# Patent

## Title
Modulating and measuring cellular adhesion

## Abstract

Methods of using compounds having Structure I or the salts or tautomers of the compounds in the treatment of disorders relating to cell adhesion and metastatic processes are presented herein.

## Background
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No. 60/546,395 filed Feb. 20, 2004, U.S. Provisional Application No. 60/547,103 filed Feb. 23, 2004, and U.S. Provisional Application No. 60/554,771 filed Mar. 19, 2004, the entire disclosures of which are each incorporated herein by reference and for all purposes as if fully set forth herein.


FIELD OF THE INVENTION
The present invention provides methods for using compounds to modulate inflammatory responses and processes related to tumor metastasis. The invention further provides methods for monitoring the effects of the compounds of the invention by measuring the levels of ICAM, VCAM, or E-selectin molecules in a subject treated with the compounds.
BACKGROUND OF THE INVENTION
Amino quinolinone benzimidazolyl compounds such as 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one and their tautomers and salts are potent inhibitors of various class kinases such as VEGFR2 (KDR, Flk-1), FGFR1 and PDGFRβ with IC50s ranging from 10-27 nM. See U.S. Pat. No. 6,605,617, U.S. patent application Ser. No. 10/644,055, and U.S. patent application Ser. No. 10/706,328, each of which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein, for a list of various tyrosine and serine/threonine kinases for which 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one has shown activity and for assay procedures. Such kinases are important for the initiation and maintenance of new blood vessel growth as well as tumor proliferation. Consequently these inhibitors have direct applications in the treatment of various disorders such as solid and hematological cancers. The identification of plasma biomarkers in subjects treated with these kinase inhibitors would therefore provide a convenient method for monitoring the subject's physiological response to the treatment.
Cell adhesion molecules play important roles in tumor cell invasion, metastasis, and interaction with immune cells. VCAM (vascular cell adhesion molecule) is a transmembrane glycoprotein and expressed in endothelial cells and various cancer types such as bladder, breast, gastrointestinal, ovarian, renal, and Hodgkin's and non-Hodgkin's lymphoma. VCAM is induced by VEGF and is predominantly expressed in activated endothelial cells. ICAM (inducible cell adhesion molecule) is also expressed in endothelial cells and various cells including fibroblasts, hematopoietic cells, and tumor cells. The soluble form of ICAM present in the plasma is generated by proteolytic cleavage of membrane-associated molecules. E-Selectin (endothelial leukocyte adhesion molecule) is a transmembrane glycoprotein expressed in endothelial cells and mediates adhesion of neutrophils, monocytes, and T cells to endothelial cells. E-selectin also mediates tumor progression and metastasis.
A high concentration of soluble ICAM, VCAM, and E-selectin is considered a marker of endothelial cell activation during tumor development, metastasis, and inflammatory responses. These cell adhesion molecules localized on endothelial cells can mediate adhesion of metastatic tumor cells and allow extravasation into the vessels. It is of interest that these molecules are inducible, being poorly expressed on normal endothelial cells but capable of being expressed highly after exposure to cytokines such as IL-1 or TNF-a. In addition, some of these molecules are preferentially expressed in different vascular beds, with VCAM being abundant in the lung and E-selectin in the liver.
Matrix metalloproteases (MMPs) are a class of proteases that degrade most components of the extracellular matrix (ECM). Under normal physiological conditions they play an important role in development, tissue remodeling and morphogenesis. However, elevated levels of certain metalloproteases have been implicated in pathological diseases such as cancer and inflammation. Degradation of the extracellular matrix in the basement membrane is essential for tissue invasion by tumor cells and metastasis at various sites, and this degradation is dependent on the activity of MMPs. The family of MMPs includes more than 20 members. Two of these proteases are MMP-2 (gelatinase A, 72 KD) and MMP-9 (gelatinase B, 92 KD). MMP-2 and MMP-9 are important regulators of cancer progression and metastasis and their levels are frequently elevated in various cancer patients.
A report by Bergers et al. (Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis; Berger, G. et al., Nature Cell Biology, 2:737-744; 2000) discloses that MMP-9/gelatinase B is a functional component of an angiogenic switch during multistage pancreatic carcinogenesis by increasing the release of VEGF.
Various quinolinone benzimidazole compounds useful in inhibiting angiogenesis and vascular endothelial growth factor receptor tyrosine kinases and in inhibiting other tyrosine and serine/threonine kinases including 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one or a tautomer thereof and the synthesis thereof are disclosed in the following documents which are each hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein: U.S. Pat. No. 6,605,617; U.S. Pat. No. 6,756,383; U.S. patent application Ser. No. 10/116,117 filed (published on Feb. 6, 2003, as U.S. 2003/0028018 A1); U.S. patent application Ser. No. 10/644,055 (published on May 13, 2004, U.S. Patent Application No. 2004/0092535); U.S. patent application Ser. No. 10/983,174; U.S. patent application Ser. No. 10/706,328 (published on Nov. 4, 2004, as 2004/0220196); U.S. patent application Ser. No. 10/982,757; and U.S. patent application Ser. No. 10/982,543.
An important need exists for methods for modulating levels of cellular adhesion molecules and matrix metalloproteases. Such methods would therefore constitute important and needed therapies in the treatment of inflammatory and metastatic diseases mediated by cellular adhesion molecules and matrix metalloproteases.
SUMMARY OF THE INVENTION
The present invention relates to methods of treating a human or animal subject with, and uses in a human or animal subject of, a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The invention also relates to the use of the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof in the preparation of a medicament for use in the methods described herein.
In one aspect, the invention provides a method of modulating an inflammatory response or reducing cellular adhesion in a subject. Such methods include administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The inflammatory response is modulated in the subject and/or cellular adhesion is reduced in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
In one aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to modulate an inflammatory response.
In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to reduce cellular adhesion.
In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to decrease ICAM, VCAM, or E-selectin levels.
In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof used to reduce the levels of circulating cell adhesion molecules.
In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to decrease circulating ICAM, VCAM, or E-selectin levels.
In another aspect, the invention provides a method of monitoring the progression of a disease or treatment in a human or animal subject. The method includes measuring the amount of at least one cell adhesion molecule in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-Selectin). Some such methods further include withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample. Other embodiments include administering the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject.
In another aspect, the invention provides a method of identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The method includes measuring the amount of at least one cell adhesion molecule in the subject before, during, or after administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule. In some embodiments, the method further includes administering the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject after measuring the amount of the cell adhesion molecule in the subject.
Structure I has the following formula:




    
    
        wherein,
        R1, R2, R3, and R4 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —CN, —NO2, —OH, —OR15 groups, —NR16R17 groups, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and —C(═O)R18 groups;
        R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —NO2, —OH, —OR19 groups, —NR20R21 groups, —SH, —SR22 groups, —S(═O)R23 groups, —S(═O)2R24 groups, —CN, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)R25 groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups;
        R13 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)2 groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R15 and R19 may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl, substituted and unsubstituted diheterocyclylaminoalkyl, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R16 and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups;
        R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)2 groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R18, R23, R24, and R25 may be the same or different and are independently selected from the group consisting of H, —NH2, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)2 groups, —N(aryl)2 groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)2 groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, —OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and
        R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.
    
    


Further objects, features and advantages of the invention will be apparent from the following detailed description.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the effects of various amount of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1) on a 4T1 murine breast tumor model (vehicle (grey outlined circle); 10 mpk (square); 30 mpk (grey triangle); 60 mpk (X); 100 mpk (diamond); and 150 mpk (filed circle)). The growth of the subcutaneous tumor was inhibited (40-80% compared to control), liver metastases were completely inhibited, and lung metastases were inhibited by 60-97% after 18 days of dosing.
FIGS. 2A and 2B are graphs showing the dose-dependent reduction of soluble ICAM (FIG. 2A; greater than 70% inhibition with 100 or 150 mg/kg) and soluble VCAM (FIG. 2B; 44-47% inhibition with 100 or 150 mg/kg) in the serum of mice with 4T1 breast tumors when dosed with varying amounts of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one.
FIG. 3 is a graph showing the dose-dependent inhibition of mouse-specific soluble E-selectin in the serum of 4T1 tumor bearing mice treated with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one.
FIGS. 4A, 4B, and 4C are graphs of the Zymography and VEGF ELISA (FIG. 4B) data that show the decrease in MMP9 and VEGF in mice with implanted KM12L4a tumor cells when dosed for 7 days with 100 mg/kg 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one.
FIG. 5 is a scanned image showing the decrease in the expression of α5 integrin, not αν integrin when HUVECs in culture were treated with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H).
FIG. 6 is a scanned image showing the decrease in the expression of ICAM, and VCAM when HUVECs in culture were treated with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H).



DETAILED DESCRIPTION OF THE INVENTION
The following abbreviations and definitions are used throughout this application:
The phrase “cellular adhesion” as used herein, refers to cell adhesion. The amount of cellular adhesion in a subject can typically be correlated with the amounts of cell adhesion molecules, such as, but not limited to VCAM, ICAM, and E-Selectin in a subject.
“VCAM” is an abbreviation that stands for vascular cell adhesion molecule.
“ICAM” is an abbreviation that stands for inducible cell adhesion molecule.
“E-Selectin” is also known as endothelial leukocyte adhesion molecule.
“4T1” is a murine breast cell line.
“BALB/C” is a mice strain used in tumor xenograph experiments.
“bFGF” is an abbreviation that stands for basic fibroblast growth factor.
“FGFR1”, also referred to as bFGFR, is an abbreviation that stands for a tyrosine kinase that interacts with the fibroblast growth factor FGF.
“FGF” is an abbreviation for the fibroblast growth factor that interacts with FGFR1.
“FGFR3” is an abbreviation that stands for the tyrosine kinase fibroblast growth factor receptor 3 that is often expressed in multiple myeloma-type cancers.
“Flk-1” is an abbreviation that stands for fetal liver tyrosine kinase 1, also known as kinase-insert domain tyrosine kinase or KDR (human), also known as vascular endothelial growth factor receptor-2 or VEGFR2 (KDR (human), Flk-1 (mouse)).
“PDGF” is an abbreviation that stands for platelet derived growth factor. PDGF interacts with tyrosine kinases PDGFRα and PDGFRβ.
“RTK” is an abbreviation that stands for receptor tyrosine kinase.
“VEGF” is an abbreviation that stands for vascular endothelial growth factor.
“VEGF-RTK” is an abbreviation that stands for vascular endothelial growth factor receptor tyrosine kinase.
“ELISA” is an abbreviation that stands for Enzyme-Linked Immunosorbent Assay.
“MMP-2” is an abbreviation that stands for matrix metalloprotease-2 [includes the 72 KD (pro MMP-2) protein and the 62 KD (active MMP-2) protein]. MMP-2 is also referred to as gelatinase A.
“MMP-9” is an abbreviation that stands for matrix metalloprotease-9 [includes the 105 KD (pro MMP-9) protein and the 92 KD (active MMP-9) protein]. MMP-9 is also referred to as gelatinase B.
“Ki67” is a marker for cellular proliferation.
“Caspase-3” is a apoptosis marker. Activation of caspase-3 requires proteolytic processing of inactive caspase-3 into “cleaved caspase-3” which is 17 KD and 19 KD in size.
“PARP” is an abbreviation that stands for poly ADP-ribose polymerase and is an apoptosis marker. It is a 116 KD protein and is cleaved into a 89 KD protein.
“CD31” is a marker for endothelial cells. Immunostaining with anti-CD31 antibody in tumor section by immunohistochemistry will indicate the number of microvessels (or microvessel density) in tumors.
Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
The phrase “unsubstituted alkyl” refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: —CH(CH3)2, —CH(CH3)(CH2CH3), —CH(CH2CH3)2, —C(CH3)3, —C(CH2CH3)3, —CH2CH(CH3)2, —CH2CH(CH3)(CH2CH3), —CH2CH(CH2CH3)2, —CH2C(CH3)3, —CH2C(CH2CH3)3, —CH(CH3)CH(CH3)(CH2CH3), —CH2CH2CH(CH3)2, —CH2CH2CH(CH3)(CH2CH3), —CH2CH2CH(CH2CH3)2, —CH2CH2C(CH3)3, —CH2CH2C(CH2CH3)3, —CH(CH3)CH2CH(CH3)2, —CH(CH3)CH(CH3)CH(CH3)2, —CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus, the phrase unsubstituted alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups have from 1 to 10 carbon atoms while even more preferred such groups have from 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include straight and branched chain alkyl groups having from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and —CH(CH3)2.
The phrase “substituted alkyl” refers to an unsubstituted alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom in halides such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. One example of a substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, aryloxy group, or heterocyclyloxy group. Still other alkyl groups include alkyl groups that have an amine, alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine group.
The phrase “unsubstituted aryl” refers to aryl groups that do not contain heteroatoms. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example. Although the phrase “unsubstituted aryl” includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below. A preferred unsubstituted aryl group is phenyl. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.
The phrase “substituted aryl group” has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. However, a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase “substituted aryl” includes, but is not limited to tolyl, and hydroxyphenyl among others.
The phrase “unsubstituted alkenyl” refers to straight and branched chain and cyclic groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, —CH═C(H)(CH3), —CH═C(CH3)2, —C(CH3)═C(H)2, —C(CH3)═C(H)(CH3), —C(CH2CH3)═CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
The phrase “substituted alkenyl” has the same meaning with respect to unsubstituted alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
The phrase “unsubstituted alkynyl” refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to —C≡C(H), —C≡C(CH3), —C≡C(CH2CH3), —C(H2)C≡C(H), —C(H)2C≡C(CH3), and —C(H)2C≡C(CH2CH3) among others.
The phrase “substituted alkynyl” has the same meaning with respect to unsubstituted alkynyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
The phrase “unsubstituted aralkyl” refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl(—CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a phenyl group, such as if the carbon of the methyl were bonded to a carbon of benzene, then the compound is an unsubstituted aralkyl group (i.e., a benzyl group). Thus the phrase includes, but is not limited to, groups such as benzyl, diphenylmethyl, and 1-phenylethyl(—CH(C6H5)(CH3)) among others.
The phrase “substituted aralkyl” has the same meaning with respect to unsubstituted aralkyl groups that substituted aryl groups had with respect to unsubstituted aryl groups. However, a substituted aralkyl group also includes groups in which a carbon or hydrogen bond of the alkyl part of the group is replaced by a bond to a non-carbon or a non-hydrogen atom. Examples of substituted aralkyl groups include, but are not limited to, —CH2C(═O)(C6H5), and —CH2(2-methylphenyl) among others.
The phrase “unsubstituted heterocyclyl” refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S. Although the phrase “unsubstituted heterocyclyl” includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g., 2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered rings containing oxygen atoms such as, but not limited to furyl; unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms such as benzodioxolyl (e.g., 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl group also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene oxide and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
The phrase “substituted heterocyclyl” refers to an unsubstituted heterocyclyl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, N-alkyl piperazinyl groups such as 1-methyl piperazinyl, piperazine-N-oxide, N-alkyl piperazine N-oxides, 2-phenoxy-thiophene, and 2-chloropyridinyl among others. In addition, substituted heterocyclyl groups also include heterocyclyl groups in which the bond to the non-hydrogen atom is a bond to a carbon atom that is part of a substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, or unsubstituted heterocyclyl group. Examples include but are not limited to 1-benzylpiperidinyl, 3-phenylhiomorpholinyl, 3-(pyrrolidin-1-yl)-pyrrolidinyl, and 4-(piperidin-1-yl)-piperidinyl. Groups such as N-alkyl substituted piperazine groups such as N-methyl piperazine, substituted morpholine groups, and piperazine N-oxide groups such as piperazine N-oxide and N-alkyl piperazine N-oxides are examples of some substituted heterocyclyl groups. Groups such as substituted piperazine groups such as N-alkyl substituted piperazine groups such as N-methyl piperazine and the like, substituted morpholine groups, piperazine N-oxide groups, and N-alkyl piperazine N-oxide groups are examples of some substituted heterocyclyl groups that are especially suited as R6 or R7 groups.
The phrase “unsubstituted heterocyclylalkyl” refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above. For example, methyl(—CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, such as if the carbon of the methyl were bonded to carbon 2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3 or 4 of the pyridine, then the compound is an unsubstituted heterocyclylalkyl group.
The phrase “substituted heterocyclylalkyl” has the same meaning with respect to unsubstituted heterocyclylalkyl groups that substituted aralkyl groups had with respect to unsubstituted aralkyl groups. However, a substituted heterocyclylalkyl group also includes groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group. In addition, a substituted heterocyclylalkyl group also includes groups in which a carbon bond or a hydrogen bond of the alkyl part of the group is replaced by a bond to a substituted and unsubstituted aryl or substituted and unsubstituted aralkyl group. Examples include but are not limited to phenyl-(piperidin-1-yl)-methyl and phenyl-(morpholin-4-yl)-methyl.
The phrase “unsubstituted alkylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above. For example, methyl(—CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an ethyl group, then the resulting compound is —CH2—N(H)(CH2CH3) which is an unsubstituted alkylaminoalkyl group.
The phrase “substituted alkylaminoalkyl” refers to an unsubstituted alkylaminoalkyl group as defined above except where one or more bonds to a carbon or hydrogen atom in one or both of the alkyl groups is replaced by a bond to a non-carbon or non-hydrogen atom as described above with respect to substituted alkyl groups except that the bond to the nitrogen atom in all alkylaminoalkyl groups does not by itself qualify all alkylaminoalkyl groups as being substituted. However, substituted alkylaminoalkyl groups does include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.
The phrase “unsubstituted dialkylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to two other similar or different unsubstituted alkyl groups as defined above.
The phrase “substituted dialkylaminoalkyl” refers to an unsubstituted dialkylaminoalkyl group as defined above in which one or more bonds to a carbon or hydrogen atom in one or more of the alkyl groups is replaced by a bond to a non-carbon and non-hydrogen atom as described with respect to substituted alkyl groups. The bond to the nitrogen atom in all dialkylaminoalkyl groups does not by itself qualify all dialkylaminoalkyl groups as being substituted.
The phrase “unsubstituted alkoxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an otherwise unsubstituted alkyl group as defined above.
The phrase “substituted alkoxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an otherwise substituted alkyl group as defined above.
The phrase “unsubstituted heterocyclyloxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise unsubstituted heterocyclyl group as defined above.
The phrase “substituted heterocyclyloxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise substituted heterocyclyl group as defined above.
The phrase “unsubstituted heterocyclyloxyalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted heterocyclyl group as defined above.
The phrase “substituted heterocyclyloxyalkyl” refers to an unsubstituted heterocyclyloxyalkyl group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclyloxyalkyl group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups or in which the heterocyclyl group of the heterocyclyloxyalkyl group is a substituted heterocyclyl group as defined above.
The phrase “unsubstituted heterocyclylalkoxy” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound, and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to an unsubstituted heterocyclyl group as defined above.
The phrase “substituted heterocyclylalkoxy” refers to an unsubstituted heterocyclylalkoxy group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclylalkoxy group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups or in which the heterocyclyl group of the heterocyclylalkoxy group is a substituted heterocyclyl group as defined above. Further, a substituted heterocyclylalkoxy group also includes groups in which a carbon bond or a hydrogen bond to the alkyl moiety of the group may be substituted with one or more additional substituted and unsubstituted heterocycles. Examples include but are not limited to pyrid-2-ylmorpholin-4-ylmethyl and 2-pyrid-3-yl-2-morpholin-4-ylethyl.
The phrase “unsubstituted arylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to at least one unsubstituted aryl group as defined above.
The phrase “substituted arylaminoalkyl” refers to an unsubstituted arylaminoalkyl group as defined above except where either the alkyl group of the arylaminoalkyl group is a substituted alkyl group as defined above or the aryl group of the arylaminoalkyl group is a substituted aryl group except that the bonds to the nitrogen atom in all arylaminoalkyl groups does not by itself qualify all arylaminoalkyl groups as being substituted. However, substituted arylaminoalkyl groups does include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.
The phrase “unsubstituted heterocyclylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to at least one unsubstituted heterocyclyl group as defined above.
The phrase “substituted heterocyclylaminoalkyl” refers to unsubstituted heterocyclylaminoalkyl groups as defined above in which the heterocyclyl group is a substituted heterocyclyl group as defined above and/or the alkyl group is a substituted alkyl group as defined above. The bonds to the nitrogen atom in all heterocyclylaminoalkyl groups does not by itself qualify all heterocyclylaminoalkyl groups as being substituted. However, substituted heterocyclylaminoalkyl groups do include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.
The phrase “unsubstituted alkylaminoalkoxy” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above.
The phrase “substituted alkylaminoalkoxy” refers to unsubstituted alkylaminoalkoxy groups as defined above in which a bond to a carbon or hydrogen atom of the alkyl group bonded to the oxygen atom which is bonded to the parent compound is replaced by one or more bonds to a non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and/or if the hydrogen bonded to the amino group is bonded to a non-carbon and non-hydrogen atom and/or if the alkyl group bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all alkylaminoalkoxy groups does not by itself qualify all such groups as substituted alkylaminoalkoxy groups.
The phrase “unsubstituted dialkylaminoalkoxy” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to two other similar or different unsubstituted alkyl groups as defined above.
The phrase “substituted dialkylaminoalkoxy” refers to an unsubstituted dialkylaminoalkoxy group as defined above in which a bond to a carbon or hydrogen atom of the alkyl group bonded to the oxygen atom which is bonded to the parent compound is replaced by one or more bonds to a non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and/or if one or more of the alkyl groups bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all dialkylaminoalkoxy groups does not by itself qualify all such groups as substituted dialkylaminoalkoxy groups.
The term “protected” with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoroacetate. Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
A “pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.
In one aspect, the invention provides a method of modulating an inflammatory response and/or reducing cellular adhesion in a subject. Such methods include administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The inflammatory response is modulated in the subject and/or cellular adhesion is reduced in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
In one embodiment, the invention provides a method of treating a disorder related to inflammation in a human or animal subject. The method includes administering to the human or animal subject an effective amount of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. Inflammation and inflammatory responses may occur with various biological conditions. Examples of such biological conditions may include cancer, autoimmune diseases, asthma, allergies, eczema, microbial infections, traumatic injuries such as burns or cuts, lupus, arthritis, cardiovascular disease such as, but not limited to, strokes and ischemic injuries, respiratory bacterial and viral infections, and other conditions associated with inflammatory responses.
In another embodiment, the invention provides a method of treating a disorder related to cellular adhesion in a human or animal subject. The method includes administering to the human or animal subject an effective amount of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof.
In another embodiment, the invention provides a method of decreasing cellular adhesion molecules such as ICAM, VCAM, E-selectin, MMP-2, or MMP-9 levels in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The amount of the cellular adhesion molecule is typically reduced in the subject after administration.
In another embodiment, the invention provides a method of decreasing circulating ICAM, VCAM, E-selectin, MMP-2, or MMP-9 levels in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof.
In another embodiment, the invention provides a method of decreasing circulating cell adhesion molecules in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof.
In yet another embodiment, the invention provides a method of monitoring the progression of a disease or treatment in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof and measuring the amounts of a molecule such as ICAM, VCAM, E-selectin, MMP-2, or MMP-9 levels in the subject.
In another aspect, the invention provides a method of monitoring the progression of a disease or treatment in a human or animal subject. The method includes measuring the amount of at least one cell adhesion molecule in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-Selectin). Some such methods further include withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample.
In another aspect, the invention provides a method of identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The method includes measuring the amount of at least one cell adhesion molecule in the subject before, during, or after administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-Selectin). Some such methods further include withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample.
In some embodiments of any of the methods described herein, the subject is a cancer patient.
Structure I has the following formula:




    
    
        wherein,
        R1, R2, R3, and R4 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —CN, —NO2, —OH, —OR15 groups, —NR16R17 groups, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and —C(═O)R18 groups;
        R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —NO2, —OH, —OR19 groups, —NR20R21 groups, —SH, —SR22 groups, —S(═O)R23 groups, —S(═O)2R24 groups, —CN, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)R25 groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups;
        R13 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)2 groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R15 and R19 may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl, substituted and unsubstituted diheterocyclylaminoalkyl, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R16 and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups;
        R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)2 groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups;
        R18, R23, R24, and R25 may be the same or different and are independently selected from the group consisting of H, —NH2, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)2 groups, —N(aryl)2 groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)2 groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, —OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and
        R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.
    
