CHEMICAL COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to substituted quinoline derivatives that are inhibitors of the activity of lactate dehydrogenase A (LDH-A). The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer.

BACKGROUND OF THE INVENTION

The Warburg effect, also known as aerobic glycolysis, is defined as a high rate of glucose utilization and lactate production despite the presence of sufficient oxygen to oxidize glucose carbon in the mitochondria. Recognition of this unusual metabolic phenomenon stems from experiments performed by the German physiologist Otto Warburg, starting in the 1920s. Today, the glycolytic activity of tumors is exploited clinically by ¹⁸ F-deoxyglucose positron emission tomography (FDG-PET), which detects tumors precisely by virtue of their enhanced ability to take up and metabolize glucose compared to normal tissue. The Warburg effect remains the most frequently cited evidence that tumors display dysfunctional metabolism.

The adenosine triphosphate (ATP) required for normal cell growth and survival comes from two main sources: glycolysis and mitochondrial oxidative phosphorylation. Glycolysis occurs by the Embden-Meyerhof pathway that requires NAD+ and involves a series of cytoplasmic enzymes that convert glucose to pyruvate. In oxygenated cells, pyruvate enters the mitochondria and is converted to acetyl-CoA by pyruvate

dehydrogenase complex (PDC). This, along with acetyl-CoA produced from fatty acid oxidation, enters the Krebs cycle producing the electron donors NADH and FADH ₂ . NADH donates electrons to complex I of the electron transport chain (ETC), whilst FADH ₂ donates electrons to complex III. Oxygen acts as the final electron acceptor. This process of oxidative phosphorylation produces 36 ATP molecules per glucose molecule. However, in conditions of limited oxygen, pyruvate is converted into lactic acid by lactate dehydrogenase (LDH) in a process termed anaerobic glycolysis. In contrast to oxidative phosphorylation, glycolysis is relatively inefficient, producing only two molecules of ATP per molecule of glucose, but with the regeneration of NAD ⁺ to enable glycolysis to continue. The reduction of pyruvate to lactate is facilitated by the increased activity of two key enzymes: pyruvate dehydrogenase kinase 1 (PDK1 ), which blocks PDH activity, and lactate dehydrogenase A (LDHA), which converts cytosolic pyruvate to lactate. The decrease in the rate of pyruvate entering the TCA cycle and the concurrent increase in lactate production is vital for the growth and survival of tumors. Inhibition of LDHA results in the stimulation of mitochondrial respiration as a compensatory mechanism. Although mitochondrial respiration increases as a result of LDHA inhibition, the proliferative and tumorigenic potential of cancer cells is diminished.

In cancer patients, serum total lactate dehydrogenase (LDH5, a tetramer of LDHA sub-units; the major LDH isoenzyme involved in glycolysis) levels are often increased, and the gene for LDHA, is up-regulated. These features have been linked to poor prognosis in several studies.

Therefore, because of its importance in tumor cell metabolism, LDHA is an attractive oncology target. Inhibition of this enzyme is expected to reduce the ability of the cell to effectively metabolize glucose and reduce tumor cell proliferation and tumor growth.

References

Warburg et al., The metabolism of tumors in the body, J. Gen. Physiol. 8 (1927), pp. 519-530.

Warburg O. On the origin of cancer cells. Science. 1956 Feb 24; 123 (3191 ):309- 314.

Warburg O. On respiratory impairment in cancer cells. Science. 1956 Aug 10; 124 (3215):269-270.

· Ferreira, L.M.R., Cancer metabolism: The Warburg effect today, Exp. Mol. Pathol.

Thomas N Seyfried and Laura M Shelton. Cancer as a metabolic disease. Nutr Metab (Lond). 2010 Jan 27;7:7.

Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.

Cancer Cell 9, 425-434 (2006).

• Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 1 18, 3930-3942 (2008).

• Han Xie, Vladimir A. Valera, Maria J. Merino, Angela M. Amato, Sabina Signoretti, William M. Linehan, Vikas P. Sukhatme, and Pankaj Seth. LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol. Cancer Ther. 2009, 8(3), 626.

• Le,A.; Cooper,C.R.; Gouw,A.M.; Dinavahi,R.; MaitraA; Deck,L.M.; Royer,R.E.;

Vander Jagt,D.L.; Semenza,G.L.; Dang,C.V. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl. Acad. Sci USA, 2010, 107(5), 2037-2042.

• Granchi C, Bertini S, Macchia M, Minutolo F. Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. 2010; 17(7):672-97. · Koukourakis Ml, Kontomanolis E, Giatromanolaki A, Sivridis E, Liberis V. Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases. Gynecol Obstet Invest. 2009;67(3): 162-8.

• Koukourakis Ml, Giatromanolaki A, Winter S, Leek R, Sivridis E, Harris AL.

Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology.

2009;77(5):285-92

• Koukourakis, M. I.; Giatromanolaki, A.; Sivridis, E.; Bougioukas,G.; Didilis,V.;

Gatter,K.C; Harris, A.L. Lactate dehydrogenase-5 (LDH-5) overexpression in non- small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. 2003 Sep 1 ;89(5):877-85

It is an object of the instant invention to provide novel compounds that are inhibitors of lactate dehydrogenase A (LDH-A). It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.

It is also an object of the present invention to provide a method for treating cancer that comprises administering such inhibitors of lactate dehydrogenase A (LDH-A) activity.

SUMMARY OF THE INVENTION

The invention is directed to substituted quinoline derivatives. Specifically, the invention is directed to compounds according to Formula I:

wherein R, R^ , R^, R3 and R^, are defined below. This invention relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a LDH-A inhibiting compound of Formula (I).

This invention relates to a method of treating solid tumors which comprises administering to a subject in need thereof an effective amount of a LDH-A inhibiting compound of Formula (I). The present invention also relates to the discovery that the compounds of Formula

(I) are active as inhibitors of LDH-A.

In a further aspect of the invention there is provided novel processes and novel intermediates useful in preparing the presently invented LDH-A inhibiting compounds.

Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.

Also included in the present invention are methods of co-administering the presently invented LDH-A inhibiting compounds with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of Formula (I):

wherein:

R is selected from: -N H2 and -NHphenyl,

where

the phenyl is optionally substituted with from one to three substituents

independently selected from: -OC -C ₆ alkyl,

-Ophenyl,

-O(fluorophenyl),

-O(difluorop enyl),

-O(difluorophenyl),

-Obenzamide,

-F,

-NHphenyl,

-NH(Ci-C6alkylphenyl),

-NH(fluorophenyl),

-NH(difluorophenyl),

-NH(carboxyp enyl),

-NH(hydroxyp enyl),

-NH((trifluoromethyl)phenyl),

-NHbenzyl,

-N(CH3)(trifluoromethylphenyl)

-CI,

-Br,

-I,

-COOCH2CH3

-COOH,

-C(NH)NH(OH)

-C(0)NCH ₃ CH ₃ ,

-C(0)NH ₂ ,

-C(0)pyrrolidine,

heteroaryl,

cycloalkyi,

-Scycloalkyl,

cycloalkyi substituted by oxo, cycloalkenyl substituted oxo,

-B(OH) ₂ ,

-S(0) ₂ NH ₂ ,

-S(0) ₂ NHC ₁ -C ₆ alkyl, -S(0) ₂ NHC(0)CH ₂ CH ₃ ,

-S(0) ₂ NHC(0)CH ₃ ,

-S(0) ₂ NHcycloalkyl,

-S(0) ₂ cycloalkyl,

-S(0) ₂ N(CH ₃ )(CH ₃ ),

-S(0) ₂ CH ₃ ,

-NH ₂ ,

-N0 ₂ , and

-C≡N; and

1 2

R and R are independently selected from: is selected from:

hydrogen,

Ci-C ₆ alkyl,

benzyl,

cycloalkyl,

-CH ₂ CH ₂ OCH ₃ ,

tetrahydropyran,

tetrahydrofruan,

thiophene,

oxetane,

-CH ₂ CH ₂ N(CH ₃ CH ₃ ),

-CH ₂ CF ₃ , and

phenyl,

or R ¹ and R ² taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;

R3 is selected from:

hydrogen,

Ci-C ₃ alkyl,

-F,

-CI,

-Br, -C≡N, and

-CF ₃ ;

selected from: aryl and heteroaryl,

where

aryl and heteroaryl are optionally substituted with from one to three substituents independently selected from:

-OCi-C ₆ alkyl,

-OC-|-C6cycloalkyl,

-OCH ₂ phenyl,

Ci-C ₆ alkyl,

-OCi-C ₃ alkyl,

Ci-C ₃ alkyl,

OH,

-F,

-CI,

-Br,

-I,

-C≡N,

-CF ₃ ,

-NH ₂ ,

-NH(d-C ₃ alkyl),

-N(C ₁ -C ₃ alkyl) ₂ ,

-NHphenyl,

-NHid-Cealkylphenyl),

-NH(fluorophenyl),

-NH(difluorophenyl),

-NH(carboxyphenyl),

-NH(hydroxyphenyl),

-NH((trifluoromethyl)phenyl),

-NHbenzyl, and

-N(CH ₃ )(trifluoromethylphenyl); or a salt thereof;

provided that R and R are not both hydrogen.

When referring to compounds of Formula (I), suitably R is -NHphenyl,

where

the phenyl is substituted with from one to three substituents independently selected from:

-Omethyl,

-Oisopropyl,

-Otert-butyl,

-COOH,

-NH(methylphenyl),

-NH(isopropylphenyl),

-NH(tert-butylphenyl),

tetrazol,

cyclohexyl,

cyclopentyl,

cyclohexanone,

cyclohexenone,

-S(0) ₂ NH ₂ ,

-S(0) ₂ NHCH ₃ ,

-S(0) ₂ NHtertbutyl,

-S(0) ₂ NHethyl

-S(0) ₂ NHisopropyl,

-S(0) ₂ NHcyclopropyl, and

-S(0) ₂ cyclopentyl.

1 2

When referring to compounds of Formula (I), suitably R and R are independently selected from: is selected from:

hydrogen,

isopropyl,

propyl, methyl,

ethyl,

isobutyl,

tert-butyl,

cyclopropyl,

cyclohexyl,

cyclopentyl, and

cyclobutyl,

or R1 and R^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring;

1 2

provided that R and R are not both hydrogen.

Included in the presently invented compounds of Formula (I) are compounds of Formula (IA):

R is selected from: -N H2 and -NHphenyl,

where

the phenyl is optionally substituted with from one to three substituents

independently selected from:

-OCi-C ₆ alkyl,

-Ophenyl,

-O(fluorophenyl),

-O(difluorophenyl),

-O(difluorophenyl), -Obenzamide,

-F,

-NHphenyl,

-NI-KCrCealkylphenyl),

-NH(fluorophenyl),

-NH(difluorophenyl),

-NH(carboxyphenyl),

-NH(hydroxyphenyl),

-NH((trifluoromethyl)phenyl),

-NHbenzyl,

-N(CH3)(trifluoromethylphenyl)

-CI,

-Br,

-I,

-COOCH2CH3

-COOH,

-C(NH)NH(OH)

-C(0)NCH ₃ CH ₃ ,

-C(0)NH ₂ ,

-C(0)pyrrolidine,

heteroaryl,

cycloalkyi,

-Scycloalkyl,

cycloalkyi substituted by oxo, cycloalkenyl substituted oxo,

-B(OH) ₂ ,

-S(0) ₂ NH ₂ ,

-S(0) ₂ NHCi-C ₆ alkyl,

-S(0) ₂ NHC(0)CH ₂ CH ₃ ,

-S(0) ₂ NHC(0)CH ₃ ,

-S(0) ₂ NHcycloalkyl,

-S(0) ₂ cycloalkyl, -S(0) ₂ N(CH ₃ )(CH ₃ ),

-S(0) ₂ CH ₃ ,

-NH ₂ ,

-NO2, and

-C≡N; and

1 2

R and R are independently selected from: is selected from:

hydrogen,

Ci-C ₆ alkyl,

benzyl,

cycloalkyl,

-CH2CH2OCH3,

tetrahydropyran,

tetrahydrofruan,

thiophene,

oxetane,

-CH2CH ₂ N(CH ₃ CH3),

-CH2CF3, and

phenyl,

or R1 and R^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; or a salt thereof;

provided that R and R are not both hydrogen.

When referring to compounds of Formula (IA), suitably R is -NHphenyl,

where

the phenyl is substituted with from one to three substituents independently selected from:

-Omethyl,

-Oisopropyl, -Otert-butyl,

-COOH,

-NH(methylphenyl),

-NH(isopropylphenyl),

-NH(tert-butylphenyl),

tetrazol,

cyclohexyl,

cyclopentyl,

cyclohexanone,

cyclohexenone,

-S(0) ₂ NHCH ₃ ,

-S(0) ₂ NHtertbutyl,

-S(0) ₂ NHethyl

-S(0) ₂ NHisopropyl,

-S(0) ₂ NHcyclopropyl, and

-S(0) ₂ cyclopentyl.

1 2

When referring to compounds of Formula (IA), suitably R and R are independently selected from: is selected from:

hydrogen,

isopropyl,

propyl,

methyl,

ethyl,

isobutyl,

tert-butyl,

cyclopropyl,

cyclohexyl,

cyclopentyl, and

cyclobutyl,

or R ¹ and R ² taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring; 1 2

provided that R and R are not both hydrogen.

Included in the presently invented compounds of Formula (I) are: 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopropylsulfamoyl) quinolin-4- yl)amino)benzoic acid;

3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-is opropylsulfamoyl)quinolin- 4-yl)amino)benzoic acid;

3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-pr opylsulfamoyl)quinolin-4- yl)amino)benzoic acid;

3-((3-(N-benzylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4- yl)amino)benzoic acid;

3-((3-(N-benzylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4-yl)amino)-5- cyclopentylbenzoic acid; 3-cyclopentyl-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethox ypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)benzoic acid;

3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(pyrr olidin-1-ylsulfonyl)quinolin-

4- yl)amino)benzoic acid;

3-((3-(N-cyclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4- yl)amino)benzoic acid;

3-((3-(N-cyclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)-

5- cyclopentylbenzoic acid; 3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(piperid in-1 -ylsulfonyl)quinolin- 4-yl)amino)benzoic acid; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-isopropoxybenzoic acid; ethyl 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(phenylamino)benzoate;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-(phenylamino)benzoic acid;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-(phenylam ino)quinoline-3- sulfonamide;

3-(benzylamino)-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dim ethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid; ethyl 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3-fluorophenyl)amino)benzoate; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3-fluorophenyl)amino)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-methoxybenzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-(4-fluorophenoxy)benzoic acid;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3- phenoxyphenyl)amino)quinoline-3-sulfonamide;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-methylsulfamoyl) quinolin-4-yl)amino)-5- isopropoxybenzoic acid; 3-((3-(N-cyclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )quinolin-4-yl)amino)- 5-isopropoxybenzoic acid; 3- cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-methyls ulfamoyl)quinolin yl)amino)benzoic acid; 3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N- dimethylsulfamoyl)quinolin-4-yl)amino)benzoic acid;

4- amino-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline -3-sulfonamide; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(3-fluorophenoxy)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((2-fluorophenyl)amino)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((4-fluorophenyl)amino)benzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-ethylsulfamoyl)q uinolin-4-yl)amino)-5- isopropoxybenzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-propylsulfamoyl) quinolin-4-yl)amino)-5- isopropoxybenzoic acid; 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N-dimethylsulfamoyl )quinolin-4-yl)amino)- 5-isopropoxybenzoic acid;

3-((3-(N-cyclopentylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4-yl)amino)- 5-isopropoxybenzoic acid;

3-(cyclohexylthio)-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid;

3-(cyclopentylthio)-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4 -dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid; 3-((3-carboxyphenyl)amino)-5-((3-(N-cyclopropylsulfamoyl)-7- (2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((3-hydroxyphenyl)amino)benzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopropylsulfamo yl)quinolin-4-yl)amino)-5- isopropoxybenzoic acid; 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isobutylsulfamoyl)q uinolin-4-yl)amino)-5- isopropoxybenzoic acid;

3- ((3-(N-cyclobutylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)q uinolin-4-yl)amino)- 5-isopropoxybenzoic acid;

4- ((3-bromophenyl)amino)-N-cyclopropyl-7-(2,4-dimethoxypyrimid in-5-yl)quinoline- 3-sulfonamide;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((3,5-difluorophenyl)amino)benzoic acid;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3- sulfamoylphenyl)amino)quinoline-3-sulfonamide; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(3,5-difluorophenoxy)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((3-(trifluoromethyl)phenyl)amino)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-(3,4-difluorophenoxy)benzoic acid;

3-((3-(N-(tert-butyl)sulfamoyl)-7-(2,4-dimethoxypyrimidin -5-yl)quinolin-4-yl)amino)- 5-isopropoxybenzoic acid; 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2-methoxyethyl)sul famoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid;

3-(3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimid in-5-yl)quinolin-4- yl)amino)phenoxy)benzamide;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahydro-2H-p yran-4- yl)sulfamoyl)quinolin-4-yl)amino)-5-isopropoxybenzoic acid; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(m-tolylamino)benzoic acid;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-(methyl(3-(trifluoromethyl)phenyl)amino)benzoic acid;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-nitro -5-(pyrrolidine-1- carbonyl)phenyl)amino)quinoline-3-sulfonamide;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((3-isopropylphenyl)amino)benzoic acid;

3-((3-(tert-butyl)phenyl)amino)-5-((3-(N-cyclopropylsulfa moyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)benzoic acid; 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2-

(dimethylamino)ethyl)sulfamoyl)quinolin-4-yl)amino)-5-iso propoxybenzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2,2,2-trifluoro ethyl)sulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-phenylsulfamoyl) quinolin-4-yl)amino)-5- isopropoxybenzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahydrofuran -3-yl)sulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid; 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(thiophen-3-yl)sulf amoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid;

(3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin -5-yl)quinolin-4- yl)amino)phenyl)boronic acid;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-f luorophenyl)amino)-5-(2H- tetrazol-5-yl)phenyl)amino)quinoline-3-sulfonamide; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(pyrrolidine-1 -carbonyl)benzoic acid;

3- ((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(oxetan-3-yl)sulfamoy l)quinolin-4- yl)amino)-5-isopropoxybenzoic acid;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3- (methylsulfonyl)phenyl)amino)quinoline-3-sulfonamide;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrr olidine-1- carbonyl)phenyl)amino)quinoline-3-sulfonamide;

4- ((3-cyanophenyl)amino)-N-cyclopropyl-7-(2,4-dimethoxypyrimid in-5-yl)quinoline- 3-sulfonamide; 4-((3-(cyclopentylsulfonyl)phenyl)amino)-N-cyclopropyl-7-(2, 4-dimethoxypyrimidin- 5-yl)quinoline-3-sulfonamide;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- methylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide;

4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-N-cyclopropy l-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- ethylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide; N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N,N- dimethylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- isopropylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide;

5-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5'-oxo-2',3',4',5'-tetrahydro-[1 ,1 '-biphenyl]-3-carboxylic acid; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-N-hydroxy-5-((3-(trifluoromethyl)phenyl)amino)benz imidamide;

N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrr olidine-1 -carbonyl)-5- sulfamoylphenyl)amino)quinoline-3-sulfonamide;

N-((3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- yl)amino)phenyl)sulfonyl)propionamide;

N-cyclopropyl-4-((3-(N-cyclopropylsulfamoyl)phenyl)amino) -7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide;

N-((3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- yl)amino)phenyl)sulfonyl)acetamide; N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-methoxy- 5- sulfamoylphenyl)amino)quinoline-3-sulfonamide;

3- ((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4- yl)amino)-5-sulfamoylbenzoic acid;

4- ((3-cyclopentyl-5-(2H-tetrazol-5-yl)phenyl)amino)-N-cyclopro pyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-(3-oxocyclohexyl)benzoic acid; 4-((3-amino-5-cyanophenyl)amino)-N-cyclopropyl-7-(2,4-dimeth oxypyrimidin-5- yl)quinoline-3-sulfonamide;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-N,N-dimethyl-5-sulfamoylbenzamide;

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-(4-fluorophenoxy)benzamide; 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)-2-methylquinolin-4- yl)amino)-5-isopropoxybenzoic acid;

3-cyclopentyl-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimet hoxypyrimidin-5-yl)-2- methylquinolin-4-yl)amino)benzoic acid;

3-((7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3-(N-methyls ulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid;

3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-2-methy l-3-(N- methylsulfamoyl)quinolin-4-yl)amino)benzoic acid;

N-cyclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)a mino)-7-(4- methoxypyrimidin-5-yl)quinoline-3-sulfonamide; N-cyclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)amin o)-7-(pyrimidin-5- yl)quinoline-3-sulfonamide;

N-cyclopropyl-7-(3,5-dimethyl-1 H-pyrazol-4-yl)-4-((3-(4-fluorophenoxy)-5- sulfamoylphenyl)amino)quinoline-3-sulfonamide;

N-cyclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)a mino)-7-(1 ,3,5- trimethyl-1 H-pyrazol-4-yl)quinoline-3-sulfonamide;

N-cyclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)a mino)-7-(pyridin-3- yl)quinoline-3-sulfonamide; N-cyclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)amin o)-7-(pyridin-2- yl)quinoline-3-sulfonamide; and

N-cyclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)a mino)-7-(2- methoxyphenyl)quinoline-3-sulfonamide; and salts thereof including pharmaceutically acceptable salts thereof.

The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base. Accordingly, the invention is further directed to salts, including pharmaceutically- acceptable salts, of the compounds according to Formula I.

The salts of the compounds of the invention are readily prepared by those of skill in the art.

The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.

The compounds according to Formula I may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

The compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form. The compounds of Formula I or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates. The skilled artisan will further appreciate that certain compounds of Formula I or salts, including pharmaceutically acceptable salts thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. The invention includes all such polymorphs.

Definitions

"Alkyl" refers to a hydrocarbon chain having the specified number of member atoms. For example, C-|-Cg alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches. Unless otherwise defined, alkyl includes methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, and butyl (n-butyl, isobutyl, and t-butyl).

"Alkoxy" refers to an -O-alkyl group wherein "alkyl" is as defined herein. For example, C-| -C4alkoxy refers to an alkoxy group having from 1 to 4 member atoms. Representative branched alkoxy groups have one, two, or three branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy. "Aryl" refers to an aromatic hydrocarbon ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Examples of such monocyclic aryl rings include phenyl naphthalene, tetrahydronaphthalene and biphenyl. Examples of such bicyclic aryl rings include napthyl and rings wherein phenyl is fused to a cycloalkyi or cycloalkenyl ring having 5, 6, or 7 member atoms.

"Cycloalkyi" refers to a saturated or unsaturated non aromatic hydrocarbon ring having the specified number of member atoms. Cycloalkyi groups are monocyclic ring systems. For example, C3-C7 cycloalkyi refers to a cycloalkyi group having from 3 to 7 member atoms. Examples of cycloalkyi as used herein includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexen, cyclobutenyl, cyclopenten, cyclopentenyl and cyclohexenyl.

"Heterocycloalkyl" refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with and aryl ring or to a heteroaryl ring having from 4 to 1 1 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 1 ,3oxazolidin-2-one, hexahydro-1 H-azepin, 4,5,6,7,tetrahydro-1 H-benzimidazol, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl and azetidinyl, suitably tetrahydrofuranyl or piperidinyl.

"Halo" or "Halogen" refers to the halogen radicals fluoro, chloro, bromo, and iodo.

"Heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups are monocyclic or bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 6 to 1 1 member atoms. Unless otherwise defined, heteroaryl includes: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, indiazole, indole, thienyl, pyrrolopyridin, pyran, dihydropyran, tetrahydropyran, tetrahydrofuranyl, piperidinyl, tetrazole, morpholinyl, and piperazinyl, suitably tetrazole.

"Heteroatom" refers to a nitrogen, sulphur or oxygen atom.

"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Unless otherwise defined, the term "Substituted" as used herein, is meant that the subject chemical moiety has from one to four substituents, suitably from one to three substituents, suitably one or two substituents, independently selected from the group consisting of: piperazinyl, -OH, -NH2, -NO2, -F, -CI, -Br, -I, -OC-|-C6alkyl,

-C0 ₂ ethyl, - C-|-C ₆ alkyl, -CONH ₂ , -OCH ₂ phenyl, oxo, -COOH, hydroxyC-|-C ₆ alkyl, -C≡N, -CF ₃ , -N(CH ₃ ) ₂ , -NHCH3. As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

Ac (acetyl);

Ac ₂ 0 (acetic anhydride);

ACN (acetonitrile);

AIBN (azobis(isobutyronitrile));

BINAP (2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl);

BMS (borane - dimethyl sulphide complex);

Bn (benzyl);

Boc (tert-Butoxycarbonyl);

Boc ₂ 0 (di-ferf-butyl dicarbonate);

BOP (Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate);

CAN (cerric ammonium nitrate);

Cbz (benzyloxycarbonyl);

CSI (chlorosulfonyl isocyanate);

DABCO (1 ,4-Diazabicyclo[2.2.2]octane);

DAST ((Diethylamino)sulfur trifluoride);

DBU (1 ,8-Diazabicyclo[5.4.0]undec-7-ene);

DCC (Dicyclohexyl Carbodiimide);

DCE (1 ,2-dichloroethane);

DCM (dichloromethane);

DDQ (2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone);

ATP (adenosine triphosphate); Bis-pinacolatodiboron (4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane);

BSA (bovine serum albumin);

C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase)

CH ₃ CN (acetonitrile);

Cy (cyclohexyl);

DCM (dichloromethane);

DIPEA (Hunig's base, N-ethyl-N-(1-methylethyl)-2-propanamine);

DMAP (4-dimethylaminopyridine);

DME (1 ,2-dimethoxyethane);

DMF (/V,/V-dimethylformamide);

DMSO (dimethylsulfoxide);

DPPA (diphenyl phosphoryl azide);

EDC (N-(3-dimethylaminopropyl)-N'ethylcarbodiimide);

EDTA (ethylenediaminetetraacetic acid);

EtOAc (ethyl acetate);

EtOH (ethanol);

Et ₂ 0 (diethyl ether);

HEPES (4-(2-hydroxyethyl)-1 -piperazine ethane sulfonic acid);

HATU (0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole);

HOBt (1-hydroxybenzotriazole);

HOAc (acetic acid);

HPLC (high pressure liquid chromatography);

HMDS (hexamethyldisilazide);

Hunig's Base (N,N-Diisopropylethylamine);

I PA (isopropyl alcohol);

Indoline (2,3-dihydro-1 H-indole) ; KHMDS (potassium hexamethyldisilazide) ;

LAH (lithium aluminum hydride) ;

LDA (lithium diisopropylamide) ;

LHMDS (lithium hexamethyldisilazide)

MeOH (methanol);

MTBE (methyl tert-butyl ether);

mCPBA (m-chloroperbezoic acid);

NaHMDS (sodium hexamethyldisilazide);

NBS (N-bromosuccinimide);

PE (petroleum ether);

Pd ₂ (dba) ₃ (Tris(dibenzylideneacetone)dipalladium(O);

Pd(dppf)CI ₂ ([1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll));

PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate);

PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);

RPHPLC (reverse phase high pressure liquid chromatography);

SFC (supercritical fluid chromatography);

SGC (silica gel chromatography);

TEA (triethylamine);

TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl, free radical);

TFA (trifluoroacetic acid); and

THF (tetrahydrofuran).

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI.

Compound Preparation

The novel compounds of Formula (I) are generally prepared as shown in Schemes 1 and 2 below, or by analogous methods, provided the 'R' substituents in Formula (I) do not include any such substituents that render inoperative the processes of any of Schemes 1 , 2 or 3. Further, the skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art.

Schemes

Scheme 1

a) CISO ₃ H, heat; b) 1 . POCI ₃ or SOCI ₂ , solvent, reflux, 2. R ¹ R ² NH, solvent; c) Ar ¹ NH ₂ , solvent, heat; d) 1. Ar ² B(OR) ₂ , Pd catalyst, base, solvent, heat, 2. aq NaOH or LiOH, solvent, if necessary.

b)

Scheme 2

a) Ar ² B(OR) ₂ , Pd catalyst, base, solvent, heat; b) Ar ¹ NH ₂ , solvent, heat

Scheme 3

a) 1 , 1 ,1 -triethoxyethane, ZnCI ₂ , heat b) 3-bromoaniline, solvent, heat; c) Ph ₂ 0, heat; d) NaOH, solvent, heat; e) Ph ₂ 0, heat; f) CIS0 ₃ H, heat; g) POCI ₃ , N,N- dimethylaniline, heat; h) R ¹ R ² NH, solvent; i) R ⁴ -B(OR) ₂ , Pd catalyst, base, solvent, heat, j) 1. Ar ¹ NH ₂ , solvent, heat; 2. aq NaOH or LiOH, solvent, if necessary.

Definitions:

Aq = aqueous

BINAP = 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene

HPLC = high performance liquid chromatography

LCMS = liquid chromatography/mass spectrometry

MgS0 ₄ = anhydrous magnesium sulfate

ODS = octadecylsilyl silica gel

PyBOP = benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate

Pd ₂ (dba) ₃ = tris(dibenzylideneacetone)dipalladium(0)

rt = room temperature.

Sat aq = saturated aqueous

TLC = thin layer chromatography

UPLC-MS = ultra performance liquid chromatography/mass spectrometry Methods of Use

The compounds according to Formula I and pharmaceutically acceptable salts thereof are inhibitors of lactate dehydrogenase A. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to (but not limited to) tumor cell metabolism, for example, cancer and more specifically cancers of the breast, colon, and lung, pancreas and skin. Accordingly, another aspect the invention is directed to methods of treating such conditions.

Suitably, the present invention relates to a method for treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of colon cancer.

Suitably the present invention relates to a method for treating or lessening the severity of pancreatic cancer.

Suitably the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma.

Suitably the present invention relates to a method for treating or lessening the severity of lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte- Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia,

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,

neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte- Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt, thereof to a patient in need thereof. The invention also provides a compound according to Formula I or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in cancer therapy. Thus, in further aspect, the invention is directed to the use of a compound according to Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disorder attributable to (but not limited to) tumor cell metabolism, such as cancer.

By the term "treating" and derivatives thereof as used herein, is meant prophylactic and therapeutic therapy. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.

As used herein, the term "effective amount" and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, "patient" or "subject" refers to a human or other animal. Suitably the patient or subject is a human.

The compounds of Formula I or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration, and parenteral administration. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.

The compounds of Formula I or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Additionally, the compounds of Formula I or pharmaceutically-acceptable salts thereof may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.

The compounds of Formula I and pharmaceutically acceptable salts thereof may be co-administered with at least one other active ingredient known to be useful in the treatment of cancer. By the term "co-administration" as used herein is meant either simultaneous administration or any manner of separate sequential administration of a lactate dehydrogenase A inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 ^th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.

Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented lactate dehydrogenase A inhibiting compounds are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids. Diterpenoids, which are derived from natural sources, are phase specific anticancer agents that operate at the G ₂ /M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5p,20-epoxy-1 ,2α,4,7β, 10β, 13a-hexa-hydroxytax-1 1 -en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971 ), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561 -1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981 ). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 1 1 1 :273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide,. 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).

Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-ferf-butyl ester, 13-ester with 5p-20-epoxy-1 ,2a,4,7p, 10p, 13a-hexahydroxytax-1 1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine. Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as

ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.

Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R ^* ,R ^* )-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin. Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.

Carboplatin, platinum, diammine [1 , 1-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.

Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.

Carmustine, 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine. Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.

Dactinomycin, also known as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12

naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy] -8- glycoloyl, 7, 8, 9, 10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G ₂ phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non- small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.

Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti- neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4- (1 H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis as well as incorporation into both RNA and DNA. The result typically is cell death. 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1-p-D-arabinofuranosyl-2 (1 H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.

Thioguanine, 2-amino-1 ,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects also occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.

Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.

Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary, and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives, are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,1 1-ethylenedioxy-20-camptothecin described below.

Irinotecan HCI, (4S)-4, 1 1-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14(4H, 12H)-dione

hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea. Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of single strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia. Also of interest, is the camptothecin derivative of Formula A following, including the racemic mixture (R,S) form as well as the R and S enantiomers:

known by the chemical name "7-(4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10, 1 1- ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 10, 1 1 -ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491 ,237 and pending U.S. patent Application No. 08/977,217 filed November 24, 1997.

Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such as those described in U.S. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment of prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myoinositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases. Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over- expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non- receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology. 15: 371-404. SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.

Suitably, the pharmaceutically active compounds of the invention are used in combination with inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta); IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1 and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1 101 -1 107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391 ; Pearce, L.R et al. Nature Reviews Molecular Cell Biology (2010) 1 1 , 9-22. and Martinez-lacaci, L., et al, Int. J. Cancer (2000), 88(1 ), 44-52.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo- phenylamino)-6,8-dimethy-2,4,7-trioxo-3,4,6,7-tetrahydro-2H- pyrido[4,3-d]pyrimidin-1- yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethyl sulfoxide solvate, thereof, which is disclosed and claimed in International Application No. PCT/JP2005/01 1082, having an International filing date of June 10, 2005; International Publication Number WO 2005/121 142 and an International Publication date of December 22, 2005, the entire disclosure of which is hereby incorporated by reference. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dime thy-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference. Suitably, the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor. Suitably, /V-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1 , 1- dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonam ide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International Application No. PCT/US2009/042682, having an International filing date of May 4, 2009, the entire disclosure of which is hereby incorporated by reference. /\/-{3-[5-(2-Amino-4- pyrimidinyl)-2-(1 , 1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide can be prepared as described in International Application No. PCT/US2009/042682. Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1 S)-2-amino-1-[(3,4- difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1 S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro- 4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-furancarboxamide is the compound of example 224 and can be prepared as described in International Application No. PCT/US2008/053269.

Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, /\/-{(1 S)-2-amino-1-[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. /\/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide is the compound of example 96 and can be prepared as described in International Application No. PCT/US2008/053269. Suitably, Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5- chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. The salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010.

Combinations with drugs against other metabolic targets, e.g. ATP citrate lyase (ACLY), hexokinase (HK), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1 ), fatty acid synthase (FASN), ΡΙ3Κβ and isocitrate dehydrogenase 1 (I DM ), should also be effective.

Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301 -3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541 -1545. Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type or mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30. As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha _v beta ₃ ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further, p21WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin- dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds that are known to induce expression of p21 WAF1/CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressing activity (Richon et al., Proc. Nat Acad. Sci. U.S.A. 97(18): 10014-10019 (2000)), and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors are implicated in the transcriptional activation of p21 WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (Jan 2002)), and are suitable cell cycle signaling inhibitors for use herein.

Examples of such HDAC inhibitors include:

1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).

Vorinostat has the following chemical structure and name: ydroxy-A/'-phenyl-octanediamide.

2. Romidepsin, including pharmaceutically acceptable salts thereof.

Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.

e following chemical structure and name:

- (1 S,4S,7Z, 10S,16E,21 R)-7-ethylidene-4,21-di(propan-2-yl)-2- -12, 13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9 , 19,

pentone.

3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the Future 32(4): 315-322 (2007).

Panobinostat, has the following chemical structure and name:

(2E)-/V-hydroxy-3-[4-({[2-(2-methyl-1 H^

4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001 ).

Valproic acid, has the following chemical structure and name:

2-propylpentanoic acid.

5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 21 1 -221 (2009).

Mocetinostat, has the following chemical structure and name:

A/-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amin o]methyl] benzamide.

Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-21 16, particularly the compounds of table 3 therein as indicated below.

Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Several proteasome inhibitors are marketed or are being studied in the treatment of cancer. Suitable proteasome inhibitors for use herein include:

1. Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-1 1.

Bortezomib has the following chemical structure and name.

[(1 R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2- ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid

2. Disulfiram, including pharmaceutically acceptable salts thereof.

Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.

Disulfiram has the following c

1 , 1 ', 1 ", 1 "'-[disulfanediylbis(carbonothioylnitrilo)]tetraethane

3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369-74. Epigallocatechin gallate has t and name.

[(2/?,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3- yl]3,4,5-trihydroxybenzoate

4. Salinosporamide A, including pharmaceutically acceptable salts thereof. Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3): 355-7.

Salinosporamide A has the following re and name.

(4R,5S)-4-(2-chloroethyl)-1-((1 S)-cyclohex-2-enyl(hydroxy)methyl) -5-methyl-6- azabicyclo3.2.0heptane-3,7-dione

Inhibitors of cancer metabolism - Many tumor cells show a markedly different metabolism from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the pyruvate generated is reduced to lactate, rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often seen even under aerobic conditions and is known as the Warburg Effect.

Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell. The enzyme has been shown to be upregulated in many tumor types. The alteration of glucose metabolism described in the Warburg effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.

D. A. Tennant et. ai, Nature Reviews, 2010, 267.

P. Leder, et. ai, Cancer Cell, 2006, 9, 425.

Inhibitors of cancer metabolism, including other inhibitors of LDH-A, are suitable for use in combination with the compounds of this invention.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.

Compositions

The pharmaceutically active compounds within the scope of this invention are useful as lactate dehydrogenase A inhibitors in mammals, particularly humans, in need thereof.

The present invention therefore provides a method of treating cancer and other conditions requiring lactate dehydrogenase A inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as lactate dehydrogenase A inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral. The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a lactate dehydrogenase A inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular lactate dehydrogenase A inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration. The method of this invention of inducing lactate dehydrogenase A inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective lactate dehydrogenase A inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a lactate dehydrogenase A inhibitor. The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer.

The invention also provides for a pharmaceutical composition for use as a lactate dehydrogenase A inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a lactate dehydrogenase A inhibitor.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

When a chemical intermediate is used in multiple examples, one method of preparation of the intermediate is described. It is understood that, regardless of the description, analogous methods of preparing the chemical intermediate may have been used where the intermediate is utilized in other examples.

Experimental

Example 1

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopropylsulfamoyl) quinolin-4-yl)amino)benzoic acid

a) 7-bromo-4-hvdroxy-3-quinolinesulfonyl chloride. A solution of 7-bromo-4- quinolinol (1.00 g, 4.46 mmol) in chlorosulfonic acid (10 ml.) was heated at 100 °C for 18 h, then cooled and poured carefully onto ice. The solid was filtered off, washed with water and dried to give the title compound (1.33 g, 85% pure, 79%) as a solid, containing a little (-12%) of the corresponding sulfonic acid by NMR.

¹ H NMR (400 MHz, DMSO-d ₆ )™ ppm 7.71 (dd, J=8.72, 1.89 Hz, 1 H) 8.04 (d, J=1.52 Hz, 1 H) 8.16 (d, J=8.84 Hz, 1 H) 8.78 (s, 1 H). b) 7-bromo-4-chloro-3-quinolinesulfonyl chloride. A mixture of 7-bromo-4-hydroxy-3- quinolinesulfonyl chloride (9 g, 27.9 mmol) and phosphorus oxychloride (50 ml_, 536 mmol) was stirred under reflux for 3 h, then cooled. The solvent was removed under reduced pressure and the residue azeotroped twice with toluene to give 7- bromo-4-chloro-3-quinolinesulfonyl chloride (9.04 g, 26.5 mmol, 95 % yield) as a tan solid, which was used without further purification.

c) 7-bromo-4-chloro-N-(1 -methylethyl)-3-quinolinesulfonamide. Isopropylamine

(0.151 ml_, 1.759 mmol) was added to a stirred solution of 7-bromo-4-chloro-3- quinolinesulfonyl chloride (500 mg, 1.466 mmol) and triethylamine (0.245 ml_, 1.759 mmol) in dichloromethane (8 ml.) at room temperature. After two hours, an additional equivalent of isopropylamine and triethylamine were added and the mixture stirred for one hour. The mixture was then concentrated and the residue purified by silica gel chromatography (0-10% methanol/dichloromethane) to give 7- bromo-4-chloro-N-(1 -methylethyl)-3-quinolinesulfonamide (156 mg, 0.377 mmol, 25.7 % yield) as a tan solid. ¹ H NMR (DMSO-d ₆ )™: 9.28 (s, 1 H), 8.45 (d, J = 2.0

Hz, 1 H), 8.29 - 8.42 (m, 2 H), 8.05 (dd, J = 9.1 , 2.0 Hz, 1 H), 3.41 - 3.49 (m, 1 H), 1.00 (d, J = 6.6 Hz, 6 H).

d) 7-[2,4-bis(methyloxy)-5-pyrimidinyll-4-chloro-N-(1-methyleth yl)-3- quinolinesulfonamide. A mixture of 7-bromo-4-chloro-N-(1 -methylethyl)-3- quinolinesulfonamide (170 mg, 0.467 mmol),(2,4-bis(methyloxy)-5- pyrimidinyl)boronic acid (129 mg, 0.701 mmol),

tetrakis(triphenylphosphine)palladium(0) (27.0 mg, 0.023 mmol), and potassium carbonate (97 mg, 0.701 mmol) in 1 ,4-dioxane (3 ml_)/water (1 ml.) was stirred at 80 °C under nitrogen for 2.5 h, then cooled. The solution was concentrated and purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water +

0.1 % trifluoroacetic acid) to give 7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4-chloro-N-(1- methylethyl)-3-quinolinesulfonamide (53 mg, 0.125 mmol, 26.8 % yield) as a white solid. LCMS (ES+) m/e 423 [M+H] ⁺ .

e) 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopropylsulfamoyl) quinolin-4- yl)amino)benzoic acid. 3-Aminobenzoic acid (10 mg, 0.073 mmol) was added to a stirred solution of 7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4-chloro-N-(1-methyleth yl)- 3-quinolinesulfonamide (25 mg, 0.059 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours, then the mixture concentrated, purified by reverse-phase preparative HPLC (ODS, 20-80% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (14 mg, 85% pure, 38.4 % yield) as a pale yellow solid. ¹ H NMR (METHANOL-d ₄ )™: 9.18 (s, 1 H), 8.54 (d, J = 2.3 Hz, 1 H), 8.29 (d, J = 1.3 Hz, 1 H), 8.12 (dt, J = 7.5, 1 .4 Hz, 1 H), 7.95 - 8.04 (m, 1 H), 7.53 - 7.75 (m, 4 H), 4.1 1 (s, 3 H), 4.08 (s, 3 H), 3.59 (quin, J = 6.5 Hz, 1 H), 1.17 (d, J = 6.6 Hz, 6 H).

