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^ , R2, R3 _; 4 _ANC | R5 _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 ¹ is selected from: -CONH ₂ and -S0 ₂ NH ₂ ;

2

R is selected from: -NHphenyl and 1 -ethyl-1 H-benzimidazole-7-carboxylic acid, where

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

the following Group A: -OH,

-COOH,

heteroaryl,

cycloalkyl,

heterocycloalkyl,

-NHS(0) ₂ CF ₃ ,

-CH2COOH,

-CO2CH3,

-CO2CH2CH3,

-OCH3,

-C0 ₂ ethyl, and

-CONH2;

and the following Group B:

10 11 10 11

-CONR R , where R and R are each independently selected from: hydrogen, methyl, ethyl and propyl,

or R10 and R^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring,

10 11

provided that R and R are not both hydrogen,

-CC>2cycloalkyl,

-CO2C3-C4,

-COH,

-C(CH ₃ ) ₂ COOH,

-C(CH ₃ )2C0 ₂ CH3,

-C(CH ₂ (CH ₃ ) ₂ )COOH,

-C(F) ₂ COOH,

1-cyclopropanecarboxylic acid,

1 -cyclopropanecarboxylate,

1-cyclobutanecarboxylic acid,

1-cyclopentanecarboxylic acid,

-NHcycloalkyl,

-NH(Ci-C ₆ alkyl)cyclohexyl, -NHphenyl,

-NHphenyl substituted with one or two substituents selected from:

-F, -CH3, -OH, -COOH, -CF3, isopropyl and tert-butyl,

-NHbenzyl,

-N(CH ₃ )phenyl,

-N(CH3)phenyl, where the phenyl is substituted with one or two substituents selected from: -F, -CH ₃ , -OH, -COOH, -CF ₃ , isopropyl and tert-butyl,

-NHS(0) ₂ phenyl,

-NHS(0)2phenyl substituted with one or two substituents selected from: cyclohexyl, cyclopentyl, furan, -F, -CH3, -OH, -COOH,

-CF ₃ and -OCH3,

-NH(d-C ₆ alkyl),

-S-cycloalkyl,

-S-Ci-C ₆ alkyl,

-S(0) ₂ NH ₂ ,

-OCi-C ₆ alkyl,

-OCH2CF3,

-Ocycloalkyl,

-Ophenyl,

-Ophenyl substituted with one or two substituents selected from:

-F, -CH ₃ , -OH, -COOH, -CF ₃ and -C(0)NH ₂ ,

-OCH2phenyl, and

-C(NH)NHOH;

3

R is selected from:

hydrogen,

-Ci-C ₆ alkyl,

-OCi-C ₆ alkyl, and

-OCH ₂ cycloalkyl;

4

R is selected from: 2,4-dimethoxypyrimidine,

2,4-dimethylpyrimidine,

-F,

-CI,

-Br,

-CH ₂ NHC(NH)NH ₂ , and

(1 , 1 dioxidothiomorpholino)methyl;

R is selected from:

hydrogen,

-CH ₃ , and

-F; or a salt thereof;

provided that when R is phenyl and at least one of the substituents on the phenyl is selected from Group A,

either;

at least one other sustituent from Group B is on the phenyl;

3 5

at least one of R and R is not hydrogen;

R4 is selected from: -CH ₂ NHC(NH)NH ₂ , and

(1 ,1 dioxidothiomorpholino)methyl; or

R1 is -S0 ₂ NH ₂ .

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

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5- (cyclohexylamino)benzoic acid; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (propylamino)benzoic acid; 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(4- fluorophenylsulfonamido)phenyl)amino)quinoline-3-carboxamide ;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(4- methoxyphenylsulfonamido)phenyl)amino)quinoline-3-carboxamid e;

4-((3-(cyclopropanesulfonamido)phenyl)amino)-7-(2,4-dimet hoxypyrimidin-5- yl)quinoline-3-carboxamide; 4-((3-(cyclohexanesulfonamido)phenyl)amino)-7-(2,4-dimethoxy pyrimidin-5- yl)quinoline-3-carboxamide;

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

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(furan-3- sulfonamido)phenyl)amino)quinoline-3-carboxamide; methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- isopropoxybenzoate;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5- isopropoxybenzoic acid; cyclopentyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- hydroxybenzoate; sec-butyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- hydroxybenzoate;

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

3-(cyclohexyloxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-s ulfamoylquinolin-4- yl)amino)benzoic acid; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cyclopentyloxy)benzoic acid;

3- (cyclopentyloxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfa moylquinolin-4- yl)amino)benzoic acid;

4- ((3-(cyclohexyloxy)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5 -yl)quinoline-3- sulfonamide; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquin olin-4- yl)amino)benzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isoprop oxyquinolin-4-yl)amino)- 5-cyclopentylbenzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethoxyq uinolin-4-yl)amino)-5- cyclopentylbenzoic acid;

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

3-(cyclohexylmethoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl) -3-sulfamoylquinolin-4- yl)amino)benzoic acid; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isobutoxyq uinolin-4-yl)amino)- 5-cyclopentylbenzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propoxy quinolin-4-yl)amino)-5- cyclopentylbenzoic acid;

3-((6-butoxy-3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)q uinolin-4-yl)amino)-5- cyclopentylbenzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propylq uinolin-4-yl)amino)-5- cyclopentylbenzoic acid; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethylquino lin-4-yl)amino)-5^ cyclopentylbenzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isoprop ylquinolin-4-yl)amino)-5 cyclopentylbenzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylq uinolin-4-yl)amino)-5- cyclopentylbenzoic acid;

3- (benzyloxy)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)q uinolin-4- yl)amino)benzoic acid;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(hydroxymethyl)phen yl)amino)quinoline-3- sulfonamide;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(trifluoromethoxy)p henyl)amino)quinoline-3- sulfonamide;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(methylcarbamoyl)ph enyl)amino)quinoline-3 carboxamide;

4- ((3-cyclohexyl-5-(trifluoromethylsulfonamido)phenyl)amino)-7 - (guanidinomethyl)quinoline-3-carboxamide;

5- ((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)a mino)-1-ethyl-1 H- benzo[d]imidazole-7-carboxylic acid;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(dimethylcarbamoyl) phenyl)amino)quinoline- 3-carboxamide;

4-((3-(diethylcarbamoyl)phenyl)amino)-7-(2,4-dimethoxypyr imidin-5-yl)quinoline-3- carboxamide;

4-((3-cyclopentyl-5-(methylcarbamoyl)phenyl)amino)-7-(2,4 -dimethoxypyrimidin-5- yl)quinoline-3-carboxamide; 3-((3-carbamoyl-6-(cyclobutylmethoxy)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4^ yl)amino)-5-cyclopentylbenzoic acid;

3- ((3-carbamoyl-6-(cyclopentylmethoxy)-7-(2,4-dimethoxypyrimid in-5-yl)quinolin-4- yl)amino)-5-cyclopentylbenzoic acid;

4- ((3-cyclopentyl-5-(hydroxymethyl)phenyl)amino)-7-(2,4-dimeth oxypyrimidin-5- yl)quinoline-3-carboxamide; 4-((3-cyclopentyl-5-(hydroxymethyl)phenyl)amino)-7-(2,4-dime thoxypyrimidin-5- yl)quinoline-3-sulfonamide; methyl 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)-2-methylpropanoate;

4-((3-cyclohexyl-5-(trifluoromethylsulfonamido)phenyl)ami no)-7-((1 , 1- dioxidothiomorpholino)methyl)quinoline-3-carboxamide;

2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)phenyl)-2- methylpropanoic acid;

2- (3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-y l)amino)phenyl)-2,2- difluoroacetic acid; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(2,2,2- trifluoroethoxy)benzoic acid;

4-((3-(1 H-tetrazol-5-yl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl )quinoline-3- sulfonamide;

3- ((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)a mino)-5- (methylcarbamoyl)benzoic acid;

3-((3-carbamoyl-6-(cyclopropylmethoxy)-7-(2,4-dimethoxypy rimidin-5-yl)quinolin-4- yl)amino)-5-cyclopentylbenzoic acid; 6-butoxy-4-((3-cyclopentyl-5-(hydroxymethyl)phenyl)amino)-7- (2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-methylq uinolin-4-yl)amino)-5- cyclopentylbenzoic acid;

1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4- yl)amino)phenyl)cyclopropanecarboxylic acid; methyl 1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)cyclopropanecarboxylate;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroq uinolin-4-yl)amino)-5- cyclopentylbenzoic acid;

3-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)quinolin-4- yl)amino)-5- isopropoxybenzoic acid;

3-((7-(2,4-dimethylpyrimidin-5-yl)-3-sulfamoylquinolin-4- yl)amino)-5- isopropoxybenzoic acid;

1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4- yl)amino)phenyl)cyclobutanecarboxylic acid; 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)phenyl)-3- methylbutanoic acid;

3-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)-8-fluoroqu inolin-4-yl)amino)-5- cyclopentylbenzoic acid; methyl 1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)cyclopentanecarboxylate;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroq uinolin-4-yl)amino)-5- isopropoxybenzoic acid; ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (phenylamino)benzoate;

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

3-((3-carbamoyl-6-(cyclohexylmethoxy)-7-(2,4-dimethoxypyr imidin-5-yl)quinolin-4- yl)amino)-5-cyclopentylbenzoic acid; ethyl 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl )amino)-5-((3- fluorophenyl)amino)benzoate; ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- fluorophenyl)amino)benzoate;

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

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

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

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

3-(sec-butylthio)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimid in-5-yl)quinolin-4- yl)amino)benzoic acid;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5- (propylthio)benzoic acid; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((2,6- difluorophenyl)amino)benzoic acid;

3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin -5-yl)quinolin-4- yl)amino)benzoic acid; methyl 3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4- yl)amino)benzoate; 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cyclohexylthio)benzoic acid;

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

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

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

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

3-((3,5-difluorophenyl)amino)-5-((7-(2,4-dimethoxypyrimid in-5-yl)-3- sulfamoylquinolin-4-yl)amino)benzoic acid; ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3,5- difluorophenyl)amino)benzoate;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5-((3,5- difluorophenyl)amino)benzoic acid; ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- (trifluoromethyl)phenyl)amino)benzoate;

3- ((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)a mino)-5-((3- (trifluoromethyl)phenyl)amino)benzoic acid;

4- ((3-(3-carbamoylphenoxy)phenyl)amino)-7-(2,4-dimethoxypyrimi din-5- yl)quinoline-3-carboxamide; 6-butoxy-4-((3-cyclopentyl-5-(hydroxymethyl)phenyl)amino)-7- (2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5-(m- tolylamino)benzoic acid;

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

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

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4 -yl)amino)-5-((3- isopropylphenyl)amino)benzoic acid; 3-((3-(tert-butyl)phenyl)amino)-5-((3-carbamoyl-7-(2,4-dimet hoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluorophenyl)am ino)-5-(2H-tetrazol-5- yl)phenyl)amino)quinoline-3-sulfonamide;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluorophenyl)am ino)-5-(2H-tetrazol-5- yl)phenyl)amino)quinoline-3-carboxamide;

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5-(pyrrolidine- 1-carbonyl)benzoic acid; 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrrolidine-1- carbonyl)phenyl)amino)quinoline-3-carboxamide;

3- ((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-((2,6-difluoroph enyl)amino)benzo acid;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N-hydroxycarbamimi doyl)-5-((3- (trifluoromethyl)phenyl)amino)phenyl)amino)quinoline-3-carbo xamide 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrrolidine-1-carbony l)-5- sulfamoylphenyl)amino)quinoline-3-carboxamide;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-methoxy-5-sulfamoyl phenyl)amino)quin 3-carboxamide;

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(dimethylcarbamoyl) -5- sulfamoylphenyl)amino)quinoline-3-carboxamide; and

4- ((3-carbamoyl-5-(4-fluorophenoxy)phenyl)amino)-7-(2,4-dimeth oxypyrimidin-5- yl)quinoline-3-carboxamide; 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,

"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 (Hijnig's base, N-ethyl-N-(1-methylethyl)-2-propanamine);

DMAP (4-dimethylaminopyridine);

DME (1 ,2-dimethoxyethane);

DMF (A/,/\/-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 to 9 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 to 9. 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) diethyl ethoxymethylenemalonate, solvent, heat; b) Ph ₂ 0, reflux; c) aq NaOH, EtOH, heat; d) 1. POCI ₃ , reflux, 2. NH ₃ , solvent; e) Ar ¹ NH ₂ , solvent, heat; f) 1. Ar ² B(OR) ₂ , Pd catalyst, base, aq dioxane, heat, or bis(pinacolato)diboron, Pd catalyst, base, dioxane, heat, then Ar ² Br, Pd catalyst, base, aq dioxane, heat, 2. aq NaOH, LiOH or KOH, solvent, if necessary. Scheme 2

a) Ar ² B(OR) ₂ , Pd catalyst, base, aq dioxane, heat; b) 1 . Ar ¹ NH ₂ , solvent, heat, 2. aq NaOH, LiOH or KOH, solvent, if necessary.

Scheme 3

a) diethyl ethoxymethylenemalonate, heat; b) Ph ₂ 0, reflux; c) aq NaOH, EtOH, heat; d) 1. POCIs, reflux, 2. NH ₃ , solvent, 0 °C; e) 1. BBr ₃ , solvent, heat, 2. R ¹ Br, K ₂ C0 ₃ , DMF, heat; f) as in scheme 1 or 2.

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, aq dioxane, heat, or

bis(pinacolato)diboron, Pd catalyst, base, dioxane, heat, then Ar ² Br, Pd catalyst, base, aq dioxane, heat, 2. aq NaOH, LiOH or KOH, solvent, if necessary.

Scheme 6

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

Scheme 7

a) ZnCN ₂ , Pd catalyst, base, solvent, heat; b) 1. H ₂ , Ni, solvent; 2. (BOCNH) ₂ C=NTf, Et ₃ N, CH ₂ CI ₂ , 3. TFA Scheme 8

a) (vinylsulfonyl)ethene, EtOH

a) 1. SOCI ₂ , cat. DMF, reflux, 2. NaN ₃ , aq THF, 3. heat; b) 1. NaN02, cone, aq HCI, 0 °C, 2. SOCI2, H ₂ 0, CuCI ₂ , 3. aq NH ₃ , THF; c) 1. BBr ₃ , solvent, heat, 2. ¹ Br, K ₂ C0 ₃ , DMF, heat; f) as in scheme 4.

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

PyBOP = benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate

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

psi = pounds/ins ²

PTFE = polytetrafluoroethylene

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-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cyclohexylamino)benzoic acid

a) 7-bromo-4-chloroquinoline-3-carboxamide. A mixture of 7-bromo-4-hydroxy-3- quinolinecarboxylic acid (3 g, 1 1 .19 mmol) in phosphorus oxychloride (10 ml_, 107 mmol) was heated under reflux overnight, then cooled and azeotroped twice with toluene (25 ml_). The brown oil was dissolved in tetrahydrofuran (25 ml.) then added dropwise to a cold (ice) solution of 30% aqueous ammonia (50 mL, 231 1 mmol). After stirring for 2 h, the solid was filtered and washed with water then a little diethyl ether to afford the title compound (2.93 g, 10.26 mmol, 92 %) as an off white solid. MS (ES+) m/e 285 [M+H] ⁺ .

b) 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide. To a

suspension of 7-bromo-4-chloroquinoline-3-carboxamide (1000 mg, 3.50 mmol), [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (773 mg, 4.20 mmol) and potassium carbonate (968 mg, 7.00 mmol) in 1 ,4-dioxane (18 mL) and water (6.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (202 mg, 0.175 mmol). The mixture was kept stirring at 75°C overnight. After cooling, the reaction was diluted with water. The precipitate was collected, washed with water, methanol and acetone, and dried under reduced pressure to afford the title compound (1025 mg, 2.97 mmol, 85 % yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 8.90 (s, 1 H), 8.64 (s, 1 H), 8.33 (d, J=8.8 Hz, 1 H), 8.31 (d, J=1.5 Hz, 1 H), 8.23 (br. s., 1 H), 8.03 (dd,J=8.7, 1 .6 Hz, 1 H), 7.98 (br. s., 1 H), 4.01 (s, 3 H), 3.99 (s, 3

H).

c) 3-amino-5-(cvclohexylamino)benzoic acid. Under nitrogen in a sealed microwave vial, methyl 3-bromo-5-nitrobenzoate (200 mg, 0.769 mmol), cyclohexylamine (0.132 mL, 1.154 mmol), cesium carbonate (376 mg, 1.154 mmol), tri- tertbutylphosphine 1 M in hexane (0.062 mL, 0.062 mmol), and palladium(ll) acetate (17.27 mg, 0.077 mmol) and toluene (5 mL) were mixed. The reaction was stirred at 80°C overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, and brine. The combined organic fractions were concentrated under reduced pressure.

Purification by reverse-phase preparative HPLC (10-90% acetonitrile/water with

0.1 % trifluoroacetic acid) afforded the intermediate nitro compound. ¹ H NMR (METHANOL-d ₄ ) : 7.86 - 7.90 (m, 1 H), 7.52 - 7.54 (m, 1 H), 7.49 - 7.52 (m, 1 H), 3.94 (s, 3H), 1.97 - 2.12 (m, 2H), 1.82 (dt, J = 13.4, 3.7 Hz, 2H), 1.70 (dt, J = 12.8, 3.6 Hz, 1 H), 1 .36 - 1 .55 (m, 2H), 1 .17 - 1 .36 (m, 4H). The crude nitro compound was stirred in methanol (3 mL) under hydrogen with 5% palladium-on-charcoal (82 mg, 0.038 mmol) at room temperature overnight. The catalyst was filtered and 6N sodium hydroxide (0.064 mL, 0.385 mmol) was added. The mixture was stirred at 50°C overnight. The mixture was concentrated and used directly in the next reaction. LCMS (ES+) m/z 235 [M+H] ⁺ . d) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5

(cvclohexylamino)benzoic acid. Crude 3-amino-5-(cyclohexylamino)benzoic acid (~ 200 mg, 0.854 mmol) was added to a stirred solution of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (80 mg, 0.232 mmol) in acetic acid (4 mL) at room temperature. The reaction was stirred for 24 hours, then the precipitate was filtered, washed with acetic acid, and dried in vacuo. Purification by reverse-phase preparative HPLC (10-50 % acetonitrile/water with 0.1 % trifluoroacetic acid) afforded 3-({3-(aminocarbonyl)-7-[2,4-bis(methyloxy)-5- pyrimidinyl]-4-quinolinyl}amino)-5-(cyclohexylamino)benzoic acid (7.6 mg, 0.013 mmol, 5.43 % yield) as a yellow solid. ¹ H NMR (METHANOL-d ₄ ) : 8.99 (s, 1 H), 8.55 (s, 1 H), 8.16 (d, J = 1 .8 Hz, 1 H), 8.04 (d, J = 9.1 Hz, 1 H), 7.77 (d, 1 H), 7.42 (d, J = 1 .5 Hz, 1 H), 7.28 (s, 1 H), 6.88 (t, J = 2.0 Hz, 1 H), 4.13 (s, 3H), 4.10 (s, 3H), 2.01 (br. s., 2H), 1.78 (d, J = 12.9 Hz, 2H), 1.68 (d, J = 1 1.4 Hz, 1 H), 1.18 - 1.46 (m, 6H).

Example 2

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (propylamino)benzoic acid

a) 3-amino-5-(propylamino)benzoic acid. Under nitrogen atmosphere in a sealed microwave vial, methyl 3-bromo-5-nitrobenzoate (250 mg, 0.961 mmol), n- propylamine (0.120 mL, 1 .442 mmol), cesium carbonate (470 mg, 1.442 mmol), tri- tertbutylphosphine 1 M in hexane (0.077 mL, 0.077 mmol), and palladium(ll) acetate (21.58 mg, 0.096 mmol) in toluene (5 mL) were mixed. The reaction was stirred at 80°C overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, and brine. The combined organic fractions were concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) afforded the crude nitro intermediate. LCMS (ES+) m/z 239 [M+H] ⁺ . The crude nitro intermediate, palladium-on-carbon (5%, 102 mg, 0.048 mmol) and methanol (3 mL) were stirred under hydrogen at room temperature overnight. The catalyst was filtered and 6N sodium hydroxide (0.160 mL, 0.961 mmol) was added. The mixture was stirred overnight at 50°C before being concentrated and used directly in the next reaction. ¹ H NMR (METHANOL-d ₄ ) : 6.71 (d, J = 8.3 Hz, 2H), 6.20 (br. s., 1 H), 3.05 (t, J = 7.1 Hz, 2H), 1 .56 - 1 .74 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H).

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

(propylamino)benzoic acid. Crude 3-amino-5-(propylamino)benzoic acid (77 mg, 0.396 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-carboxamide (65 mg, 0.189 mmol) in acetic acid (4 mL) at room temperature. The reaction was stirred for 24 hours, then the precipitate was filtered, washed with acetic acid, and dried in vacuo. Purification by reverse-phase preparative HPLC (10-50 % acetonitrile/water + 0.1 % trifluoroacetic acid) afforded 3-({3-(aminocarbonyl)-7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4 -quinolinyl}amino)-5- (propylamino)benzoic acid (40 mg, 0.065 mmol, 34.4 % yield) as a yellow solid. 1H NMR (METHANOL-d ₄ ) : 8.98 (s, 1 H), 8.54 (s, 1 H), 8.16 (d, J = 1 .5 Hz, 1 H),

8.00 (d, J = 8.8 Hz, 1 H), 7.74 (d, 1 H), 7.36 (s, 1 H), 7.15 - 7.29 (m, 1 H), 6.82 (t, J =

2.1 Hz, 1 H), 4.12 (s, 3H), 4.09 (s, 3H), 3.09 (t, J = 7.1 Hz, 2H), 1.56 - 1.75 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H).

-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(4-fluorophenylsulfonam ido)phen

3-carboxamide

a) N-(3-aminophenyl)-4-fluorobenzenesulfonamide. A solution of N-Boc-m- phenylenediamine (320 mg, 1 .537 mmol) and pyridine (0.124 ml_, 1.537 mmol) in acetonitrile (10 ml.) was kept at 0°C while adding 4-fluoro-phenylsulfonyl chloride (299 mg, 1.537 mmol) dropwise. The solution was stirred until it reached room temperature (ca. 1 h), then diluted with brine and extracted with ethyl acetate. The residue (light purple, LCMS (ES+) m/e 367 [M+H] ⁺ ) was dissolved in

dichloromethane and treated with trifluoroacetic acid (370 μΙ, 4.80 mmol). The reaction was stirred at room temperature overnight, then quenched with saturated aqueous sodium bicarbonate and extracted using dichloromethane. The organic portion was dried over magesium sulfate, filtered and concentrated to obtain the title compound (0.414 g) as a clear, thick purple oil. LCMS (ES+) m/e 267 [M+H] ⁺ . The crude was used in the next step without purification.

b) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(4- fluorophenylsulfonamido)phenyl)amino)quinoline-3-carboxamide . A mixture of N- (3-aminophenyl)-4-fluorobenzenesulfonamide (400 mg, 1.502 mmol) and 4-chloro- 7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (518 mg, 1.502 mmol) in acetic acid (10 ml.) was stirred at room temperature for 2 h. The resulting solid was filtered, then washed with ethyl ether and purified using reverse-phase preparative HPLC (0.1 % trifluoroacetic acid in acetonitrile and water) to obtain the title compound (0.070 g, 8%) as a light yellow solid. LCMS (ES+) m/e 575

[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 1 1.90 (br. s., 1 H), 10.51 (s, 1 H), 9.03 (s, 1 H), 8.62 (s, 1 H), 8.36 (br. s., 1 H), 8.20 (d, J=1.8 Hz, 1 H), 7.89 (br. s., 1 H), 7.78 - 7.84 (m, 2 H), 7.70 - 7.75 (m, 1 H), 7.64 (dd, J=9.1 , 1 .5 Hz, 1 H), 7.32 - 7.38 (m, 2 H), 7.24 - 7.31 (m, 1 H), 6.98 - 7.04 (m, 2 H), 6.95 (d, J=7.3 Hz, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H).

Example 4

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(4- methoxyphenylsulfonamido)phenyl)amino)quinoline-3-carboxamid e

a) N-(3-aminophenyl)-4-(methyloxy)benzenesulfonamide. A solution of N-Boc-m- phenylenediamine (320 mg, 1 .537 mmol) and pyridine (0.124 ml_, 1.537 mmol) in acetonitrile (10 ml.) was kept at 0 °C while adding 4- methoxybenzenesulfonylchloride (318 mg, 1.537 mmol) dropwise. The solution was stirred until it reached room temperature (ca. 1 h), then diluted with brine and extracted with ethyl acetate. The residue (light purple, LCMS (ES+) m/e 379 [M+H] ⁺ ) was dissolved into dichloromethane and treated with trifluoroacetic acid (370 μΙ, 4.80 mmol). The reaction was stirred at room temperature over 48 hours, then quenched with saturated aqueous sodium bicarbonate and extracted using dichloromethane. The organic portion was dried over magnesium sulfate, filtered and concentrated to obtain the title compound (0.450 g) as a clear, thick yellow oil. LCMS (ES+) m/e 279 [M+H] ⁺ . The crude was used in the next step without further purification.

b) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(4- methoxyphenylsulfonamido)phenyl)amino)quinoline-3-carboxamid e. A mixture of N-(3-aminophenyl)-4-(methyloxy)benzenesulfonamide (450 mg, 1 .617 mmol) and 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (557 mg, 1.617 mmol) in acetic acid (10 ml.) was stirred at room temperature for 2 h. The resulting solid was filtered, then washed with ethyl ether and purified using reverse-phase preparative HPLC (0.1 % trifluoroacetic acid in acetonitrile and water) to obtain the title compound (0.037 g, 4%) as a bright yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 10.33 (br. s., 1 H), 9.03 (s, 1 H), 8.61 (s, 1 H), 8.37 (br. s., 1 H), 8.18 (d, J=1.5 Hz, 1 H), 7.90 (br. s., 1 H), 7.63 - 7.70 (m, 3 H), 7.51 - 7.62 (m, 1 H), 7.25 (t, J=8.3 Hz, 1 H), 6.97 - 7.05 (m, 4 H), 6.84 - 6.95 (m, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.73 (s, 3 H). LCMS (ES+) m/e 587 [M+H] ⁺ .

Example 5

-((3-(cvclopropanesulfonamido)phenyl)amino)-7-(2,4-dimeth oxypyrimidin-5-v

3-carboxamide

a) N-(3-aminophenyl)cvclopropanesulfonamide. A solution of N-Boc-m- phenylenediamine (300 mg, 1 .441 mmol) and pyridine (0.1 17 ml_, 1.441 mmol) in acetonitrile (5 ml.) was stirred at room temperature, while adding

cyclopropanesulfonyl chloride (203 mg, 1 .441 mmol) dropwise. The solution was stirred at room temperature, then diluted with brine and extracted with ethyl acetate. The residue (orange, sticky oil, LCMS (ES+) m/e 313 [M+H] ⁺ ) was dissolved into dichloromethane and treated with trifluoroacetic acid (1 ml_, 12.98 mmol). The reaction was stirred at room temperature overnight, then diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The yellow solid obtained (0.430 g) was carried on to the next step without further purification. LCMS (ES+) m/e 213 [M+H] ⁺ .

b) 4-((3-(cvclopropanesulfonamido)phenyl)amino)-7-(2,4-dimethox ypyrimidin-5- yl)quinoline-3-carboxamide. A mixture of N-(3- aminophenyl)cyclopropanesulfonamide (306 mg, 1.441 mmol) and 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (497 mg, 1.441 mmol) in acetic acid (10 mL) was stirred at room temperature overnight. The resulting solid was filtered, then washed with ethyl ether and purified using reverse-phase preparative HPLC (0.1 % trifluoroacetic acid in acetonitrile and water) to obtain the title compound (0.200 g, 27%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 1 1 .89 (br. s., 1 H) 9.91 (s, 1 H) 9.03 (s, 1 H) 8.62 (s, 1 H) 8.34 (br. s., 1 H) 8.20 (d, J=1.77 Hz, 1 H) 7.97 (d, J=9.09 Hz, 1 H) 7.89 (br. s., 1 H) 7.78 (d, J=8.59 Hz, 1 H) 7.30 - 7.45 (m, 1 H) 7.15 (br. s., 2 H) 7.00 (d, J=7.58 Hz, 1 H) 4.01 (s, 3 H) 3.98 (s, 3 H) 2.60 - 2.72 (m, 1 H) 0.83 - 0.99 (m, 4 H). LCMS (ES+) m/e 521

[M+H] ⁺ .

Example 6

-((3-(cvclohexanesulfonamido)phenyl)amino)-7-(2,4-dimetho xypyrimidin-5-yl)quinoline-3- carboxamide

a) N-(3-aminophenyl)cvclohexanesulfonamide. A solution of N-Boc-m- phenylenediamine (300 mg, 1 .441 mmol) and pyridine (0.1 17 mL, 1.441 mmol) in acetonitrile (5 mL) was stirred at room temperature, while adding

cyclohexanesulfonylchloride (263 mg, 1.441 mmol) dropwise. The solution was stirred at room temperature, then diluted with brine and extracted with ethyl acetate. The residue (orange, sticky oil) was dissolved into dichloromethane and treated with trifluoroacetic acid (1 mL, 12.98 mmol). The reaction was stirred at room temperature overnight, then diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The obtained yellow solid (0.366 g) was carried on to the next step without further purification. LCMS (ES+) m/e 255 [M+H] ⁺ . b) 4-((3-(cvclohexanesulfonamido)phenyl)amino)-7-(2,4-dimethoxy pyrimidin-5- yl)quinoline-3-carboxamide. A mixture of N-(3- aminophenyl)cyclohexanesulfonamide (366 mg, 1 .44 mmol) and 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (437 mg, 1.267 mmol) in acetic acid (10 mL) was stirred at room temperature overnight. The resulting solid was filtered, then washed with ethyl ether and purified using reverse-phase preparative HPLC (0.1 % trifluoroacetic acid in acetonitrile and water) to obtain the title compound (0.120 g, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 1 1 .90 (br. s., 1 H) 9.93 (s, 1 H) 9.03 (s, 1 H) 8.62 (s, 1 H) 8.34 (br. s., 1 H) 8.21 (d, J=1.77 Hz, 1 H) 7.94 (d, J=8.84 Hz, 1 H) 7.89 (br. s., 1 H) 7.78 (dd, J=8.84, 1.39

Hz, 1 H) 7.29 - 7.43 (m, 1 H) 7.13 (d, J=7.58 Hz, 1 H) 7.10 (br. s., 1 H) 6.99 (d, J=7.58 Hz, 1 H) 4.01 (s, 3 H) 3.98 (s, 3 H) 2.91 - 3.05 (m, 1 H) 1 .95 (d, J=1 1.87 Hz, 2 H) 1.69 (d, J=12.63 Hz, 2 H) 1.50 (d, J=12.38 Hz, 1 H) 1.27 - 1.44 (m, 2 H) 0.94 - 1.28 (m, 3 H). LCMS (ES+) m/e 563 [M+H] ⁺ .