    


In some embodiments of the pharmaceutically acceptable salts of the compounds or the tautomers of the compounds of Structure I, at least one of R5, R6, R7, or R8 is selected from the group consisting of substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted saturated heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; —OR19 groups wherein R19 is selected from the group consisting of substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; —NR20R21 groups wherein R20 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups; —NR20R21 groups wherein R21 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-aryl groups, —C(═O)NH2, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)2 groups, —C(═O)N(aryl)2 groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; and —C(═O)R25 groups wherein R25 is selected from the group consisting of H, —NH2, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)2 groups, —N(aryl)2 groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)2 groups, substituted and unsubstituted aryl groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted heterocyclyl groups.
In one embodiment, the invention relates to a pharmaceutically acceptable salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1) or a tautomer thereof. In some such embodiments, the salt is selected from the group consisting of tartrate, malate, lactate, bis-acetate, citrate, mesylate, bismesylate and bishydrochloride.
In some specific embodiments, the compound of structure I is a lactate salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one or a tautomer thereof.
In some specific embodiments, the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
In some embodiments, at least one of R12 and R13 is H, and in other embodiments, both R12 and R13 are H.
In a some embodiments, R1 is selected from the group consisting of F, Cl, substituted and unsubstituted alkoxy groups, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkoxy groups, substituted and unsubstituted arylaminoalkoxy groups, substituted and unsubstituted dialkylaminoalkoxy groups, substituted and unsubstituted diarylaminoalkoxy groups, and substituted and unsubstituted (alkyl)(aryl)aminoalkoxy groups.
In some embodiments, R1 is F and R2, R3, R3, R4, R5, and R8 are all H, and one of R6 or R7 is H.
In some other embodiments, at least one of R5, R6, R7, and R8 is a substituted or unsubstituted heterocyclyl group.
In still other embodiments, at least one of R5, R6, R7, and R8 is a substituted or unsubstituted heterocyclyl group comprising at least one O or N atom.
In yet other embodiments, at least one of R5, R6, R7, and R8 is a substituted or unsubstituted heterocyclyl group and the heterocyclyl group is selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, thiomorpholine, homopiperazine, tetrahydrothiophene, tetrahydrofuran, and tetrahydropyran.
In yet other embodiments, at least one of R6 or R7 is a substituted or unsubstituted heterocyclyl group.
In yet other embodiments, at least one of R6 or R7 is a substituted or unsubstituted heterocyclyl group comprising at least one O or N atom.
In yet other embodiments, one of R6 or R7 is a substituted or unsubstituted heterocyclyl group and the heterocyclyl group is selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, thiomorpholine, homopiperazine, tetrahydrothiophene, tetrahydrofuran, and tetrahydropyran.
In still other particular embodiments, one of R6 or R7 is selected from the group consisting of substituted and unsubstituted morpholine groups, and substituted and unsubstituted piperazine groups. In some such embodiments, one of R6 or R7 is a piperazine N-oxide or is an N-alkyl substituted piperazine.
In yet other embodiments, at least one of and in some embodiments one of R6 or R7 is selected from the group consisting of —NR20R21 groups wherein R20 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups; and —NR20R21 groups wherein R21 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups, groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups.
In yet another embodiment, R1 is selected from the group consisting of H and F.
In yet another embodiment, the compounds and their corresponding salts and tautomers are provided in the following two tables below. The synthesis of these compounds is described in U.S. Pat. No. 6,605,617, published U.S. Patent Application No. 2004/0092535, published U.S. Patent Application No. 2004/0220196 as are various kinase assay procedures. Each of these references is, therefore, hereby incorporated by reference in its entirety and for all purposes as if set forth in its entirety.










TABLE of Exemplary Compounds











LC/MS m/z


Example
Name
(MH+)












1
4-amino-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
389.4



benzimidazol-2-yl}quinolin-2(1H)-one


2
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
420



yl)-6-chloroquinolin-2(1H)-one


3
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
420



yl)-6-chloroquinolin-2(1H)-one


4
3-(1H-benzimidazol-2-yl)-4-[(3R)-3-(dimethylamino)pyrrolidin-1-
374.2



yl]quinolin-2(1H)-one


5
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(3R)-3-
408.1



(dimethylamino)pyrrolidin-1-yl]quinolin-2(1H)-one


6
4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-
403.2



methylquinolin-2(1H)-one


7
4-amino-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)quinolin-
361.2



2(1H)-one


8
4-amino-3-[6-(pyridin-4-ylmethyl)-1H-benzimidazol-2-
368.2



yl]quinolin-2(1H)-one


9
4-amino-3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
389.4



benzimidazol-2-yl}quinolin-2(1H)-one


10
4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
375.2



yl]quinolin-2(1H)-one


11
4-amino-3-(6-methyl-5-morpholin-4-yl-1H-benzimidazol-2-
376



yl)quinolin-2(1H)-one


12
4-amino-3-{5-[(1-methylpiperidin-3-yl)oxy]-1H-benzimidazol-2-
390.1



yl}quinolin-2(1H)-one


13
4-amino-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-fluoro-1H-
408.2



benzimidazol-2-yl}quinolin-2(1H)-one


14
4-amino-3-{5-[(1-methylpyrrolidin-3-yl)oxy]-1H-benzimidazol-2-
376.2



yl}quinolin-2(1H)-one


15
4-amino-3-[5-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-
389.2



yl]quinolin-2(1H)-one


16
4-amino-3-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
389.2



benzimidazol-2-yl}quinolin-2(1H)-one


17
4-amino-6-chloro-3-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-
423



1H-benzimidazol-2-yl}quinolin-2(1H)-one


18
ethyl {4-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
447.2



benzimidazol-6-yl]piperazin-1-yl}acetate


19
4-amino-3-{6-[methyl(1-methylpiperidin-4-yl)amino]-1H-
403.1



benzimidazol-2-yl}quinolin-2(1H)-one


20
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
403.3



aminoquinolin-2(1H)-one


21
4-amino-3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-
443.3



yl]quinolin-2(1H)-one


22
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-be-nzimidazole-
321.2



6-carboxylic acid


23
4-amino-5-(methyloxy)-3-[6-(4-methylpiperazin-1-yl)-1H-
405.3



benzimidazol-2-yl]quinolin-2(1H)-one


24
4-amino-3-{6-[4-(1-methylethyl)piperazin-1-yl]-1H-benzimidazol-
403.3



2-yl}quinolin-2(1H)-one


25
{4-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
419.2



benzimidazol-6-yl]piperazin-1-yl}acetic acid


26
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
386.1



yl)quinolin-2(1H)-one


27
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
386.1



yl)quinolin-2(1H)-one


28
4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
389.1



yl]quinolin-2(1H)-one


29
4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5-
433.3



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)-one


30
4-amino-6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
409.2



2-yl]quinolin-2(1H)-one


31
4-amino-6-chloro-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-
423.1



1H-benzimidazol-2-yl}quinolin-2(1H)-one


32
4-amino-5,6-dichloro-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-
457.2



yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one


33
4-amino-5,6-dichloro-3-[5-(4-methylpiperazin-1-yl)-1H-
443.2



benzimidazol-2-yl]quinolin-2(1H)-one


34
4-amino-3-(1H-benzimidazol-2-yl)-6-[(pyridin-2-
384.2



ylmethyl)oxy]quinolin-2(1H)-one


35
4-amino-3-(1H-benzimidazol-2-yl)-6-[(2R,6S)-2,6-
390.1



dimethylmorpholin-4-yl]quinolin-2(1H)-one


36
4-amino-3-(1H-benzimidazol-2-yl)-6-morpholin-4-ylquinolin-
362.2



2(1H)-one


37
4-amino-3-(1H-benzimidazol-2-yl)-5-[(1-methylpiperidin-3-
390.2



yl)oxy]quinolin-2(1H)-one


38
4-amino-3-(1H-benzimidazol-2-yl)-5-[(pyridin-2-
384.1



ylmethyl)oxy]quinolin-2(1H)-one


39
4-amino-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-5-[(pyridin-
469.2



4-ylmethyl)oxy]quinolin-2(1H)-one


40
4-amino-3-(1H-benzimidazol-2-yl)-5-(methyloxy)quinolin-2(1H)-
307.1



one


41
4-amino-3-(5-methyl-1H-benzimidazol-2-yl)-5-
321.1



(methyloxy)quinolin-2(1H)-one


42
4-amino-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H-
420.2



benzimidazol-2-yl}-5-(methyloxy)quinolin-2(1H)-one


43
4-amino-3-(1H-benzimidazol-2-yl)-5-morpholin-4-ylquinolin-
362.2



2(1H)-one


44
4-amino-3-(1H-benzimidazol-2-yl)-5-[(2R,6S)-2,6-
390.2



dimethylmorpholin-4-yl]quinolin-2(1H)-one


45
4-amino-3-(1H-benzimidazol-2-yl)-5-(4-methylpiperazin-1-
375.1



yl)quinolin-2(1H)-one


46
4-amino-5,6-dichloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-
430



yl)quinolin-2(1H)-one


47
3-{5-[(2-morpholin-4-ylethyl)oxy]-1H-benzimidazol-2-
391.3



yl}quinolin-2(1H)-one


48
4-amino-3-{5-[(3-pyrrolidin-1-ylpropyl)oxy]-1H-benzimidazol-2-
404



yl}quinolin-2(1H)-one


49
4-amino-3-{5-[(3-morpholin-4-ylpropyl)oxy]-1H-benzimidazol-2-
420.4



yl}quinolin-2(1H)-one


50
4-amino-6-fluoro-3-(5-morpholin-4-yl-1H-benzimidazol-2-
380



yl)quinolin-2(1H)-one


51
4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
407



benzimidazol-2-yl}-6-fluoroquinolin-2(1H)-one


52
4-amino-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one
295


53
4-amino-3-(6-fluoro-5-morpholin-4-yl-1H-benzimidazol-2-
380



yl)quinolin-2(1H)-one


54
4-amino-3-{5-[(tetrahydrofuran-2-ylmethyl)oxy]-1H-
377



benzimidazol-2-yl}quinolin-2(1H)-one


55
4-amino-6-fluoro-3-(6-fluoro-5-morpholin-4-yl-1H-benzimidazol-
398



2-yl)quinolin-2(1H)-one


56
4-amino-3-[6-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
393



2-yl]quinolin-2(1H)-one


57
4-amino-3-(5-{[2-(methyloxy)ethyl]oxy}-1H-benzimidazol-2-
351



yl)quinolin-2(1H)-one


58
4-amino-3-[4,6-difluoro-5-(4-methylpiperazin-1-yl)-1H-
411



benzimidazol-2-yl]quinolin-2(1H)-one


59
4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
407.1



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


60
4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
393.1



2-yl]quinolin-2(1H)-one


61
4-amino-5-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
409.1



2-yl]quinolin-2(1H)-one


62
4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-6-fluoro-1H-
407.1



benzimidazol-2-yl}quinolin-2(1H)-one


63
4-amino-5-chloro-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
423.1



benzimidazol-2-yl}quinolin-2(1H)-one


64
4-amino-6-chloro-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-6-
441



fluoro-1H-benzimidazol-2-yl}quinolin-2(1H)-one


65
4-amino-5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-(3H-
391.2



imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one


66
4-amino-3-(6-thiomorpholin-4-yl-1H-benzimidazol-2-yl)quinolin-
378.4



2(1H)-one


67
4-amino-3-[5-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-
443.1



yl]quinolin-2(1H)-one


68
4-amino-3-{6-[3-(diethylamino)pyrrolidin-1-yl]-1H-benzimidazol-
417.1



2-yl}quinolin-2(1H)-one


69
4-amino-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzimidazol-2-
438.3



yl]quinolin-2(1H)-one


70
4-amino-3-[5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-
376.3



2-yl]quinolin-2(1H)-one


71
4-amino-6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-
410.2



b]pyridin-2-yl]quinolin-2(1H)-one


72
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-N-(1-
431.3



methylpiperidin-4-yl)-1H-benzimidazole-5-carboxamide


73
4-amino-3-(5-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}-1H-
431.3



benzimidazol-2-yl)quinolin-2(1H)-one


74
4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
420.2



nitroquinolin-2(1H)-one


75
4-amino-3-[5-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol-2-
471.1



yl]quinolin-2(1H)-one


76
4-amino-3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-
403.3



benzimidazol-2-yl}quinolin-2(1H)-one


77
4-amino-3-[5-(1-oxidothiomorpholin-4-yl)-1H-benzimidazol-2-
394.5



yl]quinolin-2(1H)-one


78
3-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1H-benzimidazol-2-yl}-4-
431.3



aminoquinolin-2(1H)-one


79
4-amino-3-(5-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-
417.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


80
4-amino-3-(5-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-
417.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


81
4-amino-3-(5-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-1H-
431.4



benzimidazol-2-yl)quinolin-2(1H)-one


82
methyl 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
353.2



benzimidazole-6-carboxylate


83
4-amino-3-[5-(1,3′-bipyrrolidin-1′-yl)-1H-benzimidazol-2-
415.5



yl]quinolin-2(1H)-one


84
4-amino-3-[5-(pyridin-3-yloxy)-1H-benzimidazol-2-yl]quinolin-
370.2



2(1H)-one


85
4-amino-5,6-bis(methyloxy)-3-[5-(4-methylpiperazin-1-yl)-1H-
435.5



benzimidazol-2-yl]quinolin-2(1H)-one


86
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[2-
405.3



(dimethylamino)ethyl]-N-methyl-1H-benzimidazole-5-



carboxamide


87
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-N-(1-
417.2



methylpyrrolidin-3-yl)-1H-benzimidazole-5-carboxamide


88
4-amino-3-{5-[(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
415.2



yl)carbonyl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one


89
4-amino-3-{5-[(4-cyclohexylpiperazin-1-yl)carbonyl]-1H-
471.6



benzimidazol-2-yl}quinolin-2(1H)-one


90
4-amino-3-{5-[(2-piperidin-1-ylethyl)amino]-1H-benzimidazol-2-
403.2



yl}quinolin-2(1H)-one


91
ethyl 4-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
447.3



benzimidazol-5-yl]amino}piperidine-1-carboxylate


92
4-amino-3-[5-({(5R)-5-[(methyloxy)methyl]pyrrolidin-3-
405.2



yl}amino)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


93
4-amino-3-{5-[(pyridin-2-ylmethyl)aminol]-1H-benzimidazol-2-
383.3



yl}quinolin-2(1H)-one


94
4-amino-3-[5-(piperidin-3-ylamino)-1H-benzimidazol-2-
375.2



yl]quinolin-2(1H)-one


95
4-amino-5-fluoro-3-{5-[(pyridin-2-ylmethyl)amino]-1H-
401.3



benzimidazol-2-yl}quinolin-2(1H)-one


96
ethyl 4-{[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-
465.5



1H-benzimidazol-5-yl]amino}piperidine-1-carboxylate


97
4-amino-5-fluoro-3-[5-(piperidin-3-ylamino)-1H-benzimidazol-2-
393.3



yl]quinolin-2(1H)-one


98
4-amino-3-(1H-benzimidazol-2-yl)-6-bromoquinolin-2(1H)-one
357.1


99
4-amino-3-(1H-benzimidazol-2-yl)-7-bromoquinolin-2(1H)-one
357.1


100
4-amino-3-(5-bromo-1H-benzimidazol-2-yl)quinolin-2(1H)-one
357.1


101
N,N-dimethyl-2-(2-oxo-1,2-dihydroquinolin-3-yl)-1H-
333.1



benzimidazole-5-carboxamide


102
4-amino-3-(5-thien-2-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-
359.2



one


103
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N,N-dimethyl-1H-
384.1



benzimidazole-5-sulfonamide


104
4-amino-6-iodo-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
501.1



yl]quinolin-2(1H)-one


105
4-amino-3-(5-{2-[(dimethylamino)methyl]-morpholin-4-yl}-1H-
419.2



benzimidazol-2-yl)quinolin-2(1H)-one


106
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
547



yl)-7-chloro-6-iodoquinolin-2(1H)-one


107
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
431



yl)-6-nitroquinolin-2(1H)-one


108
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
401



yl)-6-methylquinolin-2(1H)-one


109
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
422



yl)-6,7-difluoroquinolin-2(1H)-one


110
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
421



yl)-7-chloroquinolin-2(1H)-one


111
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
465



yl)-6-bromoquinolin-2(1H)-one


112
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
411



yl)-2-oxo-1,2-dihydroquinoline-6-carbonitrile


113
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
404



yl)-6-fluoroquinolin-2(1H)-one


114
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
447



yl)-6,7-bis(methyloxy)quinolin-2(1H)-one


115
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
455



yl)-6,7-dichloroquinolin-2(1H)-one


116
1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531



2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4-



carboxamide


117
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
478



yl)-6-fluoro-7-[(3-hydroxypropyl)amino]quinolin-2(1H)-one


118
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
448



yl)-7-(dimethylamino)-6-fluoroquinolin-2(1H)-one


119
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
404



yl)-5-fluoroquinolin-2(1H)-one


120
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
508



yl)-6-(4-nitrophenyl)quinolin-2(1H)-one


121
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
491



yl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoroquinolin-2(1H)-



one


122
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
471



yl)-6-fluoro-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


123
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
493



yl)-6-[4-(methyloxy)phenyl]quinolin-2(1H)-one


124
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
490



yl)-6-fluoro-7-morpholin-4-ylquinolin-2(1H)-one


125
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6,7-difluoro-3-(3H-
423



imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one


126
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
508



yl)-6-(3-nitrophenyl)quinolin-2(1H)-one


127
1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531



2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-3-



carboxamide


128
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
401



yl)-5-methylquinolin-2(1H)-one


129
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
506



(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one


130
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
421



yl)-5-chloroquinolin-2(1H)-one


131
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-fluoro-3-(3H-
491



imidazo[4,5-b]pyridin-2-yl)-7-morpholin-4-ylquinolin-2(1H)-one


132
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
460



yl)-7-(cyclopropylamino)-6-fluoroquinolin-2(1H)-one


133
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(3H-
521



imidazo[4,5-b]pyridin-2-yl)-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


134
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
503



yl)-6-fluoro-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one


135
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-fluoro-7-(1H-
472



imidazol-1-yl)-3-(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-



one


136
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
525



yl)-6-fluoro-7-[(2-pyridin-2-ylethyl)amino]quinolin-2(1H)-one


137
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
488



yl)-6-fluoro-7-piperidin-1-ylquinolin-2(1H)-one


138
6-chloro-3-(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one
298


139
ethyl 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
560



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylate


140
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
519



yl)-6-(1-benzothien-2-yl)quinolin-2(1H)-one


141
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
474



yl)-6-fluoro-7-pyrrolidin-1-ylquinolin-2(1H)-one


142
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(3H-imidazo[4,5-
532



b]pyridin-2-yl)-6-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one


143
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(3H-imidazo[4,5-
494



b]pyridin-2-yl)-6-[2-(methyloxy)phenyl]quinolin-2(1H)-one


144
ethyl 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
560



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-3-carboxylate


145
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
491



yl)-6-(4-ethylphenyl)quinolin-2(1H)-one


146
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
476



yl)-6-fluoro-7-[(2-methylpropyl)amino]quinolin-2(1H)-one


147
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
401



yl)-5-methylquinolin-2(1H)-one


148
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-(2,4-dichlorophenyl)-
532



3-(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one


149
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
531



yl)-6-[3-(trifluoromethyl)phenyl]quinolin-2(1H)-one


150
3-(1H-benzimidazol-2-yl)-4-(dimethylamino)quinoline-2(1H)-one
305


151
4-hydroxy-3-(1H-imidazo[4,5-f]quinolin-2-yl)quinolin-2(1H)-one
329


152
4-hydroxy-3-(1H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one
279


153
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
525



benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


154
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
524



benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


155
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
538



benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


156
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
525



benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


157
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
525



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


158
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H
538



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


159
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
511



yl)-7-chloro-6-(2-methylphenyl)quinolin-2(1H)-one


160
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
411



yl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile


161
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
417



yl)-7-(methyloxy)quinolin-2(1H)-one


162
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzamide


163
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
434



yl)-6-fluoro-7-(methyloxy)quinolin-2(1H)-one


164
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
464



yl)-6-chloro-7-(dimethylamino)quinolin-2(1H)-one


165
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
555



yl)-7-(dimethylamino)-6-iodoquinolin-2(1H)-one


166
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
573



benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


167
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
590



benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin-6-



yl]benzoic acid


168
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
571



yl)-7-(methyloxy)-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-



one


169
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
401



yl)-8-methylquinolin-2(1H)-one


170
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
422



yl)-6,7-difluoroquinolin-2(1H)-one


171
3-(1H-benzimidazol-2-yl)-6-methyl-4-(piperidin-3-
374



ylamino)quinolin-2(1H)-one


172
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
493



yl)-6-[2-(methyloxy)phenyl]quinolin-2(1H)-one


173
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
493



yl)-6-[3-(methyloxy)phenyl]quinolin-2(1H)-one


174
3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-(piperidin-4-
396



ylamino)quinolin-2(1H)-one


175
3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-(pyrrolidin-3-
382



ylamino)quinolin-2(1H)-one


176
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(3-morpholin-4-
439



ylpropyl)amino]quinolin-2(1H)-one


177
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(piperidin-
480



4-ylamino)quinolin-2(1H)-one


178
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
494



[(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one


179
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-
506



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


180
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(piperidin-
480



3-ylamino)quinolin-2(1H)-one


181
6-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-(5-morpholin-4-
468



yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


182
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-
506



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


183
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
494



[(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one


184
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
494



[(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one


185
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(5-morpholin-
494



4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


186
4-[(4-aminocyclohexyl)amino]-6-chloro-3-(5-morpholin-4-yl-1H-
494



benzimidazol-2-yl)quinolin-2(1H)-one


187
4-{[(2S)-2-amino-3-methylbutyl]amino}-6-chloro-3-(5-morpholin-
482



4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


188
4-({[4-(aminomethyl)phenyl]methyl}amino)-6-chloro-3-(5-
516



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


189
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
480



[(pyrrolidin-2-ylmethyl)amino]quinolin-2(1H)-one


190
4-{[(1R)-1-(aminomethyl)propyl]amino}-6-chloro-3-(5-
468



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


191
4-{[(1S)-2-amino-1-(phenylmethyl)ethyl]amino}-6-chloro-3-(5-
530



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


192
6-chloro-4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-(5-
537



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


193
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[1-
570



(phenylmethyl)piperidin-4-yl]amino}quinolin-2(1H)-one


194
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3-
524



morpholin-4-ylpropyl)amino]quinolin-2(1H)-one


195
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2-
508



piperidin-1-ylethyl)amino]quinolin-2(1H)-one


196
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(pyridin-
488



3-ylmethyl)amino]quinolin-2(1H)-one


197
6-chloro-4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-(5-morpholin-
505