Example 2

-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-iso propylsulfamoyl)quinolin-4- yl)amino)benzoic acid

a) 3-amino-5-cvclopentylbenzoic acid. A mixture of 3-amino-5-bromobenzoic acid (1 g, 4.63 mmol), cyclopenten-1 -ylboronic acid (0.777 g, 6.94 mmol),

tetrakis(triphenylphosphine)palladium(0) (.250 g, 0.216 mmol), potassium carbonate (1 .279 g, 9.26 mmol) and 1 ,4-dioxane (20 ml_)/water (6.67 ml.) was irradiated in a microwave synthesizer at 145 °C for 25 minutes. Purification was achieved by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give a semi-clear solid. 10% palladium on carbon

(0.493 g, 0.463 mmol) was added to a stirred solution of the solid in methanol (5ml_) under nitrogen. The flask was then purged with hydrogen and the mixture stirred overnight. Purification by reverse-phase preparative HPLC (ODS, 20-80% acetonitrile/water + 0.1 % trifluoroacetic acid) afforded 3-amino-5- cyclopentylbenzoic acid (883 mg, 4.30 mmol, 93 % yield) as a light tan solid. ¹ H

NMR (DMSO-d ₆ )™: 7.31 (s, 1 H), 7.27 (s, 1 H), 6.97 (s, 1 H), 2.83 - 3.07 (m, 1 H), 1.92 - 2.08 (m, 2 H), 1.71 - 1 .85 (m, 2 H), 1.57 - 1.71 (m, 2 H), 1.34 - 1.56 (m, 2 H).

b) 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopr opylsulfamoyl)quinolin- 4-yl)amino)benzoic acid. 3-Amino-5-cyclopentylbenzoic acid (17.08 mg, 0.083 mmol) was added to a stirred solution of 7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4- chloro-N-(1-methylethyl)-3-quinolinesulfonamide (32 mg, 0.076 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours, then the mixture concentrated and purified by reverse-phase preparative HPLC (ODS, 20- 80% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (1 1.8 mg, 0.020 mmol, 26.4 % yield) as a pale yellow solid. ¹ H NMR (METHANOL-d ₄ ) ™: 9.16 (s, 1 H), 8.53 (s, 1 H), 8.27 (d, J = 1 .3 Hz, 1 H), 8.00 (s, 1 H), 7.76 - 7.87 (m, 1 H), 7.61 - 7.77 (m, 2 H), 7.36 - 7.55 (m, 1 H), 4.1 1 (s, 3 H), 4.08 (s, 3 H), 3.58 (m, 1 H), 3.06 - 3.21 (m, 1 H), 2.07 - 2.21 (m, 2 H), 1 .78 - 1.89 (m, 2 H), 1.68 - 1.78 (m, 2 H), 1.54 - 1.66 (m, 2 H), 1.16 (d, J = 6.5 Hz, 6 H). LCMS (ES+) m/e 592 [M+H] ⁺ .

Example 3

3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-propy lsulfamoyl)quinolin-4- yl)amino)benzoic acid

a) 7-bromo-4-chloro-N-propyl-3-quinolinesulfonamide. n-Propylamine (0.201 ml_, 2.346 mmol) was added to a stirred solution of 7-bromo-4-chloro-3- quinolinesulfonyl chloride (500 mg, 1.466 mmol) and triethylamine (0.327 ml_, 2.346 mmol) in dichloromethane (8 ml.) at 0 °C. The reaction was allowed to warm to room temperature. An additional equivalent of n-propylamine and triethylamine were added and after 2 hours solvent was removed. The addition of methanol produced a slurry which was then filtered to give 7-bromo-4-chloro-N- propyl-3-quinolinesulfonamide (225 mg, 0.526 mmol, 35.9 % yield) as a white precipitate. ¹ H NMR (DMSO-d ₆ )™: 9.26 (s, 1 H), 8.46 (d, J = 2.0 Hz, 1 H), 8.32 - 8.42 (m, 2 H), 8.06 (dd, J = 9.1 , 2.0 Hz, 1 H), 2.83 - 2.97 (m, 2 H), 1.30 - 1 .44 (m, 2 H), 0.77 (t, J = 7.5 Hz, 3 H).

b) 3-({7-bromo-3-r(propylamino)sulfonyll-4-quinolinyl}amino)-5- cvclopentylbenzoic acid. 3-Amino-5-cyclopentylbenzoic acid (58.7 mg, 0.286 mmol) was added to a stirred solution of 7-bromo-4-chloro-N-propyl-3-quinolinesulfonamide (80 mg, 0.220 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours, then the mixture concentrated and purified by reverse-phase preparative HPLC (ODS, 20-80% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 3-({7-bromo-3-[(propylamino)sulfonyl]-4-quinolinyl}amino)-5- cyclopentylbenzoic acid (143 mg, 0.269 mmol, 122 % yield) as a pale yellow solid. 1H NMR (METHANOL-d ₄ )™: 9.12 (br. s., 1 H), 8.21 (br. s., 1 H), 7.99 (br. s., 1 H), 7.80 (br. s., 1 H), 7.56 (br. s., 3 H), 3.09 - 3.21 (m, 1 H), 3.04 (br. s., 2 H), 2.06 (br. s., 3 H), 1 .82 (br. s., 4 H), 1.55 (br. s., 4 H), 0.91 (br. s., 3 H). LCMS (ES+) m/e 532 [M+H] ⁺ .

c) 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-propy lsulfamoyl)quinolin-4- yl)amino)benzoic acid. A mixture of 3-({7-bromo-3-[(propylamino)sulfonyl]-4- quinolinyl}amino)-5-cyclopentylbenzoic acid (105 mg, 0.197 mmol),(2,4- bis(methyloxy)-5-pyrimidinyl)boronic acid (72.6 mg, 0.394 mmol),

tetrakis(triphenylphosphine)palladium(0) (1 1 .39 mg, 9.86 μηηοΙ), and potassium carbonate (60.0 mg, 0.434 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 mL) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) and reverse-phase preparative HPLC (ODS, 30-90% acetonitrile/water + 0.1 % trifluoroacetic acid) afforded the title compound (59 mg, 0.100 mmol, 50.6 % yield) as a yellow syrup. 1H NMR (METHANOL-d ₄ )™: 9.13 (s, 1 H), 8.53 (s, 1 H), 8.28 (d, J = 1.5 Hz, 1 H), 8.00 (s, 1 H), 7.78 - 7.86 (m, 1 H), 7.66 - 7.74 (m, 1 H), 7.60 - 7.66 (m, 1 H), 7.49 - 7.55 (m, 1 H), 4.1 1 (s, 3 H), 4.08 (s, 3 H), 3.09 - 3.20 (m, 1 H), 3.06 (t, J = 6.9 Hz, 2 H), 2.07 - 2.21 (m, 2 H), 1.77 - 1.89 (m, 2 H), 1 .68 - 1.77 (m, 2 H), 1.48 - 1.67 (m, 4 H), 0.92 (t, J = 7.3 Hz, 3 H).

Example 4

-((3-(N-benzylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)q uinolin-4-yl)amino)benzoic acid a) 7-bromo-4-chloro-N-(phenylmethyl)-3-quinolinesulfonamide. Benzylamine (0.320 mL, 2.93 mmol) was added to a stirred solution of 7-bromo-4-chloro-3- quinolinesulfonyl chloride (500 mg, 1.466 mmol) and triethylamine (0.409 mL, 2.93 mmol) in dichloromethane (8 mL). The mixture was stirred at room temperature overnight, then concentrated and the residue purified by silica gel chromatography (0-10% methanol/dichloromethane) to give 7-bromo-4-chloro-N-(phenylmethyl)-3- quinolinesulfonamide (186 mg, 0.452 mmol, 30.8 % yield) as a tan solid. LCMS (ES+) m/e 41 1 [M+H] ⁺ .

b) 3-r(7-bromo-3-{r(phenylmethyl)aminolsulfonyl}-4-quinolinyl)a minolbenzoic acid. 3- Aminobenzoic acid (46.5 mg, 0.339 mmol) was added to a stirred solution of 7- bromo-4-chloro-N-(phenylmethyl)-3-quinolinesulfonamide (93 mg, 0.226 mmol) in acetic acid (4 mL) at room temperature. The reaction was stirred for 24 hours, and the resulting precipitate filtered to give3-[(7-bromo-3-

{[(phenylmethyl)amino]sulfonyl}-4-quinolinyl)amino]benzoi c acid (95 mg, 0.185 mmol, 82 % yield) as an off-white solid. ¹ H NMR (DMSO-d ₆ )™: 9.00 (s, 1 H), 8.80 (br. s., 1 H), 8.22 (d, J = 1.8 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.61 (s, 1 H), 7.39 - 7.52 (m, 4 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.03 - 7.15 (m, 3 H), 4.15 (d, J = 6.1 Hz, 2 H).

c) 3-((3-(N-benzylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)qui nolin-4- yl)amino)benzoic acid. A mixture of 3-[(7-bromo-3-

{[(phenylmethyl)amino]sulfonyl}-4-quinolinyl)amino]benzoi c acid (95 mg, 0.185 mmol), (2,4-bis(methyloxy)-5-pyrimidinyl)boronic acid (68.2 mg, 0.371 mmol), tetrakis(triphenylphosphine)palladium(0) (10.71 mg, 9.27 μηηοΙ) and potassium carbonate (51 .2 mg, 0.371 mmol) was dissolved in 1 ,4-dioxane (3 mL)/water (1 mL) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel (0-10% methanol/dichloromethane) afforded the title compound (41 mg, 0.072 mmol, 38.7 % yield) as a yellow powder. ¹ H NMR (DMSO-d ₆ )™: 13.07 (br. s., 1 H), 9.04 (s, 1 H), 8.69 (t, J = 6.2 Hz, 1 H), 8.59 (s, 1 H), 8.39 (s, 1 H), 8.22 (s, 1 H), 7.61 - 7.68 (m, 3 H), 7.57 (s, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.14 - 7.26 (m, 5 H), 7.1 1 (d, J = 8.1 Hz, 1 H), 4.12 (d, J = 5.8 Hz, 2 H), 3.99 (s, 3 H), 3.97 (s, 3 H).

Example 5

3-((3-(N-benzylsulfamoyl)-7-(2,4-d^

cvclopentylbenzoic acid

a) 3-r(7-bromo-3-{r(phenylmethyl)aminolsulfonyl}-4-quinolinyl)a minol-5- cvclopentylbenzoic acid. 3-Amino-5-cyclopentylbenzoic acid (60.3 mg, 0.294 mmol) was added to a stirred solution of 7-bromo-4-chloro-N-(phenylmethyl)-3- quinolinesulfonamide (93 mg, 0.226 mmol) in acetic acid (4 ml.) at room

temperature. The reaction was stirred for 24 hours, and an additional 0.3 equivalents of the aniline was added and stirring continued for an additional 24 hours. The mixture was concentrated, then purified by reverse-phase preparative HPLC (ODS, 20-80% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 3-[(7- bromo-3-{[(phenylmethyl)amino]sulfonyl}-4-quinolinyl)amino]- 5-cyclopentylbenzoic acid (101 mg, 0.174 mmol, 77 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) ™: 8.96 (s, 1 H), 8.74 (s, 1 H), 8.43 (s, 1 H), 8.20 (d, J = 2.0 Hz, 1 H), 7.53 (s, 2 H),

7.43 - 7.51 (m, 1 H), 7.30 (s, 1 H), 7.08 - 7.18 (m, 6 H), 4.13 (d, J = 5.6 Hz, 2 H), 2.84 - 3.08 (m, 1 H), 1.92 - 2.08 (m, 2 H), 1.53 - 1.79 (m, 4 H), 1.46 (br. s., 2 H). b) 3-((3-(N-benzylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)qui nolin-4-yl)amino)-5- cvclopentylbenzoic acid. A mixture of 3-[(7-bromo-3- {[(phenylmethyl)amino]sulfonyl}-4-quinolinyl)amino]-5-cyclop entylbenzoic acid

(101 mg, 0.174 mmol), (2,4-bis(methyloxy)-5-pyrimidinyl)boronic acid (64.0 mg, 0.348 mmol), tetrakis(triphenylphosphine)palladium(0) (10.05 mg, 8.70 μηηοΙ) and potassium carbonate (48.1 mg, 0.348 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 ml.) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) afforded the title compound (62 mg, 0.095 mmol, 54.6 % yield) as a yellow powder. LCMS (ES+) m/e 640 [M+H] ⁺ . Example 6

-cvclopentyl-5-((3-(N-cvclopro

yl)amino)benzoic acid

a) 7-bromo-4-chloro-N-cvclopropyl-3-quinolinesulfonamide. Cyclopropylamine (0.165 ml_, 2.346 mmol) was added to a stirred solution of 7-bromo-4-chloro-3- quinolinesulfonyl chloride (400 mg, 1.173 mmol) and triethylamine (0.327 ml_, 2.346 mmol) in dichloromethane (8 ml.) at room temperature. The mixture was stirred overnight, then concentrated and the purified by silica gel chromatography (0-10% methanol/dichloromethane) to give 7-bromo-4-chloro-N-cyclopropyl-3- quinolinesulfonamide (1 15 mg, 0.318 mmol, 27.1 % yield) as a tan solid. ¹ H NMR (DMSO-d ₆ )™: 9.28 (s, 1 H), 8.72 (d, J = 2.5 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.07 (dd, J = 9.1 , 2.0 Hz, 1 H), 2.22 - 2.38 (m, 1 H), 0.44

- 0.57 (m, 2 H), 0.25 - 0.44 (m, 2 H).

b) 3-({7-bromo-3-[(cvclopropylamino)sulfonyll-4-quinolinyl}amin o)-5- cyclopentylbenzoic acid. 3-Amino-5-cyclopentylbenzoic acid (65.8 mg, 0.321 mmol) was added to a stirred solution of 7-bromo-4-chloro-N-cyclopropyl-3- quinolinesulfonamide (58 mg, 0.160 mmol) in acetic acid (4 ml.) at room

temperature. The reaction was stirred for 24 hours, and a precipitate was observed. The precipitate was filtered and washed with acetic acid to give 3-({7- bromo-3-[(cyclopropylamino)sulfonyl]-4-quinolinyl}amino)-5-c yclopentylbenzoic acid (68 mg, 0.128 mmol, 80 % yield) as a white solid. ¹ H NMR (DMSO-d ₆ )™: 9.09 (s, 1 H), 8.63 (br. s., 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 7.56 - 7.69 (m, 2 H), 7.46

- 7.56 (m, 1 H), 7.42 (s, 1 H), 7.22 (s, 1 H), 2.85 - 3.07 (m, 1 H), 2.28 (br. s., 1 H), 1.97 (d, J = 8.1 Hz, 2 H), 1 .69 (d, J = 4.8 Hz, 2 H), 1 .54 - 1 .64 (m, 2 H), 1.45 (br. s., 2 H), 0.31 - 0.55 (m, 4 H).

c) 3-cvclopentyl-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethox ypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid. A mixture of 3-({7-bromo-3- [(cyclopropylamino)sulfonyl]-4-quinolinyl}amino)-5-cyclopent ylbenzoic acid (68 mg, 0.128 mmol),(2,4-bis(methyloxy)-5-pyrimidinyl)boronic acid (47.2 mg, 0.256 mmol), tetrakis(triphenylphosphine)palladium(0) (7.41 mg, 6.41 μηηοΙ) and potassium carbonate (35.4 mg, 0.256 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 ml.) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) gave a yellow solid, which was then further purified by reverse-phase preparative HPLC (ODS, 20-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (21 mg, 0.030 mmol, 23.28 % yield) as a yellow powder. ¹ H NMR (DMSO-d ₆ )™: 9.09 (s, 1 H), 8.59 (s, 3 H), 8.25 (s, 1 H), 7.46 - 7.79 (m, 3 H), 7.40 (s, 1 H), 7.18 (s, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H), 2.87 - 3.14 (m, 1 H), 2.26 (d, J = 3.8 Hz, 1 H), 1.96 (br. s., 2 H), 1 .52 - 1 .79 (m, 4 H), 1 .46 (br. s., 2 H), 0.25 - 0.59 (m, 4 H). LCMS (ES+) m/e 590 [M+H] ⁺ .

Example 7

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)benzoic acid

a) 3-({7-bromo-3-r(cvclopropylamino)sulfonyll-4-quinolinyl}amin o)benzoic acid. 3- Aminobenzoic acid (44.0 mg, 0.321 mmol) was added to a stirred solution of 7- bromo-4-chloro-N-cyclopropyl-3-quinolinesulfonamide (58 mg, 0.160 mmol) in acetic acid (5 ml.) at room temperature. The reaction was stirred for 24 hours, giving a precipitate. The precipitate was filtered and washed with acetic acid to give 3-({7-bromo-3-[(cyclopropylamino)sulfonyl]-4-quinolinyl}amin o)benzoic acid (45 mg, 0.097 mmol, 60.7 % yield) as a white solid. ¹ H NMR (DMSO-d ₆ )™: 9.07 (s, 1 H), 8.56 (br. s., 1 H), 8.27 (d, J = 1.8 Hz, 1 H), 7.67 (d, J = 8.1 Hz, 1 H), 7.58 (d, J = 1.8 Hz, 2 H), 7.41 (t, J = 8.0 Hz, 2 H), 7.27 - 7.36 (m, 1 H), 7.16 - 7.27 (m, 1 H), 7.10 (br. s., 1 H), 2.24 (br. s., 1 H), 0.28 - 0.49 (m, 4 H).

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)benzoic acid. A mixture of 3-({7-bromo-3-[(cyclopropylamino)sulfonyl]-4- quinolinyl}amino)benzoic acid (45 mg, 0.097 mmol),(2,4-bis(methyloxy)-5- pyrimidinyl)boronic acid (35.8 mg, 0.195 mmol),

tetrakis(triphenylphosphine)palladium(0) (5.62 mg, 4.87 μηηοΙ) and potassium carbonate (26.9 mg, 0.195 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 ml.) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) gave a yellow solid, which was made into a slurry following the addition of methanol. Filtration afforded the title compound (15 mg, 0.024 mmol, 24.25 % yield) as a yellow powder. ¹ H NMR (METHANOL-d ₄ )™: 9.17 (s, 1 H), 8.55 (s, 1 H), 8.30 (d, J = 1.3 Hz, 1 H), 8.1 1 (dt, J = 7.1 , 1 .6 Hz, 1 H), 8.02 (s, 1 H), 7.51 - 7.80 (m, 4 H), 4.12 (s, 3 H), 4.08 (s, 3 H), 2.40 - 2.55 (m, 1 H), 0.50 - 0.77 (m, 4 H). LCMS (ES+) m/e 522 [M+H] ⁺ .

Example 8

-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(pyrro lidin-1-ylsulfonyl)quinolin-4- yl)amino)benzoic acid

a) 7-bromo-4-chloro-3-(1-pyrrolidinylsulfonyl)quinoline. Pyrrolidine (0.194 ml_, 2.35 mmol) was added to a stirred solution of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (400 mg, 1.173 mmol) and triethylamine (0.327 ml_, 2.346 mmol) in dichloromethane (8 ml.) at room temperature. The mixture was stirred overnight, then concentrated and purified by silica gel chromatography ( 0-10%

methanol/dichloromethane) to give 7-bromo-4-chloro-3-(1 - pyrrolidinylsulfonyl)quinoline (156 mg, 0.415 mmol, 35.4 % yield) as an impure tan solid. LCMS (ES+) m/e 375 [M+H] ⁺ .

b) 3-{r7-bromo-3-(1-pyrrolidinylsulfonyl)-4-quinolinyllamino}-5 -cvclopentylbenzoic acid. 3-Amino-5-cyclopentylbenzoic acid (85 mg, 0.415 mmol) was added to a stirred solution of 7-bromo-4-chloro-3-(1-pyrrolidinylsulfonyl)quinoline (78 mg, 0.208 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours, and a precipitate was observed. The precipitate was filtered and washed with acetic acid to give 3-{[7-bromo-3-(1 -pyrrolidinylsulfonyl)-4- quinolinyl]amino}-5-cyclopentylbenzoic acid (88 mg, 0.162 mmol, 78 % yield) as a white solid. ¹ H NMR (DMSO-d ₆ )™: 9.09 (br. s., 1 H), 8.93 (br. s., 1 H), 8.29 (s, 1 H), 7.61 (s, 1 H), 7.49 - 7.59 (m, 2 H), 7.44 (s, 1 H), 7.21 (s, 1 H), 2.96 (s, 1 H), 1.97 (br. s., 3 H), 1 .51 - 1 .75 (m, 10 H), 1.43 (br. s., 2 H). LCMS (ES+) m/e 544[M+H] ⁺ .

c) 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(pyrroli din-1-ylsulfonyl)quinolin- 4-yl)amino)benzoic acid. A mixture of 3-{[7-bromo-3-(1 -pyrrolidinylsulfonyl)-4- quinolinyl]amino}-5-cyclopentylbenzoic acid (88 mg, 0.162 mmol),(2,4- bis(methyloxy)-5-pyrimidinyl)boronic acid (59.5 mg, 0.323 mmol),

tetrakis(triphenylphosphine)palladium(0) (9.34 mg, 8.08 μηηοΙ) and potassium carbonate (44.7 mg, 0.323 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 ml.) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) gave a yellow solid, which was further purified by reverse-phase preparative HPLC (ODS, 20-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound, trifluoroacetate salt (31 mg, 0.043 mmol, 26.7 % yield) as a yellow powder. ¹ H

NMR (METHANOL-d ₄ )™: 9.14 (s, 1 H), 8.52 (s, 1 H), 8.25 (s, 1 H), 7.91 (s, 1 H), 7.71 (t, 1 H), 7.68 (d, J = 1.3 Hz, 2 H), 7.42 (s, 1 H), 4.1 1 (s, 3 H), 4.08 (s, 3 H), 3.39 - 3.47 (m, 4 H), 2.98 - 3.18 (m, 1 H), 2.09 (br. s., 2 H), 1.90 (dt, J = 6.5, 3.4 Hz, 4 H), 1.81 (dd, J = 7.3, 3.8 Hz, 2 H), 1 .67 - 1 .77 (m, 2 H), 1.53 - 1.65 (m, 2 H)

Example 9

-((3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid

a) 7-bromo-4-chloro-N-cvclohexyl-3-quinolinesulfonamide. Cyclohexylamine (0.269 ml_, 2.35 mmol) was added to a stirred solution of 7-bromo-4-chloro-3- quinolinesulfonyl chloride (400 mg, 1.173 mmol) and triethylamine (0.327 mL, 2.346 mmol) in dichloromethane (8 mL) at room temperature. The mixture was stirred overnight, then concentrated and purified by silica gel chromatography (0- 10% methanol/dichloromethane) to give 7-bromo-4-chloro-N-cyclohexyl-3- quinolinesulfonamide (153 mg, 0.379 mmol, 32.3 % yield) as a tan solid. ¹ H NMR

(METHANOLS)™: 9.34 (s, 1 H), 8.34 - 8.45 (m, 2 H), 7.97 (dd, J = 9.0, 1.9 Hz, 1 H), 3.13 - 3.24 (m, 1 H), 1.59 - 1.80 (m, 6 H), 1.25 (td, J = 7.6, 3.5 Hz, 4 H).

b) 3-((7-bromo-3-(N-cvclohexylsulfamoyl)quinolin-4-yl)amino)ben zoic acid. 3- Aminobenzoic acid (52.3 mg, 0.381 mmol) was added to a stirred solution of 7- bromo-4-chloro-N-cyclohexyl-3-quinolinesulfonamide (77 mg, 0.191 mmol) in acetic acid (5 mL) at room temperature. The reaction was stirred for 24 hours, and a precipitate was observed. The precipitate was filtered and washed with acetic acid to give the title compound (88 mg, 0.174 mmol, 91 % yield) as a white solid. 1H NMR (DMSO-d ₆ )™: 9.1 1 (s, 1 H), 8.27 (d, J = 2.0 Hz, 2 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.25 (dd, J = 8.0, 1 .6 Hz, 1

H), 7.21 (br. s., 1 H), 3.06 (br. s., 1 H), 1 .58 (d, J = 10.4 Hz, 2 H), 1.45 - 1.54 (m, 2 H), 1.31 - 1.43 (m, 1 H), 0.89 - 1.19 (m, 5 H).

c) 3-((3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )quinolin-4- yl)amino)benzoic acid. A mixture of 3-((7-bromo-3-(N- cyclohexylsulfamoyl)quinolin-4-yl)amino)benzoic acid (88 mg, 0.174 mmol), (2,4- bis(methyloxy)-5-pyrimidinyl)boronic acid (64.2 mg, 0.349 mmol),

tetrakis(triphenylphosphine)palladium(0) (10.08 mg, 8.72 μηηοΙ) and potassium carbonate (48.2 mg, 0.349 mmol) was dissolved in 1 ,4-dioxane (3 mL)/water (1 mL) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by reverse-phase preparative HPLC (ODS, 25-90% acetonitrile/water + 0.1 % trifluoroacetic acid) afforded the title compound, trifluoroacetate salt (22 mg, 0.032 mmol, 18.61 % yield) as a yellow powder. ¹ H NMR (DMSO-d ₆ )™: 9.12 (s, 1 H), 8.59 (s, 2 H), 8.25 (s, 2 H), 7.52 - 7.80 (m, 4 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.27 (s, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H), 3.06 (br. s., 1 H), 1.58 (br. s., 2 H), 1 .46 - 1 .55 (m, 2 H), 1 .39 (br. s., 1 H), 1.03 (br. s., 5 H). Example 10

-((3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino

cvclopentylbenzoic acid

a) 3-({7-bromo-3-[(cvclohexylamino)sulfonyll-4-quinolinyl}amino )-5- cvclopentylbenzoic acid. 3-Amino-5-cyclopentylbenzoic acid (78 mg, 0.381 mmol) was added to a stirred solution of 7-bromo-4-chloro-N-cyclohexyl-3- quinolinesulfonamide (77 mg, 0.191 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours, concentrated and purified by silica gel chromatography (0-10% methanol/dichloromethane) to give 3-({7-bromo- 3-[(cyclohexylamino)sulfonyl]-4-quinolinyl}amino)-5-cyclopen tylbenzoic acid (100 mg, 0.175 mmol, 92 % yield) as a yellow solid. ¹ H NMR (DMSO-d ₆ )™: 9.07 (s, 1 H), 8.39 (s, 1 H), 8.14 - 8.30 (m, 2 H), 7.47 - 7.55 (m, 2 H), 7.29 (s, 1 H), 7.08 (s, 1 H), 2.90 - 3.12 (m, 2 H), 1.91 (s, 2 H), 1.51 - 1.72 (m, 6 H), 1 .47 (d, J = 1.0 Hz, 5 H), 0.99 (br. s., 5 H).

b) 3-((3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )quinolin-4-yl)amino)- 5-cvclopentylbenzoic acid.

A mixture of 3-({7-bromo-3-[(cyclohexylamino)sulfonyl]-4-quinolinyl}amino )-5- cyclopentylbenzoic acid (100 mg, 0.175 mmol), (2,4-bis(methyloxy)-5- pyrimidinyl)boronic acid (64.2 mg, 0.349 mmol),

tetrakis(triphenylphosphine)palladium(0) (10.08 mg, 8.72 μηηοΙ) and potassium carbonate (48.2 mg, 0.349 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 ml.) and heated in a microwave reactor at 125 °C for 30 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) afforded 3-((3-(N- cyclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinolin -4-yl)amino)-5- cyclopentylbenzoic acid (48 mg, 0.076 mmol, 43.5 % yield) as a yellow solid. ¹ H NMR (METHANOL-d ₄ )™: 9.09 (br. s., 1 H), 8.45 (s, 1 H), 8.18 (s, 1 H), 7.60 - 7.76 (m, 2 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.46 (s, 1 H), 7.10 (s, 1 H), 4.08 (s, 3 H), 4.07 (s, 3 H), 3.07 - 3.17 (m, 1 H), 2.95 - 3.07 (m, 1 H), 1 .95 - 2.1 1 (m, 2 H), 1 .62 - 1 .80 (m, 7 H), 1.49 - 1 .62 (m, 4 H), 1.48 (br. s., 1 H), 1.00 - 1 .18 (m, 5 H). LCMS (ES+) m/e 632 [M+H] ⁺ .

Example 1 1

-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(piper idin-1-ylsulfonv

yl)amino)benzoic acid

a) 7-bromo-4-chloro-3-(piperidin-1-ylsulfonyl)quinoline. Piperidine (0.1 16 ml_, 1.173 mmol) was added to a stirred solution of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (200 mg, 0.586 mmol) and triethylamine (0.163 ml_, 1.173 mmol) in dichloromethane (5 ml.) at room temperature. The mixture was stirred overnight, then concentrated and purified by silica gel chromatography (0-10%

methanol/dichloromethane) to give a mixture of 7-bromo-4-chloro-3-(piperidin-1 - ylsulfonyl)quinoline and 7-bromo-4-(piperidin-1 -yl)-3-(piperidin-1 - ylsulfonyl)quinoline as a tan solid. The mixture was not separated further, but taken on to the next step. LCMS (ES+) m/e 389 [M+H] ⁺ .

b) 3-((7-bromo-3-(piperidin-1-ylsulfonyl)quinolin-4-yl)amino)-5 -cvclopentylbenzoic acid. 3-Amino-5-cyclopentylbenzoic acid (22 mg, 0.107 mmol) was added to a stirred solution of 7-bromo-4-chloro-3-(piperidin-1 -ylsulfonyl)quinoline (34 mg, 0.087 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours and an additional 0.3 equivalents of the aniline was added. The mixture was stirred for an additional 24 hours, then concentrated, and purified by reverse-phase preparative HPLC (ODS, 20-80% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 3-((7-bromo-3-(piperidin-1-ylsulfonyl)quinolin-4- yl)amino)-5-cyclopentylbenzoic acid, trifluoroacetate (89 mg, 0.133 mmol, 152 % yield) as a pale yellow solid. LCMS (ES+) m/e 558 [M+H] ⁺ .

c) 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(piperid in-1 -ylsulfonyl)quinolin- 4-yl)amino)benzoic acid. A mixture of 3-((7-bromo-3-(piperidin-1 - ylsulfonyl)quinolin-4-yl)amino)-5-cyclopentylbenzoic acid (58 mg, 0.104 mmol), (2,4-bis(methyloxy)-5-pyrimidinyl)boronic acid (38.2 mg, 0.208 mmol),

tetrakis(triphenylphosphine)palladium(0) (6.00 mg, 5.19 μηηοΙ) and potassium carbonate (28.7 mg, 0.208 mmol) was dissolved in 1 ,4-dioxane (3 ml_)/water (1 mL) and heated in a microwave reactor at 125 °C for 25 minutes. Purification by silica gel chromatography (0-10% methanol/dichloromethane) afforded 3- cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(piperidin -1-ylsulfonyl)quinolin-4- yl)amino)benzoic acid (20 mg, 0.032 mmol, 31 .2 % yield) as a yellow powder. ¹ H NMR (DMSO-d ₆ ) δ: 9.00 (s, 1 H), 8.50 - 8.72 (m, 2 H), 8.25 (s, 1 H), 7.57 - 7.71 (m, 2 H), 7.50 (s, 1 H), 7.42 (s, 1 H), 7.15 (s, 1 H), 3.97 (s, 6 H), 3.03 (d, J = 5.1 Hz, 4 H), 2.87 - 2.99 (m, 1 H), 1 .93 (br. s., 2 H), 1.53 - 1.76 (m, 4 H), 1.41 (d, J =

5.1 Hz, 6 H), 1.29 - 1.38 (m, 2 H).

Example 12

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) methyl 3-isopropoxy-5-nitrobenzoate. Diisopropyl azodicarboxylate (0.394 mL, 2.03 mmol) was injected propwise into a stirred mixture of methyl 3-hydroxy-5- nitrobenzoate (0.400 g, 2.03 mmol), 2-propanol (0.156 mL, 2.03 mmol), triphenylphosphine (0.532 g, 2.03 mmol) and dichloromethane (15 mL) at room temperature. The mixture was stirred for 3 h. The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 10-60% ethyl acetate/hexane) to give the title compound (0.399 g, 82%) as an oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (d, J=5.81 Hz, 6 H) 3.99 (s, 3 H) 4.71 (spt, J=6.06 Hz, 1 H) 7.87 (dd, J=2.53, 1 .26 Hz, 1 H) 7.91 (t, J=2.27 Hz, 1 H) 8.43 (dd,

J=2.02, 1 .52 Hz, 1 H).

b) methyl 3-amino-5-isopropoxybenzoate. A solution of methyl 3-isopropoxy-5- nitrobenzoate (0.399 g, 1.67 mmol) in methanol (15 mL) was stirred with 5% wet palladium on carbon (0.225 g, 0.053 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound, which was used without further purification. LCMS (ES+) m/e 210 [M+H] ⁺ .

c) 3-((7-bromo-3-(N-cvclopropylsulfamoyl)quinolin-4-yl)amino)-5 -isopropoxybenzoic acid. A solution of 7-bromo-4-chloro-N-cyclopropyl-3-quinolinesulfonamide (396 mg, 1 .095 mmol) and methyl 3-amino-5-isopropoxybenzoate (280 mg, 1 .338 mmol) in acetic acid (5 ml.) was stirred at room temperature for 24 h. LCMS indicated essentially complete coupling so the reaction was evaporated to dryness to afford the intermediate ester (51 1 mg, 0.884 mmol, 81 % yield) as an orange oil. The ester was hydrolysed directly by dissolving in methanol (5 ml_), treating with

5M aqueous sodium hydroxide (2.0 ml_, 10.00 mmol) and stirring at room temperature for 4 h. LCMS showed complete hydrolysis. The reaction was quenched with 1 M aqueous hydrochloric acid (10 mL) and filtered to afford 3-((7- bromo-3-(N-cyclopropylsulfamoyl)quinolin-4-yl)amino)-5-isopr opoxybenzoic acid (51 1 mg, 0.884 mmol, 81 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 5 ppm 0.36 - 0.47 (m, 4 H) 1.19 (s, 3 H) 1.21 (s, 3 H) 2.24 (m, 1 H) 4.56 (ddd, J=12.00, 5.94, 5.81 Hz, 1 H) 6.80 (t, J=2.02 Hz, 1 H) 7.06 (d, J=1.77 Hz, 1 H) 7.14 (dd, J=2.02, 1.26 Hz, 1 H) 7.59 (d, J=9.09 Hz, 1 H) 7.63 (dd, J=9.09, 1 .77 Hz, 1 H) 8.27 (d, J=1.26 Hz, 1 H) 8.55 (br. s., 2 H) 9.06 (s, 1 H) 12.56 - 13.43 (m, 1 H). d) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-isopropoxybenzoic acid. A mixture of 3-((7-bromo-3-(N- cyclopropylsulfamoyl)quinolin-4-yl)amino)-5-isopropoxybenzoi c acid (200 mg, 0.384 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (141 mg, 0.769 mmol), potassium carbonate (106 mg, 0.769 mmol) and

tetrakis(triphenylphosphine)palladium(0) (22.21 mg, 0.019 mmol) in 1 ,4-dioxane (5.0 mL) and water (1.5 mL) in a 20 mL sealed vial was heated in a microwave synthesizer, absorbtion setting = normal at 125 °C for 25 min. The mixture was cooled and poured into water (25 mL) then extracted with ethyl acetate (2 x 50 mL). The basic layer was then acidified to pH = 2 with 1 M aqueous hydrochloric acid, then extracted with ethyl acetate (2 x 50 mL) and finally washed with brine. The organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography (ODS silica, 75 x 30 mm, 5 micron, 75 x 30 mm; 5 micron, gradient elution, 10 - 90% acetonitrile/water + 0.1 % trifluoroacetic acid over 10 min.) to afford 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5- isopropoxybenzoic acid, 1.5 trifluoroacetic acid salt (66.2 mg, 0.084 mmol, 21.80 % yield) as a yellow solid. ¹ H NMR (400MHz ,DMSO-d ₆ ) δ = 13.60 - 12.73 (m, 1 H), 9.12 (s, 1 H), 8.79 - 8.64 (m, 1 H), 8.59 (s, 1 H), 8.58 - 8.54 (m, 1 H), 8.28 (d, J = 1.0 Hz, 1 H), 7.71 (dd, J = 1.5, 9.1 Hz, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.20 (s, 1 H), 7.19 (s, 1 H), 6.88 (s, 1 H), 4.63 - 4.52 (m, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 2.36 - 2.25 (m, 1 H), 1.21 (s, 3 H), 1.19 (s, 3 H), 0.52 - 0.39 (m, 4 H).

C2 ₈ H2 ₉ N5O7S.I .5 CF ₃ CO2H requires: %C, 49.60; %H, 4.10; %N, 9.33. Found; %C, 50.22, 49.97; %H, 4.00, 3.96; %N, 9.58, 9.54.

Example 3.13

ethyl 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)aminoV

5-(phenylamino)benzoate

a) ethyl 3-nitro-5-(phenylamino)benzoate. To a suspension of ethyl 3-bromo-5- nitrobenzoate (500 mg, 1.824 mmol), aniline (170 mg, 1 .824 mmol), cesium carbonate (892 mg, 2.74 mmol) and dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '- biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) in ferf-butanol (1 ml.) and toluene (5 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor to 120 °C for 20 minutes. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3-nitro-5-(phenylamino)benzoate (190 mg, 0.664 mmol, 36.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 1.34 (t, J=7.07 Hz, 3 H) 4.36 (q, J=7.07 Hz, 2 H) 7.07 (t, J=7.45 Hz, 1 H) 7.20 (s, 1 H) 7.22 (s, 1 H) 7.35 - 7.42 (m, 2 H) 7.93 (t, J=1 .77 Hz, 1 H) 7.96 - 8.00 (m, 2 H) 9.02 (s, 1 H). LCMS (ES+) m/e 287 [M+H] ⁺ .

b) ethyl 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(phenylamino)benzoate. To a suspension of 10% palladium on carbon (50.2 mg, 0.0472 mmol) in acetic acid (10 ml.) was added ethyl 3-nitro-5- (phenylamino)benzoate (135 mg, 0.472 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (179 mg, 0.424 mmol) was added to the filtrate. The reaction was kept stirring overnight, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford ethyl 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5- (phenylamino)benzoate, trifluoroacetic acid salt (135 mg, 0.179 mmol, 37.9 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.36 - 0.43 (m, 2 H) 0.43 - 0.50 (m, 2 H) 1 .30 (t, J=7.07 Hz, 3 H) 2.22 2.30 (m, 1 H) 3.98 (s, 6 H) 4.30 (q, J=7.07 Hz, 2 H) 6.75 - 6.82 (m, 2 H) 6.83 (s, 1 H) 6.85 (s, 1 H) 7.01 - 7.08 (m, 2 H) 7.19 (s, 1 H) 7.36 (s, 1 H) 7.77 - 7.86 (m, 2 H) 8.29 (d, J=1.52 Hz, 1 H) 8.47 (br. s., 1 H) 8.52 (br. s., 1 H) 8.62 (s, 1 H) 9.07 (s, 1 H). LCMS (ES+) m/e 641 [M+H] ⁺ .

Example 14

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amino)-5-

(phenylamino)benzoic acid

To a suspension of ethyl 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(phenylamino) benzoate (100 mg, 0.156 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 N) (0.130 mL, 0.780 mmol). The reaction mixture was kept stirring overnight, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5-

(phenylamino)benzoic acid, trifluoroacetic acid salt (58 mg, 0.080 mmol, 51 .1 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.33 - 0.43 (m, 2 H) 0.43 - 0.49 (m, 2 H) 2.17 - 2.29 (m, 1 H) 3.98 (s, 6 H) 6.74 - 6.84 (m, 2 H) 6.88 (s, 1 H) 6.89 (s, 1 H) 7.05 - 7.14 (m, 3 H) 7.35 (s, 1 H) 7.74 - 7.87 (m, 2 H) 8.28(d, J=1.01 Hz, 1 H) 8.42 (br. s., 1 H) 8.53 (br. s., 2 H) 8.62 (s, 1 H) 9.06 (s, 1 H) 13.01 (br. s., 1 H). LCMS (ES+) m/e 613 [M+H] ⁺ .

