WO2018085348A1

WO2018085348A1 - Substituted quinolines and methods for treating cancer

Info

Publication number: WO2018085348A1
Application number: PCT/US2017/059470
Authority: WO
Inventors: Elena V. DNEPROVSKAIA; Michael S. HOLZWARTH; Scott D. RYCHNOVSKY
Original assignee: Actavalon, Inc.
Priority date: 2016-11-03
Filing date: 2017-11-01
Publication date: 2018-05-11

Abstract

Substituted quinoline compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or ameliorate cancer are provided.

Description

SUBSTITUTED QUINOLINES AND METHODS FOR TREATING CANCER

RELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. Provisional Application No. 62/417,215, filed November 3, 2016, which is hereby incorporated by reference in its entirety.

BACKGROUND

Field

[0002] Substituted quinoline compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or ameliorate cancer are provided.

Description

[0003] The aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of a diverse set of genes. AhR plays an important role in cellular proliferation and differentiation and in maintaining cellular homeostasis of the immune system. Studies have shown that the AhR plays a key role in hematopoietic stem cell (HSC) growth and differentiation. Upon ligand binding, AhR protein translocates to the nucleus, where it forms a heterodimer with the Aryl hydrocarbon Receptor Nuclear Translocator (ARNT), known as the Aryl Hydrocarbon Receptor Complex (AhRC). The AhR ARNT heterodimer activates transcription of a number of genes, but it is primarily known to be involved in systemic metabolism of xenobiotics. AhR is activated by a wide variety of polyaromatic and polycyclic hydrocarbons (PAH) and other exogenous ligands. The exact mechanism of how the AhR actually mediates gene transcription has been the focus of recent investigations. It has been observed that, depending on the ligand, context and cellular phenotype, the AhR can either promote or inhibit cellular proliferation. The AhR/ARNT complex alters transcription by binding to its specific DNA recognition sites. A number of genes have been identified that are directly regulated by the AhR/ARNT complex. The most prominent of these genes involve the drug-metabolizing Cytochrome P450 (CYP1) family of enzymes - CYP1A1, CYP1A2 and CYP1B1. CYP1 enzymes are involved in metabolism of xenobiotics and bioactivation of pro-drugs. By inducing the drug-metabolizing CYP1 enzymes, a large number of the AhR ligands induce their own metabolism and clearance from the body. The resulting metabolites typically are also capable of binding to the AhR protein and exhibit different selectivity in binding to the CYPl enzymes, thus further attenuating the AhR signaling. AhR can also alter transcription via physical interaction and cross-talk with other transcription factors, including NFkB, Estrogen (ER) and Androgen (AR) nuclear receptors and the retinoblastoma (pRB) tumor suppressor protein.

[0004] The AhR pathway appears to play a prominent role in development of breast, prostate and colon cancers. AhR mediates all major stages of cancer development - initiation, promotion, progression, and metastasis. Levels of the CYP1B1 enzymes are commonly elevated in metastatic and aggressive breast cancers and in advanced prostate cancers. Increased levels of AhR and its constitutive localization in the nucleus have been observed in several types of advanced malignant cell lines. Many of the triple negative breast cancers cells have shown increased expression of AhR protein. It has been observed that depletion of AhR in metastatic breast cancer cell line can potentiate the efficacy of chemotherapeutic agents and ionizing radiation. Several studies have shown that various metabolites of the AhR ligands (metabolized by CYPl As enzymes) form DNA- adducts leading to a DNA damage response in cells. As a result, development of the AhR modulators as anti-cancer drugs was hampered by the general toxicity of produced metabolites.

SUMMARY

[0005] Compounds have now been developed that are useful for the treatment of various cancers. In some embodiments, these compounds exert their therapeutic effects by modulating the AhR pathway. AhR activation in sensitive cancer cell lines by these compounds results in formation of biologically active metabolites via CYPl -mediated oxidative metabolism. Surprisingly, unlike other known ligands of the AhR protein, in various embodiments these compounds and the associated metabolites do not induce a DNA damage response in one or more of the treated cell lines. The observed anti-proliferative activity of embodiments of these compounds in sensitive cancer cell lines was found to be abrogated by the addition of the AhR inhibitor, CH223191, or by the addition of the CYPl inhibitor, Acacetin, thus demonstrating AhR activation and the formation of active metabolite(s) via CYPl -mediated oxidative metabolism.

[0006] Some embodiments of the present disclosure relate to compounds having the structure of formula (I) or (Γ):

or a pharmaceutically acceptable salt thereof, wherein

each R¹ is selected from H, C₂-₆ alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, - CN, -NO2, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

each R², R⁴ and R⁵ is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_-6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², - C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

each R³ and R⁶ is selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_-6 alkyl, halo, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, - NR¹⁴C(0)R¹², and -S0₂R¹⁶;

each R⁷ is selected from H or C_1-6 alkyl;

each ⁸ is selected from C₆-io aryl, 5 or 6 membered heteroaryl comprising one or two heteroatoms,

, or 9 or 10 membered heteroaryl, each optionally substituted with one or more R^A;

each R⁹, R¹⁰, R¹⁴ and R¹⁵ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C₆-io aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰; or R¹⁴ and R¹⁵ together with the nitrogen atom to which they are

20 attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R^z ; each R¹¹ is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C₂-₆ alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; each R¹², R¹³ and R¹⁶ is independently selected from the group consisting of H, optionally substituted Ci-₆ alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C_2- 6 alkynyl, optionally substituted C₆-io aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R^A is independently selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)_nR¹⁸, and -(CH₂)_k- S(0)₂-R¹⁹;

each R¹⁷ is independently selected from 4 to 7 membered heterocyclyl, or 5 to 6

20

membered heteroaryl, each optionally substituted with one or more R ;

18

each R is independently selected from the group consisting of C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR⁹R¹⁰;

each R¹⁹ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci_6 alkyl, C3-7 cycloalkyl, C₆-io aryl, C_7-14 aralkyl, -NR⁹R¹⁰, 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more

each R²⁰ is independently selected from the group consisting of C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, - (CH₂CH₂0)_pCH₂CH₂N_3, halo, hydroxyl, oxo, and -CN; and

each k, m, n and p is independently an integer selected from 0 to 6;

provided that when the compound is formula (I), each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, R⁸ is phenyl, then R⁸ is substituted with one or more R^A selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (Ci.6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, - 0(CH₂)_nR¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹.

[0007] Some embodiments of the present disclosure relate to compounds having the structure of formula (II):

harmaceutically acceptable salt thereof, wherein each R¹, R², R³, R⁴ and R⁵ is independently selected from the group consisting of H, Ci-6 alkyl, C₂-₆ alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_-6 alkyl, -0-(Ci_-6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, - C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

R⁶ is selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_\. 6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

R⁷ is selected from H or C_1-6 alkyl;

Ring A is selected from C₆-io aryl, 5 or 6 membered heteroaryl, or 9 or 10 membered heteroaryl, each optionally substituted with one or more R^A;

each R⁹, R¹⁰, R¹⁴ and R¹⁵ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C -w aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰; or R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰; each R¹¹ is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R¹², R¹³ and R¹⁶ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C_2- 6 alkynyl, optionally substituted C₆-io aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R^A is independently selected from the group consisting of C_1-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -O- (Ci_-6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, - 0(CH₂)_nR¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹;

each R¹⁷ is independently selected from 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more R²⁰; each R is independently selected from the group consisting of C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR⁹R¹⁰;

each R¹⁹ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci_6 alkyl, C3_7 cycloalkyl, C₆-io aryl, C_7-14 aralkyl, -NR⁹R¹⁰, 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more

each R²⁰ is independently selected from the group consisting of C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, oxo, and -CN; and

each m, n and k is independently an integer selected from 0 to 6;

provided that when each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, ring A is phenyl, then ring A is substituted with one or more R^A.

[0008] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a compound of formula (I) or (Γ) described herein, a specific compound selected from Compounds 1-26, 28-67, 75-80, 82-84, 86-91, 94-103, 105-152, and 159-170 of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a compound of formula (II) described herein, a specific compound selected from Compounds 27, 70-74, 81, 85, 92, 93, 104 and 153-158 of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] Some further embodiments of the present disclosure relate to methods of treating cancer, comprising administering a therapeutically effective amount of a compound of formula (I), (Γ) or (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition thereof to a subject in need thereof.

[0011] Some further embodiments of the present disclosure relate to methods of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of formula (I), (Γ) or (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as described herein.

[0012] These and other embodiments are described in greater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In addition to the features described above, additional features and variations will be readily apparent from the following descriptions of the drawings and exemplary embodiments. It is to be understood that these drawings depict typical embodiments, and are not intended to be limiting in scope.

[0014] FIG. 1 is a plot that illustrates the abrogation of the anti-proliferative activity of Compound 1 in LS174T colon cancer cells by the addition of 10 uM of the AhR inhibitor, CH223191, and also by the addition of 10 uM of the CYP1 inhibitor, Acacetin. This plot shows that the therapeutic effect of Compound 1 in colon cancer is at least partially due to modulation of the AhR pathway.

[0015] FIG. 2 is a plot that illustrates the abrogation of the anti-proliferative activity of Compound 1 in the breast cancer cell line Au565 by the addition of 10 uM of the AhR inhibitor CH223191, and also by the addition of 10 uM of the CYP1 inhibitor Acacetin. This plot shows that the therapeutic effect of Compound 1 in breast cancer is at least partially due to modulation of the AhR pathway.

[0016] FIG. 3 illustrates the generation of γ-Η2ΑΧ foci in Au565 cells treated with a conventional anti-cancer drug, Doxorubicin. DNA-damage response was assessed by staining cell nuclei for phosphorylation of Serine 139 on histone H2AX. γ-Η2ΑΧ focus formation is considered to be a sensitive and selective signal for the existence of DNA double-strand breaks. Cells were treated with 2 uM of Doxorubicin and incubated for 6 hrs. Cells were stained with goat anti-γ- H2AX antibody conjugated with Alexa Fluor® 647 and nuclei were stained with DAPI. DMSO was used as a negative control. The data in FIG. 3 illustrates the levels of DNA-damage induced by the positive control, Doxorubicin.

[0017] FIG. 4 illustrates the surprising lack of DNA-damage response in Au565 cells treated with Compound 1, as indicated by the lack of generation of γ-Η2ΑΧ foci as compared to Doxorubicin (see FIG. 3). Cells were treated with 4 uM of Compound 1 and incubated for 16 hrs or 24 hrs. As in FIG. 3, DNA-damage response was assessed by staining cell nuclei for phosphorylation of Serine 139 on histone H2AX. As noted above, γ-Η2ΑΧ focus formation is considered to be a sensitive and selective signal for the existence of DNA double-strand breaks. Cells were stained with anti-y-H2AX antibody conjugated to Alexa Fluor® 647 from ThermoFisher and nuclei were stained with DAPI. DMSO was used as a negative control.

[0018] The data in FIGS. 1-4 indicates that embodiments of the compounds described herein are useful for the treatment of cancer by modulating the AhR pathway without inducing a DNA damage response typical for other known AhR modulators. DETAILED DESCRIPTION

[0019] Novel substituted quinoline compounds, including substituted quinoline-7- carboxamides and 2-(quinol-7-yl)benzimidazoles, syntheses thereof and the results of phenotypic screening for inhibition of cellular proliferation in various cancer cell lines are outlined below.

Definitions

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. Except for the claims, the use of "or" or "and" means "and/or" unless the context indicates otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0021] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0022] As used herein, common organic abbreviations are defined as follows:

Ac Acetyl

aq. Aqueous

Bn Benzyl

Bz Benzoyl

BOC or Boc tert-Butoxycarbonyl

Bu n-Butyl

°C Temperature in degrees Centigrade DCM Methylene chloride

DMF N,N'-Dimethylformamide

DMSO Dimethylsulfoxide

ee% Enantiomeric excess

Et Ethyl

EtOAc Ethyl acetate

g Gram(s)

h or hr Hour(s)

iPr Isopropyl

m or min Minute(s)

MeOH Methanol

rriL Milliliter(s)

PG Protecting group

Ph Phenyl

ppt Precipitate

rt Room temperature

Tert, t tertiary

TLC Thin-layer chromatography

Microliter(s)

[0023] "Solvate" refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0024] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al, published September 1 1, 1987 (incorporated by reference herein in its entirety).

[0025] As used herein, "C_a to Q," or "C_a-t_>" in which "a" and "b" are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "Ci to C₄ alkyl" or "Ci_-4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-.

[0026] The term "halogen" or "halo," as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g. , fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0027] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as "Ci_-4 alkyl" or similar designations. By way of example only, "Ci_-4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. [0028] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl as is defined above, such as "C1-9 alkoxy", including but not limited to methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0029] As used herein, "alkylthio" refers to the formula -SR wherein R is an alkyl as is defined above, such as "C^ alkylthio" and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, and tert-butylmercapto.

[0030] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as "C2-4 alkenyl" or similar designations. By way of example only, "C2-4 alkenyl" indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1 -methyl-propen-l-yl, 2-methyl-propen-l -yl, 1 -ethyl-ethen-l -yl, 2-methyl-propen-3-yl, buta-l,3-dienyl, buta-l ,2,-dienyl, and buta-l,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0031] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be designated as "C2-4 alkynyl" or similar designations. By way of example only, "C2-4 alkynyl" indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l -yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0032] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term "heteroalkyl" where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as "C1-4 heteroalkyl" or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "Ci_-4 heteroalkyl" indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0033] The term "aromatic" refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

[0034] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl" where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as "C6-10 aryl," "C₆ or Cio aryl," or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0035] As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an aryl as is defined above, such as "C6-10 aryloxy" or "C6-10 arylthio", including but not limited to phenyloxy.

[0036] An "aralkyl" or "arylalkyl" is an aryl group connected, as a substituent, via an alkylene group, such as "C_7-14 aralkyl", including but not limited to benzyl, 2-phenylethyl, 3- phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a Ci_-4 alkylene group).

[0037] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0038] A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C_1-4 alkylene group).

[0039] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl" where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as "C3-6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0040] A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C_4-10 (carbocyclyl)alkyl" and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cycloheptylmethyl. In some cases, the alkylene group is a lower alkylene group.

[0041] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0042] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0043] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl" where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1 ,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathiinyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, trioxanyl, hexahydro- 1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-l,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0044] A "(heterocyclyl)alkyl" is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0045] As used herein, "acyl" refers to -C(=0)R, wherein R is hydrogen, Ci-6 alkyl, C₂-₆ alkenyl, C_2-6 alkynyl, C3-7 carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0046] An "O-carboxy" group refers to a "-OC(=0)R" group in which R is selected from hydrogen, Ci-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C3-7 carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0047] A "C-carboxy" group refers to a "-C(=0)OR" group in which R is selected from hydrogen, Ci-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C3-7 carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=0)OH).

[0048] A "cyano" group refers to a "-CN" group. [0049] A "sulfonyl" group refers to an "-SO2R" group in which R is selected from hydrogen, C_1-6 alkyl, C2-₆ alkenyl, C2-₆ alkynyl, C3-₇ carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0050] An "S-sulfonamido" group refers to a "-S02NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C2-₆ alkenyl, C2-₆ alkynyl, €₃.₇ carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0051] An "N-sulfonamido" group refers to a "-N(R_A)S0₂R_B" group in which R_A and R are each independently selected from hydrogen, C_1-6 alkyl, C2-₆ alkenyl, C2-₆ alkynyl, C3-₇ carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0052] A "C-amido" group refers to a "-C(=0)NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C2-₆ alkenyl, C2-₆ alkynyl,€₃.₇ carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0053] An "N-amido" group refers to a "-N(R_A)C(=0)R_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C2-₆ alkenyl, C2-₆ alkynyl, C3-₇ carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0054] An "amino" group refers to a "-NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C2-₆ alkenyl, C2-₆ alkynyl,€₃.₇ carbocyclyl, C₆-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH2).

[0055] An "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0056] An "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as a "C2-₈ alkoxyalkyl" and the like.

[0057] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted," it is meant that the group is substituted with one or more substituents independently selected from Ci-C₆ alkyl, Ci-C₆ alkenyl, Ci-C₆ alkynyl, Ci-C₆ heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), C3-C7-carbocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), 5-10 membered heterocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), aryl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), aryl(Ci- C₆)alkyl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), 5-10 membered heteroaryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-C₆ alkyl, Ci-C₆ alkoxy, Ci-C₆ haloalkyl, and Ci-C₆ haloalkoxy), halo, cyano, hydroxy, Ci-C₆ alkoxy, Ci-C₆ alkoxy(Ci-Ce)alkyl (i.e., ether), 0-Ci-C₆ alkoxy(Ci-Ce)alkyl, aryloxy, sulfhydryl (mercapto), halo(Ci-Ce)alkyl (e.g., -CF₃), halo(Ci-Ce)alkoxy (e.g., -OCF₃), Ci- C₆ alkylthio, arylthio, amino, amino(Ci-Ce)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as "optionally substituted" that group can be substituted with the above substituents.

[0058] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di- radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH₂- -CH₂CH₂-, -CH₂CH(CI¾)CH₂-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene" or "alkenylene."

[0059] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:

and R¹ and R² are defined as selected from the group consisting of hydrogen and alkyl, or R¹ and R² together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R¹ and R² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

where ring A is a heteroaryl ring containing the depicted nitrogen.

[0060] Similarly, when two "adjacent" R groups are said to form a ring "together with the atom to which they are attached," it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:

1 2 1 2 and R and R are defined as selected from the group consisting of hydrogen and alkyl, or R and R together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R¹ and R² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

where A is an aryl ring or a carbocylyl containing the depicted double bond.

[0061] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as -AE- or ^{¾ A}\ ^E A includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

[0062] "Subject" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0063] The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.

[0064] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0065] A therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing" means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0066] "Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease or condition.

[0067] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein. [0068] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

[0069] Isotopes can be present in the compounds described. Each chemical element as represented in a compound structure can include any isotope of said element. For example, at any position of the compound that a hydrogen atom is be present, the hydrogen atom encompasses any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. Deuteration replacement of a hydrogen- 1 at a metabolically labile position of a compound may improve the pharmacokinetic properties of the compound.

Compounds

Formulae (I) and (Γ)

[0070] Some embodiments of the present disclosure relate to compounds having the structure of formula I) or (Γ):

or a pharmaceutically acceptable salt thereof, wherein

each R¹ is selected from H, C₂-₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, - CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

each R², R⁴ and R⁵ is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_-6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², - C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶; each R³ and R⁶ is selected from the group consisting of H, C_1-6 alkyl, C₂-₆ alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_-6 alkyl, halo, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, - NR¹⁴C(0)R¹², and -S0₂R¹⁶;

each R⁷ is selected from H or C_1-6 alkyl;

20 attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R ; each R¹¹ is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R^A is selected from the group consisting of C_1-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, Ci-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, halo, hydroxyl, -CN, - N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)_nR¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹;

R¹⁷ is selected from 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl,

20

each optionally substituted with one or more R ;

18

R is selected from the group consisting of C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR⁹R¹⁰; R is selected from C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci-6 alkyl, C3-7 cycloalkyl, C₆-io aryl, C_7-14 aralkyl, -NR⁹R¹⁰, 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more R²⁰;

20

each R is selected from the group consisting of C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci.6 alkyl, -0-(Ci.6 alkoxy)Ci.6 alkyl, - (CH₂CH₂0)_pCH₂CH2N3_, halo, hydroxyl, oxo, and -CN; and

each k, m, n and p is independently an integer selected from 0 to 6;

provided that when the compound is of formula (I), each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, and R⁸ is phenyl, then R⁸ is substituted with one or more R^A selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (Ci.6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, - 0(CH₂)_nR¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹.

[0071] In some embodiments of the compounds of formula (I), R¹ is selected from H, C_2- 6 alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶.

[0072] In some embodiments of the compounds of formula (I) or (Γ), R¹ is selected from H or Ci-6 alkoxy. In one embodiment, R¹ is H. In another embodiment, R¹ is methoxy.

[0073] In some embodiments of the compounds of formula (I) or (Γ), R² is selected from H, halo, Ci-6 alkyl, or C_1-6 alkoxy. In one embodiment, R² is H.

[0074] In some embodiments of the compounds of formula (I) or (Γ), R³ is selected from H or Ci-6 alkoxy. In one embodiment, R³ is H. In another embodiment, R³ is methoxy.

[0075] In some embodiments of the compounds of formula (I) or (Γ), R⁴ is selected from H, halo, or C_1-6 alkyl. In one embodiment, R⁴ is H. In another embodiment, R⁴ is methyl.

[0076] In some embodiments of the compounds of formula (I) or (Γ), R⁵ is selected from H, halo, or C_1-6 alkyl. In one embodiment, R⁵ is H. In another embodiment, R⁵ is methyl. In yet another embodiment, R⁵ is halo.

[0077] In some embodiments of the compounds of formula (I) or (Γ), R⁶ is selected from H, halo, or C_1-6 alkyl. In one embodiment, R⁴ is H. In another embodiment, R⁴ is methyl.

[0078] In some embodiments of the compounds of formula (I) or (Γ), each R¹, R², R³, R⁴, R⁵ and R⁶ is H. In some other embodiments, at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is not H.

[0079] In some embodiments of the compounds of formula (I) or (Γ), R⁷ is H. In some other embodiments, R is C_1-6 alkyl, for example, methyl. [0080] In some embodiments of the compounds of formula (I) or (Γ), R⁸ is selected from phenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl,

J N-N

benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, or S ₅ each optionally substituted with one or more R^A. In some further embodiments, R⁸ is selected from phenyl, pyrazolyl, pyridinyl,

J N-N

thiazolyl, pyrimidinyl, quinolinyl, or S ₅ each substituted with one or more R^A. In some other embodiments, R⁸ is unsubstituted.

[0081] In some embodiments of the compounds of formula (I) or (Γ), R^A is selected from the group consisting of halo, Ci-₆ alkyl, Ci-₆ haloalkyl, Ci-₆ alkoxy, Ci_6 haloalkoxy, -CN, -NR⁹R¹⁰, - C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)„R¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹. In some such embodiments, R^A is selected from the group consisting of halo, methyl, trifluoromethyl, t-butyl, methoxy, trifluoromethoxy, and -CN. In some other embodiments, R^A is -C(0)NR¹⁴R¹⁵, and wherein each R¹⁴ and R¹⁵ is selected from H or Ci-6 alkyl. In one embodiment, both R¹⁴ and R¹⁵ are H. In another embodiment, both R¹⁴ and R¹⁵ are methyl. In some further embodiments, R^A is -C(0)NR¹⁴R¹⁵, and R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰, for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

[0082] In some embodiments of the compounds of formula (I) or (Γ), R^A is -(CH₂)_mR¹⁷ and wherein m is selected from 0, 1 or 2. In one embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2. In some embodiments, R¹⁷ is selected from 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O, or 5 to 6 membered heteroaryl each comprising one to three heteroatoms selected from N, S or O. In some such embodiments, m is 0 or 1 and R is selected from imidazolyl, triazolyl, I— I , ^?

, and wherein R^a is selected from H, Ci-6 alkyl, or (Ci-6 alkoxy)Ci_6 alkyl. In some such embodiments, R¹⁷ is unsubstituted. In

17 20 20 some other embodiments, R is substituted with one or more R , for example, one to three R .

A 18

[0083] In some embodiments of the compounds of formula (I) or (Γ), R is -0(CH₂)_nR and wherein n is selected from 0, 1 or 2. In one embodiment, n is 0. In another embodiment, n is 1.

18

In yet another embodiment, n is 2. In some such embodiments, R is selected from Ci-6 haloalkyl, Ci-6 alkoxy, optionally substituted phenyl, optionally substituted pyridinyl, or -NR⁹R¹⁰. In some further embodiments, R¹⁸ is -NR⁹R¹⁰ and wherein each R⁹ and R¹⁰ is selected from H or C_1-6 alkyl. In one such embodiment, both R⁹ and R¹⁰ are H. In another such embodiment, both R⁹ and R¹⁰ are Ci-6 alkyl, for example, methyl. In some other embodiments, R¹⁸ is -NR⁹R¹⁰, and R⁹ and R¹⁰ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰, for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl. In some further embodiments, R¹⁸ is selected from phenyl or pyridinyl, each substituted with one or more R²⁰, for example, one to three R²⁰.

[0084] In some embodiments of the compounds of formula (I) or (Γ), R^A is -(CI¾)_k- S(0)₂-R¹⁹ and wherein k is selected from 0, 1 or 2. In one embodiment, k is 0. In another embodiment, k is 1. In yet another embodiment, k is 2. In some such embodiments, R¹⁹ is selected from C3-7 cycloalkyl, -NR⁹R¹⁰, or 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O. In some further embodiments, k is 0 and R¹⁹ is selected from cyclopropyl, yclohexyl,

+ + Ό o

cyclopentyl, c -h

and wherein R^a is selected from H, C_1-6 alkyl,

(CH₂CH₂0)_pCI¾CH2N3_i or (C_1-6 alkoxy)Ci_6 alkyl. In some embodiments, p is an integer in the range of 0 to 6. In some further embodiments k is 1 and R¹⁹ is selected from cyclopropyl, cyclopentyl,

,

, and wherein R^a is selected from H, Ci_-6 alkyl, -(CHjCHjC pCHjCHjNs_, or (Ci_-6 alkoxy)Ci_6 alkyl, where p is an integer in the range of 0 to 6. In some such embodiments, R^a is selected from H, methyl or -(CI¾)2C)CH3. In some embodiments, k is 0 or 1 and R¹⁹ is -NR⁹R¹⁰, and wherein each R⁹ and R¹⁰ is independently selected from H, C_1-6 alkyl, optionally substituted phenyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, k is 0 or 1 and R¹⁹ is

In some embodiments, R^a is -(CH₂CH₂0)_pCH₂CH₂N_3i for example, (Οί₂θ¾0)5θ¾Ο¾Ν3. In some such embodiments, R⁹ is selected from H or methyl, and R¹⁰ is selected from methyl, t-butyl, optionally substituted phenyl or optionally substituted C3-7 cycloalkyl.

20

In some further embodiments, the phenyl is substituted with one or more R selected from halo, C_1-6 alkyl, Ci-₆ haloalkyl, (Ci-₆ alkoxy)Ci-₆ alkyl, or -0-(Ci-₆ alkoxy)Ci-₆ alkyl.

[0085] In some embodiments of the compounds of formula (I) or (Γ), the compounds are selected from Compounds 1-26, 28-67, 75-80, 82-84, 86-91 , 94-103, 105-152, and 159-170 of Table 1, or pharmaceutically acceptable salts thereof.

Formula (II)

[0086] Some embodiments of the present disclosure relate to compounds having the structure of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

1 2 3 4 5

each R , R , R , R and R is independently selected from the group consisting of H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_-6 alkyl, -0-(Ci_-6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, - C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

R⁶ is selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C₂ -6 alkynyl, Ci_ 6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, -CN, -NO₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -SO2R¹⁶;

R is selected from H or C_1-6 alkyl;

Ring A is selected from C -w aryl, 5 or 6 membered heteroaryl, or 9 or 10 membered heteroaryl, each optionally substituted with one or more R^A;

each R⁹, R¹⁰, R¹⁴ and R¹⁵ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C₆-io aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰; each R is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R^A is selected from the group consisting of C_1-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, Ci-6 haloalkyl, Ci-₆ alkoxy, Ci-₆ haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, -0-(C_1-6 alkoxy)C_1-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)_nR¹⁸, and -(CH₂)_k- S(0)₂-R¹⁹;

R¹⁷ is selected from 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more

R¹⁸ is selected from the group consisting of C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR⁹R¹⁰;

R¹⁹ is selected from C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci_6 alkyl, C3-7 cycloalkyl, C₆-io aryl, C_7-14 aralkyl, -NR⁹R¹⁰, 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more R²⁰;

each R²⁰ is selected from the group consisting of C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, oxo, and -CN;

each m, n and k is independently an integer selected from 0 to 6;

provided that when each R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ is H, and ring A is phenyl, then ring A is substituted with one or more R^A.

[0087] In some embodiments of the compounds of formula (II), R¹ is selected from H or Ci-6 alkoxy. In one embodiment, R¹ is H. In another embodiment, R¹ is methoxy.

[0088] In some embodiments of the compounds of formula (II), R² is selected from H, halo, Ci-6 alkyl, or C_1-6 alkoxy. In one embodiment, R² is H.

[0089] In some embodiments of the compounds of formula (II), R³ is selected from H or Ci-6 alkoxy. In one embodiment, R³ is H. In another embodiment, R³ is methoxy. [0090] In some embodiments of the compounds of formula (II), R⁴ is selected from H, halo, or Ci_6 alkyl. In one embodiment, R⁴ is H. In another embodiment, R⁴ is methyl.

[0091] In some embodiments of the compounds of formula (II), R⁵ is selected from H, halo, or Ci_6 alkyl. In one embodiment, R⁵ is H. In another embodiment, R⁵ is methyl. In yet another embodiment, R⁵ is halo.

[0092] In some embodiments of the compounds of formula (II), R⁶ is selected from H, halo, or C_1-6 alkyl. In one embodiment, R⁴ is H. In another embodiment, R⁴ is methyl.

[0093] In some embodiments of the compounds of formula (II), each R¹, R², R³, R⁴, R⁵

6 1 2 3 4 5 6

and R° is H. In some other embodiments, at least one of R , R , R R , R and R° is not H.

[0094] In some embodiments of the compounds of formula (II), R is H. In some other embodiments, R is Ci-6 alkyl, for example, methyl.

[0095] In some embodiments of the compounds of formula (II), ring A is selected from phenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and quinolinyl, each optionally substituted with one or more R^A. In some further embodiments, ring A is selected from phenyl or pyridinyl, each optionally substituted with one or more R^A. In some other embodiments, ring A is unsubstituted.