4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


198
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(pyridin-
488



4-ylmethyl)amino]quinolin-2(1H)-one


199
6-chloro-4-{[2-(methylamino)ethyl]amino}-3-(5-morpholin-4-yl-
454



1H-benzimidazol-2-yl)quinolin-2(1H)-one


200
6-chloro-4-{[(2-methyl-1-piperidin-4-yl-1H-benzimidazol-5-
624



yl)methyl]amino}-3-(5-morpholin-4-yl-1H-benzimidazol-2-



yl)quinolin-2(1H)-one


201
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2-
494



pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-one


202
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
466



(pyrrolidin-3-ylamino)quinolin-2(1H)-one


203
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-[5-(4-
507



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


204
4-[(4-aminocyclohexyl)amino]-6-chloro-3-[5-(4-methylpiperazin-
507



1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


205
4-({[4-(aminomethyl)phenyl]methyl}amino)-6-chloro-3-[5-(4-
529



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


206
6-chloro-4-{[2-(methylamino)ethyl]amino}-3-[5-(4-
467



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


207
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
550



{[3-(4-methylpiperazin-1-yl)propyl]amino}quinolin-2(1H)-one


208
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
583



{[1-(phenylmethyl)piperidin-4-yl]amino}quinolin-2(1H)-one


209
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
507



[(2-pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-one


210
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
479



(pyrrolidin-3-ylamino)quinolin-2(1H)-one


211
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
493



(piperidin-4-ylamino)quinolin-2(1H)-one


212
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2-
508



piperidin-2-ylethyl)amino]quinolin-2(1H)-one


213
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-chloro-3-(5-
506



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


214
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(piperidin-
480



3-ylamino)quinolin-2(1H)-one


215
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
507



[(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one


216
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
493



{[(2S)-pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one


217
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
493



{[(2R)-pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one


218
6-chloro-4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-[5-(4-
521



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


219
6-chloro-4-({[(2R)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-[5-(4-
521



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


220
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-
493



yl)-6-[4-(methyloxy)phenyl]quinolin-2(1H)-one


221
6-(3-aminophenyl)-4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
478



(1H-benzimidazol-2-yl)quinolin-2(1H)-one



















TABLE of Additional Exemplary Compounds











LC/MS m/z


Example
Name
(MH+)












222
4-amino-3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one
277.3


223
4-amino-3-(1H-benzimidazol-2-yl)-6,7-dimethoxyquinolin-
337.3



2(1H)-one


224
3-(1H-benzimidazol-2-yl)-4-(dimethylamino)-1-methylquinolin-
319.4



2(1H)-one


225
3-(1H-benzimidazol-2-yl)-4-{[2-(dimethylamino)ethyl]amino}-
362.4



1-methylquinolin-2(1H)-one


226
4-amino-3-(1H-benzimidazol-2-yl)-1-methylquinolin-2(1H)-one
291.3


227
4-amino-3-(6-methyl-1H-benzimidazol-2-yl)quinolin-2(1H)-one
291.3


228
3-(1H-benzimidazol-2-yl)-4-{[3-(1H-imidazol-1-
385.4



yl)propyl]amino}quinolin-2(1H)-one


229
3-(1H-benzimidazol-2-yl)-4-[(pyridin-3-
368.4



ylmethyl)amino]quinolin-2(1H)-one


230
4-amino-3-(1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one
295.3


231
3-(1H-benzimidazol-2-yl)-4-pyrrolidin-1-ylquinolin-2(1H)-one
331.4


232
3-(1H-benzimidazol-2-yl)-4-[(pyridin-4-
368.4



ylmethyl)amino]quinolin-2(1H)-one


233
3-(1H-benzimidazol-2-yl)-4-{[2-(1-methylpyrrolidin-2-
388.5



yl)ethyl]amino}quinolin-2(1H)-one


234
4-amino-3-(1H-benzimidazol-2-yl)-7-methylquinolin-2(1H)-one
291.3


235
4-amino-3-(1H-benzimidazol-2-yl)-7-chloroquinolin-2(1H)-one
311.7


236
4-amino-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one
311.7


237
4-amino-3-[6-(3-aminopyrrolidin-1-yl)-1H-benzimidazol-2-
361.4



yl]quinolin-2(1H)-one


238
3-(1H-benzimidazol-2-yl)-4-(diethylamino)quinolin-2(1H)-one
333.4


239
3-(1H-benzimidazol-2-yl)-4-(1,2-dimethylhydrazino)quinolin-
320.4



2(1H)-one


240
4-amino-3-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]quinolin-
345.3



2(1H)-one


241
4-amino-3-(5,6-dichloro-1H-benzimidazol-2-yl)quinolin-2(1H)-
346.2



one


242
4-(3-aminopyrrolidin-1-yl)-3-(5-morpholin-4-yl-1H-
431.5



benzimidazol-2-yl)quinolin-2(1H)-one


243
4-amino-5-fluoro-3-(5-methyl-1H-benzimidazol-2-yl)quinolin-
309.3



2(1H)-one


244
4-amino-3-(1H-benzimidazol-2-yl)-6-nitroquinolin-2(1H)-one
322.3


245
4-amino-3-(4-methyl-1H-benzimidazol-2-yl)quinolin-2(1H)-one
291.3


246
4-amino-3-(6-ethoxy-1H-benzimidazol-2-yl)quinolin-2(1H)-one
321.4


247
4-amino-3-(7-hydroxy-1H-benzimidazol-2-yl)quinolin-2(1H)-
293.3



one


248
4-amino-3-(6-tert-butyl-1H-benzimidazol-2-yl)quinolin-2(1H)-
333.4



one


249
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzimidazole-
302.3



5-carbonitrile


250
4-amino-3-(5,6-dimethyl-1H-benzimidazol-2-yl)quinolin-2(1H)-
305.4



one


251
4-amino-3-(4,5-dimethyl-1H-benzimidazol-2-yl)quinolin-2(1H)-
305.4



one


252
4-amino-6-chloro-3-(5-methyl-1H-benzimidazol-2-yl)quinolin-
325.8



2(1H)-one


253
4-amino-3-(1H-benzimidazol-2-yl)-6,8-dichloroquinolin-2(1H)-
346.2



one


254
4-amino-3-(1H-benzimidazol-2-yl)-5-chloroquinolin-2(1H)-one
311.7


255
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N,N-dimethyl-1H-
348.4



benzimidazole-5-carboxamide


256
4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
389.5



benzimidazol-2-yl}quinolin-2(1H)-one


257
4-amino-3-(6-methoxy-5-methyl-1H-benzimidazol-2-yl)quinolin-
321.4



2(1H)-one


258
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzimidazole-
319.3



6-carboximidamide


259
4-amino-7-(3-aminophenyl)-3-(1H-benzimidazol-2-yl)quinolin-
368.4



2(1H)-one


260
4-amino-3-(1H-benzimidazol-2-yl)-7-thien-2-ylquinolin-2(1H)-
359.4



one


261
4-amino-3-(5-thien-3-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-
359.4



one


262
4-amino-3-(1H-benzimidazol-2-yl)-7-thien-3-ylquinolin-2(1H)-
359.4



one


263
4-{[(1S,2R)-2-aminocyclohexyl]amino}-3-(5-morpholin-4-yl-
459.6



1H-benzimidazol-2-yl)quinolin-2(1H)-one


264
4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(5-morpholin-4-yl-
459.6



1H-benzimidazol-2-yl)quinolin-2(1H)-one


265
4-{[(1S,2S)-2-aminocyclohexyl]amino}-3-(5-morpholin-4-yl-1H-
459.6



benzimidazol-2-yl)quinolin-2(1H)-one


266
4-amino-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H-
390.5



benzimidazol-2-yl}quinolin-2(1H)-one


267
3-(1H-benzimidazol-2-yl)-4-morpholin-4-ylquinolin-2(1H)-one-
347.4


268
3-(1H-benzimidazol-2-yl)-4-(piperidin-3-ylamino)quinolin-
360.4



2(1H)-one


269
4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(5-chloro-1H-
420.9



benzimidazol-2-yl)quinolin-2(1H)-one


270
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-methyl-
434.9



1H-benzimidazol-2-yl)quinolin-2(1H)-one


271
6-chloro-3-(5-methyl-1H-benzimidazol-2-yl)-4-(piperidin-3-
408.9



ylamino)quinolin-2(1H)-one


272
3-(1H-benzimidazol-2-yl)-4-[(2-hydroxyethyl)amino]quinolin-
321.4



2(1H)-one


273
3-(1H-benzimidazol-2-yl)-6-chloro-4-(piperidin-3-
394.9



ylamino)quinolin-2(1H)-one


274
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(1S)-1-
421.9



cyclohexylethyl]amino}quinolin-2(1H)-one


275
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(piperidin-3-
408.9



ylmethyl)amino]quinolin-2(1H)-one


276
3-(1H-benzimidazol-2-yl)-6-chloro-4-(pyridin-4-
388.8



ylamino)quinolin-2(1H)-one


277
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(piperidin-4-
408.9



ylethyl)amino]quinolin-2(1H)-one


278
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-morpholin-4-
424.9



ylethyl)amino]quinolin-2(1H)-one


279
3-(1H-benzimidazol-2-yl)-6-chloro-4-
393.9



(cyclohexylamino)quinolin-2(1H)-one


280
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[3-(1H-imidazol-1-
419.9



yl)propyl]amino}quinolin-2(1H)-one


281
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[2-
382.9



(dimethylamino)ethyl]amino}quinolin-2(1H)-one


282
3-(1H-benzimidazol-2-yl)-6-chloro-4-
407.9



[(cyclohexylmethyl)amino]quinolin-2(1H)-one


283
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(tetrahydrofuran-2-
395.9



ylmethyl)amino]quinolin-2(1H)-one


284
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(pyridin-4-
402.9



ylmethyl)amino]quinolin-2(1H)-one


285
3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-(piperidin-3-
396.4



ylamino)quinolin-2(1H)-one


286
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
465.4



2-yl)-6-bromoquinolin-2(1H)-one


287
3-(1H-benzimidazol-2-yl)-6-fluoro-4-(piperidin-3-
378.4



ylamino)quinolin-2(1H)-one


288
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
400.5



2-yl)-6-methylquinolin-2(1H)-one


289
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
404.5



2-yl)-6-fluoroquinolin-2(1H)-one


290
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-
417.5



propylquinolin-2(1H)-one


291
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(1-ethylpyrrolidin-2-
422.9



yl)methyl]amino}quinolin-2(1H)-one


292
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[3-(2-oxopyrrolidin-1-
436.9



yl)propyl]amino}quinolin-2(1H)-one


293
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(piperidin-2-
408.9



ylmethyl)amino]quinolin-2(1H)-one


294
3-(1H-benzimidazol-2-yl)-6-chloro-4-(4-methyl-1,4-diazepan-1-
408.9



yl)quinolin-2(1H)-one


295
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(pyridin-3-
402.9



ylmethyl)amino]quinolin-2(1H)-one


296
4-anilino-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one
387.8


297
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(5-methylpyrazin-2-
417.9



yl)methyl]amino}quinolin-2(1H)-one


298
3-(1H-benzimidazol-2-yl)-6-chloro-4-(piperidin-4-
402.9



ylamino)quinolin-2(1H)-one


299
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[2-(1-methylpyrrolidin-2-
422.9



yl)ethyl]amino}quinolin-2(1H)-one


300
3-(1H-benzimidazol-2-yl)-4-[(1H-benzimidazol-5-
441.9



ylmethyl)amino]-6-chloroquinolin-2(1H)-one


301
3-(1H-benzimidazol-2-yl)-6-chloro-4-(piperidin-4-
394.9



ylamino)quinolin-2(1H)-one


302
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(4-
409.9



hydroxycyclohexyl)amino]quinolin-2(1H)-one


303
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
404.5



2-yl)-5-fluoroquinolin-2(1H)-one


304
3-(1H-benzimidazol-2-yl)-6,8-dimethyl-4-(piperidin-3-
388.5



ylamino)quinolin-2(1H)-one


305
3-(1H-benzimidazol-2-yl)-5-fluoro-4-(piperidin-3-
378.4



ylamino)quinolin-2(1H)-one


306
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
414.5



2-yl)-6,8-dimethylquinolin-2(1H)-one


307
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
414.5



2-yl)-6,8-dimethylquinolin-2(1H)-one


308
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
420.9



2-yl)-7-chloroquinolin-2(1H)-one


309
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-piperidin-1-
422.9



ylethyl)amino]quinolin-2(1H)-one


310
4-({2-[(4-amino-5-nitropyridin-2-yl)amino]ethyl}amino)-3-(1H-
491.9



benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one


311
3-(1H-benzimidazol-2-yl)-6-chloro-4-({2-[(5-nitropyridin-2-
476.9



yl)amino]ethyl}amino)quinolin-2(1H)-one


312
3-(1H-benzimidazol-2-yl)-4-[(1H-benzimidazol-2-
441.9



ylmethyl)amino]-6-chloroquinolin-2(1H)-one


313
3-(1H-benzimidazol-2-yl)-6-chloro-4-(2,5-
392.9



diazabicyclo[2.2.1]hept-2-yl)quinolin-2(1H)-one


314
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-{[5-
499.9



(trifluoromethyl)pyridin-2-yl]amino}ethyl)amino]quinolin-



2(1H)-one


315
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
400.5



2-yl)-7-methylquinolin-2(1H)-one


316
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
400.5



2-yl)-7-methylquinolin-2(1H)-one


317
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[(2R)-pyrrolidin-2-
394.9



ylmethyl]amino}quinolin-2(1H)-one


318
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(pyrrolidin-2-
394.9



ylmethyl)amino]quinolin-2(1H)-one


319
6-[(2-{[3-(1H-benzimidazol-2-yl)-6-chloro-2-oxo-1,2-
474.9



dihydroquinolin-4-yl]amino}ethyl)amino]nicotinamide


320
3-(1H-benzimidazol-2-yl)-6-chloro-4-(pyrrolidin-3-
380.8



ylamino)quinolin-2(1H)-one


321
4-{[(2R)-2-aminobutyl]amino}-3-(1H-benzimidazol-2-yl)-6-
382.9



chloroquinolin-2(1H)-one


322
4-{[(2S)-2-amino-3-phenylpropyl]amino}-3-(1H-benzimidazol-
444.9



2-yl)-6-chloroquinolin-2(1H)-one


323
4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-6-
408.9



chloroquinolin-2(1H)-one


324
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
512.4



2-yl)-6-iodoquinolin-2(1H)-one


325
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
512.4



2-yl)-6-iodoquinolin-2(1H)-one


326
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-(piperidin-3-
420.5



ylamino)quinolin-2(1H)-one


327
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
446.5



2-yl)-6,7-dimethoxyquinolin-2(1H)-one


328
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
431.5



2-yl)-6-nitroquinolin-2(1H)-one


329
3-(1H-benzimidazol-2-yl)-6-iodo-4-(piperidin-3-
486.3



ylamino)quinolin-2(1H)-one


330
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
420.9



2-yl)-5-chloroquinolin-2(1H)-one


331
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(1-piperidin-4-yl-1H-
525.0



benzimidazol-6-yl)methyl]amino}quinolin-2(1H)-one


332
3-(1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-3-
388.5



ylmethyl)amino]quinolin-2(1H)-one


333
3-(1H-benzimidazol-2-yl)-6-methyl-4-(piperidin-4-
374.5



ylamino)quinolin-2(1H)-one


334
3-(1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-4-
388.5



ylmethyl)amino]quinolin-2(1H)-one


335
3-(1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-2-
388.5



ylmethyl)amino]quinolin-2(1H)-one


336
4-{[4-(2-aminoethoxy)benzyl]amino}-3-(1H-benzimidazol-2-yl)-
460.9



6-chloroquinolin-2(1H)-one


337
4-{[2-(2-aminoethoxy)benzyl]amino}-3-(1H-benzimidazol-2-yl)-
460.9



6-chloroquinolin-2(1H)-one


338
4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(5-hydroxy-1H-
402.5



benzimidazol-2-yl)quinolin-2(1H)-one


339
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
411.5



2-yl)-2-oxo-1,2-dihydroquinoline-6-carbonitrile


340
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
418.5



2-yl)-6,7-dihydroxyquinolin-2(1H)-one


341
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
418.5



2-yl)-6,7-dihydroxyquinolin-2(1H)-one


342
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
430.5



2-yl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid


343
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
404.5



2-yl)-7-fluoroquinolin-2(1H)-one


344
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
404.5



2-yl)-7-fluoroquinolin-2(1H)-one


345
2-(4-amino-2-oxo-1-propyl-1,2-dihydroquinolin-3-yl)-1H-
344.4



benzimidazole-6-carbonitrile


346
tert-butyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
567.7



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-3,6-



dihydropyridine-1(2H)-carboxylate


347
tert-butyl 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
567.7



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-3,6-



dihydropyridine-1(2H)-carboxylate


348
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
467.6



2-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one


349
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
468.6



2-yl)-6-thien-2-ylquinolin-2(1H)-one


350
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
467.6



2-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one


351
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
498.5



2-yl)-6-(2,4-difluorophenyl)quinolin-2(1H)-one


352
tert-butyl 2-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
551.7



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-1H-pyrrole-



1-carboxylate


353
tert-butyl 2-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
551.7



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-1H-pyrrole-



1-carboxylate


354
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
463.6



2-yl)-6-pyridin-2-ylquinolin-2(1H)-one


355
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
468.6



2-yl)-6-thien-2-ylquinolin-2(1H)-one


356
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
498.5



2-yl)-6-(2,4-difluorophenyl)quinolin-2(1H)-one


357
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
468.6



2-yl)-6-thien-3-ylquinolin-2(1H)-one


358
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
487.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzonitrile


359
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
497.0



2-yl)-6-(2-chlorophenyl)quinolin-2(1H)-one


360
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.6



2-yl)-6-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one


361
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
492.6



2-yl)-6-(3-methoxyphenyl)quinolin-2(1H)-one


362
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
463.6



2-yl)-6-pyridin-3-ylquinolin-2(1H)-one


363
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
463.6



2-yl)-6-pyridin-4-ylquinolin-2(1H)-one


364
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
430.5



2-yl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid


365
3-(5-hydroxy-1H-benzimidazol-2-yl)-4-(piperidin-3-
376.4



ylamino)quinolin-2(1H)-one


366
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
400.5



2-yl)-8-methylquinolin-2(1H)-one


367
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
497.0



2-yl)-6-(2-chlorophenyl)quinolin-2(1H)-one


368
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.6



2-yl)-6-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one


369
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
487.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzonitrile


370
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
468.6



2-yl)-6-thien-3-ylquinolin-2(1H)-one


371
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
463.6



2-yl)-6-pyridin-4-ylquinolin-2(1H)-one


372
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
492.6



2-yl)-6-(2-methoxyphenyl)quinolin-2(1H)-one


373
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
476.6



2-yl)-6-(2-methylphenyl)quinolin-2(1H)-one


374
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
504.6



(1H-benzimidazol-2-yl)quinolin-2(1H)-one


375
6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
504.6



(1H-benzimidazol-2-yl)quinolin-2(1H)-one


376
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoic acid


377
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
519.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


378
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
498.5



2-yl)-6-(2,6-difluorophenyl)quinolin-2(1H)-one


379
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
506.6



2-yl)-6-(1,3-benzodioxol-5-yl)quinolin-2(1H)-one


380
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
497.0



2-yl)-6-(4-chlorophenyl)quinolin-2(1H)-one


381
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
490.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-



yl]benzaldehyde


382
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
508.7



2-yl)-6-[4-(methylthio)phenyl]quinolin-2(1H)-one


383
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
505.6



2-yl)-6-[4-(dimethylamino)phenyl]quinolin-2(1H)-one


384
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
515.0



2-yl)-6-(4-chloro-2-fluorophenyl)quinolin-2(1H)-one


385
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531.5



2-yl)-6-(2,4-dichlorophenyl)quinolin-2(1H)-one


386
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
462.6



2-yl)-6-phenylquinolin-2(1H)-one


387
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(1-ethylpiperidin-3-
422.9



yl)amino]quinolin-2(1H)-one


388
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
530.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxamide


389
ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
559.7



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylate


390
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
530.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-3-carboxamide


391
ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
559.7



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-3-carboxylate


392
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
470.5



2-yl)-6-fluoro-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


393
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
490.6



2-yl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoroquinolin-



2(1H)-one


394
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
489.6



2-yl)-6-fluoro-7-morpholin-4-ylquinolin-2(1H)-one


395
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
447.5



2-yl)-7-(dimethylamino)-6-fluoroquinolin-2(1H)-one


396
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
465.4



2-yl)-7-bromoquinolin-2(1H)-one


397
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
531.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylic acid


398
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
531.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-3-carboxylic acid


399
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoate


400
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
505.6



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


401
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
540.7



2-yl)-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one


402
methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
535.6



(1H-benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


403
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
541.0



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


404
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
554.1



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


405
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
539.0



(1H-benzimidazol-2-yl)-7-chloroquinolin-2(1H)-one


406
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
527.0



2-yl)-7-chloro-6-(2-methoxyphenyl)quinolin-2(1H)-one


407
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
565.9



2-yl)-7-chloro-6-(2,4-dichlorophenyl)quinolin-2(1H)-one


408
6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
539.0



(1H-benzimidazol-2-yl)-7-chloroquinolin-2(1H)-one


409
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
540.0



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


410
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
555.0



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


411
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
504.6



2-yl)-7-[[2-(dimethylamino)ethyl](methyl)amino]-6-



fluoroquinolin-2(1H)-one


412
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
491.6



2-yl)-6-fluoro-7-[(3-methoxypropyl)amino]quinolin-2(1H)-one


413
N-{(3R)-1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
530.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]pyrrolidin-3-yl}acetamide