Example 15

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-(phenylamino )quinolin

A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (61 mg, 0.145 mmol) and aniline (100 μΙ_, 1.097 mmol) in acetic acid (0.5 ml.) in a 5 ml. sealed vial was heated in a microwave synthesizer, absorbtion setting = normal at 100 °C for 15 min. LCMS shows complete and clean conversion to desired product. The crude mixture was directly purified by chromatography (ODS silica, 75 x 30 mm, 5 micron, gradient elution, 10 - 40% acetonitrile/water (0.1 % trifluoroacetic acid) over 10 min.) to afford N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4- (phenylamino)quinoline-3-sulfonamide (27.7 mg, 0.057 mmol, 39.6 % yield). ¹ H NMR (400MHz ,DMSO-d ₆ ) δ 9.09 (s, 1 H), 8.83 (br. s., 1 H), 8.64 (br. s., 1 H), 8.58 (s, 1 H), 8.25 (d, J = 1 .5 Hz, 1 H), 7.62 (dd, J = 1.8, 8.8 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.44 - 7.36 (m, 2 H), 7.28 - 7.21 (m, 1 H), 7.19 (d, J = 7.6 Hz, 2 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 2.36 - 2.27 (m, 1 H), 0.52 - 0.42 (m, 4 H).

Example 16

3-(benzylamino)-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimeth oxypyrimidin-5-yl)quinolin-4- yl)amino)benzoic acid a) methyl 3-(benzylamino)-5-nitrobenzoate. To a solution of methyl 3-amino-5- nitrobenzoate (500 mg, 2.55 mmol) in N,N-dimethylformamide (5 mL) was added (bromomethyl)benzene (436 mg, 2.55 mmol). The reaction was heated in a microwave reactor at 120 °C for 20 minutes. After cooling, the organic solvent was removed under reduced pressure. The resulting oil was purified by flash chromagraphy (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 3- (benzylamino)-5-nitrobenzoate (330 mg, 1.153 mmol, 45.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.86 (s, 3 H) 4.41 (d, J=5.81 Hz, 2 H) 7.23 - 7.29 (m, 1 H) 7.33 - 7.40 (m, 5 H) 7.56 (d, J=1 .77 Hz, 2 H) 7.78 (t, J=1.77 Hz, 1 H). LCMS (ES+) m/e 287 [M+H] ⁺ .

b) 3-(benzylamino)-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimeth oxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid. To a suspension of platinum(IV) oxide (71 .4 mg, 0.314 mmol) in acetic acid (10 mL) was added methyl 3-(benzylamino)-5- nitrobenzoate (90 mg, 0.314 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro- N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sul fonamide (1 19 mg, 0.283 mmol) was added to the filtrate and mixture kept stirring at room

temperature overnight. The organic solvent was removed under reduced pressure. The residue was dissolved in methanol (10.00 mL) and sodium hydroxide (6. ON) (0.262 mL, 1.572 mmol) was added. The reaction was kept stirring overnight, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water (0.1 % trifluoroacetic acid) to afford 3-(benzylamino)-5-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)benzoic acid, trifluoroacetic acid salt (52 mg, 0.070 mmol, 22.33 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.37 - 0.44 (m, 2 H) 0.43 - 0.50 (m, 2 H) 2.16 - 2.29 (m, 1 H) 3.98 (s, 3H) 4.00 (s, 3 H) 4.22 (s, 2 H) 6.50 - 6.56 (m, 1 H) 6.86 (s, 1 H) 7.06 (s, 1 H) 7.1 1 - 7.18 (m, 1 H) 7.18 - 7.28(m, 4 H) 7.65 (s, 2 H) 8.25 (s, 1 H) 8.57 (br. s., 1 H) 8.60 (s, 1 H) 8.64 (br. s., 1 H) 9.06 (s, 1 H). LCMS (ES+) m/e 627 [M+H] ⁺ . Example 17

ethyl 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amino)-

5-((3-fluorophenyl)amino)benzoate

a) ethyl 3-((3-fluorophenyl)amino)-5-nitrobenzoate. To a suspension of ethyl 3- bromo-5-nitrobenzoate (500 mg, 1.824 mmol), 3-fluoroaniline (203 mg, 1.824 mmol), cesium carbonate (892 mg, 2.74 mmol) and dicyclohexyl(2',4',6'- triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) in ferf-butanol (1 ml.) and toluene (5 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 20 minutes. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3-((3-fluorophenyl)amino)-5- nitrobenzoate (350 mg, 1.150 mmol, 63.1 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 .34 (t, J=7.20 Hz, 3 H) 4.36 (q, J=7.07 Hz, 2 H) 6.82 (td, J=8.46, 2.02Hz, 1 H) 6.97 - 7.09 (m, 2 H) 7.31 - 7.44 (m, 1 H) 7.98 (dd, J=2.27, 1.26 Hz, 1 H) 8.02 (t, J=1.64 Hz, 1 H)8.04 - 8.10 (m, 1 H) 9.65 (br. s., 1 H).

b) ethyl 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3-fluorophenyl)amino)benzoate. To a suspension of 10% palladium on carbon (66.5 mg, 0.0624 mmol) in acetic acid (10 ml.) was added ethyl 3-((3- fluorophenyl)amino)-5-nitrobenzoate (190 mg, 0.624 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (237 mg, 0.562 mmol) was added to the filtrate. The reaction was kept stirring overnight, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water (0.1 % trifluoroacetic acid) to afford ethyl 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5-((3- fluorophenyl)amino)benzoate, trifluoroacetic acid salt (250 mg, 0.324 mmol, 51.8 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.35 - 0.43 (m, 2 H) 0.43 - 0.50 (m, 2 H) 1.30 (t, J=7.07 Hz, 3 H) 2.19 - 2.32 (m, 1 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 4.30 (q, J=7.07 Hz, 2 H) 6.53 - 6.68 (m, 3 H) 6.84 (s, 1 H) 7.01 - 7.09 (m, 1 H) 7.25 (s, 1 H) 7.37 (d, J=1 .77 Hz, 1 H) 7.72 - 7.85 (m, 2 H) 8.29 (d, J=1.26 Hz, 1 H) 8.51 (br. s., 1 H) 8.60 (s, 1 H) 8.63 (br. s., 1 H) 8.68 (br. s., 1 H) 9.09 (s, 1

H). LCMS (ES+) m/e 659 [M+H] ⁺ .

Example 18

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amino)-5-((3- fluorophenyl)amino)benzoic acid

To a suspension of ethyl 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3-fluorophe nyl)amino)benzoate (180 mg, 0.273 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 M) (0.046 mL, 0.273 mmol). The reaction mixture was kept stirring at room temperature overnight, then acidified to pH=5 with 6M aqueous hydrochloric acid. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5-((3- fluorophenyl)amino)benzoic acid (140 mg, 0.222 mmol, 81 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.38 - 0.43 (m, 2 H) 0.44 - 0.50 (m, 2 H) 2.20 - 2.31 (m, 1 H) 3.98 (s, 6 H) 6.54 - 6.62 (m, 1 H) 6.62 - 6.74 (m, 2 H) 6.88 (br. s., 1 H) 7.02 - 7.14 (m, 1 H) 7.19 (s, 1 H) 7.39 (s, 1 H) 7.73 - 7.85 (m, 2 H) 8.29 (d, J=1.26 Hz, 1 H) 8.56 (br. s., 1 H) 8.61 (s, 1 H) 8.67 (br. s., 2 H) 9.08 (s, 1 H). LCMS (ES+) m/e 631 [M+H] ⁺ . Example 19

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimeth^

methoxybenzoic acid

A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (42 mg, 0.100 mmol) and 3-amino-5-methoxybenzoic acid (27 mg, 0.162 mmol) in acetic acid (0.5 ml.) in a 5 ml. sealed vial was heated in a microwave

synthesizer, absorbtion setting = normal at 100 °C for 15 min. LCMS shows complete and clean conversion to mainly desired product. The crude mixture was directly purified by chromatography (ODS silica, 75 x 30 mm, 5 micron, gradient elution, 10-90% acetonitrile/water (0.1 % trifluoroacetic acid) over 10 min.). The product was further purified by HPLC (ODS silica, 75 x 30 mm, 5 micron, gradient elution, 10-60%

acetonitrile/water (0.1 % trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7- (2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-methoxyb enzoic acid, trifluoroacetic acid salt (19 mg, 0.028 mmol, 28.3 % yield) as a yellow powder. ¹ H NMR (400MHz

,DMSO-d ₆ ) δ = 13.12 (br. s., 1 H), 9.12 (s, 1 H), 8.68 (br. s., 1 H), 8.61 (s, 1 H), 8.55 (br. s., 1 H), 8.28 (d, J = 1.5 Hz, 1 H), 7.71 (dd, J = 1 .5, 8.8 Hz, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.23 (dd, J = 1.3, 2.3 Hz, 1 H), 7.16 (t, J = 1.3 Hz, 1 H), 6.95 (t, J = 2.1 Hz, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 3.77 (s, 3 H), 2.37 - 2.17 (m, 1 H), 0.55 - 0.34 (m, 4 H).

Example 20

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-di^

fluorophenoxy)benzoic acid

a) methyl 3-(4-fluorophenoxy)-5-nitrobenzoate. Anhydrous copper (II) acetate (0.253 g, 1.40 mmol) was added to a stirred mixture of 4-fluorophenylboronic acid (0.586 g, 4.18 mmol), methyl 3-hydroxy-5-nitrobenzoate (0.275 g, 1.40 mmol), triethylamine (1.36 mL, 9.76 mmol), dichloromethane (15 mL) and 4A molecular sieves (3 g). The mixture was stirred vigorously at room temperature under oxygen for 60 h. Acetic acid (0.560 mL, 9.76 mmol) was added, then the mixture filtered through a plug of Hyflo®. The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 5-30% ethyl

acetate/hexane) to give the title compound (0.284 g, 70%) as an oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.99 (s, 3 H) 7.03 - 7.12 (m, 2 H) 7.12 - 7.21 (m, 2 H) 7.91 - 7.94 (m, 1 H) 7.94 - 7.97 (m, 1 H) 8.58 (dd, J=2.02, 1 .52 Hz, 1 H).

b) methyl 3-amino-5-(4-fluorophenoxy)benzoate. A solution of methyl 3-(4- fluorophenoxy)-5-nitrobenzoate (0.282 g, 0.968 mmol) in methanol (10 mL) was stirred with 5% wet palladium on carbon (0.280 g, 0.066 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound (0.237 g, 94%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.77 (s, 3 H) 5.59 (s, 2 H) 6.40 (t, J=2.27 Hz, 1 H) 6.57

(dd, J=2.40, 1.39 Hz, 1 H) 6.96 (dd, J=2.02, 1.52 Hz, 1 H) 7.02 - 7.16 (m, 2 H) 7.17 - 7.31 (m, 2 H).

c) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(4-fluorophenoxy)benzoic acid. A mixture of 4-chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (0.070 g, 0.166 mmol), methyl 3-amino-5-(4-fluorophenoxy)benzoate (0.052 g, 0.200 mmol) in acetic acid (1 mL) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure. The residue was chromatographed (silica gel, 1-9%

methanol/dichloromethane) to give the intermediate ester (0.065 g). 1 M aqueous sodium hydroxide (1 .20 mL, 1 .20 mmol) was added dropwise to a stirred suspension of the ester in methanol (5 mL) at room temperature and the mixture stirred for 18 h. Water (20 mL) was added and the pH adjusted to 4 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.027 g, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.29 - 0.36 (m, 2 H) 0.37 - 0.47 (m, 2 H) 2.14 - 2.27 (m, 1 H) 3.99 (s, 3 H) 4.00 (s, 3 H) 6.66 (t, J=2.15 Hz, 1 H) 7.02 - 7.10 (m, 3 H) 7.10 - 7.19 (m, 2 H) 7.28 (s, 1 H) 7.65 - 7.81 (m, 2 H) 8.25 (s, 1 H) 8.44 (d, J=1 .77 Hz, 1 H) 8.49 (s, 1 H) 8.61 (s, 1 H) 9.08 (s, 1 H) 13.20 (br. s., 1 H).

Example 21

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-ph

sulfonamide

A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (46 mg, 0.109 mmol) and 3-phenoxyaniline (36 mg, 0.194 mmol) in acetic acid (0.5 mL) in a 5 mL sealed vial was heated in a microwave synthesizer, absorbtion setting = normal at 100 °C for 15 min. The crude product was directly purified by HPLC (ODS silica, 75 x 30 mm, 5 micron, gradient elution, 20 - 80% acetonitrile/water (0.1 % trifluoroacetic acid) over 10 mins.) to afford N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)- 4-((3-phenoxyphenyl)amino)quinoline-3-sulfonamide, trifluoroacetic acid salt (52.6 mg, 0.072 mmol, 66.2 % yield) as a yellow solid. ¹ H NMR (400MHz ,DMSO-d ₆ ) δ = 9.06 (s, 1 H), 8.72 (br. s., 1 H), 8.61 (s, 1 H), 8.56 (br. s., 1 H), 8.24 (d, J = 1.5 Hz, 1 H), 7.75 (dd, J = 1.8, 9.1 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.38 (t, J = 8.1 Hz, 1 H), 7.32 - 7.26 (m, 2 H), 7.08 (td, J = 1.0, 7.3 Hz, 1 H), 6.99 - 6.97 (m, 1 H), 6.97 - 6.95 (m, 1 H), 6.93 (dd, J = 1.3, 8.1 Hz, 1 H), 6.83 (dd, J = 1.8, 8.1 Hz, 1 H), 6.67 (t, J = 1.8 Hz, 1 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 2.25 (qd, J = 3.7, 6.3 Hz, 1 H), 0.46 - 0.38 (m, 4 H).

Example 22

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-methylsulfamoyl)qui nolin-4-v

isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-methylquinoline-3-sulfonamide. A mixture of 7-bromo-4- quinolinol (18 g, 80.7 mol) and chlorosulfonic acid (250 mL) was heated at 100 °C for 18 h, then cooled to room temperature and poured into ice water. The precipitate was collected by filtration, washed with water and dried in vacuo to afford 7-bromo-4-hydroxyquinoline-3-sulfonyl chloride (20 g, 77%). A mixture of the sulfonyl chloride (1.2 g, 3.94 mmol) and thionyl chloride (12 mL) was refluxed for 3 h, then cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in dichloromethane (16 mL) and triethylamine (1.1 mL) and cooled to 0 °C. Methylamine in tetrahydrofuran (3 mL, 2M) was added dropwise and the mixture was diluted with water (4 mL). The mixture was filtered and the solid washed with methanol and dried in vacuo to afford the title compound (444 mg, 35%) as a gray solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.56 (s, 3 H), 8.05 (d, J=8.7Hz, 1 H), 8.20 (s, br, 1 H), 8.37 (d, J=8.7Hz, 1 H), 8.45 (s, 1 H), 9.24 (s, 1

H). LCMS (ES+) m/e 335 [M+H] ⁺ .

b) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N-methylquinoline-3 -sulfonamide. A

mixture of 7-bromo-4-chloro-N-methylquinoline-3-sulfonamide (780 mg, 2.29 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (506 mg, 2.75 mmol),

tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.1 145 mmol) and potassium carbonate (758 mg, 5.5 mmol) in 1 ,4-dioxane (8 mL) and water (3 mL) was stirred at 80 °C under nitrogen for 1 h. TLC showed completed conversion. The mixture was cooled to room temperature, poured into water (10 mL) and stirred for 10 min. The precipitate was collected by filtration, washed with water and dried in vacuo to afford the title compound (550 mg, 61 %). LCMS (ES+) m/e 395 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-methylsulfamoyl)quin olin-4- ylamino)-5-isopropoxybenzoate. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)-N-methylquinoline-3-sulfonamide (300 mg, 0.76 mmol) and methyl 3-amino- 5-isopropoxybenzoate (240 mg, 1 .14 mmol) in acetic acid (4 mL) was stirred at 50 °C for 2 h. TLC showed complete conversion. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), neutralized with sodium

bicarbonate and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified by chromatography (silica gel, 33% ethyl acetate/petroleum ether) to afford the title compound (300 mg, 70%) as a white solid. LCMS (ES+) m/e 568 [M+H] ⁺ . d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-methylsulfamoyl)quin olin-4-ylam

isopropoxybenzoic acid. A mixture of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3- (N-methylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (300 mg, 0.53 mmol) in 1 N aqueous lithium hydroxide (2.7 ml.) and methanol (13.5 ml.) was stirred at room temperature for 20 h. LC-MS showed complete conversion. The organic solvent was removed in vacuo and the residue acidified with 1 N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20 ml. x 3). The combined organic layers were washed with water, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the title compound (150 mg, 50%). ¹ H

NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.19 (s, 3 H), 1 .21 (s, 3 H), 2.50 (s, 3 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.50-4.58 (m, 1 H), 6.72(s, 1 H), 7.07-7.10 (m, 2 H), 7.65- 7.72 (m, 2 H), 7.30-8.00 (m, 1 H), 7.24 (s, 1 H), 8.41 (s, 1 H), 8.57 (s, 1 H), 9.05 (s, 1 H), 13.03 (s, br, 1 H). LCMS (ES+) m/e 554 [M+H] ⁺ .

Example 23

-((3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-cvclohexylquinoline-3-sulfonamide. A mixture of 7-bromo-4- hydroxyquinoline-3-sulfonyl chloride (1 g, 3.3 mmol) and thionyl chloride (10 ml.) was refluxed for 3 h, then cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in dichloromethane (16 ml.) and triethylamine (1 .1 mL) and cooled to 0 °C. Cyclohexanamine (0.4 ml_, 3.6 mmol) was added dropwise at 0 °C and the mixture stirred for 30 min. TLC showed complete conversion. Water (10 mL) was added and the mixture extracted with

dichloromethane (100 mL). The organic layer was washed with water, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 25% ethyl acetate/petroleum ether) to afford the title compound (912 mg, 68%) as a gray solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm 1.02-1 .33 (m, 5 H), 1 .45-1.65 (m, 5 H), 3.13-3.23 (m, 1 H), 8.09-8.13 (m, 1 H), 8.41-8.52 (m, 3 H), 9.35 (s, 1 H). LCMS (ES+) m/e 403 [M+H] ⁺ .

b) 4-chloro-N-cvclohexyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli ne-3-sulfona A mixture of 7-bromo-4-chloro-N-cyclohexylquinoline-3-sulfonamide (900 mg, 2.96 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (654 mg, 3.55 mmol),

tetrakis(triphenylphosphine)palladium(0) (171 mg, 0.148 mmol) and potassium carbonate (980 mg, 7.1 mmol) in 1 ,4-dioxane (4 mL) and water (3.6 mL) was stirred under nitrogen at 80 °C for 1 h. TLC showed completed conversion. The mixture was then cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (5 mL). The organic layer was washed with water, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 25% ethyl acetate/petroleum ether) to afford the title compound (590 mg, 57%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.00-1.25 (m, 5 H), 1 .40-1 .60 (m, 5 H), 3.09-3.12 (m, 1 H), 4.00 (s, 3 H), 4.12 (s, 3 H), 8.1 1 (dd, J=1.8, 9.0 Hz, 1 H), 8.37-8.39 (m, 2 H), 8.46 (d, J=9.0 Hz, 1 H), 8.67 (s, 1 H), 9.29 (s, 1 H). LCMS (ES+) m/e 463 [M+H] ⁺ .

c) methyl 3-(3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4- ylamino)-5-isopropoxybenzoate. A mixture of 4-chloro-N-cyclohexyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (200 mg, 0.43 mmol) and methyl 3-amino-5-isopropoxybenzoate (1 100 mg, 0.52 mmol) in acetic acid (2 mL) was stirred at 50 °C for 1 h. TLC showed complete conversion. The mixture was then cooled to room temperature, diluted with ethyl acetate (20 mL), neutralized with sodium bicarbonate and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified by chromatography (silica gel, 33% ethyl acetate/petroleum ether) to afford the title compound (200 mg, 73%) as a white solid. LCMS (ES+) m/e 636 [M+H] ⁺ .

d) 3-(3-(N-cvclohexylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4-ylamino)-5- isopropoxybenzoic acid. A mixture methyl 3-(3-(N-cyclohexylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-ylamino)-5-isopropoxybenz oate (150 mg, 0.24 mmol) in 1 N aqueous lithium hydroxide (1 .2 mL) and methanol (5 mL) was stirred at room temperature for 20 h. LCMS showed complete conversion. The organic solvent was removed in vacuo and the aqueous layer was washed with ethyl acetate (1 mL), then acidified with 1 N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residual solid was washed with ether to afford the title compound (1 10 mg, 75%). ¹ H N MR (300 MHz, DMSO-d ₆ ) δ ppm 0.95-1.07 (m, 5 H), 1 .19 (s, 3 H), 1.21 (s, 3 H), 1.37-1 .58 (m, 5 H), 2.99-3.02 (m, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.50-4.58 (m, 1 H), 6.71 (t, J=2.1 Hz, 1 H), 7.06 (s, 1 H), 7.1 1 (s, 1 H), 7.65-7.73 (m, 2 H), 8.16 (d, J=7.2Hz, 1 H), 8.23 (s, 1 H), 8.35 (s, 1 H), 8.58, (s, 1 H), 9.10 (s,

1 H), 12.97 (s, br, 1 H). LCMS (ES+) m/e 622 [M+H] ⁺ .

Example 24

3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-me thylsulfamoyl)quinolin-4- yl)amino)benzoic acid

a) methyl 3-(cvclopent-1-en-1 -yl)-5-nitrobenzoate. Methyl 3-bromo-5-nitrobenzoate (5.9 g, 22.69 mmol), 2-(cyclopent-1 -en-1 -yl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (5 g, 25.8 mmol), cesium carbonate (22.3 g, 68.4 mmol), [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct

(0.573 g, 0.702 mmol) were dissolved in 1 ,4-dioxane (100 ml_). The mixture was heated to 100 °C for 16 h, then cooled and filtered. The filtrate was partitioned between brine and ethyl acetate. The combined organics were dried (Na ₂ S0 ₄ ), filtered, and concentrated. The residue was purified (silica gel, 10-60% ethyl acetate /hexane) to afford the title compound (4.45 g, 93% pure, 74%). LCMS

(ES+) m/e 248 [M+H] ⁺ .

b) methyl 3-amino-5-cvclopentylbenzoate. A solution of methyl 3-(cyclopent-1-en-1- yl)-5-nitrobenzoate (4.45 g, 18.00 mmol) in methanol (50 ml_)/ethanol (50 ml.) was stirred with 10% palladium-on-carbon (1 .915 g, 1 .800 mmol) under a hydrogen balloon at room temperature for 5 h. LCMS indicated complete conversion. The palladium was filtered off and the filtrate concentrated to afford the title compound (3.85 g, 98%) as a brown oil. LCMS (ES+) m/e 220 [M+H] ⁺ .

c) 7-bromo-4-chloro-3-quinolinesulfonamide. A mixture of 7-bromo-4-hydroxy-3- quinolinesulfonyl chloride (1 .32 g, 4.34 mmol) and phosphorus oxychloride (10 mL) was stirred under reflux for 3 h, then cooled. The solvent was removed under reduced pressure and the residue azeotroped twice with toluene. The flask was cooled in iced water and 0.5M ammonia in dioxane (87 mL) added rapidly with stirring. The mixture was stirred 0.25 h at room temperature, then the solvent removed under reduced pressure. The residue was slurried in water (100 mL). The solid was filtered off, washed with water and dried to give the title compound (1 .18 g, 94% pure, 84%) as a cream solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 8.05 (dd, J=9.09, 1.77 Hz, 1 H) 8.07 (s, 2 H) 8.37 (d, J=8.84 Hz, 1 H) 8.45 (d, J=1.77 Hz, 1 H) 9.30 (s, 1 H).

d) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonam ide. A mixture of 7- bromo-4-chloro-3-quinolinesulfonamide (0.500 g, 1.56 mmol), [2,4-bis(methyloxy)- 5-pyrimidinyl]boronic acid (0.343 g, 1.87 mmol), potassium carbonate (0.516 g, 3.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol), 1 ,4- dioxane (8 mL) and water (2 mL) was stirred at 80 °C under nitrogen for 2.5 h, then cooled. Water (20 mL) was added and the mixture stirred 10 min. The solid was filtered off, washed with water and dried to give the title compound (0.429 g, 73%) as a cream solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.00 (s, 3 H) 4.03 (s, 3 H) 8.04 (s, 2 H) 8.12 (dd, J=8.84, 1 .77 Hz, 1 H) 8.38 (d, J=1.52 Hz, 1 H) 8.47 (d, J=9.09 Hz, 1 H) 8.68 (s, 1 H) 9.30 (s, 1 H).

e) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N-methylquinoline-3 -sulfonamide. A

solution of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonam ide (0.381 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was made by warming a slurry of the compound until dissolved. The solution was cooled to room temperature and sodium hydride (60% oil suspension, 0.044 g, 1.10 mmol) added. The mixture was stirred under nitrogen for 0.25 h, then iodomethane (0.075 mL, 1 .20 mmol) added. The mixture was stirred for a further 2 h, then diluted slowly with water (40 mL). The precipitate was filtered off, washed with water and dried, then chromatographed (silica gel, 1 -9% methanol/dichloromethane) to give the title compound (0.086 g, 88% pure, 19%) as a solid, ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.56 (s, 3 H) 4.00 (s, 3 H) 4.02 (s, 3 H) 8.12 (dd, J=8.84, 1.77 Hz, 1 H) 8.15 (br. s., 1 H) 8.39 (d, J=1.77 Hz, 1 H) 8.47 (d, J=9.09 Hz, 1 H) 8.67 (s, 1 H) 9.24 (s,

1 H); and 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N,N-dimethylquinoli ne-3- sulfonamide (0.167 g, 70% pure, 29%) as a foam, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.90 (s, 6 H) 4.00 (s, 3 H) 4.02 (s, 3 H) 8.13 (dd, J=8.84, 1.77 Hz, 1 H) 8.39 (d, J=1.77 Hz, 1 H) 8.49 (d, J=8.84 Hz, 1 H) 8.67 (s, 1 H) 9.24 (s, 1 H). f) methyl 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N- methylsulfamoyl)quinolin-4-yl)amino)benzoate. A mixture of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)-N-methylquinoline-3-sulfonamide (0.084 g, 0.213 mmol), methyl 3-amino-5-cyclopentylbenzoate (hydrochloride salt, 0.065 g, 0.255 mmol) in acetic acid (1.5 mL) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure. The residue was chromatographed (silica gel, 1-9% methanol/dichloromethane). The product was further purified by reverse- phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (0.106 g, 86%) as a gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.36 - 1 .53 (m, 2 H) 1.53 - 1.76 (m, 4 H) 1.89 - 2.03 (m, 2 H) 2.53 (d, J=4.80 Hz, 3 H) 2.91 - 3.08 (m, 1 H) 3.81 (s, 3 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 7.24 (s, 1 H) 7.48 (s, 1 H) 7.58 (d, J=9.09 Hz, 1 H) 7.60 (s, 1 H) 7.65 (dd, J=9.09, 1 .52 Hz, 1 H) 8.05 (br. s., 1 H) 8.26 (d, J=1.26 Hz, 1 H) 8.58 (s, 1 H) 8.77 (br. s., 1 H) 9.08 (s, 1 H).

g) 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-methy lsulfamoyl)quinolin-4- yl)amino)benzoic acid. 1 M aqueous sodium hydroxide (2.50 mL, 2.50 mmol) was added dropwise to a stirred solution of methyl 3-cyclopentyl-5-((7-(2,4- dimethoxypyrimidin-5-yl)-3-(N-methylsulfamoyl)quinolin-4-yl) amino)benzoate (0.105 g, 0.182 mmol) in methanol (10 mL) at room temperature and the mixture stirred for 24 h. Water (40 mL) was added and the pH adjusted to 3-4 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.021 g, 21 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.39 - 1.52 (m, 2 H) 1.52 - 1.75 (m, 4 H) 1 .89 - 2.05 (m, 2 H) 2.50 (d, J=4.80 Hz, 3 H) 2.88 - 3.05 (m, 1 H) 3.97 (s, 3 H) 3.97 (s, 3 H) 7.13 (t, J=1.64 Hz, 1 H) 7.31 (t, J=1 .77 Hz, 1 H) 7.52 (s, 1 H) 7.58 - 7.70 (m, 2 H) 8.00 (q, J=4.97 Hz, 1 H) 8.23 (s, 1 H) 8.45 (s, 1 H) 8.58 (s, 1 H) 9.04 (s, 1 H) 12.98 (br. s., 1 H).

Example 25

-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N-d imethylsulfamoyl)quinolm

yl)amino)benzoic acid

a) methyl 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N- dimethylsulfamoyl)quinolin-4-yl)amino)benzoate. A mixture of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)-N,N-dimethylquinoline-3-sulfonamide (0.165 g, 0.404 mmol), methyl 3-amino-5-cyclopentylbenzoate (0.106 g, 0.484 mmol) in acetic acid (2 mL) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure. The residue was chromatographed (silica gel, 1-9%

methanol/dichloromethane). The product was further purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (0.088 g, 37%) as a gum. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1.38 - 1.52 (m, 2 H) 1.53 - 1.72 (m, 4 H) 1.88 - 2.00 (m, 2 H) 2.74 (s, 6 H) 2.89 - 3.03 (m, 1 H) 3.81 (s, 3 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 7.26 (s, 1 H) 7.54 -

7.57 (m, 2 H) 7.60 (d, J=9.09 Hz, 1 H) 7.66 (dd, J=9.09, 1.26 Hz, 1 H) 8.27 (s, 1 H)

8.58 (s, 1 H) 9.01 (br. s., 1 H) 9.06 (s, 1 H).

b) 3-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N- dimethylsulfamoyl)quinolin-4-yl)amino)benzoic acid. 1 M aqueous sodium hydroxide (2.00 mL, 2.00 mmol) was added dropwise to a stirred solution of methyl

3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N- dimethylsulfamoyl)quinolin-4-yl)amino)benzoate (0.088 g, 0.149 mmol) in methanol (10 mL) at room temperature and the mixture stirred for 24 h. Water (40 mL) was added and the pH adjusted to 3-4 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.024 g, 28%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.37 - 1.52 (m, 2 H) 1.52 - 1.75 (m, 4 H) 1.89 - 2.01 (m, 2 H) 2.70 (s, 6 H) 2.89 - 3.03 (m, 1 H) 3.97 (s, 3 H) 3.97 (s, 3 H) 7.19 (t, J=M1 Hz, 1 H) 7.40 (t, J=M1 Hz, 1 H) 7.50 (s, 1 H) 7.59 - 7.70 (m, 2 H) 8.25 (d, J=1.26 Hz, 1 H) 8.58 (s, 1 H) 8.72 (s, 1 H) 9.00 (s, 1 H) 12.97 (br. s., 1 H).

Example 26

4-amino-N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli ne-3-sulfonamide A slurry of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (29 mg, 0.069 mmol) in 30% aqueous ammonia (0.50 mL) in a 20 mL sealed vial was heated in a microwave synthesizer, absorbtion setting = normal at 75 °C for 15 min. More 30% aqueous ammonia (0.50 mL) and 1 ,4-Dioxane (0.50 mL) were added and the mixture was heated in a microwave synthesizer, absorbtion setting = normal at 125 °C for 30 min. LCMS shows complete and clean conversion. The reaction mixture was lyophilized to afford 4-amino-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli ne-3- sulfonamide, hydrochloride (26.9 mg, 0.059 mmol, 86 % yield). ¹ H NMR (400MHz ,DMSO-d ₆ ) δ = 8.76 (s, 1 H), 8.62 (s, 1 H), 8.53 (d, J = 9.1 Hz, 1 H), 8.23 (br. s., 1 H),

8.09 (d, J = 1 .0 Hz, 1 H), 7.84 (s, 1 H), 7.27 (s, 1 H), 7.15 (s, 1 H), 7.02 (s, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 2.24 - 2.1 1 (m, 1 H), 0.55 - 0.33 (m, 4 H).

Example 27

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amino)-5-(3- fluorophenoxy)benzoic acid

a) methyl 3-(3-fluorophenoxy)-5-nitrobenzoate. Anhydrous copper (II) acetate (0.230 g, 1.27 mmol) was added to a stirred mixture of 3-fluorophenylboronic acid (0.532 g, 3.80 mmol), methyl 3-hydroxy-5-nitrobenzoate (0.250 g, 1.27 mmol), triethylamine (1.24 ml_, 8.88 mmol), dichloromethane (15 ml.) and 4A molecular sieves (3 g). The mixture was stirred vigorously at room temperature under oxygen for 60 h. The mixture was filtered through a plug of Hyflo . The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 5-50% ethyl acetate/hexane) to give the title compound (0.172 g, 47%) as an oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.00 (s, 3 H) 6.82 (dt, J=9.41 , 2.37 Hz, 1 H) 6.87 (dd, J=8.34, 2.27 Hz, 1 H) 6.99 (m, J=8.27, 8.27, 2.40, 0.76 Hz, 1 H) 7.41 (td, J=8.34, 6.57 Hz, 1 H) 7.98 - 8.01 (m, 1 H) 8.02 - 8.04 (m, 1 H) 8.63 (dd, J=2.02, 1.26 Hz, 1 H).

b) methyl 3-amino-5-(3-fluorophenoxy)benzoate. A solution of methyl 3-(3- fluorophenoxy)-5-nitrobenzoate (0.169 g, 0.580 mmol) in methanol (10 ml.) was stirred with 5% wet palladium on carbon (0.180 g, 0.042 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound (0.145 g, 96%) as an oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.79 (s, 3 H) 5.65 (s, 2 H) 6.46 (t, J=2.27 Hz, 1 H) 6.65 (dd, J=2.27, 1 .52 Hz, 1 H) 6.83 - 6.88 (m, 1 H) 6.91 (dt, J=10.36, 2.40 Hz, 1 H) 6.96 - 7.03 (m, 2 H) 7.43 (td, J=8.27, 6.95 Hz, 1 H).

c) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(3-fluorophenoxy)benzoic acid. A mixture of 4-chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (0.082 g, 0.195 mmol), methyl 3-amino-5-(3-fluorophenoxy)benzoate (0.063 g, 0.241 mmol) in acetic acid (1 ml.) was stirred at 50 °C for 4 h, then cooled. The solvent was removed under reduced pressure. The residue was azeotroped three times with toluene, then chromatographed (silica gel, 1 -9% methanol/dichloromethane) to give the intermediate ester (0.095 g). 1 M aqueous sodium hydroxide (2.00 ml_, 2.00 mmol) was added dropwise to a stirred suspension of the ester in methanol (10 ml.) at room temperature and the mixture stirred for 18 h. Water (20 ml.) was added and the pH adjusted to 3 with 1 M aqueous hydrochloric acid. The mixture was stirred

1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.072 g, 59%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 0.29 - 0.37 (m, 2 H) 0.37 - 0.45 (m, 2 H) 2.15 - 2.26 (m, 1 H) 3.99 (s, 3 H) 3.99 (s, 3 H) 6.74 (t, J=2.15 Hz, 1 H) 6.82 (dd, J=8.08, 1 .77 Hz, 1 H) 6.89 (dt, J=10.23, 2.46 Hz, 1 H) 6.91 - 6.97 (m, 1 H) 7.15 (dd, J=2.27, 1.52 Hz, 1 H) 7.27 - 7.39 (m, 2 H) 7.71 - 7.82 (m, 2 H) 8.25 (s, 1 H) 8.45 (d, J=2.02 Hz, 1 H) 8.52 (s, 1 H) 8.60 (s, 1 H) 9.08 (s, 1 H) 13.25 (br. s., 1 H). Example 28

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)ami^

fluorophenyl)amino)benzoic acid

a) methyl 3-((2-fluorophenyl)amino)-5-nitrobenzoate. To a suspension of methyl 3- bromo-5-nitrobenzoate (500 mg, 1.923 mmol), 2-fluoroaniline (214 mg, 1.923 mmol), cesium carbonate (940 mg, 2.88 mmol), dicyclohexyl(2',4',6'-triisopropyl- [1 , 1 '-biphenyl]-2-yl)phosphine (92 mg, 0.192 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (8.63 mg, 0.038 mmol). The mixture was heated in a microwave reactor to 120 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 3-((2-fluorophenyl)amino)-5- nitrobenzoate (290 mg, 0.999 mmol, 52.0 % yield) as a yellow solid. ¹ H NMR (400

MHz, CHLOROFORM-d) δ ppm 3.98 (s, 3 H) 6.17 (br. s., 1 H) 7.06 - 7.14 (m, 1 H) 7.15 - 7.23(m, 2 H) 7.38 (td, J=8.15, 1.64 Hz, 1 H) 7.95 - 7.98 (m, 1 H) 8.02 (t, J=2.27 Hz, 1 H) 8.34 - 8.37 (m, 1 H). LCMS (ES+) m/e 291 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((2-fluorophenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (51.3 mg, 0.0482 mmol) in acetic acid (10 mL) was added methyl 3-((2-fluorophenyl)amino)-5-nitrobenzoate (140 mg, 0.482 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (183 mg, 0.434 mmol) was added to the filtrate. The reaction was kept stirring overnight, then concentrated under reduced pressure. The resulting brown oil was dissolved in methanol (10.00 mL), to which sodium hydroxide (6. ON) (0.402 mL, 2.412 mmol) was added. The mixture was kept stirring for 2 hours, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)ami

fluorophenyl)amino)benzoic acid, trifluoroacetic acid salt (281 mg, 0.377 mmol, 78 % yield) as a yellow solid. ¹ H 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.35 - 0.44 (m, 2 H) 0.44 - 0.51 (m, 2 H) 2.22 - 2.31 (m, 1 H) 3.98 (s, 3H) 3.99 (s, 3 H) 6.76 (s, 1 H) 6.88 - 7.01 (m, 2 H) 7.07 - 7.21 (m, 3 H) 7.33 (s, 1 H) 7.78 (s, 2 H) 8.25 (br. s., 1 H) 8.28 (s, 1 H) 8.54 (br. s., 1 H) 8.62 (s, 1 H) 8.65 (br. s., 1 H) 9.08 (s, 1 H). LCMS (ES+) m/e 631 [M+H] ⁺ .

Example 29

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)-5-((4- fluorophenyl)amino)benzoic acid

a) ethyl 3-((4-fluorophenyl)amino)-5-nitrobenzoate. To a suspension of ethyl 3- bromo-5-nitrobenzoate (500 mg, 1.824 mmol), 4-fluoroaniline (203 mg, 1.824 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) and cesium carbonate (892 mg, 2.74 mmol) in ferf-butanol (2 mL) and toluene (10 mL) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3-((4-fluorophenyl)amino)-5- nitrobenzoate (230 mg, 0.756 mmol, 41 .4 % yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (t, J=7.07 Hz, 3 H) 4.43 (q, J=7.07 Hz, 2 H) 5.99 (br. s., 1 H) 7.08 - 7.15 (m, 2 H)7.15 - 7.21 (m, 2 H) 7.83 - 7.86 (m, 1 H) 7.88 (t, J=2.27 Hz, 1 H) 8.25 - 8.32 (m, 1 H). LCMS (ES+) m/e 305 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((4-fluorophenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (40.3 mg, 0.0379 mmol) in acetic acid (10 mL) was added ethyl 3-((4-fluorophenyl)amino)-5-nitrobenzoate (1 10 mg, 0.362 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (144 mg, 0.341 mmol) was added to the filtrate. The reaction was kept stirring overnight, then was concentrated under reduced pressure. The resulting brown oil was dissolved in methanol (10.00 mL) and sodium hydroxide (6. ON) (0.316 mL, 1.895 mmol) added. The mixture was kept stirring at room temperature for two hours, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((4-fluorophenyl)amino)benzoic acid, trifluoroacetic acid salt (1 15 mg, 0.154 mmol, 40.7 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.34 - 0.41 (m, 2 H) 0.42 - 0.50 (m, 2 H) 2.19 - 2.29 (m, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.70 (s, 1 H) 6.90 - 6.98 (m, 4 H) 7.08 (s, 1 H) 7.29 (d, J=1 .52 Hz, 1 H) 7.74 - 7.86 (m, 2 H) 8.28 (d, J=1.26 Hz, 1 H) 8.37 (br. s., 1 H) 8.48 - 8.57 (m, 2 H) 8.62 (s, 1 H) 9.06 (s, 1 H) 12.99 (br. s., 1 H). LCMS (ES+) m/e 631 [M+H] ⁺ .