[0096] In some embodiments of the compounds of formula (II), R^A is selected from the group consisting of halo, Ci_6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci_6 haloalkoxy, -CN, -NR⁹R¹⁰, - C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)„R¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹. In some such embodiments, R^A is selected from the group consisting of halo, methyl, trifluoromethyl, t-butyl, methoxy, trifluoromethoxy, and -CN. In some other embodiments, R^A is -C(0)NR¹⁴R¹⁵, and wherein each R¹⁴ and R¹⁵ is selected from H or Ci-6 alkyl. In one embodiment, both R¹⁴ and R¹⁵ are H. In another embodiment, both R¹⁴ and R¹⁵ are methyl. In some further embodiments, R^A is -C(0)NR¹⁴R¹⁵, and R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached forms a 4 to 6 membered

20

heterocyclyl optionally substituted with one or more R , for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

[0097] In some embodiments of the compounds of formula (II), R^A is -(CH₂)_mR¹⁷ and wherein m is selected from 0, 1 or 2. In one embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2. In some embodiments, R¹⁷ is selected from 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O, or 5 to 6 membered heteroaryl each comprising one to three heteroatoms selected from N, S or O. In some such embodiments, m is 0 or 1 and R is selected from imidazolyl, triazolyl,

, and wherein R^a is selected from H, Ci-6 alkyl, or (Ci-6 alkoxy)Ci_6 alkyl. In some such embodiments, R is unsubstituted. In some other embodiments, R 17 is substituted with one or more R 20 , for example, one to three R 20.

A 18

[0098] In some embodiments of the compounds of formula (II), R is -0(CH₂)_nR and wherein n is selected from 0, 1 or 2. In one embodiment, n is 0. In another embodiment, n is 1. In

18

yet another embodiment, n is 2. In some such embodiments, R is selected from Ci-6 haloalkyl, Ci-6 alkoxy, optionally substituted phenyl, optionally substituted pyridinyl, or -NR⁹R¹⁰. In some further embodiments, R¹⁸ is -NR⁹R¹⁰ and wherein each R⁹ and R¹⁰ is selected from H or Ci-6 alkyl. In one such embodiment, both R⁹ and R¹⁰ are H. In another embodiment, both R⁹ and R¹⁰ are Ci-6 alkyl, for example, methyl. In some other embodiments, R¹⁸ is -NR⁹R¹⁰, and R⁹ and R¹⁰ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally

20

substituted with one or more R , for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl. In some further embodiments, R 18 is selected

20 20 from phenyl or pyridinyl, each substituted with one or more R , for example, one to three R .

[0099] In some embodiments of the compounds of formula (II), R^A is -(CH₂)_k-S(0)₂-R¹⁹ and wherein k is selected from 0, 1 or 2. In one embodiment, k is 0. In another embodiment, k is 1. In yet another embodiment, k is 2. In some such embodiments, R¹⁹ is selected from C3-7 cycloalkyl, -NR⁹R¹⁰, or 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O. In some further embodiments, k is 0 or 1 and R¹⁹ is selected from cyclopropyl, cyclopentyl,

cyclohexyl,

, and wherein R^a is selected from H, Ci-6 alkyl, or (Ci-6 alkoxy)Ci_6 alkyl. In some such embodiments, R is selected from H, methyl or -(CH₂)₂OCH₃. In some embodiments, k is 0 or 1 and R¹⁹ is -NR⁹R¹⁰, and wherein each R⁹ and R¹⁰ is independently selected from H, Ci-6 alkyl, optionally substituted phenyl, or optionally substituted C3-7 cycloalkyl. In some such embodiments, R⁹ is selected from H or methyl, and R¹⁰ is selected from methyl, t-butyl, optionally substituted phenyl or optionally substituted C3-7 cycloalkyl. In some further embodiments, the phenyl is substituted with one or more R selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci-6 alkyl, or -0-(Ci-6 alkoxy)Ci_6 alkyl.

[0100] In some embodiments of the compounds of formula (II), the compounds are selected from Compounds 27, 70-74, 81, 85, 92, 93, 104, and 153-158 of Table 1, or pharmaceutically acceptable salts thereof.

[0101] In some embodiments, the compounds of formula (II) may include tautomers thereof, depending on the specific synthetic procedures used in the preparation of the compounds. For example, Compounds 73 and 74 may also exist in their tautomeric forms:

respectively.

[0102] Various embodiments of the present disclosure, including but not limited to substituted quinoline compounds, pharmaceutical salts, compositions thereof, and methods of treating cancer do not include the specific compounds disclosed in PCT Publication Nos. WO 2003/062233 Al, WO 2011/080266 Al, WO 2012/177893 A2, WO 2014/037342 Al, and U.S. Publication No. 2007/0060567 Al, all of which are hereby incorporated by reference and particularly for the purpose of describing the specific compounds disclosed therein.

-29-

-30-

-31-

-33-

-34-

Table 1.

Compd. Structure

170

Administration and Pharmaceutical Compositions

[0103] Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound of formula (I), (Γ) or (II) as described herein (including enantiomers, diastereomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0104] The compounds are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. While human dosage levels have yet to be optimized for the compounds of the preferred embodiments, generally, a daily dose for most of the compounds described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

[0105] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0106] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21 st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety. [0107] In addition to the selected compound useful as described above, come embodiments include compositions containing a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.

[0108] Some examples of substances, which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0109] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

[0110] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation. [0111] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically- acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al, Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0112] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0113] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0114] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0115] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0116] Compositions described herein may optionally include other drug actives.

[0117] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0118] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants. Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster. Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0119] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0120] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al, Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-31 1 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0121] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0122] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. Methods of Treatment

[0123] Some embodiments of the present disclosure relate to a method of treating cancer, comprising administering a therapeutically effective amount of a compound of formula (I), (Γ) or (II) as described herein, a specific compound selected from Table 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof.

[0124] Some embodiments of the present disclosure relate to methods of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of formula (I), (Γ) or (II), a specific compound selected from Table 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0125] Non-limiting examples of cancer that may be treated include breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer, brain cancer, esophageal cancer, kidney cancer, leukemia, melanoma, non-Hodgkin lymphoma, pancreatic cancer, skin cancer, thyroid cancer, and endometrial cancer.

[0126] In some embodiments, the subject is a mammal. In some further embodiments, the subject is a human.

[0127] The terms "therapeutically effective amount," as used herein, refer to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, the assays disclosed in the following examples. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0128] For any compound, the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0129] Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., IC₅₀ is a measure of how effective a drug is. It indicates how much of a particular drug compound is needed to inhibit a given biological process (e.g., a cancer cell line) by half. It is commonly used as a measure of antagonist drug potency in pharmacological research. EDso (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED₅₀/LD₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. However, pharmaceutical compositions that exhibit narrow therapeutic indices are also within the scope of the invention. The data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include an EDso with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0130] The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0131] In one aspect, treating a condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days. An increase in survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. In an another preferred aspect, an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0132] In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone. In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In a further aspect, treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof. Preferably, the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%. In a preferred aspect, a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. In another preferred aspect, a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In another preferred aspect, a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.

[0133] In another aspect, treating a condition described herein results in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0134] In another aspect, treating a condition described herein results in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. In a preferred aspect, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. In another preferred aspect, the proportion of proliferating cells is equivalent to the mitotic index.

[0135] In another aspect, treating a condition described herein results in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.

[0136] The methods described herein may include identifying a subject in need of treatment. In a preferred embodiment, the methods include identifying a mammal in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing such as genomic sequencing, or any other means known to one of skill in the art, including any combination of means for identification.

[0137] As described elsewhere herein, the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition. A preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the embodiments can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.

[0138] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.

[0139] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By "coadministration," it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In some embodiments, the agents are administered simultaneously. In some such embodiments, administration in combination is accomplished by combining the agents in a single dosage form. In some embodiments, the agents are administered sequentially. In some embodiments the agents are administered through the same route, such as orally. In some other embodiments, the agents are administered through different routes, such as one being administered orally and another being administered i.v. Thus, for example, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.

[0140] Various embodiments provide methods of treating a cancer by administering to a subject in need thereof a compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition as described herein, wherein the method further comprises co-administering to the subject an effective amount of an additional medicament that is also effective for treating the cancer. For example, in an embodiment, the cancer is breast cancer and the additional medicament is a Selective Estrogen Receptor Modulator (SERM), Tamoxifen (oral and/or topical), Afimoxifene (4- hydroxytamoxifen) (oral and/or topical) and/or omeprazole.

Synthesis

[0141] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0142] Substituted quinoline compounds described herein can be prepared by using one or more of the following general synthetic schemes exemplified below. Those skilled in the art can develop modified synthetic schemes for particular compounds within the scope of Formulae (I), (Γ) and/or (II) by using routine experimentation guided by the detailed teachings provided herein.

General Schemes for the Synthesis of Compounds of Formula (I)

Scheme 1.

General Experimental Procedure I.

[0143] Quinoline-7-carboxylic acid (1.0 equiv) and corresponding aniline (1.1 equiv) were suspended in dry Ν,Ν-dimethyl formamide under argon atmosphere followed by the addition of triethylamine (1.2 equiv). Then HATU (l-[bis(dimethylamino)methylene]-lH- 1,2,3 -triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (228 mg, 0.6 mmol, 1.2 equiv) was added, and the reaction mixture was stirred for 16 hours at room temperature. After dilution with water, the mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). The fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give the desired product in >95% purity as determined by HPLC. In Scheme 1, R is defined the same as R^A in Formula (I).

Sche

-10 °C to rt,4 hrs General Experimental Procedure II.

[0144] Quinoline-7-carboxylic acid (1.0 equiv) was suspended in dry tetrahydrofuran (0.05 M) under argon atmosphere and triethylamine (1.2 equiv) was added. Then oxalyl chloride (1.2 equiv) was added slowly and the reaction mixture was stirred for 15 minutes at room temperature. Then 4-dimethylaminopyridine (0.2 equiv) was added, followed by corresponding aniline (1.2 equiv). The reaction mixture was stirred at room temperature until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F254). The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product in >95% purity as determined by HPLC. In Scheme 2, R is defined the same as in Formula (I).

Sche

-10 °C to rt, 4 hrs

General Experimental Procedure III.

[0145] To a mixture of quinoline-7-carboxylic acid (1.0 eq) in DCM was added oxalyl chloride (2.0 eq) and 2 drops of DMF. The mixture was stirred at rt for 1 hr under nitrogen atmosphere, then concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. To a mixture of the crude compound (1.0 eq) in anhydrous THF under nitrogen atmosphere was added corresponding aniline (1.0 eq), triethylamine (3.0 eq) and DMAP (0.1 eq). The mixture was stirred at r.t. for 3 hrs. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product in >95% purity as determined by HPLC. In Scheme 3, R is defined the same as R^A in Formula (I).

General Scheme for the Synthesis of Compounds of Formula (II)

Scheme 4.

General Experimental Procedure IV.

[0146] Quinoline-7-carboxylic acid (1.0 equiv) and the diamine (1.1 equiv) were suspended in polyphosphoric acid (1.25 g/mmol of the acid). The reaction mixture was heated to 140 °C for 16 hours. After cooling down to room temperature the reaction was quenched by the addition of aqueous 5N sodium hydroxide. The resulting precipitate was filtered off and purified on CIS- silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the final product in >95% purity as determined by HPLC. In Scheme 4, R is defined the same as R^A in Formula (II).

Additional General Schemes for the Synthesis of Compounds of Formula (I)

Scheme 5.

General Experimental Procedure V.

[0147] A mixture of substituted aniline (1 eq) and acrolein diethyl acetal (2.5 eq) in IN HCl was heated at 100 °C for 24 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled down to room temperature, basified to pH ~9 with solid Na₂C03 and extracted with DCM. The organic layers were combined, washed with DI water, brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using ethyl acetate in petroleum ether as eluent to give the crude product as a mixture of isomers. Reverse-phase HPLC purification afforded the final product in >95% purity as determined by HPLC. In Scheme 5, X is defined the same as R⁵ in Formula (I).

Scheme 6.

Pd(OAc)₂, t-Bu₃PHBF4

CH₃CN, 90 °C, 24 hrs

General Experimental Procedure VI.

[0148] Substituted 7-bromoquinoline (1.0 eq) and corresponding aniline (2.0 eq) were dissolved in anhydrous acetonitrile. Solid Na₂CC>3 (2.0 eq) were added, the resulting suspension was de-gassed with argon gas for 15 minutes. Then Pd(OAc)₂ (0.1 eq)_, Mo(CO)6 (1.0 eq) and t-

BU3PHBF4 (0.12 eq) were added and the resulting mixture was de-gassed with argon gas for additional 10 minutes. Then the reaction mixture was heated at 90 °C for 24 hrs. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using Ethyl Acetate in Petroleum Ether as eluent to give the final compound in >95% purity as determined by HPLC. In Scheme 6, R is defined the same as R^A in Formula (I) and X is defined the same as R⁵ in Formula (I).

Synthetic Sche

Pd(OAc)₂, t-Bu₃PHBF4

CH₃CN, 90 °C

General Experimental Procedure VII.

[0149] Substituted 7-bromoquinoline (1.0 eq) and corresponding substituted 3-amino- pyridine (2.0 eq) were dissolved in anhydrous acetonitrile. Solid Na₂CC>3 (2.0 eq) were added, the resulting suspension was de-gassed with argon gas for 15 minutes. Then Pd(OAc)₂ (0.1 eq)_,

Mo(CO)6 (1.0 eq) and t-Bu3PHBF₄ (0.12 eq) were added and the resulting mixture was de-gassed with argon gas for additional 10 minutes. Then the reaction mixture was heated at 90 °C for 2-24 hrs or irradiated in microwave at 90 °C for 2 hrs. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using ethyl acetate in petroleum ether as eluent to give the final compound in >95% purity as determined by HPLC. In Scheme 7, R is defined the same as R^A in Formula (I) and X is defined the same as R⁵ in Formula (I).

Scheme 8.

70 °C, 16 hrs

General Experimental Procedure VIII.

[0150] A mixture of substituted 7-bromoquinoline (1.0 eq) and NaOAc (3.0 eq) in 1 : 1 MeOH/DMF was de-gassed with argon for 10 min. Then Pd(dppf)Cl₂DCM (0.1 eq) was added and the reaction mixture was de-gassed with argon for another 15 min, then heated at 70 °C in steel bomb under CO atmosphere for 6 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was distilled off, diluted with EtOAc and filtered through celite, and the celite pad was washed with EtOAc. The EtOAc layer was separated from filtrate and washed with water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give crude mixture, which was purified by flash chromatography using EtOAc in hexane as eluent to provide the final product in >95% purity as determined by HPLC. In Scheme 8, X is defined the same as R⁵ in Formula (I).

Scheme 9.

General Experimental Procedure IX.

[0151] Lithium hydroxide monohydrate (2.0 eq) was added to a solution of (un)substituted methyl quinoline-7-carboxylic acid (1.0 eq) in 4:2: 1 mixture of THF/H₂0/MeOH, and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated in vacuo, diluted with DI water, acidified to pH ~ 4 with IN HC1 and extracted with EtOAc. The organic layers were combined, washed with water and brine, separated, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give the final product in >95% yield as determined by HPLC. In Scheme 9, X is defined the same as R⁵ in Formula (I).

Scheme 10.

General Experimental Procedure X.

[0152] Substituted quinoline-7-carboxylic acid (1.0 eq) was dissolved in DCM and oxalyl chloride (2.0 eq) was added, followed by 2 drops of DMF. The mixture was stirred at room temperature for 1 hr under nitrogen atmosphere, and then concentrated in vacuo to give crude product, which was used directly in the next step without further purification. In Scheme 10, X is defined the same as R⁵ in Formula (I).

Synthetic Scheme 11.

General Experimental Procedure XL

[0153] To a mixture of acid chloride (1.0 eq) in anhydrous THF under nitrogen atmosphere was added corresponding aniline (1.0 eq), triethylamine (3.0 eq) and DMAP (0.1 eq). The mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product in >95% purity as determined by HPLC. In Scheme 11, R is defined the same as R^A in Formula (I) and X is defined the same as R⁵ in Formula (I). EXAMPLE 1

iV-(4-chlorophenyl)quinoline-7-carboxamide (1)

1

[0154] Quinoline-7-carboxylic acid (87 mg, 0.5 mmol, 1.0 equiv) and 4-chloroaniline (70 mg, 0.55 mmol, 1.1 equiv) were suspended in dry Ν,Ν-dimethyl formamide (3 mL) under Argon atmosphere, and triethylamine (83 μΕ, 0.6 mmol, 1.2 equiv) was added. Then HATU (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (228 mg, 0.6 mmol, 1.2 equiv) was added, and the reaction mixture was stirred at room temperature for 16 hours. After dilution with water, the mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 59 mg of the desired product 1 as an off-white solid (42% yield) in >95% purity as determined by HPLC. 1H NMR (500 MHz, DMSO): δ 10.69 (s, 1H), 9.03 (dd, J = 4.2, 1.4, 1H), 8.69 (s, 1H), 8.48 (d, J = 8.1, 1H), 8.15-8.09 (m, 2H), 7.89 (d, J = 8.8, 2H), 7.66 (dd, J = 8.3, 4.2, 1H), 7.45 (d, J = 8.8, 2H); ESI/MS [m/z] = 283 [M+H]⁺.

EXAMPLE 2

/V-(3-(trifluoromethyl)phenyl)qui

2

[0155] Compound 2 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (600 MHz, DMSO-d₆): δ 10.87 (s, 1H), 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (s, 1H), 8.50 (dd, J = 8.3, 1.0 Hz, 1H), 8.35 (s, 1H), 8.19-8.14 (m, 3H), 7.69 (dd, J = 8.3, 4.1 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.51 (d, J= 7.8 Hz, 1H).

EXAMPLE 3

/V-(4-(trifluoromethyl)phenyl)quinoline-7-carboxamide (3)

3

[0156] Compound 3 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CDC1₃): δ 9.01 (br s, 1H), 8.63 (br s, 1H), 8.61 (br s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 8.0 Hz, 2H), 7.54 (s, 1H).

EXAMPLE 4

iV-(3-chlorophenyl)quinoline-7-carboxamide (4)

4

[0157] Compound 4 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CDCL): δ 8.97 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.22 (d, J= 8.1 Hz, 1H), 8.09 (d, J= 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.52-7.43 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H).

EXAMPLE 5

iV-(4-fluoro-3-(trifluoromethyl)phenyl)quinoline-7-carboxamide (5)

5

[0158] Compound 5 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CDC1₃): δ 9.02 (d, J = 3.6 Hz, 1H), 8.64 (s, 1H), 8.36 (bs, 1H), 8.27 (d, J= 8.1 Hz, 1H), 8.12 (dd, J= 8.5, 1.6 Hz, 1H), 8.03 (dd, J= 6.0, 2.4 Hz, 1H), 7.99 (d, J= 8.5 Hz, 1H), 7.93-7.90 (m, 1H), 7.55 (dd, J= 8.3, 4.2 Hz, 1H), 7.24-7.22 (m, 1H).

EXAMPLE 6

iV-(4-chloro-3-methylphenyl)quinoline-7-carboxamide (6)

6

[0159] Compound 6 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CDCL): δ 8.95 (bs, 1H), 8.57 (s, 1H), 8.55 (bs, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.48 (dd, J = 8.2, 3.2 Hz, 2H), 7.32 (d, J= 8.5 Hz, 1H), 2.38 (s, 3H).

EXAMPLE 7

iV-(2-methyl-5-(trifluoromethyl)phenyl)quinoline-7-carboxamide (7)

7

[0160] Compound 7 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.73 (s, 1H), 8.48 (d, J= 8.3 Hz, 1H), 8.16-8.12 (m, 2H), 7.84 (s, 1H), 7.66 (dd, J= 8.3, 4.2 Hz, 1H), 7.54 (s, 2H), 2.39 (s, 3H).

EXAMPLE 8

iV-(3,4-dichlorophenyl)quinoline-7-carboxamide (8)

8

[0161] Compound 8 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, DMSO-d₆): δ 10.81 (s, 1H), 9.03 (dd, J = 4.2, 1.7 Hz, 1H), 8.70 (s, 1H), 8.47 (dd, J = 8.3, 0.8 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.10 (dd, J = 8.5, 1.7 Hz, 1H), 7.83 (dd, J = 8.8, 2.5 Hz, 1H), 7.66 (dd, J = 8.3, 4.2 Hz, 1H), 7.64 (d, J= 8.8 Hz, 1H).

EXAMPLE 9

iV-(3-chloro-4-(trifluoromethyl)phenyl)quinoline-7-carboxamide (9)

9

[0162] Compound 9 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H-NMR (500 MHz, DMSO-d₆): δ 11.01 (s, 1H), 9.05 (dd, J= 4.2, 1.7 Hz, 1H), 8.73 (s, 1H), 8.48 (d, J= 7.4 Hz, 1H), 8.28 (d, J= 1.8 Hz, 1H), 8.16 (d, J= 8.5 Hz, 1H), 8.11 (dd,J=8.5, 1.7 Hz, 1H), 8.01 (dd,J=8.7, 1.5 Hz, 1H), 7.88 (d,J=8.7Hz, 1H), 7.67 (dd,J = 8.3, 4.2 Hz, 1H).

EXAMPLE 10

iV-(4-chloro-3-(trifluoromethyl)phenyl)quinoline-7-carboxamide (10)

10

[0163] Compound 10 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H-NMR (500 MHz, DMSO-d₆): δ 10.95 (s, 1H), 9.04 (dd, J= 4.2, 1.7 Hz, 1H), 8.73 (s, 1H), 8.48 (dd,J= 8.3, 0.9 Hz, 1H), 8.44 (d,J=2.5 Hz, 1H), 8.19 (dd,J=8.8, 2.5 Hz, 1H), 8.16(d,J=8.6Hz, 1H), 8.12 (dd, J= 8.5, 1.7 Hz, 1H), 7.75 (d,J=8.8Hz, 1H), 7.67 (dd, J = 8.3, 4.2 Hz, 1H).

EXAMPLE 11

iV-(3-(teri-butyl)-l-methyl-lH-pyr oxamide (11)

11

[0164] Compound 11 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H-NMR (500 MHz, CD₃OD): δ 9.01 (dd, J= 4.3, 1.6 Hz, 1H), 8.68 (s, 1H), 8.48 (d, J= 8.3 Hz, 1H), 8.16 (dd, J= 8.5, 1.4 Hz, 1H), 8.12 (d, J= 8.5 Hz, 1H), 7.68 (dd, J = 8.3, 4.3 Hz, 1H), 6.26 (s, 1H), 3.80 (s, 3H), 1.35 (s, 9H).

EXAMPLE 12 iV-(4-chlorophenyl)-2-methoxyq

12

[0165] Compound 12 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 8.44 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.94 (dd, J = 8.4, 1.6 Hz, 1H), 7.84-7.79 (m, 2H), 7.45-7.39 (m, 2H), 7.09 (d, J= 8.9 Hz, 1H), 4.12 (s, 3H).

EXAMPLE 13

iV-(5-chloro-2-methylphenyl)quino

13

[0166] Compound 13 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CDC1₃): δ 8.98 (dd, J = 4.1, 1.1 Hz, 1H), 8.65 (s, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.3, 4.3 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (dd, J = 8.3, 2.1 Hz, 1H), 2.34 (s, 3H).

EXAMPLE 14

iV-(4-chloro-2-methylphenyl)quino

14

[0167] Compound 14 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, DMSO-d₆): δ 8.98 (dd, J= 4.3, 1.7 Hz, 1H), 8.65 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.3, 4.3 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.27 (dd, J = 8.4, 2.2 Hz, 1H), 2.35 (s, 3H).

EXAMPLE 15 iV-(6-chloropyridin-3-yl)quinoline- -carboxamide (15)

15

[0168] Compound 15 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CDC1₃): δ 8.98 (dd, J = 4.2, 1.6 Hz, 1H), 8.80 (d, J = 2.7 Hz, 1H), 8.63 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.32 (dd, J = 8.7, 2.8 Hz, 1H), 8.13 (dd, J = 8.6, 1.6 Hz, 1H), 8.11 (d, J= 8.5 Hz, 1H), 7.66 (dd, J= 8.4, 4.3 Hz, 1H), 7.49 (d, J= 8.7 Hz, 1H).

EXAMPLE 16

iV-(3-chloro-4-fluorophenyl)quino

16

[0169] Compound 16 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 8.97 (d, J = 2.3 Hz, 1H), 8.59 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.12-8.07 (m, 2H), 8.02 (dd, J = 6.6, 2.3 Hz, 1H), 7.69-7.63 (m, 2H), 7.26 (t, J= 9.0 Hz, 1H).

EXAMPLE 17

iV-(4-chloro-3-fluorophenyl)quino

17

[0170] Compound 17 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 8.97 (dd, J = 4.1, 1.5 Hz, 1H), 8.59 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.10-8.05 (m, 2H), 7.90 (dd, J = 11.6, 2.4 Hz, 1H), 7.65 (dd, J = 8.3, 4.3 Hz, 1H), 7.54 (ddd, J= 8.8, 2.3, 0.9 Hz, 1H), 7.46 (t, J= 8.5 Hz, 1H).

EXAMPLE 18

iV-(4-chloro-3-methoxyphenyl)quinoline-7-carboxamide (18)

18

[0171] Compound 18 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H-NMR (500 MHz, CD₃OD): δ 9.01 (d, J= 4.3 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J= 8.4 Hz, 1H), 8.17-8.10 (m, 2H), 7.73-7.70 (m, 1H), 7.69 (dd, J= 8.3, 4.4 Hz, 1H), 7.38 (d, J= 8.6 Hz, 1H), 7.35 (dd, J= 8.4, 2.0 Hz, 1H), 3.97 (s, 3H).

EXAMPLE 19

iV-(5-chlorothiazol-2-yl)quinoline- -carboxamide (19)

19

[0172] Compound 19 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H-NMR (500 MHz, CD₃OD): δ 8.99 (d, J= 4.1 Hz, 1H), 8.70 (s, 1H), 8.47 (d,J=8.2Hz, 1H), 8.18 (d,J=8.7Hz, 1H), 8.13 (d,J=8.5Hz, 1H), 7.68 (dd,J=8.4, 4.4 Hz, 1H), 7.43 (s, 1H).

EXAMPLE 20

iV-(4-(pyridin-3-yloxy)phenyl)q

20

[0173] Compound 20 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H-NMR (500 MHz, CD₃OD): δ 8.99 (dd, J= 4.2, 1.3 Hz, 1H), 8.62 (s, 1H), 8.46 (d, J= 7.9 Hz, 1H), 8.35-8.32 (m, 2H), 8.13 (dd, J= 8.5, 1.5 Hz, 1H), 8.10 (d, J= 8.5 Hz, 1H), 7.85 (d, J= 9.0 Hz, 2H), 7.66 (dd, J= 8.3, 4.3 Hz, 1H), 7.49-7.44 (m, 2H), 7.14 (d, J= 9.0 Hz, 2H).

EXAMPLE 21

iV-(4-chlorophenyl)-4-methoxyquinoline-7-carboxamide (21)

21

[0174] Compound 21 was synthesized according to the protocol outlined in the General Experimental Procedure VI. 1H-NMR (500 MHz, CDC1₃): δ 8.81 (bs, 1H), 8.49 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 4.8 Hz, 1H), 4.16 (s, 3H).

EXAMPLE 22

iV-(5-chloropyridin-2-yl)quinoline- -carboxamide (22)

22

[0175] Compound 22 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 9.02 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.18 (dd, J = 8.5, 1.6 Hz, 1H), 8.15 (d, J= 8.5 Hz, 1H), 7.92 (dd, J= 8.9, 2.6 Hz, 1H), 7.70 (dd, J = 8.3, 4.3 Hz, 1H).

EXAMPLE 23

iV-(3-(trifluoromethoxy)phenyl)q

23

[0176] Compound 23 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 9.02 (dd, J = 4.3, 1.7 Hz, 1H), 8.65 (s, 1H), 8.51 (d, J= 8.4 Hz, 1H), 8.18-8.13 (m, 2H), 7.96 (s, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.70 (dd, J = 8.3, 4.3 Hz, 1H), 7.52 (app. t, J= 8.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H).

EXAMPLE 24

iV-(6-methoxypyridin-3-yl)quinoline-7-carboxamide (24)

24

[0177] Compound 24 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 9.02 (dd, J = 4.2, 1.5 Hz, 1H), 8.66 (s, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.17 (dd, J = 8.6, 1.4 Hz, 1H), 8.15 (s, 1H), 8.12 (dd, J= 8.9, 2.7 Hz, 1H), 7.69 (dd, J= 8.3, 4.3 Hz, 1H), 6.90 (d, J= 8.9 Hz, 1H), 3.97 (s, 3H).

EXAMPLE 25

iV-(4-(dimethylcarbamoyl)phenyl)quinoline-7-carboxamide (25)

25

[0178] Compound 25 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H-NMR (500 MHz, CD₃OD): δ 9.02 (dd, J = 4.3, 1.6 Hz, 1H), 8.66 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.18-8.13 (m, 2H), 7.95-7.93 (m, 2H), 7.70 (dd, J = 8.3, 4.3 Hz, 1H), 7.55-7.51 (m, 2H), 3.16 (s, 3H), 3.12 (s, 3H).

EXAMPLE 26

4-Methoxy-iV-(3-(trifluoromethyl)phenyl)quinoline-7-carboxamide (26)

26

[0179] Compound 26 was synthesized according to the protocol outlined in the General Experimental Procedure VI. 1H NMR (500 MHz, CDC1₃): δ 10.88 (s, 1H), 8.90 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.11 (dd, J = 8.7, 1.8 Hz, 1H), 7.66 (app. t, J = 7.9 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 4.12 (s, 3H).