414
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
544.6



2-yl)-6-fluoro-7-{[3-(2-oxopyrrolidin-1-



yl)propyl]amino}quinolin-2(1H)-one


415
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-azepan-1-yl-3-(1H-
501.6



benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one


416
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
469.5



2-yl)-6-fluoro-7-(1H-pyrrol-1-yl)quinolin-2(1H)-one


417
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
484.5



2-yl)-6-fluoro-7-(2-methyl-1H-imidazol-1-yl)quinolin-2(1H)-one


418
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
473.6



2-yl)-6-fluoro-7-pyrrolidin-1-ylquinolin-2(1H)-one


419
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
487.6



2-yl)-6-fluoro-7-piperidin-1-ylquinolin-2(1H)-one


420
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
502.6



2-yl)-6-fluoro-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one


421
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
477.6



2-yl)-6-fluoro-7-[(3-hydroxypropyl)amino]quinolin-2(1H)-one


422
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
506.0



2-yl)-6-chloro-7-morpholin-4-ylquinolin-2(1H)-one


423
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
519.1



2-yl)-6-chloro-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one


424
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
504.0



2-yl)-6-chloro-7-piperidin-1-ylquinolin-2(1H)-one


425
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid


426
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531.5



2-yl)-7-(2,4-dichlorophenyl)quinolin-2(1H)-one


427
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
429.5



2-yl)-7-(dimethylamino)quinolin-2(1H)-one


428
7-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
504.6



(1H-benzimidazol-2-yl)quinolin-2(1H)-one


429
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
476.6



2-yl)-7-(2-methylphenyl)quinolin-2(1H)-one


430
7-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
504.6



(1H-benzimidazol-2-yl)quinolin-2(1H)-one


431
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
492.6



2-yl)-7-(2-methoxyphenyl)quinolin-2(1H)-one


432
3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-2-
410.4



ylmethyl)amino]quinolin-2(1H)-one


433
N-[3-(1H-benzimidazol-2-yl)-6,7-difluoro-2-oxo-1,2-
371.3



dihydroquinolin-4-yl]glycine


434
N-[3-(1H-benzimidazol-2-yl)-6,7-difluoro-2-oxo-1,2-
385.3



dihydroquinolin-4-yl]-beta-alanine


435
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(6-fluoro-1H-
464.5



benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one


436
3-(6-fluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4-(piperidin-
438.5



3-ylamino)quinolin-2(1H)-one


437
3-(6-fluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4-(pyrrolidin-
424.4



3-ylamino)quinolin-2(1H)-one


438
4-[(4-aminocyclohexyl)amino]-3-(6-fluoro-1H-benzimidazol-2-
452.5



yl)-6,7-dimethoxyquinolin-2(1H)-one


439
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(6-fluoro-1H-
464.5



benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one


440
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
461.6



2-yl)-7-[ethyl(methyl)amino]-6-fluoroquinolin-2(1H)-one


441
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
475.6



2-yl)-7-(diethylamino)-6-fluoroquinolin-2(1H)-one


442
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
516.6



2-yl)-7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-6-



fluoroquinolin-2(1H)-one


443
7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-
511.6



ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one


444
ethyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
534.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoate


445
methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoate


446
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
518.6



2-yl)-7-{[2-(diethylamino)ethyl]amino}-6-fluoroquinolin-2(1H)-



one


447
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
516.6



2-yl)-6-fluoro-7-[(2-pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-



one


448
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.7



2-yl)-6-fluoro-7-[(2-piperidin-1-ylethyl)amino]quinolin-2(1H)-



one


449
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
504.6



2-yl)-7-{[3-(dimethylamino)propyl]amino}-6-fluoroquinolin-



2(1H)-one


450
N-(2-{[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
504.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]amino}ethyl)acetamide


451
N-{1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
584.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide


452
3-{[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
472.5



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]amino}propanenitrile


453
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
463.5



2-yl)-6-fluoro-7-[(2-hydroxyethyl)amino]quinolin-2(1H)-one


454
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
477.6



2-yl)-6-fluoro-7-[(2-methoxyethyl)amino]quinolin-2(1H)-one


455
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
503.6



2-yl)-6-fluoro-7-(3-hydroxypiperidin-1-yl)quinolin-2(1H)-one


456
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
504.6



2-yl)-7-[[2-(dimethylamino)ethyl](methyl)amino]-6-



fluoroquinolin-2(1H)-one


457
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
504.6



2-yl)-7-{[3-(dimethylamino)propyl]amino}-6-fluoroquinolin-



2(1H)-one


458
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
518.6



2-yl)-7-{[2-(diethylamino)ethyl]amino}-6-fluoroquinolin-2(1H)-



one


459
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
516.6



2-yl)-6-fluoro-7-[(2-pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-



one


460
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.7



2-yl)-6-fluoro-7-(3-hydroxypiperidin-1-yl)quinolin-2(1H)-one


461
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
544.6



2-yl)-6-fluoro-7-{[3-(2-oxopyrrolidin-1-



yl)propyl]amino}quinolin-2(1H)-one


462
N-(2-{[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
504.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]amino}ethyl)acetamide


463
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
491.6



2-yl)-6-fluoro-7-[(3-methoxypropyl)amino]quinolin-2(1H)-one


464
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
477.6



2-yl)-6-fluoro-7-[(2-methoxyethyl)amino]quinolin-2(1H)-one


465
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
463.5



2-yl)-6-fluoro-7-[(2-hydroxyethyl)amino]quinolin-2(1H)-one


466
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
461.6



2-yl)-7-[ethyl(methyl)amino]-6-fluoroquinolin-2(1H)-one


467
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
475.6



2-yl)-7-(diethylamino)-6-fluoroquinolin-2(1H)-one


468
N-{(3R)-1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
530.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]pyrrolidin-3-yl}acetamide


469
N-{(3S)-1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
530.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]pyrrolidin-3-yl}acetamide


470
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
516.6



2-yl)-7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-6-



fluoroquinolin-2(1H)-one


471
N-{1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
584.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide


472
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-azepan-1-yl-3-(1H-
501.6



benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one


473
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
503.6



2-yl)-6-fluoro-7-(3-hydroxypiperidin-1-yl)quinolin-2(1H)-one


474
3-{[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
472.5



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]amino}propanenitrile


475
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
469.5



2-yl)-6-fluoro-7-(1H-pyrrol-1-yl)quinolin-2(1H)-one


476
7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3S)-1-azabicyclo[2.2.2]oct-3-
511.6



ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one


477
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
484.5



2-yl)-6-fluoro-7-(2-methyl-1H-imidazol-1-yl)quinolin-2(1H)-one


478
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
516.6



2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-



fluoroquinolin-2(1H)-one


479
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
434.5



2-yl)-6-fluoro-7-methoxyquinolin-2(1H)-one


480
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
516.6



2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-



fluoroquinolin-2(1H)-one


481
N-{(3S)-1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
530.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]pyrrolidin-3-yl}acetamide


482
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
524.6



2-yl)-6-fluoro-7-[(2-pyridin-2-ylethyl)amino]quinolin-2(1H)-one


483
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
475.6



2-yl)-6-fluoro-7-(isobutylamino)quinolin-2(1H)-one


484
methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
570.1



(1H-benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


485
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
575.1



2-yl)-7-chloro-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one


486
methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
555.0



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


487
1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
531.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylic acid


488
1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
531.6



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-3-carboxylic acid


489
4-[(4-aminobenzyl)amino]-3-(1H-benzimidazol-2-yl)-6,7-
442.5



dimethoxyquinolin-2(1H)-one


490
4-(2-{[3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-2-oxo-1,2-
520.6



dihydroquinolin-4-yl]amino}ethyl)benzenesulfonamide


491
4-[(3-aminopropyl)amino]-3-(1H-benzimidazol-2-yl)-6,7-
394.4



dimethoxyquinolin-2(1H)-one


492
4-[(2-aminoethyl)amino]-3-(1H-benzimidazol-2-yl)-6,7-
380.4



dimethoxyquinolin-2(1H)-one


493
3-(1H-benzimidazol-2-yl)-4-{[2-(1H-imidazol-5-
431.5



yl)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one


494
3-(1H-benzimidazol-2-yl)-4-{[2-(1H-benzimidazol-2-
481.5



yl)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one


495
4-{[(4-amino-2-methylpyrimidin-5-yl)methyl]amino}-3-(1H-
458.5



benzimidazol-2-yl)-6,7-dimethoxyquinoln-2(1H)-one


496
3-(1H-benzimidazol-2-yl)-4-{[2-(5-fluoro-1H-indol-3-
498.5



yl)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one


497
4-{[2-(4-aminophenyl)ethyl]amino}-3-(1H-benzimidazol-2-yl)-
456.5



6,7-dimethoxyquinolin-2(1H)-one


498
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
471.6



2yl)-7-morpholin-4-ylquinolin-2(1H)-one


499
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5,6-difluoro-1H-
430.5



benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one


500
methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
535.6



(1H-benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-



yl]benzoate


501
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
540.7



2-yl)-7-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one


502
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoate


503
methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoate


504
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
519.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-



yl]phenyl}acetamide


505
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5,6-difluoro-1H-
482.5



benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one


506
3-(5,6-difluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4-
456.5



(piperidin-3-ylamino)quinolin-2(1H)-one


507
4-[(4-aminocyclohexyl)amino]-3-(5,6-difluoro-1H-benzimidazol-
470.5



2-yl)-6,7-dimethoxyquinolin-2(1H)-one


508
3-(5,6-difluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4-
442.4



(pyrrolidin-3-ylamino)quinolin-2(1H)-one


509
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
487.0



2-yl)-6-chloro-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


510
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
459.6



2-yl)-7-[(3-hydroxypropyl)amino]quinolin-2(1H)-one


511
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
526.7



2-yl)-7-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}quinolin-2(1H)-



one


512
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
484.6



2-yl)-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one


513
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
487.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzonitrile


514
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.6



2-yl)-7-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one


515
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
506.6



2-yl)-7-(1,3-benzodioxol-5-yl)quinolin-2(1H)-one


516
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
499.6



2-yl)-7-(morpholin-4-ylcarbonyl)quinolin-2(1H)-one


517
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
457.5



2-yl)-N,N-dimethyl-2-oxo-1,2-dihydroquinoline-7-carboxamide


518
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
429.5



2-yl)-2-oxo-1,2-dihydroquinoline-7-carboxamide


519
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid


520
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
465.4



2-yl)-7-bromoquinolin-2(1H)-one


521
4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
661.8



benzimidazol-2-yl)-7-[4-(ethoxycarbonyl)piperidin-1-yl]-2-oxo-



1,2-dihydroquinolin-6-yl}benzoic acid


522
4-[7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-
613.7



ylamino]-3-(1H-benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-



6-yl]benzoic acid


523
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
549.6



benzimidazol-2-yl)-7-(dimethylamino)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


524
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
572.6



benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


525
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.4



2-yl)-7-fluoro-6-iodoquinolin-2(1H)-one


526
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
558.6



2-yl)-7-fluoro-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one


527
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
523.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


528
6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
522.6



(1H-benzimidazol-2-yl)-7-fluoroquinolin-2(1H)-one


529
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
538.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


530
methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
553.6



(1H-benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


531
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
522.6



(1H-benzimidazol-2-yl)-7-fluoroquinolin-2(1H)-one


532
methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
538.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


533
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
494.6



2-yl)-7-fluoro-6-(2-methylphenyl)quinolin-2(1H)-one


534
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
510.6



2-yl)-7-fluoro-6-(2-methoxyphenyl)quinolin-2(1H)-one


535
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
549.4



2-yl)-6-(2,4-dichlorophenyl)-7-fluoroquinolin-2(1H)-one


536
ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
667.6



benzimidazol-2-yl)-6-iodo-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylate


537
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
578.4



2-yl)-7-(1H-imidazol-1-yl)-6-iodoquinolin-2(1H)-one


538
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
556.7



2-yl)-6-(2-ethylphenyl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


539
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
571.7



benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzamide


540
6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
570.7



(1H-benzimidazol-2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


541
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
587.7



(1H-benzimidazol-2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


542
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
585.7



benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]phenyl}acetamide


543
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
570.7



(1H-benzimidazol-2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


544
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
542.7



2-yl)-7-(1H-imidazol-1-yl)-6-(2-methylphenyl)quinolin-2(1H)-



one


545
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
558.7



2-yl)-7-(1H-imidazol-1-yl)-6-(2-methoxyphenyl)quinolin-2(1H)-



one


546
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
597.5



2-yl)-6-(2,4-dichlorophenyl)-7-(1H-imidazol-1-yl)quinolin-



2(1H)-one


547
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
490.6



2-yl)-6-(2-ethylphenyl)quinolin-2(1H)-one


548
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
508.6



2-yl)-6-(2-ethylphenyl)-7-fluoroquinolin-2(1H)-one


549
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoic acid


550
3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
556.0



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


551
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
541.0



benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


552
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
510.6



2-yl)-6-fluoro-7-[(pyridin-2-ylmethyl)amino]quinolin-2(1H)-one


553
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
527.6



2-yl)-6-fluoro-7-[(3-pyrrolidin-1-ylpropyl)amino]quinolin-2(1H)-



one


554
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
510.6



2-yl)-6-fluoro-7-[(pyridin-3-ylmethyl)amino]quinolin-2(1H)-one


555
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.7



2-yl)-6-fluoro-7-[(3-pyrrolidin-1-ylpropyl)amino]quinolin-2(1H)-



one


556
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
489.6



2-yl)-6-fluoro-7-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-2(1H)-



one


557
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.7



2-yl)-6-fluoro-7-{[2-(1-methylpyrrolidin-2-



yl)ethyl]amino}quinolin-2(1H)-one


558
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
510.6



2-yl)-6-fluoro-7-[(pyridin-4-ylmethyl)amino]quinolin-2(1H)-one


559
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
551.7



2-yl)-6-fluoro-7-[3-(methylsulfonyl)pyrrolidin-1-yl]quinolin-



2(1H)-one


560
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
550.7



2-yl)-6-fluoro-7-(3-pyridin-4-ylpyrrolidin-1-yl)quinolin-2(1H)-



one


561
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
532.6



2-yl)-6-fluoro-7-[(2-morpholin-4-ylethyl)amino]quinolin-2(1H)-



one


562
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
579.7



2-yl)-6-fluoro-7-[4-(pyridin-4-ylmethyl)piperazin-1-yl]quinolin-



2(1H)-one


563
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
509.6



2-yl)-7-(benzylamino)-6-fluoroquinolin-2(1H)-one


564
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
550.7



2-yl)-6-fluoro-7-(2-pyridin-3-ylpyrrolidin-1-yl)quinolin-2(1H)-



one


565
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
524.6



2-yl)-6-fluoro-7-[(2-pyridin-4-ylethyl)amino]quinolin-2(1H)-one


566
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
546.7



2-yl)-6-fluoro-7-[(3-morpholin-4-ylpropyl)amino]quinolin-



2(1H)-one


567
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
524.6



2-yl)-6-fluoro-7-[(4-hydroxycyclohexyl)amino]quinolin-2(1H)-



one


568
7-{[2-(4-aminophenyl)ethyl]amino}-4-[(3R)-1-
538.6



azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6-



fluoroquinolin-2(1H)-one


569
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
517.6



2-yl)-6-fluoro-7-[(4-hydroxycyclohexyl)amino]quinolin-2(1H)-



one


570
4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)-
516.6



6-fluoro-7-[(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one


571
4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)-
488.6



6-fluoro-7-(pyrrolidin-3-ylamino)quinolin-2(1H)-one


572
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
586.7



benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


573
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
547.1



benzimidazol-2-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxamide


574
ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
576.1



benzimidazol-2-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylate


575
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
452.5



2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one


576
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
466.6



2-yl)-7-(2-methyl-1H-imidazol-1-yl)quinolin-2(1H)-one


577
ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
541.7



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4-



carboxylate


578
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
512.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4-



carboxamide


579
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
479.6



2-yl)-6-fluoro-7-[(2-mercaptoethyl)amino]quinolin-2(1H)-one


580
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
579.7



2-yl)-6-fluoro-7-[4-(pyridin-3-ylmethyl)piperazin-1-yl]quinolin-



2(1H)-one


581
3-(1H-benzimidazol-2-yl)-4-[(2-hydroxyethyl)amino]-6,7-
381.4



dimethoxyquinolin-2(1H)-one


582
3-(1H-benzimidazol-2-yl)-4-[(3-hydroxypropyl)amino]-6,7-
395.4



dimethoxyquinolin-2(1H)-one


583
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531.6



2-yl)-6-fluoro-7-{[(1-



hydroxycyclohexyl)methyl]amino}quinolin-2(1H)-one


584
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-[(3-pyrrolidin-1-
448.5



ylpropyl)amino]quinolin-2(1H)-one


585
4[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
411.5



2-yl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile


586
3-(1H-benzimidazol-2-yl)-6-chloro-4-(pyridine-3-
388.8



ylamino)quinolin-2(1H)-one


587
3-(1H-benzimidazol-2-yl)-4-[(1-benzylpiperidin-4-yl)amino]-6-
485.0



chloroquinolin-2(1H)-one


588
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
416.5



2-yl)-7-methoxyquinolin-2(1H)-one


589
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
495.4



2-yl)-6-bromo-7-methoxyquinolin-2(1H)-one


590
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-{[(5-methylpyrazin-
443.5



2-yl)methyl]amino}quinolin-2(1H)-one


591
4-[(3-amino-2-hydroxypropyl)amino]-3-(1H-benzimidazol-2-yl)-
410.4



6,7-dimethoxyquinolin-2(1H)-one


592
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-[(2-
395.4



methoxyethyl)amino]quinolin-2(1H)-one


593
{[3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-2-oxo-1,2-
376.4



dihydroquinolin-4-yl]amino}acetonitrile


594
3-(1H-benzimidazol-2-yl)-4-{[2-(2-
425.5



hydroxyethoxy)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one


595
3-(1H-benzimidazol-2-yl)-4-[(3R)-3-hydroxypyrrolidin-1-yl]-
407.4



6,7-dimethoxyquinolin-2(1H)-one


596
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
487.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzonitrile


597
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid


598
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
505.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzamide


599
methyl 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoate


600
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[6-
587.1



(piperidin-3-yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)-



one


601
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[3-(2-
488.0



oxopyrrolidin-1-yl)propyl]amino}quinolin-2(1H)-one


602
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2-
502.0



pyridin-2-ylethyl)amino]quinolin-2(1H)-one


603
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[3-(2-
522.0



oxopyrrolidin-1-yl)propyl]amino}quinolin-2(1H)-one


604
6-chloro-4-[(6-methoxypyridin-3-yl)amino]-3-(5-morpholin-4-yl-
504.0



1H-benzimidazol-2-yl)quinolin-2(1H)-one


605
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3-
516.0



pyridin-2-ylpropyl)amino]quinolin-2(1H)-one


606
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(pyridin-
473.9



4-ylamino)quinolin-2(1H)-one


607
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[6-
601.1



(piperidin-3-ylmethoxy)pyridin-3-yl]methyl}amino)quinolin-



2(1H)-one


608
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(pyridin-
473.9



2-ylamino)quinolin-2(1H)-one


609
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
548.1



benzimidazol-2-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-7-



yl]piperidine-4-carboxylic acid


610
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
513.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4-



carboxylic acid


611
3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
506.6



benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid


612
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[2-
430.5



(piperidin-4-yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)-



one


613
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
455.4



2-yl)-6,7-dichloroquinolin-2(1H)-one


614
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[2-
587.1



(piperidin-4-yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)-



one


615
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(pyrazin-
474.9



2-ylamino)quinolin-2(1H)-one


616
4-amino-3-(6-thiomorpholin-4-yl-1H-benzimidazol-2-
378.5



yl)quinolin-2(1H)-one


617
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
550.7



2-yl)-6-fluoro-7-(3-pyridin-3-ylpyrrolidin-1-yl)quinolin-2(1H)-



one


618
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
558.6



2-yl)-5-fluoro-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one


619
6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
522.6



(1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one


620
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
538.6



benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


621
methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
553.6



(1H-benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


622
methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
538.6



benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


623
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
494.6



2-yl)-5-fluoro-6-(2-methylphenyl)quinolin-2(1H)-one


624
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
508.6



2-yl)-6-(2-ethylphenyl)-5-fluoroquinolin-2(1H)-one


625
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
510.6



2-yl)-5-fluoro-6-(2-methoxyphenyl)quinolin-2(1H)-one


626
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
549.4



2-yl)-6-(2,4-dichlorophenyl)-5-fluoroquinolin-2(1H)-one


627
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
524.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


628
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
523.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


629
N-{3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
537.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


630
3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
524.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


631
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
494.6



2-yl)-7-fluoro-6-(2-methylphenyl)quinolin-2(1H)-one


632
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
620.7



2-yl)-7-(2-methyl-1H-imidazol-1-yl)-6-[4-



(methylsulfonyl)phenyl]quinolin-2(1H)-one


633
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
599.7



benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]phenyl}acetamide


634
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
602.8



benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin-



6-yl]phenyl}acetamide


635
N-{3-[7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3R)-1-
626.7



azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-2-



oxo-1,2-dihydroquinolin-6-yl]phenyl}acetamide


636
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
562.7



benzimidazol-2-yl)-7-(dimethylamino)-2-oxo-1,2-



dihydroquinolin-6-yl]phenyl}acetamide


637
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
613.7



benzimidazol-2-yl)-7-(2-ethyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]phenyl}acetamide


638
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
498.6



2-yl)-7-(2-ethyl-1H-imidazol-1-yl)-6-fluoroquinolin-2(1H)-one


639
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
512.6



2-yl)-6-fluoro-7-(2-isopropyl-1H-imidazol-1-yl)quinolin-2(1H)-



one


640
1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
513.5



benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-yl]-



1H-pyrrole-3-carboxylic acid


641
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
546.8



2-yl)-7-chloro-6-iodoquinolin-2(1H)-one


642
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.4



2-yl)-5-fluoro-6-iodoquinolin-2(1H)-one


643
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.4



2-yl)-7-fluoro-6-iodoquinolin-2(1H)-one


644
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2-
502.0



pyridin-3-ylethyl)amino]quinolin-2(1H)-one


645
4-{[4-(aminomethyl)benzyl]amino}-3-(1H-benzimidazol-2-yl)-7-
430.9



chloroquinolin-2(1H)-one


646
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[2-
382.9



(dimethylamino)ethyl]amino}quinolin-2(1H)-one


647
3-(1H-benzimidazol-2-yl)-4-(1,4′-bipiperidin-1′-yl)-7-
463.0



chloroquinolin-2(1H)-one


648
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[3-(4-methylpiperazin-1-
452.0



yl)propyl]amino}quinolin-2(1H)-one


649
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-piperidin-1-
422.9



ylethyl)amino]quinolin-2(1H)-one


650
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[3-(1H-imidazol-1-
419.9



yl)propyl]amino}quinolin-2(1H)-one


651
3-(1H-benzimidazol-2-yl)-7-chloro-4-(pyridin-3-
388.8



ylamino)quinolin-2(1H)-one


652
3-(1H-benzimidazol-2-yl)-7-chloro-4-(pyridin-4-
388.8



ylamino)quinolin-2(1H)-one


653
3-(1H-benzimidazol-2-yl)-7-chloro-4-({[6-(piperidin-3-
502.0



yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)-one


654
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[3-(2-oxopyrrolidin-1-
436.9



yl)propyl]amino}quinolin-2(1H)-one


655
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
536.6



benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


656
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
535.6



benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


657
6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
534.6



(1H-benzimidazol-2-yl)-7-methoxyquinolin-2(1H)-one


658
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
550.6



benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


659
methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
565.6



(1H-benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-



6-yl]benzoate


660
N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
549.6



benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6-



yl]phenyl}acetamide


661
6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-
534.6



(1H-benzimidazol-2-yl)-7-methoxyquinolin-2(1H)-one


662
methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
550.6



benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


663
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
536.6



benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


664
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
506.6



2-yl)-7-methoxy-6-(2-methylphenyl)quinolin-2(1H)-one


665
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
520.6



2-yl)-6-(2-ethylphenyl)-7-methoxyquinolin-2(1H)-one


666
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
522.6



2-yl)-7-methoxy-6-(2-methoxyphenyl)quinolin-2(1H)-one


667
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
561.5



2-yl)-6-(2,4-dichlorophenyl)-7-methoxyquinolin-2(1H)-one


668
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
491.6



2-yl)-7-[2-(dimethylamino)ethoxy]-6-fluoroquinolin-2(1H)-one


669
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
503.6



2-yl)-6-fluoro-7-[(2S)-pyrrolidin-2-ylmethoxy]quinolin-2(1H)-



one


670
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531.6



2-yl)-6-fluoro-7-[2-(2-oxopyrrolidin-1-yl)ethoxy]quinolin-2(1H)-



one


671
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
624.7



2-yl)-6-fluoro-7-{[(2S)-1-(4-nitrophenyl)pyrrolidin-2-



yl]methoxy}quinolin-2(1H)-one


672
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
531.6



2-yl)-6-fluoro-7-[(1-methylpiperidin-2-yl)methoxy]quinolin-



2(1H)-one


673
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-{[2-(1-
448.5



methylpyrrolidin-2-yl)ethyl]amino}quinolin-2(1H)-one


674
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-{[2-
443.5



(methylsulfonyl)ethyl]amino}quinolin-2(1H)-one


675
3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-[(2-morpholin-4-yl-
527.6