Example 30

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-ethylsulfamoyl)quin olin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-3-quinolinesulfonyl chloride. A mixture of 7-bromo-4- hydroxyquinoline-3-sulfonyl chloride (1 g, 3 mmol) and one drop of N,N- dimethylformamide in thionyl chloride (10 mL) was heated at 80 °C for 2 h, then the solvent removed in vacuo to dryness. The residue was used for the next step directly without further purification.

b) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-ethylsulfamoyl)quino lin-4-ylamino)-

5-isopropoxybenzoate. To a solution of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (1.05 g, 3 mmol) and triethylamine (610 mg, 6 mmol) in dry

dichloromethane (20 mL) was added ethylamine (270 mg, 3.6 mmol) dropwise at 0 °C over 5 minutes. The solution was stirred for 1 h at 0 °C. TLC showed the starting material was consumed completely. Water (30 mL) was added and the mixture extracted with dichloromethane (40 mL x 3). The combined organic phases were washed with brine (60 mL x 1 ), dried over anhydrous Na ₂ S0 ₄ , and evaporated. The crude product was purified by silica gel chromatography (33% ethyl acetate/petroleum ether) to afford the 7-bromo-4-chloro-N-ethylquinoline-3- sulfonamide (870 mg, 89%) as a yellow solid. A mixture of this compound (630 mg, 1 .81 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (367 mg, 2.2 mmol), [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (147 mg, 0.18 mmol), potassium carbonate (381 mg, 3.6 mmol) and water (0.9 mL) in 1 ,4-dioxane (5 mL) was heated at 80 °C under nitrogen for 1 h. TLC showed the starting material was consumed completely. Water (40 mL) was added. The mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and

concentrated in vacuo. The residue was purified by chromatography on silica gel (17-33% tetrahydrofuran/petroleum ether) to afford 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)-N-ethylquinoline-3-sulfonamide (500 mg, 68%) as a white solid. A mixture of this solid (300mg, 0.74mmol) and methyl 3-amino-5- isopropoxybenzoate (232 mg, 1 .1 1 mmol) in ethanol (10 mL) was heated at 80 °C for 2 h. LCMS indicated that the reaction was complete. The solvent was removed under vacuum and the residue purified by chromatography on silica gel (3-9% methanol/dichloromethane) to give the title compound (350 mg, 81 %) as a white solid. LCMS (ES+) m/e 582 [M+H] ⁺ .

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-ethylsulfamoyl)q uinolin-4-yl)amino)-5- isopropoxybenzoic acid. A mixture of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3- (N-ethylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (330 mg, 0.209 mmol) and 2N aqueous lithium hydroxide (4 mL) in methanol (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 5 h. The solvent was removed in vacuo. The mixture was acidified with 2N aqueous hydrochloric acid to pH 6, then extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL), then brine (20 mL), dried over Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified by Prep-TLC to give the title compound (120 mg, 37%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.94 (t, J=7.2 Hz, 3 H), 1.20 (d, J=6.0 Hz, 6 H), 2.85-2.94 (m, 2 H), 3.967 (s, 3 H), 3.973 (s, 3 H), 4.54 (hept, J=6.0 Hz, 1 H), 6.69-6.71 (m, 1 H), 7.06-7.1 1 (m, 2 H), 7.67-7.69 (m, 2 H), 8.10 (s, br, 1 H), 8.23 (s, 1 H), 8.37 (s, 1 H), 8.57 (s, 1 H), 9.06 (s, 1 H), 13.07 (s, br, 1 H). LCMS (ES+) m/e 568 [M+H] ⁺ .

Example 31

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-propylsulfamoyl)qui nolin-4-yl)^

isopropoxybenzoic acid

a) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N-propylquinoline-3 -sulfonamide. A

mixture of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (1 .2 g, 3.3 mmol) and triethylamine (500 mg, 4.95 mmol) in dry dichloromethane (20 mL) was stirred at 0 °C for 0.5 h, then propan-1-amine (240 mg, 3.96 mmol) was added dropwise at 0 °C over 2 minutes. The solution was stirred for 1 h at 0 °C. TLC showed the starting material was consumed completely. Water (40 mL) was added and the mixture extracted with dichloromethane (20 mL x 1 ). The organic phase was washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25% tetrahydrofuran/petroleum ether) to afford 7-bromo-4-chloro-N-propylquinoline-3- sulfonamide (1 g, 78%) as a yellow solid. A mixture of this compound (800 mg, 2.2 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (485.8 mg, 2.64 mmol), [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (179.6 mg, 0.22 mmol), potassium carbonate (349.8 mg, 3.3 mmol) and water (2 mL) in dioxane (6 mL ) was stirred at 80 °C under nitrogen for 1 h. TLC showed the starting material was consumed completely. Water (30 mL) was added and the mixture extracted with dichloromethane (40 mL x 1 ). The organic layer was washed with brine (40 mL x 1 ), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (20-50% tetrahydrofuran/petroleum ether) to afford the title compound (800 mg, 85%) as a white solid. LCMS (ES+) m/e 423 [M+H] ⁺ .

b) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-propylsulfamoyl)quin olin-4- ylamino)-5-isopropoxybenzoate. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)-N-propylquinoline-3-sulfonamide (376 mg, 0.89 mmol) and methyl 3-amino-5- isopropoxybenzoate (280 mg, 1 .34 mmol) in ethanol (8 mL) was stirred at 80 °C for 2 h. LCMS indicated that the reaction was complete. The solvent was removed under vacuum and the residue purified by chromatography on silica gel (3-9% methanol/dichloromethane) to give the title compound (480 mg, 91 %) as a white solid. LCMS (ES+) m/e 596 [M+H] ⁺ .

c) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-propylsulfamoyl)quin olin-4-ylamino)-5- isopropoxybenzoic acid. A mixture of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3- (N-propylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (370 mg, 0.62 mmol) and 2N aqueous lithium hydroxide (4 mL) in tetrahydrofuran (15 mL) was stirred at room temperature for 5 h. The solvent was removed under vacuum. The mixture was acidified with 1 N aqueous hydrochloric acid to pH 6, then extracted with ethyl acetate. The organic layer was washed with water (20 mL), then brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound (125 mg, 30%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.73 (t, J=7.5 Hz, 3 H), 1 .20 (d, J=5.7 Hz, 6 H), 1.25-1.41 (m, 2 H), 2.79-2.85 (m, 2 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.56 (hept, J=5.7 Hz, 1 H), 6.82 (s, 1 H), 7.16 (s, 2 H), 7.69 (s, 2 H), 8.20 (s, br, 1 H), 8.26 (s, 1 H), 8.58 (s, 1 H), 8.64 (s, br, 1 H), 9.09 (s, 1 H), 13.06 (s, br, 1 H). LCMS (ES+) m/e 582 [M+H] ⁺ .

Example 32

-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N-dimethylsulfamo yl)quinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-N,N-dimethylquinoline-3-sulfonamide. A solution of 7-bromo-4- hydroxyquinoline-3-sulfonyl chloride (800 mg, 2.4 mmol) in thionyl chloride (10 mL) was refluxed for 2.5 h, then concentrated in vacuo. The crude product was dissolved in dichloromethane (5 mL) and triethylamine (0.5 mL) and cooled to 0 °C. Dimethylamine hydrochloride (229 mg, 2.8 mmol) was added to the mixture in portions. The reaction mixture was stirred at 0 °C for 30 min. The crude product was filtered and dried in vacuo to afford the title compound (512 mg, 64%) as a white solid. LCMS (ES+) m/e 349 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N,N-dimethylsulfamoyl)quinolin-4-ylamino)-5- isopropoxybenzoate. A solution of 7-bromo-4-chloro-N,N-dimethylquinoline-3- sulfonamide (350 mg, 1 mmol), methyl 3-amino-5-isopropoxybenzoate (230 mg, 1.1 mmol) in ethanol (20 ml.) was refluxed at 80 °C for 45 min. TLC showed no starting materials left. The reaction mixture was concentrated in vacuo to afford the crude product. Further purification by column chromatography afforded the title compound (501 mg, 96%) as a yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 1.31 (d, J = 6.0 Hz, 6 H), 2.77 (s, 6 H), 3.87 (s, 3 H), 4.47-4.56 (m, 1 H), 6.59 (s, 1 H), 7.14 (s, 1 H), 7.30 (s, 1 H), 7.38 (dd, J = 9.0, 1 .8 Hz, 1 H), 7.56 (d, J = 9.0 Hz, 1 H), 8.26 (d, J = 1.8 Hz, 1 H), 8.65 (s, 1 H), 9.04 (s, 1 H). LCMS (ES+) m/e 522 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N-dimethylsulfamoyl) quin-olin-4- ylamino)-5-isopropoxybenzoate. A mixture of methyl 3-(7-bromo-3-(N,N- dimethylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (498 mg, 1 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (246 mg, 1.33 mol), potassium carbonate (328 mg, 2.38 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.48 mmol), 1 ,4-dioxane (5 ml.) and water (1 .5 ml.) was stirred at 80 °C under nitrogen for 1 .5 h. TLC showed no starting materials left. Purification by column chromatography to afford the title compound (512 mg, 93%). ¹ H NMR (300 MHz, CDCIs) δ ppm 1.29 (d, J = 6.0 Hz, 6 H), 2.78 (s, 6 H), 3.87 (s, 3 H), 4.05 (s, 3 H), 4.07 (s, 3 H), 4.50-4.55 (m, 1 H), 6.61 (s, 1 H), 7.21 (s, 1 H), 7.30 (s, 1 H), 7.50 (dd, J = 9.0, 1.8 Hz, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 8.41 (s, 1 H), 8.66 (s, 1 H), 9.08 (s, 1 H). LCMS (ES+) m/e 582 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N,N-dimethylsulfamoyl) quinolin-4-ylamino)-5- isopropoxybenzoic acid. To a solution of methyl 3-(7-(2,4-dimethoxypyrimidin-5- yl)-3-(N,N-dimethylsulfamoyl)quinolin-4-ylamino)-5-isopropox ybenzoate (200 mg. 0.34 mmol) in tetrahydrofuran/methanol (v/v = 1/1 , 4 mL) was added 1 N aqueous lithium hydroxide (1.7 mL, 1 .7 mmol). The mixture was stirred at room

temperature for 24 h, then concentrated to half its volume under reduced pressure and acidified to pH = 1 with 1 M aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried. Further purification by prep-TLC afforded the title compound (102 mg, 52.3%) as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ ppm 1.18 (d, J = 6.0 Hz, 6 H), 2.71 (s, 6 H), 3.97 (s, 6 H), 4.49-4.57 (m, 1 H), 6.82 (s, 1 H), 7.08 (s, 1 H), 7.14 (s, 1 H), 7.65-7.72 (m, 2 H), 8.25 (s, 1 H), 8.58 (s, 1 H), 8.66 (s, 1 H), 9.01 (s, 1 H), 12.99 (s, br, 1 H). LCMS (ES+) m/e 568 [M+H] ⁺ .

Example 33

-((3-(N-cvclopentylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)ami

isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-cvclopentylquinoline-3-sulfonamide. A mixture of 7-bromo-4- hydroxy-3-quinolinesulfonyl chloride (1.06 g, 3.29 mmol) and N,N- dimethylformamide (0.1 mL) in thionyl chloride (10 mL) was heated at 90 °C for 2 h, then the solvent removed in vacuo. Dry dichloromethane (40 mL) and triethylamine (664.6 mg, 6.58 mmol) was added and the solution cooled in ice- water. A solution of cyclopentanamine (307.6 mg, 3.6 mmol) in dry

dichloromethane (10 mL) was added dropwise at 0 °C over 0.5 h. The mixture was washed with water (20 mL x 2) and 2N aqueous hydrochloric acid (10 mL x

1 ). The organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to give the crude product, which was triturated with ethyl acetate/petroleum ether = 1/3 to afford the title compound (560 mg, 47%) as a yellow solid. LCMS (ES+) m/e 389 [M+H] ⁺ .

b) 4-chloro-N-cvclopentyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3-sulfonamide. A mixture of 7-bromo-4-chloro-N-cyclopentylquinoline-3-sulfonamide (437 mg, 1 .17 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (236 mg, 1 .28 mmol),

tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.06 mmol), sodium bicarbonate (196.6 mg, 2.34 mmol) and water (2 mL) in 1 ,4-dioxane (20 mL) was heated at 80 °C under nitrogen for 4 h. TLC showed the starting material was consumed completely. Water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous

Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (33% ethyl acetate /petroleum ether) to afford the title compound (330 mg, 62%) as a yellow solid. LCMS (ES+) m/e 449 [M+H] ⁺ . c) methyl3-(3-(N-cvclopentylsulfamoyl)-7-(2,4-dimethoxypyrimidi n-5-yl)quinoli ylamino)-5-isopropoxybenzoate. A mixture of 4-chloro-N-cyclopentyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (250 mg, 0.56 mmol) and methyl 3-amino-5-isopropoxybenzoate (129 mg, 0.61 mmol) in ethanol (5 mL) was heated at 90 °C for 16 h. The mixture was purified by chromatography on silica gel (50% ethyl acetate /petroleum ether) to give the title compound (140 mg, 40%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.20 (d, J=6.0 Hz, 6 H), 1.23- 1.61 (m, 8 H), 3.49-3.54 (m, 1 H), 3.79 (s, 3 H), 3.969(s, 3 H), 3.975(s, 3 H), 4.53 (hept, J=6.0 Hz, 1 H), 6.69 (s, 1 H), 7.1 1 (s, 1 H), 7.12 (s, 1 H), 7.65-7.71 (m, 2 H), 8.16 (d, J=6.9 Hz, 1 H), 8.24 (s, 1 H), 8.35 (s, 1 H), 8.58 (s, 1 H), 9.08 (s, 1 H). LCMS (ES+) m/e 622 [M+H] ⁺ .

d) 3-(3-(N-cvclopentylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )quinolin-4-ylamino)- 5-isopropoxybenzoic acid. A mixture of methyl 3-(3-(N-cyclopentylsulfamoyl)-7- (2,4-dimethoxypyrimidin-5-yl)quinolin-4-ylamino)-5-isopropox ybenzoate (130 mg, 0.209 mmol), lithium hydroxide (50.2 mg, 2.09 mmol) and water (2 mL) in methanol (5 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo. Water (5 ml) was added and the mixture washed with ethyl acetate (5 ml x 2), then acidified with diluted acetic acid to pH 6. The precipitate was filtered to give the title compound (70 mg, 55%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.20 (d, J=6.3 Hz, 6 H), 1 .23-1.61 (m, 8 H), 3.46-3.51 (m, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.54 (hept, J=6.3 Hz, 1 H), 6.70 (s, 1 H), 7.07 (s, 1 H), 7.1 1 (s, 1 H), 7.64-7.72 (m, 2 H), 8.18 (d, J=7.2 Hz, 1 H), 8.23 (s, 1 H), 8.32 (s, 1 H), 8.58 (s, 1 H), 9.08 (s, 1 H), 13.01 (s, br, 1 H). LCMS (ES+) m/e 608 [M+H] ⁺ .

Example 34

-(cvclohexylthio)-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-d imethoxypyrimidin-5-yl)quinolin-

4-yl)amino)benzoic acid a) 3-amino-5-(cvclohexylthio)benzoic acid. (R)-1-[(S _P )-2- (Dicyclohexylphosphino)ferrocenyl]ethyldi-ferf-butylphosphin e (22.54 mg, 0.041 mmol) and palladium(ll) acetate (9.13 mg, 0.041 mmol) were dissolved in dimethoxyethane (7 mL) and stirred in a microwave vial for 1 minute. 3-bromo-5- nitrobenzoic acid (200 mg, 0.813 mmol), cesium carbonate (583 mg, 1.789 mmol), and cyclohexanethiol (0.149 mL, 1 .219 mmol) were then added and the vial irradiated in a microwave reactor for 25 min at 125 °C. The reaction was then filtered, and the filtrate concentrated then purified by preparative HPLC (10-90% acetonitrile/water + 0.1 % TFA) to give the intermediate nitro compound. ¹ H NMR (DMSO-d ₆ ) δ: 13.85 (br. s., 1 H), 8.35 - 8.44 (m, 1 H), 8.31 (t, J = 1.9 Hz, 1 H), 8.18 (t, J = 1.5 Hz, 1 H), 3.58 (d, J = 3.8 Hz, 1 H), 1.97 (d, J = 8.8 Hz, 2H), 1 .66 - 1 .77 (m, 2H), 1 .58 (br. s., 1 H), 1 .33 - 1 .45 (m, 4H), 1 .19 - 1 .32 (m, 1 H). This

intermediate was dissolved in methanol (4 mL) and 5% palladium-on-charcoal (87 mg, 0.040 mmol) added under nitrogen gas. The flask was purged with hydrogen and the mixture stirred for 2 hours. The catalyst was filtered and the solvent removed to give 3-amino-5-(cyclohexylthio)benzoic acid (52 mg, 0.145 mmol, 17.81 % yield). LCMS (ES+) m/z 252 [M+H] ⁺ . The material was taken directly to the next step.

b) 3-(cvclohexylthio)-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dim ethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid. 3-Amino-5-(cyclohexylthio)benzoic acid (46.3 mg, 0.184 mmol) was added to a stirred solution of 4-chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (50 mg, 0.1 19 mmol) in acetic acid (2 mL) at room temperature. The reaction was stirred for 24 hours, then the precipitate was filtered, washed with acetic acid, and dried in vacuo. The crude product was purified by reverse-phase preparative HPLC (ODS, 10-95% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 3-(cyclohexylthio)-5-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)benzoic acid (38.8 mg, 0.061 mmol, 51 .4 % yield) as a pale yellow solid. ¹ H NMR (DMSO- d ₆ ) δ: 9.17 (s, 1 H), 8.64 (br. s., 1 H), 8.58 (s, 1 H), 8.33 (d, J = 1 .5 Hz, 1 H), 7.69 - 7.77 (m, 1 H), 7.64 (dt, J = 4.6, 2.1 Hz, 3 H), 7.29 (t, J = 1.9 Hz, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.06 - 3.15 (m, 1 H), 2.32 - 2.41 (m, 1 H), 1 .72 - 1 .81 (m, 2 H), 1 .55 (d, J = 7.8 Hz, 2 H), 1 .42 - 1 .49 (m, 1 H), 1 .05 - 1 .27 (m, 5 H), 0.44 - 0.53 (m, 4 H). Example 35

-(cvclopentylthio)-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quin

4-yl)amino)benzoic acid

a) 3-(cvclopentylthio)-5-nitrobenzoic acid. (R)-1 -[(S _P )-2- (Dicyclohexylphosphino)ferrocenyl]ethyldi-ferf-butylphosphin e (22.54 mg, 0.041 mmol) and palladium(ll) acetate (9.13 mg, 0.041 mmol) were added to a microwave vial containing dimethoxyethane (6 mL) and stirred for 1 min. 3-bromo- 5-nitrobenzoic acid (200 mg, 0.813 mmol) was then added, followed by cesium carbonate (583 mg, 1.789 mmol) and lastly by cyclopentanethiol (0.087 mL, 0.813 mmol). The reaction was irradiated in a microwave reactor for 25 min at 125°C, then filtered, concentrated, dissolved in methanol, and activated carbon added. The mixture was stirred at room temperature for 20 minutes. The carbon was then filtered and the eluent purified by reverse-phase preparative HPLC (30-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-(cyclopentylthio)-5- nitrobenzoic acid (23 mg, 0.086 mmol, 10.58 % yield) as an off-white solid. ¹ H NMR (DMSO-d ₆ ) δ: 13.84 (s, 1 H), 8.33 - 8.38 (m, 1 H), 8.28 (t, J = 2.0 Hz, 1 H), 8.15 (t, J = 1 .5 Hz, 1 H), 3.96 (quin, 1 H), 2.09 - 2.21 (m, 2H), 1 .46 - 1 .78 (m, 6H). b) 3-amino-5-(cvclopentylthio)benzoic acid. 10% Palladium-on-charcoal (Degussa) (9.16 mg, 0.086 mmol) was added to a stirred solution of 3-(cyclopentylthio)-5- nitrobenzoic acid (23 mg, 0.086 mmol) in methanol (5 mL) under nitrogen atmosphere. Hydrogen was then flushed into the flask and the reaction stirred for 2 hours until complete disappearance of the starting material was observed in the LCMS. The mixture was concentrated and the material taken directly to the next step. LCMS (ES+) m/z 238 [M+H] ⁺ .

c) 3-(cvclopentylthio)-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-di methoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid. 3-Amino-5-(cyclopentylthio)benzoic acid (48.1 mg, 0.203 mmol) was added to a stirred solution of 4-chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (55 mg, 0.131 mmol) in acetic acid (2 mL) at room temperature. The reaction was stirred for 24 hours, then the precipitate was filtered, washed with acetic acid, and the eluent collected and dried in vacuo to give an amber syrup. The syrup was purfied by reverse-phase preparative HPLC (ODS, 10-95% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 3-(cyclopentylthio)-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4-di methoxypyrimidin- 5-yl)quinolin-4-yl)amino)benzoic acid (26 mg, 0.040 mmol, 30.4 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ: 9.18 (s, 1 H), 8.67 (br. s., 1 H), 8.59 (s, 1 H), 8.34 (d, J = 1 .8 Hz, 1 H), 7.70 - 7.80 (m, 1 H), 7.62 - 7.69 (m, 2 H), 7.56 - 7.62 (m, 1 H), 7.33 (t, J = 1.8 Hz, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 3.61 (t, J = 6.7 Hz, 1 H), 2.34 - 2.43 (m, 1 H), 1.82 - 1 .94 (m, 2 H), 1.54 - 1.68 (m, 2 H), 1.44 - 1.54 (m, 2 H), 1.34 - 1.44 (m, 2 H), 0.44 - 0.53 (m, 4 H).

Example 36

-((3-carboxyphenyl)amino)-5-((3-(N-cvclopropylsulfamoyl)- 7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid

a) ethyl 3-((3-(ethoxycarbonyl)phenyl)amino)-5-nitrobenzoate. To a suspension of ethyl 3-bromo-5-nitrobenzoate (500 mg, 1 .824 mmol), ethyl 3-aminobenzoate (301 mg, 1 .824 mmol), cesium carbonate (892 mg, 2.74 mmol) and dicyclohexyl(2',4',6'- triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) in ferf-butanol (2 mL) and toluene (10 mL) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 20 minutes. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3-((3-

(ethoxycarbonyl)phenyl)amino)-5-nitrobenzoate (155 mg, 0.433 mmol, 23.71 % yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .40 - 1 .48 (m, 6 H) 4.37 - 4.48 (m, 4 H) 6.30 (br. s., 1 H) 7.37 - 7.43 (m, 1 H) 7.44 - 7.50 (m, 1 H) 7.78 - 7.86 (m, 2 H) 7.98 (dd, J=2.40, 1 .39 Hz, 1 H) 8.04 (t, J=2.27 Hz, 1 H) 8.34 - 8.38 (m, 1 H). LCMS (ES+) m/e 359 [M+H] ⁺ .

b) 3-((3-carboxyphenyl)amino)-5-((3-(N-cvclopropylsulfamoyl)-7- (2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)benzoic acid. To a suspension of 10% palladium on carbon (23.18 mg, 0.0218 mmol) in acetic acid (10 ml.) was added ethyl 3-((3-(ethoxycarbonyl)phenyl)amino)-5-nitrobenzoate (75 mg, 0.209 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (83 mg, 0.196 mmol) was added to the filtrate. The reaction was kept stirring overnight and the organic solvent was removed. The resulting oil was dissolved in methanol (10.00 ml.) to which sodium hydroxide (6. ON) (0.182 ml_, 1 .089 mmol) was added. The mixture was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3- carboxyphenyl)amino)-5-((3-(N-cyclopropylsulfamoyl)-7-(2,4-d imethoxypyrimidin- 5-yl)quinolin-4-yl)amino)benzoic acid, trifluoroacetic acid salt (50 mg, 0.065 mmol, 29.8 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.36 - 0.43 (m, 2 H) 0.44 - 0.50 (m, 2 H) 2.20 - 2.30 (m, 1 H) 3.98 (s, 6 H) 6.85 (s, 1 H) 7.09 - 7.21 (m, 3 H) 7.36 - 7.43 (m, 2 H) 7.53 - 7.58 (m, 1 H) 7.74 - 7.84 (m, 2 H) 8.28 (d, J=1.26 Hz, 1 H) 8.47 - 8.58 (m, 2 H) 8.61 (s, 2 H) 9.08 (s, 1 H) 12.94 (br. s., 1 H). LCMS (ES+) m/e 657 [M+H] ⁺ .

Example 37

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4-yl)amino)-5-((3- hydroxyphenyl)amino)benzoic acid

a) ethyl 3-((3-hvdroxyphenyl)amino)-5-nitrobenzoate. To a suspension of ethyl 3- bromo-5-nitrobenzoate (500 mg, 1 .824 mmol), 3-aminophenol (199 mg, 1 .824 mmol), cesium carbonate (892 mg, 2.74 mmol), and dicyclohexyl(2',4',6'- triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3-((3-hydroxyphenyl)amino)-5- nitrobenzoate (155 mg, 0.513 mmol, 28.1 % yield) as a red solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 .34 (t, J=7.07 Hz, 3 H) 4.36 (q, J=7.07 Hz, 2 H) 6.46 (dd, J=8.08, 1 .52Hz, 1 H) 6.57 - 6.66 (m, 2 H) 7.15 (t, J=7.96 Hz, 1 H) 7.91 - 7.94 (m, 1 H) 7.95 - 7.97 (m, 1 H) 7.97 - 8.00 (m, 1 H) 8.91 (s, 1 H) 9.50 (s, 1 H). LCMS (ES+) m/e 303 [M+H] ⁺ .

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5-((3-hvdroxyphenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (27.7 mg, 0.0260 mmol) in acetic acid (10 ml.) was added ethyl 3-((3-hydroxyphenyl)amino)-5-nitrobenzoate (75 mg, 0.248 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (99 mg, 0.234 mmol) was added to the filtrate. The reaction was kept stirring overnight and the organic solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (10.00 ml_), to which sodium hydroxide (6. ON) (0.043 ml_, 0.260 mmol) was added. The mixture was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3-hydroxyphenyl)amino)benzoic acid, trifluoroacetic acid salt (75 mg, 0.101 mmol, 38.8 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.38 - 0.45 (m, 2 H) 0.45 - 0.51 (m, 2 H) 2.21 - 2.31 (m, 1 H) 3.98 (s, 3 H) 3.98 (s, 3 H) 6.26 (dd, J=8.08, 1.52 Hz, 1 H) 6.34 (dd, J=7.96, 1 .39 Hz, 1 H) 6.42 (t, J=2.15 Hz, 1 H) 6.81 - 6.89 (m, 2 H) 7.07 (s, 1 H) 7.39 (s, 1 H) 7.72 - 7.82 (m, 2 H) 8.27 (s, 1 H) 8.33 (br. s., 1 H) 8.54 (d, J=2.27 Hz, 1 H) 8.57 (br. s., 1 H) 8.61 (s, 1 H) 9.07 (s, 1 H) 9.28 (br. s., 1 H). LCMS (ES+) m/e 629 [M+H] ⁺ . Example 38

3-((7-(2,4-dimethoxypyrimidin-5-yl)-^

isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-isopropylquinoline-3-sulfonamide. A mixture of 7-bromo-4- hydroxyquinoline-3-sulfonyl chloride (800 mg, 2.63 mmol) and thionyl chloride (8 ml.) was stirred under reflux for 3 h, then thionyl chloride was removed in vacuo. Isopropylamine (171 mg, 2.89 mmol) and triethylamine (0.8 ml_, 5.26 mmol) in dry dichloromethane (20 ml.) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 5 h. LCMS showed that the reaction was complete. The organic solvent was removed in vacuo and the residual solid recrystallized to give the title compound (680 mg, 71 %) as a pale yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 1.12 (d, J=6.6 Hz, 6 H), 3.53-3.64 (m, 1 H), 4.92 (d, J=7.5 Hz, 1 H), 7.85 (d, J=9.0 Hz, 1 H), 8.27 (d, J=9.0 Hz, 1 H), 8.40 (s, 1 H), 9.42 (s, 1 H). LCMS (ES+) m/e 365 [M+H] ⁺ .

b) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N-isopropylquinolin e-3-sulfonamide. To a solution of 7-bromo-4-chloro-N-isopropylquinoline-3-sulfonamide (640 mg, 1.76 mmol) and 2,4-dimethoxypyrimidin-5-ylboronic acid (486 mg, 2.64 mmol) in water (2ml_) and 1 ,4-dioxane (20 ml.) was added [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (129 mg, 0.176 mmol) and potassium carbonate (291 mg, 2.1 1 mmol). The reaction mixture was stirred at 80 °C for 3.5 h under nitrogen atmosphere. TLC and LCMS showed the starting material was consumed completely. After cooling to room temperature, water (10 mL) and ethyl acetate (20 mL) were added. The aqueous phase was extracted with ethyl acetate (20mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified by silica gel chromatography (17% ethyl acetate/petroleum ether) to give the title compound (330mg, 44%) as a solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 1.13 (d, J=6.6 Hz, 6H), 3.53-3.64 (m, 1 H), 4.095 (s, 3H), 4.100 (s, 3H), 4.96 (d, J=7.5 Hz, 1 H), 7.95 (dd, J=1 .5, 8.7 Hz, 1 H), 8.37 (d, J=1 .5 Hz, 1 H), 8.44 (d, J=8.7 Hz, 1 H), 8.47 (s, 1 H), 9.45 (s, 1 H). LCMS (ES+) m/e 423 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopropylsulfamoyl)q uinolin-4- ylamino)-5-isopropoxybenzoate. To a solution of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)-N-isopropylquinoline-3-sulfonamide (320 mg, 0.758 mmol) in ethanol (10 mL) was added methyl 3-amino-5-isopropoxybenzoate (191 mg, 0.91 mmol). The reaction mixture was stirred at 80 °C overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (17% ethyl acetate/petroleum ether) to give the title compound (208 mg, 46%). LCMS (ES+) m/e 596 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isopropylsulfamoyl)q uinolin-4-ylamino)-5- isopropoxybenzoic acid. To a solution of methyl 3-(7-(2,4-dimethoxypyrimidin-5- yl)-3-(N-isopropylsulfamoyl)quinolin-4-ylamino)-5-isopropoxy benzoate (190 mg, 0.32 mmol) in methanol (5 mL) was added lithium hydroxide monohydrate (67 mg, 1.60 mmol). The reaction mixture was stirred at room temperature overnight. TLC and LCMS showed that the reaction was complete. The solvent was removed in vacuo. The residue was purified by prep-HPLC to give the title compound (120 mg, 65%) as a yellow solid. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1 .04 (d, J=6.6 Hz, 6 H), 1 .27 (d, J=6.0 Hz, 6 H), 3.41 -3.51 (m, 1 H), 4.06 (s, 3 H), 4.08 (s, 3 H), 4.50- 4.59 (m, 1 H), 6.74 (s, 1 H), 7.21 (s,1 H), 7.30 (s,1 H), 7.60 (dd, J=1 .8, 9.0 Hz, 1 H), 7.78 (d, J=9.0 Hz, 1 H), 8.20 (d, J=1.8 Hz, 1 H), 8.46 (s, 1 H), 9.09 (s, 1 H). LCMS (ES+) m/e 582 [M+H] ⁺ .

Example 39

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isobutylsulfamoyl)q uinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-isobutylquinoline-3-sulfonamide. A solution of 7-bromo-4- chloro-3-quinolinesulfonyl chloride (0.85 g, 2.63 mmol) in dichloromethane (20 mL) was added dropwise to a solution of 2-methylpropan-1-amine (21 1 .5 mg, 2.893 mmol) and triethylamine (531 mg, 5.26 mmol) in dichloromethane (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h, then diluted with water and extracted with dichloromethane (50ml_ x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title compound (980 mg, 99%) as a yellow solid. LCMS (ES+) m/e 377 [M+H] ⁺ .

b) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N-isobutylquinoline -3-sulfonamide. A mixture of 7-bromo-4-chloro-N-isobutylquinoline-3-sulfonamide (500 mg, 1.324 mmol), 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (292 mg, 1.589 mmol), potassium carbonate (365 mg, 2.648 mmol) and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (108 mg, 0.132 mmol) in 1 ,4-dioxane (15 mL) and water (5 mL) was stirred at 70 °C under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (150 mL). The solution was washed with water and brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (20% ethyl acetate/ dichloromethane) to give the title compound (302 mg, 52%) as a white solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 0.90 (d, J=6.6 Hz, 6 H), 1.67-1 .85 (m, 1 H), 2.82 (t, J=6.3 Hz, 2 H), 4.09 (s, 3 H), 4.10 (s, 3 H), 5.18 (t, J=6.3 Hz, 1 H), 7.95 (dd, J=8.7 Hz, 1.5 Hz, 1 H), 8.37 (d, J=1.5 Hz, 1 H), 8.44 (d, J=8.7 Hz, 1 H), 8.47 (s, 1 H), 9.42(s, 1 H). LCMS (ES+) m/e 437 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isobutylsulfamoyl)qu inolin-4- ylamino)-5-isopropoxybenzoate. A solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)-N-isobutylquinoline-3-sulfonamide (200 mg, 0.458 mmol) and methyl 3- amino-5-isopropoxybenzoate (1 15 mg, 0.549 mmol) in ethanol (30 mL) was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (33% ethyl acetate/ dichloromethane) to give the title compound (108 mg, 39%) as a white solid. LCMS (ES+) m/e 610 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-isobutylsulfamoyl)qu inolin-4-ylamino)-5- isopropoxybenzoic acid. A solution of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3- (N-isobutylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoat e (100 mg, 0.164 mmol) and 1 N aqueous lithium hydroxide solution (0.82 mL) in methanol (15 mL) was stirred at room temperature for 16 h and at reflux for 8 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was acidified with 1 N aqueous hydrochloric acid. The solid formed was filtered and purified by Prep-TLC to give the title compound (62 mg, 65%) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.74 (d, J=6.6 Hz, 6 H), 1.20 (d, J=5.7 Hz, 6 H), 1.53-1 .64 (m, 1 H), 2.59-2.67 (m, 2 H), 3.967 (s, 3 H), 3.974 (s, 3 H), 4.48-4.56 (m, 1 H), 6.66 (s, 1 H), 7.06 (s, 1 H), 7.1 1 (s, 1 H), 7.62-7.72 (m, 2 H), 8.21 (s, 1

H), 8.25 (s, br, 1 H), 8.46 (s, br, 1 H), 8.57 (s, 1 H), 9.05 (s, 1 H). LCMS (ES+) m/e 596 [M+H] ⁺ .

Example 40

-((3-(N-cvclobutylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-cvclobutylquinoline-3-sulfonamide. A solution of 7-bromo-4- chloroquinoline-3-sulfonyl chloride (0.85 g, 2.63 mmol) in dichloromethane (20 ml.) was added to a solution of cyclobutanamine (206 mg, 2.89 mmol) and

triethylamine (532 mg, 5.27 mmol) in dichloromethane (30 ml.) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. Dichloromethane (50 ml.) was added to the solution. The mixture was washed with water and brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the title compound (950 mg, 96%) as a yellow solid. LCMS (ES+) m/e 375 [M+H] ⁺ .

b) 4-chloro-N-cvclobutyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli ne-3-sulfonamide. A mixture of 7-bromo-4-chloro-N-cyclobutylquinoline-3-sulfonamide (500 mg, 1.33 mmol), 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (293 mg, 1 .596 mmol), potassium carbonate (367 mg, 2.66 mmol) and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (109 mg, 0.133 mmol) in

1 ,4-dioxane (15 ml.) and water (5 ml.) was stirred at 70 °C under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (150 ml_). This solution was washed with water and brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (20% ethyl acetate/ dichloromethane) to give the title compound (281 mg, 49%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.56-1.67 (m, 2 H), 1 .77-1 .90 (m, 2 H), 2.03-2.12 (m, 2 H), 3.82- 3.96 (m, 1 H), 4.09 (s, 3 H), 4.10 (s, 3 H), 5.35 (d, J=9.0 Hz, 1 H), 7.95 (dd, J=9.0 Hz, 1 .5 Hz, 1 H), 8.36 (d, J=1 .5 Hz, 1 H), 8.44 (d, J=9.0 Hz, 1 H), 8.47 (s, 1 H), 9.41 (s, 1 H). LCMS (ES+) m/e 435 [M+H] ⁺ .

c) methyl 3-(3-(N-cvclobutylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4- ylamino)-5-isopropoxybenzoate. 4-chloro-N-cyclobutyl-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-sulfonamide (200 mg, 0.46 mmol) and methyl 3-amino-5- isopropoxybenzoate (1 16 mg, 0.552 mmol) in ethanol (30 mL) was refluxed for 16 h with stirring. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (33% ethyl acetate/ dichloromethane) to give the title compound (97 mg, 35%) as a yellow solid. LCMS (ES+) m/e 608 [M+H] ⁺ .

d) 3-(3-(N-cvclobutylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4-ylamino)-5- isopropoxybenzoic acid trifluoroacetate. A solution of methyl 3-(3-(N- cyclobutylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinolin -4-ylamino)-5- isopropoxybenzoate (92 mg, 0.151 mmol) and 1 N aqueous lithium hydroxide solution (0.76 mL) in methanol (10mL) was stirred at room temperature for 16 h and at reflux for 8 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was acidified with 1 N aqueous hydrochloric acid. The solid formed was filtered, then purified by Prep-HPLC to give the title compound (57 mg) as a white solid. LCMS (ES+) m/e 594 [M+H] ⁺ .

Example 41

4-((3-bromophenyl)amino)-N-cvclopropyl-7-(2,4-dimethoxypyrim idin-5-yl)quinoline-3- sulfonamide

A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (131 mg, 0.31 1 mmol) and 3-bromoaniline (96 mg, 0.558 mmol) in acetic acid (1 .0 mL) in a 5 mL sealed vial was heated in a microwave synthesizer, absorbtion setting = normal at 100 °C for 15 min. The crude product was directly purified by HPLC (ODS silica, 75 x 30 mm, 5 micron, gradient elution, 10 - 90% acetonitrile/water + 0.1 % trifluoroacetic acid) over 10 mins.) to afford 4-((3-bromophenyl)amino)-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide, trifluoroacetic acid salt (124 mg, 0.185 mmol, 59.4 % yield) as a yellow solid. (400MHz ,DMSO-d ₆ ) δ = 9.1 1 (s, 1 H), 8.66 (br. s., 1 H), 8.60 (s, 1 H), 8.54 (br. s., 1 H), 8.28 (d, J = 1.5 Hz, 1 H), 7.72 (dd, J = 1.8, 9.1 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.41 (s, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 7.26 (d, J = 8.1 Hz, 1 H), 6.99 (d, J = 8.6 Hz, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 2.31 - 2.24 (m, 1 H), 0.48 - 0.40 (m, 4 H).

Example 42

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amino)-5-

((3,5-difluorophenyl)amino)benzoic acid

a) ethyl 3-((3,5-difluorophenyl)amino)-5-nitrobenzoate. To a suspension of ethyl 3- bromo-5-nitrobenzoate (500 mg, 1 .824 mmol), 3,5-difluoroaniline (236 mg, 1.824 mmol), cesium carbonate (892 mg, 2.74 mmol) and dicyclohexyl(2',4',6'- triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 20 minutes. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford _ethyl 3-((3,5-difluorophenyl)amino)-5- nitrobenzoate (500 mg, 1.552 mmol, 85 % yield) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-^) δ ppm 1.43 (t, J=7.07 Hz, 3 H) 4.44 (q, J=7.07 Hz, 2 H) 6.51 - 6.59 (m, 1 H) 6.74 (d, J=2.02 Hz, 1 H) 6.76 (d, J=2.27 Hz, 1 H) 8.07 (dd,

J=2.27, 1 .26 Hz, 1 H) 8.13 (t, J=2.27 Hz, 1 H) 8.26 - 8.32 (m, 1 H). LCMS (ES+) m/e 323 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3,5-difluorophenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (34.5 mg, 0.0324 mmol) in acetic acid (10 mL) was added ethyl 3-((3,5-difluorophenyl)amino)-5-nitrobenzoate (100 mg, 0.310 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (123 mg, 0.292 mmol) was added to the filtrate. The organic solvent was removed under reduced pressure. The residue was dissolved in methanol (10.00 mL), to which sodium hydroxide (6.0N) (0.270 mL, 1.622 mmol) was added. The reaction was kept stirring overnight, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3,5-difluorophenyl)amino)benzoic acid, trifluoroacetic acid salt (88 mg, 0.1 15 mmol, 35.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.37 - 0.44 (m, 2 H) 0.44 - 0.50 (m, 2 H) 2.23 - 2.31 (m, 1 H) 3.98 (s, 6 H) 6.43 - 6.57 (m, 3 H) 6.94 (s, 1 H) 7.25 (s, 1 H) 7.38 (s, 1 H) 7.74 - 7.87 (m, 2 H) 8.29 (d, J=1.26 Hz, 1 H) 8.52 (br. s., 1 H) 8.60 (s, 1 H) 8.65 (br. s., 1 H) 8.86 (s, 1 H) 9.10 (s, 1 H) 13.08 (br. s., 1 H). LCMS (ES+) m/e 649 [M+H] ⁺ .