Example 7

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- ((cvclohexylmethyl)amino)benzoic acid

3-amino-5-[(cvclohexylmethyl)aminolbenzoic acid. Under nitrogen atmosphere in a sealed microwave vial, methyl 3-bromo-5-nitrobenzoate (250 mg, 0.961 mmol), (aminomethyl)cyclohexane (0.312 mL, 2.403 mmol), cesium carbonate (470 mg, 1.442 mmol), tri-tertbutylphosphine 1 M in hexane (0.096 mL, 0.096 mmol), and palladium(ll) acetate (21.58 mg, 0.096 mmol) in toluene (5 mL) were mixed. The reaction was stirred at 80°C overnight, before being concentrated and purified by reverse-phase preparative HPLC ( 30-90% acetonitrile/water + 0.1 %

trifluoroacetic acid) to give the intermediate nitro compound. ¹ H NMR

(METHANOLS) d: 7.82 - 7.95 (m, 1 H), 7.43 - 7.58 (m, 2H), 3.94 (s, 3H), 2.99 (d, J = 6.8 Hz, 2H), 1 .88 (d, J = 13.1 Hz, 2H), 1 .75 - 1 .83 (m, 2H), 1.72 (d, J = 10.4

Hz, 1 H), 1.56 - 1.67 (m, 1 H), 1.17 - 1.40 (m, 3H), 0.93 - 1.12 (m, 2H). The intermediate nitro compound, 5% palladium-on-charcoal (102 mg, 0.048 mmol) and methanol (3 ml.) were stirred under hydrogen at room temperature overnight. The catalyst was filtered and 6N sodium hydroxide (0.080 ml_, 0.481 mmol) was added. Upon completion, the mixture was concentrated and taken directly to the next step as-is. LCMS (ES+) m/z 249 [M+H] ⁺ .

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- ((cvclohexylmethyl)amino)benzoic acid. Crude 3-amino-5- [(cyclohexylmethyl)amino]benzoic acid (108 mg, 0.435 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (50 mg, 0.145 mmol) in acetic acid (4 ml.) at room temperature. The reaction was stirred for 24 hours, then the precipitate was filtered, washed with acetic acid, and dried in vacuo. Purification by reverse-phase preparative HPLC (10-50 % acetonitrile/water + 0.1 % trifluoroacetic acid) afforded 3-({3-(aminocarbonyl)-7- [2,4-bis(methyloxy)-5-pyrimidinyl]-4-quinolinyl}amino)-5-

[(cyclohexylmethyl)amino]benzoic acid (13.3 mg, 0.020 mmol, 13.67 % yield) as a yellow solid. ¹ H NMR (METHANOL-d ₄ ) : 8.99 (s, 1 H), 8.53 (s, 1 H), 8.16 (d, J =

1.8 Hz, 1 H), 7.97 (d, J = 9.1 Hz, 1 H), 7.73 (dd, J = 9.1 , 1 .8 Hz, 1 H), 7.26 - 7.37 (m, 1 H), 7.15 (t, J = 1.6 Hz, 1 H), 6.72 (t, J = 2.0 Hz, 1 H), 4.12 (s, 3H), 4.08 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 1 .81 (d, J = 1 1.9 Hz, 3H), 1 .68 - 1 .76 (m, 3H), 1 .59 - 1 .68 (m, 2H), 1 .51 - 1 .56 (m, 1 H), 1.20 (d, J = 9.1 Hz, 2H).

Example 8

-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(furan-3-sulfonamido )phenyl)amino)quinoline-3- carboxamide

a) N-(3-aminophenyl)-3-furansulfonamide. A solution of N-Boc-m-phenylenediamine (300 mg, 1.441 mmol) and pyridine (0.1 17 ml_, 1 .441 mmol) in acetonitrile (10 ml.) was stirred at 0 °C while adding furan-3-sulfonyl chloride (240 mg, 1.441 mmol) dropwise. The solution was stirred, allowing to reach room temperature, then diluted with brine and extracted with ethyl acetate. The residue (orange, sticky oil,

LCMS (ES+) m/e 339 [M+H] ⁺ ) was dissolved into dichloromethane and treated with trifluoroacetic acid (1 mL, 12.98 mmol). The reaction was stirred at room temperature overnight, then diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The obtained yellow solid was carried on to the next reaction. LCMS (ES+) m/e 239 [M+H] ⁺ .

b) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(furan-3- sulfonamido)phenyl)amino)quinoline-3-carboxamide. A mixture of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (0.397 g, 1 .153 mmol) and N-(3- aminophenyl)-3-furansulfonamide (0.343 g, 1.441 mmol) in acetic acid (10 mL) was stirred at room temperature overnight. The resulting solid was filtered, then washed with ethyl ether and dried in vacuo to obtain a light orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 14.88 (s, 1 H), 12.24 (br. s., 1 H), 10.53 (s, 1 H), 9.09 (s, 1 H), 8.63 (s, 1 H), 8.44 (br. s., 1 H), 8.31 (dd, J=1.5, 0.8 Hz, 1 H), 8.26 (d, J=1.5 Hz, 1 H), 7.92 (br. s., 1 H), 7.79 - 7.82 (m, 1 H), 7.78 (t, J=1.8 Hz, 1 H), 7.70 (dd, J=9.1 , 1 .8 Hz, 1 H), 7.34 (t, J=8.0 Hz, 1 H), 7.13 (br. s., 1 H), 7.1 1 (d, J=8.1 Hz, 1 H), 7.02 (d, J=8.1 Hz, 1 H), 6.67 (d, J=1 .3 Hz, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H). LCMS (ES+) m/e 547 [M+H] ⁺ .

Example 9

methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- isopropoxybenzoate

a) methyl 3-ΓΠ -methylethyl)oxyl-5-nitrobenzoate. To a suspension of methyl 3- hydroxy-5-nitrobenzoate (200 mg, 1 .014 mmol) and potassium carbonate (280 mg, 2.029 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromopropane (250 mg, 2.029 mmol). The reaction mixture was heated to 120 °C for 20 minutes by microwave irradiation. After cooling, the reaction was poured into ice water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purifited via flash chromatography (0-100% ethyl acetate in hexanes) to afford methyl 3-[(1- methylethyl)oxy]-5-nitrobenzoate (150 mg, 0.627 mmol, 61 .8 % yield) as a colorless oil. LCMS (ES+) m/e 240 [M+H] ⁺ .

b) methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- isopropoxybenzoate. To a mixture of methyl 3-[(1 -methylethyl)oxy]-5- nitrobenzoate (139 mg, 0.580 mmol) and 10% palladium on carbon, wet (61.7 mg, 0.058 mmol) was added acetic acid (10 mL). The mixture was hydrogenated under a hydrogen balloon at room temperature overnight, then filtered. 4-Chloro- 7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (200 mg, 0.580 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight. The solvent was removed and the residue was purified via flash chromatography (silica gel, 0-10% methanol/dichloromethane) to afford methyl 3- ({3-(aminocarbonyl)-7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4-q uinolinyl}amino)-5-[(1 - methylethyl)oxy]benzoate (175 mg, 0.338 mmol, 58.3 % yield) as a yellow solid. LCMS (ES+) m/e 518 [M+H] ⁺ .

Example 10

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

To a suspension of methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-isopropoxybenzoate (130 mg, 0.251 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 N in water) (0.209 mL, 1.256 mmol). The mixture was kept stirring for 3 hour at room temperature, then poured into ice water. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )-5-isopropoxybenzoic acid (105 mg, 0.209 mmol, 83 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=5.98 Hz, 6 H) 3.98 (s, 3 H) 4.01 (s, 3 H) 4.62 (spt, J=5.98 Hz, 1 H) 7.00 (br. s., 1 H) 7.24 (s, 1 H) 7.30 (s, 1 H) 7.74 - 7.86 (m, 2 H) 8.08 (d, J=8.84 Hz, 1 H) 8.28 (d,J=1 .52 Hz, 1 H) 8.38 (br. s., 1 H) 8.62 (s, 1 H) 9.06 (s, 1 H) 1 1 .44 (br. s., 1 H) 12.98 (br. s., 1 H). LCMS (ES+) m/e 504 [M+H] ⁺ .

Example 1 1

cvclopentyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- hydroxybenzoate

a) 3-({3-carbamoyl-7-r2,4-bis(methyloxy)-5-pyrimidinyll-4-quino linyl}amino)-5- hydroxybenzoic acid. To a suspension of 4-chloro-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-carboxamide (1000 mg, 2.90 mmol) in acetic acid (20 ml.) was added 3-amino-5-hydroxybenzoic acid (489 mg, 3.19 mmol). The reaction was kept stirring at room temperature overnight. The precipitate was collected and washed with ether and dichloromethane to afford 3-({3-carbamoyl-7-[2,4- bis(methyloxy)-5-pyrimidinyl]-4-quinolinyl}amino)-5-hydroxyb enzoic acid (750 mg, 1.625 mmol, 56.0 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 3.99 (s, 3 H) 4.02 (s, 3 H) 6.94 (s, 1 H) 7.25 - 7.33 (m, 2 H) 7.78 - 7.92 (m, 2 H) 8.09 (d, J=9.09 Hz, 1 H) 8.31 (d, J=1 .52 Hz, 1 H) 8.42 (br. s., 1 H) 8.64 (s, 1 H) 9.08 (s, 1 H) 10.18 (s, 1 H) 12.00 (br. s., 1 H) 12.89 (br. s., 1 H). LCMS (ES+) m/e 462 [M+H] ⁺ .

b) cvclopentyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- hydroxybenzoate. To a suspension of 3-({3-carbamoyl-7-[2,4-bis(methyloxy)-5- pyrimidinyl]-4-quinolinyl}amino)-5-hydroxybenzoic acid (100 mg, 0.217 mmol) and potassium carbonate (60 mg, 0.433 mmol) in Ν,Ν-dimethylformamide was added bromocyclopentane (38.8 mg, 0.260 mmol). The reaction was heated to 150 °C for 10 minutes under microwave irridiation. The organic solvent was removed under reduced pressure, and the residue was dissolved in dimethylsulfoxide and purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (0.026 g, 23%) as a yellow solid. ¹ H NMR (400 MHz, M ETHAN OL-d4) δ ppm 1 .61 - 1.73

(m, 2 H) 1 .75 - 1 .88 (m, 4 H) 1.91 - 2.03 (m, 2 H) 4.09 (s, 3 H) 4.13 (s, 3 H) 5.37 (td, J=5.68, 3.03 Hz, 1 H) 7.00 (t, J=2.15 Hz, 1 H) 7.39 - 7.47 (m, 2 H) 7.81 (dd, J=8.84, 1 .77 Hz, 1 H) 8.04 (d, J=9.09 Hz, 1 H) 8.18 (d, J=1 .77 Hz, 1 H) 8.56 (s, 1 H) 8.98 (s, 1 H). MS(ES+) m/e 530 [M+H] ⁺ .

Example 12

sec-butyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- hvdroxybenzoate

To a suspension of 3-({3-carbamoyl-7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4- quinolinyl}amino)-5-hydroxybenzoic acid (100 mg, 0.217 mmol) and potassium carbonate (60 mg, 0.433 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromobutane (59.4 mg, 0.433 mmol). The reaction was heated to 150 °C for 10 minutes under microwave irridiation. The organic solvent was removed under reduced pressure, and the residue was dissolved in dimethylsulfoxide and purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (0.027 g, 24%) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-^) δ ppm 0.96 (t, J=7.45 Hz, 3 H) 1.33 (d, J=6.32 Hz, 3 H) 1 .71 (tq,J=14.18, 6.97 Hz, 2 H) 4.09 (s, 3 H) 4.13 (s, 3 H) 5.05 (sxt, J=6.21 Hz, 1 H) 7.01 (t, J=2.15 Hz, 1 H) 7.44 -7.50 (m, 2 H)

7.81 (dd, J=9.09, 1.77 Hz, 1 H) 8.05 (d, J=9.09 Hz, 1 H) 8.18 (d, J=1.52 Hz, 1 H) 8.55 (s, 1 H) 8.98 (s, 1 H). LCMS (ES+) m/e 518 [M+H] ⁺ . Example 13

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexyloxy)benzoic acid

a) methyl 3-(cvclohexyloxy)-5-nitrobenzoate. To a suspension of methyl 3-hydroxy- 5-nitrobenzoate (300 mg, 1 .522 mmol) and potassium carbonate (421 mg, 3.04 mmol) in N,N-dimethylformamide (10 mL) was added bromocyclohexane (248 mg, 1.522 mmol). The reaction mixture was heated to 120 °C for 20 minutes under microwave irradiation. After cooling, the reaction was poured into ice water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford methyl 3-(cyclohexyloxy)-5-nitrobenzoate (100 mg, 0.358 mmol, 23.53 % yield) as a colorless oil. LCMS (ES+) m/e 280 [M+H] ⁺ .

b) methyl 3-({3-carbamoyl-7-r2,4-bis(methyloxy)-5-pyrimidinyll-4-quino linyl}amino)-5- (cvclohexyloxy)benzoate. To a mixture of methyl 3-(cyclohexyloxy)-5- nitrobenzoate (52.7 mg, 0.189 mmol) and 5% palladium on carbon, wet (0.040 g, 0.019 mmol) was added acetic acid (10 mL). The mixture was hydrogenated under a balloon at room temperature overnight, and was filtered. 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (65 mg, 0.189 mmol) was added to the filtrate. The reaction mixture was kept stirring room temperature overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (50 mg, 0.090 mmol, 47.6 % yield) as a yellow solid. LCMS (ES+) m/e 558 [M+H] ⁺ .

c) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexyloxy)benzoic acid. To a mixture of methyl 3-({3-carbamoyl-7-[2,4- bis(methyloxy)-5-pyrimidinyl]-4-quinolinyl}amino)-5-(cyclohe xyloxy)benzoate (50 mg, 0.090 mmol) in methanol (5 mL) was added sodium hydroxide (6.0 N in water) (0.075 mL, 0.448 mmol). The reaction mixture was kept stirring at 50 °C overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(cyclohexylox y)benzoic acid (17 mg, 0.026 mmol, 28.8 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.20 - 1.55 (m, 6 H) 1.63 - 1.73 (m, 2 H) 1.85 - 1 .94 (m, 2 H) 3.99 (s, 3H) 4.02

(s, 3 H) 4.32 - 4.43 (m, 1 H) 7.06 (br. s., 1 H) 7.28 (br. s., 1 H) 7.34 (br. s., 1 H) 7.84 (br. s., 2 H) 8.1 1 (d, J=8.08 Hz, 1 H) 8.22 (d, J=1 .26 Hz, 1 H) 8.30 (br. s., 1 H) 8.64 (s, 1 H) 9.01 (s, 1 H) 13.15 (br. s., 1 H). LCMS (ES+) m/e 544 [M+H] ⁺ .

Example 14

3-(cvclohexyloxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulf amoylquinolin-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. 1H NMR (400 MHz, DMSO-de) 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-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 ) 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).

c) 7-[2,4-bis(methyloxy)-5-pyrimidinyll-4-chloro-3-quinolinesul fonamide. 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-c/ ₆ ) 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).

d) methyl 3-(cvclohexyloxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulf amoylquinolin- 4-yl)amino)benzoate. To a mixture of methyl 3-(cyclohexyloxy)-5-nitrobenzoate (44.0 mg, 0.158 mmol) and 5% palladium on carbon, wet (0.034 g, 0.016 mmol) was added acetic acid (10 mL). The mixture was hydrogenated under a balloon at room temperature overnight, and was filtered. 7-[2,4-bis(methyloxy)-5- pyrimidinyl]-4-chloro-3-quinolinesulfonamide (60 mg, 0.158 mmol) was added to the filtrate. The reaction mixture was kept stirring at 30 °C overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford methyl 3-(cyclohexyloxy)-5- ((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)a mino)benzoate (52 mg, 0.088 mmol, 55.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 1 .31 - 1.45 (m, 3 H) 1 .47 - 1.61 (m, 3 H) 1 .72 - 1 .81 (m, 2 H)1.91 - 1.99 (m, 2 H) 3.91 (s, 3 H) 4.09 (s, 3 H) 4.12 (s, 3 H) 4.35 - 4.43 (m, 1 H) 7.19 (t, J=2.15 Hz, 1 H) 7.55 - 7.57 (m, 1 H) 7.57 - 7.59 (m, 1 H) 7.71 - 7.75 (m, 2 H) 8.25 (s, 1 H) 8.53 (s, 1 H) 9.14 (s, 1 H). LCMS (ES+) m/e 594 [M+H] ⁺ .

e) 3-(cvclohexyloxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulf amoylquinolin-4- yl)amino)benzoic acid. To a mixture of methyl 3-(cyclohexyloxy)-5-((7-(2,4- dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino)benz oate (50 mg, 0.084 mmol) in methanol (5 mL) was added sodium hydroxide (6.0 N in water) (0.014 mL, 0.084 mmol). The reaction mixture was kept stirring at 50 °C overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-(cyclohexyloxy)-5-((7-(2,4- dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino)benz oic acid (21 mg, 0.030 mmol, 35.9 % yield) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-^) δ ppm 1 .29 - 1.46 (m, 3 H) 1 .46 - 1.62 (m, 3 H) 1 .72 - 1 .81 (m, 2 H) 1 .90 - 1 .99 (m, 2 H) 4.08 (s, 3 H) 4.1 1 (s, 3 H) 4.33 - 4.42 (m, 1 H) 7.18 (t, J=2.15 Hz, 1 H) 7.55 (t, J=1.52 Hz,1 H) 7.57 - 7.60 (m, 1 H) 7.71 (s, 1 H) 7.72 (s, 1 H) 8.26 (s, 1 H) 8.53 (s, 1 H) 9.13 (s, 1 H). LCMS (ES+) m/e 580 [M+H] ⁺ .

Example 15

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclopentyloxy)benzoic acid

a) methyl 3-(cvclopentyloxy)-5-nitrobenzoate. To a suspension of methyl 3-hydroxy- 5-nitrobenzoate (300 mg, 1 .522 mmol) and potassium carbonate (421 mg, 3.04 mmol) in N,N-dimethylformamide (10 ml.) was added bromocyclopentane (227 mg, 1 .522 mmol). The reaction mixture was heated to 120 °C for 20 minutes under microwave irradiation. After cooling, the reaction was poured into ice water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purifited via flash chromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford methyl 3-(cyclopentyloxy)-5-nitrobenzoate (210 mg, 0.792 mmol, 52.0 % yield) as a colorless oil. ¹ H NMR (400 MHz, METHANOL-d4) ppm 1 .64 - 1.76 (m,

2 H) 1 .76 - 1 .90 (m, 4 H) 1.94 - 2.07 (m, 2 H) 3.95 (s, 3 H) 4.88 - 4.94 (m, 1 H) 7.71 (dd, J=2.53, 1.26 Hz, 1 H) 7.79 (t, J=2.27 Hz, 1 H) 8.16 - 8.20 (m, 1 H).

LCMS (ES+) m/e 266 [M+H] ⁺ .

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclopentyloxy)benzoic acid. To a mixture of methyl 3-(cyclopentyloxy)-5- nitrobenzoate (77 mg, 0.290 mmol) and 10% palladium on carbon, wet (30.9 mg, 0.029 mmol) was added acetic acid (10 ml_). The mixture was hydrogenated under a hydrogen balloon at room temperature overnight, then filtered. 4-Chloro- 7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (100 mg, 0.290 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight. The solvent was removed and the residue was dissolved in methanol (10 mL). Sodium hydroxide (6.0 M in water) (1 16 mg, 2.90 mmol) was added to the reaction. The mixture was kept stirring at room temperature overnight and purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(cyclopentylo xy)benzoic acid (40 mg, 0.062 mmol, 21.43 % yield) as an off-white solid. ¹ H NMR (400 MHz, METHANOL-^) δ ppm 1 .62 - 1.73 (m, 2 H) 1 .74 - 1 .89 (m, 4 H) 1 .90 - 2.01 (m, 2 H) 3.35 - 3.39 (m, 1 H) 4.10 (s, 3 H) 4.13 (s, 3 H) 7.1 1 (t, J=2.15 Hz, 1 H) 7.54 (s, 1 H) 7.55 (s, 1 H) 7.82 (dd,J=9.09, 1.77 Hz, 1 H) 8.07 (d, J=9.09 Hz, 1 H) 8.18 (d, J=1.77 Hz, 1 H) 8.55 (s, 1 H) 8.97 (s, 1 H). LCMS (ES+) m/e 530 [M+H] ⁺ .

Example 16

3-(cvclopentyloxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sul famoylquinolin-4- yl)amino)benzoic acid

To a mixture of methyl 3-(cyclopentyloxy)-5-nitrobenzoate (84 mg, 0.315 mmol) and 10% palladium on carbon, wet (335 mg, 0.315 mmol) was added acetic acid (10 mL). The mixture was hydrogenated under a hydrogen balloon at room temperature overnight, then filtered. 7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4-chloro-3-quinolinesul fonamide (120 mg, 0.315 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight, then purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-(cyclopentyloxy)-5- ((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)a mino)benzoic acid (42 mg, 0.062 mmol, 19.61 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 1.49 - 1.57 (m, 2 H) 1 .58 - 1 .70 (m, 4 H) 1 .73 - 1 .85 (m, 2 H) 3.98 (s, 3H) 3.99 (s, 3 H) 4.67 - (m, 1 H) 6.74 (br. s., 1 H) 7.14 (d, J=1.77 Hz, 2 H) 7.70 (s, 2 H) 7.93 (br. s., 2 H)8.26 H) 8.59 (s, 2 H) 9.15 (s, 1 H) 13.07 (br. s., 1 H). LCMS (ES+) m/e 566 [M+H] ⁺ .

Example 17

4-((3-(cvclohexyloxy)phenyl)amino)-7-(2,4-dimethoxypyrimidin -5-yl)quinolm

sulfonamide

a) 1-(cvclohexyloxy)-3-nitrobenzene. N,N-Dimethylformamide (20 mL) was added to a mixture of 3-nitrophenol (1.10 g, 7.91 mmol) and powdered potassium carbonate

(2.19 g, 15.8 mmol) and the mixture stirred for 10 min. Cyclohexyl bromide (2.92 mL, 15.0 mmol) was added and the mixture stirred at 50 °C for 18 h, then at 100 °C for 3 h. More potassium carbonate (2.19 g, 15.8 mmol) was added, followed by cyclohexyl bromide (1.46 mL, 7.50 mmol) in 3 portions at hourly intervals. The mixture was stirred at 100 °C for 18 h, then cooled and poured into water (100 mL). The mixture was extracted with ethyl acetate. The extracts were washed with dilute aqueous potassium carbonate, water, brine, dried (MgSO^ and evaporated under reduced pressure. The residue was chromatographed (silica gel, 2-30% ethyl acetate/hexane) to give the title compound (0.472 g, 27%) as a clear oil. ¹ H NMR (400 MHz, CHLOROFORM-d) ppm 1 .32 - 1 .50 (m, 3 H) 1 .51 -

1.67 (m, 3 H) 1 .78 - 1.89 (m, 2 H) 1 .95 - 2.06 (m, 2 H) 4.32 - 4.41 (m, 1 H) 7.23 (dd, J=8.72, 2.15 Hz, 1 H) 7.42 (t, J=8.21 Hz, 1 H) 7.74 (t, J=2.27 Hz, 1 H) 7.77 - 7.84 (m, 1 H).

b) 4-((3-(cvclohexyloxy)phenyl)amino)-7-(2,4-dimethoxypyrimidin -5-yl)quinoline-3- sulfonamide. A solution of 1 -(cyclohexyloxy)-3-nitrobenzene (0.470 g, 2.12 mmol) in acetic acid (12 mL) was stirred vigorously with 5% palladium-on carbon (0.400g, 0.188 mmol) under a balloon of hydrogen at room temperature for 4 h. The hydrogen was flushed out with nitrogen and the mixture filtered through a PTFE micropore filter to give a solution ~ 0.15M in aniline. 2.63 ml. of this solution was added to a slurry of 7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4-chloro-3- quinolinesulfonamide (0.100 g, 0.263 mmol) in acetic acid (5 ml.) and the mixture stirred at 50 °C for 18 h, then cooled. The solvent was evaporated under reduced pressure and the residue chromatographed (silica gel, 1-10%

methanol/dichloromethane) to give the title compound (0.093 g, 66%) as an amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 1 .10 - 1 .40 (m, 5 H) 1 .42 - 1.52 (m, 1 H) 1 .62 (br. s., 2 H) 1.78 - 1.89 (m, 2 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 4.12 - 4.25 (m, 1 H) 6.48 - 6.54 (m, 2 H) 6.65 (dd, J=8.34, 1 .52 Hz, 1 H) 7.13 - 7.20 (m, 1 H) 7.62 (dd, J=8.84, 1 .77 Hz, 1 H) 7.69 (d, J=8.84 Hz, 1 H) 7.93 (br. s., 3 H) 8.20

(d, J=1.77 Hz, 1 H) 8.57 (s, 1 H) 9.08 (s, 1 H).

Example 18

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylqu inolin-4-yl)amino)benzoic acid a) diethyl 2-((3-bromo-4-methylphenylamino)methylene)malonate. A mixture of 3- bromo-4-methylaniline (2 g, 10.8 mmol) and diethyl 2-(ethoxymethylene)malonate (2.3 g, 10.8 mmol) in ethanol (6 ml.) was refluxed for 3 h, then cooled to room temperature. The mixture was diluted with 50% aqueous ethanol (20 ml_). The solid was filtered, washed with 50% aqueous ethanol and dried in vacuo to afford the title compound (3.3 g, 80%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 1.22-1 .28 (m, 6 H), 2.31 (s, 3 H), 4.09-4.23 (m, 4 H), 7.29-7.37 (m, 2 H), 7.69 (s, 1 H), 8.33 (d, J=13.8 Hz, 1 H), 10.61 (d, J=13.8 Hz, 1 H). LCMS (ES+) m/e 356 [M+H] ⁺ . b) ethyl 7-bromo-4-hvdroxy-6-methylquinoline-3-carboxylate. Diethyl 2-((3-bromo-4- methylphenylamino)methylene)malonate (2 g, 5.6 mmol) was added to refluxing diphenyl ether (20 ml.) in portions. The mixture was then refluxed for 15 min, cooled to room temperature, and diluted with ether (20 ml_). The precipitate was collected by filtration, washed with ether and dried to afford the title compound (1.4 g, 81 %) as a yellow solid. LCMS (ES+) m/e 310 [M+H] ⁺ . 7-bromo-4-hvdroxy-6-methylquinoline-3-carboxylic acid. A mixture of ethyl 7- bromo-4-hydroxy-6-methylquinoline-3-carboxylate (1.4 g, 4.51 mmol) and sodium hydroxide (0.903 g, 22.57 mmol) in ethanol (23 mL) and water (23 mL) was stirred at 80 °C for 2 h. LCMS showed complete conversion. The mixture was cooled, concentrated to half of its volume under reduced pressure and acidified to pH 1 with 1 M aqueous hydrochloric acid. The precipitate was filtered and dried to give the title compound (1 .3 g, 97%) as a white solid. LCMS (ES+) m/e 282 [M+H] ⁺ . 7-bromo-4-chloro-6-methylquinoline-3-carboxamide. A mixture of 7-bromo-4- hydroxy-6-methylquinoline-3-carboxylic acid (1 .3 g, 4.61 mmol) in phosphorus oxychloride (6.0 mL, 64.4 mmol) was stirred under reflux for 3 h, then cooled. The solvent was removed under reduced pressure. A solution of the residue in tetrahydrofuran (5 mL) was added to a solution of 30% ammonium hydroxide (10 mL, 257 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and the resulting solid filtered, washed with water and dried to give the title compound (1 .02 g, 66.5%) as a gray solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 2.62 (s, 3 H), 7.93 (s, br, 1 H), 8.17 (s, br, 1 H), 8.24 (s, 1 H), 8.38 (s, 1 H), 8.83 (s, 1 H). LCMS (ES+) m/e 299 [M+H] ⁺ .

4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquinoline-3 -carboxamide. A mixture of 7-bromo-4-chloro-6-methylquinoline-3-carboxamide (0.99 g, 3.30 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (0.730 g, 3.97 mmol),

tetrakis(triphenylphosphine)palladium(0) (0.382 g, 0.33 mmol) and potassium carbonate (1 .096 g, 7.93 mmol) in 1 ,4-dioxane (2.0 mL) and water (0.4 mL) was stirred under nitrogen at 80 °C for 2.5 h, then cooled. Water (4 mL) was added and the mixture was stirred for 10 min. The solid was filtered, washed with water and dried to give the title compound (0.9 g, 68.3%) as a gray solid. LCMS (ES+) m/e 359 [M+H] ⁺ .

ethyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquino lin-4- ylamino)benzoate. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-6- methylquinoline-3-carboxamide (480 mg, 1.338 mmol) and ethyl 3-aminobenzoate (332 mg, 2.007 mmol) in acetic acid (6 mL) was stirred at 50 °C for 3 h. LCMS showed complete conversion. The mixture was adjusted pH 8 and filtered. The filter cake was dried to give the crude product which was further purified by chromatography on silica gel (3% methanol/dichloromethane ) to give the title compound (300 mg, 97%) as a gray solid. LCMS (ES+) m/e 488 [M+H] ⁺ . g) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquino lin-4- ylamino)benzoic acid. To a solution of ethyl 3-(3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-methylquinolin-4-ylamino)benzoate (190 mg, 0.390 mmol) in tetrahydrofuran (10 ml.) stirring at 25 °C was added lithium hydroxide (93 mg, 3.90 mmol) in water (4 ml_). The reaction mixture was stirred at 25 °C for 16 h, then acidified to pH 6 with acetic acid. The precipitate was filtered, washed with water and the resulting solid purified by chromatography on silica gel (25% methanol/dichloromethane) to give the title compound (130 mg, 70.9%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 2.08 (s, 3 H), 3.90 (s, 3 H), 3.97 (s, 3 H), 7.16 (d, J=7.5 Hz, 1 H), 7.35 (t, J=7.5 Hz, 1 H), 7.56-7.62 (m, 3 H), 7.78 (s, 2 H), 8.19 (s, br, 1 H), 8.32 (s, 1 H), 8.94 (s, 1 H), 10.20 (s, br, 1 H), 12.94 (s, br, 1 H). LCMS (ES+) m/e 460 [M+H] ⁺ .