2-pyridin-3-ylethyl)amino]quinolin-2(1H)-one


676
7-[(2-aminoethyl)amino]-4-[(3R)-1-azabicyclo[2.2.2]oct-3-
462.5



ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one


677
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
581.7



2-yl-6-fluoro-7-(3-phenylthiomorpholin-4-yl)quinolin-2(1H)-



one


678
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
581.7



2-yl-6-fluoro-7-(2-phenylthiomorpholin-4-yl)quinolin-2(1H)-



one


679
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
587.7



2-yl)-6-fluoro-7-{[2-(phenylsulfonyl)ethyl]amino}quinolin-



2(1H)-one


680
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
525.6



2-yl)-6-fluoro-7-{[2-(methylsulfonyl)ethyl]amino}quinolin-



2(1H)-one


681
7-{[(2R)-2-aminopropyl]amino}-4-[(3R)-1-azabicyclo[2.2.2]oct-
476.6



3-ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-



one


682
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
609.7



2-yl)-6-flouro-7-[(2-moropholin-4-yl-2-pyridin-3-



ylethyl)amino]quionolin-2(1H)-one


683
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
524.6



benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


684
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
572.6



benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


685
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
586.7



benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


686
4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
589.7



benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin-



6-yl]benzoic acid


687
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
600.7



benzimidazol-2-yl)-7-(2-ethyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


688
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
586.7



benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


689
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
589.7



benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin-



6-yl]benzoic acid


690
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
507.1



4[(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one


691
3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
572.6



benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


692
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
507.1



4-[(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one


693
3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
586.7



benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2-



dihydroquinolin-6-yl]benzoic acid


694
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
493.0



4-[(pyrrolidin-2-ylmethyl)amino]quinolin-2(1H)-one


695
3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
589.7



benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin-



6-yl]benzoic acid


696
4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-[5-(4-
481.0



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


697
4-{[(2S)-2-amino-3-methylbutyl]amino}-6-chloro-3-[5-(4-
495.0



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


698
4-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-3-[5-(4-
543.1



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


699
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-[5-(4-
519.1



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


700
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
493.0



4-(piperidin-3-ylamino)quinolin-2(1H)-one


701
6-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-[5-(4-
481.0



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


702
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
480.0



(piperidin-4-ylamino)quinolin-2(1H)-one


703
4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(1H-benzimidazol-2-
408.9



yl)-7-chloroquinolin-2(1H)-one


704
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(3-morpholin-4-
438.9



ylpropyl)amino]quinolin-2(1H)-one


705
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(pyridin-3-
402.9



ylmethyl)amino]quinolin-2(1H)-one


706
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-pyridin-3-
416.9



ylethyl)amino]quinolin-2(1H)-one


707
4-{[(1R,2R)-2-aminocyclohexyl]amino}-7-chloro-3-(5-
494.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


708
4-[(4-aminocyclohexyl)amino]-7-chloro-3-(5-morpholin-4-yl-
494.0



1H-benzimidazol-2-yl)quinolin-2(1H)-one


709
7-chloro-4-{[2-(methylamino)ethyl]amino}-3-(5-morpholin-4-yl-
453.9



1H-benzimidazol-2-yl)quinolin-2(1H)-one


710
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
480.0



[(pyrrolidin-2-ylmethyl)amino]quinolin-2(1H)-one


711
4-{[(1S)-2-amino-1-benzylethyl]amino}-7-chloro-3-(5-
530.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


712
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
466.0



(pyrrolidin-3-ylamino)quinolin-2(1H)-one


713
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-pyrrolidin-1-
408.9



ylethyl)amino]quinolin-2(1H)-one


714
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-piperidin-2-
422.9



ylethyl)amino]quinolin-2(1H)-one


715
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(piperidin-3-
408.9



ylmethyl)amino]quinolin-2(1H)-one


716
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(piperidin-4-
408.9



ylmethyl)amino]quinolin-2(1H)-one


717
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[(2-methyl-1-piperidin-4-
539.1



yl-1H-benzimidazol-5-yl)methyl]amino}quinolin-2(1H)-one


718
4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-7-
408.9



chloroquinolin-2(1H)-one


719
3-(1H-benzimidazol-2-yl)-7-chloro-4-(pyrrolidin-3-
380.8



ylamino)quinolin-2(1H)-one


720
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.6



2-yl)-6-[4-(trifluoromethyl)phenyl]quinolin-2(1H)-one


721
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
530.6



2-yl)-6-[3-(trifluoromethyl)phenyl]quinolin-2(1H)-one


722
4-amino-5-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-
421.5



benzimidazol-2-yl]quinolin-2(1H)-one


723
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[(2S)-
480.0



pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one


724
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[(2R)-
480.0



pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one


725
7-chloro-4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-(5-
508.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


726
7-chloro-4-({[(2R)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-(5-
508.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


727
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-chloro-3-(5-
506.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


728
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
494.0



[(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one


729
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
494.0



[(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one


730
4-{[(2S)-2-amino-3-methylbutyl]amino}-7-chloro-3-(5-
482.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


731
4-{[4-(aminomethyl)benzyl]amino}-7-chloro-3-(5-morpholin-4-
516.0



yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


732
4-{[(1R)-1-(aminomethyl)propyl]amino}-7-chloro-3-(5-
468.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


733
7-choro-4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-(5-
537.1



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


734
7-chloro-4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-(5-
505.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


735
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2-
494.0



pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-one


736
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
494.0



[(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one


737
7-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-(5-morpholin-4-
468.0



yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


738
7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3S)-
466.0



pyrrolidin-3-ylamino]quinolin-2(1H)-one


739
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
478.6



2-yl)-6-(4-hydroxyphenyl)quinolin-2(1H)-one


740
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
478.6



2-yl)-6-(3-hydroxyphenyl)quinolin-2(1H)-one


741
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
478.6



2-yl)-6-(2-hydroxyphenyl)quinolin-2(1H)-one


742
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[(2S)-pyrrolidin-2-
394.9



ylmethyl]amino}quinolin-2(1H)-one


743
3-(1H-benzimidazol-2-yl)-7-chloro-4-({[(2S)-1-ethylpyrrolidin-
422.9



2-yl]methyl}amino)quinolin-2(1H)-one


744
3-(1H-benzimidazol-2-yl)-7-chloro-4-({[(2R)-1-ethylpyrrolidin-
422.9



2-yl]methyl}amino)quinolin-2(1H)-one


745
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(3S)-pyrrolidin-3-
380.8



ylamino]quinolin-2(1H)-one


746
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2S)-pyrrolidin-2-
394.9



ylmethyl]amino}quinolin-2(1H)-one


747
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2R)-pyrrolidin-2-
394.9



ylmethyl]amino}quinolin-2(1H)-one


748
3-(1H-benzimidazol-2-yl)-6-chloro-4-({[(2S)-1-ethylpyrrolidin-
422.9



2-yl]methyl}amino)quinolin-2(1H)-one


749
3-(1H-benzimidazol-2-yl)-6-chloro-4-({[(2R)-1-ethylpyrrolidin-
422.9



2-yl]methyl}amino)quinolin-2(1H)-one


750
4-amino-3-[5-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol-
380.8



2-yl]quinolin-2(1H)-one


751
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-bromo-3-(5-
550.5



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


752
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-bromo-3-(6-
495.4



methoxy-1H-benzimidazol-2-yl)quinolin-2(1H)-one


753
3-{[3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-2-oxo-1,2-
474.5



dihydroquinolin-4-yl]amino}bicyclo[2.2.1]heptane-2-



carboxamide


754
4-[(3-amino-2,2-dimethylpropyl)amino]-3-(1H-benzimidazol-2-
422.5



yl)-6,7-dimethoxyquinolin-2(1H)-one


755
3-(1H-benzimidazol-2-yl)-4-{[3-(dimethylamino)-2,2-
450.6



dimethylpropyl]amino}-6,7-dimethoxyquinolin-2(1H)-one


756
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(pyridin-2-
402.9



ylmethyl)amino]quinolin-2(1H)-one


757
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-pyridin-2-
416.9



ylethyl)amino]quinolin-2(1H)-one


758
3-(1H-benzimidazol-2-yl)-7-chloro-4-{[2-
368.8



(methylamino)ethyl]amino}quinolin-2(1H)-one


759
3-(1H-benzimidazol-2-yl)-7-chloro-4-[(piperidin-2-
408.9



ylmethyl)amino]quinolin-2(1H)-one


760
3-(1H-benzimidazol-2-yl)-7-chloro-4-(piperidin-4-
394.9



ylamino)quinolin-2(1H)-one


761
4-amino-3-[5-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol-
471.6



2-yl]quinolin-2(1H)-one


762
4-amino-3-{5-[(3S)-3-(dimethylnitroryl)pyrrolidin-1-yl]-1H-
405.5



benzimidazol-2-yl}quinolin-2(1H)-one


763
4-amino-3-(5-{2-[(dimethylamino)methyl]morpholin-4-yl}-1H-
419.5



benzimidazol-2-yl)quinolin-2(1H)-one


764
methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
534.6



benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6-



yl]benzoate


765
3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


766
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
519.6



benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6-



yl]benzamide


767
4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
520.6



benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6-



yl]benzoic acid


768
4-amino-3-{5-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-
429.5



1H-benzimidazol-2-yl}quinolin-2(1H)-one


769
2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-
449.5



N-(1-methylpiperidin-4-yl)-1H-benzimidazole-6-carboxamide


770
4-amino-3-(1H-benzimidazol-2-yl)-5-[(1-methylpiperidin-4-
390.5



yl)oxy]quinolin-2(1H)-one


771
4-amino-5-(1-azabicyclo[2.2.2]oct-3-yloxy)-3-(1H-
402.5



benzimidazol-2-yl)quinolin-2(1H)-one


772
4-amino-5-fluoro-3-{6-[(2-piperidin-1-ylethyl)amino]-1H-
421.5



benzimidazol-2-yl}quinolin-2(1H)-one


773
4,6-diamino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
390.5



yl]quinolin-2(1H)-one


774
2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
339.3



benzimidazole-5-carboxylic acid


775
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-pyridin-3-yl-1H-
397.4



benzimidazole-5-carboxamide


776
4-amino-3-(5-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-
390.4



benzimidazol-2-yl)quinolin-2(1H)-one


777
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
432.5



yl]-2-oxo-1,2-dihydroquinolin-6-yl}acetamide


778
4-amino-5-fluoro-3-(6-morpholin-4-yl-1H-benzimidazol-2-
380.4



yl)quinolin-2(1H)-one


779
3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2-
396.9



(dimethylamino)ethyl]amino}-6-methylquinolin-2(1H)-one


780
4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(5-chloro-1H-
422.9



benzimidazol-2-yl)-6-methylquinolin-2(1H)-one


781
3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-3-
422.9



ylmethyl)amino]quinolin-2(1H)-one


782
3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-4-
422.9



ylmethyl)amino]quinolin-2(1H)-one


783
4-[(4-aminocyclohexyl)amino]-3-(5-chloro-1H-benzimidazol-2-
422.9



yl)-6-methylquinolin-2(1H)-one


784
3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-{[2-
382.9



(methylamino)ethyl]amino}quinolin-2(1H)-one


785
3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-(pyrrolidin-3-
394.9



ylamino)quinolin-2(1H)-one


786
3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-2-
422.9



ylmethyl)amino]quinolin-2(1H)-one


787
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H-
434.9



benzimidazol-2-yl)-6-methylquinolin-2(1H)-one


788
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H-
434.9



benzimidazol-2-yl)-6-methylquinolin-2(1H)-one


789
4-amino-3-(6-{(2R,5R)-2-[(dimethylamino)methyl]-5-
433.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)-



one


790
4-amino-3-(5-{[(3R)-3-hydroxypiperidin-1-yl]carbonyl}-1H-
404.4



benzimidazol-2-yl)quinolin-2(1H)-one


791
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-(2-piperidin-1-
431.5



ylethyl)-1H-benzimidazole-5-carboxamide


792
4-amino-3-[5-(piperazin-1-ylcarbonyl)-1H-benzimidazol-2-
389.4



yl]quinolin-2(1H)-one


793
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
474.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2,2-dimethylpropanamide


794
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
522.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-3-phenylpropanamide


795
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
538.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-(benzyloxy)acetamide


796
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
514.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-thien-2-ylacetamide


797
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
484.5



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-furamide


798
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-(2-pyrrolidin-1-
417.5



ylethyl)-1H-benzimidazole-5-carboxamide


799
ethyl (4-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
475.5



benzimidazol-5-yl]carbonyl}piperazin-1-yl)acetate


800
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
509.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-phenylurea


801
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
523.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-benzylurea


802
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
537.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(2-phenylethyl)urea


803
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
494.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}benzamide


804
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-piperidin-3-yl-
403.5



1H-benzimidazole-5-carboxamide


805
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3R)-1-
429.5



azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide


806
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[2-
447.6



(diethylamino)ethyl]-N-ethyl-1H-benzimidazole-5-carboxamide


807
4-amino-3-[6-(pyridin-4-yloxy)-1H-benzimidazol-2-yl]quinolin-
370.4



2(1H)-one


808
4-amino-5-fluoro-3-{6-[(4-methylpiperazin-1-yl)carbonyl]-1H-
421.4



benzimidazol-2-yl}quinolin-2(1H)-one


809
4-amino-5-fluoro-3-{6-[(4-isopropylpiperazin-1-yl)carbonyl]-
449.5



1H-benzimidazol-2-yl}quinolin-2(1H)-one


810
4-amino-3-{6-[(4-cyclohexylpiperazin-1-yl)carbonyl]-1H-
489.6



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


811
4-amino-6-(isobutylamino)-3-[6-(4-methylpiperazin-1-yl)-1H-
446.6



benzimidazol-2-yl]quinolin-2(1H)-one


812
2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-
488.6



N-(1-methylpyrrolidin-3-yl)-1H-benzimidazole-6-carboxamide


813
4-amino-6-[(2-methylbutyl)amino]-3-[6-(4-methylpiperazin-1-
460.6



yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


814
4-amino-6-[(cyclohexylmethyl)amino]-3-[6-(4-methylpiperazin-
486.6



1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


815
4-amino-3-(6-{[(3S)-3-methylpiperazin-1-yl]carbonyl}-1H-
403.5



benzimidazol-2-yl)quinolin-2(1H)-one


816
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3S)-1-
429.5



azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide


817
4-amino-3-[6-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol-
489.6



2-yl]-5-fluoroquinolin-2(1H)-one


818
2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-
435.5



N-(1-methylpyrrolidin-3-yl)-1H-benzimidazole-6-carboxamide


819
4-amino-3-(1H-benzimidazol-2-yl)-5-[(4-
415.5



methoxyphenyl)thio]quinolin-2(1H)-one


820
4-amino-3-(1H-benzimidazol-2-yl)-5-[(4-
447.5



methoxyphenyl)sulfonyl]quinolin-2(1H)-one


821
4-amino-3-(1H-benzimidazol-2-yl)-5-[(2-
415.5



methoxyphenyl)thio]quinolin-2(1H)-one


822
N-(4-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
426.4



benzimidazol-5-yl]oxy}phenyl)acetamide


823
4-amino-6-(benzylamino)-3-[6-(4-methylpiperazin-1-yl)-1H-
480.6



benzimidazol-2-yl]quinolin-2(1H)-one


824
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
578.7



{[(3-phenoxythien-2-yl)methyl]amino}quinolin-2(1H)-one


825
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
500.6



{[(3-methylthien-2-yl)methyl]amino}quinolin-2(1H)-one


826
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
487.6



[(1,3-thiazol-2-ylmethyl)amino]quinolin-2(1H)-one


827
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
482.6



[(pyrazin-2-ylmethyl)amino]quinolin-2(1H)-one


828
4-amino-3-(5-{2-[(dimethylamino)methyl]-1,4-oxazepan-4-yl}-
433.5



1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one


829
4-amino-3-(5-{2-[(dimethylamino)methyl]-1,4-oxazepan-4-yl}-
451.5



1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one


830
6-chloro-4-{[2-(dimethylamino)-2-pyridin-3-ylethyl]amino}-3-
545.1



(5-morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


831
6-amino-4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-
401.5



benzimidazol-2-yl)quinolin-2(1H)-one


832
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2-
417.3



(dimethylamino)ethyl]amino}quinolin-2(1H)-one


833
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(5-chloro-
443.3



1H-benzimidazol-2-yl)quinolin-2(1H)-one


834
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(piperidin-3-
443.3



ylmethyl)amino]quinolin-2(1H)-one


835
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(piperidin-4-
443.3



ylmethyl)amino]quinolin-2(1H)-one


836
4-[(4-aminocyclohexyl)amino]-6-chloro-3-(5-chloro-1H-
443.3



benzimidazol-2-yl)quinolin-2(1H)-one


837
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2-
403.3



(methylamino)ethyl]amino}quinolin-2(1H)-one


838
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-(pyrrolidin-3-
415.3



ylamino)quinolin-2(1H)-one


839
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(piperidin-2-
443.3



ylmethyl)amino]quinolin-2(1H)-one


840
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-chloro-
455.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


841
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-chloro-
455.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


842
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
473.6



{[(2S)-pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one


843
4-amino-6-{[(5-methylisoxazol-3-yl)methyl]amino}-3-[6-(4-
485.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


844
4-amino-3-(5-{(2S,5R)-2-[(dimethylamino)methyl]-5-
433.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)-



one


845
3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2-
418.8



(dimethylamino)ethyl]amino}-6,7-difluoroquinolin-2(1H)-one


846
4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(5-chloro-1H-
444.9



benzimidazol-2-yl)-6,7-difluoroquinolin-2(1H)-one


847
3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-3-
444.9



ylmethyl)amino]quinolin-2(1H)-one


848
3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-4-
444.9



ylmethyl)amino]quinolin-2(1H)-one


849
4-[(4-aminocyclohexyl)amino]-3-(5-chloro-1H-benzimidazol-2-
444.9



yl)-6,7-difluoroquinolin-2(1H)-one


850
3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-{[2-
404.8



(methylamino)ethyl]amino}quinolin-2(1H)-one


851
3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-(pyrrolidin-3-
416.8



ylamino)quinolin-2(1H)-one


852
3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-2-
444.9



ylmethyl)amino]quinolin-2(1H)-one


853
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H-
456.9



benzimidazol-2-yl)-6,7-difluoroquinolin-2(1H)-one


854
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H-
456.9



benzimidazol-2-yl)-6,7-difluoroquinolin-2(1H)-one


855
4-amino-3-(6-{[(3R)-3-methylpiperazin-1-yl]carbonyl}-1H-
403.5



benzimidazol-2-yl)quinolin-2(1H)-one


856
4-amino-3-(5-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-
390.4



benzimidazol-2-yl)quinolin-2(1H)-one


857
4-amino-3-(5-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1H-
433.5



benzimidazol-2-yl)quinolin-2(1H)-one


858
4-amino-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-
433.5



yl]-5-methoxyquinolin-2(1H)-one


859
4-amino-3-(5-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-
403.5



benzimidazol-2-yl)quinolin-2(1H)-one


860
4-amino-3-(5-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-
421.5



benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one


861
4-amino-3-(6-{(2R,5S)-2-[(dimethylamino)methyl]-5-
433.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)-



one


862
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
473.6



(piperidin-4-ylamino)quinolin-2(1H)-one


863
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
479.0



4-[(3S)-pyrrolidin-3-ylamino]quinolin-2(1H)-one


864
4-amino-3-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
407.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


865
4-amino-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
407.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


866
4-amino-3-[6-(2,6-dimethylmorpholin-4-yl)-1H-benzimidazol-2-
408.4



yl]-5-fluoroquinolin-2(1H)-one


867
4-amino-3-{6-[(3-aminopyrrolidin-1-yl)carbonyl]-1H-
389.4



benzimidazol-2-yl}quinolin-2(1H)-one


868
ethyl (3S,4R)-4-({[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-
505.5



1H-benzimidazol-6-yl]carbonyl}amino)-3-methoxypiperidine-1-



carboxylate


869
6-amino-3-(1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin-3-
361.4



ylamino]quinolin-2(1H)-one


870
4-amino-3-(6-{(2R,5S)-2-[(dimethylamino)methyl]-5-
451.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin-



2(1H)-one


871
N-{(3S)-1-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
417.5



benzimidazol-6-yl]pyrrolidin-3-yl}-N-methylacetamide


872
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-piperidin-4-yl-
403.5



1H-benzimidazole-6-carboxamide


873
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[2-(1-
431.5



methylpyrrolidin-2-yl)ethyl]-1H-benzimidazole-6-carboxamide


874
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
475.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-isopropylurea


875
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
537.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(3,5-dimethylphenyl)urea


876
N-allyl-N′-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-
473.6



benzimidazol-2-yl]-2-oxo-1,2-dihydroquinolin-6-yl}urea


877
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
489.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(tert-butyl)urea


878
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
555.7



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-[2-



(methylthio)phenyl]urea


879
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
502.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}heptanamide


880
4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
460.6



(neopentylamino)quinolin-2(1H)-one


881
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
578.5



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(3,4-dichlorophenyl)urea


882
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
577.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-[3-



(trifluoromethyl)phenyl]urea


883
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
531.7



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-heptylurea


884
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
553.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(2-ethoxyphenyl)urea


885
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
460.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-methylpropanamide


886
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
522.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-4-ethylbenzamide


887
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
519.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}-4-cyanobenzamide


888
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
500.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}cyclohexanecarboxamide