Example 43

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-sulfamoy lphenyl)amino)quinoline-3- sulfonamide

A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (56 mg, 0.133 mmol) and 3-aminobenzenesulfonamide (40 mg, 0.232 mmol) in acetic acid (0.5 mL) in a 5 mL sealed vial was heated in a microwave synthesizer, absorbtion setting = normal at 100 °C for 15 min. The crude product was directly purified by HPLC (ODS silica, 75 x 30 mm, 5 micron, gradient elution, 10 - 90% acetonitrile/water (0.1 % trifluoroacetic acid) over 10 mins.) to afford N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)-4-((3-sulfamoylphenyl)amino)quinoli ne-3-sulfonamide, trifluoroacetic acid salt (30.0 mg, 0.042 mmol, 31.6 % yield) as a yellow solid. ¹ H NMR (400MHz ,DMSO-d ₆ ) δ = ¹ H NMR = 9.13 (s, 1 H), 8.68 (br. s., 1 H), 8.60 (s, 1 H), 8.55 (br. s., 1 H), 8.29 (d, J = 1.0 Hz, 1 H), 7.69 (dd, J = 1 .3, 8.8 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.57 (d, J = 1 .5 Hz, 1 H), 7.54 (dd, J = 1.3, 8.1 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.40 (s, 2 H), 7.17 - 7.1 1 (m, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 2.30 - 2.20 (m, 1 H), 0.47 - 0.40 (m, 4 H). C ₂ 4H ₂₄ N ₆ 0 ₆ S ₂ .1 .75 CF ₃ C0 ₂ H requires: %C, 43.68; %H, 3.43; %N, 1 1.1 1 . Found: %C, 43.69; %H, 3.46; %N, 1 1 .42.

Example 44

3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxy

difluorophenoxy)benzoic acid

a) methyl 3-(3,5-difluorophenoxy)-5-nitrobenzoate. Anhydrous copper (II) acetate

(0.230 g, 1.27 mmol) was added to a stirred mixture of 3,5-difluorophenylboronic acid (0.601 g, 3.80 mmol), methyl 3-hydroxy-5-nitrobenzoate (0.250 g, 1.27 mmol), triethylamine (1.24 ml_, 8.88 mmol), dichloromethane (15 ml.) and 4A molecular sieves (3 g). The mixture was stirred vigorously at room temperature under oxygen for 60 h, then filtered through a plug of Hyflo . The solvent was removed under reduced pressure and the residue chromatographed twice (silica gel, 5-50% ethyl acetate/hexane) to give the title compound (0.1 15 g, 29%) as an oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3 H) 6.54 - 6.65 (m, 2 H) 6.72 (tt, J=8.84, 2.27 Hz, 1 H) 8.03 (dd, J=2.40, 1.39 Hz, 1 H) 8.08 (t, J=2.27 Hz, 1 H) 8.68 (dd, J=2.02, 1.52 Hz, 1 H).

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(3,5-difluorophenoxy)benzoic acid. A solution of methyl 3-(3,5- difluorophenoxy)-5-nitrobenzoate (0.1 13 g, 0.365 mmol) in methanol (6 ml.) was stirred with 5% wet palladium on carbon (0.130 g, 0.031 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the crude aniline (0.095 g). A mixture of 4-chloro-N-cyclopropyl- 7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (0.1 14 g, 0.271 mmol) and the crude aniline in acetic acid (1.5 ml.) was stirred at 75 °C for 1 h, then cooled. The solvent was removed under reduced pressure. The residue was azeotroped three times with toluene, then chromatographed (silica gel, 0.5-8%

methanol/dichloromethane) to give the intermediate ester (0.126 g). 1 M aqueous sodium hydroxide (2.00 mL, 2.00 mmol) was added dropwise to a stirred suspension of the ester in methanol (10 mL) at room temperature and the mixture stirred for 18 h. Water (20 mL) was added and the pH adjusted to 5 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.094 g, 53%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.28 - 0.46 (m, 4 H) 2.15 - 2.28 (m, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.68 - 6.78 (m, 2 H) 6.80 (t, J=2.15 Hz, 1 H) 6.95 (tt, J=9.35, 2.27 Hz, 1 H) 7.20 (dd, J=2.15, 1 .39 Hz, 1 H) 7.41 - 7.46 (m, 1 H) 7.74 (dd, J=9.09, 1.77 Hz, 1 H) 7.80 (d, J=8.84 Hz, 1 H) 8.25 (d, J=1 .52 Hz, 1 H) 8.45 (d, J=2.02 Hz, 1 H) 8.55 (s, 1 H) 8.59 (s, 1 H) 9.09 (s, 1 H) 13.28 (br. s., 1 H).

Example 45

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)-5-((3-

(trifluoromethyl)phenyl)amino)benzoic acid

a) ethyl 3-nitro-5-((3-(trifluoromethyl)phenyl)amino)benzoate. To a suspension of ethyl 3-bromo-5-nitrobenzoate (500 mg, 1 .824 mmol), 3-(trifluoromethyl)aniline (294 mg, 1.824 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2- yl)phosphine (87 mg, 0.182 mmol) and cesium carbonate (892 mg, 2.74 mmol) in ferf-butanol (2 mL) and toluene (10 mL) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 1 hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash

chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3- nitro-5-((3-(trifluoromethyl)phenyl)amino)benzoate (450 mg, 1.270 mmol, 69.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (t, J=7.07 Hz, 3 H) 4.37 (q, J=7.07 Hz, 2 H) 7.35 (d, J=7.58 Hz, 1 H) 7.44 (s, 1 H) 7.50 (d, J=8.08 Hz, 1 H) 7.56 - 7.63 (m, 1 H) 7.97 - 7.99 (m, 1 H) 8.04 (t, J=2.27 Hz, 1 H) 8.05 - 8.07 (m, 1 H) 9.33 (s, 1 H). LCMS (ES+) m/e 355 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxy^

yl)amino)-5-((3-(trifluoromethyl)phenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (30.0 mg, 0.0282 mmol) in acetic acid (10 ml.) was added ethyl 3-nitro-5-((3-(trifluoromethyl)phenyl)amino)benzoate (100 mg, 0.282 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (107 mg, 0.254 mmol) was added to the filtrate. The reaction was kept stirring overnight and the organic solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (10.00 ml_), to which sodium hydroxide (6.0N) (0.047 ml_, 0.282 mmol) was added. The mixture was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3-

(trifluoromethyl)phenyl)amino)benzoic acid, trifluoroacetic acid salt (79 mg, 0.099 mmol, 35.2 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.35 - 0.43 (m, 2 H) 0.43 - 0.52 (m, 2 H) 2.23 - 2.32 (m, 1 H) 3.98 (s, 6H) 6.89 (s, 1 H) 7.1 1 (d, J=7.58 Hz, 1 H) 7.14 - 7.18 (m, 2 H) 7.20 - 7.29 (m, 2 H) 7.41 (s, 1 H) 7.74 - 7.86 (m, 2 H) 8.29 (d, J=1 .26 Hz, 1 H) 8.53 (br. s., 1 H) 8.61 (s, 1 H) 8.66 (br. s., 1 H) 8.79 (s, 1 H) 9.10 (s, 1 H) 13.12 (br. s., 1 H). LCMS (ES+) m/e 681 [M+H] ⁺ .

Example 46

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)-5-(3,4- difluorophenoxy)benzoic acid a) ethyl 3-(3,4-difluorophenoxy)-5-nitrobenzoate. A mixture of ethyl 3,5- dinitrobenzoate (0.480 g, 2.00 mmol), 3,4-difluorophenol (0.520 g, 4.00 mmol), powdered potassium carbonate (0.552 g, 4.00 mmol) and N-methyl-2-pyrrolidone (4 ml.) was stirred at 80 °C for 4 h, then cooled. The residue was

chromatographed (silica gel, 5-30% ethyl acetate/hexane) to give the title compound (0.134 g, 21 %) as an oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (t, J=7.07 Hz, 3 H) 4.46 (q, J=7.07 Hz, 2 H) 6.80 - 6.88 (m, 1 H) 6.96 (ddd, J=10.61 , 6.57, 2.78 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.95 - 8.00 (m, 2 H) 8.62 (dd, J=2.02, 1.52 Hz, 1 H).

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(3,4-difluorophenoxy)benzoic acid. A solution of ethyl 3-(3,4- difluorophenoxy)-5-nitrobenzoate (0.132 g, 0.408 mmol) in methanol (8 mL) was stirred with 5% wet palladium on carbon (0.126 g, 0.030 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the crude aniline (0.1 14 g). A mixture of 4-chloro-N-cyclopropyl- 7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (0.069 g, 0.164 mmol) and some of the crude aniline (0.060 g, 0.205 mmol) in acetic acid (1 mL) was stirred at 70 °C for 3 h, then cooled. The solvent was removed under reduced pressure. The residue was azeotroped three times with toluene, then chromatographed (silica gel, 0.5-8% methanol/dichloromethane) to give the intermediate ester (0.099 g). 1 M aqueous sodium hydroxide (2.00 mL, 2.00 mmol) was added dropwise to a stirred suspension of the ester in methanol (10 mL) at room temperature and the mixture stirred for 18 h. Water (20 mL) was added and the pH adjusted to 5 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.063 g, 59%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.29 - 0.38 (m, 2 H) 0.38 - 0.46 (m, 2 H) 2.16 - 2.26 (m, 1 H) 3.99 (s, 3 H) 3.99 (s, 3 H) 6.71 (t, J=2.15 Hz, 1 H) 6.81 - 6.91 (m, 1 H) 7.13 (dd, J=2.27, 1 .26 Hz, 1 H) 7.21 (ddd, J=1 1 .62, 6.82, 3.03 Hz, 1 H) 7.29 - 7.42 (m, 2 H) 7.71 - 7.79 (m, 2 H) 8.25 (s, 1 H) 8.45 (d, J=1.77 Hz, 1 H) 8.51 (s, 1 H) 8.60 (s, 1 H) 9.08 (s, 1 H) 13.24 (br. s., 1 H). Example 47

-((3-(N-(tert-butyl)sulfamoyl)-7-(2,4-dim

isopropoxybenzoic acid

a) 7-bromo-N-tert-butyl-4-chloroquinoline-3-sulfonamide. To a solution of 7-bromo-4- chloro-3-quinolinesulfonyl chloride (0.897 g, 2.63 mmol) and triethylamine (430 mg, 5.26 mmol) in dry dichloromethane (20 ml) was added 2-methylpropan-2- amine (230 mg, 3.15 mmol) dropwise at 0 °C. The solution was stirred for 30 min at 0°C. TLC showed the starting material was consumed completely.

Dichloromethane (100 ml.) was added and the mixture washed with water, then concentrated. The residue was purified by silica gel chromatography (14-20% ethyl acetate/petroleum ether) to afford the title compound (350 mg, 36%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.14 (s, 9 H), 8.05 (dd, J=2.1 , 9.0 Hz, 1 H), 8.25 (s, 1 H), 8.37 (d, J=9.0 Hz, 1 H), 8.44 (d, J=2A Hz, 1 H), 9.31 (s, 1 H). LCMS (ES+) m/e 377 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N-tert-butylsulfamoyl)quinolin-4-ylamino)-5- isopropoxybenzoate. A mixture of 7-bromo-N-tert-butyl-4-chloroquinoline-3- sulfonamide (342 mg, 0.78 mmol) and methyl 3-amino-5-isopropoxybenzoate (197 mg, 0.94 mmol) in ethanol (15 ml.) was refluxed for 6 h. LCMS showed complete conversion. The solvent was removed in vacuo and the residue purified by chromatography on silica gel (25% ethyl acetate/petroleum ether) to afford the title compound (390 mg, 90%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .13 (s, 9 H), 1.18 (s, 3 H), 1.20 (s, 3H), 3.81 (s, 3 H), 4.52-4.60 (m, 1 H), 6.85-6.88 (m, 1 H), 7.19-7.24 (m, 2 H), 7.53-7.64 (m, 2 H), 8.21-8.22 (m, 1 H), 8.29 (s, 1 H), 8.69 (s, br, 1 H), 9.16 (s, 1 H). LCMS (ES+) m/e 550 [M+H] ⁺ .

c) methyl 3-(3-(N-tert-butylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4- ylamino)-5-isopropoxybenzoate. A mixture of methyl 3-(7-bromo-3-(N-tert- butylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (390 mg, 0.71 mmol),

2,4-dimethoxypyrimidin-5-ylboronic acid (157 mg, 0.85 mmol),

tetrakis(triphenylphosphine)palladium(0) (82 mg, 0.071 mmol) and potassium carbonate (235 mg, 1.7 mmol) in 1 ,4-dioxane (6 ml.) and water (2 ml.) was stirred at 80 °C under nitrogen for 2 h. TLC showed complete conversion. The mixture was cooled to room temperature, then ethyl acetate (50 ml.) and water (50 ml.) added. The extracted organic layer was washed with brine (50 ml. x 2), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (33% ethyl acetate/petroleum ether) to afford the title compound (293 mg, 68%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .1 1 (s, 9 H), 1.18 (s, 3 H), 1.20 (s, 3 H), 3.79 (s, 3 H), 3.97 (s, 6 H), 4.49-4.57 (m, 1 H), 6.69 (s, 1 H), 7.12 (s, 2 H), 7.63-7.70 (m, 2 H), 8.05 (s, 1 H), 8.22 (s, 2 H), 8.57 (s, 1 H), 9.13 (s, 1 H). LCMS (ES+) m/e 610 [M+H] ⁺ .

d) 3-(3-(N-tert-butylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl) quinolin-4-ylamino)-5- isopropoxybenzoic acid. A mixture of methyl 3-(3-(N-tert-butylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-ylamino)-5-isopropoxybenz oate (150 mg, 0.245 mmol) in methanol (5 ml.) and 1 N aqueous lithium hydroxide (1.2 ml. ) was stirred at room temperature for 8 h. LCMS showed complete conversion. The mixture was washed with ethyl acetate (5 ml.) and the aqueous layer acidified with 1 N aqueous hydrochloric acid, then extracted with ethyl acetate (50 ml_). The extracts were washed with brine (50 ml. x 2), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the title compound (1 10 mg, 75%). ¹ H NMR (300 MHz, DMSO-d ₆ ) 5 ppm 1 .1 1 (s, 9 H), 1.19 (s, 3 H), 1 .21 (s, 3 H), 3.96 (s, 3 H),

3.97 (s, 3 H), 4.50-4.58 (m, 1 H), 6.70 (t, J=1.8 Hz, 1 H), 7.07 (s, 1 H), 7.12 (s, 1 H), 7.66-7.70 (m, 2 H), 8.06 (s, 1 H), 8.21 (d, J=4.5 Hz, 2 H), 8.57 (s, 1 H), 9.12 (s, 1 H), 13.00 (s, br, 1 H). LCMS (ES+) m/e 596 [M+H] ⁺ .

Example 48

-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2-methoxyethyl)s ulfamoyl)quinolin-4-yl)amino)-

5-isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(2-methoxyethyl)quinoline-3-sulfonamide. To a solution of 7- bromo-4-chloro-3-quinolinesulfonyl chloride (561 mg, 1.6 mmol) and triethylamine (323 mg, 3.2 mmol) in dry dichloromethane (10 mL) was added 2- methoxyethanamine (132 mg, 1.76 mmol) dropwise at 0 °C for 10 minutes. TLC showed the starting material was consumed completely. Water (40 mL) was added and the mixture extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with brine (60 mL x 1 ), dried over anhydrous

Na ₂ S0 ₄ , and evaporated. The residue was purified by silica gel chromatography (20% ethyl acetate/petroleum ether) to afford the title compound (453mg, 75%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.87 (s, 3 H), 3.15 (q, J=5.4 Hz, 2 H), 3.25 (t, J=5.4 Hz, 2 H), 8.04 (dd, J=1.8, 9.0 Hz, 1 H), 8.36 (d, J=9.0 Hz, 1 H), 8.42-8.46 (m, 2 H), 9.24 (s, 1 H). LCMS (ES+) m/e 379 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N-(2-methoxyethyl)sulfamoyl)quinolin-4-ylamino )-5- isopropoxybenzoate. A mixture of 7-bromo-4-chloro-N-(2-methoxyethyl)quinoline- 3-sulfonamide (400 mg, 1.05 mmol) and methyl 3-amino-5-isopropoxybenzoate (243 mg, 1.15 mmol) in ethanol (50 mL) was stirred at 80 °C for 4 h. The solvent was removed in vacuo to give the title compound (560 mg, 96%). LCMS (ES+) m/e 552 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-vn-3-(N-(2- methoxyethyl)sulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzo ate. A mixture of methyl 3-(7-bromo-3-(N-(2-methoxyethyl)sulfamoyl)quinolin-4-ylamino )-5- isopropoxybenzoate (560 mg, 1 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid

(745 mg, 4 mmol), [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (73 mg, 0.1 mmol) and potassium acetate (196 mg, 2 mmol) in 1 ,4-dioxane (20 mL) and water (3 mL) was stirred at 80 °C under nitrogen for 18 h. After cooling to room temperature, water (15 mL) was added, and the mixture extracted with ethyl acetate (50 mL x 3). The combined organic layers were concentrated and purified by chromatography on silica gel (6% methanol/dichloromethane) to afford the title compound (410 mg, 67%) as a yellow solid. LCMS (ES+) m/e 612 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2-methoxyethyl)sulf amoyl)quinolin-4- ylamino)-5-isopropoxybenzoic acid. A mixture of methyl 3-(7-(2,4- dimethoxypyrimidin-5-yl)-3-(N-(2-methoxyethyl)sulfamoyl)quin olin-4-ylamino)-5- isopropoxybenzoate (100 mg, 0.16 mmol) in methanol (5 mL) and 1 N aqueous lithium hydroxide (1.6 mL ) was stirred at room temperature for 16 h. The mixture was concentrated and the residue diluted with water (5 mL) and acidified with 1 N aqueous hydrochloric acid to pH 5. The suspension was filtered to afford the title compound (40 mg, 42%) as a white solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm

1.20 (d, J=5.7 Hz, 6 H), 3.06 (s, 5 H), 3.24-3.28 (m, 2 H), 3.97 (s, 6 H), 4.49-4.57 (m, 1 H), 6.67 (s, 1 H), 7.09 (s, 1 H), 7.1 1 (s, 1 H), 7.6-7.68 (m, 2 H), 8.22 (s, 1 H), 8.27 (s, 1 H), 8.34 (s, 1 H), 8.57 (s, 1 H), 9.06 (s, 1 H), 13.09 (s, 1 H). LCMS (ES+) m/e 598 [M+H] ⁺ .

Example 49

3-(3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)phenoxy)benzamide

a) 3-(3-nitrophenoxy)benzamide. A mixture of anhydrous copper (II) acetate (0.457 g, 2.52 mmol), 3-carbamoylphenylboronic acid (1.25 g, 7.55 mmol), 3-nitrophenol (0.350 g, 2.52 mmol), triethylamine (2.46 mL, 17.6 mmol), 4A molecular sieves (6 g) and dichloromethane (30 mL) was stirred vigorously at room temperature for 24 h. 1 M aqueous hydrochloric acid (50 mL) was added and the mixture extracted with ethyl acetate. The extracts were washed with 0.5 M aqueous potassium carbonate, water, brine, dried (MgSC^) and evaporated under reduced pressure.

The residue was chromatographed (silica gel, 50-100% ethyl acetate/hexane) to give the title compound (0.271 g, 86% pure, 36%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.33 (ddd, J=8.21 , 2.53, 0.88 Hz, 1 H) 7.42 - 7.58 (m, 3 H) 7.59 - 7.61 (m, 1 H) 7.71 (t, J=8.21 Hz, 1 H) 7.74 - 7.77 (m, 1 H) 7.77 - 7.79 (m, 1 H) 8.03 (ddd, J=8.21 , 2.27, 0.88 Hz, 1 H) 8.05 (br. s., 1 H).

b) 3-(3-aminophenoxy)benzamide. A solution of 3-(3-nitrophenoxy)benzamide

(0.270 g, 1.05 mmol) in methanol (10 mL) was stirred with 5% wet palladium on carbon (0.290 g, 0.068 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound (0.225 g, 89% pure, 84%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 5.25 (s, 2 H) 6.10 - 6.16 (m, 1 H) 6.17 - 6.20 (m, 1 H) 6.35 (ddd, J=8.08, 2.02, 0.76 Hz, 1 H) 7.01 (t, J=7.96 Hz, 1 H) 7.14 (ddd, J=8.15, 2.46, 1.01 Hz, 1 H) 7.39 - 7.49 (m, 3 H) 7.58 - 7.65 (m, 1 H) 8.00 (br. s., 1 H). c) 3-(3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)phenoxy)benzamide. A mixture of 4-chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (0.095 g, 0.226 mmol) and 3-(3- aminophenoxy)benzamide (0.067 g, 0.294 mmol) in acetic acid (1 ml.) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure. The residue was azeotroped three times with toluene, then chromatographed (silica gel, 1 -10% methanol/dichloromethane) to give the title compound (0.103 g, 75%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.30 - 0.45 (m, 4 H) 2.14 - 2.25 (m, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.63 (t, J=2.02 Hz, 1 H) 6.74 (dd, J=8.08, 1.52 Hz, 1 H) 6.80 (dd, J=7.96, 1.39 Hz, 1 H) 7.07 - 7.15 (m, 1 H) 7.32 (t, =Q.2^ Hz, 1 H) 7.37 (t, J=7.96 Hz, 1 H) 7.42 (s, 1 H) 7.45 - 7.50 (m, 1 H) 7.61 (d, J=7.83 Hz, 1 H) 7.66 - 7.77 (m, 2 H) 7.98 (s, 1 H) 8.20 (s, 1 H) 8.44 (br. s., 2 H) 8.58 (s, 1 H) 9.02 (s, 1 H).

Example 50

-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahvdro-2H-py ran-4-yl)sulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(tetrahvdro-2H-pyran-4-yl)quinoline-3-sul fonamide. A solution of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (550 mg, 1 .62 mmol) and triethylamine (327 mg, 3.24 mmol) in dry dichloromethane (20 ml.) was cooled in ice-water. A solution of tetrahydro-2H-pyran-4-amine (179.8 mg, 1 .78 mmol) in dry dichloromethane (3 ml.) was added dropwise. The reaction mixture was stirred at that temperature for 1 h. TLC showed that the reaction was complete. The mixture was poured into water and extracted with ethyl acetate (20 ml. x 3). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ and

concentrated in vacuo. The residue was purified by chromatography on silica gel (2% methanol/dichloromethane) to afford the title compound (425 mg, 65%) as a yellow solid. LCMS (ES+) m/e 405 [M+H] ⁺ . b) methyl 3-(7-bromo-3-(N-(tetrahvdro-2H-pyran-4-yl)sulfamoyl)quinolin -4-ylamino)-5- isopropoxybenzoate. To a solution of 7-bromo-4-chloro-N-(tetrahydro-2H-pyran-4- yl)quinoline-3-sulfonamide (200 mg, 0.495 mmol) in ethanol (20 ml.) was added methyl 3-amino-5-isopropoxybenzoate (1 16 mg, 0.594 mmol). The reaction mixture was heated under reflux for 2 h. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (2% methanol/dichloromethane) to afford the title compound (162 mg, 57%) as a yellow solid. LCMS (ES+) m/e 578 [M+H] ⁺ .

c) methyl 3-(7-bromo-3-(N-(tetrahvdro-2H-pyran-4-yl)sulfamoyl)quinolin -4-ylamino)-5- isopropoxybenzoate. A mixture of methyl 3-(7-bromo-3-(N-(tetrahydro-2H-pyran- 4-yl)sulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (120 mg, 0.312 mmol),

2.4- dimethoxypyrimidin-5-ylboronic acid (76 mg, 0.416 mmol), potassium carbonate (43 mg, 0.312 mmol) and tetrakis(triphenylphosphine)palladium(0) (1 1 mg, 0.0104 mmol) in 1 ,4-dioxane (4 ml.) and water (1 ml.) was heated at 80 °C under nitrogen atmosphere for 3 h. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo and purified by chromatography on silica gel (25% ethyl acetate/petroleum ether) to afford the title compound (130 mg, 98%) as a yellow solid. LCMS (ES+) m/e 638 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahydro-2H-pyran -4- yl)sulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoic acid. To a solution of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahydro-2H-pyran -4- yl)sulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (120 mg, 0.188 mmol) in methanol (15 mL) was added 1 N aqueous lithium hydroxide (2mL). The reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo. Water was added and the mixture washed with ethyl acetate (10 mL x 2). The aqueous phase was collected and acidified with 1 N aqueous acetic acid to pH 4, then extracted with ethyl acetate. The extracts were dried and concentrated to give the title compound (100 mg, 94%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) 5 ppm 1.20 (d, J=6.3 Hz, 6 H), 1 .24-1.38 (m, 2 H), 1.48-1 .54 (m, 2 H),

3.05- 3.12 (m, 2 H), 3.24-3.30 (m, 1 H), 3.56-3.67 (m, 2 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.55 (hept, J=6.3 Hz, 1 H), 6.72 (s, 1 H), 7.06 (s, 1 H), 7.1 1 (s, 1 H), 7.66-7.73 (m, 2 H), 8.23 (s, 1 H), 8.30 (d, J=7.5 Hz, 1 H), 8.34 (s, 1 H), 8.58 (s, 1 H), 9.1 1 (s, 1 H), 13.01 (s, br, 1 H). LCMS (ES+) m/e 624 [M+H] ⁺ . Example 51

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)am

tolylamino)benzoic acid

a) ethyl 3-nitro-5-(m-tolylamino)benzoate. To a suspension of ethyl 3-bromo-5- nitrobenzoate (500 mg, 1.824 mmol), m-toluidine (195 mg, 1 .824 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 ,1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) and cesium carbonate (892 mg, 2.74 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 1 hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford_ethyl 3-nitro-5-(m-tolylamino)benzoate (160 mg, 0.533 mmol, 29.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM- cQ δ ppm 1.44 (t, J=7.07 Hz, 3 H) 2.39 (s, 3 H) 4.43 (q, J=7.07 Hz, 2 H) 6.06 (s, 1

H) 6.93 - 7.07 (m, 3 H) 7.22 - 7.35 (m, 1 H) 7.85 - 7.97 (m, 1 H) 8.00 (t, J=2.15 Hz, 1 H) 8.30 (d, J=1 .52 Hz, 1 H). LCMS (ES+) m/e 301 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(m-tolylamino)benzoic acid. To a suspension of 10% palladium on carbon (37.2 mg, 0.0349 mmol) in acetic acid (10 mL) was added ethyl 3-nitro-5-

(m-tolylamino)benzoate (100 mg, 0.333 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (132 mg, 0.314 mmol) was added to the filtrate. The organic solvent was removed under reduced pressure. The residue was dissolved in methanol

(10.00 mL), to which sodium hydroxide (6. ON) (0.291 mL, 1.747 mmol) was added. The reaction was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 %

trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(m-tolylamino )ben acid, trifluoroacetic acid salt (90 mg, 0.122 mmol, 34.8 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.33 - 0.42 (m, 2 H) 0.42 - 0.50 (m, 2 H) 2.08 (s, 3 H) 2.19 - 2.28 (m, 1 H) 3.99 (s, 6 H) 6.63 (d, J=7.83 Hz, 1 H) 6.67 - 6.72 (m, 2 H) 6.78 (s, 1 H) 6.91 - 6.99 (m, 1 H) 7.12 (s, 1 H) 7.35 (s, 1 H) 7.75 - 7.87 (m, 2 H) 8.28 (d, J=1.26 Hz, 1 H) 8.36 (br. s., 1 H) 8.48 - 8.56 (m, 2 H) 8.61 (s, 1 H) 9.07 (s, 1 H) 12.99 (br. s., 1 H). LCMS (ES+) m/e 627 [M+H] ⁺ .

Example 52

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)-5-

(methyl(3-(trifluoromethyl)phenyl)amino)benzoic acid

a) 3-(methyl(3-(trifluoromethyl)phenyl)amino)-5-nitrobenzoic acid. To a suspension of ethyl 3-nitro-5-((3-(trifluoromethyl)phenyl)amino)benzoate (250 mg, 0.706 mmol) and methyl iodide (0.049 ml_, 0.776 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil suspension, 33.9 mg, 1 .41 1 mmol). The mixture was kept stirring at room temperature under nitrogen atmosphere overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The resulting brown oil was dissolved in methanol and purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-(methyl(3-(trifluoromethyl)phenyl)amino)-5- nitrobenzoic acid (150 mg, 0.441 mmol, 62.5 % yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.44 (s, 3 H) 7.53 - 7.58 (m, 2 H) 7.60 (s, 1 H) 7.63 - 7.68 (m, 1 H) 7.75 (dd, J=2.27, 1 .26 Hz, 1 H) 7.86 (t, J=2.27 Hz, 1 H) 8.07 - 8.10 (m, 1 H) 13.65 (br. s., 1 H). LCMS (ES+) m/e 341 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(methyl(3-(trifluoromethyl)phenyl)amino)benzoic acid. To a

suspension of 10% palladium on carbon (22.53 mg, 0.0212 mmol) in acetic acid (10 mL) was added 3-(methyl(3-(trifluoromethyl)phenyl)amino)-5-nitrobenzoic (75 mg, 0.221 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (80 mg, 0.191 mmol) was added to the filtrate. The organic solvent was removed under reduced pressure. The residue was dissolved in methanol (10.00 mL), to which sodium hydroxide (6. ON) (0.176 mL, 1.058 mmol) was added. The reaction was kept stirring overnight at room temperature and was purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5- (methyl(3-(trifluoromethyl)phenyl)amino)benzoic acid, trifluoroacetic acid salt (45 mg, 0.056 mmol, 26.3 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.32 - 0.38 (m, 2 H) 0.39 - 0.45 (m, 2 H) 2.20 - 2.28 (m, 1 H) 3.27 (s, 3 H) 3.99 (s, 3 H) 3.99 (s, 3 H) 6.84 (s, 1 H) 7.17 (d, J=7.58 Hz, 1 H) 7.20 - 7.36 (m, 5 H) 7.75 (s, 2 H) 8.24 (s, 1 H) 8.49 (br. s., 1 H) 8.58 - 8.66 (m, 2 H) 9.06 (s, 1 H) 13.12 (br. s., 1 H). LCMS (ES+) m/e 695 [M+H] ⁺ .

Example 53

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-nitro-5- (pyrrolidine-1 - carbonyl)phenyl)amino)quinoline-3-sulfonamide

(3,5-dinitrophenyl)(pyrrolidin-1-yl)methanone. Pyrrolidine (0.331 mL, 4.00 mmol) was added slowly to a stirred solution of 3,5-dinitrobenzoyl chloride (0.922 g, 4.00 mmol) and triethylamine (1 .00 mL, 7.17 mmol) in dichloromethane (40 mL) and the mixture stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 0.2 M aqueous hydrochloric acid (100 mL). The extracts were washed with 0.1 M aqueous hydrochloric acid, 0.5 M aqueous potassium carbonate, water, brine, dried (MgSC^) and evaporated under reduced pressure to give the title compound (1 .06 g, 100%) as a tan solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.92 - 2.13 (m, 4 H) 3.51 (t, J=6.44 Hz, 2 H) 3.73 (t, J=6.82 Hz, 2 H) 8.75 (d, J=2.02 Hz, 2 H) 9.13 (t, J=2.15 Hz, 1 H).

b) (3-amino-5-nitrophenyl)(pyrrolidin-1 -yl)methanone. Hydrazine (0.251 ml_, 8.00 mmol) was added to a stirred mixture of (3,5-dinitrophenyl)(pyrrolidin-1 - yl)methanone (1.06 g, 4.00 mmol), iron (III) chloride hexahydrate (0.005 g, 0.02 mmol), activated charcoal (0.25 g) and methanol (25 ml.) and the mixture stirred under reflux for 5.5 h, then cooled slightly and filtered through a nylon micropore filter. The solvent was removed under reduced pressure and the residue triturated with methanol. The solid was filtered off and dried to give the title compound (0.499 g, 53%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.79 - 1.91 (m, 4 H) 3.37 (t, J=6.44 Hz, 2 H) 3.45 (t, J=6.82 Hz, 2 H) 6.00 (s, 2 H) 7.05 (dd, J=2.15, 1 .39 Hz, 1 H) 7.35 (dd, J=2.27, 1.26 Hz, 1 H) 7.43 (t, J=2.27 Hz, 1 H). c) N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-nitro-5- (pyrrolidine-1- carbonyl)phenyl)amino)quinoline-3-sulfonamide. A mixture of 4-chloro-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide (0.097 g, 0.230 mmol) and (3-amino-5-nitrophenyl)(pyrrolidin-1 -yl)methanone (0.068 g, 0.288 mmol) in acetic acid (1 ml.) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure. The residue was azeotroped three times with toluene, then chromatographed (silica gel, 1-10%

methanol/dichloromethane). The product was further purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (0.077 g, 54%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-de) δ ppm 0.43 (d, J=5.31 Hz, 4 H) 1 .60 - 1 .70 (m, 2 H) 1 .71 - 1 .81 (m, 2 H) 2.22 - 2.33 (m, 1 H) 3.08 (t, J=6.44 Hz, 2 H) 3.36 (t, J=6.95 Hz, 2 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 7.29 (dd, J=2.02, 1.26 Hz, 1 H) 7.70 - 7.81 (m, 2 H) 7.86 (dd, J=2.02, 1.26 Hz, 1 H) 8.06 (t, J=2.02 Hz, 1 H) 8.32 (s, 1 H) 8.46 (br. s., 1 H) 8.60 (s, 1 H) 8.91 (br. s., 1 H) 9.17 (s, 1 H).

Example 54

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)ami^

isopropylphenyl)amino)benzoic acid

a) methyl 3-((3-isopropylphenyl)amino)-5-nitrobenzoate. To a suspension of methyl

3-bromo-5-nitrobenzoate (500 mg, 1.92 mmol), 3-isopropylaniline (247 mg, 1 .824 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) and cesium carbonate (892 mg, 2.74 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 1 hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 3-((3-isopropylphenyl)amino)-5- nitrobenzoate (305 mg, 0.929 mmol, 50 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 .22 (d, J=6.82 Hz, 6 H) 2.88 (spt, J=6.91 Hz, 1 H) 3.89

(s, 3 H) 6.95 (d, J=7.58 Hz, 1 H) 7.02 (dd, J=7.83, 1 .26 Hz, 1 H) 7.07 (d, J=1.77 Hz, 1 H) 7.30 (t, J=7.83 Hz, 1 H) 7.90 - 7.94 (m, 1 H) 7.94 - 8.00 (m, 2 H) 8.98 (s, 1 H). LCMS (ES+) m/e 315 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3-isopropylphenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (32.4 mg, 0.0305 mmol) in acetic acid (10 ml.) was added methyl 3-((3-isopropylphenyl)amino)-5-nitrobenzoate (100 mg, 0.318 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (1 15 mg, 0.274 mmol) was added to the filtrate. The reaction was kept stirring overnight and the organic solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (10.00 ml_), to which sodium hydroxide (6. ON) (0.254 ml_, 1 .523 mmol) was added. The mixture was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-((3-isopropylphenyl)amino)benzoic acid, trifluoroacetic acid salt (46 mg, 0.060 mmol, 19.65 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 0.34 - 0.41 (m, 2 H) 0.42 - 0.49 (m, 2 H) 1 .03 (d, J=6.82 Hz, 6 H) 2.20- 2.29 (m, 1 H) 2.59 (spt, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.68 - 6.75 (m, 3 H) 6.78 (s, 1 H) 6.99 (t, J=7.83 Hz, 1 H) 7.14 (s, 1 H) 7.37 (s, 1 H) 7.76 - 7.88 (m, 2 H) 8.29 (d, J=1.01 Hz, 1 H) 8.41 (br. s., 1 H) 8.52 (br. s., 1 H) 8.56 (br. s., 1 H) 8.62 (s, 1 H) 9.07 (s, 1 H) 12.98 (br. s., 1 H). LCMS (ES+) m/e 655 [M+H] ⁺ .

Example 55

-((3-(tert-butyl)phenyl)amino)-5-((3-(N-cvclopropylsulfam oyl)-7-(2,4-dimethoxypyrimidin-

5-yl)quinolin-4-yl)amino)benzoic acid

a) ethyl 3-((3-(tert-butyl)phenyl)amino)-5-nitrobenzoate. To a suspension of ethyl 3- bromo-5-nitrobenzoate (500 mg, 1 .824 mmol), 3-(ferf-butyl)aniline (272 mg, 1 .824 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol) and cesium carbonate (892 mg, 2.74 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (8.19 mg, 0.036 mmol). The mixture was heated in a microwave reactor at 120 °C for 1 hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford ethyl 3-((3-(ferf-butyl)phenyl)amino)-5- nitrobenzoate (250 mg, 0.730 mmol, 40.0 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 .30 (s, 9 H) 1 .33 (t, J=7.07 Hz, 3 H) 4.35 (q, J=l A 6 Hz, 2 H) 7.01 (dd, J=7.83, 1 .26 Hz, 1 H) 7.10 (d, J=7.83 Hz, 1 H) 7.20 - 7.25 (m, 1 H) 7.28 - 7.34 (m, 1 H) 7.92 - 7.96 (m, 2 H) 7.96 - 7.99 (m, 1 H) 9.01 (s, 1 H). LCMS (ES+) m/e 343 [M+H] ⁺ . b) 3-((3-(tert-butyl)phenyl)amino)-5-((3-(N-cvclopropylsulfamoy l)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)benzoic acid. To a suspension of 10% palladium on carbon (31 .1 mg, 0.0292 mmol) in acetic acid (10 mL) was added ethyl 3-((3-(tert-butyl)phenyl)amino)-5-nitrobenzoate (100 mg, 0.292 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (1 1 1 mg, 0.263 mmol) was added to the filtrate. The reaction was kept stirring overnight and the organic solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (10.00 mL), to which sodium hydroxide (6.0N) (0.243 mL, 1.460 mmol) was added. The mixture was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-(tert-butyl)phenyl)amino)-5-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)benzoic acid, trifluoroacetic acid salt (25 mg, 0.032 mmol, 10.93 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.36 - 0.42 (m, 2 H) 0.42 - 0.49 (m, 2 H) 1 .14 (s, 9 H) 2.21 - 2.28 (m, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.73(dd, J=7.96, 1.39 Hz, 1 H) 6.79 (s, 1 H) 6.87 (d, J=8.59 Hz, 1 H) 6.94 (d, J=1 .77 Hz, 1 H) 6.96 - 7.04 (m, 1 H) 7.12 (s, 1 H) 7.39 (s, 1 H) 7.74 - 7.85(m, 2 H) 8.28 (d, J=1.26 Hz, 1 H) 8.42 (br. s., 1 H) 8.53 (br. s., 1 H) 8.58 (br. s., 1 H) 8.61 (s, 1 H) 9.07 (s, 1 H) 12.98 (br. s., 1 H). LCMS (ES+) m/e 669 [M+H] ⁺ .

Example 56

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2-(dimethylamin o)ethyl)sulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(2-(dimethylamino)ethyl)quinoline-3-sulfo namide. To a

solution of 7-bromo-4-chloroquinoline-3-sulfonyl chloride (533 mg, 1 .56 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (10 mL) was added a solution of N ¹ ,N ¹ -dimethylethane-1 ,2-diamine (151 mg, 1 .7 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred for 20 minutes. Water (10 mL) was added and the mixture extracted with dichloromethane (50 mL x 3). The combined organic phases were concentrated and purified by silica gel chromatography (5% methanol/dichloromethane) to afford the title compound (460mg, 75%) as a yellow solid. LCMS (ES+) m/e 392 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N-(2-(dimethylamino)ethyl)sulfamoyl)quinolin-4 -ylamino)-5- isopropoxybenzoate. A mixture of 7-bromo-4-chloro-N-(2- (dimethylamino)ethyl)quinoline-3-sulfonamide (460 mg, 1 .2 mmol) and methyl 3- amino-5-isopropoxybenzoate (269 mg, 1 .3 mmol) in ethanol (10 mL) was refluxed for 20 h. The solvent was removed and the residue was purified by prep-TLC to give the title compound (455 mg, 67%) as a yellow solid. LCMS (ES+) m/e 565 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-vn-3-(N-(2- (dimethylamino)ethyl)sulfamoyl)quinolin-4-ylamino)-5-isoprop oxybenzoate. A mixture of methyl 3-(7-bromo-3-(N-(2-(dimethylamino)ethyl)sulfamoyl)quinolin-4 - ylamino)-5-isopropoxybenzoate (390 mg, 0.69 mmol), 2,4-dimethoxypyrimidin-5- ylboronic acid (507 mg, 2.8 mmol), [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (51 mg, 0.07 mmol) and potassium acetate (135 mg, 1 .38 mmol) in 1 ,4-dioxane (20 mL) and water (4 mL) was stirred at 80 °C under nitrogen for 20 h. The mixture was cooled to room temperature and water (20 mL) added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated in vacuo. The residue was purified by chromatography on silica gel (3% methanol/dichloromethane) to afford the title compound (108 mg, 25%) as a yellow solid. ¹ H N MR (300 MHz, DMSO-d ₆ ) δ ppm 1.19 (d, J=5.7 Hz, 6 H), 2.01 (s, 6 H), 2.23-2.29 (m, 2 H), 2.95-2.99 (m, 2 H), 3.79 (s, 3 H), 3.97 (s, 6 H), 4.49- 4.57 (m, 1 H), 6.68 (s, 1 H), 7.10 (s, 1 H), 7.12 (s, 1 H), 7.66-7.73 (m, 2 H), 8.25 (s, 2 H), 8.58 (s, 1 H), 9.10 (s, 1 H). LCMS (ES+) m/e 625 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-vn-3-(N-(2- (dimethylamino)ethyl)sulfamoyl)quinolin-4-ylamino)-5-isoprop oxybenzoic acid. A mixture of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2- (dimethylamino)ethyl)sulfamoyl)quinolin-4-ylamino)-5-isoprop oxybenzoate (108 mg, 0.17 mmol) in methanol (10 mL) and 1 N aqueous lithium hydroxide (1.7 mL) was stirred at room temperature for 18 h. The mixture was concentrated and the residue diluted with water (5 mL), then acidified with 1 N aqueous hydrochloric acid to pH 5. The suspension was filtered to afford the title compound (65 mg, 61 %) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .20 (d, J=6.0 Hz, 6 H), 2.26 (s, 6 H), 2.53-2.63 (m, 2 H), 3.04-3.09 (m, 2 H), 3.97 (s, 6 H), 4.50-4.58 (m, 1 H), 6.71 (s, 1 H), 7.08 (s, 2 H), 7.65-7.72 (m, 2 H), 8.23 (s, 1 H), 8.57 (s, 1 H), 9.09 (s, 1 H). LCMS (ES+) m/e 61 1 [M+H] ⁺ .