EXAMPLE 27

7-(5-Chloro-lH-benzo[i/]imidazol-2-yl)quinoline (27)

27

[0180] Quinoline-7-carboxylic acid (34.6 mg, 0.2 mmol, 1.0 equiv) and 4-chloro-l,2- diaminobenzene (34.5 mg, 0.22 mmol, 1.1 equiv) were suspended in polyphosphoric acid (1.25 g/mmol of the acid). The reaction mixture was heated to 140 °C for 16 hours. After cooling down to room temperature the reaction was quenched by the addition of aqueous 5N sodium hydroxide solution. The resulting precipitate was filtered off and purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 2 as a yellow solid (12.9 mg, 22% yield) in >95% purity as determined by HPLC. 1H NMR (500 MHz; DMSO): δ 13.26 (s, 1H), 8.99 (d, J = 2.9 Hz, 1H), 8.80 (s, 1H), 8.42 (t, J = 9.4 Hz, 2H), 8.14 (d, J = 8.6 Hz, 1H), 7.74-7.54 (m, 1H), 7.60 (dd, J = 8.2, 4.1 Hz, 1H), 2.45 (s, 3H); LC/MS [m/z]: 294 [M+H]⁺.

EXAMPLE 28

/V-(3-chloro-4-methoxyphenyl)qu

28

[0181] Compound 28 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 9.02 (dd, J = 4.3, 1.7 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J= 8.5 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J= 2.6 Hz, 1H), 7.71-7.66 (m, 2H), 7.19-7.12 (d, J = 8.8 Hz, 2H), 3.98-3.89 (m, 3H).

EXAMPLE 29

iV-(4-(4-ethylpiperazin-l-yl)phenyl)quinoline-7-carboxamide (29)

29

[0182] Compound 29 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 9.01 (dd, J = 4.3, 1.7 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J = 7.7 Hz, 1H), 8.16-8.12 (m, 2H), 7.70-7.64 (m, 3H), 7.09-7.05 (m, 2H), 3.28 (t, J = 4.9 Hz, 4H), 2.72 (t, J= 4.8 Hz, 4H), 2.57 (q, J= 7.2 Hz, 2H), 1.21 (t, J= 7.3 Hz, 3H).

EXAMPLE 30

iV-(4-(2-(diethylamino)ethoxy)phenyl)quinoline-7-carboxamide (30)

30

[0183] Compound 30 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 9.01 (dd, J = 4.3, 1.6 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.16-8.11 (m, 2H), 7.71-7.66 (m, 3H), 7.05-7.00 (m, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.01-2.99 (m, 2H), 2.77 (q, J= 6.8 Hz, 4H), 1.17 (t, J= 7.2 Hz, 6H).

EXAMPLE 31

iV-(4-morpholinophenyl)quinoline-7-carboxamide (31)

31

[0184] Compound 31 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 9.01 (dd, J = 4.3, 1.6 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8.16-8.12 (m, 2H), 7.72-7.65 (m, 3H), 7.08-7.05 (m, 2H), 3.89 (t, J = 4.8 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H).

EXAMPLE 32

iV-(4-(lH-imidazol-l-yl)phenyl)quinoline-7-carboxamide (32)

32

[0185] Compound 32 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 9.03 (dd, J = 4.3, 1.6 Hz, 1H), 8.67 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.21-8.12 (m, 3H), 8.02-7.97 (m, 2H), 7.70 (dd, J = 8.3, 4.3 Hz, 1H), 7.67-7.60 (m, 3H), 7.21 (s, 1H).

EXAMPLE 33

iV-(6-(trifluoromethyl)pyridin-3-yl)quinoline-7-carboxamide (33)

33

[0186] Compound 33 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 9.08 (d, J = 2.2 Hz, 1H), 8.98 (dd, J = 4.2, 1.5 Hz, 1H), 8.64 (s, 1H), 8.55 (dd, J = 8.6, 2.2 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.14 (dd, J = 8.5, 1.7 Hz, 1H), 8.10 (d, J= 8.5 Hz, 1H), 7.84 (d, J= 8.6 Hz, 1H), 7.65 (dd, J= 8.3, 4.3 Hz, 1H).

EXAMPLE 34

iV-(6-cyanopyridin-3-yl)quinoline- -carboxamide (34)

34

[0187] Compound 34 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 11.17 (s, 1H), 9.17 (d, J = 2.5 Hz, 1H), 9.06 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (s, 1H), 8.53 (dd, J = 8.6, 2.5 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.13 (dd, J = 8.4, 1.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.3, 4.2 Hz, 1H).

EXAMPLE 35

iV-(4-(4-ethylpiperazin-l-yl)-3-fluorophenyl)quinoline-7-carboxamide (35)

35

[0188] Compound 35 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 8.96 (dd, J = 4.3, 1.6 Hz, 1H), 8.57 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.10-8.06 (m, 2H), 7.67 (dd, J = 14.8, 2.6 Hz, 1H), 7.64 (dd, J = 8.4, 4.3 Hz, 1H), 7.43 (dd, J = 8.6, 1.5 Hz, 1H), 7.06 (app. t, J = 9.2 Hz, 1H), 3.17-3.10 (m, 4H), 2.68- 2.65 (m, 4H), 2.53 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H).

EXAMPLE 36

iV-(3-(morpholine-4-carbonyl)phenyl)quinoline-7-carboxamide (36)

36

[0189] Compound 36 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.97 (dd, J = 4.2, 1.5 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.12-8.05 (m, 2H), 7.93 (d, J = 1.4 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.64 (dd, J = 8.3, 4.3 Hz, 1H), 7.49 (app. t, J = 7.9 Hz, 1H), 7.24 (dd, J= 7.6, 1.0 Hz, 1H), 3.77 (bs, 4H), 3.67 (bs, 2H), 3.53 (bs, 2H).

EXAMPLE 37

iV-(3-fluoro-4-methoxyphenyl)quinoline-7-carboxamide (37)

37

[0190] Compound 37 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 8.96 (dd, J = 4.3, 1.4 Hz, 1H), 8.57 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.11-8.07 (m, 2H), 7.68-7.63 (m, 2H), 7.44 (d, J = 8.9 Hz, 1H), 7.11 (t, J= 9.1 Hz, 1H), 3.89 (s, 3H).

EXAMPLE 38

iV-(2-chloro-3-fluorophenyl)quinol

38

[0191] Compound 38 was synthesized according to the protocol outlined in the General

Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 8.97 (d, J = 3.6 Hz, 1H), 8.66 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.14-8.09 (m, 2H), 7.69-7.61 (m, 2H), 7.42-7.38 (m, 1H), 7.21-7.18 (m, 1H).

EXAMPLE 39

iV-(5-fluoro-2-methoxyphenyl)quinoline-7-carboxamide 39

39

[0192] Compound 39 was synthesized according to the protocol outlined in the General

Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 8.95 (dd, J = 4.2, 1.6 Hz, 1H), 8.54 (s, 1H), 8.42 (d, J= 8.4 Hz, 1H), 8.07 (d, J= 1.1 Hz, 2H), 8.02 (dd, J = 10.3, 3.1 Hz, 1H), 7.63 (dd, J = 8.3, 4.3 Hz, 1H), 7.03 (dd, J= 9.0, 4.9 Hz, 1H), 6.88 (ddd, J= 8.9, 8.3, 3.1 Hz, 1H), 3.94 (s, 3H).

EXAMPLE 40

iV-(4-chloro-2-methoxyphenyl)qui

40

[0193] Compound 40 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 8.95 (d, J = 3.0 Hz, 1H), 8.56 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.07 (app. s, 2H), 8.00 (d, J = 8.5 Hz, 1H), 7.63 (dd, J = 8.3, 4.3 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.99 (dd, J= 8.5, 2.1 Hz, 1H), 3.94 (s, 3H).

EXAMPLE 41

iV-(4-((lH-l,2,4-triazol-l-yl)methyl)phenyl)quinoline-7-carboxamide (41)

41 [0194] Compound 41 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 8.97 (dd, J = 4.2, 1.4 Hz, 1H), 8.58 (d, J = 9.4 Hz, 2H), 8.45 (d, J = 8.4 Hz, 1H), 8.12-8.07 (m, 2H), 8.01 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.65 (dd, J= 8.3, 4.3 Hz, 1H), 7.38 (d, J= 8.5 Hz, 2H), 5.44 (s, 2H).

EXAMPLE 42

iV-(2-chloro-4-(trifluoromethoxy)phenyl)quinoline-7-carboxamide (42)

42

[0195] Compound 42 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 8.98 (dd, J = 4.2, 1.4 Hz, 1H), 8.66 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.66 (dd, J= 8.3, 4.3 Hz, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.36 (d, J= 8.9 Hz, 1H).

EXAMPLE 43

iV-(4-(2,2,2-trifluoroethoxy)phenyl)quinoline-7-carboxamide (43)

43

[0196] Compound 43 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 8.97 (dd, J = 4.1, 1.3 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.13-8.07 (m, 2H), 7.75-7.68 (m, 2H), 7.65 (dd, J = 8.3, 4.3 Hz, 1H), 7.08-7.05 (m, 2H), 4.55 (q, J= 8.5 Hz, 2H).

EXAMPLE 44

iV-(4-(morpholinomethyl)phenyl)quinoline-7-carboxamide (44)

44 [0197] Compound 44 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 10.55 (s, 1H), 9.03 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8.3, 4.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 3.58 (t, J= 4.6 Hz, 4H), 3.44 (s, 2H), 2.36 (bs, 4H).

EXAMPLE 45

iV-(3-chloro-5-fluorophenyl)quinoline-7-carboxamide (45)

45

[0198] Compound 45 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.98 (dd, J = 4.2, 1.5 Hz, 1H), 8.60 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 8.11 (s, 1H), 7.71 (s, 1H), 7.68-7.65 (m, 2H), 6.99 (app. dt, J= 8.5, 2.1 Hz, 1H).

EXAMPLE 46

iV-(4-chlorophenyl)-8-methylquino

46

[0199] Compound 46 was synthesized according to the Experimental Procedure utilized for the synthesis of Compound 95 (below) with the exception that 7-bromo-8-methylquinoline was utilized as the starting material. 1H NMR (500 MHz, CD₃OD): δ 8.95 (dd, J = 4.2, 1.5 Hz, 1H), 8.35 (dd, J= 8.2, 1.5 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.73 (d, J= 8.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.58 (dd, J= 8.3, 4.2 Hz, 1H), 7.37 (d, J= 8.8 Hz, 2H), 2.86 (s, 3H).

EXAMPLE 47

iV-(4-chlorophenyl)-iV-methylquinoline-7-carboxamide (47)

[0200] Compound 47 was synthesized according to the protocol outlined in the General

Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 8.82 (dd, J = 4.2, 1.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.3, 4.4 Hz, 2H), 7.23-7.19 (m, 4H), 3.52 (s, 3H).

EXAMPLE 48

iV-(5-(morpholinosulfonyl)phenyl)quinoline-7-carboxamide (48)

48

[0201] Quinoline-7-carboxylic acid (34.6 mg, 0.2 mmol, 1.0 equiv) was suspended in dry tetrahydrofuran (0.05 M) under Argon atmosphere and triethylamine (1.2 equiv) was added. Then oxalyl chloride (1.2 equiv) was added slowly and the reaction mixture was stirred for 15 minutes at room temperature. Then 4-dimethylaminopyridine (0.2 equiv) was added, followed by 3- (morpholinosulfonyl)aniline (58.2 mg, 0.24 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F₂5₄). Then the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3x 20 rriL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 43 mg of the desired Compound 48 as a white solid (54% yield) in >95% purity as determined by HPLC. 1H-NMR (500 MHz; CD₃OD): δ 8.94 (dd, J = 4.2, 1.5 Hz, 1H), 8.59 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.10 (dd, J = 8.5, 1.6 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 8.04-8.02 (m, 1H), 7.63-7.61 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.8, 1H), 3.71 (t, J= 4.6, 4H), 3.01 (t, J= 4.5, 4H); LC/MS [m/z]: 420 [M+Na]⁺.

EXAMPLE 49

iV-(3-fluoro-5-methoxyphenyl)quinoline-7-carboxamide (49)

49

[0202] Compound 49 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.96 (dd, J = 4.3, 1.6 Hz, 1H), 8.57 (s, 1H), 8.44 (dd, J= 8.3, 0.7 Hz, 1H), 8.10-8.06 (m, 2H), 7.64 (dd, J= 8.3, 4.3 Hz, 1H), 7.26 (app. dt, J = 10.8, 2.0 Hz, 1H), 7.22 (s, 1H), 6.50 (app. dt, J= 10.7, 2.3 Hz, 1H), 3.83 (s, 3H).

EXAMPLE 50

iV-(2-chloro-6-methoxypyridin-3-yl)quinoline-7-carboxamide (50)

50

[0203] Compound 50 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.98 (dd, J = 4.2, 1.5 Hz, 1H), 8.66 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.15-8.07 (m, 2H), 7.97 (d, J = 8.6 Hz, 1H), 7.67 (dd, J= 8.3, 4.3 Hz, 1H), 6.86 (d, J= 8.6 Hz, 1H), 3.95 (s, 3H).

EXAMPLE 51

iV-(4-(trifluoromethoxy)phenyl)q

51

[0204] Compound 51 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.99-8.93 (m, 1H), 8.60 (d, J = 3.5 Hz, 1H), 8.45 (app. t, J = 7.5 Hz, 1H), 8.13-8.06 (m, 2H), 7.89-7.85 (m, 2H), 7.66-7.63 (m, 1H), 7.31 (dd, J= 8.6, 2.7 Hz, 2H).

EXAMPLE 52

8-Methyl-iV-(3-(trifluoromethyl)phenyl)quinoline-7-carboxamide (52)

52 [0205] Compound 52 was synthesized according to the Experimental Procedure utilized for the synthesis of Compound 95 (below) with the exception that 7-bromo-8-methylquinoline was used as the starting material. *H NMR (500 MHz, CDC1₃): δ 8.97 (dd, J= 4.2, 1.7 Hz, 1H), 8.36 (dd, J = 8.3, 1.6 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.3, 4.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 2.88 (s, 3H).

EXAMPLE 53

4-Chloro-iV-(quinolin-7-yl)benzamide (53)

53

[0206] Compound 53 was synthesized using similar protocol as outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 8.81 (d, J = 4.0 Hz, 1H), 8.56 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.96-7.92 (m, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.47 (dd, J= 8.3, 4.3 Hz, 1H).

EXAMPLE 54

iV-(4-((pyrrolidin-l-ylsulfonyl)methyl)phenyl)quinoline-7-carboxamide (54)

54

[0207] Compound 54 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 10.63 (s, 1H), 9.03 (dd, J= 4.1, 1.6 Hz, 1H), 8.69 (s, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.11 (dd, J = 8.5, 1.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 8.3, 4.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 4.42 (s, 2H), 3.19- 3.14 (m, 4H), 1.85-1.72 (m, 4H).

EXAMPLE 55

iV-(l,3,4-thiadiazol-2-yl)quinoline-7-carboxamide (55)

55

[0208] Compound 55 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 9.14 (s, 1H), 9.00 (d, J = 4.1 Hz, 1H), 8.75 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.21 (dd, J = 8.6, 1.7 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.68 (dd, J= 8.3, 4.3 Hz, 1H).

EXAMPLE 56

iV-(5-chloro- l,3,4-thiadiazol-2-yl)q 6)

56

[0209] Compound 56 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 13.70 (s, 1H), 9.06 (dd, J = 4.1, 1.6 Hz, 1H), 8.87 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.21 (dd, J = 8.5, 1.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.70 (dd, J= 8.3, 4.2 Hz, 1H).

EXAMPLE 57

iV-(6-methylpyridin-3-yl)quinoline- -carboxamide (57)

57

[0210] Compound 57 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, DMSO-d₆): δ 9.00 (dd, J = 4.1, 1.4 Hz, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 8.4, 2.5 Hz, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.3, 4.3 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 2.56 (s, 3H).

EXAMPLE 58

iV-(6-chloro-2-methylpyridin-3-yl)quinoline-7-carboxamide 58)

58 [0211] Compound 58 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.99 (dd, J = 4.3, 1.5 Hz, 1H), 8.67 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.15 (dd, J = 8.6, 1.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.67 (dd, J= 8.3, 4.3 Hz, 1H), 7.38 (d, J= 8.3 Hz, 1H), 2.54 (s, 3H).

EXAMPLE 59

iV-(4-bromophenyl)quinoline-7-carboxamide (59)

59

[0212] Compound 59 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.97 (dd, J = 4.2, 1.6 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.12-8.04 (m, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.65 (dd, J= 8.3, 4.3 Hz, 1H), 7.55-7.50 (m, 2H).

EXAMPLE 60

iV-(6-bromopyridin-3-yl)quinoline- -carboxamide (60)

60

[0213] Compound 60 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.99 (d, J = 3.3 Hz, 1H), 8.80 (d, J = 2.5 Hz, 1H), 8.63 (s, 1H), 8.46 (d, J= 8.3 Hz, 1H), 8.22 (dd, J= 8.6, 2.6 Hz, 1H), 8.15-8.09 (m, 2H), 7.66 (dd, J= 8.3, 4.3 Hz, 1H), 7.63 (d, J= 8.7 Hz, 1H).

EXAMPLE 61

iV-(2-chloropyrimidin-5-yl)quinoli -7-carboxamide (61)

61

[0214] Compound 61 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 9.17 (s, 1H), 9.17 (s, 1H), 8.99 (dd, J = 4.2, 1.4 Hz, 1H), 8.66 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.12 (d, J 8.6 Hz, 1H), 7.67 (dd, J= 8.3, 4.3 Hz, 1H).

EXAMPLE 62

iV-(pyrimidin-5-yl)quinoline-7-carboxamide (62)

62

[0215] Compound 62 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, DMSO-d₆): δ 9.22 (s, 2H), 9.03 (dd, J = 4.1, 1.6 Hz, 1H), 8.90 (s, 1H), 8.76 (s, 1H), 8.47 (d, J= 7.9 Hz, 1H), 8.19 (dd, J= 8.5, 1.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.66 (dd, J= 8.3, 4.2 Hz, 1H).

EXAMPLE 63

iV-(4-iodophenyl)quinoline-7-carboxamide (63)

63

[0216] Compound 63 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.97 (dd, J = 4.2, 1.6 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.12-8.05 (m, 2H), 7.73-7.69 (m, 2H), 7.65 (dd, J = 8.3, 4.3 Hz, 1H), 7.61-7.58 (m, 2H).

EXAMPLE 64

iV-(l-methyl-lH-pyrazol-4-yl)quin

64

[0217] Compound 64 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 8.96 (dd, J = 4.3, 1.6 Hz, 1H), 8.58 (s, 1H), 8.44 (d, J= 8.3 Hz, 1H), 8.11-8.07 (m, 3H), 7.69 (s, 1H), 7.63 (dd, J= 8.3, 4.3 Hz, 1H), 3.91 (s, 3H). EXAMPLE 65

iV-(6-carbamoylpyridin-3-yl)quinoline-7-carboxamide (65)

65

[0218] Compound 65 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, DMSO-d₆): δ 11.00 (s, 1H), 9.08 (d, J = 2.4 Hz, 1H), 9.05 (dd, J = 4.2, 1.4 Hz, 1H), 8.75 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.45 (dd, J = 8.7, 2.4 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.14 (dd, J = 8.4, 1.5 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.68 (dd, J = 8.3, 4.1 Hz, 1H), 7.56 (s, 1H).

EXAMPLE 66

iV-(4-(piperidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (66)

66

[0219] Compound 66 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 9.04 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.03 (d, J= 8.5 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.60 (dd, J = 8.2, 4.2 Hz, 1H), 3.13-2.98 (m, 4H), 1.77-1.66 (m, 4H), 1.49- 1.44 (m, 2H).

EXAMPLE 67

iV-(4-((4-methylpiperazin-l-yl)methyl)phenyl)quinoline-7-carboxamide (67)

67

[0220] Compound 67 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 8.98 (dd, J = 4.2, 1.6 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.10 (dd, J = 8.4, 1.7 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 3.51 (s, 2H), 2.51 (s, 8H), 2.32 (s, 3H).

EXAMPLE 68

iV-(4-chlorophenyl)-2-methylquin

68

[0221] Compound 68 was synthesized according to the Experimental Procedure utilized for the synthesis of Compound 95 (below) with the exception that 7-bromo-2-methylquinoline was used as the starting material. 1H NMR (500 MHz, CDCL): δ 8.44 (s, 1H), 8.18 (bs, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.35 (d, J= 8.7 Hz, 2H), 2.78 (s, 3H).

EXAMPLE 69

iV-(3-chlorophenyl)-2-methylquin

69

[0222] Compound 69 was synthesized according to the Experimental Procedure utilized for the synthesis of Compound 95 (below) with the exception that 7-bromo-2-methylquinoline was used as the starting material. 1H NMR (500 MHz, CDCL): δ 8.64 (bs, 1H), 8.41 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 8.4, 1.7 Hz, 1H), 7.85 (app. t, J = 2.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.33 (d, J= 8.4 Hz, 1H), 7.29-7.23 (m, 1H), 7.14-7.09 (m, 1H), 2.72 (s, 3H).

EXAMPLE 70

7-(6-Chloro-3H-imidazo[4,5-c]pyr

70 [0223] Compound 70 was synthesized according to the protocol outlined in the General Experimental Procedure IV. 1H NMR (500 MHz, CD₃OD): δ 8.90 (d, J = 2.5 Hz, 1H), 8.58 (d, J = 10.9 Hz, 2H), 8.33 (d, J= 7.9 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.2, 4.2 Hz, 1H), 7.49 (s, 1H).

EXAMPLE 71

7-(3H-imidazo[4,5-c]pyridin-2-yl)quinoline (71)

71

[0224] Compound 71 was synthesized according to the protocol outlined in the General

Experimental Procedure IV. 1H NMR (500 MHz, CD₃OD): δ 8.92-8.87 (m, 2H), 8.70 (s, 1H), 8.37 (d, J= 8.3 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.31 (d, J= 5.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.66 (d, J= 5.7 Hz, 1H), 7.58 (dd, J= 8.3, 4.3 Hz, 1H).

EXAMPLE 72

7-(6-(Trifluoromethyl)-lH-benzo[i ]imidazol-2-yl)quinoline (72)

72

[0225] Compound 72 was synthesized according to the protocol outlined in the General Experimental Procedure IV. 1H NMR (500 MHz, CD₃OD): δ 8.91-8.78 (m, 1H), 8.64-8.48 (m, 1H), 8.35-8.14 (m, 2H), 8.03-7.84 (m, 2H), 7.73-7.61 (m, 1H), 7.53-7.43 (m, 2H).

EXAMPLE 73

7-(6-Chloro-5-methyl-lH-benzo[i/] )

73

[0226] Quinoline-7-carboxylic acid (34.6 mg, 0.2 mmol, 1.0 equiv) and 4-chloro-5- methyl-l,2-diaminobenzene (34.5 mg, 0.22 mmol, 1.1 equiv) were suspended in polyphosphoric acid (1.25 g/mmol of the acid). The reaction mixture was heated to 140 °C for 16 hours. After cooling down to room temperature the reaction was quenched by the addition of aqueous 5N sodium hydroxide solution. The resulting precipitate was filtered off and purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x 20 rriL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 13 mg of the desired product 73 as a yellow solid (22% yield) in >95% purity as determined by HPLC. 1H NMR (500 MHz; DMSO): δ 13.26 (s, 1H), 8.99 (d, J = 2.9 Hz, 1H), 8.80 (s, 1H), 8.42 (t, J = 9.4 Hz, 2H), 8.14 (d, J = 8.6 Hz, 1H), 7.74-7.54 (m, 1H), 7.60 (dd, J= 8.2, 4.1 Hz, 1H), 2.45 (s, 3H); LC/MS [m/z]: 294 [M+H]⁺.

EXAMPLE 74

7-(6-(Trifluoromethoxy)-lH-benzo[i/]imidazol-2-yl)quinoline (74)

74

[0227] Quinoline-7-carboxylic acid (34.6 mg, 0.2 mmol, 1.0 equiv) and 4- trifluoromethoxy-l,2-diaminobenzene (40.3 mg, 0.21 mmol, 1.05 equiv) were suspended in dry Ν,Ν-dimethyl formamide (0.17 M) under argon atmosphere followed by the addition of triethylamine (1.2 equiv). Then HATU (N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide) (1.2 equiv) was added and the reaction mixture was stirred for 16 hours at room temperature. After dilution with water, the mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and solvent was removed in vacuo. Solid product was dissolved in glacial acetic acid (0.2 M) and the resulting solution was heated in a sealed vial at 140 °C for 2 hours. After cooling down to room temperature, acetic acid was removed in vacuo and the crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 47.5 mg of the desired product 74 as an off-white solid (38% yield) in >95% purity as determined by HPLC. 1H NMR (500 MHz; CD30D): δ 8.95 (dd, J = 4.3, 1.5 Hz, 1H), 8.71 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.35 (dd, J = 8.6, 1.7 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.61 (dd, J

(s, 1H), 7.24 (d, J= 8.8 Hz, 1H); LC/MS [m/z]: 330 [M+H]⁺.

EXAMPLE 75

iV-(5-(piperidinosulfonyl)phenyl)quinoline-7-carboxamide (75)

[0228] Quinoline-7-carboxylic acid (34.6 mg, 0.2 mmol, 1.0 equiv) was suspended in dry tetrahydrofuran (0.05 M) under argon atmosphere, and triethylamine (1.2 equiv) was added. Then oxalyl chloride (1.2 equiv) was added slowly and the reaction mixture was stirred for 15 minutes at room temperature. Then 4-dimethylaminopyridine (0.2 equiv) was added, followed by l-[(3- aminophenyl)sulfonyl]piperidine (57.7 mg, 0.24 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F254). The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3x20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 34.8 mg of the desired product 75 as a white solid (44% yield) in >95% purity as determined by HPLC. 1H-NMR (500 MHz; CDC1₃): δ 9.14 (s, 1H), 8.94 (s, 1H), 8.68 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.14-8.07 (m, 3H), 7.92 (d, J = 8.5 Hz, 1H), 7.54-7.50 (m, 2H), 7.48 (dd, J = 8.3, 4.1 Hz, 1H), 2.98 (t, J= 5.4 Hz, 4H), 1.58 (dt, J = 11.1, 5.7 Hz, 4H), 1.42-1.36 (m, 2H).

EXAMPLE 76

iV-(2-methyl-5-(morpholinosulfonyl)phenyl)quinoline-7-carboxamide (76)

[0229] Compound 76 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 8.96 (d, J = 2.9 Hz, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 8.37 (s, 1H), 8.22 (dd, J = 8.3, 0.9 Hz, 1H), 8.09 (dd, J = 8.5, 1.6 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.46 (dd, J = 8.0, 1.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 3.71 (app. t, J= 4.7 Hz, 4H), 3.03 (bs, 4H), 2.45 (s, 3H).

EXAMPLE 77

iV-(3-(iV-phenylsulfamoyl)phenyl)quinoline-7-carboxamide (77)

77

[0230] Compound 77 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 9.45 (s, 1H), 8.88 (bs, 1H), 8.78 (bs, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 8.04 (d, J= 8.3 Hz, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 8.2, 4.2 Hz, 1H), 7.26-7.22 (m, 1H), 7.18-7.12 (m, 4H), 7.05-7.02 (m, 1H).

EXAMPLE 78

iV-(3-(iV-(teri-butyl)sulfamoyl)phenyl)quinoline-7-carboxamide (78)

[0231] Compound 78 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CD₃OD): δ 10.85 (s, 1H), 9.04 (dd, J= 4.1, 1.4 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.45 (s, 1H), 8.16-8.12 (m, 2H), 8.05-8.01 (m, 1H), 7.66 (dd, J= 8.3, 4.2 Hz, 1H), 7.60-7.56 (m, 3H), 1.14 (s, 9H).

EXAMPLE 79

iV-(8-(trifluoromethoxy)quinolin- -yl)quinoline-7-carboxamide (79)

79 [0232] Compound 79 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 9.00 (dd, J = 4.1, 1.5 Hz, 1H), 8.93 (s, 2H), 8.69 (s, 1H), 8.30 (dd, J = 8.6, 1.5 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 8.3, 1.4 Hz, 1H), 7.49 (dd, J = 8.3, 4.1 Hz, 1H), 7.43 (dd, J = 8.6, 4.1 Hz, 1H).

EXAMPLE 80

7A^/-(3-fluoro-4-(pyridin-3-yloxy)phenyl)quinoline-7-carboxamide (80)

80

[0233] Compound 80 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 9.72 (s, 1H), 8.86 (d, J = 4.2 Hz, 1H), 8.64 (s, 1H), 8.33 (bs, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 (dd, J = 8.5, 1.6 Hz, 1H), 7.88 (dd, J = 12.3, 2.4 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.25-7.20 (m, 2H), 7.05 (app. t, J = 8.8 Hz, 1H).

EXAMPLE 81

4-((2-(Quinolin-7-yl)- LH-benzo [d] imidazol-6-yl)sulfonyl)morpholine (81)

[0234] Compound 81 was synthesized using the experimental protocol utilized for the synthesis of Compound 74. 1H NMR (500 MHz, CDC1₃): δ 9.19 (s, 1H), 9.00 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.59 (d, J = 8.9 Hz, 1H), 8.06-8.04 (m, 2H), 7.83-7.75 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 3.76-3.67 (m, 4H), 3.00-2.98 (m, 4H).

EXAMPLE 82

iV-(3-Fluoro-4-(2-(trifluoromethyl)phenoxy)phenyl)quinoline-7-carboxamide (82)

[0235] Compound 82 was synthesized according to the protocol outlined in the General

Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.30 (s, 1H), 8.89 (bs, 1H), 8.65 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.06 (dd, J = 8.5, 0.9 Hz, 1H), 7.92-7.82 (m, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H).

EXAMPLE 83

iV-(3-((4-methylpiperazin-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (83)

83

[0236] Compound 83 was synthesized according to the protocol outlined in the General

Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.28 (s, 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.21-8.13 (m, 2H), 8.11-8.03 (m, J = 2.4 Hz, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.44 (dd, J= 8.2, 4.2 Hz, 1H), 3.06 (bs, 4H), 2.46 (bs, 4H), 2.25 (s, 3H).