889
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
496.5



yl]-2-oxo-1,2-dihydroquinolin-6-yl}pyrazine-2-carboxamide


890
N-{4-amino-3-[6-(4-methylpiperazinyl)benzimidazol-2-yl]-2-
537.6



oxo(6-hydroquinolyl)}-2-[benzylamino]acetamide


891
4-amino-6-[methyl(1-methylpiperidin-4-yl)amino]-3-[6-(4-
501.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


892
4-amino-6-[({5-[(dimethylamino)methyl]-2-
527.6



furyl}methyl)amino]-3-[6-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]quinolin-2(1H)-one


893
4-amino-6-{[(2-ethyl-5-methyl-4H-imidazol-4-
512.6



yl)methyl]amino}-3-[6-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]quinolin-2(1H)-one


894
N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
460.6



yl]-2-oxo-1,2-dihydroquinolin-6-yl}butanamide


895
4-amino-3-(5-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-
457.5



yl]carbonyl}-1H-benzimidazol-2-yl)quinolin-2(1H)-one


896
4-amino-3-[5-({(2R,5R)-2-[(dimethylamino)methyl]-5-
461.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-



yl]quinolin-2(1H)-one


897
4-amino-3-[5-({(2S,5R)-2-[(dimethylamino)methyl]-5-
461.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-



yl]quinolin-2(1H)-one


898
4-amino-5-fluoro-3-(6-{[(3S)-3-methylpiperazin-1-yl]carbonyl}-
421.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


899
4-amino-5-fluoro-3-(6-{[(3R)-3-methylpiperazin-1-yl]carbonyl}-
421.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


900
4-amino-5-fluoro-3-(5-{[(2R)-2-(pyrrolidin-1-
475.5



ylmethyl)pyrrolidin-1-yl]carbonyl}-1H-benzimidazol-2-



yl)quinolin-2(1H)-one


901
4-amino-6-(dimethylamino)-3-[5-(4-methylpiperazin-1-yl)-1H-
418.5



benzimidazol-2-yl]quinolin-2(1H)-one


902
4-amino-6-(methylamino)-3-[5-(4-methylpiperazin-1-yl)-1H-
404.5



benzimidazol-2-yl]quinolin-2(1H)-one


903
4-amino-5-fluoro-3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-
411.4



benzimidazol-2-yl]quinolin-2(1H)-one


904
4-amino-3-[6-({(2R,5S)-2-[(dimethylamino)methyl]-5-
461.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-



yl]quinolin-2(1H)-one


905
4-amino-3-[6-({(2S,5S)-2-[(dimethylamino)methyl]-5-
461.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-



yl]quinolin-2(1H)-one


906
4-amino-3-{6-[(3,5-dimethylpiperazin-1-yl)carbonyl]-1H-
417.5



benzimidazol-2-yl}quinolin-2(1H)-one


907
4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
407.5



fluoroquinolin-2(1H)-one


908
4-amino-3-[6-({(2R,5S)-2-[(dimethylamino)methyl]-5-
479.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5-



fluoroquinolin-2(1H)-one


909
4-amino-3-[6-({(2S,5S)-2-[(dimethylamino)methyl]-5-
479.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5-



fluoroquinolin-2(1H)-one


910
4-amino-3-[5-({(2R,5R)-2-[(dimethylamino)methyl]-5-
479.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5-



fluoroquinolin-2(1H)-one


911
4-amino-3-[5-({(2S,5R)-2-[(dimethylamino)methyl]-5-
479.5



methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5-



fluoroquinolin-2(1H)-one


912
N-[3-({4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-
524.6



2-yl]-2-oxo-1,2-dihydroquinolin-5-yl}oxy)phenyl]acetamide


913
4-amino-3-{6-[(4-ethylpiperazin-1-yl)carbonyl]-1H-
417.5



benzimidazol-2-yl}quinolin-2(1H)-one


914
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N,N′-dimethyl-1H-
363.4



benzimidazole-6-carbohydrazide


915
2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-(tetrahydrofuran-
404.4



2-ylmethyl)-1H-benzimidazole-6-carboxamide


916
4-amino-5-[3-(dimethylamino)phenoxy]-3-[6-(4-
510.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


917
4-amino-5-(4-aminophenoxy)-3-[6-(4-methylpiperazin-1-yl)-1H-
482.6



benzimidazol-2-yl]quinolin-2(1H)-one


918
6-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-(6-fluoro-1H-
400.9



benzimidazol-2-yl)quinolin-2(1H)-one


919
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(6-fluoro-
426.9



1H-benzimidazol-2-yl)quinolin-2(1H)-one


920
6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-3-
426.9



ylmethyl)amino]quinolin-2(1H)-one


921
6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-4-
426.9



ylmethyl)amino]quinolin-2(1H)-one


922
4-[(4-aminocyclohexyl)amino]-6-chloro-3-(6-fluoro-1H-
426.9



benzimidazol-2-yl)quinolin-2(1H)-one


923
6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-{[2-
386.8



(methylamino)ethyl]amino}quinolin-2(1H)-one


924
6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin-
398.8



3-ylamino]quinolin-2(1H)-one


925
6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3R)-pyrrolidin-
398.8



3-ylamino]quinolin-2(1H)-one


926
6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-2-
426.9



ylmethyl)amino]quinolin-2(1H)-one


927
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-fluoro-
438.9



1H-benzimidazol-2-yl)quinolin-2(1H)-one


928
6-bromo-4-{[2-(dimethylamino)ethyl]amino}-3-(6-fluoro-1H-
445.3



benzimidazol-2-yl)quinolin-2(1H)-one


929
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-bromo-3-(6-fluoro-
471.3



1H-benzimidazol-2-yl)quinolin-2(1H)-one


930
6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-3-
471.3



ylmethyl)amino]quinolin-2(1H)-one


931
6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-4-
471.3



ylmethyl)amino]quinolin-2(1H)-one


932
4-[(4-aminocyclohexyl)amino]-6-bromo-3-(6-fluoro-1H-
471.3



benzimidazol-2-yl)quinolin-2(1H)-one


933
6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-{[2-
431.3



(methylamino)ethyl]amino}quinolin-2(1H)-one


934
6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin-
443.3



3-ylamino]quinolin-2(1H)-one


935
6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-2-
471.3



ylmethyl)amino]quinolin-2(1H)-one


936
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylaminol]-6-bromo-3-(6-fluoro-
483.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


937
6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3R)-pyrrolidin-
443.3



3-ylamino]quinolin-2(1H)-one


938
N-[4-({4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-
524.6



2-yl]-2-oxo-1,2-dihydroquinolin-5-yl}oxy)phenyl]acetamide


939
4-amino-3-{6-[(4-ethylpiperazin-1-yl)carbonyl]-1H-
435.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


940
ethyl (3S,4R)-4-({[2-(4-amino-5-fluoro-2-oxo-1,2-
523.5



dihydroquinolin-3-yl)-1H-benzimidazol-6-yl]carbonyl}amino)-3-



methoxypiperidine-1-carboxylate


941
2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3R)-1-
447.5



azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide


942
2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3S)-1-
447.5



azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide


943
4-amino-5-fluoro-3-{5-[(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
433.5



yl)carbonyl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one


944
4-amino-3-[5-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-5-
461.6



fluoroquinolin-2(1H)-one


945
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(7-
506.0



morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one


946
6-chloro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-4-
480.0



(piperidin-4-ylamino)quinolin-2(1H)-one


947
6-chloro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3S)-
466.0



pyrrolidin-3-ylamino]quinolin-2(1H)-one


948
4-amino-7-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
393.4



benzimidazol-2-yl]quinolin-2(1H)-one


949
4-amino-3-{6-[(2,6-dimethylpiperazin-1-yl)carbonyl]-1H-
417.5



benzimidazol-2-yl}quinolin-2(1H)-one


950
4-amino-3-(5-{(2S,5R)-2-[(dimethylamino)methyl]-5-
451.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin-



2(1H)-one


951
6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3S)-
466.0



pyrrolidin-3-ylamino]quinolin-2(1H)-one


952
4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5-
451.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin-



2(1H)-one


953
4-amino-3-(1H-benzimidazol-2-yl)-6-[methyl(1-methylpiperidin-
403.5



4-yl)amino]quinolin-2(1H)-one


954
4-amino-6-[isobutyl(methyl)amino]-3-[6-(4-methylpiperazin-1-
460.6



yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


955
4-amino-6-[(cyclohexylmethyl)(methyl)amino]-3-[6-(4-
500.7



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


956
4,6-diamino-3-(6,7-dimethyl-1H-benzimidazol-2-yl)quinolin-
320.4



2(1H)-one


957
4-amino-3-(6,7-dimethyl-1H-benzimidazol-2-yl)-6-
334.4



(methylamino)quinolin-2(1H)-one


958
4-amino-3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-
334.4



(methylamino)quinolin-2(1H)-one


959
4,6-diamino-3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one
292.3


960
4-amino-3-(6,7-dimethyl-1H-benzimidazol-2-yl)-6-
376.5



(isobutylamino)quinolin-2(1H)-one


961
4-amino-3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-
376.5



(isobutylamino)quinolin-2(1H)-one


962
N-(3-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
426.4



benzimidazol-6-yl]oxy}phenyl)acetamide


963
4-amino-3-[6-(3,4-dimethylpiperazin-1-yl)-1H-benzimidazol-2-
389.5



yl]quinolin-2(1H)-one


964
N-[3-({4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-
524.6



2-yl]-2-oxo-1,2-dihydroquinolin-6-yl}oxy)phenyl]acetamide


965
4-amino-3-(6-{(2R,5R)-2-[(dimethylamino)methyl]-5-
451.5



methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin-



2(1H)-one


966
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-bromo-3-(6-chloro-5-
505.8



fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one


967
6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-
505.8



[(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one


968
4-[(4-aminocyclohexyl)amino]-6-bromo-3-(6-chloro-5-fluoro-
505.8



1H-benzimidazol-2-yl)quinolin-2(1H)-one


969
6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-{[2-
465.7



(methylamino)ethyl]amino}quinolin-2(1H)-one


970
6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-
477.7



(pyrrolidin-3-ylamino)quinolin-2(1H)-one


971
6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-[(3R)-
477.7



pyrrolidin-3-ylamino]quinolin-2(1H)-one


972
6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-
505.8



[(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one


973
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-bromo-3-(6-chloro-
517.8



5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one


974
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-bromo-3-(6-chloro-
517.8



5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one


975
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-bromo-3-(6-fluoro-
483.4



1H-benzimidazol-2-yl)quinolin-2(1H)-one


976
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-fluoro-
438.9



1H-benzimidazol-2-yl)quinolin-2(1H)-one


977
4-amino-6-[bis(cyclohexylmethyl)amino]-3-(6,7-dimethyl-1H-
512.7



benzimidazol-2-yl)quinolin-2(1H)-one


978
4-amino-6-[bis(cyclohexylmethyl)amino]-3-(5,6-dimethyl-1H-
512.7



benzimidazol-2-yl)quinolin-2(1H)-one


979
4-amino-5-(methylamino)-3-[6-(4-methylpiperazin-1-yl)-1H-
404.5



benzimidazol-2-yl]quinolin-2(1H)-one


980
4-amino-6-[(cyclohexylmethyl)amino]-3-(6,7-dimethyl-1H-
416.5



benzimidazol-2-yl)quinolin-2(1H)-one


981
4-amino-6-[(cyclohexylmethyl)amino]-3-(5,6-dimethyl-1H-
416.5



benzimidazol-2-yl)quinolin-2(1H)-one


982
4-amino-6,7-difluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
411.4



benzimidazol-2-yl]quinolin-2(1H)-one


983
4-amino-5-fluoro-3-[6-(2-methylpiperazin-1-yl)-1H-
393.4



benzimidazol-2-yl]quinolin-2(1H)-one


984
4-amino-7-fluoro-3-{6-[(4-isopropylpiperazin-1-yl)carbonyl]-
449.5



1H-benzimidazol-2-yl}quinolin-2(1H)-one


985
4-amino-3-[6-(2,4-dimethylpiperazin-1-yl)-1H-benzimidazol-2-
407.5



yl]-5-fluoroquinolin-2(1H)-one


986
2-(4-amino-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-
449.5



N-(1-methylpiperidin-4-yl)-1H-benzimidazole-5-carboxamide


987
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin-
415.3



3-ylamino]quinolin-2(1H)-one


988
4-amino-7-fluoro-3-(5-{[(2R)-2-(pyrrolidin-1-
475.5



ylmethyl)pyrrolidin-1-yl]carbonyl}-1H-benzimidazol-2-



yl)quinolin-2(1H)-one


989
4-amino-3-{6-[4-(2-methoxyethyl)piperazin-1-yl]-1H-
419.5



benzimidazol-2-yl}quinolin-2(1H)-one


990
4-amino-3-[5-(methylamino)-1H-benzimidazol-2-yl]quinolin-
306.3



2(1H)-one


991
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
493.0



4-{[(3S)-1-methylpyrrolidin-3-yl]amino}quinolin-2(1H)-one


992
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-{[(3S)-1-
429.3



methylpyrrolidin-3-yl]amino}quinolin-2(1H)-one


993
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(3S)-1-methylpyrrolidin-
394.9



3-yl]amino}quinolin-2(1H)-one


994
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(1-methylpiperidin-4-
408.9



yl)amino]quinolin-2(1H)-one


995
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(1-
443.3



methylpiperidin-4-yl)amino]quinolin-2(1H)-one


996
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
507.1



4-[(1-methylpiperidin-4-yl)amino]quinolin-2(1H)-one


997
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
521.1



4-{[(1-methylpiperidin-2-yl)methyl]amino}quinolin-2(1H)-one


998
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-{5-
547.1



[methyl(1-methylpiperidin-4-yl)amino]-1H-benzimidazol-2-



yl}quinolin-2(1H)-one


999
6-chloro-3-{5-[methyl(1-methylpiperidin-4-yl)amino]-1H-
521.1



benzimidazol-2-yl}-4-(piperidin-4-ylamino)quinolin-2(1H)-one


1000
6-chloro-3-{5-[methyl(1-methylpiperidin-4-yl)amino]-1H-
507.1



benzimidazol-2-yl}-4-[(3S)-pyrrolidin-3-ylamino]quinolin-



2(1H)-one


1001
4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-{5-[methyl(1-
509.1



methylpiperidin-4-yl)amino]-1H-benzimidazol-2-yl}quinolin-



2(1H)-one


1002
4-amino-3-{6-[(3S)-3,4-dimethylpiperazin-1-yl]-1H-
389.5



benzimidazol-2-yl}quinolin-2(1H)-one


1003
4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2-
400.5



oxo-1,2-dihydroquinoline-6-carbonitrile


1004
4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2-
419.5



oxo-1,2-dihydroquinoline-6-carboxylic acid


1005
4-amino-5-fluoro-3-{5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-
419.5



2(1H)-yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one


1006
4-amino-3-{6-[(3S)-3,4-dimethylpiperazin-1-yl]-1H-
407.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1007
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-{6-[(3R)-
533.1



3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-



yl}quinolin-2(1H)-one


1008
6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
507.1



benzimidazol-2-yl}-4-(piperidin-4-ylamino)quinolin-2(1H)-one


1009
6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
493.0



benzimidazol-2-yl}-4-[(3S)-pyrrolidin-3-ylamino]quinolin-



2(1H)-one


1010
4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-{6-[(3R)-3-
495.0



(dimethylamino)pyrrolidin-1-yl]1H-benzimidazol-2-yl}quinolin-



2(1H)-one


1011
6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
507.1



benzimidazol-2-yl}-4-{[(3S)-1-methylpyrrolidin-3-



yl]amino}quinolin-2(1H)-one


1012
6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H-
521.1



benzimidazol-2-yl}-4-[(1-methylpiperidin-4-yl)amino]quinolin-



2(1H)-one


1013
4-amino-7-(methylamino)-3-[6-(4-methylpiperazin-1-yl)-1H-
404.5



benzimidazol-2-yl]quinolin-2(1H)-one


1014
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-morpholin-4-yl-2-
502.0



pyridin-3-ylethyl)amino]quinolin-2(1H)-one


1015
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[2-(dimethylamino)-2-
460.0



pyridin-3-ylethyl]amino}quinolin-2(1H)-one


1016
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-{3-
547.1



[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-benzimidazol-2-



yl)quinolin-2(1H)-one


1017
6-chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-
521.1



benzimidazol-2-yl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one


1018
6-chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-
507.1



benzimidazol-2-yl)-4-[(3S)-pyrrolidin-3-ylamino]quinolin-



2(1H)-one


1019
4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-(6-{3-
509.1



[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-benzimidazol-2-



yl)quinolin-2(1H)-one


1020
chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-
521.1



benzimidazol-2-yl)-4-{[(3S)-1-methylpyrrolidin-3-



yl]amino}quinolin-2(1H)-one


1021
6-chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H-
535.1



benzimidazol-2-yl)-4-[(1-methylpiperidin-4-yl)amino]quinolin-



2(1H)-one


1022
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(3S)-piperidin-3-
408.9



ylmethyl]amino}quinolin-2(1H)-one


1023
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(3R)-piperidin-3-
408.9



ylmethyl]amino}quinolin-2(1H)-one


1024
N-(3-{[4-amino-3-(1H-benzimidazol-2-yl)-2-oxo-1,2-
426.4



dihydroquinolin-5-yl]oxy}phenyl)acetamide


1025
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-{6-[3-
533.1



(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}quinolin-



2(1H)-one


1026
6-chloro-3-{6-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
507.1



benzimidazol-2-yl}-4-(piperidin-4-ylamino)quinolin-2(1H)-one


1027
4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-{6-[3-
495.0



(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}quinolin-



2(1H)-one


1028
6-chloro-3-{6-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
521.1



benzimidazol-2-yl}-4-[(1-methylpiperidin-4-yl)amino]quinolin-



2(1H)-one


1029
4-amino-7-[[2-(dimethylamino)ethyl](methyl)amino]-3-[6-(4-
475.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


1030
4-amino-5-fluoro-3-[6-(1,4-oxazepan-4-ylcarbonyl)-1H-
422.4



benzimidazol-2-yl]quinolin-2(1H)-one


1031
methyl 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
433.5



2-yl]-2-oxo-1,2-dihydroquinoline-6-carboxylate


1032
4-amino-N-benzyl-3-[5-(4-methylpiperazin-1-yl)-1H-
508.6



benzimidazol-2-yl]-2-oxo-1,2-dibydroquinoline-6-carboxamide


1033
4-amino-3-{6-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-1H-
474.6



benzimidazol-2-yl}quinolin-2(1H)-one


1034
4-amino-7-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-
421.5



benzimidazol-2-yl]quinolin-2(1H)-one


1035
4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-7-
407.5



fluoroquinolin-2(1H)-one


1036
4-amino-3-{6-[(2-aminoethyl)(methyl)amino]-1H-benzimidazol-
349.4



2-yl}quinolin-2(1H)-one


1037
4-amino-3-{6-[[(2-ethyl-4-methyl-1H-imidazol-5-
428.5



yl)methyl](methyl)amino]-1H-benzimidazol-2-yl}quinolin-



2(1H)-one


1038
4-amino-3-[6-(hydroxymethyl)-1H-benzimidazol-2-yl]quinolin-
307.3



2(1H)-one


1039
4-amino-3-(6-{methyl[(2R)-pyrrolidin-2-ylmethyl]amino}-1H-
389.5



benzimidazol-2-yl)quinolin-2(1H)-one


1040
4-amino-3-{6-[(1H-imidazol-2-ylmethyl)(methyl)amino]-1H-
386.4



benzimidazol-2-yl}quinolin-2(1H)-one


1041
4-amino-3-{6-[(2-furylmethyl)(methyl)amino]-1H-benzimidazol-
386.4



2-yl}quinolin-2(1H)-one


1042
4-amino-3-{6-[methyl(piperidin-4-ylmethyl)amino]-1H-
403.5



benzimidazol-2-yl}quinolin-2(1H)-one


1043
4-amino-3-{6-[methyl(piperidin-3-ylmethyl)amino]-1H-
403.5



benzimidazol-2-yl}quinolin-2(1H)-one


1044
4-amino-3-(6-{methyl[2-(methylamino)ethyl]amino}-1H-
363.4



benzimidazol-2-yl)quinolin-2(1H)-one


1045
6-acetyl-4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-
417.5



benzimidazol-2-yl]quinolin-2(1H)-one


1046
4-amino-5-[2-(methylamino)phenoxy]-3-[6-(4-methylpiperazin-
496.6



1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


1047
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2S)-piperidin-2-
408.9



ylmethyl]amino}quinolin-2(1H)-one


1048
4-amino-3-[6-(1,4-oxazepan-4-yl)-1H-benzimidazol-2-
376.4



yl]quinolin-2(1H)-one


1049
4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
407.5



fluoroquinolin-2(1H)-one


1050
6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(3R)-pyrrolidin-
415.3



3-ylamino]quinolin-2(1H)-one


1051
4-amino-6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
478.5



benzimidazol-2-yl]-7-morpholin-4-ylquinolin-2(1H)-one


1052
4-amino-6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
462.5



benzimidazol-2-yl]-7-pyrrolidin-1-ylquinolin-2(1H)-one


1053
4-amino-7-(dimethylamino)-6-fluoro-3-[5-(4-methylpiperazin-1-
436.5



yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


1054
4-amino-6-fluoro-7-(4-methylpiperazin-1-yl)-3-[5-(4-
491.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


1055
4-amino-6-fluoro-7-[(4-methoxybenzyl)amino]-3-[5-(4-
528.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