Example 57

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2,2,2-trifluoroeth yl)sulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(2,2,2-trifluoroethyl)quinoline-3-sulfona mide. To a solution of

7-bromo-4-chloro-3-quinolinesulfonyl chloride (345 mg, 1 mmol) in dry

dichloromethane (5 mL) was added pyridine (0.5 mL, 6.3 mmol) with stirring over 10 min, while maintaining the temperature below 0 °C. 2,2,2-trifluoroethanamine (248 mg, 2.5 mmol) was added slowly. The resulting solution was allowed to warm to room temperature and stirred for 2 h. Water (25 mL) was added, and the mixture extracted with ethyl acetate (50 mL x 3). The extracts were washed with saturated aqueous copper sulfate (50 mL x 3), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (150 mg, 37%) as a yellow solid. LCMS (ES+) m/e 403 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N-(2,2,2-trifluoroethyl)sulfamoyl)quinolin-4-y lamino)-5- isopropoxybenzoate. A solution of 7-bromo-4-chloro-N-(2,2,2- trifluoroethyl)quinoline-3-sulfonamide (150 mg, 0.37 mmol) and methyl 3-amino-5- isopropoxybenzoate (85 mg, 0.40 mmol) in ethanol (5 mL) was stirred at 80 °C for 3 h, then cooled and concentrated in vacuo to give the crude methyl 3-(7-bromo-3-

(N-(2,2,2-trifluoroethyl)sulfamoyl)quinolin-4-ylamino)-5- isopropoxybenzoate (201 mg, 94.4%) as a yellow solid. LCMS (ES+) m/e 576 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-ylV3-(N-(2,2,2- trifluoroethyl)sulfamoyl)quinolin-4-ylamino)-5-isopropoxyben zoate. To a solution of methyl 3-(7-bromo-3-(N-(2,2,2-trifluoroethyl)sulfamoyl)quinolin-4-y lamino)-5- isopropoxybenzoate (201 mg, 0.35 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) in 1 ,4- dioxane (8 mL) was added a solution of potassium carbonate (145 mg, 1 .05 mmol) in water (2 mL). The reaction mixture was stirred at 100 °C for 1 h in a sealed- tube. TLC showed no starting mateirals left. The mixture was cooled. Water (20 mL) was added and the mixture stirred for 10 min. The solid was filtered, washed with water and dried to give the title compound (141 mg, 63%) as a yellow solid. LCMS (ES+) m/e 636 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(2,2,2-trifluoroethy l)sulfamoyl)quinolin-4- ylamino)-5-isopropoxybenzoic acid. To a solution of methyl 3-(7-(2,4- dimethoxypyrimidin-5-yl)-3-(N-(2,2,2-trifluoroethyl)sulfamoy l)quinolin-4-ylamino)-5- isopropoxybenzoate (141 mg, 0.22 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 1 N aqueous lithium hydroxide (1.0 mL, 1 .0 mmol). The mixture was stirred at room temperature for 24 h, then concentrated to half its volume under reduced pressure and acidified to pH = 1 with 1 M aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried. Further purification by prep-TLC afforded the title compound (1 10 mg, 80.3%) as a pale yellow solid. ¹ H N MR (300 MHz, DMSO-d ₆ ) δ ppm 1.19 (d, J=6.0 Hz, 6 H), 3.84- 3.90 (m, 2 H), 3.97 (s, 6 H), 4.49-4.57 (m, 1 H), 6.69 (s, 1 H), 7.12 (s, 2 H), 7.66- 7.71 (m, 2 H), 8.22 (s, 1 H), 8.36-8.39 (m, 1 H), 8.57 (s, 1 H), 9.08-9.14 (m, 2 H), 13.00 (s, br, 1 H). LCMS (ES+) m/e 622 [M+H] ⁺ .

Example 58

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-phenylsulfamoyl)qui nolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-phenylquinoline-3-sulfonamide. To a solution of 7-bromo-4- chloro-3-quinolinesulfonyl chloride (531 mg, 1 .4 mmol) and pyridine (2 mL) in dry dichloromethane (8 mL) was added a solution of aniline (131 mg, 1.4 mmol) in dichloromethane (5 mL) dropwise at 0 °C. The mixture was stirred for 10 minutes. TLC showed the starting material was consumed completely. Water (50 mL) was added and the mixture extracted with dichloromethane (50 mL x 3). The combined organic phases were concentrated and purified by silica gel chromatography (2% methanol/dichloromethane) to afford the title compound (213 mg, 34%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 7.01 (t, J=7.5 Hz, 1 H), 7.13 (d, J=7.5 Hz, 2 H), 7.22 (t, J=7.5 Hz, 2 H), 8.03(dd, J=2.1 , 9.0 Hz, 1 H), 8.32(d, J=9.0 Hz, 1 H), 8.41 (d, J=2A Hz, 1 H), 9.26 (s, 1 H), 1 1.03 (s, 1 H). LCMS (ES+) m/e 397 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N-phenylsulfamoyl)quinolin-4-ylamino)-5- isopropoxybenzoate. A mixture of 7-bromo-4-chloro-N-phenylquinoline-3- sulfonamide (213 mg, 0.54 mmol) and methyl 3-amino-5-isopropoxybenzoate (123 mg, 0.59 mmol) in ethanol (15 mL) was refluxed for 2 h. The solvent was removed to give the crude title compound (306 mg, 99%) as a yellow solid. LCMS (ES+) m/e 570 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-phenylsulfamoyl)quin olin-4- ylamino)-5-isopropoxybenzoate. A mixture of methyl 3-(7-bromo-3-(N- phenylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (306 mg, 0.54 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (395 mg, 2.1 mmol), [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (39 mg, 0.05 mmol) and potassium acetate (98 mg, 1.08 mmol) in 1 ,4-dioxane (20 mL) and water (4 mL) was stirred at 80 °C under nitrogen for 16 h. TLC showed complete conversion. The mixture was cooled to room temperature, diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated and purified by chromatography on silica gel (2% methanol/dichloromethane) to afford the title compound (281 mg, 83%) as a yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 1.28 (d, J=6.0 Hz, 6 H), 3.88 (s, 3 H), 4.03 (s, 3 H), 4.05 (s, 3 H), 4.46 (hept, J=6.0 Hz, 1 H), 6.31-6.32 (m, 1 H), 6.93- 7.01 (m, 2 H), 7.09 (d, J=4.5 Hz, 4 H), 7.28-7.29 (m, 1 H), 7.45 (dd, J=1.8, 8.7 Hz,

1 H), 7.64 (d, J=8.7 Hz, 1 H), 8.24 (s, 1 H), 8.31 (s, br, 1 H), 8.38 (s, 1 H), 9.13 (s, 1 H). LCMS (ES+) m/e 630 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-phenylsulfamoyl)quin olin-4-ylamino)-5- isopropoxybenzoic acid. A mixture of methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3- (N-phenylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (150 mg, 0.24 mmol) in methanol (10 mL) and 1 N aqueous lithium hydroxide (2.4 mL ) was stirred at room temperature for 18 h. The mixture was concentrated and the residue diluted with water (10 mL ) and acidified with 1 M aqueous hydrochloric acid to pH 5. The suspension was filtered and the solid recrystallized with methanol to afford the title compound (120 mg, 81 %) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.20 (d, J=6.0 Hz, 6 H), 3.95 (s, 6 H), 4.44-4.52 (m, 1 H), 6.52 (s, 1 H), 6.92-6.95 (m, 2 H), 7.04-7.15 (m, 5 H), 7.61 (s, 2 H), 8.13 (s, 1 H), 8.43 (s, br, 1 H), 8.53 (s, 1 H), 8.99 (s, 1 H), 10.77 (s, 1 H), 12.99 (s, 1 H).

LCMS (ES+) m/e 616 [M+H] ⁺ .

Example 59

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahvdrofuran -3-yl)sulfamoyl)quinolin-4- yl)amino)-5-isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(tetrahydrofuran-3-yl)quinoline-3-sulfona mide. To a solution of 7-bromo-4-chloro-3-quinolinesulfonyl chloride (530 mg, 1 .56 mmol) and triethylamine (313 mg, 3.1 mmol) in dry dichloromethane (8 mL) was added a solution of tetrahydrofuran-3-amine (149 mg, 1 .7 mmol) in dichloromethane (2 mL) dropwise at 0 °C. The mixture was stirred for 10 minutes. TLC showed the starting material was consumed completely. Water (10 mL) was added and the mixture extracted with dichloromethane (20 mL x 3). The combined organic phases were concentrated and purified by silica gel chromatography (25% ethyl acetate/petroleum ether) to afford the title compound (420 mg, 69%) as a solid. ¹ H

NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.67-1.75 (m, 1 H), 1.87-1.98 (m, 1 H), 3.41 - 3.46 (m, 1 H), 3.54-3.76 (m, 3 H), 3.86-3.92 (m, 1 H), 8.05 (dd, J=2.1 , 9.0 Hz, 1 H), 8.37 (d, J=9.0 Hz, 1 H), 8.45 (d, J=2A Hz, 1 H), 8.73 (d, J=7.5 Hz, 1 H), 9.27 (s, 1 H). LCMS (ES+) m/e 391 [M+H] ⁺ .

b) methyl 3-(7-bromo-3-(N-(tetrahvdrofuran-3-yl)sulfamoyl)quinolin-4-y lamino)-5- isopropoxybenzoate. A mixture of 7-bromo-4-chloro-N-(tetrahydrofuran-3- yl)quinoline-3-sulfonamide (420 mg, 1.1 mmol) and methyl 3-amino-5- isopropoxybenzoate (247 mg, 1 .2 mmol) in ethanol (20 mL) was refluxed for 2 h.

The mixture was cooled to room temperature and concentrated, then purified by silica gel chromatography (3% methanol/dichloromethane) to give the title compound (430 mg, 69%) as a yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 1.30 (d, J=6.0 Hz , 6 H), 1 .63-1.74 (m, 1 H), 2.00-2.1 1 (m, 1 H), 3.49-3.54 (m, 1 H), 3.60-3.68 (m, 2 H), 3.73-3.81 (m, 1 H), 3.86 (s,3 H), 3.89-4.00 (m, 1 H), 4.54 (hept, J=6.0 Hz, 1 H), 5.27 (d, J=8.1 Hz, 1 H), 6.58 (t, J=2A Hz, 1 H), 7.09 (s, 1 H), 7.29 (s, 1 H), 7.40 (dd, J=2.1 , 9.0 Hz, 1 H), 7.57 (d, J=9.0 Hz, 1 H), 8.15 (s, 1 H), 8.27 (d, J=2A Hz, 1 H), 9.15 (s, 1 H). LCMS (ES+) m/e 564 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahvdrofuran-3- yl)sulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate. A mixture of methyl 3-(7- bromo-3-(N-(tetrahydrofuran-3-yl)sulfamoyl)quinolin-4-ylamin o)-5- isopropoxybenzoate (430 mg, 0.76 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (561 mg, 3 mmol), [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (56 mg, 0.076 mmol) and potassium acetate (147 mg, 1 .5 mmol) in 1 ,4-dioxane (20 ml.) and water (4 ml.) was stirred at 80 °C under nitrogen for 16 h, then cooled. The mixture was diluted with water (20 ml.) and extracted with ethyl acetate (30 ml. x 3). The combined organic layers were concentrated, purified by chromatography on silica gel (2%

methanol/dichloromethane) to afford the title compound (381 mg, 80%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .18 (d, J=6.0 Hz, 6 H), 1.53-1 .63 (m,

1 H), 1 .82-1 .94 (m, 1 H), 3.17 (d, J=4.8 Hz, 1 H), 3.35-3.39 (m, 1 H), 3.50-3.70 (m,

2 H), 3.80 (s, 3 H), 3.85 (s, 1 H), 3.97 (s, 6 H), 4.54 (hept, J=6.0 Hz, 1 H), 6.70 (s, 1 H), 7.12-7.13 (m, 2 H), 7.65-7.72 (m, 2 H), 8.24 (s, 1 H), 8.33 (s, br, 1 H), 8.46 (s, br, 1 H), 8.57 (s, 1 H), 9.10 (s, 1 H). LCMS (ES+) m/e 624 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(tetrahvdrofuran-3-y l)sulfamoyl)quinolin-4- ylamino)-5-isopropoxybenzoic acid. A mixture of methyl 3-(7-(2,4- dimethoxypyrimidin-5-yl)-3-(N-(tetrahydrofuran-3-yl)sulfamoy l)quinolin-4-ylamino)- 5-isopropoxybenzoate (150 mg, 0.24 mmol) in methanol (10 ml.) and 1 N aqueous lithium hydroxide (2.4 ml.) was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (15 ml.) and acidified pH to 5. The precipitate was filtered and dried to afford the title compound (127 mg, 86%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm 1.19 (d, J=6.0 Hz, 6 H), 1 .53-1.63 (m, 1 H), 1.82-1 .94 (m, 1 H), 3.34-3.39 (m, 1 H), 3.49-3.70 (m, 3 H), 3.81 -3.90 (m, 1 H), 3.97 (s, 6 H), 4.54 (hept, J=6.0 Hz, 1 H), 6.72 (s, 1 H), 7.08 (s, 1 H), 7.12 (s, 1 H), 7.64-7.72 (m, 2 H), 8.23 (s, 1 H), 8.32 (s, 1 H), 8.49 (d, J=7.5 Hz, 1 H), 8.58 (s, 1 H), 9.09 (s, 1 H), 13.01 (s, br, 1 H). LCMS (ES+) m/e 610 [M+H] ⁺ . Example 60

-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(thiophen-3-yl)su lfamoyl)quinolin-4-v

isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(thiophen-3-yl)quinoline-3-sulfonamide. To a solution of 7- bromo-4-chloro-3-quinolinesulfonyl chloride (1.02 g, 3 mmol) in dichloromethane (10 mL) was added pyridine (1 mL), followed by thiophen-3-amine (247 mg, 2.5 mmol) at about 0 °C over 30 min. The reaction was concentrated and purified by silica gel chromatography (9% ethyl acetate/petroleum ether) to provide the title compound (470 mg) as a yellow oil. LCMS (ES+) m/e 402 [M+H] ⁺ .

b) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-thiophen-3-ylsulfamo yl) quinolin-4- ylamino)-5-isopropoxybenzoate. To a solution of 7-bromo-4-chloro-N-(thiophen-3- yl)quinoline-3-sulfonamide (230 mg, 0.58 mmol) in ethanol (10 mL) was added methyl 3-amino-5-isopropoxybenzoate (132 mg, 0.63 mmol). The mixture was stirred at 80 °C for 3 h under nitrogen atmosphere, then concentrated to afford crude methyl 3-(7-bromo-3-(N-thiophen-3-ylsulfamoyl)quinolin-4-ylamino) -5- isopropoxybenzoate (370 mg) as a yellow solid. To a solution of this compound in dioxane (10 mL) was added 2,4-dimethoxypyrimidin-5-ylboronic acid (474 mg, 2.58 mmol) and potassium acetate (125 mg, 1 .28 mmol) in water (1 mL), followed by [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (47 mg, 0.064 mmol). The mixture was stirred at 90 °C for 16 h under nitrogen atmosphere, then concentrated. Water (25 mL) was added, and the mixture extracted with ethyl acetate (50 mL x 3). The extracts were washed with brine (50 mL x 3), dried over Na ₂ S0 ₄ , then concentrated to provide the crude title compound (550 mg) as a yellow solid. LCMS (ES+) m/e 636 [M+H] ⁺ .

c) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-thiophen-3-ylsulfamo yl)quinolin-4- ylamino)-5-isopropoxybenzoic acid. To a solution of methyl 3-(7-(2,4- dimethoxypyrimidin-5-yl)-3-(N-thiophen-3-ylsulfamoyl)quinoli n-4-ylamino)-5- isopropoxybenzoate ( 500 mg, 0.8 mmol) in methanol (20 mL) was added 1 N aqueous lithium hydroxide (8 mL). The mixture was stirred at 28 °C for 16 h, then concentrated to half its volume under reduced pressure and acidified to pH = 1 with 1 N aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried to give a yellow solid. Further purification by prep-TLC afforded the title compound (35 mg, 8.7% for two steps) as a pale yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.19 (d, J = 5.7 Hz, 6 H), 3.96 (s, 6 H), 4.51 (hept, J = 5.7 Hz, 1 H), 6.59 (s, 1 H), 6.77 (d, J = 5.1 Hz, 1 H), 6.94 (d, J = 3.0 Hz, 1 H), 7.01 (s, 1 H), 7.13 (s, 1 H), 7.33 (dd, J = 5.1 , 3.0 Hz, 1 H), 7.63 (s, 2 H), 8.16 (s, 1 H), 8.42 (s, br, 1 H), 8.54 (s, 1 H), 9.01 (s, 1 H) 10.82 (s, br, 1 H), 13.00 (s, br, 1 H). LCMS (ES+) m/e 622 [M+H] ⁺ .

Example 61

(3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4- yl)amino)phenyl)boronic acid

a) 7-bromo-4-chloro-N-cvclopropyl-3-quinolinesulfonamide. 7-bromo-4-hydroxy-3- quinolinesulfonyl chloride (33 g, 0.108 mol) and thionyl chloride (300 mL) was stirred under reflux for 3 h, then cooled. The volatiles were removed and the residue dissolved in dichloromethane (300 mL) and triethylamine (30 mL), then cooled to 0 °C. Cyclopropylamine (1 1.5 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. TLC showed complete conversion. The mixture was diluted with water (50 mL). The solid was filtered and washed with water and 50% methanol/dichloromethane (100 mL), then dried in vacuo to give the title product (17.8 g, 46%) as a gray solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.37-0.52 (m, 4 H), 2.30-2.31 (m, 1 H), 8.04-8.08 (m, 1 H), 8.36-8.37 (m, 2 H), 8.72 (s, 1 H), 9.28 (s, 1 H). LCMS (ES+) m/e 361 [M+H] ⁺ .

b) 4-chloro-N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3-sulfonamide. A mixture of 7-bromo-4-chloro-N-cyclopropyl-3-quinolinesulfonamide (17.68 g, 49.1 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (10.84 g, 58.9 mmol),

tetrakis(triphenylphosphine)palladium(0) (2.8 g, 2.45 mmol) and potassium carbonate (16.26 g, 1 17.84 mmol) in 1 ,4-dioxane (240 mL) and water (60 mL) was stirred at 80°C for 1 h. TLC showed complete conversion. The mixture was cooled. The solid was filtered, washed with water (10 mL x 3), and dried to give the title compound (13.0 g, 63%) as a white solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm 0.37-0.51 (m, 4 H), 2.27-2.34 (m, 1 H), 4.00 (s, 3 H), 4.02 (s, 3 H), 8.12 (dd, J=8.7, 1 .5 Hz, 1 H), 8.39 (d, J=1 .5 Hz, 1 H), 8.46 (d, J = 8.7 Hz, 1 H), 8.67 (s, 2 H), 9.28 (s, 1 H). LCMS (ES+) m/e 421 [M+H] ⁺ .

c) 3-(3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )quinolin-4- ylamino)phenylboronic acid. A mixture of 4-chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (300 mg, 0.72 mmol), 3- aminophenylboronic acid (107 mg, 0.78 mmol) and one drop of acetic acid in 1 ,4- dioxane (8 mL) was stirred at 80 °C for 2 h. The mixture was concentrated in vacuo, diluted with water (20 mL) and extracted with dichloromethane (20 mL x 1 ). The extracts were washed with brine (20 mL x 1 ), dried over Na ₂ S0 ₄ , filtered, concentrated in vacuo, then purified by Prep-HPLC to give the title compound (100 mg, 27%) as a yellow solid. ¹ H NMR (300 MHz, DMSO- cfe) δ ppm 0.42-0.44 (m, 4 H), 2.21-2.27 (m, 1 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 7.05-7.08 (m, 1 H), 7.30 (t, J=7.8 Hz, 1 H),7.52-7.62 (m, 4 H), 8.05 (s, 2 H), 8.19 (d, J=1.8 Hz, 1 H), 8.40 (s, 1 H), 8.49 (d, J=1.8 Hz, 1 H), 8.56 (s, 1 H), 9.00 (s, 1 H). LCMS (ES+) m/e 522 [M+H] ⁺ .

Example 62

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluo rophenyl)amino)-5-(2H- tetrazol-5-yl)phenyl)amino)quinoline-3-sulfonamide

a) 3-((4-fluorophenyl)amino)-5-nitrobenzonitrile. To a suspension of 3-bromo-5- nitrobenzonitrile (500 mg, 2.202 mmol), 4-fluoroaniline (245 mg, 2.202 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 ,1 '-biphenyl]-2-yl)phosphine (105 mg, 0.220 mmol) and cesium carbonate (1076 mg, 3.30 mmol) in ferf-butanol (2 mL) and toluene (10 mL) was added palladium(ll) acetate (9.89 mg, 0.044 mmol). The mixture was heated in a microwave synthesiser at 120 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford 3-((4-fluorophenyl)amino)-5- nitrobenzonitrile (355 mg, 1 .380 mmol, 62.7 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.19 - 7.30 (m, 4 H) 7.60 (dd, J=2.27, 1 .26 Hz, 1 H) 7.89 (t, J=2.15 Hz, 1 H) 7.94 - 7.99 (m, 1 H) 9.06 (s, 1 H). LCMS (ES+) m/e 258 [M+H] ⁺ .

b) N-(4-fluorophenyl)-3-nitro-5-(2H-tetrazol-5-yl)aniline. To a suspension of 3-((4- fluorophenyl)amino)-5-nitrobenzonitrile (350 mg, 1 .361 mmol), in N, N- dimethylformamide (10 ml.) was added sodium azide (133 mg, 2.041 mmol). The mixture was heated in a microwave reactor at 150 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified via reverse-phase preparative HPLC (YMC 20X50 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford N-(4-fluorophenyl)-3-nitro-5-(2H-tetrazol-5-yl)aniline (250mg, 0.833 mmol, 61 .2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.20 - 7.26 (m, 4 H) 7.61 (t, J=2.27 Hz, 1 H) 8.01 (dd, J=2.15, 1 .14 Hz, 1 H) 8.12 - 8.15 (m, 1 H) 8.77 (s, 1 H). LCMS (ES+) m/e 301 [M+H] ⁺ .

c) N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluo rophenyl)amino)-5-(2H- tetrazol-5-yl)phenyl)amino)quinoline-3-sulfonamide. To a suspension of 10% palladium on carbon (28.4 mg, 0.0266 mmol) in acetic acid (10 ml.) was added N- (4-fluorophenyl)-3-nitro-5-(2H-tetrazol-5-yl)aniline (80 mg, 0.266 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (101 mg, 0.240 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 %

trifluoroacetic acid) to afford N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3- ((4-fluorophenyl)amino)-5-(2H-tetrazol-5-yl)phenyl)amino)qui noline-3-sulfonamide (55 mg, 0.084 mmol, 31 .5 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- cf6) δ ppm 0.47 - 0.53 (m, 4 H) 2.34 - 2.40 (m, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.89 (s, 1 H) 6.96 - 7.08 (m, 4 H) 7.35 (s, 1 H) 7.54 (s, 1 H) 7.78 - 7.84 (m, 1 H) 7.85 - 7.91 (m, 1 H) 8.38 (d, J=1 .52 Hz, 1 H) 8.62 (s, 1 H) 8.78 (br. s., 1 H) 9.12 (s, 1 H). LCMS (ES+) m/e 655 [M+H] ⁺ . Example 63

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimeth^

(pyrrolidine-l-carbonyl)benzoic acid

a) methyl 3-nitro-5-(pyrrolidine-1-carbonyl)benzoate. (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate (1 .56 g, 3.00 mmol) was added to a stirred solution of 3-(methoxycarbonyl)-5-nitrobenzoic acid (0.450 g, 2.00 mmol), pyrrolidine (0.496 mL, 6.00 mmol) and triethylamine (0.836 mL, 6.00 mmol) in dichloromethane (10 mL) and the mixture stirred at room temperature for 4 h. 1 M aqueous hydrochloric acid (50 mL) was added and the mixture extracted with dichloromethane. The extracts were washed with 1 M aqueous hydrochloric acid, 0.5M aqueous potassium carbonate, water, brine, dried (MgSC^) and evaporated under reduced pressure. The residue was chromatographed (silica gel, 30-100% ethyl acetate/hexane) to give the title compound (0.585 g, 92% pure, 97%) as a colourless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.93 - 2.07 (m, 4 H) 3.47 (t, J=6.57 Hz, 2 H) 3.71 (t, J=6.82 Hz, 2 H) 4.02 (s, 3 H) 8.53 (t, J=1.52 Hz, 1 H) 8.59 (dd, J=2.15, 1 .64 Hz, 1 H) 8.92 (dd, J=2.02, 1.52 Hz, 1 H). b) methyl 3-amino-5-(pyrrolidine-1 -carbonvDbenzoate. A solution of methyl 3-nitro-5- (pyrrolidine-l-carbonyl)benzoate (0.583 g, 2.10 mmol) in methanol (20 mL) was stirred with 5% wet palladium on carbon (0.500 g, 0.1 17 mmol) under 1 atm hydrogen for 1 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound (0.492 g, 95%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .70 - 1.92 (m, 4 H) 3.30 - 3.37 (m, 2 H) 3.43 (t, J=6.69 Hz, 2 H) 3.82 (s, 3 H) 5.58 (s, 2 H) 6.90 (dd, J=2.27, 1.52 Hz, 1 H) 7.15 (t, J=1.52 Hz, 1 H) 7.24 (dd, J=2.27, 1.77 Hz, 1 H).

c) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(pyrrolidine-1 -carbonyl)benzoic acid. A mixture of 4-chloro-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide (0.097 g, 0.230 mmol) and methyl 3-amino-5-(pyrrolidine-1-carbonyl)benzoate (0.072 g, 0.290 mmol) in acetic acid (1 mL) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure. The residue was azeotroped three times with toluene, then chromatographed (silica gel, 1-8%

methanol/dichloromethane) to give the intermediate ester (0.090 g). 1 M aqueous sodium hydroxide (2.00 mL, 2.00 mmol) was added dropwise to a stirred solution of the ester in methanol (10 mL) at room temperature and the mixture stirred for 18 h. Water (20 mL) was added and the pH adjusted to 4-5 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h, then the solid filtered off, washed with water, and dried to give the title compound (0.065 g, 46%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.37 - 0.46 (m, 4 H) 1 .60 - 1 .72 (m, 2 H) 1 .72 - 1.83 (m, 2 H) 2.17 - 2.28 (m, 1 H) 3.1 1 (t, J=6.44 Hz, 2 H) 3.35 - 3.39 (m, 2 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 7.17 - 7.21 (m, 1 H) 7.59 - 7.76 (m, 4 H) 8.27 (d, J=1.01 Hz, 1 H) 8.48 (d, J=2.02 Hz, 1 H) 8.51 (s, 1 H) 8.59 (s, 1 H) 9.10 (s, 1 H) 13.24 (br. s., 1 H).

Example 64

-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-(oxetan-3-yl)sulf amoyl)quinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 7-bromo-4-chloro-N-(oxetan-3-yl)quinoline-3-sulfonamide. 7-bromo-4-chloro-3- quinolinesulfonyl chloride (1 .0 g, 2.9 mmol) and triethylamine (666 mg, 5.8 mmol) were dissolved in dichloromethane (50 mL). The solution was cooled to 0 °C, then oxetan-3-amine (260 mg, 3.25 mmol) in dichloromethane (5 mL) added dropwise. The solution was stirred for 1 h at 0 °C. After the starting material was consumed completely, 1 M aqueous hydrochloric acid (20 mL) was added. The organic layer was separated and washed with aqueous sodium bicarbonate (30 mL x 2), brine (30 mL x 1 ), and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure. The crude product was used in the next step directly. LCMS (ES+) m/e 377 [M+H] ⁺ . b) methyl 3-(7-bromo-3-(N-oxetan-3-ylsulfamoyl)quinolin-4-ylamino)-5- isopropoxybenzoate. 7-bromo-4-chloro-N-(oxetan-3-yl)quinoline-3-sulfonamide (200 mg, 0.53 mmol), and methyl 3-amino-5-isopropoxybenzoate (0.58 mg) were dissolved in ethanol (25 mL). The mixture was heated to reflux and stirred for about 8 h at this temperature. The solvent was removed under reduced pressure and the crude product purified by chromatography on silica gel (9-33% ethyl acetate/petroleum ether) to afford the title compound (140 mg, 47%) as a yellow gum. LCMS (ES+) m/e 550 [M+H] ⁺ .

c) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-oxetan-3-ylsulfamoyl )quinolin-4- ylamino)-5-isopropoxybenzoate. Methyl 3-(7-bromo-3-(N-oxetan-3- ylsulfamoyl)quinolin-4-ylamino)-5-isopropoxybenzoate (130 mg , 0.236 mmol) and 2,4-dimethoxypyrimidin-5-ylboronic acid (47.8 mg, 0.260 mmol) were dissolved in 1 ,4-dioxane:water (4:1 , 15 mL). After degassing and placing under nitrogen, tetrakis(triphenylphosphine)palladium(0) was added. The reaction was heated to 60 °C and stirred for about 15 h at this temperature. After cooling to room temperature, the solution was diluted with ethyl acetate (60 mL), washed with brine (30 mL x 2) and dried over Na ₂ S0 ₄ . The solvent was removed and the crude product purified by chromatography on silica gel (17-50% ethyl

acetate/petroleum ether) to afford the title compound (90 mg, 62%). LCMS (ES+) m/e 610 [M+H] ⁺ .

d) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-3-(N-oxetan-3-ylsulfamoyl )quinolin-4-ylamino)- 5-isopropoxybenzoic acid. Methyl 3-(7-(2, 4-dimethoxypyrimidin-5-yl)-3-(N-oxetan- 3-ylsulfamoyl) quinolin-4-ylamino)-5-isopropoxybenzoate (70 mg, 0.1 15 mmol) was dissolved in methanol (30 mL). Aqueous sodium hydroxide (2. ON, 4 mL) was added. The mixture was stirred about 4 h at room temperature. The pH was adjusted to 3.0 with formic acid. The methanol was removed under reduced pressure. The solid was filtered and washed with water (5.0 mL x 3) to give the expected product (38 mg). LCMS (ES+) m/e 596 [M+H] ⁺ . Following the same procedure, another batch of crude product (40 mg) was obtained. The two batches were combined and suspended in acetone (2.0 mL) and methanol (0.5 mL). The mixture was stirred for about 1 h at 60 °C. After cooling to room temperature, a filtration was performed. The solid was washed with acetone (0.5 mL x 2) to obtain the title compound (46 mg, 58%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .21 (d, J=6.0 Hz, 6 H), 3.97 (s, 6 H), 4.26-4.30 (m, 2 H), 4.46-4.58 (m, 4 H), 6.72(s, 1 H), 7.06 (s, 1 H), 7.1 1 (s, 1 H), 7.69 (s, 2 H), 8.24 (s, 1 H), 8.35 (s, 1 H) , 8.58 (s, 1 H) , 9.04-9.12 (m, 2 H),13.02 (s, 1 H). LCMS (ES+) m/e 596 [M+H] ⁺ .

Example 65

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3- (methylsulfonyl)phenyl)amino)quinoline-3-sulfonamide

3-(Methylsulfonyl)aniline (27.5 mg, 0.160 mmol) was added to a stirred solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3-sulfonamide (45 mg, 0.107 mmol) in acetic acid (5 ml.) at room temperature. The reaction was stirred for 24 hours, then the precipitate filtered and washed with methanol. The eluent was collected and evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)-4-((3-(methylsulfonyl)phenyl)amino) quinoline-3-sulfonamide (45 mg, 0.077 mmol, 72.0 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ: 9.19 (s, 1 H), 8.66 (br. s., 1 H), 8.60 (s, 1 H), 8.34 (d, J = 1.5 Hz, 1 H), 7.79 (t, J = 1.8 Hz, 1 H), 7.70 - 7.75 (m, 2 H), 7.58 - 7.66 (m, 2 H), 7.44 (dd, J = 8.1 , 1.3 Hz, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 3.97 (s, 1 H), 3.21 (s, 3 H), 0.39 - 0.56 (m, 4 H).

Example 66

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrroli dine-1- carbonyl)phenyl)amino)quinoline-3-sulfonamide A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (0.097 g, 0.230 mmol) and (3-aminophenyl)(pyrrolidin-1-yl)methanone (0.055 g, 0.290 mmol) in acetic acid (1 mL) was stirred at 50 °C for 2 h, then cooled slowly over 18 h. The mixture was purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (0.125 g, 94%) as an orange-yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 0.43 - 0.53 (m, 4 H) 1 .63 - 1.74 (m, 2 H) 1 .74 - 1 .85 (m, 2 H) 2.30 - 2.36 (m, 1 H) 3.17 (t, J=6.57 Hz, 2 H) 3.38 (t, J=6.95 Hz, 2 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 7.22 (s, 1 H) 7.27 - 7.36 (m, 2 H) 7.46 (t, J=7.7^ Hz, 1 H) 7.63 (d, J=9.09 Hz, 1 H) 7.68 (dd, J=9.09, 1.77 Hz, 1 H) 8.28 (d, J=1.52 Hz, 1 H) 8.58 (s, 1 H) 8.63 (s, 1 H) 8.85 (br. s., 1 H) 9.1 1 (s, 1 H).

Example 67

4-((3-cvanophenyl)amino)-N-cvclopropyl-7-(2,4-dimethoxypyrim idin-5-yl)quinoline-3- sulfonamide

To a suspension of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (100 mg, 0.238 mmol) in acetic acid (10 mL) was added 3- aminobenzonitrile (28.1 mg, 0.238 mmol). The reaction was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 4-((3-cyanophenyl)amino)-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide, trifluoroacetic acid salt (12 mg, 0.019 mmol, 8.19 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.41 (s, 2 H) 0.42 (br. s., 2 H) 2.20 - 2.29 (m, 1 H) 3.98 (s, 3 H) 3.99 (s,3 H) 7.19 - 7.27 (m, 1 H) 7.42 - 7.52 (m, 2 H) 7.56 (s, 1 H) 7.60 - 7.67 (m, 1 H) 7.69 - 7.74 (m, 1 H) 8.28 (s, 1 H) 8.48 (br. s., 1 H) 8.56 - 8.63 (m, 2 H) 9.12 (s, 1 H). LCMS (ES+) m/e 503 [M+H] ⁺ . Example 68

4-((3-(cvclopentylsulfonyl)phenyl)amino)-N-cvclopropyl-7-(2, 4-dimethoxypyrimid

yl)quinoline-3-sulfonamide

3-(Cyclopentylsulfonyl)aniline (40.2 mg, 0.178 mmol) was added to a stirred solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3-sulfonamide (50 mg, 0.1 19 mmol) in acetic acid (5 mL) at room temperature. The reaction was stirred for 24 hours, the precipitate filtered and washed with methanol. The eluent was collected and evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 4-((3-

(cyclopentylsulfonyl)phenyl)amino)-N-cyclopropyl-7-(2,4-d imethoxypyrimidin-5- yl)quinoline-3-sulfonamide (20 mg, 0.031 mmol, 26.2 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ: 9.19 (s, 1 H), 8.65 (br. s., 1 H), 8.58 (s, 1 H), 8.34 (d, J = 1 .5 Hz, 1 H), 7.51 - 7.79 (m, 6 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.71 (t, J = 7.7 Hz, 1 H), 2.28 - 2.42 (m, 1 H), 1.69 - 1.81 (m, 4 H), 1.42 - 1.62 (m, 4 H), 0.39 - 0.50 (m, 4 H).

Example 69

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- methylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide

A solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (150 mg, 0.36 mmol) and 3-amino-N-methylbenzenesulfonamide (85 mg, 0.46 mmol) in 1 ,4-dioxane (5 mL) and acetic acid (0.5 mL) was stirred at 95 °C for 3 h, then concentrated in vacuo. Aqueous sodium carbonate (10 mL) was added, and the mixture extracted with ethyl acetate (10 mL x 3). The organic layers were concentrated in vacuo, purified by prep-TLC. The product (135 mg) was recrystallized from aqueous methanol to give the title compound (55 mg, 27 %) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.39 (d, J = 4.8 Hz, 4 H), 2.14-2.25 (m, 1 H), 2.33 (d, J = 4.8 Hz, 3 H), 3.98 (s, 6 H), 7.23 - 7.70 (m, 7 H), 8.27 (s, 1 H), 8.49 (s, 1 H), 8.54 (s, 1 H), 8.57 (s, 1 H), 9.1 1 (s, 1 H). LCMS (ES+) m/e 571 [M+H] ⁺ .

Example 70

4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-N-cvclopropyl-7 -(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide

To a solution of 4-chloro-N-cyclopropyl-7-(2, 4-dimethoxypyrimidin-5-yl)quinoline- 3-sulfonamide (147 mg, 0.35 mmol) in 1 ,4-dioxane (5 mL) and acetic acid (1 mL) was added 3-amino-N-ferf-butylbenzenesulfonamide (80 mg, 0.35 mmol). The mixture was stirred at 80 °C for 2 h. TLC showed no starting materials left. Water (20 mL) was added with stirring. The reaction mixture was extracted with ethyl acetate (50 mL x 2). The extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (2% methanol/dichloromethane) afforded the title compound (124 mg, 57.7%) as a colorless solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.39 (d, J=5.1 Hz, 4 H), 0.99 (s, 9 H), 2.18-2.22 (m, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 7.24-7.64 (m, 7 H), 8.26 (s, 1 H), 8.49-8.55 (m, 3 H), 9.10 (s, 1 H). LCMS (ES+) m/e 613 [M+H] ⁺ .

Example 71

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- ethylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide

To a solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (147 mg, 0.35 mmol) in 1 ,4-dioxane (5 mL) and acetic acid (1 mL) was added 3-amino-N-ethylbenzenesulfonamide(70 mg, 0.35 mmol) and the mixture stirred at 80 °C for 2 h. TLC showed no starting material left. Water (20 mL) was added with stirring. The reaction mixture was extracted with ethyl acetate (50 mL x 2). The extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (2% methanol/dichloromethane) afforded the title compound (1 10 mg, 54.0%) as a colorless solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm 0.39 (d, J = 5.1 Hz, 4 H), 0.87 (t, J = 7.2 Hz, 3 H), 2.18-2.24 (m, 1 H), 2.61-2.70 (m, 2 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 7.25-7.28 (m, 2 H), 7.41-7.70 (m, 5 H), 8.27 (s, 1 H), 8.50- 8.57 (m, 3 H), 9.1 1 (s, 1 H). LCMS (ES+) m/e 585 [M+H] ⁺ .