Example 19

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isopropo xyquinolin-4-yl)amino)-5- cvclopentylbenzoic acid

a) diethyl 2-((3-chloro-4-methoxyphenylamino)methylene)malonate. A solution of 3- chloro-4-methoxyaniline (15.76 g, 100 mmol) and diethyl 2- (ethoxymethylene)malonate (21 .62 g, 100 mmol) in ethanol (100 mL) was stirred under reflux for 4 h. The mixture was allowed to cool to room temperature. The solid was collected by filtration and washed with ethanol to give the title compound (24.36g, 74%) as a white solid. LCMS (ES+) m/e 328 [M+H] ⁺ .

b) ethyl 7-chloro-4-hvdroxy-6-methoxyquinoline-3-carboxylate. A solution of diethyl 2-((3-chloro-4-methoxyphenylamino)methylene)malonate (24 g, 73.21 mmol) in diphenyl ether (200 mL) was stirred at 220 °C for 1 .5 h. The mixture was allowed to cool to room temperature. The solid was collected by filtration, washed with ether and dried in vacuo to give the title compound (10.1 g, 49%) as a white solid. LCMS (ES+) m/e 282 [M+H] ⁺ .

c) 4,7-dichloro-6-methoxyquinoline-3-carboxamide. A solution of ethyl 7-chloro-4- hydroxy-6-methoxyquinoline-3-carboxylate (10 g, 35.6 mmol) in 2N aqueous sodium hydroxide (55 ml_), ethanol (100 ml.) and water (55 ml.) was stirred at 100 °C for 3 h. The mixture was allowed to cool to room temperature and evaporated in vacuo to remove ethanol. The resulting solution was acidified with 4N aqueous hydrochloric acid. The solid was collected by filtration, washed with water and dried in vacuo to give 7-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid (9.122 g, 100%) as a white solid. 6.14 g of the acid in phosphorus oxychloride (50 ml.) was stirred at reflux for 3 h. The mixture was allowed to cool to room temperature, then evaporated in vacuo to give the crude acid chloride as a yellow solid (7.0 g, 99%). A solution of the crude acid chloride in tetrahydrofuran (40 ml.) was added dropwise to a solution of 30% aqueous ammonia at 0 °C. The mixture was stirred at 0 °C for 1 h. The solid was collected by filtration, washed with water and dried in vacuo to give the title compound (4.3 g, 77%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 4.08 (s, 3 H), 7.63 (s, 1 H), 7.92 (s, br, 1 H), 8.16 (s, br, 1 H), 8.24 (s, 1 H), 8.75 (s, 1 H). LCMS (ES+) m/e 271 [M+H] ⁺ .

d) 4,7-dichloro-6-hvdroxyquinoline-3-carboxamide. To a solution of 4,7-dichloro-6- methoxyquinoline-3-carboxamide (5 g, 18.44 mmol) in dichloromethane (300 ml_), stirred under nitrogen at 0°C, was added boron tribromide (17.44 ml_, 184 mmol) in dichloromethane (100 ml_). The reaction mixture was stirred at 40 °C for 84 h. After cooling to room temperature, the mixture was evaporated in vacuo and diluted with saturated aqueous sodium bicarbonate solution. The solid was collected by filtration and dried in vacuo to give the crude product as a yellow solid. The crude product was chromatographed (silica gel, 9%

methanol/dichloromethane) to give a product with some starting material in the mixture. The product was diluted with aqueous sodium carbonate solution and extracted with dichloromethane (80 ml. x 3). The organic phases were discarded and the water phase adjusted to pH 6-7. The solid was collected by filtration and dried in vacuo to give the title compound (2.2g, 44%) as a yellow solid with 4- bromo-7-chloro-6-hydroxyquinoline-3-carboxamide as a major impurity. LCMS (ES+) m/e 257 [M+H] ⁺ .

e) 4,7-dichloro-6-isopropoxyquinoline-3-carboxamide. A solution of 4,7-dichloro-6- hydroxyquinoline-3-carboxamide (500 mg, 1.945 mmol), 2-bromopropane (478 mg, 3.89 mmol) and potassium carbonate (538 mg, 3.89 mmol) in N,N- dimethylformamide (15 ml.) in a sealed tube was stirred at 70 °C for 3 h. The mixture was concentrated and the residue purified by chromatography (silica gel, 3% methanol/dichloromethane) to give the title compound (500 mg) as a yellow solid. LCMS (ES+) m/e 299 [M+H] ⁺ .

f) methyl 3-(3-carbamoyl-7-chloro-6-isopropoxyquinolin-4-ylamino)-5- cvclopentylbenzoate. A solution of 4,7-dichloro-6-isopropoxyquinoline-3- carboxamide (147 mg, 0.493 mmol ) and methyl 3-amino-5-cyclopentylbenzoate (120 mg, 0.547 mmol) in ethanol (20 ml_), was stirred under reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated. The residue was recrystallized with ethyl acetate (20 ml.) to give the title compound (100mg) as a white solid. LCMS (ES+) m/e 482 [M+H] ⁺ .

g) methyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isopropoxyq uinolin-4- ylamino)-5-cvclopentylbenzoate. A mixture of methyl 3-(3-carbamoyl-7-chloro-6- isopropoxyquinolin-4-ylamino)-5-cyclopentylbenzoate (100 mg, 0.207 mmol), 2,4- dimethoxypyrimidin-5-ylboronic acid (153 mg, 0.830 mmol), potassium carbonate (57.4 mg, 0.415 mmol) and tetrakis(triphenylphosphine)palladium(0) (1 1 .99 mg, 10.37 μηηοΙ) in 1 ,4-dioxane (20.00 ml.) and water (5 ml.) under nitrogen was stirred at 80 °C for 16 h, then purified by silica gel chromatography (5%

methanol/dichloromethane) to give the title compound (50mg) as a yellow solid. LCMS (ES+) m/e 586 [M+H] ⁺ .

h) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isopropoxyq uinolin-4-ylamino)-5- cvclopentylbenzoic acid. To a solution of methyl 3-(3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-isopropoxyquinolin-4-ylamino)-5-c yclopentylbenzoate (50 mg, 0.085 mmol ) in tetrahydrofuran (26.0 ml) and water (26 ml) was added lithium hydroxide (10.22 mg, 0.427 mmol). The reaction mixture was stirred at 25 °C for 48 h. TLC (9% methanol/dichloromethane) showed full consumption of the starting material. The reaction solution was evaporated to remove tetrahydrofuran and the pH of the residue adjusted to 6 - 7 with 10% aqueous acetic acid. The solid formed was filtered, and recrystallized with methanol (5 mL) and water (10 mL) to give the title compound (45 mg) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.87 (d, J = 5.7 Hz, 6 H), 1.48-1 .73 (m, 6 H), 1 .94-1.96 (m, 2 H), 2.87-2.97 (m, 1 H), 3.85-3.94 (m, 7 H), 6.89 (s, 1 H), 6.99 (s, 1 H), 7.28 (s, 1 H), 7.53 (s, 1 H), 7.71 (s, br, 1 H), 7.76 (s, 1 H), 8.29 (s, 1 H), 8.34 (s, br, 1 H), 8.90 (s, 1 H), 10.72 (s, 1 H). LCMS (ES+) m/e 572 [M+H] ⁺ . Example 20

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethoxyquin olin-4-yl)amin

cvclopentylbenzoic acid

a) 4,7-dichloro-6-ethoxyquinoline-3-carboxamide. A mixture of 4,7-dichloro-6- hydroxyquinoline-3-carboxamide (260 mg, 1.01 1 mmol), bromoethane (0.453 ml_, 6.07 mmol) and potassium carbonate (280 mg, 2.023 mmol) in N,N- dimethylformamide (15 ml.) in a sealed tube was stirred at 70 °C for 3 h, then cooled and concentrated. The crude product was added to a silica gel column and was eluted with 3% methanol/dichloromethane to give the title compound (200 mg, 70%) as a yellow solid. LCMS (ES+) m/e 285 [M+H] ⁺ .

b) methyl 3-(3-carbamoyl-7-chloro-6-ethoxyquinolin-4-ylamino)-5- cyclopentylbenzoate. A solution of 4,7-dichloro-6-ethoxyquinoline-3-carboxamide (200 mg, 0.701 mmol) and methyl 3-amino-5-cyclopentylbenzoate (185 mg, 0.842 mmol) in ethanol (20 ml.) was stirred at reflux for 16 h, then allowed to cool to room temperature and concentrated. The residue was recrystallized with ethyl acetate (20 ml.) to give the title compound (130 mg, 40%) as a white solid. LCMS (ES+) m/e 468 [M+H] ⁺ .

c) methyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethoxyquino lin-4- ylamino)-5-cvclopentylbenzoate. Methyl 3-(3-carbamoyl-7-chloro-6- ethoxyquinolin-4-ylamino)-5-cyclopentylbenzoate (300 mg, 0.641 mmol), 2,4- dimethoxypyrimidin-5-ylboronic acid (472 mg, 2.56 mmol), potassium carbonate (133 mg, 0.962 mmol) and tetrakis(triphenylphosphine)palladium(0) (74.1 mg, 0.064 mmol) in 1 ,4-dioxane (20 ml.) and water (5 ml.) was stirred at 80 °C under nitrogen atmosphere for 16 h. Purification by silica gel chromatography (5% methanol/dichloromethane) gave the title compound (200 mg, 55%) as a yellow solid. LCMS (ES+) m/e 572 [M+H] ⁺ . d) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethoxyquino lin-4-ylam

cvclopentylbenzoic acid. To a solution of methyl 3-(3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-ethoxyquinolin-4-ylamino)-5-cyclo pentylbenzoate (150 mg, 0.262 mmol) in tetrahydrofuran (26.0 ml.) and water (26 ml.) was added lithium hydroxide (31 .4 mg, 1.312 mmol). The reaction mixture was stirred at 25

°C for 48 h. TLC (methanol/dichloromethane 10/1 ) showed full consumption of the starting material. The reaction solution was evaporated to remove tetrahydrofuran and the pH of the residue adjusted to 6 - 7 with 10% aqueous acetic acid. The solid formed was filtered, and the filter cake recrystallized with methanol (5 ml.) and water (10 ml.) to give the title compound (72 mg, 48%) as a yellow solid. ¹ H

NMR (300 MHz, DMSO-d ₆ ) ppm 1.07 (t, J = 6.6 Hz, 3 H), 1 .42-1.72 (m, 6 H), 1.91-1 .99 (m, 2 H), 2.90-3.01 (m, 1 H), 3.73 (d, J = 6.6 Hz, 2 H), 3.88 (s, 3 H), 3.95 (s, 3 H), 7.05 (s, 1 H), 7.16 (s, 1 H), 7.37 (s, 1 H), 7.46 (s, 1 H), 7.63 (s, br, 1 H), 7.83 (s, 1 H), 8.19 (s, br, 1 H), 8.33 (s, 1 H), 8.83 (s, 1 H), 10.15 (s, 1 H), 12.91 (s, br, 1 H). LCMS (ES+) m/e 558 [M+H] ⁺ .

Example 21

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexylmethoxy)benzoic acid

a) methyl 3-[(cvclohexylmethyl)oxyl-5-nitrobenzoate. To a suspension of methyl 3- hydroxy-5-nitrobenzoate (300 mg, 1 .522 mmol) and potassium carbonate (421 mg, 3.04 mmol) in N,N-dimethylformamide (10 ml.) was added

(bromomethyl)cyclohexane (269 mg, 1.522 mmol). The reaction mixture was heated to 120 °C for 20 minutes under microwave irradiation. After cooling, the reaction was poured into ice water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 3-[(cyclohexylmethyl)oxy]-5- nitrobenzoate (250 mg, 0.852 mmol, 56.0 % yield) as a wax-like solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 - 1.16 (m, 2 H) 1 .20 - 1.40 (m, 3 H) 1.70 - 1.93 (m, 6 H)3.89 (d, J=6.06 Hz, 2 H) 3.99 (s, 3 H) 7.84 - 7.89 (m, 1 H) 7.90 -

7.95 (m, 1 H) 8.42 - 8.47 (m, 1 H). LCMS (ES+) m/e 294 [M+H] ⁺ .

b) methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexylmethoxy)benzoate. To a mixture of methyl 3-[(cyclohexylmethyl)oxy]- 5-nitrobenzoate (125 mg, 0.426 mmol) and 10% palladium on carbon (45.4 mg, 0.043 mmol) was added acetic acid (10 mL). The mixture was hydrogenated under a balloon of hydrogen at room temperature overnight. After filtration, 4- chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamid e (147 mg, 0.426 mmol) was added to the filtrate. The reaction was kept stirring at room

temperature overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cyclohexylmethoxy)benzoate (120 mg, 0.175 mmol, 41 .1 % yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) ppm 0.96 - 1 .09 (m, 2 H) 1 .1 1 - 1 .30 (m, 3 H) 1 .60 - 1.74 (m, 4 H) 1 .73 -1.84 (m, 2 H) 3.82 (d, J=6.32 Hz, 2 H) 3.85 (s, 3 H) 3.99 (s, 3 H) 4.02 (s, 3 H) 7.10 (br. s., 1 H) 7.30 (s, 1 H)7.40 (s, 1 H) 7.80 (br. s., 1

H) 7.88 (dd, J=9.09, 1 .26 Hz, 1 H) 8.20 (d, J=9.09 Hz, 1 H) 8.25 (d, J=1.77 Hz, 1 H) 8.27 (br. s., 1 H) 8.66 (s, 1 H) 9.00 (s, 1 H) 1 1.48 (br. s., 1 H). LCMS (ES+) m/e 572 [M+H] ⁺ .

c) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexylmethoxy)benzoic acid. To a suspension of methyl 3-((3-carbamoyl-7-

(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(cycl ohexylmethoxy)benzoate (100 mg, 0.175 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 N solution in water) (0.029 mL, 0.175 mmol). The reaction was kept stirring at room temperature overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5- (cyclohexylmethoxy)benzoic acid (50 mg, 0.074 mmol, 42.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.96 - 1 .09 (m, 2 H) 1.12 - 1.30 (m, 3 H) 1 .59 - 1.74 (m, 4 H) 1 .74 -1.83 (m, 2 H) 3.82 (d, J=6.32 Hz, 2 H) 3.99 (s, 3 H) 4.02 (s, 3 H) 7.14 (t, J=2.02 Hz, 1 H) 7.34 (s, 1 H) 7.43 (s, 1 H) 7.84 (br. s., 1 H)

7.90 (dd, J=8.97, 1.64 Hz, 1 H) 8.21 (d, J=9.09 Hz, 1 H) 8.27 (d, J=1.77 Hz, 1 H) 8.30(br. s., 1 H) 8.66 (s, 1 H) 9.00 (s, 1 H) 1 1 .80 (br. s., 1 H) 13.22 (br.

LCMS (ES+) m/e 558 [M+H] ⁺ .

Example 22

3-(cvclohexylmethoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3- sulfamoylquino

yl)amino)benzoic acid

a) methyl 3-(cvclohexylmethoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3- sulfamoylquinolin-4-yl)amino)benzoate. To a mixture of methyl 3- [(cyclohexylmethyl)oxy]-5-nitrobenzoate (125 mg, 0.426 mmol) and 10% palladium on carbon (45.4 mg, 0.043 mmol) was added acetic acid (10 ml_). The reaction was hydrogenated under a hydrogen balloon at room temperature overnight. After filtration, 7-[2,4-bis(methyloxy)-5-pyrimidinyl]-4-chloro-3-quinolinesul fonamide (162 mg, 0.426 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford methyl 3-(cyclohexylmethoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3- sulfamoylquinolin-4-yl)amino)benzoate (1 10 mg, 0.152 mmol, 35.8 % yield) as a yellow solid. ¹ H N MR (400 MHz, METHANOL-d4) δ ppm 0.98 - 1.10 (m, 2 H) 1.21 - 1.33 (m, 3 H) 1 .63 - 1 .83 (m, 6 H) 3.74 (d, J=6.32 Hz, 2 H) 3.84 (s, 3 H) 4.06 (s, 3 H) 4.08 (s, 3 H) 6.83 (t, J=2.15 Hz, 1 H) 7.24 (s, 1 H) 7.30 (d,J=1.26 Hz, 1 H) 7.56 (dd, J=8.97, 1.89 Hz, 1 H) 7.70 (d, J=8.84 Hz, 1 H) 8.18 (d, J=1.77 Hz, 1 H) 8.44 (s, 1 H) 9.13 (s, 1 H). LCMS (ES+) m/e 608 [M+H] ⁺ .

b) 3-(cvclohexylmethoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3- sulfamoylquinolin-4- yl)amino)benzoic acid. To a mixture of methyl 3-(cvclohexylmethoxy)-5-((7-(2,4- dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino)benz oate (1 10 mg, 0.181 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 N in water) (0.030 ml_, 0.181 mmol). The reaction was kept stirring at room temperature overnight and acidified. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-(cyclohexylmethoxy)-5-((7-(2,4-dimethoxypyrimidin-5- yl)-3-sulfamoylquinolin-4-yl)amino)benzoic acid (83 mg, 0.140 mmol, 77 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.92 - 1.05 (m, 2 H) 1 .09 - 1.27 (m, 3 H) 1 .56 - 1 .70 (m, 4 H) 1 .70 -1.79 (m, 2 H) 3.80 (d, J=6.06 Hz, 2 H) 3.98 (s, 3 H) 4.00 (s, 3 H) 7.14 (br. s., 1 H) 7.32 (s, 1 H) 7.35 (s, 1 H)7.65 (d, J=9.09 Hz, 1 H) 7.75 (d, J=1 .77 Hz, 1 H) 8.17 (br. s., 2 H) 8.40 (d, J=1.01 Hz, 1 H) 8.62 (s, 1 H) 9.15 (s, 1 H) 9.34 (br. s., 1 H). LCMS (ES+) m/e 594 [M+H] ⁺ .

Example 23

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isobutoxyq uinolin-4-yl)amino)-5- cyclopentylbenzoic acid

a) 4,7-dichloro-6-isobutoxyquinoline-3-carboxamide. A mixture of 4,7-dichloro-6- hydroxyquinoline-3-carboxamide (400 mg, 1.556 mmol), 1-bromo-2- methylpropane (2132 mg, 15.56 mmol) and potassium carbonate (430 mg, 3.1 1 mmol) in N,N-dimethylformamide (15 ml.) in a sealed tube was stirred at 50 °C for 3 h. After cooling and concentrating, the crude product was added to a silica gel column and eluted with 3% methanol/dichloromethane to give the title compound (356 mg, 73%) as a yellow solid. LCMS (ES+) m/e 313 [M+H] ⁺ .

b) methyl 3-(3-carbamoyl-7-chloro-6-isobutoxyquinolin-4-ylamino)-5- cvclopentylbenzoate. A solution of 4,7-dichloro-6-isobutoxyquinoline-3- carboxamide (330 mg, 1.054 mmol) and methyl 3-amino-5-cyclopentylbenzoate (254 mg, 1.159 mmol) in ethanol (30 ml.) was stirred under reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated. The residue was recrystallized with ethyl acetate (30 ml.) to give the title compound (300 mg, 57%) as a white solid. LCMS (ES+) m/e 496 [M+H] ⁺ . c) methyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isobutoxyqu inolin-4- ylamino)-5-cvclopentylbenzoate. A solution of methyl 3-((3-carbamoyl-7-chloro-6- isobutoxyquinolin-4-yl)amino)-5-cyclopentylbenzoate (300 mg, 0.605 mmol), 2,4- dimethoxypyrimidin-5-ylboronic acid (445 mg, 2.419 mmol), potassium carbonate (125 mg, 0.907 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.9 mg,

0.060 mmol) in 1 ,4-dioxane (20.00 ml.) and water (5 ml.) was stirred at 80 °C under nitrogen atmosphere for 16 h. Purification by silica gel chromatography (5% methanol/dichloromethane) gave the title compound (210 mg, 58%) as a yellow solid. LCMS (ES+) m/e 600 [M+H] ⁺ .

d) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isobutoxyqu inolin-4-ylamino)-5- cvclopentylbenzoic acid. To a solution of methyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-isobutoxyquinolin-4-yl)amino)-5-c yclopentylbenzoate (210 mg, 0.350 mmol) in tetrahydrofuran (30 ml.) and water (26 ml.) was added lithium hydroxide (41 .9 mg, 1.751 mmol). The reaction mixture was stirred at 25 °C for 48 h. TLC (methanol/dichloromethane 10/1 ) showed full consumption of the starting material. The reaction solution was evaporated to remove tetrahydrofuran and the pH of the residue adjusted to 6 - 7 with 10% aqueous acetic acid. The solid formed was filtered, and the filter cake recrystallized with methanol (5 ml.) and water (10 ml_). The product was further purified by silica gel chromatography (methanol/dichloromethane = 1/5) to give the title compound (60 mg, 29%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.73 (d, J = 6.6 Hz, 6 H), 1.44 - 1 .74 (m, 7 H), 1 .93 - 2.01 (m, 2 H), 2.92 - 3.03 (m, 1 H), 3.37 (d, J = 6.6 Hz, 2 H), 3.85 (s, 3 H), 3.96 (s, 3 H), 7.1 1 (s, 2 H), 7.42 (s, 1 H), 7.51 (s, 1 H), 7.66 (s, 1 H), 7.83 (s, 1 H), 8.23 (s, 1 H), 8.32 (s, 1 H), 8.87 (s, 1 H), 10.42 (s, 1 H), 12.91 (s, 1 H). LCMS (ES+) m/e 586 [M+H] ⁺ .

Example 24

3-((3-carbamoyl-7-(2,4-dimethoxypyrim^

cvclopentylbenzoic acid

a) 4,7-dichloro-6-propoxyquinoline-3-carboxamide. A mixture of 4,7-dichloro-6- hydroxyquinoline-3-carboxamide (400 mg, 1.556 mmol), 1-bromopropane (1914 mg, 15.56 mmol) and potassium carbonate (430 mg, 3.1 1 mmol) in N,N- dimethylformamide (15 ml.) in a sealed tube was stirred at 50 °C for 3 h. The mixture was added to a silica gel column and was eluted with 3%

methanol/dichloromethane to give the title compound (350 mg, 78%) as a yellow solid. LCMS (ES+) m/e 299 [M+H] ⁺ .

b) methyl 3-(3-carbamoyl-7-chloro-6-propoxyquinolin-4-ylamino)-5- cyclopentylbenzoate. A solution of 4,7-dichloro-6-propoxyquinoline-3- carboxamide (260 mg, 0.869 mmol) and methyl 3-amino-5-cyclopentylbenzoate (200 mg, 0.912 mmol) in ethanol (50 ml.) was stirred under reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated. The residue was recrystallized with ethyl acetate (20 ml.) to give the title compound (290 mg, 69%) as a white solid. LCMS (ES+) m/e 482 [M+H] ⁺ .

c) methyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propoxy-qui nolin-4- ylamino)-5-cvclopentylbenzoate. A solution of methyl 3-(3-carbamoyl-7-chloro-6- propoxyquinolin-4-ylamino)-5-cyclopentylbenzoate (260 mg, 0.524 mmol), 2,4- dimethoxypyrimidin-5-ylboronic acid (397 mg, 2.158 mmol), potassium carbonate (149 mg, 1.079 mmol) and tetrakis(triphenylphosphine)palladium(0) (62.3 mg, 0.054 mmol) in 1 ,4-dioxane (40 ml.) and water (10.00 ml.) was stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by silica gel chromatography (5% methanol/dichloromethane) to give the title compound (155 mg, 49%) as a yellow solid. LCMS (ES+) m/e 586 [M+H] ⁺ .

d) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propoxyquin olin-4-ylamino)-5- cvclopentylbenzoic acid. To a solution of methyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-propoxyquinolin-4-yl)amino)-5-cyc lopentylbenzoate (150 mg, 0.256 mmol) in tetrahydrofuran (26.0 ml.) and water (26 ml.) was added lithium hydroxide (30.7 mg, 1.281 mmol). The reaction mixture was stirred at 25 °C for 48 h. TLC (9% methanol/dichloromethane) showed full consumption of the starting material. The reaction solution was evaporated to remove

tetrahydrofuran, the pH of the residue adjusted to 6 - 7 with 10% aqueous acetic acid, and the precipitate filtered. The filter cake was recrystallized with methanol (5 ml.) and water (10 ml.) to give the title compound (95 mg, 63%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.73 (t, J=7.2 Hz, 3 H), 1 .41-1.70 (m, 8 H), 1 .91-1 .98 (m, 2 H), 2.90-3.02 (m, 1 H), 3.59 (t, J=6.6 Hz, 2 H), 3.86 (s, 3 H), 3.96 (s, 3 H), 7.05 (s, 1 H), 7.12 (s, 1 H), 7.38 (s, 1 H), 7.47 (s, 1 H), 7.65 (s, br, 1 H), 7.83 (s, 1 H), 8.24 (s, br, 1 H), 8.32 (s, 1 H), 8.86 (s, 1 H), 10.24 (s, 1 H), 12.93 (s, br, 1 H). LCMS (ES+) m/e 572 [M+H] ⁺ .

Example 25

3-((6-butoxy-3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quin olin-4-yl)amino)-5- cvclopentylbenzoic acid

a) 6-butoxy-4,7-dichloroquinoline-3-carboxamide. A mixture of 4,7-dichloro-6- hydroxyquinoline-3-carboxamide (530 mg, 2.062 mmol), 1-bromobutane (1412 mg, 10.31 mmol) and potassium carbonate (570 mg, 4.12 mmol) in N,N- dimethylformamide (25 mL) was heated to 50 °C for 3 h in a sealed tube. The mixture was cooled to room temperature and the solvent was removed in vacuo.

The residue was purified using flash chromatography (silica gel, 5% methanol/dichloromethane) to give 6-butoxy-4,7-dichloroquinoline-3-carboxamide (410 mg, 1.309 mmol, 63.5 % yield) as a yellow solid. LCMS (ES+) m/e 313

[M+H] ⁺ .

b) methyl 3-(6-butoxy-3-carbamoyl-7-chloroquinolin-4-ylamino)-5- cvclopentylbenzoate. A mixture of methyl 3-amino-5-cyclopentylbenzoate (1 148 mg, 5.24 mmol) and 6-butoxy-4,7-dichloroquinoline-3-carboxamide (410 mg, 1.309 mmol) in ethanol (15 ml.) was heated to reflux overnight. The solvent was removed in vacuo and the residue recrystallized with ethyl acetate to give the crude methyl 3-(6-butoxy-3-carbamoyl-7-chloroquinolin-4-ylamino)-5- cyclopentylbenzoate (618 mg, 1 .246 mmol, 95 % yield) as a yellow solid. The crude product was used for the next step without further purification. LCMS (ES+) m/e 496 [M+H] ⁺ .

c) methyl 3-(6-butoxy-3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quino lin-4- ylamino)-5-cvclopentylbenzoate. A mixture of methyl 3-(6-butoxy-3-carbamoyl-7- chloroquinolin-4-ylamino)-5-cyclopentylbenzoate (510 mg, 1 .028 mmol), 2,4- dimethoxypyrimidin-5-ylboronic acid (851 mg, 4.63 mmol), potassium carbonate (213 mg, 1.542 mmol) and tetrakis(triphenylphosphine)palladium(0) (71 .3 mg, 0.062 mmol) in 1 ,4-dioxane (40 ml.) and water (10 ml.) was heated to 80 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature and extracted with ethyl acetate (30ml_ ^* 3). The extracts were washed with brine (30 ml_). The organic phase was concentrated and purified by chromatography (silica gel, 5% methanol/dichloromethane) to give methyl 3-(6- butoxy-3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -ylamino)-5- cyclopentylbenzoate (230 mg, 0.384 mmol, 37.3 % yield) as a yellow solid. LCMS (ES+) m/e 600 [M+H] ⁺ .

d) 3-(6-butoxy-3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quino lin-4-ylamino)-5- cvclopentylbenzoic acid. A mixture of methyl 3-(6-butoxy-3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-ylamino)-5-cyclopentylben zoate (200 mg, 0.334 mmol) and lithium hydroxide (47.9 mg, 2.001 mmol) in tetrahydrofuran (15 mL) and water (8 mL) was stirred at 25 °C for three days. The tetrahydrofuran was removed in vacuo at 25 °C and the insoluble was removed by filtration. The pH was adjusted to 6 with acetic acid (1 mL in 50 mL water). The precipitate was filtered to give 3-(6-butoxy-3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quino lin-4- ylamino)-5-cyclopentylbenzoic acid (55 mg, 0.093 mmol, 27.8 % yield) as a yellow solid. ¹ H NMR (300 MHz, DMSO-de) ppm 0.76 (t, J=7.2 Hz, 3 H), 1 .1 1-1.18 (m, 2 H), 1 .35-1 .71 (m, 8 H), 1.92-1.96 (m, 2 H), 2.90-2.98 (m, 1 H), 3.45-3.50 (m, 2 H), 3.85 (s, 3 H), 3.94 (s, 3 H), 6.94 (s, 1 H), 7.05 (s, 1 H), 7.31 (s, 1 H), 7.48 (s, 1 7.68 (s, br, 1 H), 7.78 (s, 1 H), 8.26-8.30 (m, 2 H), 8.88 (s, 1 H), 10.55 (s, br, 1 LCMS (ES+) m/e 586 [M+H] ⁺ .

Example 26

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propylquin olin-4-yl)ami

cvclopentylbenzoic acid

a) 2-bromo-4-nitro-1 -propylbenzene. To a solution of 1-nitro-4-propylbenzene (0.165 g, 1 mmol), silver sulfate (0.312 g, 1.000 mmol) and water (0.100 ml, 5.55 mmol) in concentrated sulphuric acid (2 ml.) stirred in air at room temperature was added bromine (0.103 ml, 2.000 mmol) dropwise. The reaction mixture was stirred at 25 °C for 2 h, then poured into dilute sodium hydrogensulfite solution (100 ml_, 10%). The mixture was extracted with dichloromethane (100 ml. 2). The combined organics were dried over Na ₂ S0 ₄ and then concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 100/1 ) to give 2-bromo-4-nitro-1 -propylbenzene (1 10 mg, 45 %) as a colorless oil. LCMS (ES+) m/e 244 [M+H] ⁺ .

b) 3-bromo-4-propylaniline. A solution of 2-bromo-4-nitro-1 -propylbenzene (2.1 g, 8.60 mmol) and tin(ll) chloride dihydrate (1 1.65 g, 51.6 mmol) in concentrated hydrochloric acid (5 ml_, 165 mmol) was stirred at 70 °C for 3 h. TLC showed no starting material left. The reaction mixture was cooled to room temperature, diluted with water (50 ml.) and neutralized with 1 M aqueous sodium hydroxide to pH = 8. The residue was filtered off and the filtrate extracted with dichloromethane (150 ml. x 2). The extracts were dried over Na ₂ S0 ₄ , concentrated in vacuo and the residue purified by column chromatography (9% ethyl acetate/petroleum ether) to afford the title compound (663 mg, 36%) as a colorless solid. LCMS (ES+) m/e 214 [M+H] ⁺ . diethyl 2-((3-bromo-4-propylphenylamino)methylene)malonate. A solution of 3- bromo-4-propylaniline (663 mg, 3.10 mmol) and diethyl 2-

(ethoxymethylene)malonate (670 mg, 3.10 mmol) in ethanol (5 mL) was heated at 70 °C for 1 h, then cooled. The mixture was diluted with 50% aqueous ethanol (30 mL). The solid was filtered, washed with 50 % aqueous ethanol and dried to give the title compound (1 g, 84%) as a white solid. LCMS (ES+) m/e 384 [M+H] ⁺ . ethyl 7-bromo-4-hvdroxy-6-propylquinoline-3-carboxylate. Diethyl 2-((3-bromo-4- propylphenylamino)methylene)malonate (1 g, 3.20 mmol) was added portionwise to a flask of refluxing diphenyl ether (16 mL). After the addition, the solution was refluxed for 15 min, then cooled and diluted with hexane (50 mL). The precipitate was filtered, washed with hexane and dried to give the title compound (672 mg, 62%). LCMS (ES+) m/e 338 [M+H] ⁺ .