1056
4-amino-6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
499.6



benzimidazol-2-yl]-7-[(pyridin-4-ylmethyl)amino]quinolin-



2(1H)-one


1057
4-amino-7-[[2-(dimethylamino)ethyl](methyl)amino]-6-fluoro-3-
493.6



[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-



2(1H)-one


1058
4-amino-3-[6-(4-cyclopentylpiperazin-1-yl)-1H-benzimidazol-2-
447.5



yl]-5-fluoroquinolin-2(1H)-one


1059
4-amino-6-[1-(methylamino)ethyl]-3-[6-(4-methylpiperazin-1-
432.5



yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one


1060
4-amino-5-fluoro-3-[6-(1,4-oxazepan-4-yl)-1H-benzimidazol-2-
394.4



yl]quinolin-2(1H)-one


1061
4-amino-3-{6-[methyl(pyridin-3-ylmethyl)amino]-1H-
397.5



benzimidazol-2-yl}quinolin-2(1H)-one


1062
4-amino-3-{6-[({5-[(dimethylamino)methyl]-2-
443.5



furyl}methyl)(methyl)amino]-1H-benzimidazol-2-yl}quinolin-



2(1H)-one


1063
4-amino-3-[6-(4-oxopiperidin-1-yl)-1H-benzimidazol-2-
374.4



yl]quinolin-2(1H)-one


1064
4-amino-3-{6-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-1H-
458.6



benzimidazol-2-yl}quinolin-2(1H)-one


1065
4-amino-3-[6-(4-{[(4-benzylmorpholin-2-
564.7



yl)methyl]amino}piperidin-1-yl)-1H-benzimidazol-2-yl]quinolin-



2(1H)-one


1066
3-(1H-benzimidazol-2-yl)-6-bromo-4-{[2-
427.3



(dimethylamino)ethyl]amino}quinolin-2(1H)-one


1067
4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(1H-benzimidazol-2-
453.4



yl)-6-bromoquinolin-2(1H)-one


1068
3-(1H-benzimidazol-2-yl)-6-bromo-4-[(piperidin-4-
453.4



ylmethyl)amino]quinolin-2(1H)-one


1069
4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-6-
453.4



bromoquinolin-2(1H)-one


1070
3-(1H-benzimidazol-2-yl)-6-bromo-4-{[2-
413.3



(methylamino)ethyl]amino}quinolin-2(1H)-one


1071
3-(1H-benzimidazol-2-yl)-6-bromo-4-[(3S)-pyrrolidin-3-
425.3



ylamino]quinolin-2(1H)-one


1072
3-(1H-benzimidazol-2-yl)-6-bromo-4-[(3R)-pyrrolidin-3-
425.3



ylamino]quinolin-2(1H)-one


1073
3-(1H-benzimidazol-2-yl)-6-bromo-4-[(piperidin-2-
453.4



ylmethyl)amino]quinolin-2(1H)-one


1074
4-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-[5-(4-
527.6



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2-oxo-1,2-



dihydroquinoline-6-carboxamide


1075
4-amino-N-methyl-3-[5-(4-methylpiperazin-1-yl)-1H-
529.7



benzimidazol-2-yl]-N-(1-methylpiperidin-4-yl)-2-oxo-1,2-



dihydroquinoline-6-carboxamide


1076
4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2-
502.6



oxo-N-(tetrahydrofuran-2-ylmethyl)-1,2-dihydroquinoline-6-



carboxamide


1077
3-(1H-benzimidazol-2-yl)-6-chloro-4-[(3R)-pyrrolidin-3-
380.8



ylamino]quinolin-2(1H)-one


1078
3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2R)-piperidin-2-
408.9



ylmethyl]amino}quinolin-2(1H)-one


1079
4-amino-3-{6-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-
407.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1080
6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-{[2-
435.3



(dimethylamino)ethyl]amino}quinolin-2(1H)-one


1081
4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(6-chloro-5-
461.3



fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one


1082
6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-
461.3



[(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one


1083
4-[(4-aminocyclohexyl)amino]-6-chloro-3-(6-chloro-5-fluoro-
461.3



1H-benzimidazol-2-yl)quinolin-2(1H)-one


1084
6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-{[2-
421.3



(methylamino)ethyl]amino}quinolin-2(1H)-one


1085
6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-[(3S)-
433.3



pyrrolidin-3-ylamino]quinolin-2(1H)-one


1086
6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-[(3R)-
433.3



pyrrolidin-3-ylamino]quinolin-2(1H)-one


1087
6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-
461.3



[(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one


1088
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-chloro-
473.3



5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one


1089
4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-chloro-
473.3



5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one


1090
4-amino-6-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-
393.4



benzimidazol-2-yl]quinolin-2(1H)-one


1091
4-amino-3-(1H-benzimidazol-2-yl)-5-(methylamino)quinolin-
306.3



2(1H)-one


1092
4-amino-3-{6-[(2S)-2,4-dimethylpiperazin-1-yl]-1H-
407.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1093
4-amino-5-fluoro-3-{6-[(2S)-2-methylpiperazin-1-yl]-1H-
393.4



benzimidazol-2-yl}quinolin-2(1H)-one


1094
4-amino-3-{6-[(2S)-4-isopropyl-2-methylpiperazin-1-yl]-1H-
417.5



benzimidazol-2-yl}quinolin-2(1H)-one


1095
4-amino-5,7-difluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
411.4



benzimidazol-2-yl]quinolin-2(1H)-one


1096
3-(1H-benzimidazol-2-yl)-6-bromo-4-{[(2S)-piperidin-2-
453.4



ylmethyl]amino}quinolin-2(1H)-one


1097
3-(1H-benzimidazol-2-yl)-6-bromo-4-{[(2R)-piperidin-2-
453.4



ylmethyl]amino}quinolin-2(1H)-one


1098
4-amino-3-{6-[methyl(1,3-thiazol-2-ylmethyl)amino]-1H-
403.5



benzimidazol-2-yl}quinolin-2(1H)-one


1099
4-amino-3-{6-[(1-ethylpiperidin-4-yl)(methyl)amino]-1H-
417.5



benzimidazol-2-yl}quinolin-2(1H)-one


1100
4-amino-3-[6-(4-morpholin-4-ylpiperidin-1-yl)-1H-
445.5



benzimidazol-2-yl]quinolin-2(1H)-one


1101
4-amino-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-
432.5



yl]-5-(methylamino)quinolin-2(1H)-one


1102
4-amino-3-{6-[methyl(pyridin-2-ylmethyl)amino]-1H-
397.5



benzimidazol-2-yl}quinolin-2(1H)-one


1103
4-amino-3-{6-[(2S)-2,4-dimethylpiperazin-1-yl]-1H-
389.5



benzimidazol-2-yl}quinolin-2(1H)-one


1104
4-amino-3-{6-[(2S)-2-methylpiperazin-1-yl]-1H-benzimidazol-2-
375.4



yl}quinolin-2(1H)-one


1105
N-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
348.4



benzimidazol-6-yl]-N-methylacetamide


1106
4-amino-5-fluoro-3-{6-[(2S)-4-isopropyl-2-methylpiperazin-1-
435.5



yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one


1107
4-amino-3-{6-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-
389.5



benzimidazol-2-yl}quinolin-2(1H)-one


1108
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-
429.5



2-yl)-6-(dimethylamino)quinolin-2(1H)-one


1109
4-amino-3-{6-[(2S)-4-cyclobutyl-2-methylpiperazin-1-yl]-1H-
429.5



benzimidazol-2-yl}quinolin-2(1H)-one


1110
4-amino-5-fluoro-3-[6-(methylamino)-1H-benzimidazol-2-
324.3



yl]quinolin-2(1H)-one


1111
4-amino-3-(1H-benzimidazol-2-yl)-5-(dimethylamino)quinolin-
320.4



2(1H)-one


1112
4-amino-3-(1H-benzimidazol-2-yl)-5-{[2-
363.4



(dimethylamino)ethyl]amino}quinolin-2(1H)-one


1113
4-amino-5-fluoro-3-(5-piperazin-1-yl-1H-benzimidazol-2-
379.4



yl)quinolin-2(1H)-one


1114
4-amino-3-{5-[[2-(dimethylamino)ethyl](methyl)amino]-1H-
395.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1115
4-amino-5-fluoro-3-{5-[methyl(piperidin-3-ylmethyl)amino]-1H-
421.5



benzimidazol-2-yl}quinolin-2(1H)-one


1116
4-amino-3-(1H-benzimidazol-2-yl)-5-[[2-
377.5



(dimethylamino)ethyl](methyl)amino]quinolin-2(1H)-one


1117
4-amino-5-fluoro-3-{5-[(2R)-4-isopropyl-2-methylpiperazin-1-
435.5



yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one


1118
4-amino-3-{5-[(2S)-4-ethyl-2-methylpiperazin-1-yl]-1H-
421.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1119
4-amino-3-(5-{[(1-ethylpyrrolidin-2-yl)methyl]amino}-1H-
421.5



benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one


1120
4-amino-3-(5-{[2-(dimethylamino)-1-methylethyl]amino}-1H-
395.5



benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one


1121
4-amino-3-{5-[[2-(dimethylamino)-1-
409.5



methylethyl](methyl)amino]-1H-benzimidazol-2-yl}-5-



fluoroquinolin-2(1H)-one


1122
4-amino-3-(1H-benzimidazol-2-yl)-5-(1,2-
335.4



dimethylhydrazino)quinolin-2(1H)-one


1123
4-amino-5-fluoro-3-{6-[4-(2-methoxyethyl)piperazin-1-yl]-1H-
437.5



benzimidazol-2-yl}quinolin-2(1H)-one


1124
4-amino-5-fluoro-3-{6-[methyl(1-methylpiperidin-4-yl)amino]-
421.5



1H-benzimidazol-2-yl}quinolin-2(1H)-one


1125
4-amino-5-fluoro-3-(6-{[3-(4-methylpiperazin-1-
450.5



yl)propyl]amino}-1H-benzimidazol-2-yl)quinolin-2(1H)-one


1126
4-amino-5-fluoro-3-(6-{methyl[3-(4-methylpiperazin-1-
464.6



yl)propyl]amino}-1H-benzimidazol-2-yl)quinolin-2(1H)-one


1127
N-[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
366.4



benzimidazol-6-yl]-N-methylacetamide


1128
4-amino-6-fluoro-3-(5-{[(2R)-2-(pyrrolidin-1-
475.5



ylmethyl)pyrrolidin-1-yl]carbonyl}-1H-benzimidazol-2-



yl)quinolin-2(1H)-one


1129
4-amino-3-(1H-benzimidazol-2-yl)-5-(ethylamino)quinolin-
320.4



2(1H)-one


1130
4-amino-3-{5-[(2R)-2,4-dimethylpiperazin-1-yl]-1H-
407.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1131
4-amino-5-fluoro-3-{5-[(2R)-2-methylpiperazin-1-yl]-1H-
393.4



benzimidazol-2-yl}quinolin-2(1H)-one


1132
4-amino-3-{5-[(2R)-4-cyclobutyl-2-methylpiperazin-1-yl]-1H-
447.5



benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one


1133
4-amino-5-(dimethylamino)-3-[6-(4-isopropylpiperazin-1-yl)-
446.6



1H-benzimidazol-2-yl]quinolin-2(1H)-one


1134
4-amino-5-{[2-(dimethylamino)ethyl]amino}-3-[6-(4-
489.6



isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-



one


1135
4-amino-5-[[2-(dimethylamino)ethyl](methyl)amino]-3-[6-(4-
503.7



isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-



one


1136
4-amino-5-(ethylamino)-3-[6-(4-isopropylpiperazin-1-yl)-1H-
446.6



benzimidazol-2-yl]quinolin-2(1H)-one


1137
N-[2-(4-amino-2-oxo(3-hydroquinolyl))benzimidazol-6-yl]-2-
391.4



(dimethylamino)-N-methylacetamide


1138
4-amino-5-fluoro-3-[6-(9-isopropyl-1-oxa-4,9-
491.6



diazaspiro[5.5]undec-4-yl)-1H-benzimidazol-2-yl]quinolin-



2(1H)-one


1139
4-amino-7-fluoro-3-[6-fluoro-5-(4-methylpiperazin-1-yl)-1H-
411.4



benzimidazol-2-yl]quinolin-2(1H)-one


1140
4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5-
469.5



methylmorpholin-4-yl}-6-fluoro-1H-benzimidazol-2-yl)-5-



fluoroquinolin-2(1H)-one


1141
4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5-
451.5



methylmorpholin-4-yl}-6-fluoro-1H-benzimidazol-2-yl)quinolin-



2(1H)-one


1142
4-amino-5-methyl-3-[5-(4-methylpiperazin-1-yl)-1H-
389.5



benzimidazol-2-yl]quinolin-2(1H)-one


1143
4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
443.4



(trifluoromethyl)quinolin-2(1H)-one


1144
4-amino-5-fluoro-3-[6-(2-isopropyl-5-oxa-2,8-
463.5



diazaspiro[3.5]non-8-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-



one


1145
4-amino-6-fluoro-3-[5-(4-isopropylpiperazin-1-yl)-1H-
421.5



benzimidazol-2-yl]quinolin-2(1H)-one


1146
N-[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
464.5



benzimidazol-6-yl]-N-methyl-2-(4-methylpiperazin-1-



yl)acetamide


1147
N-[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-
451.5



benzimidazol-6-yl]-N-methyl-2-morpholin-4-ylacetamide


1148
N-[2-(4-amino-5-fluoro-2-oxo(3-hydroquinolyl))benzimidazol-6-
492.6



yl]-N-methyl-2-morpholin-4-ylacetamide


1149
4-amino-5-fluoro-3-(6-methyl-1H-benzimidazol-2-yl)quinolin-
309.3



2(1H)-one


1150
4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
403.5



methylquinolin-2(1H)-one


1151
4-amino-3-{6-[(4-methylpiperazin-1-yl)methyl]-1H-
389.5



benzimidazol-2-yl}quinolin-2(1H)-one


1152
4-amino-3-[6-(1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-5-
393.4



fluoroquinolin-2(1H)-one


1153
4-amino-5-fluoro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
407.5



benzimidazol-2-yl]quinolin-2(1H)-one


1154
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-amino-5-
421.4



fluoroquinolin-2(1H)-one


1155
4-amino-3-[6-(4-ethyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-
421.5



yl]-5-fluoroquinolin-2(1H)-one


1156
4-amino-5-fluoro-3-[6-(4-isopropyl-1,4-diazepan-1-yl)-1H-
435.5



benzimidazol-2-yl]quinolin-2(1H)-one









In yet another embodiment, the compound of Structure I is a compound of Structure II, where Structure II has the following formula:




wherein,

    A is a group having one of the following Structures:






wherein,

    Ra is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms.


In some embodiments, where the compound of Structure I is a compound of Structure II, Ra is a methyl group, and the compound of Structure II is a compound of Structure IIA




In some specific embodiments, the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
In some embodiments, where the compound of Structure I is a compound of Structure II, Ra is a H, and the compound of Structure II is a compound of Structure IIB




In some embodiments, where the compound of Structure I is a compound of Structure II, Ra is a methyl group, and the compound of Structure II is a compound of Structure IIC




The compounds of any of the embodiments may be used to prepare medicaments or pharmaceutical formulations for use in any of the methods of the invention.
Pharmaceutical formulations for use with the invention may include any of the compounds, tautomers, or salts of any of the embodiments described above in combination with a pharmaceutically acceptable carrier such as those described herein.
The instant invention also provides for compositions which may be prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts tautomers thereof, or mixtures thereof with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat or ameliorate disorders related to metastacized tumors. The compositions of the inventions may be used to create formulations for use in any of the methods of the invention. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by nasal administration, by rectal administration, subcutaneous injection, intravenous injection, intramuscular injections, or intraperitoneal injection. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.
For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, pharmaceutically acceptable salts, tautomers, or mixtures thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
As noted above, suspensions may include oils. Such oil include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
For nasal administration, the pharmaceutical formulations and medicaments may be a spray or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference in its entirety for all purposes as if fully set forth herein.
The formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.
The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
A therapeutically effective dose may vary depending upon the route of administration and dosage form. The preferred compound or compounds of the instant invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
Pharmaceutical formulations and medicaments according to the invention include the compound of Structure I or the tautomers, salts, or mixtures thereof in combination with a pharmaceutically acceptable carrier. Thus, the compounds of the invention may be used to prepare medicaments and pharmaceutical formulations. Such medicaments and pharmaceutical formulations may be used in any of the methods of treatment described herein.
The compounds and formulations of the present invention are particularly suitable for use in combination therapy. Kinase inhibitors for use as anticancer agents in conjunction with the methods or compositions of the present invention include inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as small molecule quinazolines, for example gefitinib (U.S. Pat. No. 5,457,105, U.S. Pat. No. 5,616,582, and U.S. Pat. No. 5,770,599), ZD-6474 (WO 01/32651), erlotinib (Tarceva®, U.S. Pat. No. 5,747,498 and WO 96/30347), and lapatinib (U.S. Pat. No. 6,727,256 and WO 02/02552). Kinase inhibitors for use as anticancer agents in conjunction with the methods of compositions of the present invention also include inibitors of Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitor such as, but not limited to, SU-11248 (WO 01/60814), SU 5416 (U.S. Pat. No. 5,883,113 and WO 99/61422), SU 6668 (U.S. Pat. No. 5,883,113 and WO 99/61422), CHIR-258 (U.S. Pat. No. 6,605,617 and U.S. Pat. No. 6,774,237), vatalanib or PTK-787 (U.S. Pat. No. 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WO-09606116), fenretinide (retinoic acid p-hydroxyphenylamine) (U.S. Pat. No. 4,323,581), IM-862 (WO 02/62826), bevacizumab or Avastin® (WO 94/10202), KRN-951, 3-[5-(methylsulfonylpiperadine methyl)-indolyl]-quinolone, AG-13736 and AG-13925, pyrrolo[2,1-f][1,2,4]triazines, ZK-304709, Veglin®, VMDA-3601, EG-004, CEP-701 (U.S. Pat. No. 5,621,100), and Cand5 (WO 04/09769).
The compounds of the invention may be used to treat a variety of subjects. Suitable subjects include animals such as mammals and humans. Suitable mammals include, but are not limited to, primates such as, but not limited to lemurs, apes, and monkeys; rodents such as rats, mice, and guinea pigs; rabbits and hares; cows; horses; pigs; goats; sheep; marsupials; and carnivores such as felines, canines, and ursines. In some embodiments, the subject or patient is a human. In other embodiments, the subject or patient is a rodent such as a mouse or a rat. In some embodiments, the subject or patient is an animal other than a human and in some such embodiments, the subject or patient is a mammal other than a human.
Purification and Characterization of Compounds
Compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module (Milford, Mass.). The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm from Alltech (Deerfield, Ill.). A gradient elution was used, typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburg, Pa.). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 5-95% acetonitrile in water with 0.05% TFA; Flow rate 0.8 mL/minute; Molecular weight range 150-850; Cone Voltage 20 V; Column temperature 40° C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 1-95% acetonitrile in water with 0.05% TFA; Flow rate 0.4 mL/minute; Molecular weight range 150-850; Cone Voltage 50 V; Column temperature 30° C.). All masses are reported as those of the protonated parent ions.
GCMS analysis was performed on a Hewlet Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; Injector volume: 1 μL; Initial column temperature: 50° C.; Final column temperature: 250° C.; Ramp time: 20 minutes; Gas flow rate: 1 mL/minute; Column: 5% Phenyl Methyl Siloxane, Model #HP 190915-443, Dimensions: 30.0 m×25 μm×0.25 μm).
Preparative separations were carried out using either a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by HPLC using a C-18 reversed phase column. Typical solvents employed for the Flash 40 Biotage system were dichloromethane, methanol, ethyl acetate, hexane and triethyl amine. Typical solvents employed for the reverse phase HPLC were varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
Synthesis of 4-Amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one




A. Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitroaniline
Procedure A




5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N2. The flask was placed in an oil bath at 100° C. and heated until the 5-chloro-2-nitroaniline was completely reacted (typically overnight) as determined by HPLC. After HPLC confirmed the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) into 2500 mL of room temperature water with mechanical stirring. The resulting mixture was stirred until it reached room temperature and then it was filtered. The yellow solid thus obtained was added to 1000 mL of water and stirred for 30 minutes. The resulting mixture was filtered, and the resulting solid was washed with TBME (500 mL, 2×) and then was dried under vacuum for one hour using a rubber dam. The resulting solid was transferred to a drying tray and dried in a vacuum oven at 50° C. to a constant weight to yield 670 g (97.8%) of the title compound as a yellow powder.
Procedure B
5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2. 1-Methylpiperazine (758.1 g, 840 mL, 7.57 mol) and 200 proof ethanol (508 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97° C. (+/−5° C.) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 20° C. to 25° C. with stirring, and the reaction was stirred for 2 to 3 hours. Seed crystals (0.20 g, 0.85 mmol) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline were added to the reaction mixture unless precipitation had already occurred. Water (2,450 mL) was added to the stirred reaction mixture over a period of about one hour while the internal temperature was maintained at a temperature ranging from about 20° C. to 30° C. After the addition of water was complete, the resulting mixture was stirred for about one hour at a temperature of 20° C. to 30° C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (3×2.56 L). The golden yellow solid product was dried to a constant weight of 416 g (98.6% yield) under vacuum at about 50° C. in a vacuum oven.
Procedure C
5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2. 1-Methylpiperazine (977 g, 1.08 L, 9.75 mol) and 100% ethanol (650 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97° C. (+/−5° C.) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 80° C. with stirring, and water (3.15 L) was added to the mixture via an addition funnel over the period of 1 hour while the internal temperature was maintained at 82° C. (+/−3° C.). After water addition was complete, heating was discontinued and the reaction mixture was allowed to cool over a period of no less than 4 hours to an internal temperature of 20-25° C. The reaction mixture was then stirred for an additional hour at an internal temperature of 20-30° C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (1×1 L), 50% ethanol (1×1 L), and 95% ethanol (1×1 L). The golden yellow solid product was placed in a drying pan and dried to a constant weight of 546 g (99% yield) under vacuum at about 50° C. in a vacuum oven.
B. Synthesis of [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester
Procedure A




A 5000 mL, 4-neck flask was fitted with a stirrer, thermometer, condenser, and gas inlet/outlet. The equipped flask was charged with 265.7 g (1.12 mol. 1.0 eq) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2125 mL of 200 proof EtOH. The resulting solution was purged with N2 for 15 minutes. Next, 20.0 g of 5% Pd/C (50% H2O w/w) was added. The reaction was vigorously stirred at 40-50° C. (internal temperature) while H2 was bubbled through the mixture. The reaction was monitored hourly for the disappearance of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline by HPLC. The typical reaction time was 6 hours.
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Procedure B
A 5000 mL, 4-neck jacketed flask was fitted with a mechanical stirrer, condenser, temperature probe, gas inlet, and oil bubbler. The equipped flask was charged with 300 g (1.27 mol) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2400 mL of 200 proof EtOH (the reaction may be and has been conducted with 95% ethanol and it is not necessary to use 200 proof ethanol for this reaction). The resulting solution was stirred and purged with N2 for 15 minutes. Next, 22.7 g of 5% Pd/C (50% H2O w/w) was added to the reaction flask. The reaction vessel was purged with N2 for 15 minutes. After purging with N2, the reaction vessel was purged with H2 by maintaining a slow, but constant flow of H2 through the flask. The reaction was stirred at 45-55° C. (internal temperature) while H2 was bubbled through the mixture until the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline was completely consumed as determined by HPLC. The typical reaction time was 6 hours.
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. The diamine intermediate is air sensitive so care was taken to avoid exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added to the reaction mixture over a period of about 30 minutes. The reaction was stirred at 45-55° C. (internal temperature) under N2 until the diamine was completely consumed as determined by HPLC. The typical reaction time was about 2 hours. After the reaction was complete, the reaction was filtered while warm through a pad of Celite. The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL). The filtrates were combined in a 5000 mL flask, and about 3300 mL of ethanol was removed under vacuum producing an orange oil. Water (530 mL) and then 1M HCL (350 mL) were added to the resulting oil, and the resulting mixture was stirred. The resulting solution was vigorously stirred while 30% NaOH (200 mL) was added over a period of about 20 minutes maintaining the internal temperature at about 25-30° C. while the pH was brought to between 9 and 10. The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C. The resulting mixture was filtered, and the filter cake was washed with H2O (3×300 mL). The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an alternative work up procedure, the filtrates were combined and the ethanol was removed under vacuum until at least about 90% had been removed. Water at a neutral pH was then added to the resulting oil, and the solution was cooled to about 0° C. An aqueous 20% NaOH solution was then added slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The resulting mixture was then filtered and dried as described above. The alternative work up procedure provided the light tan to light yellow product in yields as high as 97%.
Method for Reducing Water Content of [6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester
[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (120.7 grams) that had been previously worked up and dried to a water content of about 8-9% H2O was placed in a 2000 mL round bottom flask and dissolved in absolute ethanol (500 mL). The amber solution was concentrated to a thick oil using a rotary evaporator with heating until all solvent was removed. The procedure was repeated two more times. The thick oil thus obtained was left in the flask and placed in a vacuum oven heated at 50° C. overnight. Karl Fisher analysis results indicated a water content of 5.25%. The lowered water content obtained by this method provided increased yields in the procedure of the following Example. Other solvents such as toluene and THF may be used in place of the ethanol for this drying process.
C. Synthesis of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one
Procedure A