Example 72

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N,N- dimethylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide To a solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (100 mg, 0.24 mmol) in 1 ,4-dioxane (20 mL) and acetic acid (1 mL) was added 3-amino-N,N-dimethylbenzenesulfonamide (57 mg, 0.29 mmol) and the mixture stirred at 95 °C for 4 h. TLC showed the starting material was consumed completely. The mixture was cooled to room temperature and concentrated. The residue was d in water (10 mL). Ethyl acetate (20 ml) and sodium carbonate solution (2 mL) were added and the mixture extracted with ethyl acetate (15 mL x 3). The combined organic layers were concentrated, purified by prep-TLC to afford the title compound (88 mg, 63%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.38-0.41 (m, 4 H), 2.18-2.25 (m, 1 H), 2.53 (s, 6 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 7.17 (s, 1 H), 7.31-7.38 (m, 2 H), 7.55 (t, J=7.8 Hz, 1 H), 7.69 (s, 2 H), 8.26 (s, 1 H), 8.53 (s, br, 1 H), 8.57 (s, 2 H), 9.1 1 (s, 1 H). LCMS (ES+) m/e 585 [M+H] ⁺ . Example 73

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- isopropylsulfamoyl)phenyl)amino)quinoline-3-sulfonamide To a solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (150 mg, 0.36 mmol) in 1 ,4-dioxane (5 ml.) and ethanol (10 ml.) was added 3-amino-N-isopropylbenzenesulfonamide (92 mg, 0.43 mmol). The mixture was stirred at 95 °C for 4 h. TLC showed the starting material was consumed completely. The mixture was cooled to room temperature and concentrated. Water (20 ml.) and ethyl acetate (40 mL) were added. The mixture was extracted with ethyl acetate (20 ml. x 3). The combined organic layers were concentrated and purified by prep-TLC to afford the title compound (107 mg, 50%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm 0.39- 0.40 (m, 4 H), 0.87 (d, J=6.3 Hz, 6 H), 2.17-2.24 (m, 1 H), 3.06-3.18 (m, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 7.25-7.29 (m, 2 H), 7.43-7.53 (m, 3 H), 7.64 (s, 2 H), 8.27 (s, 1 H), 8.49- 8.52 (m, 2 H), 8.57 (s, 1 H), 9.10 (s, 1 H). LCMS (ES+) m/e 599 [M+H] ⁺ .

Example 74

5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amino)-5'-oxo-

2',3',4',5'-tetrahvdro-ri,1 '-biphenyll-3-carboxylic acid a) 5-amino-5'-oxo-2',3',4',5'-tetrahvdro-ri, 1 '-biphenyll-3-carboxylic acid.

Bis(pinacolato)diboron (290 mg, 1.143 mmol) was added to a stirred solution of 3- bromocyclohex-2-enone (100 mg, 0.571 mmol), [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (20.89 mg, 0.029 mmol) and potassium acetate (168 mg, 1 .714 mmol) in dry 1 ,4-dioxane (5 ml.) under nitrogen. The reaction was allowed to slowly warm to room temperature, and was stirred for an additional 3 hours. The solution was filtered. Potassium carbonate (158 mg, 1.143 mmol) in water (2 ml_), 3-amino-5-bromobenzoic acid (61.4 mg, 0.286 mmol) and tetrakis(triphenylphosphine)palladium(0) (33.0 mg, 0.029 mmol) were added to the filtrate. The mixture was heated under reflux for 4 hours, filtered, concentrated and purified by reverse-phase preparative HPLC (ODS, 10- 90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 5-amino-5'-oxo-2',3',4',5'- tetrahydro-[1 , 1 '-biphenyl]-3-carboxylic acid (49 mg, 0.193 mmol, 33.7 % yield) as a pale yellow syrup. ¹ H NMR (METHANOL-d ₄ ) δ: 8.16 (t, J = 1 .5 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 7.70 (t, J = 1.9 Hz, 1 H), 6.39 - 6.58 (m, 1 H), 2.82 - 2.94 (m, 2 H), 2.45 - 2.56 (m, 1 H), 2.20 (q, 3 H).

5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)-5'-oxo-2',3',4',5'-tetrahvdro-ri,1 '-biphenyll-3-carboxylic acid. 5-Amino-5'- oxo-2',3',4',5'-tetrahydro-[1 , 1 '-biphenyl]-3-carboxylic acid (49 mg, 0.212 mmol) was added to a stirred solution of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (50 mg, 0.1 19 mmol) in acetic acid (5 ml.) at room temperature. The reaction was stirred for 24 hours, then the precipitate filtered and washed with methanol. The eluent was collected and evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 5-((3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)-5'-oxo- 2',3',4',5'-tetrahydro-[1 , 1 '-biphenyl]-3-carboxylic acid (10 mg, 0.016 mmol, 13.13 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ: 9.18 (s, 1 H), 8.63 (br. s., 1 H), 8.59 (s, 1 H), 8.33 (d, J = 1.5 Hz, 1 H), 7.94 (s, 1 H), 7.77 (s, 1 H), 7.72 (s, 1 H), 7.70 (d, J = 1 .8 Hz, 1 H), 7.61 - 7.68 (m, 1 H), 6.26 (s, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H), 2.74 (t, J = 5.4 Hz, 2 H), 2.28 - 2.44 (m, 3 H), 2.08 (s, 1 H), 1.99 - 2.06 (m, 2 H), 0.35 - 0.58 (m, 4 H). Example 75

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amm

hvdroxy-5-((3-(trifluoromethyl)phenyl)amino)benzimidamide

a) 3-nitro-5-((3-(trifluoromethyl)phenyl)amino)benzonitrile. To a suspension of 3- bromo-5-nitrobenzonitrile (600 mg, 2.64 mmol), 3-(trifluoromethyl)aniline (426 mg, 2.64 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (126 mg, 0.264 mmol), cesium carbonate (1292 mg, 3.96 mmol) in ferf-butanol (2 ml.) and toluene (10 ml.) was added palladium(ll) acetate (1 1.87 mg, 0.053 mmol). The mixture was heated in a microwave reactor at 120 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford 3-nitro-5-((3-

(trifluoromethyl)phenyl)amino)benzonitrile (580 mg, 1 .888 mmol, 71.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=6.82 Hz, 1 H) 7.44

(s, 1 H) 7.52 - 7.63 (m, 2 H) 7.80 (s, 1 H) 8.03 (t, J=2.02 Hz, 1 H) 8.09 (s, 1 H) 9.39 (s, 1 H). LCMS (ES+) m/e 308 [M+H] ⁺ .

b) N-hvdroxy-3-nitro-5-((3-(trifluoromethyl)phenyl)amino)benzim idamide. To a

suspension of 3-nitro-5-((3-(trifluoromethyl)phenyl)amino)benzonitrile (580 mg, 1.888 mmol) and hydroxylamine hydrochloride (262 mg, 3.78 mmol) in ethanol (10 ml.) was added sodium carbonate (400 mg, 3.78 mmol). The mixture was heated in a microwave reactor at 120 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford N-hydroxy-3-nitro-5-((3-

(trifluoromethyl)phenyl)amino)benzimidamide (250 mg, 0.735 mmol, 38.9 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.05 (br. s., 2 H) 7.29 (d, J=7.58 Hz, 1 H) 7.38 (s, 1 H) 7.47 - 7.52 (m, 1 H) 7.52 - 7.60 (m, 1 H) 7.80 - 7.86 (m, 2 H) 7.95 - 8.00 (m, 1 H) 9.12 (s, 1 H) 9.93 (s, 1 H). LCMS (ES+) m/e

341 [M+H] ⁺ .

c) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-N-hvdroxy-5-((3-(trifluoromethyl)phenyl)amino)benz imi To a suspension of 10% palladium on carbon (31.3 mg, 0.0294 mmol) in acetic acid (10 mL) was added N-hydroxy-3-nitro-5-((3-

(trifluoromethyl)phenyl)amino)benzimidamide (100 mg, 0.294 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (1 1 1 mg, 0.265 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 %

trifluoroacetic acid) to afford 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-N-hydroxy-5-((3 - (trifluoromethyl)phenyl)amino)benzimidamide, trifluoroacetic acid salt (60 mg, 0.074 mmol, 25.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.37 - 0.42 (m, 2 H) 0.42 - 0.47 (m, 2 H) 2.21 - 2.28 (m, 1 H) 3.98 (s, 6H) 6.63 (d, J=2.02 Hz, 1 H) 7.01 (s, 1 H) 7.07 (br. s., 1 H) 7.12 (d, J=7.07 Hz, 1 H) 7.16 (br. s., 1 H) 7.18 -7.29 (m, 2 H) 7.74 - 7.80 (m, 1 H) 7.80 - 7.87 (m, 1 H) 8.26 - 8.33 (m, 1 H) 8.44 - 8.57 (m, 2 H) 8.61 (s, 1 H) 8.75 (br. s., 1 H) 9.01 - 9.1 1 (m, 2 H) 9.32 (s, 1 H). LCMS (ES+) m/e 695 [M+H] ⁺ .

Example 76

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrroli dine-1 -carbonyl)-5- sulfamoylphenyl)amino)quinoline-3-sulfonamide

a) 3-amino-5-sulfamoylbenzoic acid. A solution of 4-chloro-3-nitro-5- sulfamoylbenzoic acid (1.00 g, 3.56 mmol) in methanol (20 mL) and 5M aqueous sodium hydroxide (2.00 mL, 10 mmol) was stirred with 5% wet palladium on carbon (1 .00 g, 0.235 mmol) under 1 atm hydrogen for 3 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. Most of the solvent was removed under reduced pressure. The pH of the residue was adjusted to 4 with 6M aqueous hydrochloric acid and the mixture allowed to stand for 16 h, then cooled in ice. The solid was filtered off, washed with cold water and dried to give the title compound (0.323 g, 42%) as a light brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.57 (br. s., 2 H) 7.07 (t, J=2.02 Hz, 1 H) 7.18 (s, 2 H) 7.31 (dd, J=2.27, 1.26 Hz, 1 H) 7.53 (t, J=1.52 Hz, 1 H).

b) 3-amino-5-(pyrrolidine-1 -carbonyl)benzenesulfonamide. (Benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.722 g, 1 .39 mmol) was added to a stirred solution of 3-amino-5-sulfamoylbenzoic acid (0.200 g, 0.925 mmol), pyrrolidine (0.229 mL, 2.78 mmol) and triethylamine (0.387 mL, 2.78 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (5 mL) and the mixture stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was chromatographed (silica gel, 2-10%

methanol/dichloromethane) to give the title compound (0.302 g, 75% pure, 91 %) as a gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.68 - 2.00 (m, 4 H) 3.36 (t, J=6.32 Hz, 2 H) 3.44 (t, J=6.69 Hz, 2 H) 5.72 (s, 2 H) 6.82 (dd, J=2.02, 1 .52 Hz, 1 H) 7.02 (t, J=1 .52 Hz, 1 H) 7.04 - 7.08 (m, 1 H) 7.24 (s, 2 H).

c) N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrroli dine-1 -carbonyl)-5- sulfamoylphenyl)amino)quinoline-3-sulfonamide. A mixture of 4-chloro-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide (0.090 g, 0.214 mmol) and 3-amino-5-(pyrrolidine-1 -carbonyl)benzenesulfonamide (0.092 g, 0.342 mmol) in acetic acid (1 mL) was stirred at 50 °C for 2 h, then cooled slowly over 18 h. The mixture was diluted with acetic acid ( 2mL). The precipitate was filtered off, washed with acetic acid and dried to give the title compound (0.080 g, 57%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.42 - 0.51 (m, 4 H) 1 .62 - 1 .72 (m, 2 H) 1 .72 - 1 .85 (m, 2 H) 2.24 - 2.32 (m, 1 H) 3.09 (br. s., 2 H) 3.37 (t, J=6.95 Hz, 2 H) 3.98 (s, 3 H) 4.00 (s, 3 H) 7.26 (s, 1 H) 7.51 (s, 2 H) 7.63 (s, 1 H) 7.67 - 7.71 (m, 2 H) 7.75 (dd, J=8.84, 1 .52 Hz, 1 H) 8.33 (d, J=1.26 Hz, 1 H) 8.57 (br. s., 1 H) 8.60 (s, 1 H) 8.89 (br. s., 1 H) 9.17 (s, 1 H). Example 77

N-((3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin -5-yl)quinolin-4^ yl)amino)phenyl)sulfonyl)propionamide

a) N-(3-nitrophenylsulfonyl)propionamide. A mixture of 3-nitrobenzenesulfonamide (700 mg, 3.46 mmol), propionic anhydride (5 ml.) and concentrated sulphuric acid (0.4 ml.) was stirred at 80 °C for 12 h. TLC showed the starting material was consumed completely. The mixture was evaporated in vacuo, adjusted to pH 1 1 with 4N aqueous sodium hydroxide, and extracted with ethyl acetate (30 ml. x 3). The aqueous phase was adjusted to pH 5 with concentrated aqueous hydrochloric acid and extracted with ethyl acetate (40 ml. x 2). The extracts were washed with brine (80 mL x 2), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was washed with petroleum ether and the solid collected to give the title compound (895 mg, 99%) as a brown solid. LCMS (ES+) m/e 259 [M+H] ⁺ .

b) N-(3-aminophenylsulfonyl)propionamide. A mixture of N-(3- nitrophenylsulfonyl)propionamide (895 mg, 3.5 mmol) and 10% wet palladium on carbon (90 mg) in methanol (25 mL) was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 12 h. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound (760 mg, 96%) as a white solid. LCMS (ES+) m/e 229 [M+H] ⁺ .

c) N-(3-(3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4- ylamino)phenylsulfonyl)propionamide. To a solution of 4-chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (200 mg, 0.48 mmol) in 1 ,4- dioxane (3 mL) and ethanol (10 mL) was added N-(3- aminophenylsulfonyl)propionamide (130 mg, 0.57 mmol). The mixture was stirred at 90 °C for 4 h. TLC showed the starting material was consumed completely. The mixture was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and ethyl acetate (10 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were concentrated, purified by silica gel chromatography, then prep-TLC to afford the title compound (125 mg, 43%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.37-0.39 (m, 4 H), 0.82 (t, J=7.2Hz, 3 H), 2.1 1 (q, J=7.2Hz, 2 H), 2.16-2.23 (m, 1 H), 3.97 (s, 3 H), 3.99 (s, 3 H), 7.28-7.30 (m, 1 H), 7.36 (s, 1 H), 7.48-7.55 (m, 2 H), 7.61 (d, J=9.0 Hz, 1 H), 7.68(d, J=9.0 Hz, 1 H), 8.29 (s, 1 H), 8.48 (s, 1 H), 5.57-8.59 (m, 2 H), 9.12 (s, 1 H), 1 1.92 (s, 1 H). LCMS (ES+) m/e 613 [M+H] ⁺ .

Example 78

N-cvclopropyl-4-((3-(N-cvclopropylsulfamoyl)phenyl)amino)-7- (2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide

To a solution of 4-chloro-N-cyclopropyl-7-(2, 4-dimethoxypyrimidin-5-yl)quinoline-

3- sulfonamide (147 mg, 0.35 mmol) in 1 ,4-dioxane (5 mL) and acetic acid (1 mL) was added 3-amino-N-cyclopropylbenzenesulfonamide(74 mg, 0.35 mmol) and the mixture stirred at 80 °C for 2 h. TLC showed no starting material left. Water (20 mL) was added with stirring. The reaction mixture was extracted with ethyl acetate (50 mL x 2). The extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (2% methanol/dichloromethane) afforded the title compound (88 mg, 42%) as a colorless solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) δ ppm 0.32-0.41 (m, 8 H), 1 .95-2.01 (m, 1 H), 2.18-2.24 (m, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 7.28-7.31 (m, 2 H), 7.44-7.55 (m, 2 H), 7.67 (s, 2 H), 7.88 (d, J = 2.4 Hz, 1 H), 8.27 (s, 1 H), 8.52-8.56 (m, 3 H), 9.1 1 (s, 1 H). LCMS (ES+) m/e 597 [M+H] ⁺ .

Example 79

N-((3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin -5-yl)quinolin-4- yl)amino)phenyl)sulfonyl)acetamide N-(3-nitrophenylsulfonyl)acetamide. A mixture of 3-nitrobenzenesulfonamide (500 mg, 2.47 mmol) in acetic anhydride (1 .5 mL) and concentrated sulphuric acid (0.2 mL) was stirred at 70 °C for 12 h. TLC and LCMS showed desired product and no starting material left. The mixture was cooled to room temperature and the solid filtered and washed with ethanol (10 mL) to give the title compound (380 mg) as a yellow solid. LCMS (ES+) m/e 245 [M+H] ⁺ .

N-(3-aminophenylsulfonyl)acetamide. A mixture of N-(3- nitrophenylsulfonyl)acetamide (330 mg, 1.35 mmol) and 10% palladium on carbon (33 mg) in methanol (15 mL) was stirred at room temperature under hydrogen atmosphere for 12 h. TLC and LCMS showed desired product and no starting material left. The mixture was filtered and evaporated in vacuo to give the title compound (270 mg) as a yellow solid. LCMS (ES+) m/e 215 [M+H] ⁺ .

N-((3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- yl)amino)phenyl)sulfonyl)acetamide. To a solution of 4-chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (147 mg, 0.35 mmol) in 1 ,4- dioxane (5 mL) and acetic acid (1 mL) was added N-(3- aminophenylsulfonyl)acetamide (75 mg, 0.35 mmol). The mixture was stirred at 80 °C for 2 h. TLC showed no starting material left. Water (20 mL) was added with stirring. The reaction mixture was extracted with ethyl acetate (50 mL x 2). The extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (2%

methanol/dichloromethane) afforded the title compound (75 mg, 36%) as colorless solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.37-0.39 (m, 4 H), 1.84 (s, 3 H), 2.15-2.23 (m, 1 H), 3.97 (s, 3 H), 3.99 (s, 3 H), 7.26-7.72 (m, 6 H), 8.30 (d, J = 1 .5 Hz, 1 H), 8.48 (d, J = 2.4 Hz, 1 H), 8.57 (s, br, 1 H), 8.59 (s, 1 H), 9.12 (s, 1 H), 1 1 .98 (s, br, 1 H). LCMS (ES+) m/e 599 [M+H] ⁺ .

N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-methoxy- 5- sulfamoylphenyl)amino)quinoline-3-sulfonamide

a) 3-methoxy-5-nitrobenzenesulfonamide. ferf-Butyl nitrite (0.594 ml_, 5.00 mmol) was injected dropwise into an ice-cooled, stirred solution of 3-methoxy-5- nitroaniline (0.560 g, 3.33 mmol) and 48% aqueous tetrafluoroboric acid (0.653 ml_, 5.00 mmol) in acetonitrile (5 ml_). The mixture was stirred in ice for 0.75 h. Meanwhile, an ice-cooled mixture of copper(l) chloride (0.495 g, 5.00 mmol) and acetic acid (6 ml.) was saturated with sulfur dioxide (5.0 g, 78 mmol). The mixture was added to the diazonium salt mixture and the resulting black suspension stirred for 5 min at 0 °C, then allowed to warm to room temperature over 1 h. The mixture was poured onto ice, and extracted with diethyl ether. The extracts were washed with water twice, brine, dried (MgS0 ₄ ) and evaporated under reduced pressure. 0.5M Ammonia in 1 ,4-dioxane was poured into the crude residue cooled in ice and the mixture stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue slurried in ethyl acetate. The solution was dried

(MgS0 ₄ ) and evaporated under reduced pressure to give the title compound (0.754 g, 97%) as an orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.97 (s, 3 H) 7.72 (s, 2 H) 7.75 (dd, J=2.27, 1 .52 Hz, 1 H) 7.94 (t, J=2.27 Hz, 1 H) 8.18 (dd, J=2.02, 1 .52 Hz, 1 H).

b) 3-amino-5-methoxybenzenesulfonamide. A solution of 3-methoxy-5- nitrobenzenesulfonamide (0.348 g, 1.50 mmol) in methanol (10 mL) was stirred with 5% wet palladium on carbon (0.340 g, 0.080 mmol) under 1 atm hydrogen for 3 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound (0.277 g, 91 %) as a light brown solid. ¹ H NMR (400 MHz,

DMSO-d ₆ ) δ ppm 3.71 (s, 3 H) 5.55 (br. s., 2 H) 6.27 (t, J=2.02 Hz, 1 H) 6.48 - 6.55 (m, 1 H) 6.64 (t, J=1 .64 Hz, 1 H) 7.14 (s, 2 H).

c) N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-methoxy- 5- sulfamoylphenyl)amino)quinoline-3-sulfonamide. A mixture of 4-chloro-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide (0.090 g,

0.214 mmol) and 3-amino-5-methoxybenzenesulfonamide (0.055 g, 0.272 mmol) in acetic acid (1 mL) was stirred at 50 °C for 2 h, then cooled slowly over 18 h. The mixture was diluted with acetic acid ( 2ml_). The precipitate was filtered off, washed with acetic acid and dried to give the title compound (0.062 g, 49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.43 - 0.52 (m, 4 H) 2.22 - 2.37

(m, 1 H) 3.76 (s, 3 H) 3.98 (s, 3 H) 4.00 (s, 3 H) 6.91 (s, 1 H) 7.1 1 - 7.19 (m, 2 H) 7.41 (s, 2 H) 7.67 (d, J=9.09 Hz, 1 H) 7.74 (dd, J=9.09, 1 .77 Hz, 1 H) 8.34 (d, J=1.26 Hz, 1 H) 8.62 (s, 1 H) 8.66 (br. s., 1 H) 8.94 (br. s., 1 H) 9.15 (s, 1 H).

Example 81

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4-yl)amin

sulfamoylbenzoic acid

A mixture of 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinol ine-3- sulfonamide (0.075 g, 0.178 mmol) and 3-amino-5-sulfamoylbenzoic acid (0.050 g, 0.232 mmol) in acetic acid (1 mL) was stirred at 50 °C for 2 h. Triethylamine (0.032 mL, 0.232 mmol) was added and the mixture stirred a further 2 h, then cooled. The mixture was diluted with acetic acid (2 mL). The precipitate was filtered off, washed with acetic acid and dried. The solid was purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (0.042 g, 39%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.33 - 0.49 (m, 4 H) 2.20 - 2.30 (m, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 7.49 (s, 2 H) 7.58 - 7.64 (m, 2 H) 7.69 (d, J=8.84 Hz, 1 H) 7.75 (d, J=9.35 Hz, 1 H) 8.02 (t, J=1.39 Hz, 1 H) 8.33 (s, 1 H) 8.47 (br. s., 1 H) 8.61 (s, 1 H) 8.76 (br. s., 1 H) 9.18 (br. s., 1 H) 13.45 (br. s., 1 H).

Example 82

4-((3-cvclopentyl-5-(2H-tetrazol-5-yl)phenyl)amino)-N-cvclop ropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide

a) 3-(cvclopent-1-en-1-yl)-5-nitrobenzonitrile. To a suspension of 3-bromo-5- nitrobenzonitrile (100 mg, 0.440 mmol), cyclopent-1-en-1-ylboronic acid (99 mg, 0.881 mmol) and potassium carbonate (122 mg, 0.881 mmol) in 1 ,4-dioxane (12 mL) and water (4.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (50.9 mg, 0.044 mmol). The mixture was heated at 120 °C for 0.5 h. After cooling, the mixture was diluted with water, acidified with 6M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography (0-100% ethyl acetate in hexanes) to afford 3-(cyclopent-1 - en-1 -yl)-5-nitrobenzonitrile (55 mg, 0.257 mmol, 58.3 % yield). ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 2.06 - 2.19 (m, 2 H) 2.58 - 2.69 (m, 2 H) 2.74 - 2.88 (m, 2 H) 6.60 - 6.68 (m, 1 H) 8.21 (t, J=1.52 Hz, 1 H) 8.45 (t, J=1 .64 Hz, 1 H) 8.51 (t, J=1.89 Hz, 1 H). LCMS (ES+) m/e 215 [M+H] ⁺ .

b) 5-(3-(cvclopent-1-en-1-yl)-5-nitrophenyl)-2H-tetrazole. To a suspension of 3- (cyclopent-1 -en-1 -yl)-5-nitrobenzonitrile (100 mg, 0.467 mmol) in N,N- dimethylformamide (10 mL) was added sodium azide (60.7 mg, 0.934 mmol). The mixture was heated under mircowave irradiation at 150 °C for one hour. After cooling, the reaction was filtered and organic solvent was removed under reduced pressure. The resulting brown oil was purified via preparative HPLC (YMC 20X50 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 5-(3- (cyclopent-1 -en-1-yl)-5-nitrophenyl)-2H-tetrazole (90 mg, 0.350 mmol, 74.9 % yield). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.97 - 2.09 (m, 2 H) 2.54 - 2.62 (m, 2 H) 2.74 - 2.82 (m, 2 H) 6.58 (t, J=2.02 Hz, 1 H) 8.12 (t, J=2.02 Hz, 1 H) 8.42 (t,

J=1.52 Hz, 1 H) 8.56 - 8.61 (m, 1 H). LCMS (ES+) m/e 258 [M+H] ⁺ .

c) 4-((3-cvclopentyl-5-(2H-tetrazol-5-yl)phenyl)amino)-N-cvclop ropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide. To a suspension of 10% palladium on carbon (33.1 mg, 0.031 1 mmol) in acetic acid (10 mL) was added 5- (3-(cyclopent-1 -en-1-yl)-5-nitrophenyl)-2H-tetrazole (80 mg, 0.31 1 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide (1 18 mg, 0.280 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature, then purified via preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 %

trifluoroacetic acid) to afford 4-((3-cyclopentyl-5-(2H-tetrazol-5-yl)phenyl)amino)-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide, trifluoroacetic acid salt (90 mg, 0.124 mmol, 39.8 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.40 - 0.49 (m, 4 H) 1.48 - 1.58 (m, 2 H) 1.58 - 1.66 (m, 2 H) 1.66 -1 .76 (m, 2 H) 1 .96 - 2.05 (m, 2 H) 2.25 - 2.32 (m, 1 H) 2.96 - 3.08 (m, 1 H) 3.97 (s, 6 H) 7.15 (s, 1 H) 7.56 (s, 1 H) 7.61 - 7.70 (m, 2 H) 7.71 (s, 1 H) 8.27 (d,

J=1.01 Hz, 1 H) 8.52 - 8.60 (m, 2 H) 8.68 (br. s., 1 H) 9.12 (s, 1 H). LCMS (ES+) m/e 614 [M+H] ⁺ .

Example 83

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)amino)-5-(3- oxocyclohexyDbenzoic acid

a) 3-amino-5-(3-oxocvclohexyl)benzoic acid. 10% palladium on carbon (31 .5 mg, 0.030 mmol) was added to a stirred solution of 5-amino-5'-oxo-2',3',4',5'- tetrahydro-[1 , 1 '-biphenyl]-3-carboxylic acid (137 mg, 0.592 mmol) in methanol (5 ml.) under nitrogen. The flask was then purged with hydrogen and the reaction stirred at room temperature overnight. The flask was purged with nitrogen, and the catalyst filtered. Purification by reverse-phase preparative HPLC (ODS, 10- 90% acetonitrile/water + 0.1 % trifluoroacetic acid) gave 3-amino-5-(3- oxocyclohexyl)benzoic acid (17 mg, 0.064 mmol, 10.83 % yield) as clear glassy solid. ¹ H NMR (DMSO-d ₆ ) δ: 7.38 (s, 1 H), 7.34 (d, J = 1.8 Hz, 1 H), 7.00 (s, 1 H), 2.94 - 3.05 (m, 1 H), 2.19 - 2.36 (m, 2 H), 2.03 (ddd, J = 12.9, 6.4, 3.2 Hz, 1 H), 1.88 (ddd, J = 19.0, 12.3, 3.3 Hz, 2 H), 1 .62 - 1 .82 (m, 3 H).

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(3-oxocvclohexyl)benzoic acid. 4-Chloro-N-cyclopropyl-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (23 mg, 0.055 mmol) and 3- amino-5-(3-oxocyclohexyl)benzoic acid (16.57 mg, 0.071 mmol) were dissolved in acetic acid (5 mL) and the mixture stirred at room temperature over the weekend. Purification by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) afforded 3-((3-(N-cyclopropylsulfamoyl)-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(3-oxocyclohe xyl)benzoic acid (5 mg, 7.69 mol, 14.07 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ: 9.14

(s, 1 H), 8.61 - 8.69 (m, 1 H), 8.59 (s, 1 H), 8.29 (d, J = 1.8 Hz, 1 H), 7.49 - 7.83 (m, 4 H), 7.34 (s, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 2.95 - 3.1 1 (m, 1 H), 2.56 - 2.66 (m, 1 H), 2.13 - 2.45 (m, 4 H), 1.97 (td, J = 6.4, 3.3 Hz, 1 H), 1.76 - 1.91 (m, 2 H), 1.59 - 1.72 (m, 1 H), 0.38 - 0.56 (m, 4 H).

Example 84

4-((3-amino-5-cvanophenyl)amino)-N-cvclopropyl-7-(2,4-dimeth oxypyrimidin-5- yl)quinoline-3-sulfonamide

3,5-Diaminobenzonitrile (28.5 mg, 0.214 mmol) was added to a stirred solution of

4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)qui noline-3-sulfonamide (50 mg, 0.1 19 mmol) in acetic acid (5 mL) at room temperature. The reaction was stirred over a weekend. The resulting precipitate was filtered and washed with acetic acid to give 4-((3- amino-5-cyanophenyl)amino)-N-cyclopropyl-7-(2,4-dimethoxypyr imidin-5-yl)quinoline-3- sulfonamide (18 mg, 0.033 mmol, 27.8 % yield) as a pale yellow solid. LCMS (ES+) m/e 518 [M+H] ⁺ .

Example 85

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5 -yl)quinolin-4-yl)ami^

dimethyl-5-sulfamoylbenzamide

a) 3-amino-N,N-dimethyl-5-sulfamoylbenzamide. (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.722 g, 1 .39 mmol) was added to a stirred solution of 3-amino-5-sulfamoylbenzoic acid (0.200 g, 0.925 mmol), 2.7M dimethylamine in methanol (1.03 mL, 2.78 mmol) and triethylamine (0.387 mL, 2.78 mmol) in N,N-dimethylformamide (5 mL) and the mixture stirred at room temperature for 18 h. The solvent was removed under reduced pressure.

The residue was chromatographed (silica gel, 2-10% methanol/dichloromethane) to give the title compound (0.321 g) as a gum, containing impurities, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.91 (br. s., 3 H) 2.96 (br. s., 3 H) 5.74 (s, 2 H) 6.69 (dd, J=2.15, 1.39 Hz, 1 H) 6.90 (t, J=1 .52 Hz, 1 H) 7.03 - 7.07 (m, 1 H) 7.25 (s, 2 H). LCMS (ES+) m/z

244 [M+H] ⁺ .

b) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-N,N-dimethyl-5-sulfamoylbenzamide. A mixture of 4-chloro-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfo namide (0.090 g, 0.214 mmol) and 3-amino-N,N-dimethyl-5-sulfamoylbenzamide (60% pure, 0.139 g, 0.342 mmol) in acetic acid (1 mL) was stirred at 50 °C for 2 h, then cooled slowly over 18 h. The solvent was removed under reduced pressure. The residue was chromatographed (silica gel, 1-9% methanol/dichloromethane) to give the title compound (0.080 g, 60%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 0.37 - 0.45 (m, 4 H) 2.17 - 2.28 (m, 1 H) 2.76 (s, 3 H) 2.89 (s, 3 H) 3.98 (s, 3

H) 3.99 (s, 3 H) 6.96 (s, 1 H) 7.41 (s, 1 H) 7.47 (br. s., 2 H) 7.55 (s, 1 H) 7.61 - 7.79 (m, 2 H) 8.26 (s, 1 H) 8.55 (br. s., 2 H) 8.58 (s, 1 H) 9.09 (br. s., 1 H). Example 86

-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimeth^

fluorophenoxy)benzamide

a) 3-(4-fluorophenoxy)-5-nitrobenzamide. A mixture of 3, 5-dinitrobenzamide (0.500 g, 2.37 mmol), 4-fluorophenol (0.531 g, 4.74 mmol), powdered potassium carbonate (0.655 g, 4.74 mmol) and N-methyl-2-pyrrolidone (5 mL) was stirred at 80 °C for 22 h, then cooled. 0.1 M aqueous potassium carbonate (50 mL) was added and the mixture stirred 5 min. The solid was filtered off, washed with water, dried and chromatographed (silica gel, 1-5% methanol/dichloromethane) to give the title compound (0.191 g, 29%) as a cream solid. ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 7.23 - 7.30 (m, 2 H) 7.30 - 7.38 (m, 2 H) 7.79 (s, 1 H) 7.85 (t, J=2.15 Hz, 1 H) 7.90 (dd, J=2.27, 1 .52 Hz, 1 H) 8.38 (s, 1 H) 8.45 - 8.47 (m, 1 H).

b) 3-amino-5-(4-fluorophenoxy)benzamide. A solution of 3-(4-fluorophenoxy)-5- nitrobenzamide (0.189 g, 0.684 mmol) in methanol (10 mL) was stirred with 5% wet palladium on carbon (0.190 g, 0.045 mmol) under 1 atm hydrogen for 2 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a nylon micropore filter. The solvent was removed under reduced pressure to give the title compound (0.156 g, 93%) as a colourless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.39 (s, 2 H) 6.26 (t, J=2.15 Hz, 1 H) 6.62 (dd, J=2.27, 1 .52 Hz,

1 H) 6.79 - 6.83 (m, 1 H) 6.97 - 7.10 (m, 2 H) 7.18 (br. s., 1 H) 7.20 - 7.27 (m, 2 H) 7.75 (br. s., 1 H).

c) 3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)quinolin-4- yl)amino)-5-(4-fluorophenoxy)benzamide. A mixture of 4-chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (0.090 g, 0.214 mmol) and 3-amino-5-(4-fluorophenoxy)benzamide (0.075 g, 0.305 mmol) in acetic acid (1 mL) was stirred at 50 °C for 2 h, then cooled slowly over 18 h. Acetic acid (2 mL) was added, then the precipitate filtered off, washed with acetic acid and dried to give the title compound (0.101 g, 75%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.40 - 0.49 (m, 4 H) 2.27 - 2.34 (m, 1 H) 3.99 (s, 3 H) 4.00 (s, 3 H) 6.85 (br. s., 1 H) 7.01 - 7.09 (m, 2 H) 7.09 - 7.17 (m, 2 H) 7.34 (s, 1 H) 7.49 (br. s., 1 H) 7.50 (br. s., 1 H) 7.70 (d, J=8.84 Hz, 1 H) 7.78 (dd, J=8.84, 1.77 Hz, 1 H) 8.01 (s, 1 H) 8.30 (d, J=1.77 Hz, 1 H) 8.61 (s, 1 H) 8.64 (br. s., 1 H) 8.92 (br. s., 1 H) 9.1 1 (s, 1 H).

Example 87

3-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-y l)-2-methylquino

yl)amino)-5-isopropoxybenzoic acid

a) diethyl 2-(1-ethoxyethylidene)malonate. A mixture of diethyl 2-acetylmalonate (10 g, 0.049 mol), 1 , 1 ,1 -triethoxyethane (24 g, 0.15 mol) and ZnCI ₂ (70 mg, 0.0049 mol) was stirred at 95 °C for 4 h under an inert atmosphere. The mixture was concentrated and the residue was purified by silica gel chromatography (10% pet. ether in ethyl acetate) to give the desired product as an oil (6.4 g, 56%). LC/MS: MS (ES ⁺ ) m/e 231 (MH ⁺ ); ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 1.22-1.33 (m, 9 H), 2.43 (s, 3H), 4.06 (q, J = 6.9 Hz, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.26 (q, J = 7.2 Hz, 2 H).

b) diethyl 2-(1-(3-bromophenylamino)ethylidene)malonate. A mixture of diethyl 2-(1 - ethoxyethylidene)malonate (6.4 g, 0.028 mol) and 3-bromobenzenamine (4.4 g, 0.025 mol) was stirred at 105 °C for 18 h. Then the mixture was cooled and purified by silica gel chromatography (10% pet. ether in ethyl acetate) to afford the desired product as a yellow solid (6.6 g, 72%). LC/MS: MS (ES ⁺ ) m/e 356, 358 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .26-1.24 (m, 6 H), 2.05 (s, 3 H), 4.06-4.17 (m, 4 H), 7.26 (d, J = 8.1 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.52 (s, 1 H), 10.88 (br, 1 H)

c) ethyl 7-bromo-4-hvdroxy-2-methylquinoline-3-carboxylate. A mixture of diethyl 2- (1 -(3-bromophenylamino)ethylidene)malonate (5.6 g, 15.7 mmol) and Ph ₂ 0 (25 mL) was heated under reflux for 0.5 h. Then the mixture was cooled and filtered. The filter cake was washed with diethyl ether (25 mL) to give the desired product as a white solid (3.7 g, 76%). LC/MS: MS (ES ⁺ ) m/e 310, 312 (MH ⁺ ), ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .27 (t, J = 7.2 Hz, 3 H), 2.38 (s, 3 H), 4.24 (q, J = 7.2 Hz, 2 H), 7.49 (dd, J = 8.4, 1 .8 Hz, 1 H), 7.70 (d, J = 1 .8 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 1 1.90 (br, 1 H).

d) 7-bromo-4-hvdroxy-2-methylquinoline-3-carboxylic acid. A mixture of ethyl 7- bromo-4-hydroxy-2-methylquinoline-3-carboxylate (13 g, 0.042 mol), sodium hydroxide (33.5 g, 0.84 mol), water (140 mL) and ethanol (200 mL) was stirred and heated under reflux for 18 h. The solvent was removed and adjusted to pH = 3 with 1 N HCI. The precipitate was collected by filtration and washed with water (100 mL) to give the desired product as a white solid (1 1 g, crude). LC/MS: MS

(ES ⁺ ) m/e 282, 284 (MH ⁺ ), ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.89 (s, 3 H), 7.71 (dd, J = 8.4, 1.8 Hz, 1 H), 8.02 (d, J = 1.8 Hz, 1 H), 8.15 (d, J = 8.7 Hz, 1 H). e) 7-bromo-2-methylquinolin-4-ol. A mixture of 7-bromo-4-hydroxy-2- methylquinoline-3-carboxylic acid (1 g, 3.55 mmol) in Ph ₂ 0 (7 mL) was heated under reflux for 1 .5 h. Then the mixture was cooled and filtered. The filter cake was washed with ether (10 mL). The filter cake was dried to give the product as a brown solid (860 mg, crude). LC/MS: MS (ES ⁺ ) m/e 238, 240 (MH ⁺ ), ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.34 (s, 3 H), 5.93 (s, 1 H), 7.41 (dd, J = 8.7, 1.8 Hz, 1 H), 7.69 (d, J = 1 .8 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 1 1 .67 (s, 1 H).

f) 7-bromo-4-hvdroxy-2-methylquinoline-3-sulfonic acid. A solution of 7-bromo-2- methylquinolin-4-ol (860 mg crude) in sulfurochloridic acid (2 mL) was heated at 100 °C for 3 h. Then the mixture was cooled and poured into ice-water. A filtration was done and the filter cake was washed with water to afford the desired product as a brown solid (982 mg, crude). LC/MS: MS (ES ⁺ ) m/e 318, 320 (MH ⁺ ), 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 3.03 (s, 3 H), 7.97 (dd, J = 8.7, 1.8 Hz, 1 H),

8.16 (d, J = 1 .8 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H).

g) Preparation of 7-bromo-4-chloro-2-methylquinoline-3-sulfonyl chloride. A mixture of methyl 7-bromo-4-hydroxy-2-methylquinoline-3-sulfonic acid (500 mg, 1 .57 mmol) and N,N-dimethylbenzenamine (0.05 mL) in phosphoryl trichloride (10 mL) was stirred at 96 °C for 1 h. The mixture was concentrated to dryness and the residue (558mg, crude) was used for the next step directly.

h) 7-bromo-4-chloro-N-cvclopropyl-2-methylquinoline-3-sulfonami de. To a residue 7- bromo-4-chloro-2-methylquinoline-3-sulfonyl chloride (558 mg, crude) was added a solution of cyclopropanamine (447 mg 7.85 mmol) in DCM (10 mL) in one portion. Two minutes later, water (20 mL) was added. The mixture was extracted with DCM (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over Na ₂ S0 ₄ , filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (20% pet. ether in ethyl acetate) to afford desired product as a yellow solid (440 mg, 74%). LC/MS: MS (ES ⁺ ) m/e 377 (MH ⁺ ); ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 0.50-0.59 (m, 4H), 2.24-2.34 (m, 1 H), 3.06 (s, 3 H), 7.85 (dd, J = 9.0, 2.1 Hz, 1 H), 8.21 (d, J = 2.1 Hz, 1 H), 8.34 (d, J = 9.0 Hz, 1 H).