7-bromo-4-hvdroxy-6-propylquinoline-3-carboxylic acid. A solution of ethyl 7- bromo-4-hydroxy-6-propylquinoline-3-carboxylate (672 mg, 2.086 mmol) in methanol (10 mL) and 1 M aqueous sodium hydroxide (10.4 mL, 10.4 mmol) was stirred at 50 °C for 2 h. TLC showed no starting material left. It was cooled to room temperature and poured into water (50mL). 4M aqueous hydrochloric acid was added until a precipitate formed. The precipitate was collected by filtration to give the title compound (497 mg, 81 %) as a white solid. LCMS (ES+) m/e 310 [M+H] ⁺ .

7-bromo-4-chloro-6-propylquinoline-3-carboxamide. A solution of 7-bromo-4- hydroxy-6-propylquinoline-3-carboxylic acid (497 mg, 1 .602 mmol) in phosphorus oxychloride (4 mL) was heated to 103 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude acid chloride (550 mg). A solution of the crude acid chloride in tetrahydrofuran (5 mL) was added to 30% aqueous ammonia (2 mL) at 0 °C dropwise. The precipitate was filtered and dried in vacuo to afford the title compound (512 mg, 99%) as a white solid. LCMS (ES+) m/e 327 [M+H] ⁺ .

4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-6-propylquinoline-3 -carboxamide. To a solution of 7-bromo-4-chloro-6-propylquinoline-3-carboxamide (512 mg, 1.563 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (374 mg, 2.032 mmol) and tetrakis(triphenylphosphine)palladium(0) (181 mg, 0.156 mmol) in 1 ,4-dioxane (8 mL) stirred under nitrogen was added a solution of potassium carbonate (653 mg, 4.69 mmol) in water (2 mL, 1 1 1 mmol) dropwise. The reaction mixture was stirred at 80 °C for 2.5h. TLC showed no starting material 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 (519 mg, 86%). LCMS (ES+) m/e 387 [M+H] ⁺ .

h) methyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propylquino lin-4- ylamino)-5-cvclopentylbenzoate. A solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)-6-propylquinoline-3-carboxamide (495 mg, 1.280 mmol) and methyl 3-amino-

5-cyclopentylbenzoate (421 mg, 1.919 mmol) in ethanol (2 mL) was stirred at reflux for 1 h. The reaction mixtrue was concentrated in vacuo to give the crude product (418 mg, 57.3%) as a yellow solid. LCMS (ES+) m/e 570 [M+H] ⁺ .

i) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-propylquino lin-4-ylamino)-5- cvclopentylbenzoic acid. To a solution of methyl 3-(3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-propylquinolin-4-ylamino)-5-cyclo pentylbenzoate (318 mg, 0.558 mmol) in methanol (25.00 mL) and tetrahydrofuran (25.00 mL) stirred in air at room temperature was added a solution of lithium hydroxide (66.8 mg, 2.79 mmol) in water (25 mL) dropwise. The reaction mixture was stirred at 25 °C for 24 h. The solution was evaporated to remove tetrahydrofuran and the pH of the residue was adjusted to 6 - 7 with 10 % aqueous acetic acid. The solid formed was filtered and recrystallized with methanol (5 mL) and water (10 mL) to give the title compound (70 mg, 21 .9%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) ppm 0.63 (t, J = 7.2 Hz, 3 H), 1 .16-1.71 (m, 8 H), 1 .94-2.02 (m, 2 H), 2.28-2.32 (m, 2 H), 2.94-3.00 (m, 1 H), 3.86 (s, 3 H), 3.97 (s, 3 H), 7.12 (s, 1 H), 7.36 (s, 1

H), 7.49 (s, 1 H), 7.65-7.67 (m, 2 H), 7.72 (s, 1 H), 8.24 (s, br, 1 H), 8.29 (s, 1 H), 8.95 (s, 1 H), 10.48 (s, 1 H), 12.88 (s, br, 1 H). LCMS (ES+) m/e 556 [M+H] ⁺ .

Example 27

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethylquino lin-4-yl)amino)-5- cvclopentylbenzoic acid 2- bromo-1 -ethyl-4-nitrobenzene. To a mixture of 1 -ethyl-4-nitrobenzene (4.0 g, 26.4 mmol), silver sulfate (8.18 g, 26.4 mmol), concentrated sulphuric acid (24 mL) and water (2.8 mL), was added bromine (4.23 g, 26.4 mmol) dropwise at ambient temperature. After the addition, the mixture was stirred for 4 h at ambient temperature, then poured into dilute sodium hydrogen sulfite solution (10%, 150 mL) and extracted with ethyl acetate (300 mL x 3). The extracts were dried over Na ₂ S0 ₄ . The solvent was concentrated under vacuum to provide the title compound (5.95 g, 98%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 1.20 (t, J=7.5 Hz, 3 H), 2.82 (q, J=7.5 Hz, 2 H), 7.65 (d, J=8.4 Hz, 1 H), 8.19 (dd, J=2.4, 8.4 Hz, 1 H), 8.38 (d, J=2.4 Hz, 1 H).

3- bromo-4-ethylaniline. 2-Bromo-1 -ethyl-4-nitrobenzene (28.3 g, 123.5 mmol) was dissolved in methanol (70 mL) and acetic acid (70 mL). Iron powder (34.6 g, 617 mmol) was added batchwise. The mixture was stirred for 3 h at room temperature and the reaction was monitored by TLC (17% ethyl acetate/petroleum ether). After the starting material was consumed completely, the solvent was removed by evaporation. The residue was neutralized with aqueous ammonia (300 mL) and extracted with ethyl acetate (300 mL x 5). The extracts were washed with brine (500mL) and dried over Na ₂ S0 ₄ . After the solvent was removed, the crude product was purified by chromatography (silica gel, 5-17% ethyl acetate/petroleum ether) to give the title compound (16.0 g, 65%). LCMS (ES+) m/e 200 [M+H] ⁺ . diethyl 2-((3-bromo-4-ethylphenylamino)methylene)malonate. 3-bromo-4- ethylaniline (9.2 g, 46.2 mmol) and diethyl 2-(ethoxymethylene)malonate (9.98 g, 46.2 mmol) were dissolved with ethanol (46 mL). The reaction was refluxed for 2 h with stirring and the reaction was monitored by TLC (17% ethyl

acetate/petroleum ether). After the starting material was consumed completely, aqueous ethanol (50%, 100 mL) was added. The white solid which precipitated was filtered to give the title compound (13.0 g, 76%). LCMS (ES+) m/e 370

[M+H] ⁺ .

ethyl 7-bromo-6-ethyl-4-hvdroxyquinoline-3-carboxylate. To refluxing diphenyl ether (40 mL) was added diethyl 2-((3-bromo-4- ethylphenylamino)methylene)malonate (5.0 g, 13.50 mmol) batchwise. The reaction was stirred for 15 min at reflux, then the solution cooled to room temperature. The precipitated yellow solid was filtered, washed with ethyl acetate (20 mL x 2) and dried to give the title compound (3.9 g, 89%). LCMS (ES+) m/e 324 [M+H] ⁺ . e) 7-bromo-6-ethyl-4-hvdroxyquinoline-3-carboxylic acid. Ethyl 7-bromo-6-ethyl-4- hydroxyquinoline-3-carboxylate (1 .59 g, 4.90 mmol) was dissolved in ethanol (25.00 ml.) and water (25 ml_), then sodium hydroxide (0.981 g, 24.52 mmol) was added. The solution was heated to reflux and stirred for 4 h at this temperature. After the starting material was consumed completely, the ethanol (25.00 ml.) was removed and the residue neutralized with 4M aqueous hydrochloric acid. The precipitated white solid was filtered, washed with water (20 ml. x 3) and dried to give the crude product as yellow solid. LCMS (ES+) m/e 296 [M+H] ⁺ .

f) methyl 3-(7-bromo-3-carbamoyl-6-ethylquinolin-4-ylamino)-5-cvclopen tylbenzoate.

7-bromo-6-ethyl-4-hydroxyquinoline-3-carboxylic acid (2.0 g, 6.75 mmol) was dissolved in phosphorus oxychloride (15 ml_, 161 mmol). The mixture was stirred for 4 h at reflux. The phosphorus oxychloride was removed. A solution of the acid chloride (2.0 g, 6.01 mmol) in tetrahydrofuran (5 ml.) was added to aqueous ammonium hydroxide (20 ml_, 514 mmol) dropwise at 0 °C. The mixture was stirred for 30 min. The precipitate yellow precipitate was filtered to give the crude product, 7-bromo-4-chloro-6-ethylquinoline-3-carboxamide (2.0 g). 377 mg (1 .202 mmol) of this crude amide and methyl 3-amino-5-cyclopentylbenzoate (290 mg, 1.322 mmol) were dissolved in ethanol (4 ml_). The solution was stirred overnight at reflux. After the starting material was consumed completely, the solvent was removed and the residue was triturated with ethyl acetate to give methyl 3-(7- bromo-3-carbamoyl-6-ethylquinolin-4-ylamino)-5-cyclopentylbe nzoate (480 mg, 80 % yield).

g) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-ethylquinol in-4-ylamino)-5- cvclopentylbenzoic acid. Methyl 3-(7-bromo-3-carbamoyl-6-ethylquinolin-4- ylamino)-5-cyclopentylbenzoate (480 mg, 0.967 mmol), 2,4-dimethoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (309 mg, 1.160 mmol) and potassium carbonate (334 mg, 2.417 mmol) were dissolved in 1 ,4-dioxane (1 ml.) and water (0.1 ml_). Tetrakis(triphenylphosphine)palladium(0) (1 12 mg, 0.097 mmol) was added under nitrogen atmosphere. The mixture was stirred for 6 h at 80 °C. The solution was cooled to room temperature and water (2.0 ml.) added. The mixture was stirred for 10 min, then extracted with ethyl acetate (10 mL x 3). The extracts were dried (Na ₂ S0 ₄ ), evaporated and the crude product purified by chromatography (silica gel, 5% methanol/dichloromethane) to give the

intermediate ester (300 mg, 0.540 mmol). The intermediate ester was dissolved in tetrahydrofuran (4.5 mL) and lithium hydroxide (2.70 mL, 5.40 mmol) added. The resulting mixture was stirred overnight at 25 °C. The tetrahydrofuran was removed under reduced pressure and the pH of the residue adjusted to about 4.0 with formic acid. The precipitated yellow solid was filtered, washed with water (5 ml x 3), then acetone (3 mL) and dried to give the title compound (120 mg, 40%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.80 (t, J=7.2 Hz, 3 H), 1.40- 1.74 (m, 6 H), 1.92-2.00 (m, 2 H), 2.34 (q, J=7.2 Hz, 2 H), 2.90-3.02 (m, 1 H), 3.87 (s, 3 H), 3.97 (s, 3 H), 7.08 (s, 1 H), 7.40 (s, 1 H), 7.50 (s, 1 H), 7.67 (s, 2 H), 7.72 (s, 1 H), 8.25 (s, br, 1 H), 8.29 (s, 1 H), 8.96 (s, 1 H), 10.55 (s, 1 H), 13.00 (s, br, 1 H). LCMS (ES+) m/e 542 [M+H] ⁺ .

Example 28

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isopropylq uinolin-4-yl)amino)-5- cvclopentylbenzoic acid

a) 2-bromo-1-isopropyl-4-nitrobenzene. To a mixture of 1-isopropyl-4-nitrobenzene (1 .0 g, 6.02 mmol), silver sulfate (1 .04 g, 3.01 mmol), concentrated sulphuric acid (5.5 mL) and water (0.61 mL) was added bromine (0.964 g, 6.02 mmol) dropwise at ambient temperature. After the addition, the mixture was stirred for 2 h at ambient temperature, then poured into dilute sodium hydrogensulfite solution (10%, 30 mL). The mixture was extracted with ethyl acetate (30 mL x 3) and dried over Na ₂ S0 ₄ . The solvent was removed under vacuum to provide the title compound (1.5 g) used crude in the next step.

b) 3-bromo-4-isopropylaniline. 2-Bromo-1-isopropyl-4-nitrobenzene (5.86 g, 24.2 mmol) was dissolved in methanol (50 mL) and acetic acid (50 mL). Iron powder (6.78 g, 121 mmol) was added batchwise. The mixture was stirred for 4 h at room temperature and the reaction was monitored by TLC (ethyl acetate/petroleum ether 1 :5). After the starting material was consumed completely, the mixture was filtered. Methanol was removed by evaporation. The residue was neutralized with aqueous ammonia (100 mL) and extracted with ethyl acetate (100 mL x 3). The extracts were washed with brine, dried (Na ₂ S0 ₄ ), and evaporated under reduced pressure. The crude product was purified by chromatography (silica gel, 2-10% ethyl acetate/petroleum ether) to give the title compound (3.0 g, 58%). LCMS (ES+) m/e 214 [M+H] ⁺ .

c) diethyl 2-((3-bromo-4-isopropylphenylamino)methylene)malonate. 3-Bromo-4- isopropylaniline (19.7 g, 92.48 mmol) and diethyl 2-(ethoxymethylene)malonate (21.97 g, 101 .7 mmol) were dissolved with ethanol (93 mL). The mixture was stirred for 2 h under reflux and the reaction monitored by TLC (ethyl

acetate/petroleum ether 1 :5). After the starting material was consumed completely, aqueous ethanol (50%, 160 mL) was added. The white precipitate was filtered, washed with aqueous ethanol (50%, 20 mL x 2) and dried in an oven to give the title compound (31.1 g, 76%) as a solid. LCMS (ES+) m/e 384 [M+H] ⁺ . d) ethyl 7-bromo-4-hvdroxy-6-isopropylquinoline-3-carboxylate. Diethyl 2-((3-bromo- 4-isopropylphenylamino)methylene)malonate (1 .0 g, 2.6 mmol) was added to diphenyl ether (10 mL) at reflux. The solution was stirred for 15 min at this temperature. The reaction monitored by TLC (ethyl acetate/petroleum ether 1 :5). The solution was cooled to room temperature and the product collected by filtration and washed with petroleum ether (5 mL x 2)to give the title compound (600 mg, 67%) as a yellow solid. LCMS (ES+) m/e 338 [M+H] ⁺ .

e) 7-bromo-4-hvdroxy-6-isopropylquinoline-3-carboxylic acid. Ethyl 7-bromo-4- hydroxy-6-isopropylquinoline-3-carboxylate (6.26 g, 18.51 mmol) was dissolved in ethanol (50 mL) and water (50 mL), and sodium hydroxide (3.70 g, 93 mmol) added. The solution was heated to reflux and stirred for 4 h at this temperature. After the starting material was consumed completely, the ethanol was removed and the residue was neutralized with 4M aqueous hydrochloric acid. The white solid precipitated was filtered and washed with water (20 mL x 3) to give the crude product (5.58 g). LCMS (ES+) m/e 310 [M+H] ⁺ .

f) 7-bromo-4-chloro-6-isopropylquinoline-3-carboxamide. 7-Bromo-4-hydroxy-6- isopropylquinoline-3-carboxylic acid (5.5 g, 17.73 mmol) was dissolved in phosphorus oxychloride (50 mL, 536 mmol) and the solution stirred under reflux for 4 h. The phosphorus oxychloride was removed to give the crude intermediate acid chloride (6.0 g)._A solution of the crude intermediate acid chloride in tetrahydrofuran (10 mL) was added to aqueous ammonium hydroxide (100 mL) at 0 °C. The solution was stirred for 30 min at 0 °C. The yellow precipitate was filtered, washed with water and dried in an oven to give the crude title compound (5.2 g), which was used directly in the next step. g) methyl 3-(7-bromo-3-carbamoyl-6-isopropylquinolin-4-ylamino)-5- cvclopentylbenzoate. 7-bromo-4-chloro-6-isopropylquinoline-3-carboxamide (392 mg, 1 .197 mmol) and methyl 3-amino-5-cyclopentylbenzoate (289 mg, 1.316 mmol) was dissolved in ethanol (4 mL). The solution was stirred overnight at reflux. The solvent was removed and the residue was triturated with ethyl acetate to give the title compound (390 mg, 63.9%). LCMS (ES+) m/e 510 [M+H] ⁺ .

h) methyl 3-(3-carbamoyl-7-(2, 4-dimethoxypyrimidin-5-yl)-6-isopropylquinolin-4- ylamino)-5-cvclopentylbenzoate. Methyl 3-(7-bromo-3-carbamoyl-6- isopropylquinolin-4-ylamino)-5-cyclopentylbenzoate (390 mg, 0.764 mmol), 2,4- dimethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (244 mg, 0.917 mmol) and potassium carbonate (264 mg, 1 .910 mmol) were dissolved in 1 ,4-dioxane (1 mL) and water (0.1 mL). Tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mmol) was added under nitrogen atmosphere. The mixture was stirred for 6 h at 80 °C. The solution was diluted with water (10 mL) and stirred 10 min. The solid was filtered and washed with water (10mL x 3). The crude was purified by chromatography (silica gel, 1 -5% methanol/dichloromethane) to give the title compound (323 mg, 74.2%). LCMS (ES+) m/e 570 [M+H] ⁺ .

i) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-isopropylqu inolin-4-ylamino)-5- cvclopentylbenzoic acid. Methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)- 6-isopropylquinolin-4-yl)amino)-5-cyclopentylbenzoate (200 mg, 0.351 mmol) was dissolved in methanol (30 mL) and aqueous sodium hydroxide (14.04 mL, 14.04 mmol) added. The mixture was stirred for 7 h at 25 °C. The solvent was removed under reduced pressure and the pH of the residue adjusted to about 4.0 with formic acid. The yellow precipitate was filtered, washed with water (5 mL x 3), then acetone (3 mL) to give the title compound (120 mg, 61 .0%) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) ppm 0.76-0.87 (m, 6 H), 1.45-1.76 (m, 6 H), 1 .95- 2.03 (m, 2 H), 2.50-2.61 (m, 1 H), 2.95-3.01 (m, 1 H), 3.86 (s, 3 H), 3.97 (s, 3 H), 7.17 (s, 1 H), 7.39 (s, 1 H), 7.53 (s, 1 H), 7.68 (s, 3 H), 8.25 (br s, 1 H), 8.30 (s, 1 H), 8.96 (s, 1 H), 10.69 (s, 1 H), 12.92 (br s, 1 H). LCMS (ES+) m/e 556 [M+H] ⁺ . Example 29

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquin olin-4-yl)amino)-5- cvclopentylbenzoic acid

a) methyl 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquino lin-4- ylamino)-5-cvclopentylbenzoate. A solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)-6-methylquinoline-3-carboxamide (400 mg, 1.1 15 mmol) and methyl 3-amino- 5-cyclopentylbenzoate (367 mg, 1 .672 mmol) in acetic acid (3 ml.) was stirred at 50°C for 3 h. LCMS showed complete conversion. The mixture was adjusted pH 8, filtered and concentrated in vacuo. The residue was purified by

chromatography (silica gel, 3% methanol/dichloromethane) to afford the title compound (368 mg, 57.9%) as a gray solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) ppm 1.42-1 .71 (m, 6 H), 1 .91 -1 .99 (m, 2 H), 2.09 (s, 3 H), 2.90-3.02 (m, 1 H), 3.83 (s, 3 H), 3.90 (s, 3 H), 3.98 (s, 3 H), 7.03 (s, 1 H), 7.45 (s, 2 H), 7.59 (s, br, 1 H), 7.78 (s, 2 H), 8.15 (s, br, 1 H), 8.31 (s, 1 H), 8.91 (s, 1 H), 10.20 (s, 1 H). LCMS (ES+) m/e 542 [M+H] ⁺ .

b) 3-(3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-6-methylquino lin-4-ylamino)-5- cyclopentylbenzoic acid. A mixture of methyl 3-(3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-6-methylquinolin-4-ylamino)-5-cyclo pentylbenzoate (368 mg, 0.679mmol) in 1 N lithium hydroxide (7 ml.) and tetrahydrofuran (7 ml.) was stirred at 25 °C for 20 h. LCMS showed completed conversion. Tetrahydrofuran was removed in vacuo and the mixture was acidified with 1 M aqueous

hydrochloric acid to pH 5. The precipitate was collected by filtration, then purified by chromatography (silica gel, 3% methanol/dichloromethane) to afford the title compound (200 mg, 69%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 1 .43-1.68 (m, 6 H), 1.92-1 .98 (m, 2 H), 2.08 (s, 3 H), 2.90-3.01 (m, 1 H), 3.90 (s, 3 H), 3.98 (s, 3 H), 7.02 (s, 1 H), 7.40 (s, 1 H), 7.45 (s, 1 H), 7.61 (s, br, 1 H), 7.75 (s, br, 1 H), 7.77 (s, 1 H), 8.18 (s, br, 1 H), 8.30 (s, 1 H), 8.92 (s, 1 H), 10.25 (s, 1 H), 12.85 (s, br, 1 H). LCMS (ES+) m/e 528 [M+H] ⁺ .

Example 30

-(benzyloxy)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-v

acid

a) methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)q^

hydroxybenzoate. To a mixture of methyl 3-hydroxy-5-nitrobenzoate (100 mg, 0.507 mmol) and 10% palladium on carbon (54.0 mg, 0.051 mmol) was added acetic acid (10 mL). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature overnight. After filtration, 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (175 mg, 0.507 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight. The precipitate was collected, washed with acetic acid and dried under reduced pressure to afford methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin- 4-yl)amino)-5-hydroxybenzoate (190 mg, 0.400 mmol, 79 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.83 (s, 3 H) 3.99 (s, 3 H) 4.02 (s, 3 H) 6.99 (s, 1 H) 7.32 (d, J=8.59Hz, 2 H) 7.82 - 7.89 (m, 2 H) 8.15 (d, J=8.84 Hz, 1 H) 8.31 (d, J=1.77 Hz, 1 H) 8.39 (br. s., 1 H) 8.65 (s, 1 H) 9.06 (s, 1 H) 10.28 (br. s., 1 H) 12.01 (br. s., 1 H). LCMS (ES+) m/e 476 [M+H] ⁺ .

b) 3-(benzyloxy)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl )quinolin-4- yl)amino)benzoic acid. To a suspension of methyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-hydroxybenzoa te (100 mg, 0.210 mmol) and benzyl bromide (0.025 mL, 0.210 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (29.1 mg, 0.210 mmol). The reaction mixture was heated at 60 °C for 3 hours. After cooling, the solvent was removed, and the residue was dissolved in methanol (10 mL). Sodium hydroxide (6. ON in water, 0.035 mL, 0.210 mmol) was added. The mixture was stirred at room temperature overnight and purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3- (benzyloxy)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)q uinolin-4- yl)amino)benzoic acid, trifluoroacetic acid salt (55 mg, 0.083 mmol, 39.3 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.02 (s, 3 H) 5.16 (s, 2 H) 7.21 (br. s., 1 H) 7.30 - 7.36 (m, 1 H) 7.37 - 7.47 (m, 6 H) 7.82 - 7.90 (m, 2 H) 8.19 (d, J=8.84 Hz, 1 H) 8.24 (d, J=1.77 Hz, 1 H) 8.31 (br. s., 1 H) 8.66 (s, 1 H) 9.00 (s, 1 H) 1 1.60 (br. s., 1 H) 13.23 (br. s., 1 H). LCMS (ES+) m/e 552

[M+H] ⁺ .

Example 31

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(hvdroxymethyl)phenyl) amino)quinoline-3- sulfonamide

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. 1H 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-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 ) 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).

c) 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 ) 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).

d) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(hvdroxymethyl)phenyl) amino)quinoline-3- sulfonamide. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- sulfonamide (150 mg, 0.39 mmol) and (3-aminophenyl)methanol (63 mg, 0.51 mmol) in acetic acid (4 mL) was stirred at 50 °C for 2 h. TLC showed complete conversion. The mixture was neutralized with 1 M aqueous sodium bicarbonate, then extracted with dichloromethane. The extracts were concentrated in vacuo. The residue was purified by chromatography (silica gel, 5%

methanol/dichloromethane) to afford the title compound (90 mg, 51 %). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 3.97 (s, 3 H), 3.98 (s, 3 H), 4.45 (d, J=5.4 Hz, 2 H), 5.20 (t, J=5.4 Hz, 1 H), 6.76-6.79 (m, 1 H), 7.02-7.05 (m, 2 H), 7.23 (t, J=6.9 Hz, 1 H), 7.57 (dd, J=1 .8 Hz, J=9.0 Hz, 1 H), 7.66 (d, J=9.0 Hz, 1 H), 7.89 (s, 2 H), 8.20 (d, J=1.8 Hz, 1 H), 8.34 (s, 1 H), 8.57 (s, 1 H), 9.08 (s, 1 H). LCMS (ES+) m/e 468 [M+H] ⁺ .

Example 32

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(trifluoromethoxy)phen yl)amino)quino

sulfonamide

To a suspension of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- sulfonamide (50 mg, 0.131 mmol) in acetic acid (10 ml.) was added 3- (trifluoromethoxy)aniline (23.26 mg, 0.131 mmol). The reaction mixture was stirred at room temperature overnight and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 7-(2,4- dimethoxypyrimidin-5-yl)-4-((3-(trifluoromethoxy)phenyl)amin o)quinoline-3-sulfonamide, trifluoroacetic acid salt (24 mg, 0.038 mmol, 28.8 % yield) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 4.08 (s, 3 H) 4.12 (s, 3 H) 7.37 - 7.48 (m, 3 H) 7.60 - 7.75 (m, 3 H) 8.28 (s, 1 H) 8.53 (s, 1 H) 9.16 (s, 1 H). LCMS (ES+) m/e 522 [M+H] ⁺ .

Example 33

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(methylcarbamoyl)pheny l)amino)quinoline-3- carboxamide

A mixture of 3-amino-N-methylbenzamide (43.6 mg, 0.290 mmol) and 4-chloro-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (100 mg, 0.290 mmol) in acetic acid (5 mL) was kept stirring overnight. The reaction was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-

(methylcarbamoyl)phenyl)amino)quinoline-3-carboxamide, trifluoroacetic acid salt (70 mg, 0.122 mmol, 42.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3 H) 3.98 (s, 3 H) 4.01 (s, 3 H) 7.44 - 7.49 (m, 1 H)

7.50 - 7.57 (m, 1 H) 7.78 - 7.84 (m, 3 H) 7.88 (br. s., 1 H) 8.04 (d, J=9.09 Hz, 1 H) 8.28 (d, J=1.52 Hz, 1 H) 8.40 (br. s., 1 H) 8.50 (q, J=4.21 Hz, 1 H) 8.64 (s, 1 H) 9.05 (s, 1 H) 12.09 (br. s., 1 H).

Example 34

4-((3-cvclohexyl-5-(trifluoromethylsulfonamido)phenyl)amino) -7- (quanidinomethyl)quinoline-3-carboxamide

3',5'-dinitro-2,3A5-tetrahvdro-1 ,1 '-biphenyl. A mixture of 1 -bromo-3,5- dinitrobenzene (4.8 g, 19.43 mmol), cyclohexen-1-ylboronic acid (1.399 mL, 25.3 mmol), cesium carbonate (18.99 g, 58.3 mmol), and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (1 .587 g, 1.943 mmol), 1 ,4-dioxane (36.1 mL) and water (18.04 mL) was purged with nitrogen, then irradiated in a microwave reactor for 20 minutes at 1 10 °C. The mixture was cooled and filtered. Sat. aq. sodium bicarbonate was added and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), and concentrated. The residual black material was purifed (silica gel, 5-50% ethyl acetate/hexane) to give the title compound (3.30 g, 68%) as a tan solid. LCMS (ES+) m/e 249 [M+H] ⁺ .