EXAMPLE 84

iV-(3-(iV-(4-fluorophenyl)sulfamoyl)phenyl)quinoline-7-carboxamide (84)

84

[0237] Compound 84 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 9.43 (s, 1H), 8.78 (bs, 1H), 8.72 (bs, 1H), 8.67 (s, 1H), 8.32 (app. t, J = 1.8 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.97 (dd, J = 8.5, 1.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.3, 4.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.26-7.22 (m, 2H), 7.11-7.05 (m, 2H), 6.87-6.81 (m, 2H).

EXAMPLE 85

7-(6-(Trifluoromethyl)-3H-imida -c]pyridin-2-yl)quinoline (85)

-82- [0238] Compound 85 was synthesized using the experimental protocol utilized for the synthesis of Compound 74. 1H NMR (500 MHz, CDC1₃): δ 8.96 (s, 1H), 8.93 (dd, J = 4.2, 1.5 Hz, 1H), 8.71 (s, 1H), 8.40 (d, J = 8.3 Hz, 1H), 8.33 (dd, J = 8.5, 1.7 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.60 (dd, J= 8.3, 4.3 Hz, 1H).

EXAMPLE 86

iV-(4-chlorophenyl)-6-methylquinoline-7-carboxamide (86)

Synthesis of 7-Bromo-6-methylquinoline (Int-1)

Int-1

Int-1 Int-IA

[0239] A mixture of 3-bromo-4-methylaniline (15 g, 80.6 mmol, 1 eq) and acrolein diethyl acetal (26.2 g, 201 mmol, 2.5 eq) in IN HC1 (1500 mL) was heated at 100 °C for 24 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled down to room temperature, basified to pH^~9 with solid Na₂C03 and extracted with DCM (3 x 500 mL). Organic layers were combined, washed with DI water (200 mL), brine (200 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using 20% EtOAc in Petroleum ether as eluent to give 5 g of compound Int-1 & Int-IA as a mixture of isomers. Reverse-phase HPLC purification afforded 500 mg of the desired compound Int-1 as a pale-yellow liquid. H₂N

[0240] To a cooled solution of 3-bromo-4-methylaniline (20 g, 107.5 mmol) in nitrobenzene (11.1 rriL, 107.5 mmol) and glycerol (19.6 mL, 268.8 mmol) at 0 °C was added cone. H₂SO₄ (48 mL, 2.4 vol per g) slowly over a period of 24 min. The reaction temperature was gradually increased to 150 °C, and the reaction mixture was stirred at 150 °C for 6 hrs. Then it was allowed to cool down to r.t, poured into crushed ice, and extracted with Ethyl Acetate (3 x 500 mL). Combined organic layers were washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 20% Ethyl Acetate in Hexane as eluent to afford 15 g (63% yield) of isomeric mixture of 7-bromo-6-methylquinoline Int-1 and 8-bromo-7- methylquinoline Int-1 A as a brown solid. The isomeric mixture of compound Int-1 and Int-IA (13 g) was separated by prep-HPLC purification to afford 5 g (21% yield) of Compound Int-1.

MS (ESI) m/z 223.98 [M+H] .

[0241] Int-1 : 1H NMR (400 MHz, CDC1₃): δ 8.87-8.84 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.329-8.301 (d, J = 11.2 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), Ί .53-1.51 (dd, J = 5.6 Hz, 5.2 Hz, 1H), 2.5 (s, 3H).

[0242] Compound 86 was synthesized using Int-1 according to the protocol outlined in the General Experimental Procedure VI. 1H NMR (500 MHz, CD₃OD): δ 8.92 (bs, 1H), 8.81 (bs, 1H), 8.50 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.81-7.69 (m, 2H), 7.60 (dd, J = 7.9, 4.1 Hz, 1H), 7.39 (d, J= 8.7 Hz, 2H), 2.74 (s, 3H).

EXAMPLE 87

iV-(3-Chlorophenyl)-6-methylquin

87

[0243] Compound 87 was synthesized using Int-1 (Example 86) according to the protocol outlined in the General Experimental Procedure VI. 1H NMR (500 MHz, CDC1₃): δ 8.89 (bs, 1H), 8.82 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.56 (d, J = 6.3 Hz, 2H), 7.29 (t, J= 8.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 2.68 (s, 3H). EXAMPLE 88

iV-(3-((3-oxopiperazin-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (88)

88

[0244] Compound 88 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, DMSO-d₆): δ 10.92 (s, 1H), 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (s, 1H), 8.49 (dd, J = 8.4, 1.0 Hz, 1H), 8.37 (t, J = 1.9 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.18-8.13 (m, 2H), 8.10 (s, 1H), 7.70-7.66 (m, 2H), 7.56 (d, J= 7.8 Hz, 1H), 3.56 (bs, 2H), 3.23 (bs, 4H).

EXAMPLE 89

iV-(4-chloro-3-(iV-(4-chlorophenyl)sulfamoyl)phenyl)quinoline-7-carboxamide (89)

89

[0245] Compound 89 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, DMSO-d₆): δ 10.94 (s, 1H), 10.82 (s, 1H), 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.74 (s, 1H), 8.68 (d, J = 2.6 Hz, 1H), 8.48 (dd, J = 8.3, 0.9 Hz, 1H), 8.17-8.09 (m, 3H), 7.68 (dd, J = 8.3, 4.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.33-7.28 (m, 2H), 7.15-7.11 (m, 2H).

EXAMPLE 90

iV-(3-(iV-(3-chlorophenyl)sulfamoyl)phenyl)quinoline-7-carboxamide (90)

90

[0246] Compound 90 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 8.97 (dd, J = 4.3, 1.6 Hz, 1H), 8.59 (s, 1H), 8.46-8.43 (m, 2H), 8.11 (dd, J= 8.5, 1.7 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.97 (d, J= 8.1 Hz, 1H), 7.64 (dd, J = 8.3, 4.3 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.11 (d, J= 8.2 Hz, 1H), 7.07 (d, J= 8.0 Hz, 1H).

EXAMPLE 91

iV-(3-(iV-methyl-iV-phenylsulfamoyl)phenyl)quinoline-7-carboxamide (91)

91

[0247] Compound 91 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.47 (s, 1H), 8.90 (s, 1H), 8.67 (s, 1H), 8.27 (dd, J= 8.2, 1.2 Hz, 1H), 8.21 (d, J= 7.7 Hz, 1H), 8.10 (dd, J = 8.5, 1.6 Hz, 1H), 7.98 (app. t, J = 1.7 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.52-7.43 (m, 2H), 7.29-7.21 (m, 4H), 7.09-7.08 (m, 2H), 3.22 (s, 3H).

EXAMPLE 92

iV-(4-chlorophenyl)-2-(quino amide (92)

92

[0248] Compound 92 was synthesized according to the experimental protocol utilized for the synthesis of Compound 74. Rotamers were observed. 1H NMR (500 MHz, CDCL): δ 13.68 (bs, 3.1H), 10.50 (bs, 1.3H), 10.33 (bs, 3.1H), 9.01 (dd, J = 4.1, 1.5 Hz, 2.0H), 8.99-8.97 (m, 1.0H), 8.83 (s, 2.3H), 8.69 (d, J= 10.1 Hz, 1.2H), 8.46-8.41 (m, 4.8H), 8.27 (d, J= 2.1 Hz, 0.8H), 8.20-8.02 (m, 3. OH), 8.13-8.06 (m, 2.3H), 7.97 (d, J = 8.6 Hz, 1.0H), 7.77 (bs, 3.1H), 7.70-7.61 (m, 5.2H), 7.35- 7.31 (m, 1.1H), 7.31-7.24 (m, 3.8H), 7.21-7.17 (m, 1.2H), 7.17-7.11 (m, 3.8H).

EXAMPLE 93

2-(Quinolin-7-yl)-iV-(3-(trifluoromethyl)phenyl)-lH-benzo[i ]imidazole-6-sulfonamide (93)

93 [0249] Compound 93 was synthesized according to the experimental protocol utilized for the synthesis of Compound 74. Rotamers were observed. 1H NMR (500 MHz, DMSO-d₆): δ 13.69 (bs, 2.0H), 10.76 (bs, 2.3H), 10.49 (bs, 1.3H), 9.01 (d, J = 4.2 Hz, 1.7H), 8.99-8.97 (m, 1.0H), 8.83 (s, 1.9H), 8.69 (d, J = 7.0 Hz, 1.0H), 8.46-8.38 (m, 4.3H), 8.29 (s, 0.7H), 8.17 (d, J = 8.6 Hz, 2.2H), 8.20-8.04 (m, 1.0H), 8.11 (d, J= 7.7 Hz, 1.8H), 7.98 (d, J= 8.6 Hz, 1.0H), 7.85-7.71 (m, 3.1H), 7.68 (bs, 1.9H), 7.64-7.60 (m, 2.8H), 7.53-7.39 (m, 7.4H), 7.36-7.32 (m, 2.5H).

EXAMPLE 94

iV-(4-(iV-phenylsulfamoyl)phenyl)quinoline-7-carboxamide (94)

94

[0250] Compound 94 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.61 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.13-8.06 (m, 2H), 7.86-7.82 (m, 3H), 7.66 (dd, J = 8.3, 4.3 Hz, 1H), 7.26 (bs, 1H), 7.12-7.07 (m, 2H), 7.02 (d, J= 7.4 Hz, 2H), 6.82 (app. t, J= 6.8 Hz, 1H).

EXAMPLE 95

-(4-Chlorophenyl)-5-methylquinoline-7-carboxamide (95)

Int-2 Int-2A [0251] 3-Bromo-5-methylaniline (372.2 mg, 2.0 mmol) was dissolved in aqueous 1 N hydrochloric acid (160 mL), and acrolein diethylacetal (762 μΐ_^, 5.0 mmol) was added. The reaction mixture was heated to reflux for 24 hours. After cooling to room temperature, the dark brown solution was neutralized with solid potassium carbonate and extracted with dichloromethane (3 x 150 mL). Combined organic layers were washed with brine (1 x 150 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel using a mixture of dichloromethane and methanol (100:0 to 90: 10 gradient) as eluent. The product was obtained as brown oil as a mixture of isomers Int-2 and Int-2A (1.5: 1) in 35% yield. Major isomer: 'H- MR (500 MHz, CDC1₃): δ 8.88 (dd, J = 4.2, 1.3 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.42 (dd, J= 8.5, 4.2 Hz, 1H), 2.65 (s, 3H); Minor isomer: 1H-NMR (500 MHz, CDC1₃): δ 8.90 (dd, J = 4.1, 1.4 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 7.48 (s, 1H), 7.42 (dd, J = 8.5, 4.2 Hz, 1H), 2.54 (s, 3H).

[0252] A 10 mL microwave vial was charged with the bromoquinoline isomer mixture Int-2 & Int-2A (44.4 mg, 0.2 mmol), ira«^-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]- dipalladium(II) (18.8 mg, 0.02 mmol; CAS: 172418-32-5), molybdenumhexacarbonyl (52.8 mg, 0.2 mmol), dry THF (0.5 mL) and 4-chloroaniline (77 mg, 0.6 mmol). Then l,8-diazabicycloundec-7- ene (90 μL, 0.6 mmol) was added and the microwave vial was sealed immediately (a gas evolution was observed). The reaction mixture was heated to 150 °C for 2 hours. After cooling down to room temperature, the reaction mixture was filtered through Celite plug, washed with DCM and the filtrate was concentrated in vacuo. The first purification was performed on silica gel with DCM/methanol (gradient: 0% to 40% methanol). The isomers were separated in a second purification on CI 8 column with (water + 0.1% TFA)/(acetonitrile + 0.1% TFA) as eluent. The desired product 95 was obtained as a light yellow solid in 15% yield (9 mg). 1H NMR (500 MHz, CDC1₃): δ 9.06 (bs, 1H), 8.63-8.48 (m, 3H), 8.04 (s, 1H), 7.75 (d, J= 8.8 Hz, 2H), 7.65 (dd, J = 8.1, 3.7 Hz, 1H), 7.41 (d, J - 8.8 Hz, 2H), 2.83 (s, 3H).

EXAMPLE 96

iV-(3-chlorophenyl)-5-methylquinoline-7-carboxamide (96)

[0253] A 10 mL microwave vial was charged with the bromoquinoline isomer mixture Int-2 & Int-2A (Example 95) (22.2 mg, 0.1 mmol), iram-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]-dipalladium(II) (9.4 mg, 0.01 mmol; CAS: 172418-32-5), molybdenumhexacarbonyl (26.4 mg, 0.1 mmol), dry THF (0.25 mL) and 3- chloroaniline (32 μΕ, 0.3 mmol). Then, l,8-diazabicycloundec-7-ene (45 μΕ, 0.3 mmol) was added and the microwave vial was sealed immediately (a gas evolution is observed). The reaction mixture was heated to 150 °C for 2 hours. After cooling down to room temperature, the reaction mixture was filtered through Celite plug. The plug was washed with DCM, and the filtrate was concentrated in vacuo. The first purification was performed on silica gel with DCM/methanol (gradient: 0% to 40% methanol). The isomers were separated in a second purification on reversed-phase CI 8 column with (water + 0.1% TFA)/(acetonitrile + 0.1% TFA). The desired product 96 was obtained as a white solid in 12% yield (7 mg). 1H NMR (500 MHz, CDCL): δ 8.96 (bs, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.60-7.57 (m, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.12 (dd, J= 8.0, 1.1 Hz, 1H), 2.76 (s, 3H).

EXAMPLE 97 iV-(3-(iV-cyclopropylsulfamoyl)phenyl)quinoline-7-carboxamide (97)

[0254] Compound 97 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 9.57 (s, 1H), 8.78 (d, J = 3.0 Hz, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (dd, J = 8.5, 1.6 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.41-7.32 (m, 2H), 6.78 (s, 1H), 2.27- 2.23 (m, 1H), 0.56-0.48 (m, 4H).

EXAMPLE 98

iV-(3-(iV-cyclohexylsulfamoyl)phenyl)quinoline-7-carboxamide (98)

98

[0255] Compound 98 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 9.56-9.52 (m, 1H), 8.82 (bs, 1H), 8.70 (bs, 1H), 8.32-8.28 (m, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.13-8.05 (m, 1H), 8.01-7.97 (m, 1H), 7.83- 7.74 (m, 1H), 7.60 (dd, J = 7.8, 0.9 Hz, 1H), 7.45-7.34 (m, 2H), 6.08-5.96 (m, 1H), 3.13 (bs, 1H), 1.74 (bs, 2H), 1.57 (bs, 2H), 1.46-1.41 (m, 1H), 1.19-1.08 (m, 4H), 1.04-0.97 (m, 1H).

EXAMPLE 99

iV-(3-(iV^V-diethylsulfamoyl)phenyl)quinoline-7-carboxamide (99)

[0256] Compound 99 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.65 (s, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 8.18 (s, 1H), 8.11 (dd, J = 8.3, 0.9 Hz, 1H), 8.06-8.04 (m, 1H), 8.03 (dd, J = 8.6, 1.7 Hz, 1H), 7.81 (d, J= 8.5 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.38 (dd, J= 7.9, 3.8 Hz, 1H), 3.16 (q, J = 7.2 Hz, 4H), 1.02 (t, J= 7.2 Hz, 6H). EXAMPLE 100

iV-(3-(pyrrolidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (100)

100

[0257] Compound 100 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, DMSO-d₆): δ 9.68 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 8.23-8.21 (m, 2H), 8.10 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H), 3.23-3.11 (m, 4H), 1.66-1.62 (m, 4H).

EXAMPLE 101

iV-(4-chloro-3-(iV^V-diethylsulfamoyl)phenyl)quinoline-7-carboxamide (101)

101

[0258] Compound 101 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 9.19 (bs, 1H), 8.94 (bs, 1H), 8.68 (bs, 1H), 8.26 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.16 (dd, J = 8.7, 2.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 4.1 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 3.36 (q, J = 7.1 Hz, 4H), 1.08 (t, J= 7.1 Hz, 6H).

EXAMPLE 102

iV-(4-chloro-3-(piperidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (102)

102

[0259] Compound 102 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.36 (s, 1H), 8.94 (s, 1H), 8.73 (s, 1H), 8.26-8.16 (m, 3H), 8.11 (d,J=8.5Hz, 1H), 7.91 (d,J=8.5Hz, 1H), 7.50 (dd, J

7.45 (d,J=8.7Hz, 1H), 3.32-3.10 (m, 4H), 1.63-1.59 (m, 4H), 1.45-1.43 (m, 2H)

EXAMPLE 103

iV-(3-(cyclohexylsulfonyl)phenyl)quinoline-7-carboxamide (103)

[0260] Compound 103 was synthesized according to the protocol outlined in the General Experimental Procedure I.1H NMR (500 MHz, CDCL): δ 9.28 (s, 1H), 8.93 (s, 1H), 8.70 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 8.20 (d, J= 8.4 Hz, 1H), 8.14 (s, 1H), 8.10 (dd, J= 8.5, 1.4 Hz, 1H), 7.90 (d, J= 8.5 Hz, 1H), 7.62-7.56 (m, 1H), 7.51 (t, J= 7.9 Hz, 1H), 7.47 (dd, J= 8.3, 4.3 Hz, 1H), 2.96- 2.86 (m, 1H), 2.07-1.95 (m, 2H), 1.83-1.73 (m, 2H), 1.65-1.56 (m, 1H), 1.41-1.26 (m, 2H), 1.25-1.00 (m, 3H).

EXAMPLE 104

iV-(2-chlorophenyl)-2-(quinoli -7-yl)-lH-benzo[i]imidazole-6-sulfonamide (104)

104

[0261] Compound 104 was synthesized according to the experimental protocol utilized for the synthesis of Compound 74.1H NMR (500 MHz, CDC1₃): δ 10.22 (bs, 1H), 10.07 (bs, 1H), 8.91 (d,J=24.8Hz, 1H), 8.67 (d,J=16.7Hz, 1H), 8.63 (bs, 1H), 8.35 (d, J = 6.6 Hz, 1H), 8.11 (d, J= 8.2 Hz, 1H), 7.94 (d, J= 8.1 Hz, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.76 (dd, J= 8.5, 6.2 Hz, 1H), 7.68 (bs, 1H), 7.55 (bs, 1H), 7.36-7.29 (m, 1H), 7.25-7.19 (m, 1H), 7.17 (bs, 1H).

EXAMPLE 105

iV-(3-(cyclopentylsulfonyl)phenyl)quinoline-7-carboxamide (105)

[0262] Compound 105 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.37 (s, 1H), 8.92 (s, 1H), 8.70 (s, 1H), 8.27-8.16 (m, 3H), 8.10 (dd, J = 8.5, 1.2 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H), 3.57-3.51 (m, 1H), 2.09-1.94 (m, 2H), 1.91- 1.75 (m, 2H), 1.75-1.64 (m, 2H), 1.61-1.48 (m, 2H).

EXAMPLE 106

iV-(4-(iV-cyclohexylsulfamoyl)phenyl)quinoline-7-carboxamide (106)

106

[0263] Compound 106 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.63 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.67 (dd, J = 8.3, 4.3 Hz, 1H), 3.06-3.00 (m, 1H), 1.80-1.60 (m, 4H), 1.60-1.54 (m, 1H), 1.29-1.10 (m, 5H).

EXAMPLE 107

iV-(4-chloro-3-(iV^V-dimethylsulfamoyl)phenyl)quinoline-7-carboxamide (107)

107

[0264] Compound 107 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDCL): δ 9.31 (s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 8.28-8.14 (m, 3H), 8.07 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.47 (app. d, J = 8.5 Hz, 2H), 2.84 (s, 6H).

EXAMPLE 108

iV-(4-chloro-3-(pyrrolidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (108)

108

[0265] Compound 108 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CDC1₃): δ 9.82 (s, 1H), 8.93 (d, J = 3.0 Hz, 1H), 8.74 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.22 (dd, J = 8.7, 2.6 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.10 (dd, J= 8.5, 1.6 Hz, 1H), 7.88 (d, J= 8.5 Hz, 1H), 7.47 (dd, J= 8.3, 4.2 Hz, 1H), 7.44 (d, J= 8.7 Hz, 1H), 3.42-3.33 (m, 4H), 1.87-1.82 (m, 4H).

EXAMPLE 109

iV-(2-chloro-5-(morpholinosulfonyl)phenyl)quinoline-7-carboxamide (109)

109

[0266] Compound 109 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 9.05 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.16 (dd, J = 8.5, 1.4 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.59 (dd, J= 8.3, 4.2 Hz, 1H), 7.53 (dd, J= 8.4, 2.1 Hz, 1H), 3.78 (t, J= 4.7 Hz, 4H), 3.13 (t, J= 4.6 Hz, 4H).

EXAMPLE 110

iV-(2-chloro-5-(pyrrolidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (110)

110

[0267] Compound 110 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDCL): δ 9.04-9.03 (m, 2H), 8.78 (s, 1H), 8.67 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 7.58 (dd, J= 8.3, 4.2 Hz, 1H), 3.39-3.32 (m, 4H), 1.89-1.80 (m, 4H).

EXAMPLE 111

iV-(4-chloro-3-(morpholinosulfonyl)phenyl)quinoline-7-carboxamide (111)

111

[0268] Compound 111 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.97 (dd, J = 4.3, 1.6 Hz, 1H), 8.60 (s, 1H), 8.55 (d, J= 2.6 Hz, 1H), 8.44 (dd, J = 8.4, 0.8 Hz, 1H), 8.11 (dd, J= 8.5, 1.7 Hz, 1H), 8.09 (t, J = 8.5 Hz, 1H), 8.05 (dd, J= 8.7, 2.6 Hz, 1H), 7.64 (dd, J= 8.3, 4.3 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 3.72 (t, J= 4.8 Hz, 4H), 3.32-3.29 (m, 4H).

EXAMPLE 112

iV-(2-chloro-5-(iV^V-dimethylsulfamoyl)phenyl)quinoline-7-carboxamide (112)

112

[0269] Compound 112 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (600 MHz, CDC1₃): δ 9.05 (bs, 1H), 9.02 (bs, 1H), 8.75 (bs, 1H), 8.64 (bs, 1H), 8.28 (bs, 1H), 8.15 (bs, 1H), 8.02 (bs, 1H), 7.63-7.47 (m, 3H), 2.82 (s, 6H).

EXAMPLE 113

iV-(2-chloro-5-(piperidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (113)

113

[0270] Compound 113 was synthesized according to the protocol outlined in the General Experimental Procedure II. 1H NMR (500 MHz, CDC1₃): δ 9.05 (d, J = 3.3 Hz, 1H), 8.99 (d, J = 2.1 Hz, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 8.30 (dd, J = 8.3, 0.8 Hz, 1H), 8.16 (dd, J = 8.5, 1.7 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.3, 4.2 Hz, 1H), 7.53 (dd, J = 8.4, 2.1 Hz, 1H), 3.11 (t, J= 5.5 Hz, 4H), 1.70-1.66 (m, 4H), 1.51-1.43 (m, 2H).

EXAMPLE 114

iV-(3-fluoro-4-(2-methoxyethoxy)phenyl)quinoline-7-carboxamide (114)

114

[0271] Compound 114 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.97 (dd, J = 4.3, 1.7 Hz, 1H), 8.58 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.10 (s, 2H), 7.69 (dd, J= 13.2, 2.5 Hz, 1H), 7.65 (dd, J= 8.3, 4.3 Hz, 1H), 7.44 (dt, J = 8.7, 1.9 Hz, 1H), 7.14 (t, J = 9.1 Hz, 2H), 4.21-4.20 (m, 2H), 3.78-3.76 (m, 2H), 3.45 (s, 3H).

EXAMPLE 115

iV-(3-(iV A^/-dimethylsulfamoyl)-4-fluorophenyl)quinoline-7-carboxamide (115)

115

[0272] Compound 115 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.99 (dd, J = 4.3, 1.7 Hz, 1H), 8.63 (s, 1H), 8.47 (d, J = 9.0 Hz, 1H), 8.33 (dd, J = 6.1, 2.8 Hz, 1H), 8.15-8.07 (m, 3H), 7.66 (dd, J = 8.3, 4.3 Hz, 1H), 7.40 (t, J= 9.4 Hz, 1H), 2.86 (s, 3H), 2.85 (s, 3H).

EXAMPLE 116

iV-(3-(iV-cyclohexyl-iV-methylsulfamoyl)phenyl)quinoline-7-carboxamide (116)

116

[0273] Compound 116 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.98 (dd, J = 4.3, 1.6 Hz, 1H), 8.62 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.41 (s, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.99 (dt, J = 7.0, 2.1 Hz, 1H), 7.66 (dd, J = 8.3, 4.3 Hz, 1H), 7.62-7.58 (m, 2H), 3.80-3.72 (m, J = 3.3 Hz, 1H), 2.81 (s, 3H), 1.76-1.59 (m, 3H), 1.50-1.29 (m, 5H), 1.11-1.03 (m, 2H).

EXAMPLE 117

iV-(3-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (117)

117

[0274] Compound 117 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.96 (dd, J = 4.3, 1.6 Hz, 1H), 8.60 (s, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.39 (s, 1H), 8.11 (dd, J = 8.5, 1.6 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.00-7.97 (m, 1H), 7.63 (dd, J = 8.3, 4.3 Hz, 1H), 7.59 (d, J = 5.2 Hz, 2H), 3.48-3.44 (m, 2H), 3.42 (t, J = 6.3 Hz, 2H), 2.75-2.71 (m, 2H), 2.68-2.62 (m, 2H), 2.36 (s, 3H), 1.89 (dt, J = 11.4, 5.8 Hz, 2H).

EXAMPLE 118

iV-(4-methoxy-3-(piperidin-l-ylsulfonyl)phenyl)quinoline-7-carboxamide (118)

[0275] Compound 118 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.98 (dd, J = 4.2, 1.6 Hz, 1H), 8.61 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 8.14-8.08 (m, 2H), 8.03 (dd, J = 8.9, 2.7 Hz, 1H), 7.66 (dd, J = 8.3, 4.3 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.23 (t, J = 5.3 Hz, 4H), 1.68-1.52 (m, 6H).

EXAMPLE 119

iV-(4-fluoro-3-(morpholinosulfonyl)phenyl)quinoline-7-carboxamide (119)

119

[0276] Compound 119 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.94 (dd, J = 4.3, 1.7 Hz, 1H), 8.58 (s, 1H), 8.41 (d, J= 8.3 Hz, 1H), 8.31 (dd, J = 6.1, 2.7 Hz, 1H), 8.08 (td, J= 7.2, 1.8 Hz, 2H), 8.05 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 8.3, 4.3 Hz, 1H), 7.37 (t, J = 9.4 Hz, 1H), 3.72-3.66 (m, 4H), 3.21-3.13 (m, 4H).

EXAMPLE 120

iV-(4-fluoro-3-(iV-methylsulfamoyl)phenyl)quinoline-7-carboxamide (120)

120

[0277] Compound 120 was synthesized according to the protocol outlined in the General Experimental Procedure I. 1H NMR (500 MHz, CD₃OD): δ 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.62 (s, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.34 (dd, J = 6.2, 2.7 Hz, 1H), 8.15-8.06 (m, 3H), 7.66 (dd, J = 8.4, 4.3 Hz, 1H), 7.37 (t, J= 9.4 Hz, 1H), 2.65 (s, 3H).

EXAMPLE 121

6-Methyl-N-(4-(trifluoromethoxy)phenyl)quinoline-7-carboxamide (121)

121

[0278] Pd(OAc)₂ (10 mg, 0.045 mmol, 0.1 eq)_, Mo(CO)₆ (118 mg, 0.45 mmol, 1.0 eq) and t-Bu3PHBF₄ (16 mg, 0.055 mmol, 0.12 eq) were added to the de-gassed reaction mixture of the compound Int-1 (100 mg, 0.45 mmol, 1.0 eq) (see Example 85) and 4-(trifluoromethoxy)-aniline (161 mg, 0.91 mmol, 2.0 eq) in a mixture of dry acetonitrile and Na₂C03 (96 mg, 0.91 mmol, 2.0 eq) and the reaction mixture was irradiated at 90 °C under microwave conditions for 90 min. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc in petroleum ether as eluent to give 25 mg of the desired product 121 as a white solid in 15% yield. 99.35% purity by LCMS; MS (ESI) m/z = 347.19 [M+H]⁺. 1H NMR (400 MHz, CDC1₃): δ 8.90-8.88 (dd, J= 4.4 Hz, 1.6 Hz, 1H), 8.247 (s, 1H), 8.11-8.08 (m, 2H), 7.75-7.73 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.46-7.42 (dd, J = 8.0 Hz, 4.4 Hz, 1H), 7.27-7.25 (m, 2H), 2.65 (s, 3H).

EXAMPLE 122

6-Chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-7-carboxamide (122)

122

Synthesis of 7-Bromo-6-chloroquinoline (Int-3)

Int-3

[0279] A mixture of 3-bromo-4-chloroaniline (10 g, 48 mmol, 1.0 eq), acrolein diethyl acetal (15.75 g, 121 mmol, 2.5 eq) in IN HC1 (1000 mL) was heated at 120 °C for 24 hrs. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was cooled down to room temperature and basified to pH ~ 9 with solid Na₂CC>3. The aqueous layer was extracted with DCM (3 x 300 mL). The organic layers were combined, washed with water (100 mL), brine (100 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give crude product. The crude was purified by silica gel column chromatography using 20% EtOAc in petroleum ether as eluent to give 5 g of compound Int-3 & Int-3A as a mixture of isomers. Reverse phase HPLC purification provided 500 mg of the desired compound Int-3 as a pale-yellow liquid.1H NMR (400 MHz, DMSO-d6): δ 8.93-8.95(dd, J = 3.6, 2.4 Hz, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 7.63-7.59 (dd, J= 5.6 Hz, 1H). 98.25% purity by LCMS; MS (ESI) m/z =244.12 [M+2H]⁺.