4-chloro-N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-2-met hylquinoline-3- sulfonamide. A mixture of 7-bromo-4-chloro-N-cyclopropyl-2-methylquinoline-3- sulfonamide (400 mg, 1 .07 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (294 mg, 1 .6 mmol), Pd(dppf)CI ₂ (70mg, 0.1 mmol) and aq. 1 N K ₂ C0 ₃ (2 mL) in dioxane (20 mL) was stirred at 68 °C for 1 10 minutes under N ₂ . The mixture was purified by silica gel chromatography (50% pet. ether in ethyl acetate) to afford the desired product as a brown solid (400 mg, 86%). LC/MS: MS (ES ⁺ ) m/e 435 (MH ⁺ ); ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 0.59-0.77 (m, 4H), 2.20-2.30 (m, 1 H), 3.17 (s, 3 H), 4.09 (s, 3 H), 4.10 (s, 3 H), 7.87 (dd, J = 8.7, 1 .8 Hz, 1 H), 8.26 (br, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.46 (s, 1 H).

methyl 3-(3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )-2- methylquinolin-4-ylamino)-5-isopropoxybenzoate. A mixture of 4-chloro-N- cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-2-methylquinolin e-3-sulfonamide (200 mg, 0.46 mmol) and methyl 3-amino-5-isopropoxybenzoate (144 mg, 0.69 mmol) in ethanol (25 mL) was stirred at 85 °C for 16 h. The solvent was removed and purified by preparative-TLC (silica gel, 50% pet. ether in ethyl acetate) to give the desired product as a yellow solid (166 mg, 59%). LC/MS: MS (ES ⁺ ) m/e 608 (MH ⁺ ); ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 0.42-0.59 (m, 4H), 1 .25 (d, J = 6.0 Hz, 6 H), 2.25-2.35 (m, 1 H), 3.05 (s, 3 H), 3.86 (s, 3 H), 4.05 (s, 3 H), 4.06 (s, 3 H) 4.42- 4.52 (m, 1 H), 5.25 (br, 1 H), 6.54 (s, 1 H), 7.17 (s, 1 H), 7.44 (dd, J = 9.0, 1.8 Hz, 1 H), 7.72 (d, J = 9.0 Hz 1 H), 8.16 (br, 1 H), 8.40 (s, 1 H), 9.16 (br, 1 H).

3-(3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )-2-methylquinolin-4- ylamino)-5-isopropoxybenzoic acid. To a solution of methyl 3-(3-(N- cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)-2-meth ylquinolin-4- ylamino)-5-isopropoxybenzoate (150 mg, 0.25 mmol) in methanol (5 mL) was added aq. 1 N LiOH (2.5 mL). The solution was stirred at room temperature for 16 h. The solvent was removed and water (10 mL) was added. It was extracted with ethyl acetate (10 mL), the aqueous layer was adjusted pH to 6 with 1 N HCI, then it was extracted with ethyl acetate (3 x 12 mL), the combined organic phases were washed with brine (10 mL), dried over Na ₂ S0 ₄ and purified by preparative-TLC (silica gel, DCM/MeOH = 8/1 ) to give the desired product as a yellow solid (120 mg, 82%). LC/MS: MS (ES ⁺ ) m/e 594 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.29-0.39 (m, 4 H), 1 .17 (d, J = 6.0 Hz, 6 H), 2.17-2.25 (m, 1 H), 2.92 (s, 3 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.46-4.56 (m, 1 H), 6.64 (s, 1 H), 6.97 (s, 1 H), 7.05 (s, 1 H) 7.57-7.69 (m, 2 H), 8.10 (s, 1 H), 8.57 (s, 1 H), 8.60 (br, 1 H), 9.08 (br, 1 H).

Example 88

3-cvclopentyl-5-((3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethox ypyrimidin-5-yl)-2- methylquinolin-4-yl)amino)benzoic acid

a) methyl 3-cvclopentyl-5-(3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxy pyrimidin-5- yl)-2-methylquinolin-4-ylamino)benzoate. A mixture of 4-chloro-N-cyclopropyl-7- (2,4-dimethoxypyrimidin-5-yl)-2-methylquinoline-3-sulfonamid e (157 mg, 0.36 mmol) and methyl 3-amino-5-cyclopentylbenzoate (158 mg, 0.72 mmol) in ethanol (20 mL) was stirred at 85 °C for 16 h. The solvent was removed and the residue was purified by preparative-TLC (silica gel, 50% pet. ether in ethyl acetate) to give the desired product as a yellow solid (156 mg, 70%). LC/MS: MS (ES+) m/e 618 (MH+). 1 H NMR (300 MHz, CDCI3) δ ppm 0.40-0.60 (m, 4 H), 1.36-2.06 (m, 8 H), 2.26-2.36 (m, 1 H), 2.85-2.98 (m, 1 H), 3.04 (s, 3 H), 3.86 (s, 3 H), 4.04 (s, 3 H), 4.06 (s, 3 H), 5.41 (br, 1 H), 6.90 (s, 1 H), 7.39-7.41 (m, 2 H), 7.62-7.67 (m, 2 H), 8.13 (d, J = 1 .5 Hz, 1 H), 8.39 (s, 1 H), 9.30 (br, 1 H).

b) 3-cvclopentyl-5-(3-(N-cvclopropylsulfamoyl)-7-(2,4-dimethoxy pyrimidin-5-yl)-2- methylquinolin-4-ylamino)benzoic acid acid. To a solution of methyl 3-cyclopentyl- 5-(3-(N-cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl )-2-methylquinolin-4- ylamino)benzoate (146 mg, 0.23 mmol) in methanol (15 mL) was added aq 1 N LiOH (2.3 mL). The solution was stirred at room temperature for 6 h. The solvent was removed and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL). The aqueous layer was adjusted to PH = 6 with 1 N HCI. Then it was extracted with ethyl acetate (3 x15 mL). The combined organic layers were washed with brine (10 ml_), dried over Na2S04 and concentrated to give a residue. The residue was purified by preparative-TLC (silica gel, DCM/MeOH = 8/1 ) to give the desired product as a yellow solid (80 mg, 56%). LC/MS: MS (ES+) m/e 604 (MH+); 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.29-0.37 (m, 4H), 1 .36- 1.48 (m, 2 H), 1.51-1 .69 (m, 4 H), 1 .88-2.00 (m, 2 H), 2.14-2.24 (m, 1 H), 2.88-

2.99 (m, 4 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 7.02 (s, 1 H), 7.22 (s, 1 H), 7.46 (s, 1 H), 7.52-7.64 (m, 2 H), 8.10 (d, J = 1.5 Hz, 1 H), 8.56 (s, 1 H), 8.61 (d, J = 1.5 Hz, 1 H), 9.15 (s, 1 H), 12.92 (br, 1 H).

Example 89

-((7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3-(N-methylsu lfamoyl)quinolin-4-yl)amino)-5- isopropoxybenzoic acid

a) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-N,2-dimethylquinoli ne-3-sulfonamide. A mixture of 7-bromo-4-chloro-N,2-dimethylquinoline-3-sulfonamide (220 mg, 0.64 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (1 18 mg, 0.64 mmol) and

Pd(PPh ₃ ) ₂ CI ₂ (45 mg, 0.064 mmol) in dioxane (30 ml.) and 1 N K ₂ C0 ₃ (1.5 ml.) was stirred at 80 °C under nitrogen for 50 min. It was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by

chromatography on silica gel (25% then 50% pet. ether in ethyl acetate) to afford the desired product as a yellow solid (233 mg, 89%). LC/MS: MS (ES ⁺ ) m/e 409 (MH ⁺ ); ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 2.73 (d, J = 5.4 Hz, 3 H), 3.13 (s, 3 H), 4.08 (s, 3 H), 4.09 (s, 3 H), 5.30 (q, J = 5.1 Hz, 1 H), 7.86 (dd, J = 8.7, 1.5 Hz, 1 H), 8.20 (d, J = 1 .5 Hz, 1 H), 8.38 (d, J = 8.7 Hz, 1 H), 8.45 (s, 1 H).

b) methyl 3-(7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3-(N-methylsulfa moyl)quinolin-

4-ylamino)-5-isopropoxybenzoate. A mixture of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)-N,2-dimethylquinoline-3-sulfonamide (82 mg, 0.2 mmol) and methyl 3-amino-5-isopropoxybenzoate (42 mg, 0.2 mmol) in EtOH (10 mL) was refluxed for 3h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, elution with ethyl acetate/pet. ether (1/1 ) then MeOH/DCM (1/20), to afford the desired product as a brown solid (103 mg, 89%). LC/MS: MS(ES ⁺ ) m/e 582 (MH ⁺ ); 1H NMR (300 MHz, CDCI ₃ ) δ ppm 1 .26 (d, J = 6.0 Hz, 6 H), 2.64 (d, J = 4.5 Hz, 3 H), 3.05 (s, 3 H), 3.86 (s, 3 H), 4.05 (s, 3 H), 4.06 (s, 3 H), 4.42-4.54 (m, 1 H), 4.70 (br, 1 H), 6.53 (s, 1 H), 7.15 (s, 1 H), 7.43 (dd, J = 9.0, 1.8 Hz, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 8.14 (br, 1 H), 8.39 (s, 1 H), 9.00 (br, 1 H).

c) 3-(7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3-(N-methylsulfa moyl)quinolin-4- ylamino)-5-isopropoxybenzoic acid. A solution of methyl 3-(7-(2,4- dimethoxypyrimidin-5-yl)-2-methyl-3-(N-methylsulfamoyl)quino lin-4-ylamino)-5- isopropoxybenzoate (97 mg, 0.17 mmol) in 1 N NaOH (10 ml.) and THF (10 ml.) was stirred at 30 °C for 16h. THF was removed in vacuo. The mixture was diluted with water (20 mL). It was washed with DCM (3 x 30 mL). The water phase was then acidized with formic acid to pH = 6. The precipitate was collected by filtration to afford the desired product as a brown solid (75 mg, 79%). LC/MS: MS(ES ⁺ ) m/e 568 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1 .17 (d, J = 5.7 Hz, 6 H), 2.44 (s, 3 H), 2.92 (s, 3H), 3.96 (s, 3 H), 3.97 (s, 3 H), 4.43-4.57 (m, 1 H), 6.56 (s, 1 H), 6.96 (s, 1 H), 7.06 (s, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.97- 8.10 (m, 2 H), 8.55 (s, 1 H), 9.05 (br, 1 H).

Example 90

-cvclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl -3-(N-methylsulfamoyl)quinolin-

4-yl)amino)benzoic acid

a) methyl 3-(7-bromo-2-methyl-3-(N-methylsulfamoyl)quinolin-4-ylamino) -5- cvclopentylbenzoate. A mixture of 7-bromo-4-chloro-N,2-dimethylquinoline-3- sulfonamide (138 mg, 0.4 mmol) and methyl 3-amino-5-cyclopentylbenzoate (88 mg, 0.4 mmol) in EtOH (20 mL) was heated under reflux for 3h. The mixture was cooled to room temperature and the solvent was removed in vacuo to afford the desired product as a yellow solid (210 mg, 99%). LC/MS: MS (ES ⁺ ) m/e 532, 534 (MH ⁺ ). ¹ H NMR (300 MHz, CHCI ₃ ) δ ppm 1.38-2.08 (m, 8 H), 2.63 (d, J = 5.1 Hz, 3 H), 2.87-2.98 (m, 1 H), 3.01 (s, 3 H), 3.86 (s, 3 H), 4.62-4.73 (m, 1 H), 6.92 (s, 1 H), 7.26-7.33 (m, 2 H), 7.47 (d, J = 9.0 Hz, 1 H), 7.63 (s, 1 H), 8.63 (d, J = 1.8 Hz, 1 H), 9.1 1 (br, 1 H).

b) methyl 3-cvclopentyl-5-(7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3- (N- methylsulfamoyl)quinolin-4-ylamino)benzoate. A mixture of methyl 3-(7-bromo-2- methyl-3-(N-methylsulfamoyl)quinolin-4-ylamino)-5-cyclopenty lbenzoate (183 mg, 0.34 mmol) 2,4-dimethoxypyrimidin-5-ylboronic acid (125 mg, 0.68 mmol) and Pd(PPh ₃ ) ₂ CI ₂ (24 mg, 0.034 mmol), X-Phos (32 mg, 0.068 mmol) and Cs ₂ C0 ₃ (222 mg, 0.6 mmol) in dioxane (30 mL) and H ₂ 0 (7.5 mL) was stirred at 80 °C under nitrogen for 16h. It was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (50% pet. ether in ethyl acetate) to afford the desired product as a yellow solid (196 mg, 97%). LC/MS: MS (ES ⁺ ) m/e 592 (MH ⁺ ). ¹ H NMR (300 MHz, CHCI ₃ ) δ ppm 1.38-2.04 (m, 8 H), 2.64 (d, J = 4.8 Hz, 3 H), 2.84-3.00 (m, 1 H), 3.06 (s, 3 H), 3.86 (s, 3 H), 4.04 (s, 3 H), 4.06 (s, 3 H), 4.70 (br, 1 H), 6.92 (s, 1 H), 7.34-7.72 (m, 5 H), 8.39 (s, 1 H), 9.10 (br, 1 H).

c) 3-cyclopentyl-5-(7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3- (N- methylsulfamoyl)quinolin-4-ylamino)benzoic acid. A solution of methyl 3- cyclopentyl-5-(7-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3-(N - methylsulfamoyl)quinolin-4-ylamino)benzoate (190 mg, 0.32 mmol) in 1 N NaOH (10 mL) and THF (10 mL) was stirred at 30 °C for 16h. THF was removed in vacuo. The mixture was diluted with water (20 mL). It was washed with DCM (3 x 30 mL). The water phase was then acidized with formic acid to pH = 6. The precipitate was collected by filtration and then purified by preparative-TLC (silica gel, MeOH/DCM = 1/10) to afford the desired product as a yellow solid (72 mg, 39%). LC/MS: MS (ES ⁺ ) m/e 578 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.35-1 .49 (m, 2 H), 1 .53-1 .70 (m, 4 H), 1.88-2.00 (m, 2 H), 2.43 (s, 3H), 2.91 -2.97 (m, 4 H), 3.96-3.98 (m, 6 H), 7.00 (s, 1 H), 7.19 (s, 1 H), 7.45 (s, 1 H), 7.51-7.63 (m, 2H), 7.98-8.09 (m, 2 H), 8.55-8.56 (m, 1 H), 9.1 1 (s, 1 H). Example 91

N-cvclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)amin o)-7-(4-methoxypyrimidin

5-yl)quinoline-3-sulfonamide

a) 4-methoxypyrimidin-5-ylboronic acid. A solution of 5-bromo-4-methoxypyrimidine

(275 mg, 1.5 mmol) in THF (10 mL) was treated with n-BuLi (1 mL, 1.6 mmol) at - 70 °C dropwise over 10 min. The reaction mixture was stirred at -70 °C for 30min, and then warmed to -20 °C. A solution of triisopropyl borate (328 mg, 1 .7 mmol) in THF (2 mL) was added to the reaction mixture. The reaction mixture was stirred at -20 °C for additional 30 min, and then quenched by sat. NH ₄ CI (5 mL). The mixture was concentrated in vacuo to dryness. The residue was dissolved in CH ₂ CI ₂ /MeOH (5:1 ). Un-dissolved solid was filtered off and the mother liquor was concentrated in vacuo to afford desired crude product (300 mg) as a white solid which was used to the next step without further purification. LC/MS: MS (ES ⁺ ) m/e 155 (MH ⁺ ).

b) 7-bromo-N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphen ylamino)quinoline- 3-sulfonamide. A solution of 7-bromo-4-chloro-N-cyclopropylquinoline-3- sulfonamide (159 mg, 0.5 mmol) and 3-amino-5-(4- fluorophenoxy)benzenesulfonamide (169 mg, 0.6 mmol) in ethanol (10 mL) was heated to reflux for 2h. TLC showed no starting materials left. The reaction mixture was concentrated in vacuo to afford the crude product (328 mg) as a yellow solid which was used to the next step without further purification. LC/MS: MS (ES ⁺ ) m/e 607, 609 (MH ⁺ ).

c) N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(4- methoxypyrimidin-5-yl)quinoline-3-sulfonamide. A solution of 7-bromo-N- cyclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino)qu inoline-3- sulfonamide (200 mg, 0.33 mmol), 4-methoxypyrimidin-5-ylboronic acid (101 mg, 0.66 mmol), Pd(dppf)CI ₂ .CH ₂ CI ₂ (27 mg, 0.033 mmol), K ₂ C0 ₃ (91 mg, 0.66 mmol) in 1 ,4-dioxane (5 mL) and water (1 mL) was stirred at 80 °C under nitrogen atmosphere for 2h. TLC showed no starting materials left. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by column chromatography (silica gel, DCM/MeOH = 50/1 ) to afford N-cyclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(4- methoxypyrimidin-5-yl)quinoline-3-sulfonamide (120 mg, 57%) as a yellow solid.

LC/MS: MS (ES ⁺ ) m/e 637 (MH ⁺ ); 1 H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.32-0.42 (m, 4 H), 2.15-2.23 (m, 1 H), 4.02 (s, 3 H), 6.52 (t, J = 1.8 Hz, 1 H), 6.95-7.20 (m, 6 H), 7.43 (br, 2 H), 7.74-7.86 (m, 2 H), 8.34 (s, 1 H), 8.48 (br, 1 H), 8.62 (br, 1 H), 8.80 (s, 1 H), 8.89 (s, 1 H), 9.12 (s, 1 H).

Example 92

N-cvclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)a mino)-7-(pyrimidin-5- yl)quinoline-3-sulfonamide 3,5-dinitrobenzene-1-sulfonyl chloride. A solution of 3,5-dinitrobenzenamine (30.0 g, 164 mmol) in HBF ₄ (200 mL, 50% in H ₂ 0) and MeCN (50 mL) was stirred at 0 °C. NaN0 ₂ (10.7 g, 164 mmol) dissolved in H ₂ 0 (50 mL) was added dropwise, and then stirred at 0 °C for 30min. The solid was formed, filtered and washed with cold water (250 mL), ethanol (250 mL) and ether (250 mL), then dried in vacuo to afford intermediate (fluooboric acid diazonium salt, 23.0 g) as a yellow solid. In a round bottom flask (500 mL), crushed ice (200 g) and CuCI ₂ (7.7 g, 57.4mmol) were added. The mixture was cold to -5 °C, and then 40 mL of SOCI ₂ was added dropwise keeping the temperature below 0 °C. The previously prepared diazonium salt was added portionwise slowly keeping the temperature was below 0 °C. When the addition was complete, the reaction mixture was warmed to room temperature with stirring for 30 min. The resulting was filtered to give the crude 3,5-dinitrobenzene-1-sulfonyl chloride (23.0 g) as a yellow solid which was used to the next step without further purification.

) 3,5-dinitrobenzenesulfonamide. A solution of 3,5-dinitrobenzene-1-sulfonyl chloride (23.0 g, 86 mmol) in THF (100 mL) was added to 37% ammonia (50 ml.) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was treated with water (200ml_) and extracted with ethyl acetate (3 x 250 m). The combined organic layers were dried over Na ₂ S0 ₄ , then filtered and concentrated in vacuo to afford the crude product. Further purification by chromatography (silica gel, 50% pet. ether in ethyl acetate then 100% ethyl acetate) afford the title compound (1 1.8 g, 56%) as an off-white solid. LC/MS: MS (ES ^" ) m/e 246 (M-H ^" ), ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.02 (br, 2 H), 8.89 (d, J = 2.1 Hz, 2 H), 8.98 (t, J = 2.1 Hz, 1 H).

) 3-(4-fluorophenoxy)-5-nitrobenzenesulfonamide. A solution of 3,5- dinitrobenzenesulfonamide (1 1.8 g, 48 mmol), 4-fluorophenol (10.7 g, 96 mmol) and K ₂ C0 ₃ (13.2 g, 96 mmol) in DMF (100 mL) was heated to 80 °C for 12h. TLC showed no starting materials left. The reaction mixture was cooled to room temperature and neutralized by 0.5M HCI to pH = 8, then extracted by ethyl acetate (250 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (pet. ether/ethyl acetate, 6/1 ) afford the title compound (3.5 g, 26%) as a white solid. LC/MS: MS (ES ^" ) m/e 31 1 (M-H ^" ), ¹ H NMR (300 MHz, DMSO-de) δ ppm 7.28-7.44 (m, 4 H), 7.67-7.70 (m, 1 H), 7.78 (br, 2 H), 7.93 (t, J = 2.1 Hz, 1 H), 8.29 (t, J = 1.5 Hz, 1 H).

) 3-amino-5-(4-fluorophenoxy)benzenesulfonamide. A solution of 3-(4- fluorophenoxy)-5-nitrobenzenesulfonamide (2.0 g, 6.4 mmol) in MeOH (15 mL) was stirred with 5% wet palladium on carbon (300 mg) under 1 atm hydrogen for 3h. The hydrogen was flushed out with nitrogen and the mixture filtered through celite. The solvent was removed under reduced pressure to give the title compound (1.7 g, 94%) as a white solid. LC/MS: MS (ES ⁺ ) m/e 283 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 5.72 (br, 2 H), 6.27 (t, J = 2.1 Hz, 1 H). 6.48 (t, J = 1 .8 Hz, 1 H), 6.76 (t, J = 1.8 Hz, 1 H), 7.08-7.32 (m, 6 H).

) 5-chloro-N-cvclopropyl-7-(pyrimidin-5-yl)quinoline-3-sulfona mide. A solution of 7- bromo-4-chloro-N-cyclopropylquinoline-3-sulfonamide (200 mg, 0.55 mmol), pyrimidin-5-ylboronic acid (75 mg, 0.6 mmol), Pd(dppf)CI ₂ .CH ₂ CI ₂ (22 mg, 0.028 mmol), K ₂ C0 ₃ (91 mg, 0.66 mmol) in 1 ,4-dioxane (10 mL) and water (2.5 mL) was stirred at 80 °C under nitrogen atmosphere for 2.5 h. TLC showed no starting materials left. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by chromatography (silica gel, DCM/MeOH, 70/1 ) to afford 4-chloro-N-cyclopropyl-7-(pyrimidin-5-yl)quinoline-3- sulfonamide (1 10 mg, 56%) as a pale-yellow solid. LC/MS: MS (ES ⁺ ) m/e 361 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.37-0.52 (m, 4 H), 2.25-2.36 (m, 1 H), 8.36 (dd, J = 9.0, 1.5 Hz, 1 H). 8.56 (d, J = 8.7 Hz, 1 H), 8.70 (dd, J = 7.2, 1.5 Hz, 2 H), 9.33 (d, J = 5.7 Hz, 1 H), 9.43 (s, 2 H).

N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(pyrimidin-5- yl)quinoline-3-sulfonamide. A solution of 4-chloro-N-cyclopropyl-7-(pyrimidin-5- yl)quinoline-3-sulfonamide (100 mg, 0.28 mmol), 3-amino-5-(4- fluorophenoxy)benzenesulfonamide (78 mg, 0.28 mmol) in ethanol (20 ml.) was heated under reflux for 2h. TLC showed no starting materials left. The reaction mixture was concentrated in vacuo to give a crude product. Further purification by chromatography (silica gel, DCM/MeOH, 50/1 ) gave N-cyclopropyl-4-(3-(4- fluorophenoxy)-5-sulfamoylphenylamino)-7-(pyrimidin-5-yl) quinoline-3- sulfonamide (1 10 mg, 65%) as a yellow solid. LC/MS: MS (ES ⁺ ) m/e 607 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.33-0.45 (m, 4 H), 2.15-2.25 (m, 1 H), 6.57 (s, 1 H). 6.95 (s, 1 H), 7.04-7.21 (m, 6 H), 7.42 (br, 2 H), 7.82 (d, J = 9.3 Hz, 1 H). 8.02 (d, J = 8.1 Hz, 1 H), 8.56 (br, 2 H), 9.12 (s, 1 H), 9.29 (s, 1 H), 9.37 (s, 2 H).

Example 93

N-cvclopropyl-7-(3,5-dimethyl-1 H-pyrazol-4-yl)-4-((3-(4-fluorophenoxy)-5- sulfamoylphenyl)amino)quinoline-3-sulfonamide 4-chloro-N-cvclopropyl-7-(3,5-dimethyl-1 H-pyrazol-4-yl)quinoline-3-sulfonamide. A mixture of 7-bromo-4-chloro-N-cyclopropylquinoline-3-sulfonamide (200 mg, 0.553 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (140 mg, 0.608 mmol), K ₂ C0 ₃ (92 mg, 0.664 mmol) and Pd(dppf)CI ₂ .CH ₂ CI ₂ (23 mg, 0.028 mmol) in dioxane (10 mL) and water (2.5 mL) was stirred at 80 °C under nitrogen atmosphere for 2.5 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative-TLC (silica gel, 100% ethyl acetate) to afford the desired product as a yellow solid (120 mg, 58%). LC/MS: MS (ES ⁺ ) m/e 377 (MH ⁺ ).

b) N-cvclopropyl-7-(3,5-dimethyl-1 H-pyrazol-4-yl)-4-(3-(4-fluorophenoxy)-5- sulfamoylphenylamino)quinoline-3-sulfonamide. A solution of 4-chloro-N- cyclopropyl-7-(3,5-dimethyl-1 H-pyrazol-4-yl)quinoline-3-sulfonamide (80 mg, 0.212 mmol) and 3-amino-5-(4-fluorophenoxy)benzenesulfonamide (60 mg, 0.212 mmol) in ethanol (20 mL) was heated to reflux for 3h. The reaction mixture was concentrated and purified by preparative-TLC (silica gel, DCM/MeOH, 10/1 ) to afford the desired product as a yellow solid (35 mg, 26%). LC/MS: MS (ES ⁺ ) m/e 623 (MH ⁺ ). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.38-0.41 (m, 4 H), 2.15-2.21 (m, 1 H), 2.27 (s, 3H), 2.33 (s, 3H), 6.57 (s, 1 H), 6.94 (s, 1 H), 7.05-7.18 (m, 5H), 7.39 (s, 2H), 7.58 (d, J = 8.7 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.91 (s, 1 H), 8.41 (br, 1 H), 8.56 (br, 1 H), 9.06 (s, 1 H), 12.53 (br, 1 H).

Example 94

N-cvclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)amin o)-7-(1 ,3,5-trimethyl-1 H- pyrazol-4-yl)quinoline-3-sulfonamide

a) 1 ,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole. To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (2.00 g, 9.0 mmol) and K ₂ C0 ₃ (2.48 g, 18.0 mmol) in acetone (20 mL) was added iodomethane (2 mL) at room temperature. The mixture was then stirred at 55 °C for 10 h. It was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with water (20 ml_). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and

concentrated in vacuo to afford the desired product as a white solid (1 .5 g, 71 %) which was used without further purification. LC/MS: MS (ES ⁺ ) m/e 237 (MH ⁺ ). b) 4-chloro-N-cvclopropyl-7-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)quinoline-3-sulfonamide.

A mixture of 7-bromo-4-chloro-N-cyclopropylquinoline-3-sulfonamide (200 mg, 0.553 mmol), 1 ,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (144 mg, 0.608 mmol), K ₂ C0 ₃ (92 mg, 0.664 mmol) and Pd(dppf)CI ₂ . CH ₂ CI ₂ (23 mg, 0.028 mmol) in dioxane (10 mL) and water (2.5 mL) was stirred at 80 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative-TLC (silica gel, DCM/MeOH, 10/1 ) to afford the desired product as a red solid (80 mg, 37%). LC/MS: MS (ES ⁺ ) m/e 391 (MH ⁺ ).

c) N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(1 ,3,5-trimethyl- 1 H-pyrazol-4-yl)quinoline-3-sulfonamide. A solution of 4-chloro-N-cyclopropyl-7-

(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)quinoline-3-sulfonamide (70 mg, 0.179 mmol) and 3-amino-5-(4-fluorophenoxy)benzenesulfonamide (50 mg, 0.179 mmol) in ethanol (20 mL) was heated under reflux for 2h. The reaction mixture was concentrated and purified by preparative-HPLC (ODS) to afford the desired product as a white solid (24 mg, 21 %). LC/MS: MS (ES ⁺ ) m/e 637 (MH ⁺ ). ¹ H NMR (300 MHz,

DMSO-d ₆ ) δ ppm 0.34-0.43 (m, 4 H), 2.13-2.19 (m, 1 H), 2.22 (s, 3H), 2.32 (s, 3H), 3.75 (s, 3 H), 6.59 (s, 1 H), 6.94 (s, 1 H), 7.03-7.18 (m, 5 H), 7.41 (s, 2 H), 7.54 (d, J = 9.0 Hz, 1 H), 7.73 (d, J = 9.0 Hz, 1 H), 7.88 (s, 1 H), 8.44 (s, 1 H), 8.58 (s, 1 H), 9.07 (s, 1 H).

Example 95

N-cvclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)amin o)-7-(pyridin-3-yl)quinoline-

3-sulfonamide a) 4-chloro-N-cvclopropyl-7-(pyridin-3-yl)quinoline-3-sulfonami de. A mixture of 7- bromo-4-chloro-N-cyclopropylquinoline-3-sulfonamide (500 mg, 1 .4 mmol) pyridin- 3-ylboronic acid (340 mg, 2.8 mmol) and Pd(dppf)CI ₂ , (102 mg, 0.14 mmol), KOAc (274 mg, 2.8 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 80 °C under nitrogen for 1 h. It was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL X 3). The combined organic layers were dried over Na ₂ S0 ₄ , filtered, concentrated, purified by chromatography on silica gel, eluted with 25% pet. ether in ethyl acetate, then crystallised from MeOH to afford the desired product as a yellow solid (207 mg, 41 %). LC/MS: MS (ES ⁺ ) m/e 360 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.38-0.52 (m, 4 H), 2.27-2.36 (m, 1 H), 7.57-7.65 (m, 1 H), 8.30-8.41 (m, 2 H), 8.54-8.58 (m, 2 H), 8.68-8.73 (m, 2 H), 9.17 (d, J = 2.1 Hz, 1 H), 9.32 (s, 1 H). b) N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(pyridin-3- yl)quinoline-3-sulfonamide. A mixture of 4-chloro-N-cyclopropyl-7-(pyridin-3- yl)quinoline-3-sulfonamide (205 mg, 0.57 mmol) and 3-amino-5-(4- fluorophenoxy)benzenesulfonamide (193 mg, 0.69 mmol) in EtOH (10 mL) and AcOH (2 mL) was stirred at 90 °C for 20 h. The mixture was cooled to room temperature. NaHC0 ₃ solution (5 mL) was added and extracted with ethyl acetate (20 mL X 3). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to give a residue. The residue was purified by chromatography on silica gel eluted with DCM/MeOH (20/1 ) to afford the desired product as a white solid (163 mg, 47%). LC/MS: MS (ES ⁺ ) m/e 606 (MH ⁺ ); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.36-0.42 (m, 4 H), 2.16-2.23 (m, 1 H), 6.57 (s, 1 H), 6.96 (s, 1 H), 7.04-7.19 (m, 5 H), 7.41 (s, 2 H), 7.56-7.61 (m, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 7.99 (dd, J = 8.7, 1.2 Hz, 1 H), 8.32 (d, J = 8.7 Hz, 1 H), 8.44 (s, 1 H ), 8.47 (s, 1 H), 8.62 (s, 1 H), 8.68 (dd, J = 4.8, 0.9 Hz, 1 H), 9.10-9.14 (m, 2 H).

Example 96

N-cvclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)am

3-sulfonamide

a) 3-(N-cvclopropylsulfamoyl)-4-(3-(4-fluorophenoxy)-5- sulfamoylphenylamino)quinolin-7-ylboronic acid. A solution of 7-bromo-N- cyclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino)qu inoline-3- sulfonamide (282 mg, 0.5 mmol), 4,4,4\4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane (254 mg, 1 mmol), KOAc (98mg, 1 mmol) and Pd(dppf)CI ₂ .CH ₂ CI ₂ (41 mg, 0.05 mmol) in 1 ,4-dioxane (5 ml.) was heated to 100 °C for 24h, then cooled to room temperature. To the mixture, H ₂ 0 (15 ml.) was added. Then the mixture was extracted by ethyl acetate (3 x 50 ml_), washed by brine (50 ml_), dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the crude compound (280 mg) as a brown solid. The crude product was used to the next step without further purification. LC/MS: MS (ES ⁺ ) m/e 573 (MH ⁺ ).

b) N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(pyridin-2- yl)quinoline-3-sulfonamide. A solution of 3-(N-cyclopropylsulfamoyl)-4-(3-(4- fluorophenoxy)-5-sulfamoylphenylamino)quinolin-7-ylboronic acid (280 mg, 0.5 mmol), 2-bromopyridine (158 mg, 1 mmol), Pd(dppf)CI ₂ .CH ₂ CI ₂ (41 mg, 0.05 mmol), K ₂ C0 ₃ (138 mg, 1 mmol) in 1 ,4-dioxane (5 ml.) and water (1 ml.) was stirred at 80 °C under nitrogen atmosphere for 1 h. TLC showed no starting materials left. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by preparative-HPLC (ODS) to afford N-cyclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(pyridin-2- yl)quinoline-3-sulfonamide (55 mg, 18%) as an off-white solid. LC/MS: MS (ES+) m/e 606 (MH+); 1 H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.35-0.43 (m, 4 H), 2.13- 2.24 (m, 1 H), 6.57 (t, J = 1.8 Hz, 1 H), 6.96 (t, J = 1 .5 Hz, 1 H), 7.04-7.19 (m, 5 H), 7.41 (br, 2 H), 7.48 (dd, J = 7.5, 4.8 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 1 H), 7.99 (td, J = 7.8, 1 .8 Hz, 1 H), 8.23-8.32 (m, 2 H), 8.47 (br, 1 H), 8.61 (br, 1 H), 8.71 - 8.81 (m, 2 H), 9.13 (s, 1 H).

Example 97

N-cvclopropyl-4-((3-(4-fluorophenoxy)-5-sulfamoylphenyl)a mino)-7-(2- methoxyphenyl)quinoline-3-sulfonamide

a) 7-bromo-N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphen ylamino)quinoline- 3-sulfonamide. A solution of 7-bromo-N-cyclopropyl-4-(3-(4-fluorophenoxy)-5- sulfamoylphenylamino)quinoline-3-sulfonamide (200 mg, 0.55 mmol) and 3-amino- 5-(4-fluorophenoxy)benzenesulfonamide (160 mg, 0.56 mmol) in ethanol (20 ml.) was heated to reflux for 18 h. The reaction mixture was concentrated in vacuo to afford the crude product as a yellow solid (360 mg, crude) which was used directly for next step without further purification. LC/MS: MS (ES ⁺ ) m/e 607, 609 (MH ⁺ ). b) N-cvclopropyl-4-(3-(4-fluorophenoxy)-5-sulfamoylphenylamino) -7-(2- methoxyphenyl)quinoline-3-sulfonamide. A mixture of 7-bromo-N-cyclopropyl-4- (3-(4-fluorophenoxy)-5-sulfamoylphenylamino)quinoline-3-sulf onamide (300 mg, 0.49 mmol), 2-methoxyphenylboronic acid (300 mg, 1.97 mmol), KOAc (105 mg, 1.07 mmol) and Pd(dppf)CI ₂ .CH ₂ CI ₂ (18 mg, 0.025mmol) in dioxane (25 ml.) and water (2 ml.) was stirred at 100 °C under nitrogen atmosphere for 18 h. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo. Then the mixture was dissolved in ethyl acetate and filtered again, the filtrate was concentrated in vacuo to afford crude product (400 mg). Then the crude was purified by preparative-TLC (silica gel, DCM/MeOH, 20:1 ) to afford the desired product as a yellow solid (280 mg, 90%). LC/MS: MS (ES ⁺ ) m/e 635 (MH ⁺ ). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.35-0.41 (m, 4 H), 2.14-2.23 (m, 1 H), 3.82 (s, 3 H), 6.49 (s, 1 H), 6.96 (s, 1 H), 7.03-7.22 (m, 7 H), 7.42-7.48 (m, 4 H), 7.73 (s, 2 H), 8.15 (s, 1 H), 8.44 (br, 1 H), 8.58 (br, 1 H), 9.08 (s, 1 H). Example 98 - Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.

Table I

INGREDIENTS AMOUNTS

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N- 7 mg

isopropylsulfamoyl)quinolin-4-yl)amino)benzoic acid

(Compound of Example 1 )

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg

Example 99 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1.7% by weight of 3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N- isopropylsulfamoyl)quinolin-4-yl)amino)benzoic acid (Compound of Example 2) in 10% by volume propylene glycol in water.

Example 100 - Tablet Composition

The sucrose, calcium sulfate dihydrate and a lactate dehydrogenase A inhibitor as shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.

Table II

INGREDIENTS AMOUNTS

3-cyclopentyl-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(N- 12 mg

propylsulfamoyl)quinolin-4-yl)amino)benzoic acid

(Compound of Example 3)

calcium sulfate dihydrate 30 mg

sucrose 4 mg

starch 2 mg

talc 1 mg

stearic acid 0.5 mg Biological Activity

Enzymatic Assay Assay buffer (50mM potassium phosphate, pH 7.0, 50mM NaCI, 0.25mM CHAPS, 0.0025% BSA) is added to one column of a standard assay plate stamped with DMSO solutions of test compounds. A solution of LDH-A and NAD+ (final concentrations: 300 pM LDH-A and 150 uM NAD+) in assay buffer is added to remaining plate wells containing DMSO solutions of test compounds and DMSO only control wells and the mixtures incubated for 10 min at room temperature. A solution of lactate, resazurin, diaphorase (final concentrations: 2mM lactate, 6.25uM resazurin, 0.4U/mL diaphorase) in assay buffer is added to all wells and the mixtures incubated for 30 min at room temperature. Stop solution (2 uL, components: assay buffer and 25mM oxamate) is added to each well and the fluoresecence intensity increase (FLINT) measured at 590 nm on a ViewLux ^® imager.

Cell -based Assay 1

A 384 well plate is stamped with DMSO solutions of test compounds and DMSO only controls. Frozen U20S cells are thawed in assay medium (DMEM/F12 (HAM's) 1 :1 with L-glutamine with 15mM Hepes/1 % FBS without phenol red). The cell suspension is centrifuged for 3min at 1200rpm. The supernatant is removed and the cell pellet re- suspended in 5-1 OmL assay medium (volume may vary). 1.5mL is removed from the re- suspended cell pellet and counted on Cedex counter. The remaining cell pellet is re- suspended to 0.75x10 ⁶ cells/mL in appropriate volume of assay medium.

0.75x10 ⁶ cells/mL cell suspension is gently stirred to keep in suspension. 20uL of 0.75x10 ⁶ cells/mL cell suspension is plated to pre-stamped compound plate except column 18 which is left blank. 20uL assay media is added to column 18. Plates are centrifuged at 500rpm for 20-30sec, placed into incubator and incubated overnight (18- 24hr) at 37 °C with 5% carbon dioxide.

5uL cell medium is transferred from cell compound plate to Greiner low volume black 384 plate using a Cybio CyBi®-Well 384-Channel Pipettor. The plate is centrifuged for 30sec at 500 rpm. 5uL of 2x enzyme mix (components: 1 mM thiamine pyrophosphate, 2U/mL horseradish peroxidase in Tris pH 7.5, 0.08U/mL pyruvate oxidase in HEPES pH 7.5, 0.2mM Amplex UltraRed made up in assay buffer (50mM sodium phosphate pH 7.5 and 5mM magnesium chloride) containing 0.01 % BSA) is added into the low volume black 384 plate containing 5uL cell medium. The plate is centrifuge for 30sec at 500rpm (protected from light), then incubated in the dark at room temperature for 60min. The plate is read on ViewLux ^® imager for fluorescence intensity at excitation/emission wavelengths of 525/598, respectively.

Cell -based Assay 2

Snu-398 hepatocellular carcinoma cells are plated at 75,000 cells/well in 100ml of R10 medium (RPMI 1640 supplemented with 10% fetal bovine serum) in white 96 well plates and allowed to attach overnight in 37C 5% C0 ₂ - 95% humidified air incubator. The following morning, the compound dose response is prepared ranging from 4.5 nM to 30 mM in 3-fold increments in low glucose medium (RPMI without glucose, supplemented with 1.7 mM glucose). The R10 medium is removed from the cells, the cells are rinsed with PBS, and then pre-incubated with the compound dose response for 1 hour at 37C. Following the pre-incubation, the medium is removed and replaced with the fresh compound dose response and cells are incubated for the further 2 hours at 37C. The preincubation step ensures that LDHA is inhibited at the start of incubation and lowers the background lactate concentration. At the end of the incubation, 20 ml of conditioned medium is transferred to a new 96 well plate and subjected to mass-spectroscopy analysis to determined lactate concentrations. The lactate amount in each well is normalized to the number of live cells in the well obtained by Cell Titer Fluor assay (Promega Corp) per manufacturer's instructions.

Compounds of the invention are tested for activity against lactate dehydrogenase A generally according to one of the above assays or in an analogous assay.

The compounds of Examples 1 to 97 were tested generally according to either the above Enzymatic Assay, one of the above Cell-based Assays or in an analogous assay and in at least one set of experimental runs exhibited an average plC ₅₀ value≥ 5.0.

The compound of Example 5 was tested generally according to the above lactate dehydrogenase A enzyme assay and in at least one set of experimental runs exhibited an average lactate dehydrogenase A pICso value of 7.0 against lactate dehydrogenase A. The compound of Example 93 was tested generally according to either the above

Enzymatic Assay, one of the above Cell-based Assays or in an analogous assay and in at least one set of experimental runs exhibited an average lactate dehydrogenase A pICso value of 7.1 against lactate dehydrogenase A. While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.