5-nitro-2',3',4',5'-tetrahvdro-[1 , 1 '-biphenyll-3-amine. To a round-bottom flask, 3',5'- dinitro-2,3,4,5-tetrahydro-1 , 1 '-biphenyl (1.7 g, 6.85 mmol) and ethanol (60 mL) were added followed by pyridine (2.77 mL, 34.2 mmol). The mixture was refluxed at 1 10 °C for 30 minutes. The solution was cooled to room temperature and ammonium sulfide (7.00 ml_, 20.55 mmol) in water (30 ml.) was added via an addition funnel over 20 minutes. This mixture was then refluxed at 1 10 °C for 40 minutes. LCMS indicated complete conversion. The solution was cooled to room temperature and then poured into -50 ml. ice. A yellow solid began to precipitate out immediately. This suspension was stirred for 5 minutes and then filtered, to afford the desired product (2.97 g). LCMS (ES+) m/e 219 [M+H] ⁺ .

c) 1.1.1 -Trifluoro-N-(5-nitro-2'.3'.4'.5'-tetrahvdro-n .1 '-biphenyll-3- vDmethanesulfonamide. To a round-bottom flask, a solution of 5-nitro-2',3',4',5'- tetrahydro-[1 , 1 '-biphenyl]-3-amine (1 .50 g, 6.87 mmol) in dichloromethane (100 ml.) was added, and cooled to -78 °C. N,N-diisopropylethylamine (3.60 ml_, 20.62 mmol) was added slowly, followed by triflic anhydride (1.196 ml_, 7.08 mmol) very slowly. The mixture was stirred for 15 minutes, at -78 °C, and then allowed to warm to room temperature for 45 min. LCMS showed incomplete conversion. The mixture was recooled to -78 °C and more triflic anhydride (9 mL, 53.3 mmol) added in 3 portions, allowing to warm to room temperature each time. The reaction was concentrated, and redissolved in methanol (100 mL). 6N Aqueous sodium hydroxide (2.5 mL, 15 mmol) was added and mixture stirred for 18 h, at room temperature. The reaction was concentrated, and redissolved in ethyl acetate and water, and adjusted to pH 2 with 1 N aqueous hydrochloric acid, then extracted with ethyl acetate. The extracts were washed with brine, dried

(Na ₂ S0 ₄ ), filtered and concentrated to a brown oil. The residue was purified (silica gel, 3-15% ethyl acetate/hexane) to give the title compound (1.85 g, 90% pure, 65%). LCMS (ES+) m/e 351 [M+H] ⁺ .

d) N-(3-amino-5-cvclohexylphenyl)-1 ,1 , 1-trifluoromethanesulfonamide. A solution of 1 , 1 ,1 -trifluoro-N-(5-nitro-2',3',4',5'-tetrahydro-[1 , 1 '-biphenyl]-3- yl)methanesulfonamide (1 .85 g, 4.75 mmol) in acetic acid (100 mL) was shaken with 10% palladium on carbon (0.506 g, 0.475 mmol) under hydrogen atmosphere at 40 psi. After 3 h, LCMS indicated incomplete conversion. Another 150 mg of 10% palladium on carbon was added to the vessel, and the reaction continued at 50 psi for 1 h. LCMS analysis indicated comple conversion. The mixture was filtered through Celite ^® and the filtrate used directly in the next experiment. LCMS (ES+) m/e 323 [M+H] ⁺ .

e) 7-cvano-4-((3-cvclohexyl-5-(trifluoromethylsulfonamido)pheny l)amino)quinoline-3- carboxamide. To a round-bottomed flask, 7-bromo-4-chloroquinoline-3- carboxamide (664 mg, 2.327 mmol) was added to N-(3-amino-5- cyclohexylphenyl)-1 ,1 , 1-trifluoromethanesulfonamide (750mg, 2.327 mmol) in acetic acid (80 ml_). The mixture was stirred at room temperature for 16 hours, which then showed a precipitate. The solid was filtered and washed with ether to afford the bromo intermediate (1 .51 g, 88%). A mixture of the bromo intermediate (1 .5 g, 2.336 mmol), zinc cyanide (1.89 g, 16.10 mmol), bis(tri-f- butylphosphine)palladium(O) (0.035 g, 0.068 mmol) and N,N-dimethylformamide (22 ml.) was heated conventionally and under microwave irradiation between 120- 150 °C for 30 minutes, along with intermittent additions of additional zinc cyanide and bis(tri-f-butylphosphine)palladium(0). The mixture was cooled, filtered and washed with ethyl acetate. The filtrate was worked up with sat. aq. sodium bicarbonate and extracted with ethyl acetate 3 times. The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified (40g silica gel, 5-10% 2-propanol/dichloromethane) to afford the title compound (1.34 g, 90% pure, 100%) as a yellow crystaline solid. LCMS (ES+) m/e 518 [M+H] ⁺ .

f) 7-(aminomethyl)-4-((3-cvclohexyl-5- (trifluoromethylsulfonamido)phenyl)amino)quinoline-3-carboxa mide. To an erlenmeyer flask, was added to 7-cyano-4-((3-cyclohexyl-5- (trifluoromethylsulfonamido)phenyl)amino)quinoline-3-carboxa mide (690 mg, 1.187 mmol) in methanol (60 ml_). This solution was continuously passed through the H cube with Raney nickel catalyst for 6 hours at room temperature, until nearly complete conversion occurred. The solution was concentrated and the purified by reverse-phase preparative HPLC (ODS, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (0.355 g,~ 47%) as an impure yellow solid. Most was carried forward for next reaction, while 50 mg was repurifed by HPLC as before to afford the title compound as a pure yellow compound. LCMS (ES+) m/e 522 [M+H] ⁺ .

g) 4-((3-cvclohexyl-5-(trifluoromethylsulfonamido)phenyl)amino) -7- (quanidinomethyl)quinoline-3-carboxamide. To a round-bottomed flask, 7- (aminomethyl)-4-((3-cyclohexyl-5-

(trifluoromethylsulfonamido)phenyl)amino)quinoline-3-carb oxamide (108 mg, 0.184 mmol) and N,N'-bis(ferf-butoxycarbonyl)-N"-triflylguanidine (75 mg, 0.192 mmol) were added and dissolved in dichloromethane (1 mL) and triethylamine (25.7 μΙ, 0.184 mmol). The mixture was stirred for 4 h at room temperature, and LCMS analysis indicated the desired intermediate. This mixture was concentrated and purified by reverse-phase preparative HPLC (ODS, acetonitrile/water + 0.1 % trifluoroacetic acid). The desired fractions were collected and concetrated. The yellow residue was dissolved in trifluoroacetic acid (3 mL), and stirred at room temperature, until LCMS analysis indicated conversion to the desired product. The mixture was concentrated and purified on reverse-phase preparative HPLC (ODS, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (0.040 g, 39%) as a yellow fluffy solid. LCMS (ES+) m/e 564 [M+H] ⁺ .

Example 35

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)-1-ethyl-1 H- benzordlimidazole-7-carboxylic acid

ethyl 5-bromo-1 -ethyl-1 H-benzo[dlimidazole-7-carboxylate. To a mixture of 6- bromo-1 H-benzo[d]imidazole-4-carboxylic acid (200 mg, 0.830 mmol) in N,N- dimethylformamide (4 mL) were added cesium carbonate (1 190 mg, 3.65 mmol) and ethyl iodide (0.148 mL, 1 .825 mmol). The flask was equipped with a nitrogen balloon and the reaction mixture was heated to 50 °C. After 30 minutes, LCMS indicated that no starting material remained and ~1 :1 mixture of regioisomers was present. The reaction mixture was allowed to cool to room temperature and diluted with water (40 mL; no precipitation observed) and ethyl acetate (50 mL). The ethyl acetate layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid). Appropriate fractions for the first peak to elute were combined, adjusted to pH ~7 and extracted with ethyl acetate twice. The combined extracts were dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to provide ethyl 6-bromo-1-ethyl-1 H- benzo[d]imidazole-4-carboxylate (89 mg, 0.300 mmol, 36.1 % yield) as a white solid. LCMS (ES+) m/e 297 [M+H] ⁺ . The work-up procedure described above was repeated with the second product to elute to provide ethyl 5-bromo-1 -ethyl- 1 H-benzo[d]imidazole-7-carboxylate (109 mg, 0.367 mmol, 44.2 % yield) as a pale yellow solid. LCMS (ES+) m/e 297 [M+H] ⁺ .

b) ethyl 5-amino-1-ethyl-1 H-benzo[dlimidazole-7-carboxylate. To a 20 mL

microwave vial were added ethyl 5-bromo-1 -ethyl-1 H-benzo[d]imidazole-7- carboxylate (69 mg, 0.232 mmol), diphenylmethanimine (84 mg, 0.464 mmol), 8,8'-bis(diphenylphosphino)-1 , 1 '-binaphthalene (36.1 mg, 0.058 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (59.4 mg, 0.058 mmol), sodium tert-butoxide (49.1 mg, 0.51 1 mmol) and degassed toluene (6 ml.) (degassed by bubbling nitrogen through the solvent for -20 minutes). The vial was purged with nitrogen, sealed and heated to 1 10 °C in a microwave reactor (pressure = 0 bar). LCMS indicated -90% conversion. The reaction was reheated in the microwave reactor at 1 10 °C for 20 minutes (pressure = 0-1 bar), then cooled. The mixture was diluted with ethyl acetate and washed with water and brine. The combined aqueous layers were back-extracted with ethyl acetate and the combined organics were dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (8 mL) and 1 M aqueous hydrochloric acid (0.464 mL, 0.464 mmol) was added. The mixture was stirred for 45 minutes at room temperature then concentrated under reduced pressure. The residue was dissolved in dimethylsulfoxide (3 mL) and purified by reverse phase HPLC (YMC-Pack ODS-A 75 x 30 mm I.D. S-5um, 12nm, 10-90%

acetonitrile/water + 0.1 % trifluoroacetic acid). The appropriate fractions containing product by LCMS were concentrated under reduced pressure to remove a majority of the acetonitrile. The aqueous mixture was then neutralized to pH -7 with saturated aqueous sodium bicarbonate and extracted with two portions of ethyl acetate. The combined extracts were dried over Na ₂ S0 ₄ , filtered and

concentrated under reduced pressure to provide a mixture of desired product plus unhydrolyzed imine. The residue was taken up in ethanol (3 mL) again and treated with 1 M aqueous hydrochloric acid (0.464 mL, 0.464 mmol). After 1 h, the reaction was concentrated under reduced pressure to provide ethyl 5-amino-1 - ethyl-1 H-benzo[d]imidazole-7-carboxylate, hydrochloride (44 mg, 0.163 mmol, 70.3 % yield) as a pale yellow tacky solid. LCMS (ES+) m/e 233.9 [M+H] ⁺ , -57% pure. This material was carried on without further purification.

c) 5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-1-ethyl-1 H- benzordlimidazole-7-carboxylic acid. To a mixture of ethyl 5-amino-1-ethyl-1 H- benzo[d]imidazole-7-carboxylate, hydrochloride (44 mg, 0.163 mmol) in acetic acid (3 mL) was added 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (56.2 mg, 0.163 mmol) and the suspension stirred at room

temperature under nitrogen. After 3 hours, the reaction mixture was concentrated under reduced pressure and left under high vacuum overnight. The yellow tacky residue was suspended in methanol (4 mL) and treated with 1 M aqueous sodium hydroxide (0.5 mL, 0.500 mmol) at room temperature. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure and diluted with water. The resulting precipitate was removed by filtration. The filtrate containing product by LCMS was adjusted to pH ~5 with 1 M aqueous hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in

dimethylsulfoxide (3 mL) and purified by reverse phase HPLC (ODS, 2-35% acetonitrile/water + 0.1 % trifluoroacetic acid). The appropriate fractions were concentrated under reduced pressure and dried to constant weight to provide 5- ((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)a mino)-1-ethyl-1 H- benzo[d]imidazole-7-carboxylic acid, trifluoroacetic acid salt (18.2 mg, 0.029 mmol, 17.78 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 13.63 (br. s., 1 H), 12.13 (br. s., 1 H), 8.98 (s, 1 H), 8.64 (s, 1 H), 8.52 (s, 1 H), 8.32 (br. s., 1 H), 8.22 (d, J = 1 .52 Hz, 1 H), 8.10 (br. s., 1 H), 7.90 (d, J = 1 .77 Hz, 1 H), 7.79 - 7.86 (m, 2H), 7.75 (d, J = 2.02 Hz, 1 H), 4.59 (q, J = 7.24 Hz, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 1 .33 (t, J = 7.24 Hz, 3H). LCMS (ES+) m/e 514.2 [M+H] ⁺ .

Example 36

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(dimethylcarbamoyl)phe nyl)amino)quinoline-3- carboxamide

A mixture of 3-amino-N,N-dimethylbenzamide (52.4 mg, 0.319 mmol) and 4- chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamid e (100 mg, 0.290 mmol) in acetic acid (5 mL) was kept stirring overnight. The mixture was diluted with ether. The precipitate was collected, washed with ether and dried under reduced pressure to afford 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(dimethylcarbamoyl)phe nyl)am

carboxamide (94 mg, 0.199 mmol, 68.6 % yield) as an yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.89 (s, 3 H) 2.95 (s, 3 H) 3.99 (s, 3 H) 4.02 (s, 3 H) 7.32 - 7.36 (m, 2 H) 7.44 (d, J=8.08 Hz, 1 H) 7.49 - 7.56 (m, 1 H) 7.82 (dd, J=8.97, 1.64 Hz, 1 H) 7.89 (br. s., 1 H) 8.09 (d, J=9.09 Hz, 1 H) 8.32 (d, J=1.52 Hz, 1 H) 8.47 (br. s., 1 H) 8.63 (s, 1 H) 9.10 (s, 1 H) 12.21 (br. s., 1 H). LCMS (ES+) m/e 473 [M+H] ⁺ .

Example 37

4-((3-(diethylcarbamoyl)phenyl)amino)-7-(2,4-dimethoxypyrimi din-5-yl)quinoline-3- carboxamide

To a suspension of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (100 mg, 0.290 mmol) in acetic acid (10 ml.) was added 3-amino-N,N- diethylbenzamide (55.8 mg, 0.290 mmol). The reaction mixture was stirred at room temperature overnight. The precipitate was collected, washed with ether and dried under reduced pressure to afford 4-((3-(diethylcarbamoyl)phenyl)amino)-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide hydrochloride (85 mg, 0.170 mmol, 58.5 % yield) as a yellow solid. LCMS (ES+) m/e 501 [M+H] ⁺ .

Example 38

4-((3-cvclopentyl-5-(methylcarbamoyl)phenyl)amino)-7-(2,4-di methoxypyrimidin-5- yl)quinoline-3-carboxamide

a) 3-(cvclopent-1-en-1-yl)-N-methyl-5-nitrobenzamide. To a suspension of 3-bromo- N-methyl-5-nitrobenzamide (200 mg, 0.772 mmol), cyclopent-1-en-1-ylboronic acid (173 mg, 1.544 mmol) and potassium carbonate (213 mg, 1.544 mmol) in 1 ,4- dioxane (12 ml.) and water (4.00 ml.) was added

tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.077 mmol). The mixture was heated to 120 °C for 20 minutes under microwave irradiation. After cooling, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was dried over MgS0 ₄ , filtered, concentrated under reduced pressure and purified by flash chromatography (0-100% ethyl acetate in hexanes) to afford 3-(cyclopent- 1-en-1-yl)-N-methyl-5-nitrobenzamide (150 mg, 0.609 mmol, 79 % yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.05 - 2.16 (m, 2 H) 2.62 (ddd, J=9.85, 5.05, 2.53 Hz, 2 H) 2.74 - 2.82 (m, 2 H) 3.09 (d, J=4.80 Hz, 3 H) 6.33 (br. s., 1 H) 6.47 (quin, J=2.21 Hz, 1 H) 8.20 (t, J=1.52 Hz, 1 H) 8.34 - 8.38 (m, 2 H). LCMS (ES+) m/e 247 [M+H] ⁺ .

b) 4-((3-cvclopentyl-5-(methylcarbamoyl)phenyl)amino)-7-(2,4-di methoxypyrimidin-5- yl)quinoline-3-carboxamide. To a suspension of 10% palladium on carbon (24.69 mg, 0.023 mmol) in acetic acid (10 ml.) was added 3-(cyclopent-1-en-1-yl)-N- methyl-5-nitrobenzamide (57.1 mg, 0.232 mmol). The mixture was hydrogenated under a hydrogen balloon at room temperature overnight, and filtered. 4-Chloro-7- (2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (80 mg, 0.232 mmol) was added to the filtrate. The reaction mixture was stirred at room temperature overnight and was purified by preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 4-((3-cyclopentyl-5- (methylcarbamoyl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-y l)quinoline-3- carboxamide, trifluoroacetic acid salt (45 mg, 0.070 mmol, 30.3 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.49 - 1.68 (m, 4 H) 1.70 - 1.79 (m, 2 H) 1 .96 - 2.05 (m, 2 H) 2.78 (d, J=4.55 Hz, 3 H) 2.95 - 3.07 (m, 1 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 7.31 (s, 1 H) 7.59 (s, 1 H) 7.68 (s, 1 H) 7.81 (dd, J=8.97, 1 .39 Hz, 1 H) 7.86 (br. s., 1 H) 8.06 (d, J=8.59 Hz, 1 H) 8.22 (d, J=1.52 Hz, 1 H) 8.35 (br. s., 1 H) 8.46 (q, J=4.46 Hz, 1 H) 8.64 (s, 1 H) 9.01 (s, 1 H) 1 1.96 (br. s., 1 H). LCMS (ES+) m/e 527 [M+H] ⁺ .

Example 39

3-((3-carbamoyl-6-(cvclobutylmethoxy)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- yl)amino)-5-cvclopentylbenzoic acid

a) 4-bromo-7-chloro-6-hvdroxyquinoline-3-carboxamide. To a suspension of 4,7- dichloro-6-methoxyquinoline-3-carboxamide (5 g, 18.44 mmol) in 1 ,2- dichloroethane (250 ml.) stirred under nitrogen at 0 °C was added a solution of boron tribromide (17.44 ml_, 184 mmol) in 1 ,2-dichloroethane (50 ml.) dropwise. The reaction mixture was stirred at 0 °C for 0.5 h and at 75 °C for 24 h. The reaction was monitored by LCMS and TLC. After cooling to room temperature, the solution was evaporated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate solution. The solid was collected by filtration and dried in vacuo. The solid was washed with ether to give the title compound (4.9g, 88%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 7.73 (s, 1 H), 7.95 (s, 1 H), 8.19 (s, 2 H), 8.61 (s, 1 H), 1 1.46 (s, br, 1 H). LCMS (ES+) m/e 301

[M+H] ⁺ .

b) 4-bromo-7-chloro-6-(cvclobutylmethoxy)quinoline-3-carboxamid e. A mixture of 4- bromo-7-chloro-6-hydroxyquinoline-3-carboxamide (602 mg, 2 mmol),

(bromomethyl)cyclobutane (894 mg, 6 mmol) and potassium carbonate (552 mg, 4 mmol) in N,N-dimethylformamide (10 ml.) was stirred at 50 °C for 4 h, then diluted with water, and extracted with ethyl acetate (50 ml. x 3). The combined organic layers were washed with water and brine, dried and concentrated in vacuo. The residue was purified by chromatography on silica gel (9%

methanol/dichloromethane) to afford the title compound (460 mg, 62%) as a yellow solid. LCMS (ES+) m/e 369 [M+H] ⁺ .

c) methyl 3-(3-carbamoyl-7-chloro-6-(cvclobutylmethoxy)quinolin-4-ylam ino)-5- cvclopentylbenzoate. A mixture of 4-bromo-7-chloro-6-

(cyclobutylmethoxy)quinoline-3-carboxamide (460 mg, 1.25 mmol) and methyl 3- amino-5-cyclopentylbenzoate (274 mg, 1 .25 mmol) in ethanol (10 mL) was refluxed overnight, then concentrated in vacuo and the residue purified by chromatography on silica gel (9% methanol/dichloromethane) to afford the title compound (600 mg, 78%) as a white solid. LCMS (ES+) m/e 508 [M+H] ⁺ .

d) methyl 3-(3-carbamoyl-6-(cvclobutylmethoxy)-7-(2,4-dimethoxypyrimid in-5- yl)quinolin-4-ylamino)-5-cvclopentylbenzoate. A mixture of methyl 3-(3-carbamoyl- 7-chloro-6-(cyclobutylmethoxy)quinolin-4-ylamino)-5-cyclopen tylbenzoate (200 mg, 0.394 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (81.6 mg, 0.592 mmol) potassium carbonate (81.6 mg, 0.592 mmol) and

tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.0197 mmol) in dioxane (3 mL) and water (1 mL) was heated at 80 °C under nitrogen atmosphere for 8 h. LCMS showed incomplete conversion. More 2,4-dimethoxypyrimidin-5-ylboronic acid (81.6 mg, 0.592 mmol) was added and the reaction mixture was stirred at 80 °C under nitrogen atmosphere for another 16 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel (ethyl acetate) to afford the title compound (204 mg, 85%) as a pale yellow solid. LCMS (ES+) m/e 612 [M+H] ⁺ . e) 3-(3-carbamoyl-6-(cvclobutylmethoxy)-7-(2,4-dimethoxypyrimid in-5-yl)quinolin-4- ylamino)-5-cvclopentylbenzoic acid. To a solution of methyl 3-(3-carbamoyl-6- (cyclobutylmethoxy)-7-(2,4-dimethoxypyrimidin-5-yl)quinolin- 4-ylamino)-5- cyclopentylbenzoate (150 mg, 0.245 mmol) in tetrahydrofuran (10 mL) was added 0.03N aqueous lithium hydroxide solution (8 mL, 0.24 mmol) dropwise. The reaction mixture was stirred at 40 °C for 48 h. The solvent was removed in vacuo and the pH of the residue was adjusted to 5 with 10% aqueous acetic acid. The resulting solid was filtered and washed with water to give the title compound (85 mg, 58%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 1 .42-2.02 (m, 14 H), 2.36-2.45 (m, 1 H), 2.92-3.04 (m, 1 H), 3.57 (d, J=6.6Hz, 2 H), 3.86 (s, 3 H), 3.95 (s, 3 H), 7.08 (s, 1 H), 7.10 (s, 1 H), 7.39 (s, 1 H), 7.50 (s, 1 H), 7.65 (s, br, 1 H), 7.83 (s, 1 H), 8.22 (s, br, 1 H), 8.30 (s, 1 H), 8.87 (s, 1 H), 10.30 (s, 1 H), 12.94 (1 , br, 1 H). LCMS (ES+) m/e 598 [M+H] ⁺ .

Example 40

3-((3-carbamoyl-6-(cvclopentylmethoxy)-7-(2,4-dimethoxypyrim idin-5-yl)quinolin-4- yl)amino)-5-cvclopentylbenzoic acid

a) 4-bromo-7-chloro-6-(cvclopentylmethoxy)quinoline-3-carboxami de. A mixture of 4- bromo-7-chloro-6-hydroxyquinoline-3-carboxamide (903 mg, 3 mmol),

(bromomethyl)cyclopentane (978 mg, 6 mmol) and potassium carbonate (828 mg, 6 mmol) in N,N-dimethylformamide (10 ml.) was stirred for 4 h at 50 °C. LCMS showed some starting material remained. More (bromomethyl)cyclopentane (300 mg, 1 .2 mmol) was added and the reaction mixture stirred overnight at 80 °C. The mixture was diluted with water and extracted with ethyl acetate (50 ml. x 3). The ethyl acetate layer was washed with water and brine, concentrated and purified by chromatography on silica gel to give the title compound (290 mg, 27%) as an off- white solid.

b) methyl 3-(3-carbamoyl-7-chloro-6-(cvclopentylmethoxy)quinolin-4-yla mino)-5- cvclopentylbenzoatebenzoate. A solution of 4-bromo-7-chloro-6- (cyclopentylmethoxy)quinoline-3-carboxamide (290 mg, 0.75 mmol) and methyl 3- amino-5-isopropoxybenzoate (165 mg, 0.75 mmol) in ethanol (10 ml.) was heated at reflux overnight. The reaction solution was concentrated and purified by chromatography on silica gel (9% methanol/dichloromethane) to give the title compound (360 mg, 76%) as a yellow solid.

c) methyl 3-(3-carbamoyl-6-(cvclopentylmethoxy)-7-(2,4-dimethoxypyrimi din-5- yl)quinolin-4-ylamino)-5-cvclopentylbenzoate. A mixture of methyl 3-(3-carbamoyl- 7-chloro-6-(cyclopentylmethoxy)quinolin-4-ylamino)-5-cyclope ntylbenzoate (312 mg, 0.6 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (444 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol), potassium carbonate (126 mg, 0.9 mmol) and water (3 mL) in dioxane (9 mL) was stirred at 80 °C for 4 h under nitrogen. More 2,4-dimethoxypyrimidin-5-ylboronic acid (444 mg, 2.4 mmol) was added and the mixture stirred overnight at 80 °C under nitrogen. The mixture was purified by chromatography on silica gel (5% methanol/dichloromethane) to give the title compound (300 mg, 81 %) as a yellow solid. LCMS (ES+) m/e 626 [M+H] ⁺ .

3-(3-carbamoyl-6-(cvclopentylmethoxy)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- ylamino)-5-cvclopentylbenzoic acid. To a solution of methyl 3-(3-carbamoyl-6-

(cyclopentylmethoxy)-7-(2,4-dimethoxypyrimidin-5-yl)quino lin-4-ylamino)-5- cyclopentylbenzoate (50 mg, 0.08 mmol) in tetrahydrofuran (26 mL) and water (26 mL) was added lithium hydroxide (17 mg, 0.4 mmol). The reaction mixture was stirred at 25 °C for 48 h. TLC (9% methanol/dichloromethane) showed full consumption of the starting material. The reaction solution was evaporated to remove tetrahydrofuran and the pH of the residue was adjusted to 6 - 7 with 10% aqueous acetic acid. The solid formed was filtered and recrystallized with methanol (5 mL) and water (10 mL) to give the title compound (40 mg) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.97-1.96 (m, 17 H), 2.87-2.98 (m, 1 H), 3.24 (d, J=7.2 Hz, 2 H), 3.85 (s, 3 H), 3.94 (s, 3 H), 6.87 (s, 1 H), 6.99 (s, 1 H),

7.31 (s, 1 H), 7.52 (s, 1 H), 7.67 (s, br, 1 H), 7.74 (s, 1 H), 8.28 (s, 2 H), 8.90 (s, 1 H), 10.77(s, 1 H). LCMS (ES+) m/e 612 [M+H] ⁺ .

Example 41

-((3-cvclopentyl-5-(hvdroxymethyl)phenyl)amino)-7-(2,4-di methoxypyrimidin-5- yl)quinoline-3-carboxamide A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (90 mg, 0.261 mmol) and (3-amino-5-cyclopentylphenyl)methanol (53 mg, 0.274 mmol) in ethanol (10 mL) was refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo to 5 mL. The solid was filtered and purified by prep-TLC to give the title compound (80 mg, 61 %) as a yellow solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) ppm

1.39-1 .72 (m, 6 H), 1 .88-1 .97 (m, 2 H), 2.88 (pent, J=8.4 Hz, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 4.40 (d, J=6.0 Hz, 2 H), 5.10 (t, J=6.0 Hz, 1 H), 6.73 (s, 1 H), 6.79 (s, 1 H), 6.91 (s, 1 H), 7.51 (dd, J=8.7, 1 .8 Hz, 1 H), 7.72-7.75 (m, 2 H), 8.1 1 (d, J=1 .8Hz, 1 H), 8.32 (s, br, 1 H), 8.55 (s, 1 H), 9.03 (s, 1 H), 10.75 (s, 1 H). LCMS (ES+) m/e 500 [M+H] ⁺ .

Example 42

4-((3-cvclopentyl-5-(hvdroxymethyl)phenyl)amino)-7-(2,4-dime thoxypyrimidin-5- yl)quinoline-3-sulfonamide

To a solution of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonam ide (130 mg, 0.34 mmol) in acetic acid (5 mL) was added (3-amino-5- cyclopentylphenyl)methanol (98 mg, 0.51 mmol) and the mixture stirred at 50 °C for 2 h. TLC showed complete conversion. The mixture was cooled to room temperature and the pH adjusted to 8 with sodium bicarbonate solution (6 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was washed with methanol and purified by prep-TLC to afford the title compound (90 mg, 50%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 1 .37-1.71 (m, 6 H), 1.87-1.99 (m, 2 H), 2.83-2.94 (m, 1 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 4.41 (d, J=5.4 Hz, 2 H), 5.15 (t, J=5.4 Hz, 1 H), 6.71 (s, 1 H), 6.80 (s, 1 H), 6.94 (s, 1 H), 7.56 (dd, J=1.5, 9.0 Hz, 1 H), 7.64 (d, J=9.0 Hz, 1 H), 7.95 (s, br, 2 H), 8.18(d, J=1.5 Hz, 1 H), 8.57 (s, 1 H), 9.05 (s, 1 H). LCMS (ES+) m/e 536 [M+H] ⁺ . Example 43

methyl 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)phenyl)-2 methylpropanoate

a) methyl 2-(3-nitrophenyl)acetate. To 2-(3-nitrophenyl)acetic acid (1 g, 5.52 mmol) in methanol (20 ml.) was added trimethylchlorosilane (1 .41 1 ml_, 1 1 .04 mmol). The reaction was kept stirring for 2 h, then was quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over MgS0 ₄ , filtered, concentrated under reduced pressure and purified via flash

chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 2- (3-nitrophenyl)acetate (850 mg, 4.36 mmol, 79 % yield) as a colorless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.74 (s, 3 H) 3.76 (s, 2 H) 7.50 - 7.55 (m, 1 H) 7.64 (d, J=7.83 Hz, 1 H) 8.12 - 8.21 (m, 2 H). LCMS (ES+) m/e 391 [2M+H] ⁺ . b) methyl 2-methyl-2-(3-nitrophenyl)propanoate. To methyl 2-(3-nitrophenyl)acetate (400 mg, 2.049 mmol) in Ν,Ν-dimethylformamide was added potassium tert- butoxide (460 mg, 4.10 mmol), followed by iodomethane (1025 μΙ, 2.049 mmol). The reaction was kept stirring for 3 h, quenched with water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered, concentrated and purified via flash chromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford methyl 2-methyl-2-(3-nitrophenyl)propanoate (250 mg, 1.120 mmol, 54.6 % yield) as a yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .66 (s, 6 H) 3.70 (s, 3 H) 7.48 - 7.56 (m, 1 H) 7.69 (d, J=7.83Hz, 1 H) 8.12 - 8.16 (m, 1 H) 8.25 (t, J=2.02 Hz, 1 H). LCMS (ES+) m/e 224 [M+H] ⁺ .

c) methyl 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)-2-methylpropanoate. To a mixture of methyl 2-methyl-2-(3- nitrophenyl)propanoate (250 mg, 1 .120 mmol) and 10% palladium on carbon

(1 19.2 mg, 0.1 12 mmol) was added acetic acid (10 mL). The reaction mixture was hydrogenated in a Parr shaker under 40 psi hydrogen for 2 h, then filtered. 4- chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamid e (347 mg, 1.008 mmol) was added to the filtrate. The resulting mixture was kept stirring at room temperature overnight and diluted with ether. The precipitate was collected, washed with ether and acetone and dried under reduced pressure to afford methyl

2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)amino)phenyl)-2- methylpropanoate (350 mg, 0.569 mmol, 50.8 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (s, 6 H) 3.53 (s, 3 H) 3.98 (s, 3 H) 4.01 (s, 3 H) 7.18 - 7.28 (m, 3H) 7.38 - 7.46 (m, 1 H) 7.73 (dd, J=8.97, 1.39 Hz, 1 H) 7.85 - 7.95 (m, 2 H) 8.28 (d, J=1 .52 Hz, 1 H) 8.49 (br.s., 1 H) 8.62 (s, 1 H) 9.1 1 (s, 1 H) 12.20

(br. s., 1 H). LCMS (ES+) m/e 502 [M+H] ⁺ .

Example 44

4-((3-cvclohexyl-5-(trifluoromethylsulfonamido)phenyl)amino) -7-((1 , 1- dioxidothiomorpholino)methyl)quinoline-3-carboxamide

7-(aminomethyl)-4-((3-cyclohexyl-5- (trifluoromethylsulfonamido)phenyl)amino)quinoline-3-carboxa mide (50 mg, 0.085 mmol) was dissolved in ethanol (1 ml_), and (vinylsulfonyl)ethene (0.043 mL, 0.427 mmol) added. The mixture was stirred at room temperature for 15 h. LCMS showed complete conversion. The mixture was concentrated, and purified by reverse-phase preparative HPLC (ODS, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (0.015 g, 28%) as a yellow solid. LCMS (ES+) m/e 640 [M+H] ⁺ . Example 45

2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidm

methylpropanoic acid

To a mixture of methyl 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)phenyl)-2-methylpropanoate (200 mg, 0.399 mmol) and methanol (10 mL) was added sodium hydroxide (6. ON water) (0.369 mL, 2.215 mmol). The reaction mixture was kept stirring at 40 °C overnight, then purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)phenyl)-2- methylpropanoic acid, trifluoroacetic acid salt (65 mg, 0.108 mmol, 24.39 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 3.98 (s, 3 H) 4.01 (s, 3 H) 7.22 (d, J=8.08 Hz, 1 H) 7.28 -7.34 (m, 2 H) 7.39 - 7.46 (m, 1 H) 7.72 (dd, J=8.97, 1 .39 Hz, 1 H) 7.89 (d, J=8.84 Hz, 1 H) 7.94 (br. s., 1 H) 8.23 (d, J=1.77 Hz, 1 H) 8.43 (br. s., 1 H) 8.63 (s, 1 H) 9.04 (s, 1 H) 12.24 (br. s., 1 H) 12.43 (br. s., 1 H). LCMS (ES+) m/e 488 [M+H] ⁺ .