HoN

[0280] To a cooled solution of 3-bromo-4-chloroaniline (20 g, 97.087 mmol) in nitrobenzene (10 mL, 97.087 mmol) and glycerol (17.69 g, 242.71 mmol) at 0 °C was added concentrated H₂S0₄ (48 mL, 2.4 vol per g) slowly over a period of 24 min. The reaction temperature was gradually increased to 150 °C and the reaction mixture was stirred at 150 °C for 6 hrs. Then the reaction mixture was allowed to cool down to r.t., poured into crushed ice, and then extracted with Ethyl Acetate (3 x 500 mL). Combined organic layers were washed with water (300 mL), brine (300 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 20% Ethyl Acetate in Hexane as eluent to give 13 g (56% yield) of racemic mixture of 7-bromo-6- chloroquinoline Int-3 and 5-bromo-6-chloroquinoline Int-3A as a brown solid. The racemic mixture of compound Int-3 and Int-3A (13 g) was separated by SFC purification using C0₂ gas and IPA as a co-solvent to give 3.4 g (26% Yield) of the desired compound Int-3. MS (ESI) m/z 241.9 [M+H]⁺ 1H NMR (400 MHz, DMSO-d6): δ 8.93-8.95(dd, J= 3.6, 2.4 Hz, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 7.63-7.59 (dd, J= 5.6 Hz, 1H).

Synthesis of Methyl 6-Chloroquinoline-7-carboxylate (Int-4)

Int-4

[0281] A mixture of compound Int-3 (1.0 g, 4.13 mmol, 1.0 eq) and NaOAc (1.02 g, 12.5 mmol, 3.0 eq) in 1 : 1 MeOH/DMF (20 mL) was de-gassed with Argon gas for 10 min. Then PdCl₂(dppf).DCM (340 mg, 0.413 mol, 0.1 eq) was added, and the mixture was de-gassed with Argon for additional 15 min. Then the reaction mixture was heated at 70 °C in steel bomb under CO atmosphere for 6 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using 50% EtOAc in petroleum ether to give 350 mg of the desired compound Int-4 as a pale-yellow solid in 38% yield. 1H NMR (400 MHz, CDC1₃): δ 8.975- 8.990 (dd, J = 1.6 Hz, 2.4 Hz, 1H), 8.58 (s, 1H), 8.097- 8.118 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.48 - 7.52 (dd, J= 4.4 Hz, 0.4 Hz, 1H), 4.01 (s, 3H). LCMS: 99.90 % (m/z =222.15 [M+H]⁺).

Synthesis of 6-Chloroquinoline-7-carboxylic acid (Int-5)

Int-5

[0282] Lithium hydroxide monohydrate (114 mg, 2.71 mmol, 2.0 eq) was added to a solution of compound Int-4 (300 mg, 1.35 mmol, 1.0 eq) in 4:2: 1 mixture of THF/H₂0/MeOH (1 mL), and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with DI water, acidified to pH ~ 4 with IN HC1 and extracted with EtOAc. Organic layers were combined, washed with water and brine, separated, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 210 mg of the desired compound Int-5 as a pale-yellow solid in 74% yield. LCMS: 99.46 % purity (m/z =208.16 [M+H]⁺). 1H NMR (400 MHz, CDC1₃): δ 9.174 -9.184 (d, J = 4.0 Hz, 1H), 8.921 (s, 1H), 8.185- 8.912 (d, J = 10.8 Hz, 1H), 8.003 (s, 1H), 7.579 - 7.622 (m, 1H).

[0283] Compound Int-5 (90 mg, 0.43 mmol, 1.0 eq) and 4-(trifluoromethoxy)aniline (84 mg, 0.47 mmol, 1.1 eq) were dissolved in DMF (3 rriL), and the resulting mixture was cooled down to 0 °C. HATU (181 mg, 0.47 mmol, 1.1 eq) and DIPEA (0.16 mL, 0.868 mmol, 2.0 eq) were added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 3 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried in vacuo to give 40 mg of the desired compound 122 as a white solid in 25% yield. 98.85% purity by LCMS; MS (ESI) m/z =367.12 [M+H]⁺. 1H NMR

(400 MHz, CDC1₃): δ 8.98-8.97 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.37 (s, 1H), 8.31 (brs, 1H), 8.09-8.08 (d, J =7.6 Hz, 1H), 7.85 (s, 1H), 7.78-7.76 (d, J = 8.8 Hz, 2H), 7.52-7.49 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 7.28-7.26 (d, J= 8.8 Hz, 2H).

EXAMPLE 123

6-Fluoro-N-(4-(trifluoromethoxy)phenyl)quinoline-7-carboxamide (123)

123

Synthesis of 7-Bromo-6-fluoroquinoline (Int-6)

Int-6 Int-6A [0284] A mixture of 3-bromo-4-fluoroaniline (15 g, 78.9 mmol, 1.0 eq), acrolein diethyl acetal (25.8 g, 197 mmol, 2.5 eq) in IN HC1 (1500 mL) was heated at 120 °C for 24 hrs. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was cooled down to room temperature and basified to pH ~ 9 with solid Na₂CC>3. The aqueous layer was extracted with DCM (3 x 300 mL). Organic layers were combined, washed with water (200 mL), brine (200 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 20% EtOAc in petroleum ether as eluent to give 6 g of compound Int-6 & Int-6A as a mixture of isomers. Reverse phase HPLC purification provided 600 mg of the desired compound Int-6 as a pale-yellow solid. 1H NMR (400

MHz, CDC1₃): δ 8.94-8.92 (dd, J = 3.6 Hz, 1.6 Hz, 1H), 8.43 (d, J = 18.4 Hz, 1H), 8.41 (s, 1H), 8.03-8.0 (d, J = 12.4 Hz, 1H), 7.65-7.60 (dd, J = 5.6 Hz, 5.2 Hz, 1H). 98.70% purity by LCMS; MS (ESI) m/z =228.09 [M+H])⁺.

[0285] A solution of 3-bromo-4-fluoroaniline (20 g, 105.2 mmol) and glycerol (20.1 mL, 263.1 mmol) in nitrobenzene (10.8 mL, 105.2 mmol) was cooled to 0 °C, and cone. H₂S0₄ (48 mL, 2.4 vol per g) was added slowly over a period of 24 min. The reaction temperature was gradually increased to 150 °C and the reaction mixture was stirred at 150 °C for 5 hrs. Then the reaction mixture was allowed to cool down to r.t., poured into crushed ice, and extracted with Ethyl Acetate (3 x 500 mL). Combined organic layers were washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 20% Ethyl Acetate in Hexane as eluent to afford 14 g (59% yield) isomeric mixture of 7-bromo-6-fluoroquinoline Int-6 and 8-bromo-7-fluoroquinoline Int-6A as a brown solid. The isomeric mixture of compound Int-6 and Int-6A (14 g) was separated by prep-HPLC purification to afford 3.6 g (15% yield) of compound Int-6. MS (ESI) m/z 227.95 [M+H]⁺.

[0286] A mixture of compound Int-6 (100 mg, 0.442 mmol, 1.0 eq), 4- (trifluoromethoxy)-aniline (156 mg, 0.88 mmol, 2.0 eq) and Na₂CC>3 (94 mg, 0.884 mmol, 2.0 eq) in dry acetonitrile (1 mL) was de-gassed with argon for 10 min. Then Pd(OAc)₂ (10 mg, 0.044 mmol, 0.1 eq)_, Mo(CO)₆ (118 mg, 0.44 mmol, 1.0 eq) and t-Bu₃PHBF₄ (15.4 mg, 0.05 mmol, 0.12 eq) were added, and the resulting mixture was de-gassed with argon gas for additional 10 min. Then the reaction mixture was irradiated at 90 °C under microwave for 90 min. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography using 50% EtOAc in petroleum ether as eluent to give 25 mg of the desired compound 123 as a white solid in 17% yield. 1H NMR (400 MHz, CDC1₃): δ 9.01-9.0 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.96-8.94 (d, J = 7.6 Hz, 1H), 8.53-8.50 (d, J = 14 Hz, 1H), 8.17-8.15 (d, J = 8.0 Hz, 1H), 7.77-7.75 (d, J = 8.8 Hz, 2H), 7.62- 7.58 (d, J = 12.4 Hz, 1H), 7.54-7.51 (dd, J = 8.8 Hz, 4.4 Hz, 1H), 7.27-7.25 (d, J = 8.8 Hz, 2H). 99.40% purity by LCMS; m/z =351.15 [M+H]⁺.

EXAMPLE 124

6-Chloro-N-(4-chlorophenyl)quin

124

[0287] Compound Int-5 (Example 122) (90 mg, 0.43 mmol, 1.0 eq) and 4-chloroaniline (61 mg, 0.48 mmol, 1.1 eq) were dissolved in DMF (3 mL), and the resulting mixture was cooled down to 0 °C. HATU (181 mg, 0.47 mmol, 1.1 eq) and DIPEA (0.16 mL, 0.868 mmol, 2.0 eq) were added to the reaction mixture at 0 °C, then the reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 3 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried in vacuo to give 35 mg of the desired compound 124 as a white solid in 25% yield. 1H NMR (400 MHz, CDC1₃): δ 8.98-8.97 (dd, J =4.0 Hz, 1.6 Hz, 1H), 8.38 (s, 1H), 8.19 (brs, 1H), 8.10-8.08 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.69-7.66 (d, J = 8.8 Hz, 2H), 7.52-7.48 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.38-7.36 (d, J = 8.8 Hz, 2H). 98.96% purity by LCMS; m/z =317.17 [M+H]⁺.

EXAMPLE 125

N-(4-chlorophenyl)-6-fluoroquinol

125 [0288] A mixture of compound Int-6 (Example 123) (120 mg, 0.53 mmol, 1.0 eq), 4- chloroaniline (135 mg, 1.06 mmol, 2.0 eq) and Na₂CC>3 (112 mg, 1.06 mmol, 2.0 eq) in dry acetonitrile (1 mL) was de-gassed with Argon gas for 10 min. Then Pd(OAc)₂ (11.8 mg, 0.063 mmol, 0.1 eq)_, Mo(CO)₆ (139 mg, 0.53 mmol, 1.0 eq) and t-Bu₃PHBF₄ (18.5 mg, 0.05 mmol, 0.12 eq) were added, and the resulting mixture was de-gassed with argon gas for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography using 50% EtOAc in petroleum ether as eluent to give 20 mg of the desired compound 125 as a white solid in 12% yield. 1H NMR (400 MHz, CDC1₃): δ 9.01-9.0 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.96-8.94 (d, J = 7.6 Hz, 1H), 8.5-8.46 (d, J = 14.0 Hz, 1H), 8.17-8.15 (d, J = 8.0 Hz, 1H), 7.69-7.67 (d, J = 8.8 Hz, 2H), 7.61-7.58 (d, J = 12.4 Hz, 1H), 7.53-7.50 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.38-7.36 (d, J = 8.8 Hz, 2H). 99.20% purity by LCMS; MS (ESI) m/z =301.2 [M+H]⁺.

EXAMPLE 126

N-(6-(trifluoromethoxy)pyridin- -yl)quinoline-7-carboxamide (126)

126

[0289] Quinoline-7-carboxylic acid (70 mg, 0.404 mmol, 1.0 eq) and 6- (trifluoromethoxy)-pyridin-3-amine (79 mg, 0.44 mmol, 1.1 eq) were dissolved in 1 mL of DMF and the resulting mixture was cooled down to 0 °C. HATU (168 mg, 0.44 mmol, 1.1 eq) and DIPEA (0.144 mL, 0.808 mmol, 2.0 eq) were added at 0 °C, and then the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 4 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried in vacuo to give 20 mg of the desired compound 126 as a pale-yellow solid in 15% yield. 1H NMR (400 MHz, CDC1₃): δ 9.03-9.02 (dd, J = 2.8 Hz, 1.6 Hz, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 8.46-8.45 (d, J = 2.8 Hz, 1H), 8.26 (s, 1H), 8.24 (brs, 1H), 8.09-8.12 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 8.0-7.97 (d, J = 8.8 Hz, 1H), 7.56-7.52 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.12-7.10 (d, J = 8.8 Hz, 1H). 99.15% purity by LCMS; m/z =334.19 [M+H]⁺.

EXAMPLE 127

6-Methyl-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide (127)

127

Synthesis of methyl 6-methylquinoline- -carboxylate (Int-7)

Int-7

[0290] A mixture of the compound Int-1 (Example 86) (1.0 g, 4.5 mmol, 1.0 eq) and NaOAc (1.13 g, 13.6 mmol, 3.0 eq) in 1 : 1 MeOH/DMF (20 mL) was de-gassed with argon for 10 min. Then Pd(dppf)Cl₂DCIVI (370 mg, 0.452 mmol, 0.1 eq) was added and the reaction mixture was de-gassed with argon for another 15 min, then heated at 70 °C in steel bomb under CO atmosphere for 6 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was distilled off, diluted with EtOAc and filtered through celite, and the celite pad was washed with EtOAc. The EtOAc layer was separated from filtrate and washed with water (50 mL), brine (50 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give crude product. The crude product was purified by flash chromatography using EtOAc in hexane as eluent to provide 300 mg of the desrired compound Int-7 as a pale-yellow solid in 33% yield. 1H NMR (400 MHz, CDC1₃): δ 8.921-8.936 (dd, J = 2.4 Hz, 2.0 Hz, 1H), 8.688 (s, 1H), 8.085-8.105 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.43 - 7.46 (m, 1H), 3.978 (s, 3H), 2.75 (s, 3H). 99.01% purity by LCMS; m/z =202.22 [M+H]⁺.

Synthesis of 6-methylquinoline-7-carboxylic acid (Int-8)

Int-8

[0291] Lithium hydroxide monohydrate (125 mg, 2.98 mmol, 2.0 eq) was added to a solution of the compound Int-7 (300 mg, 1.49 mmol, 1.0 eq) in 4:2: 1 mixture of THF/H₂0/MeOH (3.0 mL), and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated in vacuo to give crude product. The crude product was diluted with DI water, acidified to pH ~ 4 with IN HCl and extracted with EtOAc. The organic layers were combined, washed with water and brine, then dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 110 mg of the compound Int-8 as a pale-yellow solid in 39% yield. 1H NMR (300 MHz, DMSO): 5 13.1 (br s, 1 H), 8.914-8.932 (dd, J = 2.4 Hz, 2.0 Hz, 1H), 8.444 (s, 1H), 8.311-8.338 (d, J=8.1 Hz, 1H), 7.869 (s, 1H), 7.574- 7.616 (m, 1H), 2.61 (s, 3H). 98.85% purity by LCMS; ESI m/z =188.17 [M+H]⁺.

[0292] Compound Int-8 (100 mg, 0.53 mmol, 1.0 eq) and 6-(trifluoromethoxy)pyridin- 3-amine (190 mg, 1.06 mmol, 2.0 eq) were dissolved in DMF (3.0 mL) and the reaction mixture was cooled down to 0 °C. HATU (221 mg, 0.58 mmol, 1.1 eq) and DIPEA (136 mg, 1.06 mmol, 2.0 eq) were added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 4 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried under vacuum to give 40 mg of the desired compound 127 as a pale-yellow solid in 21% yield. 97.88% purity as determined by HPLC at 215 nm. 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.94 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.60 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 2.57 (s, 3H). ESI m/z =348.27 [M+H]⁺.

EXAMPLE 128

6-Chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide (128)

128

[0293] Compound Int-5 (Example 122) (90 mg, 0.43 mmol, 1.0 eq) and 6- (trifluoromethoxy)pyridin-3-amine (84 mg, 0.47 mmol, 1.1 eq) were dissolved in DMF (3 mL), and the resulting mixture was cooled down to 0 °C. Then HATU (181 mg, 0.47 mmol, 1.1 eq) and DIPEA (0.16 mL, 0.868 mmol, 2.0 eq) were added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 3 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried in vacuo to give 40 mg of the desired compound 128 as an off-white solid in 25% yield. 1H NMR (400 MHz, DMSO-de): δ 11.12 (s, 1H), 9.03-9.02 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.68-8.69 (d, J = 2.4 Hz, 1H), 8.46-8.44 (d, J = 7.6 Hz, 1H), 8.39-8.36 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.30-8.31 (m, 2H), 7.70- 7.67 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.39-7.37 (d, J = 8.8 Hz, 1H). 99.45% purity by LCMS; m/z =368.11 [M+H]⁺.

EXAMPLE 129

6-Fluoro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide (129)

[0294] A stirred solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (100 mg, 0.442 mmol), 6-(trifluoromethoxy)pyridin-3-amine (157 mg, 0.884 mmol, 2.0 eq) and Na₂CC>3 (112 mg, 0.884 mmol) in dry acetonitrile (2 mL) was degassed with Argon gas in a microwave vessel for 15 min. Then Mo(CO)₆ (117 mg, 0.442 mmol, 1.0 eq), T3u₃PHBF₄ (15.3 mg, 0.05 mmol 0.12 eq) and Pd(OAc)₂ (10 mg, 0.044 mmol, 0.1 eq) were added to this mixture, and degassing was continued for additional 10 min. The reaction mixture was irradiated in microwave at 90 °C for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography using 50% EtOAc in petroleum ether as eluent to give 25 mg (16% yield) of the desired compound 129 as a pale-yellow solid. 99.2 % HPLC purity at 215 nm. 1H NMR (400 MHz, CDC1₃): δ 9.03- 9.02 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.97-8.99 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.55 (s, 1H), 8.47-8.49 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.45-8.46 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.61-7.64 (d, J = 12.8 Hz, 1H), 7.56-7.52 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.12-7.10 (d, J = 8.0 Hz, 1H). 99.7% purity by LCMS; MS (ESI) m/z =352.14 [M+H]⁺.

EXAMPLE 130

N-(3-(N-(4-chlorophenyl)-N-methylsulfamoyl)phenyl)quinoline-7-carboxamide (130)

130

Synthesis of quinoline-7-carbonyl chloride (Int-9)

Int-9

[0295] To a mixture of quinoline-7-carboxylic acid (205 mg, 1.16 mmol, 1.0 eq) in DCM (10 rriL) was added oxalyl chloride (294 mg, 2.31 mmol, 2.0 eq) and 2 drops of DMF. The mixture was stirred at rt for 1 h under nitrogen atmosphere, and concentrated in vacuo to give the crude compound Int-9 (205 mg), which was used directly in the next step without further purification. Synthesis of 3-(quinoline-7-carboxamido)benzenesulfonic acid (Int-10)

Int-10

[0296] To a mixture of the crude compound Int-9 (205 mg, 1.07 mmol, 1.0 eq) in DCM (10 rriL) under nitrogen atmosphere was added 3-aminobenzenesulfonic acid (185 mg, 1.07 mmol, 1.0 eq) and triethylamine (325 mg, 3.21 mmol, 3.0 eq). The mixture was stirred at rt for 3 hrs. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated to give the crude Compound Int-10 (250 mg), which was used directly in the next step without further purification.

Synthesis of 3-(quinoline-7-carboxamido)benzenesulfonyl chloride (Int-11)

Int-11

[0297] A mixture of the crude compound Int-10 in thionyl chloride (5 mL) was stirred at 80 °C for 2 hrs under nitrogen atmosphere. The resulting mixture was concentrated to give the crude compound Int-11 (260 mg), which was used directly in the next step without further purification.

[0298] To a mixture of the crude compound Int-11 (260 mg) in DCM (10 mL) was added 4-chloro-N-methylaniline (106 mg, 0.75 mmol, 1.0 eq), triethylamine (329 mg, 3.25 mmol,

3.0 eq) and DMAP (18.3 mg, 0.15 mmol, 0.2 eq). The mixture was stirred at r.t. for 16 hrs under nitrogen atmosphere. The reaction was monitored by LCMS. Then DCM (10 mL) was added, and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 34 mg of the desired Compound 130 (6.7% over four steps) as a light yellow solid in > 95% purity as determined by HPLC analysis. 100% HPLC purity at 254 nm. 1H-NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H),

9.01 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.70 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.22-8.18 (m, 2H), 8.14- 8.07 (m, 2H), 7.64 (dd, J = 8.0, 4.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.42-7.39 (m, 1H), 7.40 (d, J 9.2 Hz, 1 H), 7.19-7.11 (m, 3H), 3.15 (s, 3H); ESI/MS [m/z] = 452 [M+H]⁺.

EXAMPLE 131

N-(3-(N-(3-chlorophenyl)-N-methylsulfamoyl)phenyl)quinoline-7-carboxamide (131)

131

[0299] To a mixture of the compound Int-11 (Example 130) (200 mg, 0.58 mmol, 1.0 eq) in DCM (10 rriL) was added 3-chloro-N-methylaniline (82.4 mg, 0.58 mmol, 1.0 eq), triethylamine (176 mg, 1.74 mmol, 3.0 eq) and DMAP (14.6 mg, 0.12 mmol, 0.2 eq). The mixture was stirred at r.t. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. DCM (10 mL) was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 53 mg of the desired Compound 131 (20% yield) as a light yellow solid in >95% purity as determined by HPLC analysis. 100% HPLC purity at 254 nm. 1H-NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 9.01 (dd, J = 4.0, 1.6 Hz, 1H), 8.70 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.22-8.19 (m, 2H), 8.14-8.07 (m, 2H), 7.64 (dd, J = 8.0, 4.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42-7.33 (m, 2H), 7.23-7.10 (m, 3H), 3.17 (s, 3H); ESI/MS [m/z] = 452 [M+H]⁺

EXAMPLE 132

N-(3-(N-(2-chlorophenyl)-N-methylsulfamoyl)phenyl)quinoline-7-carboxamide (132)

132

[0300] To a mixture of compound Int-11 (Example 129) (200 mg, 0.58 mmol, 1.0 eq) in DCM (10 mL) was added 2-chloro-N-methylaniline (82.4 mg, 0.58 mmol, 1.0 eq), triethylamine (176 mg, 1.74 mmol, 3.0 eq) and DMAP (14.6 mg, 0.12 mmol, 0.2 eq). The mixture was stirred at rt for 16 h under nitrogen atmosphere, then diluted with DCM (10 mL). The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 22 mg of the desired compound 132 (8% yield) as a light-yellow solid in >95% purity as determined by HPLC analysis. 100% HPLC purity at 254 nm. 1H-NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.02 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.72 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.35 (t, J = 1.6 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.15-8.09 (m, 2H), 7.64 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.41-7.31 (m, 2H), 7.09 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 3.14 (s, 3H); ESI/MS [m/z] = 452 [M+H]⁺

EXAMPLE 133

N-(3-(N-(4-(2-methoxyethoxy)phenyl)-N-methylsulfamoyl)phenyl)quinoline-7-carboxamide (133)

133

Synthesis of tert-butyl (4-hydroxyphenyl)(methyl)carbamate (Int-12)

Int-12

[0301] To a mixture of 4-(methylamino)phenol (500 mg, 4.06 mmol, 1.0 eq) in DCM (15 mL) was added (Boc)₂0 (1.77 g, 8.13 mmol, 2.0 eq). The resulting mixture was stirred at r.t. for 3 hrs under nitrogen atmosphere. The reaction was monitored by TLC. Then DCM (15 mL) was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 5: 1) to afford 805 mg of the desired compound Int-12 (88% yield) as yellow oil.

Synthesis of tert-butyl (4-(2-methoxyethoxy)phenyl)(methyl)carbamate (Int-13)

Int-13

[0302] To a solution of the compound Int-12 (800 mg, 3.59 mmol, 1.0 eq) in DMF (20 mL) was added l-bromo-2-methoxy-ethane (598 mg, 4.3 mmol, 1.2 eq), followed by NaH (60%, 430 mg, 10.8 mmol, 3.0 eq). The resulting mixture was stirred at rt for 1 hr under nitrogen atmosphere. The reaction was monitored by TLC. Then water (10 mL) was added and the mixture was extracted with Ethyl Acetate (3 x 20 mL). The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 5: 1) to give 498 mg of the desired compound Lit- 13 (49% yield) as yellow oil.

Synthesis of 4-(2-methoxyethoxy)-N-methylaniline

Int-14

[0303] A solution of compound Int-13 (498 mg, 1.78 mmol, 1.0 eq) in HCl/Ethyl Acetate (20 mL) was stirred at r.t. for 30 min under nitrogen atmosphere. The progress of the reaction was monitored by LC/MS. Then the mixture was concentrated to give 420 mg of the crude compound Int-14 (100% yield) as a light yellow solid, which was used directly in the next step without further purification.

[0304] To a mixture of compound Int-11 (Example 130) (1.0 g, 2.88 mmol, 1.0 eq) in DCM (20 mL) was added compound Int-14 (420 mg, 1.93 mmol, 0.67 eq), triethylamine (873 mg, 8.64 mmol, 3.0 eq) and DMAP (70.3 mg, 0.58 mmol, 0.2 eq). The mixture was stirred at rt for 16 h under nitrogen atmosphere, then diluted with DCM (20 mL). The resulting mixture was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 80 mg of the desired compound 133 (6% yield) as a beige solid in >95% purity as determined by HPLC analysis. 1H-NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 9.02 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.71 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.20-8.18 (m, 1H), 8.15-8.09 (m, 2H), 7.65 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 9.2 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.60 (t, J= 4.4 Hz, 2H), 3.25 (s, 3H), 3.14 (s, 3H); ESI/MS [m/z] = 492 [M+H]⁺.

EXAMPLE 134

N-(3-(N-(3-(2-methoxyethoxy)phenyl)-N-methylsulfamoyl)phenyl)quinoline-7-carboxamide

(134)

134

Synthesis of tert-butyl (3-hydroxyphenyl)(methyl)carbamate (Int-15)

Int-15

[0305] To a solution of 3-(methylamino)phenol (600 mg, 4.88 mmol, 1.0 eq) in DCM (15 niL) was added di-tert-butyl di carbonate (2.13 g, 9.76 mmol, 2.0 eq). The reaction mixture was stirred at rt for 3 h under nitrogen atmosphere. The reaction was monitored by TLC. Then DCM (15 mL) was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 5: 1) to give 980 mg of the desired compound Int-15 (92% yield) as yellow oil.

Synthesis of 3-(2-methoxyethoxy)-N-methylaniline

Int-16

[0306] To a solution of compound Int-15 (500 mg, 2.24 mmol, 1.0 eq) in DMF (20 mL) was added 1 -bromo-2-methoxy-ethane (371 mg, 2.69 mmol, 1.2 eq) and NaH (60%, 269 mg, 6.72 mmol, 3.0 eq). The reaction mixture was stirred at rt for 1 h under nitrogen atmosphere. The reaction was monitored by TLC. Then water (10 mL) was added and the mixture was extracted with Ethyl Acetate (3 x 20 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 5: 1) to give 230 mg of the desired compound Int-16 (57% yield, Boc group was removed during the reaction or workup) as yellow oil.

[0307] To a suspension of the compound Int-11 (1 g, 2.88 mmol, 1.3 eq) in DCM (20 mL) was added compound Int-16 (400 mg, 2.21 mmol, 1.0 eq), triethylamine (671 mg, 6.63 mmol, 3.0 eq) and DMAP (54 mg, 0.44 mmol, 0.2 eq). The mixture was stirred at rt for 16 h under nitrogen atmosphere. The reaction was monitored by LCMS. Then DCM (20 mL) was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 110 mg the desired compound 134 (10% yield) as a brown solid in >95% purity as determined by HPLC analysis. 98% HPLC purity at 254 nm. 1H-NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 9.02 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.71 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.22-8.20 (m, 2H), 8.15-8.08 (m, 2H), 7.65 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1H), 7.26-7.21 (m, 2H), 6.86 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.68-6.66 (m, 1H), 4.00 (t, J = 4.4 Hz, 2H), 3.58 (t, J = 3.2 Hz, 2H), 3.23 (s, 3H), 3.17 (s, 3H). ESI/MS [m/z] = 492 [M+H]⁺.

EXAMPLE 135

N-(3-(N-(2-(2-methoxyethoxy)phenyl)-N-methylsulfamoyl)phenyl)quinoline-7-carboxamide (135)

135

Synthesis of 2-(2-methoxyethoxy)-N-methylaniline (Int-17)

Int-17

[0308] To a solution of 2-(methylamino)phenol (500 mg, 4.1 mmol, 1.0 eq) in DMF (15 mL) was added l-bromo-2-methoxy-ethane (679 mg, 4.9 mmol, 1.2 eq) and potassium carbonate (1.15 g, 8.2 mmol, 2.0 eq). The reaction mixture was stirred at rt for 1 h under nitrogen atmosphere. The reaction was monitored by TLC. Then water (10 mL) was added and the mixture was extracted with Ethyl Acetate (3 x 20 mL). Combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 5: 1) to give 160 mg of the desired Compound Int-17 (22% yield) as yellow oil.

[0309] To a mixture of the compound Int-11 (Example 130) (500 mg, 1.45 mmol, 1.6 eq) in DCM (20 mL) was added Int-17 (160 mg, 0.88 mmol, 1.0 eq), triethylamine (267 mg, 2.64 mmol, 3.0 eq) and DMAP (22 mg, 0.18 mmol, 0.2 eq). The reaction mixture was stirred at r.t. for 16 h under nitrogen atmosphere. The reaction was monitored by LCMS. Then DCM (20 mL) was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 20 mg of the desired compound 135 (4.6% yield) as a beige solid. 99% HPLC purity at 254 nm. ESI/MS [m/z] = 492 [M+H]⁺. 1H-NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 9.02 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.71 (s, 1H), 8.46 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 8.25-8.19 (m, 1H), 8.13-8.09 (m, 2H), 7.64 (dd, J = 8.4, 4.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.33-7.22 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 6.94 (dt, J = 7.6 Hz, 1.2 Hz, 2H), 3.77 (t, J = 4.4 Hz, 2H), 3.18 (t, J = 5.2 Hz, 2H), 3.15 (s, 3H), 3.14 (s, 3H). EXAMPLE 136

N-(5-(N-methyl-N-phenylsulfamoyl)pyridin-3-yl)quinoline-7-carboxamide (136)

136

Synthesis of pyridine-3-sulfonyl chloride (Int-18)

Int-18

[0310] A mixture of pyridine-3 -sulfonic acid (5.0 g, 31.4 mmol, 1.0 eq) and PC1₅ (14.2 g, 69.1 mmol, 2.2 eq) was refluxed at 135 °C for 2.5 hrs. The resulting mixture was cooled to r.t., triturated with chloroform, filtered and dried to give 3.6 g of Compound Int-18 (64% yield) as a white solid.

