piperazinyl}-3-(4-fluorophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(2-chlorophenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-methoxyphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-3-(3,4-dichlorophenyl)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)prop-2-en-1-one;
(2E)-3-phenyl-1-[4-benzylpiperazinyl]prop-2-en-1-one;
(2E)-1-{4-[(3,5-dimethylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-{4-[(2-bromophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-{4-[(2,5-difluorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-{4-[(3-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-{4-[(2-chlorophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-3-(4-bromo-2-fluorophenyl)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}prop-2-en-1-one;
(2E)-1-{4-[(3-methoxyphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-methoxyphenyl)prop-2-en-1-one;
(2E)-1-{4-[(3-nitrophenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one;
(2E)-1-{4-[(2-methylphenyl)methyl]piperazinyl}-3-phenylprop-2-en-1-one;
(2E)-3-(4-bromo-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one;
(2E)-3-(4-chloro-2-fluorophenyl)-1-[4-(phenylsulfonyl)piperazinyl]prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(5-bromo-2-fluorophenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-methylphenyl)prop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one;
(2E)-1-[4-(diphenylmethyl)piperazinyl]-3-(4-methylphenyl)prop-2-en-1-one;
(2E)-1-{4-[(4-bromophenyl)sulfonyl]piperazinyl}-3-(2-fluorophenyl)prop-2-en-1-one;
3-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-{4-[(4-fluorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(2E)-1-(4-{[4-(tert-butyl)phenyl]sulfonyl}piperazinyl)-3-(2-methylphenyl)prop-2-en-1-one;
(2E)-3-(4-bromophenyl)-1-{4-[(4-chlorophenyl)methyl]piperazinyl}prop-2-en-1-one;
(E)-1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-phenylprop-2-en-1-one;
(E)-3-(3,4-dichlorophenyl)-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)prop-2-en-1-one;
(E)-3-(4-bromophenyl)-1-(4-(mesitylsulfonyl)piperazin-1-yl)prop-2-en-1-one;
(E)-1-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one;
(E)-3-(4-methoxyphenyl)-1-(4-(phenylsulfonyl)piperazin-1-yl)prop-2-en-1-one;
(E)-1-(4-((4-acetylphenyl)sulfonyl)piperazin-1-yl)-3-(4-bromo-2-fluorophenyl)prop-2-en-1-one;
or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.