Example 46

2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)phe

difluoroacetic acid

a) methyl 2,2-difluoro-2-(3-nitrophenyl)acetate. To a mixture of methyl 2-(3- nitrophenyl)acetate (100 mg, 0.512 mmol) in tetrahydrofuran (10 mL) cooled at -78 °C was added a solution of potassium bis(trimethylsilyl)amide (225 mg, 1.127 mmol) in tetrahydrofuran (5 mL) dropwise. The mixture was kept at -78 °C for 45 minutes, then manganese(ll) bromide (242 mg, 1.127 mmol) was added. 30 minutes later, a solution of N-fluorobenzenesulfonimide (355 mg, 1 .127 mmol) in tetrahydrofuran (5 mL) was added dropwise. The reaction was kept stirring at -78 °C for 0.5 h, then the cooling bath was removed. After the reaction temperature had risen to room temperature, the reaction was filtered. The filtrate was quenched with water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered, concentrated under reduced pressure and purifed via flash chromatography (silica gel, 0-100% thyl acetate in hexanes) to afford methyl 2,2-difluoro-2-(3-nitrophenyl)acetate (65 mg, 0.281 mmol, 54.9 % yield) as a colorless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.89 (s, 3 H) 7.67 - 7.74 (m, 1 H) 7.96 (d, J=7.83 Hz, 1 H) 8.37 (d, J=8.08 Hz, 1 H) 8.47 (s, 1 H). LCMS (ES+) m/e 232 [M+H] ⁺ .

b) 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)phenyl)-2,2- difluoroacetic acid. To a mixture of methyl 2,2-difluoro-2-(3-nitrophenyl)acetate

(65 mg, 0.281 mmol) and 10% palladium on carbon (29.9 mg, 0.028 mmol) was added acetic acid (10 mL). The reaction mixture was hydrogenated in a Parr shaker under 40 psi hydrogen for 2 h, then filtered. 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (87 mg, 0.253 mmol) was added to the filtrate. The resulting mixture was kept stirring at room temperature overnight and concentrated under reduced pressure. The oily residue was dissolved in methanol (10.00 mL), to which sodium hydroxide (6. ON in water) (0.234 mL, 1.406 mmol) was added. The mixture was kept stirring at room temperature overnight, then acidified. The precipitate was collected, washed with water, ether and acetone and dried under reduced pressure to afford 2-(3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )phenyl)-2,2- difluoroacetic acid, hydrochloride (55 mg, 0.103 mmol, 36.8 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) ppm 3.98 (s, 3 H) 3.99 (s, 3 H) 7.1 1 (d, J=7.58 Hz, 1 H) 7.19 - 7.26 (m, 2 H)7.34 - 7.42 (m, 1 H) 7.66 (d, J=8.84 Hz, 1 H) 7.76 (br. s., 1 H) 7.85 (d, J=8.84 Hz, 1 H) 8.19 (s, 1 H) 8.30 (br.s., 1 H) 8.59 (s, 1

H) 9.03 (s, 1 H) 10.62 - 10.73 (m, 1 H). LCMS (ES+) m/e 496 [M+H] ⁺ . Example 47

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

trifluoroethoxy)benzoic acid

a) ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amin

trifluoroethoxy)benzoate. To a suspension of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-carboxamide (100 mg, 0.290 mmol) in acetic acid (5 ml.) was added ethyl 3-amino-5-(2,2,2-trifluoroethoxy)benzoate, hydrochloride (87 mg,

0.290 mmol). The reaction mixture was kept stirring overnight. The precipitate was collected, washed with ether and dried under reduced pressure to afford ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(2,2,2- trifluoroethoxy)benzoate (65 mg, 0.1 14 mmol, 39.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (t, J=7.07 Hz, 3 H) 4.00 (s, 3 H) 4.03 (s, 3

H) 4.34 (q, J=7.07 Hz,2 H) 4.83 (q, J=8.84 Hz, 2 H) 7.28 (s, 1 H) 7.45 (s, 1 H) 7.57 (s, 1 H) 7.78 (s, 1 H) 7.94 (dd, J=8.97, 1.39 Hz, 1 H) 8.29 - 8.39 (m, 3 H) 8.67 (s, 1 H) 9.03 (s, 1 H) 1 1 .68 (br. s., 1 H). LCMS (ES+) m/e 572 [M+H] ⁺ .

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(2,2,2- trifluoroethoxyQbenzoic acid. To a suspension of ethyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(2,2,2-triflu oroethoxy)benzoate (55 mg, 0.096 mmol) in methanol (10 ml.) was added sodium hydroxide (6. ON in water) (0.016 ml_, 0.096 mmol). The reaction mixture was kept stirring at room temperature overnight, then was acidified. The precipitate was collected, washed with ether and dried under reduced pressure to afford 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(2,2,2-triflu oroethoxy)benzoic acid (45 mg, 0.083 mmol, 86 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d6) δ ppm 3.98 (s, 3 H) 3.99 (s, 3 H) 4.79 (q, J=8.93 Hz, 2 H) 6.92 (t, J=2.15 Hz, 1 H) 7.18 (s, 2 H) 7.65 - 7.75 (m, 2 H) 7.93 (d, J=8.84 Hz, 1 H) 8.19 (d, J=1 .52 Hz, 1 H) 8.25 (br. s., 1 H) 8.59(s, 1 H) 9.01 (s, 1 H) 10.22 (s, 1 H) 13.10 (br. s., 1 H). LCMS (ES+) m/e 544 [M+H] ⁺ .

Example 48

4-( 3-(1 H-tetrazol-5-yl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl )quinoline-3- sulfonamide

A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonam ide (194 mg, 0.51 mmol) and 3-(1 H-tetrazol-5-yl)aniline (82 mg, 0.51 mmol) in ethanol (50 mL) was refluxed for 2 h. TLC showed complete conversion. The mixture was concentrated in vacuo. The residue was washed with methanol and purified by prep-TLC using methanol to afford the title compound (20 mg, 8%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 3.97 (s, 6 H), 7.07-7.10 (m, 1 H), 7.49 (t, J=7.8 Hz, 1 H), 7.64-7.75 (m, 4 H), 7.90 (s, 2 H), 8.27 (s, 1 H), 8.49 (s, 1 H), 8.58 (s, 1 H), 9.17 (s, 1 H), 16.88 (s, br, 1 H). LCMS (ES+) m/e 506 [M+H] ⁺ .

Example 49

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (methylcarbamoyl)benzoic acid To a suspension of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (100 mg, 0.290 mmol) in acetic acid (10 ml.) was added 3-amino-5- (methylcarbamoyl)benzoic acid (56.3 mg, 0.290 mmol). The reaction mixture was stirred at room temperature overnight. The precipitate was collected, washed with ether and dried under reduced pressure to afford 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-(methylcarbamoyl)benzoic acid (120 mg, 0.239 mmol, 82 % yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.79 (d, J=4.55 Hz, 3 H) 4.00 (s, 3 H) 4.03 (s, 3 H) 7.74 (s, 1 H) 7.94 (dd, J=9.09, 1 .52 Hz, 1 H) 7.96 (br. s., 1 H) 8.01 (br. s., 1 H) 8.32 - 8.40 (m, 4 H) 8.66 - 8.70 (m, 2 H) 9.01 (s, 1 H) 1 1.78 (br. s., 1 H). LCMS (ES+) m/e 503 [M+H] ⁺ .

Example 50

3-((3-carbamoyl-6-(cvclopropylmethoxy)-7-(2,4-dimethoxypyrim idin-5-yl)quinolin-4- yl)amino)-5-cvclopentylbenzoic acid

a) 4-bromo-7-chloro-6-(cvclopropylmethoxy)quinoline-3-carboxami de. 4-bromo-7- chloro-6-hydroxyquinoline-3-carboxamide (800 mg, 2.77 mmol),

(bromomethyl)cyclopropane (556.6 mg, 4.15 mmol) and potassium carbonate (764 mg, 5.54 mmol) in N,N-dimethylformamide (10 ml.) were stirred at 50 °C for 3 h.

LCMS showed the desired product and starting material was consumed. The mixture was diluted with water (40 ml_). The precipitate was filtered, washed with water (10 mL x 3) and dried in vacuo to afford the title compound (563 mg, 57%). LCMS (ES+) m/e 355 [M+H] ⁺ .

b) methyl 3-(3-carbamoyl-7-chloro-6-(cvclopropylmethoxy)quinolin-4-yla mino)-5- cvclopentylbenzoate. A mixture of 4-bromo-7-chloro-6-

(cyclopropylmethoxy)quinoline-3-carboxamide (538 mg, 1.5 mmol) and methyl 3- amino-5-cyclopentylbenzoate (278 mg, 1 .27 mmol) in ethanol (50 mL) was refluxed for 16 h. LCMS showed methyl 3-amino-5-cyclopentylbenzoate was consumed and some 4-bromo-7-chloro-6-(cyclopropylmethoxy)quinoline-3- carboxamide remained. Another 70 mg of methyl 3-amino-5-cyclopentylbenzoate was added and the resulting mixture was refluxed for 8 h. LCMS showed no 4- bromo-7-chloro-6-(cyclopropylmethoxy)quinoline-3-carboxamide left. The solvent was removed in vacuo and the residue was washed with ether (20 mL x 2) to afford the title compound (740 mg, 99%). LCMS (ES+) m/e 494 [M+H] ⁺ .

c) methyl 3-(3-carbamoyl-6-(cvclopropylmethoxy)-7-(2,4-dimethoxypyrimi din-5- yl)quinolin-4-ylamino)-5-cvclopentylbenzoate. A mixture of methyl 3-(3-carbamoyl- 7-chloro-6-(cyclopropylmethoxy)quinolin-4-ylamino)-5-cyclope ntylbenzoate (200 mg, 0.4 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (294 mg, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) and sodium bicarbonate (50 mg, 0.6 mmol) in dioxane (12 mL) and water (4 mL) was stirred at 80 °C under nitrogen for 12 h. The mixture was cooled to room temperature and extracted with dichloromethane (50 mL). The organic layers were washed with brine (50 mL x 2) and concentrated in vacuo. The residue was purified by prep- TLC (9% methanol/dichloromethane) to afford the title compound (170 mg, 71 %) as a yellow solid. LCMS (ES+) m/e 598 [M+H] ⁺ .

d) 3-(3-carbamoyl-6-(cvclopropylmethoxy)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- ylamino)-5-cvclopentylbenzoic acid. A mixture of methyl 3-(3-carbamoyl-6- (cyclopropylmethoxy)-7-(2,4-dimethoxypyrimidin-5-yl)quinolin -4-ylamino)-5- cyclopentylbenzoate (158 mg, 0.26 mmol) in 2N aqueous hydrochloric acid (10 mL) and tetrahydrofuran (10 mL ) was stirred at 50 °C for 12 h. The mixture was cooled to room temperature and tetrahydrofuran removed in vacuo. The mixture was acidified with formic acid to pH=3. The precipitate was collected by filtration and the crude product purified by prep-HPLC to afford the title compound (60 mg, 39%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.05-0.1 1 (m, 2 H), 0.38-0.44 (m, 2 H), 0.87-0.91 (m, 1 H), 1.43-1 .52 (m, 6 H), 1 .91-2.01 (m, 2 H), 2.91-3.02 (m, 1 H), 3.48 (d, J=6.3 Hz, 2 H), 3.88 (s, 3 H), 3.96 (s, 3 H), 7.08 (s, 1 H), 7.1 1 (s, 1 H), 7.36 (s, 1 H), 7.47 (s, 1 H), 7.64 (s, br, 1 H), 7.83 (s, 1 H), 8.17 (s, 1 H), 8.21 (s, br, 1 H), 8.34 (s, 1 H), 8.85 (s, 1 H), 10.25 (s, 1 H). LCMS (ES+) m/e 584 [M+H] ⁺ . Example 51

-butoxy-4-((3-cvclopentyl-5-(hvdroxymethyl)phenyl)amino)- 7-(2,4-dimethoxypy

yl)quinoline-3-carboxamide

a) methyl 3-cvclopent-1 -en-1 -yl-5-nitrobenzoate. A mixture of 2-cyclopent-1 -en-1 -yl- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (20 g, 103.8 mmol), methyl 3-bromo-5- nitrobenzoate (18 g, 69.2 mmol), tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol) and potassium carbonate (14 g, 103.8 mmol) in N,N- dimethylformamide (300 ml.) was stirred under nitrogen at 80 °C for 16 h. The mixture was cooled to room temperature, poured into water (600 ml.) and extracted with ethyl acetate (600 ml. x 2). The extracts were concentrated in vacuo and the residue purified by chromatography on slica gel (14% ethyl acetate/petroleum ether) to afford the title compound (14.5 g, 85%) as a yellow oil. 1H NMR (300 MHz, CDCI ₃ ) ppm 2.05-2.14 (m, 2 H), 2.58-2.64 (m, 2 H), 2.75- 2.81 (m, 2 H), 3.99 (s, 3 H), 6.46-6.47 (m, 1 H), 8.38 (d, J=1.5 Hz, 1 H), 8.40 (d, J=1.5 Hz, 1 H), 8.67 (d, J=1.5 Hz, 1 H).

b) methyl 3-amino-5-cvclopentylbenzoate. A mixture of methyl 3-cyclopent-1-en-1-yl- 5-nitrobenzoate (14.5 g, 58.7 mmol) and 10% palladium on carbon (1 g) in methanol (200 ml.) and acetic acid (10 ml.) was stirred at 50 °C under hydrogen (4 bar) for 12 h, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue purified by prep-HPLC to afford the title compound (9.6 g, 66%) as a yellow oil. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) ppm 1.44-1 .49 (m, 2 H), 1 .61 -1.77 (m, 4 H), 1.93-2.00 (m, 2 H), 2.82-2.93 (m, 1 H), 3.78 (s, 3 H), 5.29 (s, br, 2 H), 6.70 (d, J=1 .8 Hz,1 H), 6.99-7.01 (m, 2 H). LCMS (ES+) m/e 220 [M+H] ⁺ .

c) (3-amino-5-cvclopentylphenyl)methanol. A mixture of methyl 3-amino-5- cyclopentylbenzoate (500 mg, 2.28 mmol) and lithium aluminum hydride (86.6 mg, 2.28 mmol) in tetrahydrofuran (15 ml.) was stirred at room temperature for 3 h. TLC showed complete conversion. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (5%

methanol/dichloromethane) to afford the title compound (400 mg, 43%) as a gray solid. ¹ H NMR (300 MHz, DMSO-de) ppm 1 .41 -1.78 (m, 6 H), 1 .88-1.97 (m, 2 H), 2.73-2.84 (m, 1 H), 4.30 (d, J=6.0 Hz, 2 H), 4.86-4.93 (m, 3 H), 6.31 -6.35 (m, 3 H). LCMS (ES+) m/e 192 [M+H] ⁺ .

d) 4-bromo-6-butoxy-7-chloroquinoline-3-carboxamide. A mixture of 4-bromo-7- chloro-6-hydroxyquinoline-3-carboxamide (500 mg, 1.67 mmol), 1-bromobutane (342 mg, 2.5 mmol), and potassium carbonate (691 mg, 5 mmol) in N,N- dimethylformamide (5 mL) was stirred at 50 °C for 3 h. TLC showed completed conversion. The mixture was cooled to room temperature and water (10 mL) added. The precipitate was collected by filtration, washed with water and dried in vacuo to afford the title compound (500 mg, 84%). ¹ H NMR (300 MHz, DMSO-c/ ₆ ) ppm 0.99 (t, J=7.5 Hz, 3 H), 1.47-1 .60 (m, 2 H), 1 .80-1.89 (m, 2 H), 4.28 (d, J=6.3 Hz, 2 H), 7.60 (s, 1 H), 7.94 (s, br, 1 H), 8.18 (s, br, 1 H), 8.23 (s, 1 H), 8.65 (s, 1 H). LCMS (ES+) m/e 357 [M+H] ⁺ .

e) 6-butoxy-7-chloro-4-(3-cvclopentyl-5-(hvdroxymethyl)phenylam ino)quinoline-3- carboxamide. A mixture of 4-bromo-6-butoxy-7-chloroquinoline-3-carboxamide (300 mg, 0.84 mmol) and (3-amino-5-cyclopentylphenyl)methanol (192 mg, 1 mmol) in ethanol (50 mL ) was refluxed for 3 h. LCMS showed complete conversion. The mixture was cooled to room temperature and ethanol was removed in vacuo. The residue was washed with methanol and dried in vacuo to afford the title compound (350 mg, 89%) as a gray solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.89 (t, J=7.5 Hz, 3 H), 1 .29-1.39 (m, 2 H), 1.51-1 .78 (m, 8 H), 1.94-2.00 (m, 2 H), 2.89-2.99 (m, 1 H), 3.64 (t, J=3.6 Hz, 2 H), 4.44 (s, 1 H), 4.67 (s, 2 H), 7.04 (m, 2 H), 7.14 (s, 1 H), 7.34 (s, 1 H), 7.85 (s, br, 1 H), 8.06 (s, 1 H), 8.36 (s, br, 1 H), 8.95 (s, 1 H), 1 1.84 (s, br, 1 H). LCMS (ES+) m/e 468 [M+H] ⁺ . f) 6-butoxy-4-(3-cvclopentyl-5-(hvdroxymethyl)phenylamino)-7-(2 ,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide. A mixture of 6-butoxy-7-chloro- 4-(3-cyclopentyl-5-(hydroxymethyl)phenylamino)quinoline-3-ca rboxamide (400 mg, 0.856 mol), 2,4-dimethoxypyrimidin-5-ylboronic acid (630 mg, 3.4 mmol), tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.0856 mmol) and potassium carbonate (177 mg, 1.2 mmol) in dioxane (3 mL) and water (1 mL) was stirred under nitrogen at 100 °C for 20 h. LCMS showed complete conversion. The mixture was cooled to room temperature and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (5% methanol/dichloromethane) to afford the crude product, which was further purified by washing with methanol 3 times to afford the title compound (80 mg, 16%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.80 (t, J=7.2 Hz, 3 H), 1.12-1.19 (m, 2 H), 1.39-1 .71 (m, 8 H), 1 .88-1.97 (m, 2 H), 2.84-2.92 (m,

1 H), 3.50-3.54 (m, 2 H), 3.85 (s, 3 H), 3.95 (s, 3 H), 4.42 (d, J=5.7 Hz, 2 H), 5.14 (t, J=5.7 Hz, 1 H), 6.84 (s, 1 H), 6.92 (s, 1 H), 7.03 (s, 1 H), 7.67 (s, br, 1 H), 7.78 (s, 1 H), 8.30 (s, 2 H), 8.54 (s, 1 H), 8.89 (s, 1 H), 10.65 (s, 1 H). LCMS (ES+) m/e 572 [M+H] ⁺ .

Example 52

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-methylquin olin-4-yl)amino)-5- cyclopentylbenzoic acid

a) methyl 3-(cyclopent-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) diethyl 2-(((3-bromo-2-methylphenyl)amino)methylene)malonate. A mixture of 3- bromo-2-methylaniline (9.78 g, 52.6 mmol) and diethyl 2-

(ethoxymethylene)malonate (10.7 mL, 53.4 mmol) was heated at 100 °C for 1.5h. The solution was allowed to cool to room temperature, and nitrogen passed over it, which immediately induced solid formation. The material (20.1 g, 107%) was used in the next step without further purification. LCMS (ES+) m/e 356 [M+H] ⁺ . d) ethyl 7-bromo-4-hvdroxy-8-methylquinoline-3-carboxylate. A solution of diethyl 2-

(((3-bromo-2-methylphenyl)amino)methylene)malonate (4.45g, 12.49 mmol) in diphenyl ether (80 mL) was heated at 250 °C for 16 h. Upon cooling to room temperature, a precipitate fomred. The solid was filtered and washed with heptane to afford the title compound (3.18 g, 83% pure, 68%) as a tan solid.

LCMS (ES+) m/e 310 [M+H] ⁺ .

e) 7-bromo-4-hvdroxy-8-methylquinoline-3-carboxylic acid. A solution of ethyl 7- bromo-4-hydroxy-8-methylquinoline-3-carboxylate (1.575 g, 4.21 mmol) and potassium hydroxide (2.2 g, 39.2 mmol) in tetrahydrofuran (8 mL), methanol (3 mL) and water (1 mL) was heated at 45 °C for 2 h, then cooled. 6M aqueous hydrochloric acid was added to the mixture until a precipitate formed. The solid was filtered off and dried to afford the title compound (1.47 g, 93% pure, 1 15%). LCMS (ES+) m/e 282 [M+H] ⁺ .

f) 7-bromo-4-chloro-8-methylquinoline-3-carboxamide. A mixture of 7-bromo-4- hydroxy-8-methylquinoline-3-carboxylic acid (1 .47 g, 4.85 mmol) and phosphorus oxychloride (2.71 mL, 29.1 mmol) was heated at 1 10 °C for 3 h, then

concentrated. The residue was dissolved in a minimum amount of 1 ,4-dioxane. This solution was cooled and slowly and carefully added to an ice cooled solution of ammonium hydroxide. A tan solid immediately formed and was filtered to afford the title compound (1 .16 g, 80%). LCMS (ES+) m/e 299 [M+H] ⁺ .

g) methyl 3-((7-bromo-3-carbamoyl-8-methylquinolin-4-yl)amino)-5- cvclopentylbenzoate. A mixture of 7-bromo-4-chloro-8-methylquinoline-3- carboxamide (670 mg, 2.080 mmol) and methyl 3-amino-5-cyclopentylbenzoate (0.456 g, 2.080 mmol) and acetic acid (20 mL) was stirred at room temperature for 65 h. A precipitate had formed and was filtered, washed with ether and dried to afford the title compound (1 .06 g, 86% pure, 91 %) as a tan solid. LCMS (ES+) m/e 482 [M+H] ⁺ . h) methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-methylquin olin-4- yl)amino)-5-cvclopentylbenzoate. A mixture of methyl 3-((7-bromo-3-carbamoyl-8- methylquinolin-4-yl)amino)-5-cyclopentylbenzoate (203 mg, 0.362 mmol), (2,4- dimethoxypyrimidin-5-yl)boronic acid (0.061 ml_, 0.543 mmol), cesium carbonate (354 mg, 1.086 mmol), [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (14.78 mg, 0.018 mmol), 1 ,4-dioxane (2 ml.) and water (1 ml.) was heated at 100 °C for 0.5 h. The mixture was filtered and purified by reverse-phase preparative HPLC (ODS, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (232 mg, 83% pure, 98%) as a yellow solid. LCMS (ES+) m/e 542 [M+H] ⁺ .

i) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-methylquin olin-4-yl)amino)-5- cvclopentylbenzoic acid. A mixture of methyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-8-methylquinolin-4-yl)amino)-5-cycl opentylbenzoate (232 mg, 0.356 mmol), potassium hydroxide (300 mg, 5.35 mmol), tetrahydrofuran (2 ml_), methanol (1 ml.) was heated at 45 °C for 16 h, then cooled and concentrated. The mixture was neutralized with trifluoroacetic acid, and diluted with

dimethylsulfoxide. This solution was purified by acidic gilson HPLC, the desired fractions were combined, and concetrated to afford a yellow solid. This solid was then purified by reverse-phase preparative HPLC (ODS, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford the title compound (33mg, 17%). LCMS (ES+) m/e 528 [M+H] ⁺ .

Example 53

1 -(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)phenyl)cvclopropanecarboxylic acid

To a suspension of methyl 1 -(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)phenyl)cyclopropanecarboxylate (see next example, 100 mg, 0.200 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 N in water) (0.167 mL, 1.001 mmol). The reaction mixture was kept stirring overnight at room temperature and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column,

acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 1 -(3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)phenyl)cycloprop anecarboxylic acid, trifluoroacetic acid salt (65 mg, 0.108 mmol, 54.2 % yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.14 - 1.20 (m, 2 H) 1.38 - 1.44 (m, 2 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 7.24- 7.33 (m, 3 H) 7.38 - 7.45 (m, 1 H) 7.69 (dd, J=8.97, 1 .64 Hz, 1 H) 7.88 - 7.97 (m, 2 H) 8.29 (d, J=1.77 Hz, 1 H) 8.48 (br. s., 1 H) 8.64 (s, 1 H) 9.06 (s, 1 H) 12.39 (br. s., 1 H). LCMS (ES+) m/e 486 [M+H] ⁺ .

Example 54

methyl 1 -(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)phenyl)cvclopropanecarboxylate

a) methyl 1-(3-nitrophenyl)cvclopropanecarboxylate. To a solution of 1 ,2- dibromoethane (289 mg, 1.537 mmol) and methyl 2-(3-nitrophenyl)acetate (300 mg, 1 .537 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil suspension, 61 .5 mg, 1.537 mmol). The reaction was kept stiring overnight, then quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over MgS0 ₄ , filtered, concentrated under reduced pressure and purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 1 -(3-nitrophenyl)cyclopropanecarboxylate (250 mg, 1.130 mmol, 73.5 % yield) as a colorless oil. ¹ H NMR (400 MHz,

CHLOROFORM-d) δ ppm 1.24 - 1.29 (m, 2 H) 1 .70 - 1.74 (m, 2 H) 3.65 (s, 3 H) 7.51 (t,J=7.96 Hz, 1 H) 7.69 - 7.73 (m, 1 H) 8.12 - 8.16 (m, 1 H) 8.21 (t, J=1.89 Hz, 1 H). LCMS (ES+) m/e 222 [M+H] ⁺ . b) methyl 1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)cvclopropanecarboxylate. To a suspension of 10% palladium on carbon (120 mg, 0.1 13 mmol) in acetic acid (15 ml_) was added methyl 1-(3- nitrophenyl)cyclopropanecarboxylate (250 mg, 1.130 mmol). The reaction was hydrogenated under 40psi hydrogen in a Parr shaker for 1 h at room temperature, then was filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (351 mg, 1.017 mmol) was added to the filtrate. The mixture was kept stirring overnight, quenched with water and neutralized with sodium hydroxide (6.0 N in water). The precipitate was collected, washed with ether, methanol and dried under reduced pressure to afford methyl 1-(3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)phenyl)cycloprop anecarboxylate (310 mg, 0.621 mmol, 54.9 % yield) as a yellow solid. LCMS (ES+) m/e 500 [M+H] ⁺ .

Example 55

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroquin olin-4-yl)amino)-5- cvclopentylbenzoic acid

a) 3-bromo-2-fluoroaniline. A mixture of 1-bromo-2-fluoro-3-nitrobenzene (10q, 45.5 mmol), tin(ll) chloride dihydrate (46 g, 204 mmol) and ethanol (1 14 ml.) was heated under reflux at 90 °C for 1 h, then cooled and diluted with ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate 4 times and the combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), filtered, and concetrated to afford the title compound (7.30 g, 85%) as a tan solid.

No further purification was performed. LCMS (ES+) m/e 190 [M+H] ⁺ .

b) diethyl 2-(((3-bromo-2-fluorophenyl)amino)methylene)malonate. A mixture of 3- bromo-2-fluoroaniline (7.27 g, 38.3 mmol) and diethyl 2- (ethoxymethylene)malonate (8 ml_, 39.9 mmol) was heated at 100 °C for 1 h. The solution was cooled to room temperature, and nitrogen passed over it, which immediately induced solid formation. The solid was collected (14.0 g, 93% pure, 94%) and used as is without further purification. LCMS (ES+) m/e 360 [M+H] ⁺ . c) ethyl 7-bromo-8-fluoro-4-hvdroxyquinoline-3-carboxylate. A mixture of diethyl 2-

(((3-bromo-2-fluorophenyl)amino)methylene)malonate (6 g, 16.66 mmol) and diphenyl ether (80 ml.) was heated at 240 °C for 16 h. A precipitate formed while cooling to room temperature, and was filtered and washed with heptane to afford the title compound (4.30 g, 82%). LCMS (ES+) m/e 314 [M+H] ⁺ .

d) 7-bromo-8-fluoro-4-hvdroxyquinoline-3-carboxylic acid. A mixture of ethyl 7- bromo-8-fluoro-4-hydroxyquinoline-3-carboxylate (2.65 g, 7.00 mmol), potassium hydroxide (3.22 g, 57.4 mmol), tetrahydrofuran (12 ml_), methanol (5 ml.) and water (4 ml.) was heated at 45 °C for 20h. 6M aqueous hydrochloric acid was added to the cooled solution to produce a white precipitate which was filtered and dried to afford the title compound (2.1 g, 92% pure, 96%). LCMS (ES+) m/e 286

[M+H] ⁺ .

e) 7-bromo-4-chloro-8-fluoroquinoline-3-carboxamide. A mixture of 7-bromo-8-fluoro- 4-hydroxyquinoline-3-carboxylic acid (1 .20g, 4.03 mmol) and phosphorus oxychloride (4 mL, 42.9 mmol) was heated at 1 10 °C for 3h. The mixture was concentrated and then dissolved in minimal 1 ,4-dioxane (~3mL). The solution was added slowly and cautiously to ice cooled concentrated aqueous ammonia (-10 mL). A tan solid immediately formed which was filtered and dried to afford the title compound (1.12 g, 73% pure, 67%), which was used without further purification. LCMS (ES+) m/e 303 [M+H] ⁺ .

f) methyl 3-((7-bromo-3-carbamoyl-8-fluoroquinolin-4-yl)amino)-5- cvclopentylbenzoate. A mixture of 7-bromo-4-chloro-8-fluoroquinoline-3- carboxamide (750 mg, 1.804 mmol), methyl 3-amino-5-cyclopentylbenzoate (0.275 mL, 2.061 mmol) and acetic acid (10 mL) was stirred at room temperature for 2 hours, and a tan precipitate formed. The solid was filtered and washed with ether to give the title compound (1 .30 g, 148%). LCMS (ES+) m/e 486 [M+H] ⁺ .

g) methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroquin olin-4- yl)amino)-5-cvclopentylbenzoate. A mixture of methyl 3-((7-bromo-3-carbamoyl-8- fluoroquinolin-4-yl)amino)-5-cyclopentylbenzoate (225 mg, 0.453 mmol), (2,4- dimethoxypyrimidin-5-yl)boronic acid (0.076 mL, 0.680 mmol), cesium carbonate (443 mg, 1.360 mmol) and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (18.51 mg, 0.023 mmol), 1 ,4-dioxane (2 mL) and water (1 m) was purged with nitrogen for 15minut.es, then heated in a microwave reactor at 120 °C for 30 min 3 times. The mixture was filtered and purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia). The desired fractions were combined and concentrated to a brown residue, which was purified by chromatography (silca gel, 0-10% 2-propanol/ethyl acetate) to afford the tilte compound (60 mg, 24%). LCMS (ES+) m/e 546 [M+H] ⁺ .

h) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroquin olin-4-yl)amino)-5- cvclopentylbenzoic acid. A mixture of methyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-8-fluoroquinolin-4-yl)amino)-5-cycl opentylbenzoate (60 mg, 0.108 mmol) and potassium hydroxide (200 mg, 3.56 mmol) in 1 ,4-dioxane (2 mL) and water (1 mL) was stirred at room temperature for 16 h. LCMS indicated conversion to desired product. The mixture was concentrated, then 6M aqueous hydrochloric acid added until a precipitate formed. The solid was filtered, dissolved in dimethylsulfoxide and purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to give the title compound (1 1 mg, 19%) as a fluffy yellow solid. LCMS (ES+) m/e 532 [M+H] ⁺ .