[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40° C. When all the solids had dissolved and the solution temperature had reached 40° C., solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62° C. After a period of 60 minutes, the internal temperature decreased back to 40° C., and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring it into H2O (6000 mL) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 mL 2×). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.
Procedure B
A 5000 mL 4-neck jacketed flask was equipped with a distillation apparatus, a temperature probe, a N2 gas inlet, an addition funnel, and a mechanical stirrer. [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (173.0 g, 570 mmol) was charged into the reactor, and the reactor was purged with N2 for 15 minutes. Dry THF (2600 mL) was then charged into the flask with stirring. After all the solid had dissolved, solvent was removed by distillation (vacuum or atmospheric (the higher temperature helps to remove the water) using heat as necessary. After 1000 mL of solvent had been removed, distillation was stopped and the reaction was purged with N2. 1000 mL of dry THF was then added to the reaction vessel, and when all solid was dissolved, distillation (vacuum or atmospheric) was again conducted until another 1000 mL of solvent had been removed. This process of adding dry THF and solvent removal was repeated at least 4 times (on the 4th distillation, 60% of the solvent is removed instead of just 40% as in the first 3 distillations) after which a 1 mL sample was removed for Karl Fischer analysis to determine water content. If the analysis showed that the sample contained less than 0.20% water, then reaction was continued as described in the next paragraph. However, if the analysis showed more than 0.20% water, then the drying process described above was continued until a water content of less than 0.20% was achieved.
After a water content of less than or about 0.20% was achieved using the procedure described in the previous paragraph, the distillation apparatus was replaced with a reflux condenser, and the reaction was charged with 2-amino-6-fluoro-benzonitrile (66.2 g, 470 mmol) (in some procedures 0.95 equivalents is used). The reaction was then heated to an internal temperature of 38-42° C. When the internal temperature had reached 38-42° C., KHMDS solution (1313 g, 1.32 mol, 20% KHMDS in THF) was added to the reaction via the additional funnel over a period of 5 minutes maintaining the internal temperature at about 38-50° C. during the addition. When addition of the potassium base was complete, the reaction was stirred for 3.5 to 4.5 hours (in some examples it was stirred for 30 to 60 minutes and the reaction may be complete within that time) while maintaining the internal temperature at from 38-42° C. A sample of the reaction was then removed and analyzed by HPLC. If the reaction was not complete, additional KHMDS solution was added to the flask over a period of 5 minutes and the reaction was stirred at 38-42° C. for 45-60 minutes (the amount of KHMDS solution added was determined by the following: If the IPC ratio is <3.50, then 125 mL was added; if 10.0≧IPC ratio≧3.50, then 56 mL was added; if 20.0≧IPC ratio≧10, then 30 mL was added. The IPC ratio is equal to the area corresponding to 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one) divided by the area corresponding to the uncyclized intermediate). Once the reaction was complete (IPC ratio>20), the reactor was cooled to an internal temperature of 25-30° C., and water (350 mL) was charged into the reactor over a period of 15 minutes while maintaining the internal temperature at 25-35° C. (in one alternative, the reaction is conducted at 40° C. and water is added within 5 minutes. The quicker quench reduces the amount of impurity that forms over time). The reflux condenser was then replaced with a distillation apparatus and solvent was removed by distillation (vacuum or atmospheric) using heat as required. After 1500 mL of solvent had been removed, distillation was discontinued and the reaction was purged with N2. Water (1660 mL) was then added to the reaction flask while maintaining the internal temperature at 20-30° C. The reaction mixture was then stirred at 20-30° C. for 30 minutes before cooling it to an internal temperature of 5-10° C. and then stirring for 1 hour. The resulting suspension was filtered, and the flask and filter cake were washed with water (3×650 mL). The solid thus obtained was dried to a constant weight under vacuum at 50° C. in a vacuum oven to provide 103.9 g (42.6% yield) of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one as a yellow powder.




[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (608 g, 2.01 mol) (dried) and 2-amino-6-fluoro-benzonitrile (274 g, 2.01 mol) were charged into a 4-neck 12 L flask seated on a heating mantle and fitted with a condenser, mechanical stirrer, gas inlet, and temperature probe. The reaction vessel was purged with N2, and toluene (7.7 L) was charged into the reaction mixture while it was stirred. The reaction vessel was again purged with N2 and maintained under N2. The internal temperature of the mixture was raised until a temperature of 63° C. (+/−3° C.) was achieved. The internal temperature of the mixture was maintained at 63° C. (+/−3° C.) while approximately 2.6 L of toluene was distilled from the flask under reduced pressure (380+/−10 torr, distilling head t=40° C. (+/−10° C.) (Karl Fischer analysis was used to check the water content in the mixture. If the water content was greater than 0.03%, then another 2.6 L of toluene was added and distillation was repeated. This process was repeated until a water content of less than 0.03% was achieved). After a water content of less than 0.03% was reached, heating was discontinued, and the reaction was cooled under N2 to an internal temperature of 17-19° C. Potassium t-butoxide in THF (20% in THF; 3.39 kg, 6.04 moles potassium t-butoxide) was then added to the reaction under N2 at a rate such that the internal temperature of the reaction was kept below 20° C. After addition of the potassium t-butoxide was complete, the reaction was stirred at an internal temperature of less than 20° C. for 30 minutes. The temperature was then raised to 25° C., and the reaction was stirred for at least 1 hour. The temperature was then raised to 30° C., and the reaction was stirred for at least 30 minutes. The reaction was then monitored for completion using HPLC to check for consumption of the starting materials (typically in 2-3 hours, both starting materials were consumed (less than 0.5% by area % HPLC)). If the reaction was not complete after 2 hours, another 0.05 equivalents of potassium t-butoxide was added at a time, and the process was completed until HPLC showed that the reaction was complete. After the reaction was complete, 650 mL of water was added to the stirred reaction mixture. The reaction was then warmed to an internal temperature of 50° C. and the THF was distilled away (about 3 L by volume) under reduced pressure from the reaction mixture. Water (2.6 L) was then added dropwise to the reaction mixture using an addition funnel. The mixture was then cooled to room temperature and stirred for at least 1 hour. The mixture was then filtered, and the filter cake was washed with water (1.2 L), with 70% ethanol (1.2 L), and with 95% ethanol (1.2 L). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. until a constant weight was obtained providing 674 g (85.4%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.
Purification of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one
A 3000 mL 4-neck flask equipped with a condenser, temperature probe, N2 gas inlet, and mechanical stirrer was placed in a heating mantle. The flask was then charged with 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (101.0 g, 0.26 mol), and the yellow solid was suspended in 95% ethanol (1000 mL) and stirred. In some cases an 8:1 solvent ratio is used. The suspension was then heated to a gentle reflux (temperature of about 76° C.) with stirring over a period of about 1 hour. The reaction was then stirred for 45-75 minutes while refluxed. At this point, the heat was removed from the flask and the suspension was allowed to cool to a temperature of 25-30° C. The suspension was then filtered, and the filter pad was washed with water (2×500 mL). The yellow solid was then placed in a drying tray and dried in a vacuum oven at 50° C. until a constant weight was obtained (typically 16 hours) to obtain 97.2 g (96.2%) of the purified product as a yellow powder.
D. Preparation of Lactic Acid Salt of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one




A 3000 mL 4-necked jacketed flask was fitted with a condenser, a temperature probe, a N2 gas inlet, and a mechanical stirrer. The reaction vessel was purged with N2 for at least 15 minutes and then charged with 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (484 g, 1.23 mol). A solution of D,L-Lactic acid (243.3 g, 1.72 mol of monomer-see the following paragraph), water (339 mL), and ethanol (1211 mL) was prepared and then charged to the reaction flask. Stirring was initiated at a medium rate, and the reaction was heated to an internal temperature of 68-72° C. The internal temperature of the reaction was maintained at 68-72° C. for 15-45 minutes and then heating was discontinued. The resulting mixture was filtered through a 10-20 micron frit collecting the filtrate in a 12 L flask. The 12 L flask was equipped with an internal temperature probe, a reflux condenser, an addition funnel, a gas inlet an outlet, and an overhead stirrer. The filtrate was then stirred at a medium rate and heated to reflux (internal temperature of about 78° C.). While maintaining a gentle reflux, ethanol (3,596 mL) was charged to the flask over a period of about 20 minutes. The reaction flask was then cooled to an internal temperature ranging from about 64-70° C. within 15-25 minutes and this temperature was maintained for a period of about 30 minutes. The reactor was inspected for crystals. If no crystals were present, then crystals of the lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (484 mg, 0.1 mole %) were added to the flask, and the reaction was stirred at 64-70° C. for 30 minutes before again inspecting the flask for crystals. Once crystals were present, stirring was reduced to a low rate and the reaction was stirred at 64-70° C. for an additional 90 minutes. The reaction was then cooled to about 0° C. over a period of about 2 hours, and the resulting mixture was filtered through a 25-50 micron fritted filter. The reactor was washed with ethanol (484 mL) and stirred until the internal temperature was about 0° C. The cold ethanol was used to wash the filter cake, and this procedure was repeated 2 more times. The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven yielding 510.7 g (85.7%) of the crystalline yellow lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one. A rubber dam or inert conditions were typically used during the filtration process. While the dry solid did not appear to be very hygroscopic, the wet filter cake tends to pick up water and become sticky. Precautions were taken to avoid prolonged exposure of the wet filter cake to the atmosphere.
Commercial lactic acid generally contains about 8-12% w/w water, and contains dimers and trimers in addition to the monomeric lactic acid. The mole ratio of lactic acid dimer to monomer is generally about 1.0:4.7. Commercial grade lactic acid may be used in the process described in the preceding paragraph as the monolactate salt preferentially precipitates from the reaction mixture.
Identification of Metabolites
Two metabolites of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (Compound 1) have been identified and characterized in pooled rat plasma from a 2 week toxicology study as described in the references incorporated herein. The two identified metabolites were the piperazine N-oxide compound (Compound 2) and the N-demethylated compound (Compound 3) shown below.




IC50s of Compounds 1-3

The kinase activity of a number of protein tyrosine kinases was measured using the procedures described in the various references incorporated herein. Some of these are shown in the following Table.
Table. IC50s of Compounds 1-3













IC50 (μM)














VEGFR
VEGFR






Compound
flt
flk1
bFGFR
PDGFR
Flt3
c-kit





Compound 1
0.010
0.013
0.008
0.027
0.0001
0.0015


Compound 2
0.004
0.009
0.005
0.010
0.0004
0.0002


Compound 3
0.019
0.012
0.019
0.037
0.0001
0.0002









Synthesis of 4-Amino-5-fluoro-3-[6-(4-methyl-4-oxidopiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 2) and 4-Amino-5-fluoro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one (Compound 3)
To confirm the structures of the identified metabolites of Compound 1, the metabolites were independently synthesized.
Compound 2, the N-oxide metabolite of Compound 1, was synthesized as shown in the scheme below. Compound 1 was heated in a mixture of ethanol, dimethylacetamide and hydrogen peroxide. Upon completion of the reaction, Compound 2 was isolated by filtration and washed with ethanol. If necessary, the product could be further purified by column chromatography.




Compound 3, the N-desmethyl metabolite of Compound 1, was synthesized as shown in the scheme below. 5-Chloro-2-nitroaniline was treated with piperazine to yield 4 which was subsequently protected with a butyloxycarbonyl (Boc) group to yield 5. Reduction of the nitro group followed by condensation with 3-ethoxy-3-iminopropionic acid ethyl ester gave 6. Condensation of 6 with 6-fluoroanthranilonitrile using potassium hexamethyldisilazide as the base yielded 7. Crude 7 was treated with aqueous HCl to yield the desired metabolite as a yellow/brown solid after purification.




To identify plasma biomarkers of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one treatment, the 4T 1 spontaneously metastatic mouse breast tumor model was used, and circulating serum markers were analyzed by ELISA.
4T1 breast tumor cells were grown as subcutaneous tumors in BALB/C mice, and treatment (10, 30, 60, 100, and 150 mg/kg) with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1) were initiated when tumors were approximately 150 mm3. Mice were dosed orally, daily for 18 days.
The serum was collected from individual animals after 18 days, and the levels of circulating cell adhesion molecules, soluble ICAM, VCAM, and E-selectin, were measured by ELISA assay.
FIG. 1 is a graph showing the effects of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one in the 4T1 murine breast tumor model. The growth of subcutaneous tumors was inhibited (40-80% compared to control), liver metastases were completely inhibited, and lung metastases were inhibited by 60-97% after 18 days of dosing. Various data regarding the incidence of metastases is shown in FIG. 1 and included in the following Table

















% Inhi-





# of Liver
bition
P values


Liver Metastases
Incidence of
Metastases
vs.
vs.


Treatment Group (n)
Metastases
Mean +/− SD
Vehicle
Vehicle







Vehicle (water) (9)
8/9
17.9 +/− 15.4
n/a
n/a


 10 mpk (8)
7/8
22.0 +/− 32.3
0
0.810


 30 mpk (10)
 6/10
3.1 +/− 3.5
83
0.014


 60 mpk (10)
 5/10
0.7 +/− 0.9
94
0.002


100 mpk (10)
 1/10
 4.1 +/− 13.0
77
0.010


150 mpk (9)
0/9
0.0 +/− 0.0
100
0.002









Wells of a Nunc Maxisorb “U” bottom microtiter plate (#449824) were coated with monoclonal capture antibody, rat anti-mouse VCAM-1 (R&D Systems #BCA12), at 5 μg/mL in phosphate buffered saline (PBS), 50 μL/well, and incubated at 37° C. for 1 hour. The plates were washed 3 times with wash buffer [PBS containing 0.1% Tween 20 and 1% goat serum (Gibco BRL #16210-072)]. Wells were blocked with 150 μL/well wash buffer and incubated at 37° C. for 1 hour. The blocking solution was removed from the wells and the standard (recombinant mouse VCAM-1/Fc Chimera NOS derived R&D Systems #643-VM) and samples were diluted in wash buffer and added to the wells.
The standard was used at a range of 4000 pg/mL to 31 pg/mL. The serum samples were diluted 1/200 followed by 3-fold serial dilutions. The samples and standards were added at 50 μL/well and incubated at 37° C. for 1 hour. The plates were washed three times and incubated at 37° C. for 1 hour with the primary antibody (biotinylated goat anti-mouse VCAM-1, R&D Systems #BAF643) diluted 1/200 in wash buffer, 50 μL/well. The plates were washed as described above and incubated at 37° C. for 1 hour with stepavidin-HRP (R&D Systems #DY998) 1/200 in PBS/1% goat serum without Tween 20.
The plates were washed three times with wash buffer and three times with PBS. They were then developed with TMB substrate (Kirkegaard & Perry labs # 50-76-00) 50 μL/well and incubated at room temperature for 10 minutes. The reaction was stopped with the addition of 50 μL/well 4N H2SO4, and the plates were read at 450-550 dual wavelength on the Molecular Devices Vmax plate reader.
Wells of a Nunc Maxisorb “U” bottom microtiter plate (#449824) were coated with monoclonal capture antibody, rat anti-mouse ICAM-1 (R&D Systems #BSA2), at 5 μg/mL in phosphate buffered saline (PBS), 50 μL/well and incubated at 37° C. for 1 hour. The plates were washed 3 times with wash buffer [PBS containing 0.1% Tween 20 and 1% Carnation Nonfat Dry Milk]. Wells were blocked with 150 μL/well wash buffer and incubated at 37° C. for 1 hour. The blocking solution was removed from the wells and the standard (a pool of serum from mice implanted with KM12L4a or 4T1 tumors) and samples were diluted in wash buffer and added to the wells.
The standard was used at a dilution range of 1/10- 1/1280. The serum samples were diluted 1/15 followed by 3-fold serial dilutions. The samples and standards were added at 50 μL/well and incubated at 37° C. for 1 hour. The plates were washed three times and incubated at 37° C. for 1 hour with the primary antibody (goat anti-ICAM-1, Santa Cruz Biotechnology #sc-1511) diluted 1/250 in wash buffer, 50 μL/well. The plates were washed as above and incubated at 37° C. for 1 hour with 50 μL/well of the secondary antibody (swine anti-goat IgG HRPO labeled, Caltag #G50007) 1/2000 in wash buffer.
The plates were washed three times with wash buffer and three times with PBS, then developed with TMB substrate (Kirkegaard & Perry labs # 50-76-00) 50 μL/well and incubated at room temperature for 10 minutes. The reaction was stopped with the addition of 50 μL/well 4N H2SO4, and the plates were read at 450-550 dual wavelength on the Molecular Devices Vmax plate reader.
Serum samples were assayed by the R&D Systems Quantikine M, Mouse sE-Selectin Immunoassay kit #MESOO according to the manufacturer's protocol.
In Vivo KM12L4a Human Colon Xenografts
Female Nu/nu mice (6-8 weeks old, 18-22 grams) were obtained from Charles River Laboratories (Wilmington, Mass.). Tumor cells (2×106 KM12L4a) were implanted subcutaneous into the flank of mice and allowed to grow to the desired size before treatment was initiated. Tumor bearing mice were administered with 100 mg/kg of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one for 7 days, and individual mice were euthanized. The tumors were resected and flash frozen in liquid nitrogen.
Zymography for MMP-2 and MMP-9 Activity
Resected tumors were lysed in RIPA buffer (1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% Sodium Dodecylsulphate in 1× Phosphate Buffered Saline, pH 7.2) containing protease inhibitors (Roche Molecular Biochemicals) and phosphatase inhibitors (Sigma). 50 μg of total proteins were analyzed by gelatin zymography on 12% SDS polyacrylamide with gelatin substrate. After electrophoresis, gels were washed twice for 15 minutes in 2.5% Triton X-100, incubated overnight at 37° C. in 50 mM Tris-HCl and 10 mM CaCl2, pH 7.6, and stained with 0.5% Comassie Blue and destained with 50% methanol.
ELISA
VEGF-A protein levels in KM12L4a tumor lysates were quantified using a commercially available ELISA kit (R and D Systems, Minneapolis, Minn.) according to the manufacturer's procedures.
Analysis of KM12L4a human colon tumors, removed after in vivo administration of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, showed reduced VEGF production and decreased MMP-9 activity. These changes were accompanied by decreased tumor cell proliferation (Ki67), induced apoptosis (increased PARP cleavage and caspase-3) and reduced vascular density (CD31) as seen by antibody immunohistochemistry staining.
The preparation of numerous quinolinone benzimidazole compounds useful in inhibiting angiogenesis and vascular endothelial growth factor receptor tyrosine kinases and in inhibiting other tyrosine and serine/threonine kinases including 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one or a tautomer thereof is disclosed in the following documents which are each hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein: U.S. Pat. No. 6,605,617; U.S. Pat. No. 6,756,383; U.S. patent application Ser. No. 10/116,117 filed (published on Feb. 6, 2003, as U.S. 2003/0028018 A1); U.S. patent application Ser. No. 10/644,055 (published on May 13, 2004, U.S. Patent Application No. 2004/0092535); U.S. patent application Ser. No. 10/983,174; U.S. patent application Ser. No. 10/706,328 (published on Nov. 4, 2004, as 2004/0220196); U.S. patent application Ser. No. 10/982,757; and U.S. patent application Ser. No. 10/982,543.
Western Blot Analysis
HUVECs were cultured in EGM (Endothelial Cell Growth Media) with or without 100 nM 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1), and cell lysates were collected at 0, 16, and 24 hours post-treatment. Equal amounts of proteins were loaded in 4-20% SDS-PAGE, and the gels were probed with antibodies against ICAM, VCAM, α5 integrin, and αv integrin. The equal loading and efficiency was evaluated by probing with anti β-actin antibody. The expression of ICAM, VCAM, and α5 integrin was decreased with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one treatment in HUVECs in vitro.
It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms at a time, it should be understood that the invention encompasses any tautomeric form of the drawn structure. For example, the compound of Structure IIIB is shown below with one tautomer, Tautomer IIIBa:




Other tautomers of the compound of Structure IIIB, Tautomer IIIBb and Tautomer IIIBc, are shown below:




All documents or references cited herein are hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein.
It is understood that the invention is not limited to the embodiments set forth herein for illustration, but embraces all such forms thereof as come within the scope of the invention.

## Claims

1. A method of reducing cellular adhesion in a cancer patient, comprising: administering to the cancer patient a compound of Structure II, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, and measuring the amount of at least one of inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule in at least a portion of a blood sample withdrawn from the cancer patient after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof, wherein cellular adhesion and the levels of circulating adhesion molecules are reduced in the cancer patient after administration, and Structure II has the following formula:



wherein,
A is a group having one of the following Structures:




wherein,
Ra is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms.

2. A method of monitoring the progression of a cancer or cancer treatment in a cancer patient, comprising: measuring the amount of at least one cell adhesion molecule in at least a portion of a blood sample withdrawn from the cancer patient after administration of a compound of Structure II, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the cancer patient, wherein the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule, and Structure II has the following formula:



wherein,
A is a group having one of the following Structures:




wherein,
Ra is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms.

3. The method of claim 2, wherein Ra is a methyl group, and the compound of Structure II has the Structure IIA having the following formula:

4. The method of claim 3, wherein the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the cancer patient, and the salt is a lactate salt.

5. The method of claim 2, wherein Ra is a hydrogen, and the compound of Structure II has the Structure IIB having the following formula:

6. The method of claim 2, wherein Ra is a methyl group, and the compound of Structure II has the Structure IIC having the following formula:

7. The method of claim 1, wherein the amount of at least one of inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule is reduced in the cancer patient after administration.

8. The method of claim 1, wherein the amount of a matrix metalloprotease is reduced in the cancer patient after administration.

9. The method of claim 8, wherein the matrix metalloprotease is matrix metalloprotease-2 or matrix metalloprotease-9.

10. The method of claim 1, wherein Ra is a methyl group, and the compound of Structure II has the Structure IIA having the following formula:

11. The method of claim 10, wherein the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the cancer patient, and the salt is a lactate salt.

12. The method of claim 1, wherein the pharmaceutically acceptable salt of the compound of Structure II, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the cancer patient, and the salt is a lactate salt.

13. The method of claim 1, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, gastrointestinal cancer, ovarian cancer, renal cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

14. The method of claim 13, wherein the cancer is breast cancer.

15. The method of claim 2, wherein the levels of circulating adhesion molecules are reduced in the cancer patient after administration.

16. The method of claim 2, wherein the amount of at least one of inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule is reduced in the cancer patient after administration.

17. The method of claim 2, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, gastrointestinal cancer, ovarian cancer, renal cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

18. The method of claim 17, wherein the cancer is breast cancer.