Synthesis of 5-bromopyridine-3-sulfonyl chloride

Int-19

[0311] A mixture of compound Int-18 (1.0 g, 5.63 mmol, 1.0 eq) and bromine (2.0 mL) was stirred at 130 °C for 16 h in a sealed tube. The resulting mixture was cooled to r.t. to give 2.1 g of the crude Compound Int-19, which was used directly in the next step without further purification. Synthesis of 5-bromo-N-methyl-N-phenylpyridine-3-sulfonamide (Int-20)

Int-20

[0312] A mixture of the crude compound Int-19 (2.1 g) and N-methylaniline (15 mL) in water was stirred at r.t. for 3 hrs. The resulting mixture was extracted with Ethyl Acetate (3 x 20 mL). Combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (PE/EA = 10: 1) to give 303 mg of the desired Compound Int-20 (16% over two steps) as a yellow solid.

Synthesis of 5-amino-N-methyl-N-phenylpyridine-3-sulfonamide (Int-21)

Int-21

[0313] A mixture of compound Int-20 (100 mg, 0.31 mmol, 1.0 eq) and CuCl (20 mg, 0.2 mmol, 0.65 eq) in ammonium hydroxide (2.0 mL) was stirred in a sealed tube at 170 °C for 16 hrs. Then the resulting mixture was mixed with water and extracted with Ethyl Acetate (3 x 10 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 20: 1) to give 65 mg of the desired compound Int-21 (81% yield) as a yellow solid.

[0314] A mixture of the compound Int-21 (65 mg, 0.25 mmol, 1.0 eq) and compound Int-11 (Example 130) (100 mg, 0.52 mmol, 2.1 eq) and DMAP (2.4 mg, 0.02 mmol, 0.1 eq) in pyridine (2 mL) was stirred at r.t. for 16 hrs. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM/MeOH = 10: 1) to afford 10 mg of the desired compound 136 (10% yield) as a beige solid in >95% purity as determined by HPLC analysis. 1H-NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 9.32 (d, J = 2.4 Hz, 1H), 9.03 (dd, J = 4.0, 1.6 Hz, 1H), 8.74 (s, 1H), 8.55-8.53 (m, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.16-8.10 (m, 2H), 7.66 (dd, J = 8.0, 4.4 Hz, 1H), 7.39-7.31 (m, 3H), 7.17 (d, J = 7.6 Hz, 2H), 3.22 (s, 3H); ESI/MS [m/z] = 419 [M+H]⁺.

EXAMPLE 137

N-(5-(piperidin-l-ylsulfonyl)py de (137)

137

Synthesis of 3-bromo-5-(cyclohexylsulfonyl)pyridine (Int-22)

Int-22

[0315] A mixture of compound Int-19 (Example 136) (2.1 g) and piperidine (5 rriL) in water (10 ml) was stirred at r.t. for 3 hrs. The reaction was monitored by LCMS. The resulting mixture was extracted with Ethyl Acetate (3 x 10 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (PE/EA = 10: 1) to give 100 mg of the desired Compound Int-22 as a yellow solid.

Synthesis of 5-(piperidin-l-ylsulfonyl)pyridin-3-amine (Int-23)

Int-23

[0316] A mixture of the compound Int-22 (100 mg, 0.33 mmol, 1.0 eq) and CuCl (20 mg, 0.2 mmol, 0.6 eq) in ammonium hydroxide (2.0 mL) was stirred in a sealed tube at 170 °C for 16 h. The reaction was monitored by TLC. Then water (5 mL) was added to the resulting mixture, and it was extracted with Ethyl Acetate (3 x 10 mL). Combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 20: 1) to give 55 mg of the desired Compound Int-23 (70% yield) as a yellow solid.

[0317] A mixture of the compound Int-23 (55 mg, 0.23 mmol, 1.0 eq), compound Int-9 (Example 130) (100 mg, 0.52 mmol, 2.3 eq) and DMAP (2.4 mg, 0.02 mmol, 0.1 eq) in pyridine (2 mL) was stirred at rt for 16 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM/MeOH = 10: 1) to give 29 mg of the desired compound 137 (32% yield) as a beige solid. 100% HPLC purity at 254 nm. ESI/MS [m/z] = 397 [M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.29 (d, J = 2.4 Hz, 1H), 9.03 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.75 (s, 1H), 8.65 (t, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.47 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 8.16-8.11 (m, 2H), 7.66 (dd, J = 8.0, 3.6 Hz, 1H), 2.98 (t, J = 5.6 Hz, 4H), 1.61-1.49 (m, 4H), 1.40-1.34 (m, 2H).

EXAMPLE 138 N-(3-((4-(2-methoxyethyl -l,4-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (138)

138

Synthesis of Tert-butyl 4-(2-methoxyethyl)-l,4-diazepane-l-carboxylate (Int-24)

Int-24

[0318] To a mixture of tert-butyl- 1,4-diazepane-l-carboxylate (10 g, 50 mmol) and 1- bromo-2-methoxy ethane (8 mL, 60 mmol) in DMF was added K₂CO₃ (20 g, 150 mmol) at r.t. The reaction mixture was stirred at r.t. for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 150 mL). Combined organic layers were washed with water (2 x 30 mL), brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 10 g (77.4% yield) of tert-butyl 4-(2-methoxyethyl)- 1,4-diazepane-l-carboxylate Int-24 as pale-yellow oil. MS (ESI) m/z 259.45[M+H]⁺.

Synthesis of 4-(2-Methoxyethyl)-l,4-diazepane (Int-25)

Int-25

[0319] To a solution of tert-butyl 4-(2-methoxy ethyl)- 1,4-diazepane-l-carboxylate Int- 24 (10 g, 18.28 mmol) in 1,4-dioxane (50 mL) was added 4M HC1 in 1,4-dioxane (100 mL) at 0 °C, and the reaction mixture stirred at r.t. for 16 hrs. After completion of the reaction, the solvent was distilled-off to give crude compound. The crude compound was washed with diethyl ether to afford 7 g (93% yield) of 1 -(2-methoxy ethyl)- 1 ,4-diazepane hydrochloride Int-25 as pale-yellow oil.

Synthesis -(2-Methoxyethyl)-4-((3-nitrophenyl)sulfonyl)-l,4-diazepane (Int-26)

[0320] To a stirred solution of 3 -nitrobenzene- 1-sulfonyl chloride (2 g, 9.02 mmol) in dry THF (20 mL) was added TEA (6.29 mL, 45.11 mmol), followed by 1 -(2-methoxy ethyl)- 1,4- diazepane hydrochloride Int-25 (2.47 g, 13.53 mmol) at 0 °C, and the reaction mixture was stirred at r.t. for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 100 mL). Combined organic layers were washed with water (2 x 30 mL), brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 30% Ethyl Acetate in Hexane as eluent to afford 1.2 g (39% yield) of 1 -(2-methoxy ethy l)-4- (3-nitrophenylsulfonyl)-l,4-diazepane Int-26 as brown oil. MS (ESI) m/z 343.40[M+H]⁺.

Synthe

[0321] To a stirred solution of l-(2-methoxyethyl)-4-((3-nitrophenyl)sulfonyl)-l,4- diazepane Int-26 (1.2 g, 1.0 eq) in MeOH (20 niL) was added 10% Pd/C (20% by wt), and the reaction mixture was stirred under hydrogen balloon atmosphere for 4 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. Collected filtrates were concentrated under reduced pressure. The resultant crude compound was purified by neutral alumina column chromatography using 5% methanol in DCM as eluent to afford 0.6 g (55% yield) of 3-(4- (2-methoxyethyl)-l,4-diazepan-l-ylsulfonyl)aniline Int-27 as brown oil. MS (ESI) m/z 314.03[M+H]⁺.

[0322] To a solution of quinoline-7-carboxylic acid (150 mg, 0.8670 mmol) in DCM (3 mL) was added oxalyl chloride (0.22 mL, 2.601mmol), followed by catalytic amount of DMF at 0 C, and the reaction mixture stirred at r.t. for 1 hr. Then the reaction mixture was directly concentrated under argon atmosphere to get the crude acid chloride. Acid chloride was dissolved in THF (2.0 mL) and TEA (0.72mL, 5.202 mmol) was added. The reaction mixture was cooled to 0 C. Then 3-(4-(2-methoxyethyl)-l,4-diazepan-l-ylsulfonyl)aniline Int-27 (0.325 g, 1.04 mmol) in THF (2 mL) was added and the reaction mixture was stirred at r.t. for 4 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in CH₃CN as eluent to afford 30 mg (8.6 % yield) of the desired Compound 138 as a pale-brown oily solid. 95.15 % HPLC purity at 215 nm. 1H NMR (400 MHz, CD₃OD): δ 8.98 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.63 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.15 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.99-8.02 (m, 1H), 7.66 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.60 (d, J = 4.8 Hz, 2H), 3.50-3.41 (m, 6H), 2.83-2.81 (m, 2H), 2.76 (t, J = 5.6 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H), 1.87 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 469.42 [M+H]⁺.

EXAMPLE 139

N-(5-((4-methyl-l,4-diazepan- -yl)sulfonyl)pyridin-3-yl)quinoline-7-carboxamide (139)

139

Synthesis of 5-bromopyridine-3-sulfonyl chloride (Int-28)

Int-28

1) NaN0₂, HCl

[0323] To a cooled (0 °C) solution of 5-bromopyridin-3-amine (10 g, 57.80 mmol) in HC1 (122V, 78 mL) was added NaN0₂ (5.78 g, 52.63 mmol) in H₂0 (24 mL). In another flask, SOCl₂ (24 mL) was mixed with H₂0 (150 mL) and the solution was cooled to 10 °C. Then Cu(I)Cl (0.087 g, 0.878 mmol) was added in portions and the reaction mixture was stirred at 10 °C for 1 hr. To this solution was added the diazotization mixture at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then allowed to warm up to r.t. over a period of 1 hr. Then the reaction mixture was poured into crushed ice. The resultant solid was filtered and dried under reduced pressure to afford 5 g (34% yield) of crude 5-bromopyridine-3-sulfonyl chloride Int-28 as a pale brown solid. The crude product was taken to the next step without further purification. MS (ESI) m/z 257.96 [M+H]⁺.

Synthesis of l-((5-Bromopyridin-3-yl)sulfonyl)-4-methyl-l,4-diazepane (Int-29)

Int-29

[0324] To a stirred solution of 5-bromopyridine-3-sulfonyl chloride (5 g, 119.53 mmol) in dry THF (50 mL) was added TEA (8.17 mL, 58.59 mmol), followed by l-methyl-l,4-diazepane ( 3.64 mL, 29.29 mmol) at 0 °C and the reaction mixture was stirred at r.t. for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 150 mL). Combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 silica gel) using 40% Ethyl Acetate in Hexane as eluent to afford 5 g (62% yield) of l-((5-bromopyridin-3-yl)sulfonyl)-4-methyl-l,4- diazepane Int-29 as a yellow solid. MS (ESI) m/z 336.09[M+H]⁺.

Synthesis of 5-((4-Methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine (Int-30)

-30

[0325] To a stirred solution of l-((5-bromopyridin-3-yl)sulfonyl)-4-methyl-l,4-diazepane Int-29 (5 g, 14.97 mmol) in MeOH (100 mL) was added Cu(I)Br (2.1 g, 14.97 mmol), followed by liquid N¾ (freshly condensed ammonia gas using Dewar flask) in a sealed vessel and the reaction mixture was stirred at 140 °C for 16 hrs. Then the reaction mixture filtered through a pad of Celite and the collected fraction were concentrated under reduced pressure to afford 5 g of crude compound. The resultant crude compound was purified by neutral alumina column afforded 3 g (46% yield) of 5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-30 as a brown semisolid. MS (ESI) m/z 271.23[M+H]⁺.

[0326] To a solution of quinoline-7-carboxylic acid (150 mg, 0.8670 mmol) in DCM (3 mL) was added oxalyl chloride (0.22 mL, 2.601 mmol) followed by catalytic DMF at 0 C, and the reaction mixture was stirred at r.t. for lhr. Then the reaction mixture was directly concentrated under argon atmosphere to afford the crude acid chloride. Acid chloride was dissolved in THE (2.0 mL) and TEA was added (0.72mL, 5.202 mmol), followed by 5-((4-methyl-l,4-diazepan-l- yl)sulfonyl)pyridin-3 -amine Int-30 (0.28 g, 1.040 mmol) in THF (2 mL) at 0 °C and the reaction mixture was stirred at r.t. for 4 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 70 mg (18% yield) of Compound 139 as an off-white solid. 98.5 % HPLC purity at 215 nm. 1H NMR (400 MHz, CD₃OD) δ 9.14 (d, J = 2.4 Hz, 1H), 8.99 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.81 (t, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.16 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 3.46-3.53 (m, 4H), 2.71-2.73 (m, 2H), 2.64-2.67 (m, 2H), 2.36 (s, 3H), 1.91 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 425.99 [M+H]⁺.

EXAMPLE 140

6-Methyl-N-(5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)quinoline-7-carboxamide (140)

[0327] A solution of 7-bromo-6-methylquinoline Int-1 (Example 86) (150 mg, 0.675 mmol), 5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-30 (Example 139) (182 mg, 0.675 mmol) and Na₂C03 (143 mg, 1.350 mmol) in acetonitrile (10 mL) was de-gassed with Argon in a microwave vessel at r.t. for 15 min. Then Mo(CO)6 (178 mg 0.675 mmol), TiusPHEtf^ (19 mg, 0.067 mmol) and Pd(OAc)₂ (45 mg, 0.067 mmol) were added, and degassing was continued for another 10 min. Then the reaction mixture irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 65 mg (21% yield) of the desired compound 140 as an off- white solid. 99.87 % HPLC purity at 215 nm. 1H NMR (400 MHz, CD₃OD) δ 9.04 (d, J = 2.4 Hz, 1H), 8.88 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.77-8.79 (m, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.60 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 3.46-3.53 (m, 4H), 2.71-2.73 (m, 2H), 2.63-2.68 (m, 2H), 2.65 (s, 3H), 2.36 (s, 3H), 1.91 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 440.11 [M+H]⁺.

EXAMPLE 141

6-Chloro-N-(5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)quinoline-7-carboxamide (141)

141

[0328] A solution of 7-bromo-6-chloroquinoline Int-3 (Example 122) (150 mg, 0.619 mmol), 5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3 -amine Int-30 (Example 139) (167 mg, 0.619 mmol) and Na₂C03 (131 mg, 1.238 mmol) in acetonitrile (10 mL) was de-gassed with Argon in a microwave vessel at r.t. for 15 min. Then Mo(CO)₆ (163 mg 0.619 mmol) and iusPHBT^ (18 mg, 0.061 mmol) were added, followed by Pd(OAc)₂ (41 mg, 0.061 mmol), and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2 x 40 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 55 mg (19 % yield) of the desired compound 141 as an off-white solid. 99.8 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 9.07 (d, J = 2.4 Hz, 1H), 9.03 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.64-8.66 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 7.69 (dd, J= 8.0 Hz, 4.4 Hz, 1H), 3.40-3.28 (m, 4H), 2.58-2.55 (m, 2H), 2.49-2.47 (m, 2H), 2.24 (s, 3H), 1.77 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 460.01 [M+H]⁺.

EXAMPLE 142

6-Fluoro-N-(5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)quinoline-7-carboxamide

(142)

142

[0329] A solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (150 mg, 0.663 mmol), 5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-30 (Example 139) (179 mg, 0.663 mmol) and Na₂C03 (140 mg, 1.326 mmol) in acetonitrile (10 mL) was de-gassed with Argon in a microwave vessel at r.t. for 15 min. Then Mo(CO)6 (175 mg 0.663 mmol), TiusPHE^ (19 mg, 0.066 mmol) were added, followed by Pd(OAc)₂ (44 mg, 0.066 mmol) and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with Ethyl Acetate (3 x 30 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 70 mg (23% yield) of the desired compound 142 as an off- white solid. 98.00 % HPLC purity at 215 nm. 1H NMR (400 MHz, CD₃OD): δ 9.04 (d, J = 2.0 Hz, 1H), 8.94 (dd, J = 4.4 Hz, 1.2 Hz, 1H), 8.77 (t, J = 2.0 Hz, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 6.8 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 10.4 Hz, 1H), 7.65 (dd, J = 8.8 Hz, 4.4 Hz, 1H), 3.46-3.52 (m, 4H), 2.73-2.71 (m, 2H), 2.67-2.65 (m, 2H), 2.36 (s, 3H), 1.91 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 444.03 [M+H]⁺.

EXAMPLE 143

N-(5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)quinoline-7-carboxamide (143)

143

Synthesis of l-((5-Bromopyridin-3-yl)sulfonyl)-4-(2-methoxyethyl)-l,4-diazepane (Int-31)

[0330] To a stirred solution of 5-bromopyridine-3-sulfonyl chloride Int-28 (Example 139) (5 g, 119.53 mmol) in dry THF (50 mL) was added TEA (8.17 mL, 58.59 mmol), followed by l-(2-methoxy ethyl)- 1 ,4-diazepane hydrochloride Int-25 (Example 138) (5.6 g, 29.29 mmol) at 0 °C, and the reaction mixture was stirred at r.t. for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 150 mL). Combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 40% Ethyl Acetate in Hexane as eluent afforded 4.5 g (61% yield) of l-((5-bromopyridin-3-yl)sulfonyl)-4-(2-methoxy ethyl)- 1 ,4-diazepane Int-31 as a yellow solid. MS (ESI) m/z 379.95[M+H]⁺.

Synthesis of 5-((4-(2-Methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine (Int-32)

Int-32

[0331] To a stirred solution of l-((5-bromopyridin-3-yl)sulfonyl)-4-(2-methoxyethyl)- 1,4-diazepane Int-31 (4.5 g, 11.90 mmol) in MeOH (90 mL) was added Cu(I)Br (1.7 g, 11.90 mmol), followed by liquid N¾ (freshly condensed ammonia gas using Dewar flask) in a sealed vessel and the reaction mixture stirred at 140 °C for 16 rsh. Then the reaction mixture was filtered through a pad of Celite, and the collected fraction were concentrated under reduced pressure to afford 5 g of crude product. The resultant crude compound was purified by neutral alumina column to afford 2.5 g (67% yield) of 5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-32 as a brown oily solid. MS (ESI) m/z 315.04 [M+H]⁺.

[0332] To a solution of quinoline-7-carboxylic acid (150 mg, 0.8670 mmol) in DCM (3 mL) was added oxalyl chloride (0.22 mL, 2.601mmol), followed by catalytic amount of DMF at 0 C, and the reaction mixture was stirred at r.t. for 1 hr. Then the reaction mixture was directly concentrated under Argon atmosphere to afford crude acid chloride. Acid chloride was dissolved in THF (2.0 mL) and the solution was cooled to 0 °C. Then TEA (0.72mL, 5.202 mmol) and 5-((4-(2- methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3 -amine Int-32 (0.32 g, 1.040 mmol) in THF (2 mL) were added to the acid chloride solution, and the reaction mixture was stirred at r.t. for 4 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % Acetic acid in Acetonitrile as eluent to afford 60 mg (50% yield) of the desired compound 143 as an off-white solid. Isolated as a di-acetate salt. 99.32 % HPLC purity at 215 nm. 1H-NMR (400 MHz, CD₃OD): δ 9.14 (d, J = 2.4 Hz, 1H), 8.99 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.81 (t, J = 2.4 Hz, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.67 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.16 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 3.51-3.30 (m, 6H), 2.86-2.83 (m, 2H), 2.75-2.78 (t, J = 5.2 Hz, 2H), 2.71-2.74 (t, J = 5.2 Hz, 2H), 1.91 (s, 6H), 1.92-1.85 (m, 2H); ESI/MS [m/z] = 470.09 [M+H]⁺.

EXAMPLE 144

N-(5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)-6-methylquinoline-7- carboxamide (144)

144

[0333] A solution of 7-bromo-6-methylquinoline Int-1 (Example 86) (150 mg, 0.675 mmol), 5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-32 (Example 143) (211 mg, 0.675 mmol) and Na₂CC>3 (143 mg, 1.350 mmol) in acetonitrile (10 mL) was degassed with Argon in a microwave vessel at r.t. for 15 min. Then Mo(CO)₆ (178 mg 0.675 mmol), tBu3PHBF₄ (19 mg, 0.067 mmol) and Pd(OAc)₂ (45 mg, 0.067 mmol) were added, and degassing with Argon was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in CH₃CN as eluent to afford 65 mg (20% yield) of the desired compound 144 as a brown oily solid. 99.04 % HPLC purity at 215 nm. 1H-NMR (400 MHz, DMSO-d₆): δ 1 l. lo (s, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.94 (dd, J= 4.4 Hz, 2.0 Hz, 1H), 8.68 (br. s, 2H), 8.35 (d, J= 7.2 Hz, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.60 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 3.37-3.34 (m, 6H), 3.20 (s, 3H), 2.74- 2.71 (m, 2H), 2.65-2.59 (m, 4H), 2.59 (s, 3H), 1.74 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] =

[M+H]⁺.

EXAMPLE 145

6-Chloro-N-(5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)quinoline-7- carboxamide (145)

[0334] A solution of 7-bromo-6-chloroquinoline Int-3 (Example 122) (150 mg, 0.619 mmol), 5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-32 (Example 143) (194 mg, 0.619 mmol) and Na₂CC>3 (131 mg, 1.238 mmol) in acetonitrile (10 mL) was de-gassed with Argon in a microwave vial for 15 min. Then Mo(CO)6 (163 mg 0.619 mmol), t-Bu₃PHBF₄ (18 mg, 0.061 mmol) were added, followed by Pd(OAc)₂ (41 mg, 0.061 mmol) and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2 x 40 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH: ACN as eluent to give 70 mg (22% yield) of Compound 145 as a pale-yellow solid. 98.97 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 9.03 (dd, J = 4.4 Hz, 1.2 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.66 (t, J = 2.4 Hz, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 7.69 (dd, J = 8.0 Hz, 3.6 Hz, 1H), 3.38-3.34 (m, 6H), 3.21 (s, 3H), 2.74-2.71 (m, 2H), 2.59-2.65 (m, 4H), 1.74 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 504.01 [M+H]⁺.

EXAMPLE 146

6-Fluoro-N-(5-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)pyridin-3-yl)quinoline-7- carboxamide (146)

146

[0335] A solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (150 mg, 0.663 mmol), 5-((4-methyl-l,4-diazepan-l-yl)sulfonyl)pyridin-3-amine Int-32 (Example 143) (208 mg, 0.663 mmol) and Na₂C03 (140 mg, 1.326 mmol) in a acetonitrile (10 mL) was degassed with Argon in a microwave vessel at r.t. for 15 min. Then Mo(CO)6 (175 mg 0.663 mmol), TiusPHEtf^ (19 mg, 0.066 mmol) and Pd(OAc)₂ (44 mg, 0.066 mmol) were added and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 75 mg (23% yield) of the desired compound 146 as a light- brown solid. Isolated as a salt of formic acid. 96.73 % HPLC purity at 215 nm. 1H-NMR (400 MHz,

CD₃OD): δ 9.01 (d, J= 2.8 Hz, 1H), 8.95 (dd, J= 5.2 Hz, 1.2 Hz, 1H), 8.81-8.83 (m, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.47-8.41 (m, 3H), 8.34 (br s, 1H), 7.85 (d, J = 14.4 Hz, 1H), 7.67 (dd, J = 10.8 Hz, 5.6 Hz, 1H), 3.60-3.57 (m, 2H), 3.49 (t, J = 8.4 Hz, 1H), 3.16-3.13 (m, 2H), 3.07-3.3.11 (m, 2H), 3.01-3.05 (t, J= 6.8 Hz, 2H), 2.02 (quint, J= 6.8 Hz, 2H); ESI/MS [m/z] = 488.02 [M+H]⁺.

EXAMPLE 147

N-(4-fluoro-3-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (147)

147

Synthesis of 5-Bromo-2-fluorobenzene-l-sulfonyl chloride (Int-33)

Int-33

1) NaN0₂, HCl

[0336] To a cooled (0 °C) solution of 5-bromo-2-fluoroaniline (10 g, 52.63 mmol) in HC1 (122V, 80 mL) was added NaN0₂ (3.6 g, 52.63 mmol) in H₂0 (24 mL). In another flask SOCl₂ (24 mL) was mixed with H₂0 (160 mL) and the solution was cooled to 10 °C. Then Cu(I)Cl (2 g, 21.05 mmol) was added in portions and the mixture was stirred at 10 °C for 1 hr. To this solution was added diazotization mixture at 0 °C, the reaction mixture was stirred at 0 °C for 30 min and then allowed to warm up to r.t. over a period of 1 hr. Then the reaction mixture was poured in crushed ice, and the resultant solid was filtered and dried under reduced pressure to afford 5 g (34% yield) of crude 5-bromo-2-fluorobenzene-l-sulfonyl chloride Int-33 as a pale brown solid. The crude was directly taken to the next step without further purification.

Synthesis of l-(5-bromo-2-fluorophenylsulfonyl)-4-methyl-l,4-diazepane (Int-34)

Int-34

[0337] To a stirred solution of 5-bromo-2-fluorobenzene-l-sulfonyl chloride Int-33 (5 g, 18.28 mmol) in dry THF (50 mL) was added TEA (10.6 mL, 76.78 mmol), followed by 1-methyl- 1,4-diazepane (3.13 g, 27.42 mmol) at 0 °C and the reaction mixture was stirred at r.t. for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 150 mL). Combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica gel) using 40% Ethyl Acetate in Hexane as eluent to give 4 g (62% yield) of l-(5-bromo-2-fluorophenylsulfonyl)-4- methyl-l,4-diazepane Int-34 as a brown solid. MS (ESI) m/z 351.08[M-H]^"

Synthesis of 4-Fluoro-3-(4-methyl-l -diazepan-l-ylsulfonyl) aniline (Int-35)

Int-35

[0338] To a stirred solution of l-(5-bromo-2-fluorophenylsulfonyl)-4-methyl-l,4- diazepane Int-34 (4 g, 11.39 mmol) in MeOH (40 mL) was added Cu(I)Br (0.163 g, 1.139 mmol), followed by liquid N¾ (freshly condensed ammonia gas using Dewar flask) in a sealed vessel, and the reaction mixture stirred at 140 °C for 16 hrs. Then the reaction mixture was filtered through a pad of Celite, and the collected fractions were concentrated under reduced pressure to afford 3 g of the crude product. The resultant crude compound was purified by neutral alumina column to give 1.47 g (46% yield) of 4-fluoro-3-(4-methyl-l,4-diazepan-l-ylsulfonyl) aniline Int-35 as a brown semi-solid. MS (ESI) m/z 288.26[M+H]⁺.

[0339] To a solution of quinoline-7-carboxylic acid (150 mg, 0.87 mmol) in DCM (3 mL) was added oxalyl chloride (0.22 mL, 2.6 mmol), followed by catalytic amount of DMF at 0 C and the reaction mixture was stirred at r.t. for 1 hr. The reaction mixture was directly concentrated under Argon atmosphere to afford the crude acid chloride. The resultant crude acid chloride was dissolved in THF (2.0 mL) and TEA (0.72mL, 5.202 mmol) was added, followed by 4-fluoro-3-(4- methyl-l,4-diazepan-l-ylsulfonyl)aniline Int-35 (0.29 g, 1.04 mmol) in THF (2 mL) at 0 °C, and the reaction mixture was stirred at r.t. for 4 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 70 mg (18% yield) of the desired compound 147 as an off-white solid. 98.52 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-de) δ 10.85 (s, 1H), 9.02 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.73 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.38 (dd, J= 6.4 Hz, 2.4 Hz, 1H), 8.20-8.11 (m, 3H), 7.66 (dd, J= 8.4 Hz, 4.4 Hz, 1H), 7.51 (t, J= 9.6 Hz, 1H), 3.44-3.42 (m, 2H), 3.39 (t, J = 6.4 Hz, 1H), 2.52-2.59 (m, 4H), 2.27 (s, 3H), 1.80 (quint, J= 5.6 Hz, 2H); ESI/MS [m/z] = 443.29 [M+H]⁺

EXAMPLE 148

N-(4-fluoro-3-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)-6-methylquinoline-7-carboxamide

(148)

148 [0340] A solution of 7-bromo-6-methylquinoline Int-1 (Example 86) (150 mg, 0.675 mmol), 4-fluoro-3-(4-methyl-l,4-diazepan-l-ylsulfonyl) aniline Int-35 (Example 147) (194 mg, 0.675 mmol) and Na₂CC>3 in acetontrile (143 mg, 1.350 mmol) was de-gassed with Argon in a microwave vial for 15 min. Then Mo(CO)₆ (178 mg 0.675 mmol), t-Bu₃PHBF₄ (19 mg, 0.067 mmol) and Pd(OAc)₂ (45 mg, 0.067 mmol) were added and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 60 mg (19% yield) of the desired compound 148 as an off-white solid. 96.62 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.93 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.36-8.33 (m, 2H), 8.18 (s, 1H), 8.07-8.03 (m, 1H), 7.89 (s, 1H), 7.58 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.48 (t, J = 9.6 Hz, 1H), 3.44-3.40 (m, 4H), 2.59-2.52 (m, 4H), 2.49-2.53 (m, 2H), 2.25 (s, 3H), 1.79 (quint, J= 5.2 Hz, 2H); ESI/MS [m/z] = 457.07 [M+H]⁺

EXAMPLE 149

6-Chloro-N-(4-fluoro-3-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl) quinoline-7- carboxamide (149)

149

[0341] A solution of 7-bromo-6-chloroquinoline Int-3 (Example 122) (150 mg, 0.619 mmol), 4-fluoro-3-(4-methyl-l,4-diazepan-l-ylsulfonyl)aniline Int-35 (Example 147) (177 mg, 0.619 mmol) and Na₂CC>3 (131 mg, 1.238 mmol) in acetonitrile (10 mL) was de-gassed with Argon in a microwave vial at r.t. for 15 min. Then Mo(CO)₆ (163 mg 0.619 mmol) and TiusPHBFzt (18 mg, 0.061 mmol) were added, followed by Pd(OAc)₂ (41 mg, 0.061 mmol) and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH: ACN as eluent to afford 60 mg (20% yield) of the desired compound 149 as an off- white solid. 95.1 % HPLC purity at 254 nm. 1H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.03 (m, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.26-8.31 (m, 3H), 7.98-8.02 (m, 1H), 7.70-7.67 (m, 1H), 7.49- 7.54 (t, J = 8.4 Hz, 1H), 3.45-3.36 (m, 4H), 2.59-2.52 (m, 4H), 2.25 (s, 3H), 1.79-1.77 (m, 2H); ESI/MS [m/z] = 477.01 [M+H]⁺.