Example 56

-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)quinolin-4-y l)amino)-5-isopropoxybenzoic acid

a) 5-bromo-2,6-dimethylpyrimidin-4-ol. Bromine (2.075 mL, 40.3 mmol) was added slowly to a solution of 2,6-dimethylpyrimidin-4-ol (5 g, 40.3 mmol) in 1 ,4-dioxane

(100 mL) and the mixture stirred for 45 minutes at room temperature. Water was added to the solution and the pH was adjusted to 6 with 1 M aqueous hydrochloric acid and 1 M aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate 4 times, tetrahydrofuran 3 times and dichloromethane 3 times. The combined organics were dried (Na ₂ S0 ₄ ), filtered, and concentrated to afford the title compound (3.95 g, 48%) as a dark colored solid. LCMS (ES+) m/e 203

[M+H] ⁺ .

b) 5-bromo-4-chloro-2,6-dimethylpyrimidine. A mixture of 5-bromo-2,6- dimethylpyrimidin-4-ol (3.95 g, 19.45 mmol) and phosphorus oxychloride (6 mL,

64.4 mmol) was heated at 1 10 °C for 3h. The solution was concentrated, and water was then added slowly and cautiously to afford a precipitate. The solid was filtered and washed with water, and dried to give the title compound (2.73 g, 63%). LCMS (ES+) m/e 221 [M+H] ⁺ .

c) 5-bromo-2,4-dimethylpyrimidine. A mixture of 5-bromo-4-chloro-2,6- dimethylpyrimidine (2.73 g, 12.33 mmol), 4-methylbenzenesulfonohydrazide (4.19 mL, 37.0 mmol) and chloroform (40 mL) was heated at 90 °C for 16 hours. The solution was cooled and the solid filtered and washed with chloroform. LCMS revealed this solid (4.75g) was the desired intermediate. A mixture of this solid and 0.94M aqueous sodium carbonate (40 mL, 37.7 mmol) was heated at 90 °C for 1 .5 hours. The cooled solution was extracted with ethyl acetate 3 times, and the combined organics were washed with brine, dried (Na ₂ S0 ₄ ) and concentrated to afford the title compound (1 .17 g, 51 %) as a tan oil, which crystallized upon standing. LCMS (ES+) m/e 187 [M+H] ⁺ .

d) methyl 3-isopropoxy-5-nitrobenzoate. 2-Bromopropane (3 mL, 32.0 mmol) was added to a mixture of methyl 3-hydroxy-5-nitrobenzoate (2.3 g, 1 1 .67 mmol), cesium carbonate (8.79 g, 27.0 mmol) and N,N-dimethylformamide (55.3 mL). The mixture was heated at 120 °C for 2.5 h, then cooled and filtered. The filtrate was diluted with water and extracted with ethyl acetate 3 times. The combined organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered, and concentrated to a tan oil, which was chromatographed (silica gel, 1-13% ethyl acetate /hexanes) to give the title compound (900 mg, 32%), LCMS (ES+) m/e 240 [M+H] ⁺ ; along with isopropyl 3-isopropoxy-5-nitrobenzoate (1.70 g, 55%), LCMS (ES+) m/e 268

[M+H] ⁺ .

e) methyl 3-amino-5-isopropoxybenzoate. A solution of methyl 3-isopropoxy-5- nitrobenzoate (1 g, 4.18 mmol) in ethanol (25 mL) was stirred with 10% palladium- on-carbon (4.45 g, 4.18 mmol) under a balloon of hydrogen for 16 h at room temperature. The catalyst was filtered off through Celite ^® and the filtrate concentrated to afford the title compound (985 mg, 88% pure, 99%) as a brown oil. LCMS (ES+) m/e 210 [M+H] ⁺ . f) methyl 3-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-isopropoxybenz oate. A suspension of 7-bromo-4-chloroquinoline-3-carboxamide (800 mg, 2.80 mmol) and methyl 3-amino-5-isopropoxybenzoate (0.377 ml_, 2.61 mmol in acetic acid (10 ml.) was stirred for 1 h at room temperature whereupon a precipitate formed. The precipitate was filtered and dried to give the title compound (1 .30 g, 101 %) as a yellow solid. LCMS (ES+) m/e 458 [M+H] ⁺ .

g) methyl 3-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)quinolin-4-yl) amino)-5- isopropoxybenzoate. A mixture of methyl 3-((7-bromo-3-carbamoylquinolin-4- yl)amino)-5-isopropoxybenzoate (300 mg, 0.655 mmol) bis(pinacolato)diboron (183 mg, 0.720 mmol), potassium acetate (225 mg, 2.291 mmol), [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (26.7 mg, 0.033 mmol) and 1 ,4-dioxane (3 ml.) was heated at 1 10 °C for 45 minutes in a microwave reactor. Cesium carbonate (427 mg, 1 .309 mmol), 5- bromo-2,4-dimethylpyrimidine (0.045 ml_, 0.393 mmol), [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct

(26.7 mg, 0.033 mmol), and water (1 ml.) were added and the mixture heated again in a microwave reactor at 1 10 °C for 1 hour. LCMS indicated formation of the desired product. The mixture was filtered and purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to afford the title compound (150 mg, 47%). LCMS (ES+) m/e 486 [M+H] ⁺ .

h) 3-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)quinolin-4-yl) amino)-5- isopropoxybenzoic acid. A solution of methyl 3-((3-carbamoyl-7-(2,4- dimethylpyrimidin-5-yl)quinolin-4-yl)amino)-5-isopropoxybenz oate (75 mg, 0.154 mmol) and potassium hydroxide (300 mg, 5.35 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was heated at 35 °C for 4 h, then cooled and concentrated.

The mixture was neutralized with 6M aqueous hydrochloric acid and further diluted with dimethylsulfoxide. This solution was purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to give the title compound (21 mg, 29%) as a yellow solid. LCMS (ES+) m/e 472 [M+H] ⁺ . Example 57

-((7-(2,4-dimethylpyrimidin-5-yl)-3-sulfamoylquinolin-4-y l)amino)-5-isopropoxy

acid

a) methyl 3-((7-bromo-3-sulfamoylquinolin-4-yl)amino)-5-isopropoxybenz oate. A mixture of 7-bromo-4-chloroquinoline-3-sulfonamide (400 mg, 1.244 mmol) and methyl 3-amino-5-isopropoxybenzoate (0.167 mL, 1 .157 mmol) in acetic acid (10 mL) was stirred at room temperature for 3 hours. A precipitate formed, and was filtered off in 2 batches. These were combined to give the title compound (455 mg, 74%) as a yellow/orange solid. LCMS (ES+) m/e 494 [M+H] ⁺ .

b) methyl 3-((7-(2,4-dimethylpyrimidin-5-yl)-3-sulfamoylquinolin-4-yl) amino)-5- isopropoxybenzoate. A mixture of methyl 3-((7-bromo-3-sulfamoylquinolin-4- yl)amino)-5-isopropoxybenzoate (250 mg, 0.506 mmol) bis(pinacolato)diboron (141 mg, 0.556 mmol), potassium acetate (174 mg, 1.770 mmol) [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (20.65 mg, 0.025 mmol) and 1 ,4-dioxane (3 mL) was purged with nitrogen for 15 minutes, and then heated at 1 10 °C for 30 minutes in a microwave reactor. 5- bromo-2,4-dimethylpyrimidine (0.036 mL, 0.321 mmol), cesium carbonate (330 mg, 1 .01 1 mmol), [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (20.65 mg, 0.025 mmol) and water (1 mL) were added to the mixture and this again purged with nitrogen for 15 minutes. The mixture was heated in a microwave reactor at 1 10 °C for 30 min, then cooled and filtered. The filtrate was purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to give the title compound (120 mg, 80% pure, 36%) as a brown solid. LCMS (ES+) m/e 522 [M+H] ⁺ .

c) 3-((7-(2,4-dimethylpyrimidin-5-yl)-3-sulfamoylquinolin-4-yl) amino)-5- isopropoxybenzoic acid. A mixture of methyl 3-((7-(2,4-dimethylpyrimidin-5-yl)-3- sulfamoylquinolin-4-yl)amino)-5-isopropoxybenzoate (120 mg, 0.184 mmol) and potassium hydroxide (300 mg, 5.35 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was heated at 35 °C for 1 h. The solution was concentrated and neutralized with trifluoroacetic acid. This was diluted with dimethylsulfoxide and purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to afford the title compound (38 mg, 41 %) as a yellow solid. LCMS

(ES+) m/e 508 [M+H] ⁺ .

Example 58

1 -(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)phenyl)cvclobutanecarboxylic acid

a) methyl 1-(3-nitrophenyl)cvclobutanecarboxylate. To a solution of methyl 2-(3- nitrophenyl)acetate (250 mg, 1.281 mmol) and 1 ,3-dibromopropane (259 mg, 1.281 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil suspension, 51 .2 mg, 1.281 mmol). The reaction was kept stirring at room temperature overnight, 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 oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 1-(3- nitrophenyl)cyclobutanecarboxylate (230 mg, 0.978 mmol, 76 % yield) as a colorless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .87 - 2.01 (m, 1 H) 2.16 (m, 1 H) 2.50 - 2.60 (m, 2 H) 2.88 - 2.98 (m, 2 H) 3.69 (s, 3 H) 7.50 - 7.56 (m, 1 H) 7.63 (dd, J=7.71 , 1 .14 Hz, 1 H)8.09 - 8.15 (m, 1 H) 8.18 (t, J=1.89 Hz, 1 H). LCMS (ES+) m/e 236 [M+H] ⁺ .

b) 1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)cvclobutanecarboxylic acid. To a suspension of 10% palladium on carbon (104 mg, 0.098 mmol) in acetic acid (10 mL) was added methyl 1 -(3- nitrophenyl)cyclobutanecarboxylate (230 mg, 0.978 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (303 mg, 0.880 mmol) was added to the filtrate. The reaction was kept stirring overnight. The organic solvent was removed and the residue dissolved in methanol (10.00 ml_). Sodium hydroxide (6. ON) (0.815 ml_, 4.89 mmol) was added. The mixture was kept stirring for 5 hours, then purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)phenyl)cyclobutanecarboxylic acid, trifluoroacetic acid salt (81 mg, 0.132 mmol, 13.50 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- cf6) δ ppm 1 .74 - 1.84 (m, 1 H) 1 .86 - 1 .99 (m, 1 H) 2.36 - 2.45 (m, 2 H) 2.61 -2.70 (m, 2 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 7.17 - 7.27 (m, 3 H) 7.38 - 7.47 (m, 1 H) 7.71 (dd, J=9.09, 1.77 Hz, 1 H) 7.90 (d, J=9.09 Hz, 1 H) 7.95 (br. s., 1 H) 8.24 (d, J=1.52 Hz, 1 H) 8.43 (br. s., 1 H) 8.64 (s, 1 H) 9.05 (s, 1 H) 12.25 (br. s., 1 H) 12.45 (br. s., 1 H). LCMS (ES+) m/e 500 [M+H] ⁺ .

Example 59

-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin -4-yl)amino)phenyl)-3- methylbutanoic acid

methyl 3-methyl-2-(3-nitrophenyl)butanoate. To methyl 2-(3-nitrophenyl)acetate

(300 mg, 1.537 mmol) in Ν,Ν-Dimethylformamide was added potassium tert- butoxide (345 mg, 3.07 mmol), followed by 2-bromopropane (189 mg, 1.537 mmol). The reaction was kept stirring overnight, quenched with water and extracted with ethyl acetate. The organic layer was collected, dried over MgS0 ₄ , filtered, concentrated and purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 3-methyl-2-(3-nitrophenyl)butanoate

(185 mg, 0.780 mmol, 50.7 % yield) as a colorless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.75 (d, J=6.82 Hz, 3 H) 1 .08 (d, J=6.57 Hz, 3 H) 2.40 (m, 1 H) 3.32 (d, J=10.36 Hz, 1 H) 3.71 (s, 3 H) 7.52 (t, J=7.96 Hz, 1 H) 7.72 (d, J=7.83 Hz, 1 H) 8.1 1 - 8.19 (m, 1 H) 8.24 (t, J=1.89 Hz, 1 H). LCMS (ES+) m/e 238 [M+H] ⁺ .

2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinoli n-4-yl)ami

methylbutanoic acid. To a suspension of 10% palladium on carbon (81 mg, 0.076 mmol) in acetic acid (10 ml.) was added methyl 3-methyl-2-(3- nitrophenyl)butanoate (180 mg, 0.759 mmol). The mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro- 7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (235 mg, 0.683 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature, then the organic solvent was removed and the residue dissolved in methanol (10.00 ml_). Sodium hydroxide (6. ON) (0.126 ml_, 0.759 mmol) was added. The mixture was kept stirring overnight at 40 °C and was purified by reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water +

0.1 % trifluoroacetic acid) to afford 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)phenyl)-3-methylbutanoic acid, trifluoroacetic acid salt (45 mg, 0.073 mmol, 9.64 % yield) as a yellow solid.. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.68 (d, J=6.57 Hz, 3 H) 0.97 (d, J=6.32 Hz, 3 H) 2.09 - 2.24 (m, 1 H) 3.12 (d, J=10.36 Hz, 1 H) 3.98 (s, 3 H) 4.00 (s, 3 H) 7.25 - 7.35 (m, 3 H) 7.42 - 7.49 (m, 1

H) 7.67 (dd, J=9.09,1 .77 Hz, 1 H) 7.82 (d, J=9.09 Hz, 1 H) 7.98 (br. s., 1 H) 8.22 (d, J=1.52 Hz, 1 H) 8.47 (br. s., 1 H) 8.61 (s, 1 H) 9.07 (s, 1 H) 12.39 (br. s., 1 H).

Example 60

-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)-8-fluoroqui nolin-4-yl)amino)-5- cyclopentylbenzoic acid a) methyl 3-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)-8-fluoro

5-cyclopentylbenzoate. A mixture of methyl 3-((7-bromo-3-carbamoyl-8- fluoroquinolin-4-yl)amino)-5-cyclopentylbenzoate (220 mg, 0.452 mmol), bis(pinacolato)diboron (132 mg, 0.520 mmol), potassium acetate (155 mg, 1 .583 mmol), [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

dichloromethane adduct (18.47 mg, 0.023 mmol) and 1 ,4-dioxane (3 mL) was purged with nitrogen for 15 minutes, then heated at 1 10 °C for 30 minutes in a microwave reactor. 5-Bromo-2,4-dimethylpyrimidine (67.7 mg, 0.362 mmol), cesium carbonate (368 mg, 1.131 mmol), [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (18.47 mg, 0.023 mmol) and water (1 mL) were added. The mixture was purged again with nitrogen for 15 minutes, then heated in a microwave reactor at 1 10 °C for 30 min. After cooling, the mixture was filtered and then partitioned between ethyl acetate and brine. The combined organics were dried (Na ₂ S0 ₄ ), filtered, and concentrated to a brown residue. This residue was purified on silica gel (0-10% 2- propanol/ethyl acetate, then 10-30% 2-propanol/ethyl acetate) to afford a yellow solid. The solid was further purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to afford the title compound (135 mg, 58%) as a yellow solid. LCMS (ES+) m/e 514 [M+H] ⁺ .

b) 3-((3-carbamoyl-7-(2,4-dimethylpyrimidin-5-yl)-8-fluoroquino lin-4-yl)amino)-5- cyclopentylbenzoic acid. A mixture of methyl 3-((3-carbamoyl-7-(2,4- dimethylpyrimidin-5-yl)-8-fluoroquinolin-4-yl)amino)-5-cyclo pentylbenzoate (135 mg, 0.263 mmol), potassium hydroxide (200 mg, 3.56 mmol), tetrahydrofuran (2 mL) and methanol (1 mL) was stirred at 30 °C for 16 h. The solution was concentrated. 6M aqueous hydrochloric acid was added until a precipitate formed. The mixture was diluted with water, and the solid filtered to give the title compound (75 mg, 57%) as a yellow solid. LCMS (ES+) m/e 500 [M+H] ⁺ .

Example 61

methyl 1 -(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)phenyl)cvclopentanecarboxylate

a) methyl 1-(3-nitrophenyl)cvclopentanecarboxylate. To a solution of methyl 2-(3- nitrophenyl)acetate (300 mg, 1.537 mmol) and 1 ,4-dibromobutane (332 mg, 1 .537 mmol) in N,N-Dimethylformamide (10 ml.) was added sodium hydride (60% oil suspension, 61 .5 mg, 1.537 mmol). The reaction was kept stirring at room temperature overnight, 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 oil was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 1-(3- nitrophenyl)cyclopentanecarboxylate (235 mg, 0.943 mmol, 61 .3 % yield). LCMS (ES+) m/e 250 [M+H] ⁺ .

b) methyl 1-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 - yl)amino)phenyl)cvclopentanecarboxylate. To a suspension of 10% palladium on carbon (98 mg, 0.092 mmol) in acetic acid (10 ml.) was added methyl 1 -(3- nitrophenyl)cyclopentanecarboxylate (230 mg, 0.923 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours, then filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (286 mg, 0.830 mmol) was added to the filtrate. Then the reaction was kept stirring overnight and was quenched with water. The precipitate was collected, washed with ether and methanol to afford methyl 1-(3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)phenyl)cyclopent anecarboxylate (250 mg, 0.474 mmol, 51 .4 % yield) as a yellow solid. LCMS (ES+) m/e 528 [M+H] ⁺ . Example 62

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroquin olin-4-yl)amino)-5- isopropoxybenzoic acid

a) isopropyl 3-amino-5-isopropoxybenzoate. A solution of isopropyl 3-isopropoxy-5- nitrobenzoate (1 .7g, 6.36 mmol) in methanol (50 ml.) was stirred with 10% palladium-on-carbon (0.677 g, 0.636 mmol) under a balloon of hydrogen for 70 hours. The mixture was filtered and concentrated to afford the title compound

(1 .47 g, 97%). LCMS (ES+) m/e 238 [M+H] ⁺ .

b) isopropyl 3-((7-bromo-3-carbamoyl-8-fluoroquinolin-4-yl)amino)-5- isopropoxybenzoate. A mixture of 7-bromo-4-chloro-8-fluoroquinoline-3- carboxamide (975 mg, 2.345 mmol), isopropyl 3-amino-5-isopropoxybenzoate (0.422 ml_, 2.93 mmol) and acetic acid (20 ml.) was stirred at room temperature for 16 hours, then filtered. The filtrate was concentrated and the residue triturated with dichloromethane:ether:heptane (-2:1 :1 ) to afford one batch of the desired product. The washings were concentrated and purified on silica (0-10% 2- propanol/ethyl acetate, then 25% 2-propanol/ethyl acetate) to produce a second batch of the desired product. Both batches were combined to give the title compound (837 mg, 71 %). LCMS (ES+) m/e 504 [M+H] ⁺ .

c) isopropyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroquin olin-4- yl)amino)-5-isopropoxybenzoate. A mixture of isopropyl 3-((7-bromo-3-carbamoyl- 8-fluoroquinolin-4-yl)amino)-5-isopropoxybenzoate (215 mg, 0.418 mmol), (2,4- dimethoxypyrimidin-5-yl)boronic acid (0.069 ml_, 0.620 mmol), cesium carbonate (410 mg, 1.258 mmol), [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (30 mg, 0.037 mmol), 1 ,4-dioxane (2 ml.) and water (1 ml.) was heated in a microwave reactor at 1 10 °C for 30 min, then cooled. The mixture was filtered and then partitioned between ethyl acetate and brine. The combined organics were dried (Na ₂ S0 ₄ ), filtered, and concentrated. The residue was purified on silica gel (0-7% 2-propanol/ethyl acetate, then 30% 2- propanol/ethyl acetate) to afford the title compound (247 mg, 93% pure, 98%). LCMS (ES+) m/e 564 [M+H] ⁺ .

d) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)-8-fluoroquin olin-4-yl)amino)-5- isopropoxybenzoic acid. A mixture of isopropyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)-8-fluoroquinolin-4-yl)amino)-5-isop ropoxybenzoate (247 mg, 0.408 mmol), potassium hydroxide (200 mg, 3.56 mmol), tetrahydrofuran (2 mL) and methanol (1 mL) was stirred at 35 °C for 16 h. The solution was concentrated, then cooled to -78 °C and neutralized with trifluoroacetic acid. The mixture was purified twice by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia, then ODS, acetonitrile/water + 0.1 % trifluoroacetic acid). The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), filtered and concentrated to a yellow solid. The yellow solid was re-dried to afford the title compound (25 mg, 1 1 %). LCMS (ES+) m/e 522 [M+H] ⁺ .

Example 63

ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-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] ⁺ .

ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (phenylamino)benzoate. To a suspension of 10% palladium on carbon (33.5 mg, 0.031 mmol) in acetic acid (10 ml.) was added ethyl 3-nitro-5- (phenylamino)benzoate (90 mg, 0.314 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours, then filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (98 mg, 0.283 mmol) was added to the filtrate. The reaction was kept stirring overnight, then purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford ethyl 3-((3-carbamoyl-7- (2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(phenyla mino)benzoate, trifluoroacetic acid salt (75 mg, 0.1 1 1 mmol, 35.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.07 Hz, 3 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 4.30 (q, J=7.07 Hz, 2 H) 6.87 (t, J=7.33 Hz, 1 H) 7.03 (s, 1 H) 7.05 (s, 1 H) 7.08 (br. s., 1 H) 7.15 - 7.21 (m, 2 H) 7.24 (s, 1 H) 7.48 (br. s., 1 H) 7.83 - 7.91 (m, 2 H) 8.12 - 8.17 (m, 1 H) 8.22 (d, J=1 .77 Hz, 1 H) 8.30 (br. s., 1 H) 8.57 (br. s., 1 H) 8.65 (s, 1 H) 9.01 (s, 1 H). LCMS (ES+) m/e 565 [M+H] ⁺ .

Example 64

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidi^

(phenylamino)benzoic acid

To a suspension of methyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-(phenylamino)benzoate (50mg, 0.091 mmol) in methanol (10 mL) was added sodium hydroxide (6. ON) (0.076 mL, 0.454 mmol). The reaction mixture was kept stirring at room temperature overnight, then purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (phenylamino)benzoic acid, trifluoroacetic acid salt (36 mg, 0.055 mmol, 60.9 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.01 (s, 3 H) 6.88 (t, J=7.20 Hz, 1 H) 7.05 (s, 1 H) 7.07 (s, 1 H) 7.09 (br. s., 1 H) 7.16 - 7.24 (m, 3 H) 7.49 (s, 1 H) 7.83 - 7.92 (m, 2 H) 8.12 (d, J=9.09 Hz, 1 H) 8.22 (d,J=1.52 Hz, 1 H) 8.32 (br. s., 1 H) 8.54 (s, 1 H) 8.65 (s, 1 H) 9.01 (s, 1 H) 1 1 .70 (br. s., 1 H). LCMS (ES+) m/e 537 [M+H] ⁺ .

Example 65

3-((3-carbamoyl-6-(cvclohexylmethoxy)-7-(2,4-dimethoxypyrimi din-5-yl)quinolin-4- yl)amino)-5-cvclopentylbenzoic acid

a) 4-bromo-7-chloro-6-(cvclohexylmethoxy)quinoline-3-carboxamid e. 4-Bromo-7- chloro-6-hydroxyquinoline-3-carboxamide (1.5 g, 5.0 mmol),

(bromomethyl)cyclohexane (1 .32 g, 7.5 mmol) and potassium carbonate (1.38 g, 10 mmol) were dissolved in N,N-dimethylformamide (20 mL). The solution was heated to 50 °C and stirred for 15 h at this temperature. Water (100 mL) was added. The yellow precipitate was filtered, washed with water (10 mL x 3) and then ether (10 mL x 3) to give the title compound (1.3g) as a yellow solid. LCMS (ES+) m/e 397 [M+H] ⁺ . b) methyl 3-(3-carbamoyl-7-chloro-6-(cvclohexylmethoxy)quinolin-4-ylam ino)-5- cvclopentylbenzoate. 4-Bromo-7-chloro-6-(cyclohexylmethoxy)quinoline-3- carboxamide (1.1 g, 2.76 mmol) and methyl 3-amino-5-cyclopentylbenzoate were dissolved with ethanol (20 mL). The solution was heated to reflux and the mixture stirred overnight. After the starting material was consumed completely, the solvent was removed under reduced pressure. The crude product was purified by chromatography (silica gel, 0.5-2% methanol/dichloromethane) to afford the title compound (760 mg, 51.3%) as solid. LCMS (ES+) m/e 536 [M+H] ⁺ .

c) methyl 3-(3-carbamoyl-6-(cvclohexylmethoxy)-7-(2,4-dimethoxypyrimid in-5- yl)quinolin-4-ylamino)-5-cvclopentylbenzoate. Methyl 3-(3-carbamoyl-7-chloro-6- (cyclohexylmethoxy)quinolin-4-ylamino)-5-cyclopentylbenzoate (750 mg, 1.4 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (527 mg, 2.8 mmol), and sodium bicarbonate (2.8 mmol, 235 mg) were dissolved in 1 ,4- dioxane:water = 4:1 (20 mL). After degassing with nitrogen, tetrakis(triphenylphosphine)palladium(0) (161 mg, 0.14 mmol) was added. The solution was heated to 80 °C and stirred for about 3 h, then more 2,4-dimethoxypyrimidin-5-ylboronic acid (527 mg, 2.8 mmol) was added. The solution was stirred overnight at 80 °C. The solvent was evaporated under reduced pressure. The crude product was purified by chromatography (silica gel and eluted with 1 -5% methanol/dichloromethane) to afford the title compound (500 mg, 55%). LCMS (ES+) m/e 640 [M+H] ⁺ .

d) 3-(3-carbamoyl-6-(cvclohexylmethoxy)-7-(2,4-dimethoxypyrimid in-5-yl)quinolin-4- ylamino)-5-cvclopentylbenzoic acid. Methyl 3-(3-carbamoyl-6- (cyclohexylmethoxy)-7-(2,4-dimethoxypyrimidin-5-yl)quinolin- 4-ylamino)-5- cyclopentylbenzoate(100 mg, 0.156 mmol) was dissolved in methanol (60 mL). Aqueous sodium hydroxide (2. ON, 30 mL) was added. The mixture was stirred for 5 h at room temperature. The pH was adjusted to about 3-4 by the addition of formic acid. The solvent was removed. The solid was filtered and washed with water (10 mL x 3) then acetone (5.0 mL x 3) to give the title compound (45 mg, 46%). ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.72-1.74 (m, 17 H), 1.93-2.02 (m, 2 H), 2.92-3.02 (m, 1 H), 3.34 (d, J=4.2 Hz, 2 H), 3.85 (s, 3 H), 3.95 (s, 3 H), 7.03 (s, 1 H), 7.07 (s, 1 H), 7.35 (s, 1 H), 7.50 (s, 1 H), 7.67 (s, 1 H), 7.80 (s, 1 H), 8.25 (s, br, 1 H), 8.30 (s, 1 H), 8.35 (s, br, 1 H), 8.88 (s, 1 H), 10.45 (s, br, 1 H). LCMS (ES+) m/e 626 [M+H] ⁺ . Example 66

ethyl 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-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-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl )amino)-5-((3- fluorophenyl )amino)benzoate. To a suspension of 10% palladium on carbon (35.0 mg, 0.033 mmol) in acetic acid (10 ml.) was added ethyl 3-((3- fluorophenyl)amino)-5-nitrobenzoate (100 mg, 0.329 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonam ide (1 13 mg, 0.296 mmol) was added to the filtrate. The reaction was kept stirring overnight and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford ethyl 3-((7-(2,4- dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino)-5-( (3- fluorophenyl)amino)benzoate, trifluoroacetic acid salt (90mg, 0.123 mmol, 37.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.20 Hz, 3 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 4.30 (q, J=7.07 Hz, 2 H) 6.49 - 6.61 (m, 3 H) 6.69 (s, 1 H) 6.96 - 7.05 (m, 1 H) 7.23 (s, 1 H) 7.31 (s, 1 H) 7.76 - 7.92 (m, 4 H) 8.28 (s, 1 H) 8.50 (br. s., 1 H) 8.60 (s, 1 H) 8.65 (s, 1 H) 9.12 (s, 1 H). LCMS (ES+) m/e

619 [M+H] ⁺ .

Example 67

ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- fluorophenyl)amino)benzoate

To a suspension of 10% palladium on carbon (35.0 mg, 0.033 mmol) in acetic acid (10 mL) was added ethyl 3-((3-fluorophenyl)amino)-5-nitrobenzoate (100 mg, 0.329 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (102 mg, 0.296 mmol) was added to the filtrate. Then the reaction was kept stirring overnight and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford ethyl 3-((3-carbamoyl- 7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3-fl uorophenyl)amino)benzoate, trifluoroacetic acid salt (120 mg, 0.172 mmol, 52.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.07 Hz, 3 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 4.31 (q, J=7.07 Hz,2 H) 6.65 (td, J=8.46, 2.27 Hz, 1 H) 6.80 - 6.90 (m, 2 H) 7.21 (q, J=7.92 Hz, 1 H) 7.27 (br. s., 1 H) 7.34 (s, 1 H) 7.54 (s, 1 H) 7.86 (br. s., 1 H) 7.91 (dd, J=8.97, 1 .39 Hz, 1 H) 8.23 (d, J=8.84 Hz, 1 H) 8.28 (d, J=1.52 Hz,1 H) 8.33 (br. s., 1 H) 8.65 (s, 1 H) 8.86 (br. s., 1 H) 9.04 (s, 1 H) 1 1 .89 (br. s., 1 H). LCMS (ES+) m/e 583 [M+H] ⁺ . Example 68

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

To a suspension of ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin- 4-yl)amino)-5-((3-fluorophenyl)amino)benzoate (100 mg, 0.172 mmol) in methanol (10 mL) was added sodium hydroxide (6.0 N in water) (0.032 mL, 0.191 mmol). The reaction mixture was kept stirring at room temerature overnight, then acidified. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )-5-((3- fluorophenyl)amino)benzoic acid (66 mg, 0.1 19 mmol, 62.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) ppm 3.97 (s, 6 H) 6.49 (td, J=8.53, 2.40 Hz, 1 H) 6.59 - 6.66 (m, 2 H) 6.67 -6.73 (m, 1 H) 6.99 - 7.09 (m, 2 H) 7.38 (s, 1 H) 7.60 (dd, J=8.84, 1.77 Hz, 1 H) 7.76 (br. s., 1 H) 7.85 (d, J=8.84 Hz, 1 H) 8.13 (d, J=1.77 Hz, 1 H) 8.37 (br. s., 2 H) 8.56 (s, 1 H) 9.05 (s, 1 H) 10.68 (s, 1 H). LCMS (ES+) m/e 555 [M+H] ⁺ .