EXAMPLE 150

6-Fluoro-N-(4-fluoro-3-((4-methyl- 1 ,4-diazepan- l-yl)sulfonyl)phenyl) quinoline-7-carboxamide (150)

[0342] A solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (150 mg, 0.663 mmol), 4-fluoro-3-(4-methyl-l,4-diazepan-l-ylsulfonyl)aniline Int-35 (Example 147) (190 mg, 0.663 mmol) and Na₂C03 (140 mg, 1.326 mmol) in a acetonitrile (10 mL) was de-gassed with Argon for 15 min in a microwave vial. Then Mo(CO)₆ (175 mg 0.663 mmol), t-Bu3PHBF₄ (19 mg, 0.066 mmol) were added, followed by Pd(OAc)₂ (44 mg, 0.066 mmol) and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 60 mg (20% yield) of the desired compound 150 as an off- white solid. 95.01 % HPLC purity at 254 nm. 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.99 (m, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 6.8 Hz, 1H), 8.31 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 8.06- 8.02 (m, 1H), 7.97 (d, J= 10.8 Hz, 1H), 7.67 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.51 (t, J = 10.8 Hz, 1H), 3.45-3.46 (m, 4H), 2.59-2.55 (m, 2H), 2.52-2.45 (m, 2H), 2.25 (s, 3H), 1.79 (quint, J = 8.0 Hz, 2H); ESI/MS [m/z] = 461.31 [M+H]⁺

EXAMPLE 151

N-(3-((4-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-l,4-diazepan-l-yl)

sulfonyl)phenyl)quinoline-7-carboxamide (151)

151

[0343] N-(3-((l,4 ²-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (20 mg, 0.0487 mmol) was dissolved in methanol (450 μΐ.) and 17-azido-3,6,9,12,15-pentaoxaheptadecanal (29.7 mg, 0.0974 mmol) was added at r.t, followed by 1 drop of glacial acetic acid. Then sodium cyanoborohydride (12 mg, 0.195 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Then the reaction mixture was quenched with water (150 μΐ.) and purified on reverse-phase CI 8 silica gel with water/acetonitrile + 0.1% trifluoroacetic acid. The product 151 was obtained as yellow oil in 94% yield (32 mg). 1H-NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.74 (s, 1H), 8.49 (ddd, J = 8.3, 1.7, 0.7 Hz, 1H), 8.37 (t, J = 1.9 Hz, 1H), 8.17-8.12 (m, 3H), 7.67 (dd, J = 8.3, 4.2 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.52 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 3.61-3.26 (m, 26H), 2.73-2.70 (m, 2H), 2.64-2.59 (m, 2H), 1.75-1.69 (m, 2H); MS m/z = 700 [M+H]⁺ and 722 [M+Na]⁺.

EXAMPLE 152

N-(3-((l,4-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (152)

152

Synthesis of Tert-butyl 4-((3-nitrophenyl)sulfonyl)-l,4-diazepane-l-carboxylate (Int-36)

Int-36

[0344] Triethylamine (9.4 mL, 67.7 mmol) was added to a stirred solution of 3- nitrobenzene-l-sulfonyl chloride (3 g, 13.5 mmol) in dry THF (30 mL) at 0 °C, followed by tert- butyl 1,4-diazepane-l-carboxylate (4 mL, 20.3 mmol), and the reaction mixture was stirred at r.t. for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 100 mL). Combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 silica-gel) using 30% Ethyl Acetate in Hexane as eluent to afford 2.5 g (48% yield) of tert-butyl 4-((3- nitrophenyl)sulfonyl)-l,4-diazepane-l-carboxylate Int-36 as brown liquid. MS (ESI) m/z 386.02[M+H]⁺.

Synthesis of Tert-butyl 4-((3-aminophenyl)sulfonyl)-l,4-diazepane-l-carboxylate (Int-37)

Int-37

[0345] 10% Pd/C (20% by wt) was added to a stirred solution of tert-butyl 4-((3- nitrophenyl)sulfonyl)-l,4-diazepane-l-carboxylate Int-36 (2.5 g, 6.5 mmol) in MeOH (30 mL) and the reaction mixture was stirred under hydrogen balloon atmosphere for 3 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the collected filtrates were concentrated under reduced pressure. The crude product was purified by neutral alumina column chromatography using 5% methanol in DCM as eluent to afford 1.2 g (57% yield) of tert-butyl 4-((3- aminophenyl)sulfonyl)-l,4-diazepane-l-carboxylate Int-37 as brown oil. MS (ESI) m/z 356.27[M+H]⁺

[0346] Step 1. Oxalyl chloride (1.5 mL, 11.56 mmol) was added to a solution of quinoline-7-carboxylic acid (0.5 g, 2.9 mmol) in DCM (10 mL), followed by catalytic amount of DMF at 0 C and the reaction mixture was stirred at r.t. for 1 hr. Then the reaction mixture was directly concentrated under Argon atmosphere to afford the crude acid chloride. The resultant acid chloride was dissolved in THF (10 mL), then TEA (2 mL, 14.4 mmol) was added, followed by tert- butyl 4-((3-aminophenyl)sulfonyl)-l,4-diazepane-l-carboxylate Int-37 (1.0 g, 2.890 mmol) in THF (5 mL) at r.t. The reaction mixture was stirred at r.t. for 4 hrs. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified by column chromatography (100-200 silica-gel) using 60% Ethyl Acetate in Hexane as eluent to afford 0.4 g (27% yield) of tert-butyl 4-((3-(quinoline-7-carboxamido)phenyl)sulfonyl)-l,4-diazepane-l- carboxylate as an off-white solid. MS (ESI) m/z 511.78 [M+H]⁺

[0347] Step 2. Tert-butyl 4-((3-(quinoline-7-carboxamido)phenyl)sulfonyl)-l,4- diazepane-l-carboxylate (0.4 g, 0.784 mmol) was dissolved in 5 mL of 1,4-Dioxane, and 5 mL of 4M HC1 in 1,4-Dioxane were added to this solution at 0 °C. The reaction mixture was stirred at r.t. for 12 hrs. After completion of the reaction, the excess solvent was distilled-off to afford crude compound. The resultant crude compound was diluted with water and washed with Diethyl Ether (2 x 20 mL). The pH of the aqueous layer was adjusted with saturated sodium bicarbonate solution up to 8-9. The resultant suspension was extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 200 mg (93% yield) of the desired compound 152 as an off-white solid. 95.01 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 9.04 (dd, J = 5.2 Hz, 1.6 Hz, 1H), 8.74 (s, 1H), 8.48 (dd, J= 11.2 Hz, 1.6 Hz, 1H), 8.37 (t, J = 2.4 Hz, 1H), 8.17 (br s, 1H), 8.13-8.15 (m, 2H), 7.67 (dd, J= 11.2 Hz, 5.2 Hz, 1H) 7.63 (d, J= 10.8 Hz, 1H), 7.52 (d, J = 10.8 Hz, 1H), 3.26-3.24 (m, 2H), 3.23-3.21 (m, 2H), 2.76-2.80 (m, 2H), 2.72 (t, J = 8.0 Hz, 2H), 1.68 (q, J= 8.0 Hz, 2H); ESI/MS [m/z] = 411.07 [M+H]⁺.

EXAMPLE 153

-(6-((4-Methylpiperazin-l-yl)sulfonyl)-lH-benzo[d]imidazol-2-yl)quinoline (153)

Int-38

[0348] To a cooled (0 °C) solution of 2-nitroaniline (10 g, 72.37 mmol) was added chlorosulfonic acid (20 mL, 289.5 mmol) and the reaction mixture was heated at 100 °C for 4 hrs. After completion of the reaction, the reaction mixture was poured into crushed ice and extracted into Ethyl Acetate (2 x 150 mL). Combined organic layers were washed with water (2 x 45 mL), brine (45 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 6 g (35% yield) of crude 4-amino-3-nitrobenzenesulfonyl chloride Int-38 as a pale-brown liquid. The crude product was directly taken to the next step without further purification. MS (ESI) m/z 234.84 [M-H]^"

Synthesis of 4-((4-Methylpiperazin- -yl)sulfonyl)-2-nitroaniline (Int-39)

Int-39

[0349] To a stirred solution of 4-amino-3-nitrobenzenesulfonyl chloride Int-38 (3 g, 12.71 mmol) in dry THF (30 mL) was added TEA (10.64 mL, 76.27 mmol), followed by N- methylpiperazine (1.69 mL, 15.25 mmol) at 0 °C, and the reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with Ethyl Acetate (2 x 100 mL). Combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica gel) using 40% Ethyl Acetate in Hexane as eluent to afford 2 g (52% yield) of 4-((4-methylpiperazin-l- yl)sulfonyl)-2-nitroaniline Int-39 as a brown solid. MS (ESI) m/z 301.21 [M+H]⁺.

Synthesis of N-(4-((4-methylpiperazin- l-yl)sulfonyl)-2-nitrophenyl)quinoline-7-carboxamide (Int-40)

Int-40

[0350] To a stirred solution of quinoline-7-carboxylic acid (0.3 g, 1.754 mmol) in DMF (10 mL) at r.t. was added DIPEA (1.51 mL 8.771 mmol), followed by HATU (0.9 g, 2.631 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 4-((4-methylpiperazin-l-yl)sulfonyl)-2- nitroaniline Int-39 (0.52 g, 1.754 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica-gel) using 30% Ethyl Acetate in Hexane as eluent to afford 0.15 g (20% yield) of N-(4-((4-methylpiperazin-l-yl)sulfonyl)-2-nitrophenyl)quinoline-7-carboxamide Int- 40 as a pale-yellow solid. MS (ESI) m/z 456.02 [M+H]⁺

Synthesis of N-(2-amino-4-((4-methylpiperazin-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (Int-41)

Int-41

[0351] To a stirred solution of N-(4-((4-methylpiperazin-l-yl)sulfonyl)-2-nitrophenyl) quinoline-7-carboxamide Int-40 (0.15 g, 0.329 mmol) in methanol (10 mL) was added 10% Pd/C (20% by wt), and the reaction mixture was stirred under hydrogen balloon atmosphere for 5 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the collected filtrates were concentrated under reduced pressure to afford 90 mg (64% yield) of N-(2- amino-4-((4-methylpiperazin-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide Int-41 as a pale-yellow solid. The crude product was directly taken to the next step without further purification. MS (ESI) «¾/ 425.99[M+H]⁺.

[0352] To a solution of N-(2-amino-4-((4-methylpiperazin-l- yl)sulfonyl)phenyl)quinoline-7-carboxamide Int-41 (90 mg, 0.2117 mmol) in acetic acid (5 mL) was added xylene (1 mL) at r.t, and the reaction mixture was heated at 100 °C for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (13 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 35 mg (40% yield) of the desired compound 153 as an off- white solid. 95.41 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆) δ 13.65 (br. s, 1H), 9.02 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.87 (s, 1H), 8.47-8.44 (m, 2H), 8.19 (d, J = 8.4 Hz, 1H), 8.06 (br s, 1H), 7.86 (br s, 1H), 7.63 (dd, J = 8.4 Hz, 4.4 Hz, 1H) 7.60 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 2.95-2.88 (m, 4H), 2.38-2.33 (m, 4H), 2.13 (s, 3H); ESI/MS [m/z] = 408.20 [M+H]⁺.

EXAMPLE 154

7-(6-((4-Methyl- 1 ,4-diazepan- l-yl)sulfonyl)- lH-benzo [d] imidazol-2-yl) quinoline (154)

154

Synthesis of 4-((4-Methyl-l,4-diazepan-l-yl)sulfonyl)-2-nitroaniline (Int-42)

Int-42

[0353] To a stirred solution of 4-amino-3-nitrobenzenesulfonyl chloride Int-38 (Example 153) (3 g, 12.71 mmol) in dry THF (30 mL) was added TEA (10.64 mL, 76.27 mmol), followed by l-methyl-l,4-diazepane (1.9 mL, 15.25 mmol) at 0 °C and the reaction mixture stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with Ethyl Acetate (2 x 100 mL). Combined organic layers were washed with water (2 x 60 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 40% Ethyl Acetate in Hexane as eluent to afford 1.9 g (47% yield) of 4-((4-methyl-l,4- diazepan-l-yl)sulfonyl)-2-nitroaniline Int-42 as a brown solid. MS (ESI) m/z 315.23[M+H]⁺.

Synthesis of N-(4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)-2-nitrophenyl)quinoline-7- carboxamide (Int-43)

Int-43

[0354] DIPEA (1.51 mL 8.771 mmol) was added to a stirred solution of quinoline-7- carboxylic acid (0.3 g, 1.75 mmol) in DMF (10 mL) at r.t, followed by HATU (0.9 g, 2.631 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 4-((4-methyl-l,4-diazepan-l- yl)sulfonyl)-2-nitroaniline Int-42 (0.55 g, 1.754 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 30% Ethyl Acetate in Hexane as eluent afforded 0.16 g (20 % yield) of N-(4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)-2-nitrophenyl) quinoline-7- carboxamide Int-43 as a pale yellow solid. MS (ESI) m/z 470.04[M+H]⁺.

Synthesis of N-(2-amino-4-((4-methyl-l,4-diazepan-l-yl) sulfonyl)phenyl)quinoline-7- carboxamide (Int-44)

Int-44

[0355] To a stirred solution of N-(4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)-2- nitrophenyl) quinoline-7-carboxamide Int-43 (0.16 g, 0.341 mmol) in Methanol (10 mL) was added 10% Pd/C (20% by wt) and the reaction mixture was stirred under hydrogen balloon atmosphere for 5 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the collected filtrates were concentrated under reduced pressure to afford 85 mg (57 % yield) of N- (2-amino-4-((4-methyl-l,4-diazepan-l-yl) sulfonyl)phenyl)quinoline-7-carboxamide Int-44 as a pale-yellow solid. The crude was directly taken to the next step without further purification. MS (ESI) «¾/ 440.08[M+H]⁺

[0356] To a mixture of N-(2-amino-4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl) quinoline-7-carboxamide Int-44 (85 mg, 0.193 mmol) in acetic acid (5 mL) was added xylene (2 mL) at r.t, and the reaction mixture was heated at 100 °C for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 30 mg (37% yield) of the desired compound 154 as an off-white solid. 95.83 %

HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 13.71 (br s, 1H), 9.01 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.87 (s, 1H), 8.47-8.44 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 8.04 (br s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.66-7.61 (m, 2H), 3.36-3.29 (m, 4H), 2.54-2.49 (m, 2H), 2.46 (t, J = 5.6 Hz, 2H), 2.20 (s, 3H), 1.72 (quint, J = 5.6 Hz, 2H); ESI/MS [m/z] = 420.27 [M-H]^". EXAMPLE 155

7-(6-((4-(2-Methoxyethyl)piperazin- l-yl)sulfonyl)- IH-benzo [d] imidazol-2-yl) quinoline (155)

155

Synthesis of 4-((4-(2-Methoxyethyl)piperazin-l-yl)sulfonyl)-2-nitroaniline (Int-45)

Int-45

[0357] To a stirred solution of 4-amino-3-nitrobenzenesulfonyl chloride Int-38 (Example 153) (3 g, 12.71 mmol) in dry THF (30 mL) was added TEA (10.64 mL, 76.27 mmol), followed by l-(2-methoxyethyl)piperazine (2.57 g, 15.25 mmol) at 0 °C, and the reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with Ethyl Acetate (2 x 150 mL). Combined organic layers were washed with water (2 x 90 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica-gel) using 40% Ethyl Acetate in Hexane as eluent to afford 2.1 g (yield 52%) of 4-((4-(2- methoxyethyl)piperazin-l-yl)sulfonyl)-2-nitroaniline Int-45 as a brown solid. MS (ESI) m/z 345.07[M+H]⁺

Synthesis of N-(4-((4-(2-methoxyethyl)piperazin-l-yl)sulfonyl)-2-nitrophenyl)quinoline-7- carboxamide (Int-46)

Int-46

[0358] DIPEA (2.5 mL 14.45 mmol) was added to a stirred solution of quinoline-7- carboxylic acid (0.5 g, 2.890 mmol) in DMF (10 mL) at r.t., followed by HATU (1.6 g, 4.34 mmol) at 0 °C and the reaction mixture was stirred for 15 min. Then 4-((4-(2-methoxy ethyl) piperazin-1 - yl)sulfonyl)-2-nitroaniline Int-45 (1.0 g, 2.890 mmol) was added to reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 30% Ethyl Acetate in Hexane as eluent to afford 0.25 g (34% yield) of N-(4-((4-(2-methoxyethy l)piperazin- 1 -yl)sulfony l)-2-nitropheny l)quinoline-7-carboxamide Int-46 as a pale yellow solid. MS (ESI) m/z 500.29[M+H]⁺.

Synthesis of N-(2-amino-4-((4-(2-methox ethyl) piperazin-l-yl)sulfonyl)phenyl)quinoline-7- carboxamide (Int-47)

Int-47

[0359] 10% Pd/C (20% by wt) was added to a stirred solution of N-(4-((4-(2- methoxyethyl) piperazin-l-yl)sulfonyl)-2-nitrophenyl)quinoline-7-carboxamide Int-46 (0.2 g, 0.400 mmol) in methanol (10 mL), and the reaction mixture was stirred under hydrogen balloon atmosphere for 5 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the combined filtrates were concentrated under reduced pressure to afford 110 mg (58% yield) of N-(2-amino-4-((4-(2-methoxyethyl) piperazin-l-yl)sulfonyl)phenyl)quinoline-7- carboxamide Int-47 as a pale-yellow solid. The crude was directly taken to the next step without further purification. MS (ESI) m/z 470.04 [M+H]⁺.

[0360] To a solution of N-(2-amino-4-((4-(2-methoxyethyl)piperazin-l- yl)sulfonyl)phenyl) quinoline-7-carboxamide Int-47 (110 mg, 0.234 mmol) in acetic acid (5 mL) was added xylene (2 mL) at r.t.. The reaction mixture was heated at 100 °C for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2 x 60 mL). Combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in CH₃CN as eluent to afford 40 mg (39% yield) of the desired compound 155 as a pale- yellow solid. 95.25 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 13.78 (br s, 1H), 9.01 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.89 (s, 1H), 8.48-8.44 (m, 2H), 8.19 (d, J = 8.8 Hz, 1H), 8.02 (br s, 1H), 7.87 (br s, 1H), 7.64 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 3.33 (t, J = 5.6 Hz, 2H), 3.14 (s, 3H), 2.91 (m, 4H), 2.51-2.45 (m, 4H), 2.44 (t, J = 5.6 Hz, 2H); ESI/MS [m/z] = 452.23 [M+H]⁺.

EXAMPLE 156

7-(6-((4-(2-Methoxy ethyl)- 1 ,4-diazepan- l-yl)sulfonyl)- lH-benzo [d] imidazol-2-yl)quinoline (156)

156

Synthesis of 4-((4-(2-Methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)-2-nitroaniline (Int-48)

Int-48

[0361] Triethylamine (10.64 mL, 76.27 mmol) was added to a stirred solution of 4- amino-3-nitrobenzenesulfonyl chloride Int-38 (Example 153) (3 g, 12.71 mmol) in dry THF (30 mL), followed by l-(2-methoxyethyl)-l,4-diazepane (2.7 g, 15.25 mmol) at 0 °C, and the reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with Ethyl Acetate (2 x 100 mL). Combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica-gel) using 40% Ethyl Acetate in Hexane as eluent to afford 2.1 g (46% yield) of 4-((4-(2-methoxy ethyl)- l,4-diazepan-l-yl)sulfonyl)-2-nitroaniline Int-48 as a brown solid. MS (ESI) m/z 359.09 [M+H]⁺

Synthesis of N-(4-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)-2-nitrophenyl) quinoline-7- carboxamide (Int-49)

Int-49

[0362] DIPEA (2.5 mL 14.45 mmol) was added to a stirred solution of quinoline-7- carboxylic acid (0.5 g, 2.89 mmol) in DMF (10 mL) at r.t, followed by HATU (1.6 g, 4.335 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 4-((4-(2-methoxy ethyl)- 1 ,4-diazepan- l-yl)sulfonyl)-2-nitroaniline Int-48 (1.0 g, 2.89 mmol) was added to the reaction mixture at 0 °C . The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 30 mL). Combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 30% Ethyl Acetate in Hexane as eluent to afford 0.15 g (10% yield) of N-(4-((4-(2-methoxy ethyl)- 1,4-diazepan-l-y l)sulfonyl)-2-nitrophenyl)quinoline-7- carboxamide Int-49 as a pale-yellow solid. MS (ESI) m/z 514.34[M+H]⁺

Synthesis of N-(2-amino-4-((4-(2-methoxyethyl)-l,4-diazepan-l-yl)sulfonyl)phenyl) quinoline- 7-carboxamide (Int-50)

Int-50

[0363] 10% Pd/C (20% by wt) was added to a stirred solution of N-(4-((4-(2- methoxy ethyl)- 1 ,4-diazepan- 1 -y l)sulfonyl)-2-nitrophenyl)quinoline-7-carboxamide Int-49 (0.15 g, 0.292 mmol) in methanol (10 mL) and the reaction mixture was stirred under hydrogen balloon atmosphere for 5 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the collected filtrates were concentrated under reduced pressure to afford 90 mg (63% yield) of N-(2-amino-4-((4-(2-methoxy ethyl)- 1,4-diazepan-l-y l)sulfonyl)phenyl)quinoline-7- carboxamide Int-50 as a pale-yellow solid. The crude was directly taken to the next step without further purification. MS (ESI) m/z 484.04 [M+H]⁺.

[0364] Xylene (2 mL) was added to a solution of N-(2-amino-4-((4-(2-methoxyethyl)- l,4-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide Int-50 (90 mg, 0.186 mmol) in acetic acid (5 mL) at r.t., and the reaction mixture was heated at 100 °C for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH: ACN as eluent to afford 35 mg (41% yield) of the desired compound 156 as a pale-yellow solid. 96.54 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d6): δ 13.75 (br s, 1H), 9.01 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.87 (s, 1H), 8.48-8.44 (m, 2H), 8.17 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.62 (d, J = 4.0 Hz, 1H), 3.25-3.35 (m, 6H), 3.18 (s, 3H), 2.66- 2.69 (m, 2H), 2.55-2.61 (m, 4H), 1.66-1.72 (m, 2H); ESI/MS [m/z] = 466.24 [M+H]⁺.

EXAMPLE 157

6-Methyl-7-(6-((4-methylpipe dazol-2-yl)quinoline (157)

157

Synthesis of 6-Methyl-N-(4-((4-methylpiperazin-l-yl)sulfonyl)-2-nitrophenyl) quinoline-7- carboxamide (Int-51)

Int-51

[0365] DIPEA (2.2 mL 13.25 mmol) was added to a stirred solution of 6- methylquinoline-7-carboxylic acid Int-8 (Example 127) (0.5 g, 2.65 mmol) in DMF (10 mL), followed by HATU (1.48 g, 3.989 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 4-((4-methylpiperazin-l-yl)sulfonyl)-2-nitroaniline Int-39 (Example 153) (0.78 g, 2.65 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 100 mL). Combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica gel) using 30% Ethyl Acetate in Hexane as eluent to give 0.21 g (17 % yield) of 6-methyl-N-(4-((4-methylpiperazin- l-yl)sulfonyl)-2-nitrophenyl) quinoline-7-carboxamide Int-51 as a pale-yellow solid. MS (ESI) m/z 470.28 [M+H]⁺.

Synthesis of N-(2-amino-4-((4-methylpiperazin-l-yl)sulfonyl)phenyl)-6-methylquinoline-7- carboxamide (Int-52)

Int-52

[0366] 10% Pd/C (20% by wt) was added to a stirred solution of 6-methyl-N-(4-((4- methylpiperazin-l-yl)sulfonyl)-2-nitrophenyl)quinoline-7-carboxamide Int-51 (0.21 g, 0.45 mmol) in Methanol (10 mL), and the reaction mixture was stirred under hydrogen balloon atmosphere for 5 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the collected filtrates were concentrated under reduced pressure to afford 150 mg (76% yield) of N- (2-amino-4-((4-methylpiperazin-l -yl)sulfonyl)phenyl)-6-methylquinoline-7-carboxamide Int-52 as a pale-yellow solid. The crude was directly taken to the next step without further purification. MS (ESI) m/z 440.05 [M+H]⁺.

[0367] Xylene (1 mL) was added to the solution of N-(2-amino-4-((4-methylpiperazin-l- yl) sulfonyl)phenyl)-6-methylquinoline-7-carboxamide Int-52 (150 mg, 0.34 mmol) in acetic acid (5 mL) at r.t., and the reaction mixture was heated at 100 °C for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 35 mg (40% yield) of the desired compound 157 as a pale-yellow solid. 96.0 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.96-8.94 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.50 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 8.05 (br s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 4.4 Hz, 1H), 7.61 (d, J = 4.4 Hz, 1H), 2.93-2.89 (m, 4H), 2.83 (s, 3H), 2.45- 2.35 (m, 4H), 2.13 (s, 3H); ESI/MS [m/z] = 422.28 [M+H]⁺.

EXAMPLE 158

6-Methyl-7-(6-((4-methyl-l,4-diazepan-l-yl)sulfonyl)-lH-benzo[d]imidazol-2-yl)quinoline (158)

158

Synthesis of 6-Methyl-N-(4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)-2-nitrophenyl) quinoline-7- carboxamide (Int-53)

Int-53

[0368] DIPEA (2.2 mL 13.25 mmol) was added to the stirred solution of 6- methylquinoline-7-carboxylic acid Int-8 (Example 127) (0.5 g, 2.65 mmol) in DMF (10 mL), followed by HATU (1.48 g, 3.99 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)-2-nitroaniline Int-42 (Example 154) (0.8 g, 2.65 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica gel) using 30% Ethyl Acetate in Hexane as eluent to give 0.2 g (16% yield) of 6-methyl-N-(4-((4-methyl-l,4- diazepan-l-yl)sulfonyl)-2-nitrophenyl) quinoline-7-carboxamide Int-53 as a pale-yellow solid. MS (ESI) m/z 484.04 [M+H]⁺.

Synthesis of N-(2-amino-4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)-6-methyl quinoline-7- carboxamide (Int-54) —

Int-54

[0369] 10% Pd/C (20% by wt) was added to a stirred solution of 6-methyl-N-(4-((4- methyl-l,4-diazepan-l-yl)sulfonyl)-2-nitrophenyl)quinoline-7-carboxamide Int-53 (0.2 g, 0.414 mmol) in Methanol (10 mL) and the reaction mixture was stirred under hydrogen balloon atmosphere for 5 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the combined filtrates were concentrated under reduced pressure to afford 140 mg (76% yield) of N-(2-amino-4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)-6-methylquinoline-7- carboxamide Int-54 as a pale-yellow solid. The crude was directly taken to the next step without further purification. MS (ESI) m/z 454.04 [M+H]⁺.

[0370] To a solution of N-(2-amino-4-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)-6- methylquinoline-7-carboxamide Int-54 (140 mg, 0.31 mmol) in acetic acid (5 mL) was added xylene (2 mL) at r.t, and then the reaction mixture was heated at 100 °C for 12 hrs. After completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 30 mg (22% yield) of the desired product 158 as an off-white solid.

MS (ESI) m/z 436.30 [M+H]⁺. 1H NMR (DMSO-d₆, 400 MHz): δ 13.42 (s, 1H), 8.94 (dd, J = 3.6, 1.2 Hz, 1H), 8.49 (s, 1H), 8.36 (dd, J = 8.0 Hz, 1H), 8.12-8.04 (m, 1H), 7.99 (s, 1H), 7.86-7.74 (m, 1H), 7.71-7.62 (m, 1H), 7.60 (dd, J = 8.4, 4.4 Hz, 1H), 3.35-3.28 (m, 4H), 2.82 (s, 3H), 2.55-2.45 (m, 4H), 2.21 (s, 3H), 1.72 (q, J = 5.2, Hz, 2H).

EXAMPLE 159

N-(4-Chlorophenyl)-8-hydroxyqui

159 [0371] 8-Hydroxyquinoline-7-carboxylic acid (37.8 mg, 0.2 mmol) and 4-chloroaniline (38.3 mg, 0.3 mmol) were suspended in dry N,N-dimethylformamide (1.2 mL) and triethylamine (33 μΐ_^, 0.24 mmol) was added. Then HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (91.3 mg, 0.24 mmol) was added, and the reaction mixture was stirred for 16 hours at room temperature. After dilution with water, the mixture was extracted with dichloromethane (3 x 15 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Crude product was purified on reverse-phase CI 8 silica gel with water/acetonitrile + 0.1% trifluoroacetic acid. Fractions containing the desired product were combined and treated with aqueous saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane (3 x 50 mL). Combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 26 mg of the desired product 159 as a red crystalline solid in 44% yield. ^-NMR (400 MHz, DMSO-d₆): δ 11.28 (bs, 1H), 8.92 (dd, J = 4.3, 1.4 Hz, 1H), 8.49 (dd, J = 8.3, 1.3 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.73 (dd, J = 8.3, 4.3 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.41 (dd, J = 13.7, 8.9 Hz, 1H); MS m/z = 299 [M+H]⁺.

EXAMPLE 160

6-Methyl-N-(6-(trifluoromethyl)pyridin-3-yl)quinoline-7-carboxamide (160)

160

[0372] A stirred solution of 7-bromo-6-methylquinoline Int-1 (Example 86) (150 mg, 0.675 mmol), 6-(trifluoromethyl)pyridin-3-amine (131 mg, 0.810 mmol) and Na₂CC>3 (142 mg, 1.351 mmol) in acetonitrile (5 mL) was degassed with Argon in a microwave vessel for 15 min. Then Mo(CO)₆ (178 mg, 0.675 mmol), 3¾ΡΗΒΕ₄ (19.6 mg, 0.0675 mmol) and Pd(OAc)₂ (15.1 mg, 0.0675 mmol) were added, and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion (checked by TLC), the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2x50 mL). Combined organic layer was washed with water (2x20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford crude product. The crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 50 mg (21% yield) of the desired compound 160 as an off- white solid. MS (ESI) m/z: 332.21 [M+H]⁺. 1H NMR (DMSO-i/₆, 400 MHz): δ 11.18 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.94 (dd, J = 4.4, 2.0 Hz, 1H), 8.50 (dd, J = 8.0, 1.6 Hz, 1H), 8.35 (dd, J Hz, 1H), 8.24 (s, 1H), 7 ^'.95-7 ^'.92 (m, 2H), 7.60 (dd, J= 8.4, 4.0 Hz, 1H), 2.61 (s, 3H).

EXAMPLE 161

6-Chloro-N-(6-(trifluoromethyl)pyridin-3-yl)quinoline-7-carboxamide (161)

161

[0373] A solution of 7-bromo-6-chloroquinoline (1 g, 4.13 mmol), 6-(trifluoromethyl) pyridin-3 -amine (660 mg, 4.13 mmol) and Na₂CC>3 (871 mg, 8.26 mmol) in acetonitrile (30 mL) was degassed with Argon in a sealed vial. Then Mo(CO)₆ (1.09 g, 4.13 mmol), t-Bu₃PHBF₄ (119 mg, 0.413 mmol) and Pd(OAc)₂ (273 mg, 0.041 mmol) were added and degassing was continued for 10 min. Then the reaction mixture was heated at 100 °C for 18 hrs. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with Ethyl Acetate (2 x 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The resultant crude compound was purified by silica-gel column chromatography using 1-5 % MeOH in DCM as eluent to afford 300 mg (20% yield) of the desired compound 161 as an off-white solid with 98.4% HPLC purity at 215 nm. MS

(ESI) m/z 352.05 [M+H]⁺. 1H NMR (DMSO-i/₆, 400 MHz): 5 11.35 (s, 1H), 9.05-9.03 (m, 2H), 8.50 (dd, J= 8.4, 1.2 Hz, 1H), 8.46 (d, J= 8.4 Hz, 1H), 8.36 (s, 1H), 8.34 (s, 1H) 7.97 (d, J= 8.8 Hz, 1H), 7.70 (dd, J= 8.4, 4.0 Hz, 1H).

EXAMPLE 162

6-Fluoro-N-(6-(trifluoromethyl)pyridin-3-yl)quinoline-7-carboxamide (162)

162

[0374] A stirred solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (200 mg, 0.884 mmol), 6-(trifluoromethyl)pyridin-3-amine (143 mg, 0.884 mmol) and Na₂CC>3 (186 mg, 1.769 mmol) in acetonitrile (5 mL) was degassed with Argon gas in a microwave vessel for 15 min. Then Mo(CO)₆ (234 mg, 0.884 mmol), T3u₃PHBF₄ (25 mg, 0.088 mmol) and Pd(OAc)₂ (20 mg, 0.088 mmol) were added to this mixture, and degassing was continued for additional 10 min. The reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction (checked by TLC), the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2x50 mL). Combined organic layers were washed with water (20 mL), brine (20 mL) and dried over sodium sulfate. The organic layer was evaporated under reduced pressure to afford crude product. The crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in CH₃CN as eluent to afford 40 mg (13.5 % yield) of the desired compound 162 as an off-white solid. 99.2 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 11.23 (s, 1H), 9.05 (d, J = 2.0 Hz, 1H), 9.00 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.51-8.42 (m, 3H), 7.99 (d, J = 10.8 Hz, 1H), 7.96 (d, J= 8.8 Hz, 1H), 7.68 (dd, J= 8.4, 4.4 Hz, 1H). ESI/MS [m/z] = 336.24 [M+H]⁺.

EXAMPLE 163

6-Methyl-N-(6-chloropyridin-3-yl)quinoline-7-carboxamide (163)

163

[0375] A stirred solution of 7-bromo-6-methylquinoline Int-1 (150 mg, 0.675 mmol), 6- chloropyridin-3 -amine (104 mg, 0.810 mmol) and Na₂C0₃ (142 mg, 1.351 mmol) in acetonitrile (5 mL) was degassed with Argon in a microwave vessel for 15 min. Then Mo(CO)₆ (178 mg, 0.675 mmol), 3U3PHBF₄ (19.6 mg, 0.0675 mmol) and Pd(OAc)₂ (15.1 mg, 0.0675 mmol) were added, and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction (checked by TLC), the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2x20 mL). Combined organic layers were washed with water (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford crude product. The crude product was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in C¾CN as eluent to afford 40 mg (20 % yield) of the desired compound 163 as an off- white solid. 98.9 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 8.93 (dd, J = 4.4, 1.6 Hz, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 8.8, 3.2 Hz, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.59 (dd, J = 8.4, 4.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 2.57 (s, 3H). ESI/MS [m/z] = 298.18 [M+H]⁺

EXAMPLE 164

6-Chloro-N-(6-chloropyridin-3-yl)quinoline-7-carboxamide (164)

164

[0376] A solution of 7-bromo-6-chloroquinoline 2 A (Example 95) (200 mg, 0.826 mmol) and 6-chloropyridin-3 -amine (105 mg, 0.826 mmol) in acetonitrile (5 mL) was degassed with Argon gas in a microwave vessel. Then Na₂C03 (173 mg, 1.652 mmol) was added, followed by Mo(CO)6 (218 mg, 0.826 mmol), T3u₃PHBF₄ (24 mg, 0.082 mmol) and Pd(OAc)₂ (18.5 mg, 0.082 mmol), and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2 x 50 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in CH₃CN as eluent to afford 45 mg (17% yield) of the desired compound 164 as an off-white solid. 96.8 % HPLC purity at 215 nm. 1H NMR (400 MHz,

DMSO-de): δ 11.02 (s, 1H), 9.02 (dd, J = 4.4, 1.2 Hz, 1H), 8.76 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.31 (s, 1H), 8.305 (s, 1H), 8.24 (dd, J = 8.8, 2.8 Hz, 1H), 7.68 (dd, J = 8.4, 4.4 Hz, 1H), 7.56 (d, J= 8.8 Hz, 1H). ESI/MS [m/z] = 318.18 [M+H]⁺

EXAMPLE 165

6-Fluoro-N-(6-chloropyridin-3-yl)quinoline-7-carboxamide (165)

165

[0377] A stirred solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (200 mg, 0.884 mmol), 6-chloropyridin-3 -amine (113 mg, 0.884 mmol) and Na₂C03 (186 mg, 1.769 mmol) in acetonitrile (5 mL) was degassed with Argon gas in a microwave vessel for 15 min. Then Mo(CO)6 (234 mg, 0.884 mmol), T3u₃PHBF₄ (25 mg, 0.088 mmol) and Pd(OAc)₂ (20 mg, 0.088 mmol) were added to this mixture, and degassing was continued for additional 10 min. Then the reaction mixture was irradiated in microwave at 90 °C for 3 hrs. After completion of the reaction (checked by TLC), the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (2x50 mL). Combined organic layer was washed with water (2x20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford crude product. The crude product was purified by Grace (reverse phase) column chromatography using 0.05 % HCOOH in CH₃CN as eluent to afford 45 mg (17 % yield) of the desired compound 165 as an off-white solid. 97.02 % HPLC purity at 215 nm. 1H NMR (400 MHz, DMSO-d₆): δ 11.02 (s, 1H), 9.00 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 8.77 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 6.8 Hz, 1H), 8.24 (dd, J = 8.8, 2.8 Hz, 1H), 7.98 (d, J = 10.8 Hz, 1H), 7.68 (dd, J = 8.4, 4.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H). ESI/MS [m/z] = 302.22 [M+H]⁺.

EXAMPLE 166

8-Chloro-N-(4-chlorophenyl)quin

166

Synthesis of 3-Amino-2-chlorobenzoic acid (Int-55)

Int-55

[0378] To a stirred solution of 2-chloro-3-nitrobenzoic acid (3 g, 14.88 mmol) in a mixture of EtOH/water (1 : 1) (60 mL) was added iron powder (12.46 g, 223.2 mmol), followed by ammonium chloride (3.9 g, 74.04 mmol). The reaction mixture was heated at 80 °C for 3 hrs. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the collected filtrate was concentrated under reduced pressure to afford 1.5 g (60% yield) of 3-amino-2- chlorobenzoic acid Int-55 as a brown solid. MS (ESI) m/z: 172.11 [M+H]⁺

Synthesis of 8-Chloroquinoline-7-carboxylic acid (Int-56)

Int-56

[0379] Concentrated H₂SO₄ (3 mL) was added slowly over a period of 5 min to a cooled solution of 3-amino-2-chlorobenzoic acid Int-55 (1 g, 5.85 mmol) in nitrobenzene (0.6 mL, 5.847 mmol) and glycerol (1 mL, 14.61 mmol) at 0 °C. The reaction temperature was gradually increased to 150 °C and the reaction mixture was stirred at 150 °C for 5 hrs. Then the reaction mixture was allowed to cool down to r.t., poured into crushed ice, then extracted with Ethyl Acetate (3 x 20 mL). Combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 0.5 g (41% yield) of 8-chloroquinoline-7- carboxylic acid Int-56 as an off-white solid. MS (ESI) m/z: 207.96 [M+H]⁺.

[0380] To a stirred solution of 8-chloroquinoline-7-carboxylic acid Int-56 (0.23 g, 1.13 mmol) in DMF (5 mL) was added DIPEA (0.82 mL 4.705 mmol), followed by HATU (0.71 g, 1.88 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 4-chloroaniline (0.12 g, 0.990 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2x40 mL). Combined organic layers were washed with water (2x20 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified by column chromatography (100-200 silica gel) using 50% Ethyl Acetate in Hexane as eluent to afford 70 mg (38% yield) of 8-chloro-N-(4- chlorophenyl)quinoline-7-carboxamide Compound 166 as an off-white solid. 'H-NMR (400 MHz,

DMSO-de): δ 10.80 (s, 1H), 9.11 (dd, J = 4.0, 1.6 Hz, 1H), 8,54 (d, J = 8.4 Hz, 1H), 8.10 (d, J= 8.4 Hz, 1H), 7.81-7.51 (m, 4H), 7.44 (d, J= 8.8 Hz, 2H); MS (ESI) m/z 317.21 [M+H]⁺.

EXAMPLE 167

8-Chloro-N-(6-chloropyridin-3-yl)quinoline-7-carboxamide (167)

167

[0381] To a solution of 8-chloroquinoline-7-carboxylic acid Int-56 (Example 166) (0.23 g, 1.12 mmol) in DMF (5 mL) was added DIPEA (0.81 mL 4.665 mmol), followed by HATU (0.70 g, 1.87 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 6-chloropyridin-3- amine (0.12 g, 0.933 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2x40 mL). Combined organic layers were washed with water (2x20 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was purified by column chromatography (100-200 silica) using 50% Ethyl Acetate in Hexane as eluent afforded 70 mg (23% yield) of 8-chloro-N-(6- chloropyridin-3-yl)quinoline-7-carboxamide Compound 167 as an off-white solid. 1H-NMR (400 MHz, DMSO-d₆): δ 11.04 (s, 1H), 9.12 (dd, J = 3.6, 1.2 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.55 (dd, J = 8.4, 1.2 Hz, 1H), 8.23 (dd, J = 8.8, 2.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.78 (d, J

1H), 7.75 (dd, J= 8.4, 4.4 Hz, 1H), 7.56 (d, J= 8.8 Hz, 1H); MS (ESI) m/z 318.22 [M+H]⁺

EXAMPLE 168

8-Chloro-N-(6-(trifluoromethyl)pyridin-3-yl)quinoline-7-carboxamide (168)

168

[0382] To a solution of 8-chloroquinoline-7-carboxylic acid Int-56 (Example 166) (0.18 g, 0.888 mmol) in DMF (5 mL) was added DIPEA (0.64 mL 3.701 mmol), followed by HATU (0.56 g, 1.480 mmol) at 0 °C, and the reaction mixture was stirred for 15 min. Then 6- (trifluoromethyl)pyridin-3 -amine (0.12 g, 0.740 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2x40 mL). Combined organic layers were washed with water (2x20 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified by column chromatography (100-200 silica gel) using 50% Ethyl Acetate in Hexane as eluent to afford 80 mg (30% yield) of 8-chloro-N-(6-(trifluoromethyl)pyridin-3-yl)quinoline-7-carboxamide Compound 168 as an off-white solid.1H-NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 9.13 (dd, J = 4.4, 1.6 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.56 (dd, J = 8.4, 1.2 Hz, 1H), 8.48 (dd, J = 8.4, 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.4, 4.0 Hz, 1H); MS (ESI) m/z 352.24 [M+H]⁺.

EXAMPLE 169

8-Chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide (169)

169

[0383] To a solution of 8-chloroquinoline-7-carboxylic acid Int-56 (Example 166) (0.139 g, 0.674 mmol) in DMF (5 mL) was added DIPEA (0.49 mL 2.808 mmol), followed by HATU (0.42 g, 1.123 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 15 min. Then 6- (trifluoromethoxy)pyridin-3 -amine (0.1 g, 0.561 mmol) was added to reaction mixture at 0 °C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2x50 mL). Combined organic layers were washed with water (2x30 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified by column chromatography (100-200 silica gel) using 50% Ethyl Acetate in Hexane as eluent to afford 50 mg (24% yield) of 8-chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide 169 as an off-white solid. 1H-NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 9.12 (dd, J = 4.4, 1.6 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.55 (J = 8.4, 1.6 Hz, 1H), 8.37 (dd, J = 8.8, 2.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (dd, J= 8.4, 4.0 Hz, 1H), 7.38 (d, J= 8.8 Hz, 1H); MS (ESI) m/z 368.24 [M+H]⁺.

EXAMPLE 170

6-chloro-N-(4-methyl-3-((4-methyl-l,4-diazepan-l-yl)sulfonyl)phenyl)quinoline-7-carboxamide (170)

170

[0384] Compound 170 is prepared in accordance with the experimental protocol described in Example 150 except that 7-bromo-6-chloroquinoline Int-3 (Example 122) is used in place of 7-bromo-6-fluoroquinoline and 4-methyl-3-(4-methyl-l,4-diazepan-l-ylsulfonyl)aniline is used in place of 4-fluoro-3-(4-methyl-l,4-diazepan-l-ylsulfonyl)aniline.

Example A. Cell Proliferation Assays

[0385] The general protocol for the cellular proliferation assays is provided below.

[0386] Materials: The tissue culture was prepared in T25 culture flasks, 15 mL and 50 mL conical tubes. RPMI-10 complete media: RPMI 1640 media containing 2 mM L-Glutamine and supplemented with 10% heat-inactivated FBS, 100 U/mL Penicillin G and 100 μg/mL Streptomycin.

[0387] DMEM-10 complete media: DMEM containing 4 mM L-Glutamine and supplemented with 10% heat-inactivated FBS, 100 U/mL Penicillin G and 100 μg/mL Streptomycin.

[0388] Assay Conditions:

[0389] Protocol 1.

[0390] Cells were maintained in logarithmic phase growth prior to testing. Desired density prior to harvesting was approximately 75% confluent. Cells were harvested with the preferred dissociating reagent and washed once with complete media, then re-suspended to a density of 4 x 10⁵ cells/mL in complete growth media. Cells were plated at

(20,000 cells/well) in a 384-well plate. Compounds were arrayed into appropriate wells of a 384-well plate (100

with the starting concentration of 1,000-fold above the desired test concentration. Compounds were diluted using serial half-log dilutions in 100% DMSO using an automated liquid handler. Compounds were distributed using a pin tool array or similar device. A 50 nL pin results in final DMSO concentrations of 0.1% in a 384-well plate. Cell lines, once distributed into microplates with appropriate test and control compounds, were incubated at 37°C/5% C0₂ for 48 hrs. DMSO was used as control. CellTiter Glo reagent (Promega, Inc., #G7572) was added at rt at a volume of 15 for 384-well plates. The plates were incubated for 5 minutes at rt and luminescence was measured in luminescence plate reader.

[0391] Protocol 2.

[0392] Cells (5,000 cells/well) were plated on 96-well BD Falcon culture plates (Corning Life Sciences) in 100 ul media (RPMI supplemented with 10% FBS). Cells were allowed to attach for 24 hours, treated with compounds in a dose response manner and then incubated at 37°C/5% C0₂ for 72 hrs. Cytotoxicity was determined using 100 ul CellTiter-Glo (Promega, Inc., #G7572) and 10 minutes of incubation at room temperature. DMSO was used as control. Luminescence was visualized with an Alpha Innotech Multi -Image Light Cabinet CCD camera (30 second exposure at medium sensitivity). The IC50 values were determined using Prism software.

[0393] The following three cancer cell lines were used: Au565 breast cancer cell line; MDA-MB-468 breast cancer cell line; and LS174T colon cancer cell line.

Assay Data for Compounds

[0394] Compounds of some embodiments were prepared according to synthetic methods described herein and assay data obtained for IC₅₀ of the various cancer cell lines. The assay data obtained is presented in Table 2, in which A = IC₅₀ less than 1 μΜ, B = IC₅₀ greater than or equal to 1 μΜ and less than or equal to 10 μΜ; and C = IC₅₀ greater than 10 μΜ.

-1

[0395] While the disclosure has been illustrated and described in detail in the foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure and the appended claims.

[0396] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0397] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated.

[0398] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0399] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including' should be read to mean 'including, without limitation,' 'including but not limited to,' or the like; the term 'comprising' as used herein is synonymous with 'including,' 'containing,' or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term 'having' should be interpreted as 'having at least;' the term 'includes' should be interpreted as 'includes but is not limited to;' the term 'example' is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as 'known', 'normal', 'standard', and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like 'preferably,' 'preferred,' 'desired,' or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, except for the claims, a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless the context indicates otherwise. Similarly, except for the claims, a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless the context indicates otherwise.

[0400] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0401] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to "at least one of A, B, or C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, except in the claims, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, except in the claims, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0402] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term 'about.' Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0403] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

A com ound of formula (I) or (Γ):

or a pharmaceutically acceptable salt thereof, wherein

each R¹ is selected from H, C₂-₆ alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci.6 alkyl, -0-(Ci.6 alkoxy)Ci.6 alkyl, halo, hydroxyl, - CN, -NO₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -SO2R¹⁶;

each R³ and R⁶ is selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci.6 alkyl, -0-(Ci.6 alkoxy)Ci_-6 alkyl, halo, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, - NR¹⁴C(0)R¹², and -S0₂R¹⁶;

each R⁷ is selected from H or C_1-6 alkyl;

each R⁸ is selected from C₆-io aryl, 5 or 6 membered heteroaryl comprising one or two i N-N

heteroatoms, S , or 9 or 10 membered heteroaryl, each optionally substituted with one or more R^A;

each R⁹, R¹⁰, R¹⁴ and R¹⁵ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C₆-io aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰; or R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰; each R¹¹ is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C₂-₆ alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R¹², R¹³ and R¹⁶ is independently selected from the group consisting of H, optionally substituted Ci-₆ alkyl, optionally substituted C2-6 alkenyl, optionally substituted C_2- 6 alkynyl, optionally substituted C₆-io aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;

each R^A is independently selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)_nR¹⁸, and -(CH₂)_k- S(0)₂-R¹⁹;

each R 17 is independently selected from 4 to 7 membered heterocyclyl, or 5 to 6

20

membered heteroaryl, each optionally substituted with one or more R ;

each R¹⁸ is independently selected from the group consisting of C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR⁹R¹⁰;

each R¹⁹ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci_6 alkyl, C3-7 cycloalkyl, C₆-io aryl, C_7-14 aralkyl, -NR⁹R¹⁰, 4 to 7 membered heterocyclyl, or 5 to

20

6 membered heteroaryl, each optionally substituted with one or more R ;

each R²⁰ is independently selected from the group consisting of C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, - (CH₂CH₂0)pCH₂CH₂N₃, halo, hydroxyl, oxo, and -CN; and

each k, m, n and p is independently an integer selected from 0 to 6;

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I).

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from H or C_1-6 alkoxy.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R² is H.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is selected from H or Ci-₆ alkoxy.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from H or C_1-6 alkyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H, halo, or C_1-6 alkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from H or C_1-6 alkyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is H.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is selected from phenyl, pyrazolyl, pyridinyl, thiazolyl, pyrimidinyl, quinolinyl,

J N-N

or S each substituted with one or more R^A.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R^A is selected from the group consisting of halo, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, d.₆ haloalkoxy, -CN, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)„R¹⁸, and -(CH₂)_k- S(0)₂-R¹⁹.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R^A is selected from the group consisting of halo, methyl, trifluoromethyl, t-butyl, methoxy, trifluoromethoxy, and -CN.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R^A is -C(0)NR¹⁴R¹⁵, and wherein each R¹⁴ and R¹⁵ is selected from H or C_1-6 alkyl.

14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R^A is -C(0)NR¹⁴R¹⁵ and wherein R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R²⁰.

15. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R^A is -(CH₂)_mR¹⁷ and wherein m is selected from 0, 1 or 2.

17

16. The compound of claim 15, or a pharmaceutically acceptab thereof, wherein R

selected from imidazolyl, triazolyl.

-HO ^"HO -HO

, and wherein R^a is selected from H, C_1-6 alkyl, or (C_1-6 alkoxy)Ci.6 alkyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is unsubstituted.

18. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt

A 18

thereof, wherein R is -0(CH2)_nR and wherein n is selected from 0, 1 or 2.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R¹⁸ is selected from C_1-6 haloalkyl, C_1-6 alkoxy, optionally substituted phenyl, optionally substituted pyndinyl, or -NR⁹R¹⁰.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R¹⁸ is -NR⁹R¹⁰ and wherein each R⁹ and R¹⁰ is Ci_-6 alkyl.

18

21. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R

20

is selected from phenyl or pyridinyl, each substituted with one or more R .

22. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R^A is -(CH₂)_k-S(0)2-R¹⁹and wherein k is selected from 0, 1 or 2.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R¹⁹ is selected from C3-7 cycloalkyl, -NR⁹R¹⁰, or 4 to 7 membered heterocyclyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R¹⁹

is selected from cyclopropyl, cyclopentyl, cyclohexyl,

+0 +0 *Ό

, and wherein R^a is selected from H, Ci. alkyl, -(CH₂CH₂0)_pCH₂CH₂N₃, or (Ci_-6 alkoxy)Ci_-6 alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R^a is selected from H, methyl, -(CH₂CH₂0)₅CH₂CH₂N₃ or -(CH₂)₂OCH₃.

26. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R¹⁹ is -NR⁹R¹⁰, and wherein each R⁹ and R¹⁰ is independently selected from H, C_1-6 alkyl, optionally substituted phenyl, or optionally substituted C3-7 cycloalkyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted with one or more substituents selected from halo, Ci-₆ alkyl, Ci-₆ haloalkyl, (C_1-6 alkoxy)Ci-6 alkyl, or -0-(Ci_6 alkoxy)Ci_6 alkyl.

28. The compound of claim 1, selected from Compounds 1-26, 28-67, 75-80, 82-84, 86- 91, 94-103, 105-152, and 159-170 of Table 1, or pharmaceutically acceptable salts thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A method of treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29, to a subject in need thereof.

31. The method of claim 30, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer, brain cancer, esophageal cancer, kidney cancer, leukemia, melanoma, non- Hodgkin lymphoma, pancreatic cancer, skin cancer, thyroid cancer, and endometrial cancer.

32. The method of claim 30 or 31 , wherein the subject is a mammal.

33. The method of claim 31 or 32, wherein the cancer is breast cancer.

34. The method of claim 33, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of a Selective Estrogen Receptor Modulator (SERM).

35. The method of claim 33, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of Tamoxifen.

36. The method of claim 33, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of Afimoxifene.

37. The method of claim 33, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of omeprazole.

38. A method of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of claims 1 to 28, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29.

39. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

each R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of H, Ci-6 alkyl, C₂-₆ alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_-6 alkyl, -0-(Ci_-6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, - C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

R⁶ is selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_ 6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, -CN, -N0₂, -NR⁹R¹⁰, -OR¹¹, -C(0)R¹², -C(0)OR¹³, -C(0)NR¹⁴R¹⁵, -NR¹⁴C(0)R¹², and -S0₂R¹⁶;

R is selected from H or C_1-6 alkyl;

each R^A is independently selected from the group consisting of C_1-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -O- (Ci.6 alkoxy)Ci_-6 alkyl, halo, hydroxyl, -CN, -N0₂, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, - 0(CH₂)_nR¹⁸, and -(CH₂)_k-S(0)₂-R¹⁹;

20

membered heteroaryl, each optionally substituted with one or more R ;

each R¹⁸ is independently selected from the group consisting of Ci_-6 haloalkyl, Ci_-6 alkoxy, Ci_6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR⁹R¹⁰;

each R¹⁹ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkoxy)Ci_6 alkyl, C3-7 cycloalkyl, C₆-io aryl, C_7-14 aralkyl, -NR⁹R¹⁰, 4 to 7 membered heterocyclyl, or 5 to

20

6 membered heteroaryl, each optionally substituted with one or more R ;

20

each R is independently selected from the group consisting of C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, oxo, and -CN; and

each m, n and k is independently an integer selected from 0 to 6;

provided that when each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, and ring A is phenyl, then ring A is substituted with one or more R^A.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from H or C_1-6 alkyl.

41. The compound of claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R² is H.

42. The compound of any one of claims 39 to 41, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from H or C_1-6 alkoxy.

43. The compound of any one of claims 39 to 42, or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from H or C_1-6 alkyl.

44. The compound of any one of claims 39 to 43, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H, halo, or C_1-6 alkyl.

45. The compound of any one of claims 39 to 44, or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from H, or C_1-6 alkyl.

46. The compound of any one of claims 39 to 45, or a pharmaceutically acceptable salt thereof, wherein R⁷ is H.

47. The compound of any one of claims 39 to 46, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl or pyridinyl, each optionally substituted with one or more R .

48. The compound of any one of claims 39 to 47, or a pharmaceutically acceptable salt thereof, wherein R^A is selected from the group consisting of halo, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, Ci_-6 haloalkoxy, -CN, -NR⁹R¹⁰, -C(0)NR¹⁴R¹⁵, -(CH₂)_mR¹⁷, -0(CH₂)_nR¹⁸, and -(CH₂)_k- S(0)₂-R¹⁹.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R^A is selected from the group consisting of halo, methyl, t-butyl, methoxy, trifluoromethyl, trifluoromethoxy, and -CN.

50. The compound of any one of claims 39 to 47, or a pharmaceutically acceptable salt thereof, wherein R^A is -(CH₂)_k-S(0)₂-R¹⁹ and wherein k is selected from 0, 1 or 2.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R¹⁹ is selected from C3-7 cycloalkyl, -NR⁹R¹⁰, or 4 to 7 membered heterocyclyl.

52. The compound of claim 51, or a pharmac

is selected from cyclopropyl, cyclopentyl, cyclohexyl

, ₅ and wherein R^a is selected from H, C_1-6 alkyl, or (C_1-6 alkoxy)C_1-6 alkyl.

53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R^a is selected from H, methyl or -(Οί₂)₂0Ο¾.

54. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein R¹⁹ is -NR⁹R¹⁰, and wherein each R⁹ and R¹⁰ is independently selected from H, C_1-6 alkyl, optionally substituted phenyl, or optionally substituted C3-7 cycloalkyl.

55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted with one or more substituents selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, (C_1-6 alkoxy)Ci_6 alkyl, or -0-(Ci_6 alkoxy)Ci_6 alkyl.

56. The compound of claim 39, or a pharmaceutically acceptable salt thereof, selected from Compounds 27, 70-74, 81, 85, 92, 93, 104 and 153-158 of Table 1, or pharmaceutically acceptable salts thereof.

57. A pharmaceutical composition comprising a compound of any one of claims 39 to 56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

58. A method of treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 39 to 56, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57, to a subject in need thereof.

59. The method of claim 58, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer, brain cancer, esophageal cancer, kidney cancer, leukemia, melanoma, non- Hodgkin lymphoma, pancreatic cancer, skin cancer, thyroid cancer, and endometrial cancer.

60. The method of claim 58 or 59, wherein the subject is a mammal.

61. The method of claim 59 or 60, wherein the cancer is breast cancer.

62. The method of claim 61, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of a Selective Estrogen Receptor Modulator (SERM).

63. The method of claim 61, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of Tamoxifen.

64. The method of claim 61, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of Afimoxifene.

65. The method of claim 61, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with an effective amount of omeprazole.

66. A method of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of claims 39 to 56, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57.