Example 69

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cyclopentylthio)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 ) : 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-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclopentylthio)benzoic acid. 3-amino-5-(cyclopentylthio)benzoic acid (20.65 mg, 0.087 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-carboxamide (20 mg, 0.058 mmol) in acetic acid (2 mL) at 55°C. The reaction was stirred for 10 hours and then purified by reverse-phase preparative HPLC (10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cyclopentylthio)benzoic acid (5 mg, 8.89 μηηοΙ, 15.32 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) : 1 1.71 (br. s., 1 H), 8.99 (s, 1 H), 8.66 (s, 1 H), 8.18 - 8.36 (m, 4H), 7.92 (dd, J = 9.0, 1 .6 Hz, 1 H), 7.82 (br. s., 1 H), 7.71 (s, 1 H), 7.64 (s, 1 H), 7.45 (s, 1 H), 4.02 (s, 3H), 4.00 (s, 3H), 2.02 (dd, J = 12.1 , 6.6 Hz, 2H), 1.63 - 1.73 (m, 2H), 1 .41 - 1 .61 (m, 4H). Example 70

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (isopropylamino)benzoic acid

a) ethyl 3-(isopropylamino)-5-nitrobenzoate. A mixture of ethyl 3-bromo-5- nitrobenzoate (1 .37 g, 5.00 mmol), isopropylamine (0.591 g, 10.0 mmol), cesium carbonate (2.44 g, 7.50 mmol), palladium(ll) acetate (0.056 g, 0.250 mmol), bis(tri- t-butylphosphine)palladium(O) (0.128 g, 0.250 mmol) and 1 ,4-dioxane (10 mL) was stirred at 140 °C in a microwave reactor for 0.5 h, then cooled. Dichloromethane was added and the mixture filtered through a plug of Hyflo®. The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 5- 20% ethyl acetate/hexane) to give the title compound (0.314 g, 25%) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) ppm 1 .28 (d, J=6.32 Hz, 6 H) 1 .43 (t, J=7.07 Hz, 3 H) 3.69 - 3.82 (m, 1 H) 4.01 (d, J=7.33 Hz, 1 H) 4.42 (q, J=7.24 Hz, 2 H) 7.50 - 7.56 (m, 2 H) 8.1 1 (dd, J=2.02, 1.52 Hz, 1 H).

b) ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (isopropylamino)benzoate. A solution of ethyl 3-(isopropylamino)-5-nitrobenzoate (0.185 g, 0.733 mmol) in methanol (10 mL) was stirred with 5% wet palladium on carbon (0.150 g, 0.035 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 intermediate aniline. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (0.088 g, 0.256 mmol) was added to a solution of the aniline (0.071 g, 0.319 mmol) in acetic acid (3 mL) and the mixture stirred at 50 °C for 18 h, then cooled. The acetic acid was removed under reduced pressure and the residue chromatographed twice (silica gel, 2-10% methanol/dichloromethane, then 2-8% methanol/dichloromethane) to give the title compound (0.060 g, , 44%) as a gum. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 1.04 (d, J=6.32 Hz, 6 H) 1.26 (t, J=7.07 Hz, 3 H) 3.36 - 3.46 (m, 1 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 4.23 (q, J=7.24 Hz, 2 H) 5.81 (d, J=7.83 Hz, 1 H) 6.34 (t, J=1.89 Hz, 1 H) 6.74 (s, 1 H) 6.89 (s, 1 H) 7.59 (dd, J=8.84, 1 .77 Hz, 1 H) 7.75 (br. s., 1 H) 7.81 (d, J=8.84 Hz, 1 H) 8.13 (d, J=1.77 Hz, 1 H) 8.32 (br. s., 1 H) 8.55 (s, 1 H) 9.04 (s, 1 H) 10.54 (s, 1 H).

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

(isopropylamino)benzoic acid. 1 M aqueous sodium hydroxide (1 .50 ml_, 1 .50 mmol) was added to a stirred slurry of ethyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(isopropylami no)benzoate (0.057 g, 0.107 mmol) in ethanol (8 ml.) and the mixture stirred at room temperature for 18 h. Water (20 ml.) was added. The pH was adjusted to 5 with 1 M aqueous hydrochloric acid. The mixture was stirred 1 h and the precipitate filtered off, washed with water and dried (42 mg). The solid was purified by reverse-phase preparative HPLC (ODS, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid). The product was reprecipitated at pH 5 as above, filtered, washed with water and dried to give the title compound (0.024 g, 45%) as an orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 1 .06 (d, J=6.32 Hz, 6 H) 3.41 - 3.46 (m, 1 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 5.71 (d, J=7.83 Hz, 1 H) 6.36 (s, 1 H) 6.68 (s, 1 H) 6.88 (s, 1 H) 7.58 (dd, J=8.84, 1.77 Hz, 1 H) 7.76 (br. s., 1 H) 7.80 (d, J=8.84 Hz, 1 H) 8.12 (d, J=1.52 Hz, 1 H) 8.34 (br. s., 1 H) 8.56 (s, 1 H) 9.05 (s, 1 H) 10.58 (s, 1 H) 12.66 (br. s., 1 H).

Example 71

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(4- fluorophenoxy)benzoic acid a) methyl 3-(4-fluorophenoxy)-5-nitrobenzoate. Anhydrous copper(ll) acetate (0.138 g, 0.761 mmol) was added to a stirred mixture of 4-fluorophenylboronic acid (0.319 g, 2.28 mmol), methyl 3-hydroxy-5-nitrobenzoate (0.150 g, 0.761 mmol), triethylamine (0.742 mL, 5.53 mmol), dichloromethane (8 mL) and 4A molecular sieves (2 g). The mixture was stirred at room temperature under oxygen for 18 h, then 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 (0.153 g, 69%) as a gum. ¹ H NMR (400 MHz, CHLOROFORM-d) ppm 3.99 (s, 3 H) 7.04 - 7.12 (m, 2 H) 7.1 1 - 7.21 (m, 2 H) 7.92 - 7.94 (m, 1 H) 7.94 - 7.97 (m, 1 H) 8.58 (dd, J=2.02, 1 .52 Hz, 1 H). b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(4- fluorophenoxy)benzoic acid. A solution of methyl 3-(4-fluorophenoxy)-5- nitrobenzoate (0.153 g, 0.525 mmol) in methanol (10 mL) was stirred with 5% wet palladium on carbon (0.150 g, 0.035 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 intermediate aniline. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (0.063 g, 0.184 mmol) was added to a solution of the aniline (0.060 g, 0.230 mmol) in acetic acid (2 mL) and the mixture 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 ester intermediate (0.083 g). 1 M aqueous sodium hydroxide (2.50 mL, 2.50 mmol) was added dropwise to a stirred suspension of the ester in methanol (10 mL) at room temperature. 1 ,4-Dioxane (8 mL) was added 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 (0.061 g, 60%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 3.99 (s, 3 H) 4.01 (s, 3 H) 6.81 (br. s., 1 H) 7.06 (s, 1 H) 7.08 - 7.15 (m, 2 H) 7.15 - 7.23 (m, 2 H) 7.32 (s, 1 H) 7.69 - 7.81 (m, 2 H) 8.00 (d, J=8.84 Hz, 1 H) 8.18 (d, J=1.52 Hz, 1 H) 8.25 (br. s., 1 H) 8.61 (s, 1 H) 8.99 (s, 1 H) 10.43 (br. s., 1 H) 13.15 (br. s., 1 H). Example 72

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl )amino)-5-((3- fluorophenyl)amino)benzoic acid

To a suspension of ethyl 3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4- yl)amino)-5-((3-fluorophenyl)amino)benzoate (70 mg, 0.1 13 mmol) in methanol (10 mL) was added sodium hydroxide (6. ON) (0.105 mL, 0.629 mmol). The reaction mixture was kept stirring at room temperature overnight and acidified afterwards. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-((7-(2,4- dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino)-5-( (3- fluorophenyl)amino)benzoic acid (56 mg, 0.095 mmol, 75 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 3 H) 3.97 (s, 3 H) 6.46 (td, J=8.46, 2.02 Hz, 1 H) 6.52 - 6.58 (m, 2 H) 6.61 (d, J=8.08 Hz, 1 H) 6.99 (q, J=8.08 Hz, 1 H) 7.25 (s, 1 H) 7.37 (s, 1 H) 7.67 (dd, J=8.97, 1.64Hz, 1 H) 7.83 (d, J=8.84 Hz, 1 H) 8.04 (br. s., 1 H) 8.20 (d, J=1.52 Hz, 1 H) 8.41 (s, 1 H) 8.58 (s, 1 H) 9.05 (s, 1 H). LCMS (ES+) m/e 591 [M+H] ⁺ .

Example 73

3-(sec-butylthio)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)benzoic acid a) 3-amino-5-(sec-butylthio)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 (662 mg, 2.032 mmol), and 2-butanethiol (0.176 mL, 1 .626 mmol) were then added and the vial irradiated in a microwave reactor for 25 min at 125°C. Purification by reverse-phase preparative HPLC (10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) gave 3- nitro-5-(sec-butylthio)benzoic acid (80 mg, 37.6 % yield) in 86% purity. LCMS (ES+) m/z 256 [M+H] ⁺ . The crude nitro intermediate was then dissolved in methanol (5 mL). 5% Palladium-on-charcoal (87 mg, 0.040 mmol) was added and the flask purged with hydrogen gas. The reaction was stirred for 2 hours, flushed with nitrogen, and filtered through an acrodisc. The solvent was removed to give 3- amino-5-(sec-butylthio)benzoic acid (34 mg, 0.091 mmol, 1 1 .14 % yield). LCMS (ES+) m/z 226 [M+H] ⁺ . The material was taken directly to the next step.

b) 3-(sec-butylthio)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin- 5-yl)quinolin-4- yl)amino)benzoic acid. 3-amino-5-(sec-butylthio)benzoic acid (34.3 mg, 0.152 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-carboxamide (35 mg, 0.102 mmol) in acetic acid (5 mL) at room temperature. The reaction was stirred for 48 hours, the precipitate filtered and washed with methanol. The eluent was collected and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10-90%

acetonitrile/water + 0.1 %trifluoroacetic acid) to give 3-(sec-butylthio)-5-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )benzoic acid (17 mg, 0.031 mmol, 30.8 % yield) as a pale yellow solid. ¹ H NMR (METHANOL-d ₄ )

: 8.97 (s, 1 H), 8.56 (s, 1 H), 8.20 (d, J = 1 .8 Hz, 1 H), 8.1 1 (d, J = 9.1 Hz, 1 H), 7.98 (t, J = 1 .5 Hz, 1 H), 7.81 - 7.88 (m, 2H), 7.56 (t, J = 1 .9 Hz, 1 H), 4.14 (s, 3H), 4.10 (s, 3H), 2.68 (s, 1 H), 1.49 - 1.77 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1 .02 (t, J = 7.3 Hz, 3H). Example 74

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)-5-(propy

acid

a) 3-amino-5-(propylthio)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 (662 mg, 2.032 mmol), and 1 -propanediol (0.147 ml_, 1 .626 mmol) were then added and the vial irradiated in a microwave reactor for 25 min at 125°C. The reaction was purifed by reverse-phase preparative HPLC (10-90% acetonitrile/water) to give 3-nitro-5- (propylthio)benzoic acid as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) : 13.83 (br. s., 1 H), 8.31 - 8.38 (m, 1 H), 8.26 (t, J = 2.0 Hz, 1 H), 8.14 (t, J = 1 .5 Hz, 1 H), 3.15 (t, J = 7.1 Hz, 2H), 1.66 (sxt, 2H), 1.01 (t, 3H). The material was then dissolved in methanol, the atmosphere purged with nitrogen gas, and 10% palladium-on- charcoal (43.3 mg, 0.041 mmol) added. The flask was then purged with hydrogen and stirred at room temperature for 3 h. The solution was filtered through an acrodisc syringe filter and concentrated to give 3-amino-5-(propylthio)benzoic acid (30 mg, 50% pure, 8.73 %) as a light brown residue. LCMS (ES+) m/z 212

[M+H] ⁺ . This material was taken directly to the next step without further purification.

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (propylthio)benzoic acid. 3-amino-5-(propylthio)benzoic acid (30.6 mg, 50% pure, 0.072 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-carboxamide (25 mg, 0.073 mmol) in acetic acid (5 ml.) at room temperature. The reaction was stirred for 48 hours, then the precipitate filtered off, and washed with methanol. The filtrate was collected and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10-90%

acetonitrile/water + 0.1 %trifluoroacetic acid) to give 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(propylthio)b enzoic acid (4 mg, 7.31 mol, 10.09 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) : 13.31 (br, s, 1 H), 1 1 .4 (br, s, 11-1)8.99 (s, 1 H), 8.65 (s, 1 H), 8.23 - 8.35 (m, 2H), 8.18 (d, J = 8.8 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.79 (br. s., 1 H), 7.64 (s, 1 H), 7.56 (s, 1 H), 7.39 (s, 1 H), 4.02 (s, 3H), 4.00 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 1 .51 - 1 .64 (m, 2H), 0.93 (t, 3H).

Example 75

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((2,6- difluorophenyl)amino)benzoic acid

a) ethyl 3-((2,6-difluorophenyl)amino)-5-nitrobenzoate. To a mixture of 2,6- difluoroaniline (236 mg, 1.824 mmol), ethyl 3-bromo-5-nitrobenzoate (500 mg, 1.824 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (87 mg, 0.182 mmol), cesium carbonate (892 mg, 2.74 mmol), ferf-butanol (1 mL) and toluene (5.00 mL) was added palladium(ll) acetate (20.48 mg, 0.091 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-((2,6-difluorophenyl)amino)-5- nitrobenzoate (320 mg, 0.993 mmol, 54.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 .33 (t, J=7.07 Hz, 3 H) 4.35 (q, J=7.07 Hz, 2 H) 7.24 - 7.40 (m, 3 H) 7.63 (s, 2 H) 7.99 - 8.03 (m, 1 H) 8.88 (s, 1 H). LCMS (ES+) m/e 323 [M+H] ⁺ .

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((2,6- difluorophenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (33.0 mg, 0.031 mmol) in acetic acid (10 ml.) was added ethyl 3-((2,6- 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (96 mg, 0.279 mmol) was added to the filtrate and the mixture was kept stirring at room temperature. Then organic solvent was removed under reduced pressure. The residue was dissolved in methanol (10.00 ml.) and sodium hydroxide (6.0 N) (0.259 ml_, 1 .552 mmol) was added. The reaction was kept stirring overnight and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )-5-((2,6- difluorophenyl)amino)benzoic acid, trifluoroacetic acid salt (122 mg, 0.178 mmol, 57.3 % yield) as a grey solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3 H) 3.99 (s, 3 H) 6.39 (s, 1 H) 6.87 (s, 1 H) 6.95 (s, 1 H) 7.04 -7.21 (m, 3 H) 7.52 (dd, J=8.97, 1 .89 Hz, 1 H) 7.70 - 7.81 (m, 3 H) 8.09 (d, J=2.02 Hz, 1 H) 8.39 (br. s., 1 H) 8.55 (s, 1 H) 9.05 (s, 1 H) 10.74 (s, 1 H). LCMS (ES+) m/e 573 [M+H] ⁺ .

Example 76

3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4- yl)amino)benzoic acid

A mixture of methyl 3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoate (next example, 60 mg, 0.106 mmol), sodium hydroxide (6M, 0.020 ml_, 0.1 18 mmol) and methanol (10 mL) was stirred at room temperature overnight. The reaction was acidified, and the precipitate was collected, washed with water and dried under reduced pressure to afford 3-(benzylamino)-5-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)benzoic acid (25 mg, 0.045 mmol, 38.5 % yield) as a yellow solid. LCMS (ES+) m/e 551 [M+H] ⁺ . Example 77

methyl 3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4 yl)amino)benzoate

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) methyl 3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4- yl)amino)benzoate. 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-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-carboxamide (98 mg, 0.283 mmol) was added to the filtrate. The reaction was kept stirring overnight and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford methyl 3-(benzylamino)-5-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoate, trifluoroacetic acid salt (75 mg, 0.1 1 1 mmol, 35.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (s, 3 H) 3.99 (s, 3 H) 4.02 (s, 3 H) 4.29 (s, 2 H) 6.74 (s, 1 H) 6.84 (br. s., 1 H) 6.99 (s, 1 H) 7.13

- 7.20 (m, 2 H) 7.24 - 7.35 (m, 4 H) 7.74 (dd, J=8.97, 1 .39 Hz, 1 H) 7.89 - 7.98(m, 2 H) 8.19 (d, J=1 .52 Hz, 1 H) 8.37 (br. s., 1 H) 8.63 (s, 1 H) 9.02 (s, 1 H) 1 1 .97 (br. s., 1 H). LCMS (ES+) m/e 565 [M+H] ⁺ .

Example 78

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexylthio)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 reverse-phase preparative HPLC (10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the intermediate nitro compound. ¹ H NMR (DMSO-d ₆ ) : 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-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5- (cvclohexylthio)benzoic acid. 3-amino-5-(cyclohexylthio)benzoic acid (52.5 mg, 0.209 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin- 5-yl)quinoline-3-carboxamide (48 mg, 0.139 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 purfied by reverse-phase preparative HPLC (10-95% acetonitrile/water +

0.1 %trifluoroacetic acid) to give 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-(cyclohexylthio)benzoic acid (33 mg, 0.057 mmol, 40.7 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) : 1 1.83 (br. s., 1 H), 9.01 (s, 1 H), 8.65 (s, 1 H), 8.26 - 8.39 (m, 2H), 8.20 (d, J = 9.1 Hz, 1 H), 7.90 (dd, J = 9.1 , 1.8 Hz, 1 H), 7.83 (br. s., 1 H), 7.72 (d, J = 15.4 Hz, 2H), 7.44 - 7.59 (m, 1 H), 4.02 (s, 3H), 3.99 (s, 3H), 3.23 - 3.38 (m, 1 H), 1.84 - 1.96 (m, 2H), 1 .64 (d, J = 5.1 Hz, 2H), 1 .45 - 1 .57 (m, 1 H), 1 .1 1 - 1 .36 (m, 5H).

Example 79

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)-5-(ethylthio)benzoic acid

a) 3-amino-5-(ethylthio)benzoic acid. (R)-1 -[(S _P )-2-

(Dicyclohexylphosphino)ferrocenyl]ethyldi-ferf-butylphosp hine (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 ethanethiol (0.078 ml_, 1.057 mmol) were then added and the vial capped. The reaction was conducted in a microwave reactor for 25 min at 125°C. The reaction was then filtered, and the filtrate concentrated before being purified by reverse-phase preparative HPLC (10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the intermediate nitro compound. ¹ H NMR (DMSO-d ₆ ) : 13.84 (br. s., 1 H), 8.32 - 8.37 (m, 1 H), 8.26 (t, J = 1 .9 Hz, 1 H), 8.13 (t, J = 1 .6 Hz, 1 H), 3.18

(q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.3 Hz, 3H). This intermediate was dissolved in methanol (4 mL) and 5% palladium-on-charcoal (87 mg, 0.040 mmol) added under nitrogen. 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- (ethylthio)benzoic acid (46 mg, 0.163 mmol, 20.08 % yield). LCMS (ES+) m/z 198 [M+H] ⁺ . No purification was performed and the compound was taken directly to the next step.

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-

(ethylthio)benzoic acid. 3-amino-5-(ethylthio)benzoic acid (46.1 mg, 0.234 mmol) was added to a stirred solution of 4-chloro-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-carboxamide (50 mg, 0.145 mmol) in acetic acid (5 mL) at room temperature. The reaction was stirred for 48 hours, the precipitate filtered and washed with methanol. The filtrate was evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC (10-90% acetonitrile/water +

0.1 %trifluoroacetic acid) to give 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-(ethylthio)benzoic acid (28 mg, 0.053 mmol, 36.7 % yield) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) : 1 1.78 (br. s., 1 H), 8.97 (s, 1 H), 8.64 (s, 1 H), 8.22 - 8.38 (m, 3H), 7.92 (dd, J = 9.1 , 1 .5 Hz, 1 H), 7.78 (s, 1 H), 7.67 - 7.73 (m, 1 H), 7.64 (t, J = 1 .8 Hz, 1 H), 7.46 (t, J = 1.9 Hz, 1 H), 4.02 (s, 3H), 3.98 (s, 3H), 3.02 (q, J = 7.3 Hz, 2H), 1 .23 (t, J = 7.3 Hz, 3H).

Example 80

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((2- 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] ⁺ .

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5-((2- fluorophenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (49.0 mg, 0.046 mmol) in acetic acid (10 ml.) was added methyl 3-((2- fluorophenyl)amino)-5-nitrobenzoate (140 mg, 0.460 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (143 mg, 0.414 mmol) was added to the filtrate. The reaction was kept stirring overnight and was concentrated under reduced pressure. The resulting brown oil was dissolved in methanol (10.00 ml_), to which sodium hydroxide (6. ON) (0.384 ml_, 2.301 mmol) was added. The mixture was kept stirring at room temperature for two hours and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )-5-((2- fluorophenyl)amino)benzoic acid (135 mg, 0.243 mmol, 52.9 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.01 (s, 3 H) 6.96 - 7.07 (m, 3 H) 7.18 - 7.32 (m, 3 H) 7.43(s, 1 H) 7.82 - 7.90 (m, 2 H) 8.09 (d, J=9.09 Hz, 1 H) 8.22 (d, J=1 .52 Hz, 1 H) 8.34 (br. s., 2 H) 8.64 (s, 1 H) 9.01 (s, 1 H) 1 1 .72 (br. s., 1 H). LCMS (ES+) m/e 555 [M+H] ⁺ .

Example 81

3-((3-carbamoyl-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-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((4- fluorophenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (38.5 mg, 0.036 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (1 12 mg, 0.325 mmol) was added to the filtrate. The reaction was kept stirring overnight and was concentrated under reduced pressure. The resulting brown oil was dissolved in methanol (10.00 mL), to which sodium hydroxide (6. ON) (0.384 mL, 2.301 mmol) was added. The mixture was kept stirring at room temperature for two hours and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )-5-((4- fluorophenyl)amino)benzoic acid, trifluoroacetic acid salt (95 mg, 0.142 mmol, 39.3 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.01 (s, 3 H) 7.01 - 7.14 (m, 5 H) 7.20 (s, 1 H) 7.44 (s, 1 H) 7.85 - 7.90 (m, 2 H) 8.13 (d, J=9.09 Hz, 1 H) 8.22 (d, J=1 .52 Hz, 1 H) 8.31 (br. s., 1 H) 8.50 (br. s., 1 H) 8.65 (s, 1 H) 9.01 (s, 1 H) 1 1.80 (br. s., 1 H) 13.06 (br. s., 1 H). LCMS (ES+) m/e 555

[M+H] ⁺ .

Example 82

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- hvdroxyphenyl)amino)benzoic acid

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] ⁺ . b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amin

hvdroxyphenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (26.4 mg, 0.025 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (77 mg, 0.223 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight and organic solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (10.00 mL), to which sodium hydroxide (6.0 N) (0.207 mL, 1.241 mmol) was added. The mixture was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- hydroxyphenyl)amino)benzoic acid, trifluoroacetic acid salt (80 mg, 0.120 mmol, 48.4 % yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.01 (s, 3 H) 6.26 - 6.34 (m, 1 H) 6.48 - 6.54 (m, 2 H) 6.97 (t, J=8.34 Hz, 1 H) 7.09 (br. s., 1 H) 7.17 (s, 1 H) 7.50 (s, 1 H) 7.82 - 7.92 (m, 2 H) 8.09 (d, J=8.84 Hz, 1 H) 8.22 (d, J=1 .77 Hz, 1 H) 8.33 (br. s., 1 H) 8.43 (br. s., 1 H) 8.64 (s, 1 H) 9.02 (s, 1 H) 9.32 (br. s., 1 H) 1 1 .74 (br. s., 1 H) 12.99 (br. s., 1 H). LCMS (ES+) m/e 553 [M+H] ⁺ .

Example 83

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- carboxyphenyl)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] ⁺ .

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5-((3- carboxyphenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (22.27 mg, 0.0209 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (64.9 mg, 0.188 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 (6.0 N) (0.174 ml_, 1 .046 mmol) was added. The reaction was kept stirring overnight at 40 °C and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-((3-carboxyphenyl)amino)benzoic acid, trifluoroacetic acid salt (35 mg, 0.050 mmol, 24.08 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.00 (s, 3 H) 7.01 (br. s., 1 H) 7.17 (s, 1 H) 7.21 - 7.29 (m, 2 H) 7.38 - 7.47 (m, 2 H) 7.62 (s, 1 H) 7.77 - 7.86 (m, 2 H) 8.06 (d, J=8.59 Hz, 1 H) 8.20 (s, 1 H) 8.29 (br. s., 1 H) 8.63 (s, 1 H) 8.66 (br. s., 1 H) 9.02 (s, 1 H) 1 1 .17 (br. s., 1 H) 12.89 (br. s., 1 H). LCMS (ES+) m/e 581 [M+H] ⁺ . Example 84

-((3,5-difluorophenyl)amino)-5-((7-(2,4-dimethoxypyrimidi n-5-yl)-3-sulfamoylquin

yl)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-((3,5-difluorophenyl)amino)-5-((7-(2,4-dimethoxypyrimidin- 5-yl)-3- sulfamoylquinolin-4-yl)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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- sulfonamide (1 1 1 mg, 0.292 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature, then the organic solvent was removed under reduced pressure. The residue was dissolved in methanol (10.00 mL), to which sodium hydroxide (6.0 N) (0.054 mL, 0.324 mmol) was added. The mixture was kept stirring overnight and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3,5-difluorophenyl)amino)-5-((7-(2,4-dimethoxypyrimidin- 5-yl)-3- sulfamoylquinolin-4-yl)amino)benzoic acid, trifluoroacetic acid salt (85 mg, 0.1 18 mmol, 36.3 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 3.98 (s, 6 H) 6.38 - 6.48 (m, 2 H) 6.49 - 6.56 (m, 1 H) 6.84 (s, 1 H) 7.24 (s, 1 H) 7.35 (s, 1 H) 7.76 - 7.85 (m, 2 H) 7.87 - 7.96 (m, 2 H) 8.28 (d, J=1.01 Hz, 1 H) 8.54 - 8.62 (m, 2 H) 8.86 (s, 1 H) 9.14 (s, 1 H) 13.08 (br. s., 1 H). LCMS (ES+) m/e 609

[M+H] ⁺ .

Example 85

ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3,5- difluorophenyl)amino)benzoate

To a suspension of 10% palladium on carbon (33.0 mg, 0.0310 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (96 mg, 0.279 mmol) was added to the filtrate. The reaction was kept stirring overnight and the precipitate was collected, washed with ether and dried under reduced pressure to afford ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin- 4-yl)amino)-5-((3,5-difluorophenyl)amino)benzoate (85 mg, 0.142 mmol, 45.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.20 Hz, 3 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 4.32 (q, J=7.24 Hz, 2 H) 6.55 - 6.64 (m, 1 H) 6.64 - 6.73 (m, 2 H) 7.37 (s, 1 H) 7.42 (s, 1 H) 7.56 (s, 1 H) 7.84 (br. s., 1 H) 7.92 (dd, J=8.97, 1.64 Hz, 1 H) 8.28 (d, J=9.09 Hz, 1 H) 8.34 (d, J=1 .77 Hz, 1 H) 8.38 (br. s., 1 H) 8.64 (s, 1 H) 9.07 (s, 1 H) 9.14 (s, 1 H) 1 1 .99 (br. s., 1 H). LCMS (ES+) m/e 601 [M+H] ⁺ . Example 86

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

a) ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3,5- difluorophenyl)amino)benzoate. To a suspension of 10% palladium on carbon (33.0 mg, 0.031 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (96 mg, 0.279 mmol) was added to the filtrate. The reaction was kept stirring overnight and the precipitate was collected, washed with ether and dried under reduced pressure to afford ethyl 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3,5- difluorophenyl)amino)benzoate (85 mg, 0.142 mmol, 45.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.20 Hz, 3 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 4.32 (q, J=7.24 Hz, 2 H) 6.55 - 6.64 (m, 1 H) 6.64 - 6.73 (m, 2 H) 7.37 (s, 1 H) 7.42 (s, 1 H) 7.56 (s, 1 H) 7.84 (br. s., 1 H) 7.92 (dd, J=8.97, 1.64 Hz, 1 H)

8.28 (d, J=9.09 Hz, 1 H) 8.34 (d, J=1 .77 Hz, 1 H) 8.38 (br. s., 1 H) 8.64 (s, 1 H) 9.07 (s, 1 H) 9.14 (s, 1 H) 1 1 .99 (br. s., 1 H). LCMS (ES+) m/e 601 [M+H] ⁺ .

b) 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3,5- difluorophenyl)amino)benzoic acid. To a suspension of ethyl 3-((3-carbamoyl-7- (2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3,5- difluorophenyl)amino)benzoate (70 mg, 0.1 17 mmol) in methanol (10 mL) was added sodium hydroxide (6. ON) (0.108 mL, 0.648 mmol). The reaction was kept stirring overnight, then acidified to pH 6.0. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3,5-difluor ophenyl)am

acid (45 mg, 0.079 mmol, 60.7 % yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 6 H) 6.37 - 6.52 (m, 3 H) 6.65 (br. s., 1 H) 7.16 (s, 1 H) 7.40 (br. s., 1 H) 7.59 (br. s., 1 H) 7.75 (br. s., 1 H) 7.83 (d, J=8.59 Hz, 1 H) 8.12 (s, 1 H) 8.39 (br. s., 1 H) 8.54 (s, 1 H) 8.67 (s, 1 H) 9.05 (s, 1 H) 10.68 (br. s., 1 H). LCMS (ES+) m/e 573 [M+H] ⁺ .

Example 87

ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- (trifluoromethyl)phenyl)amino)benzoate

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) ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- (trifluoromethyl)phenyl)amino)benzoate. 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (88 mg, 0.254 mmol) was added to the filtrate. The reaction was kept stirring at room temperature overnight. The precipitate was collected, washed with ether and dried under reduced pressure to afford ethyl 3-((3- carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino )-5-((3- (trifluoromethyl)phenyl)amino)benzoate (1 10 mg, 0.174 mmol, 61.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.07 Hz, 3 H) 4.00 (s, 3 H) 4.02 (s, 3 H) 4.31 (q, J=7.07 Hz, 2 H) 7.18 (d, J=7.58 Hz, 1 H) 7.28 (br. s. 1 H) 7.33 (s, 1 H) 7.34 - 7.44 (m, 3 H) 7.57 (s, 1 H) 7.85 (br. s., 1 H) 7.91 (dd, J=9.09, 1 .52 Hz, 1 H) 8.26 (d, J=9.09 Hz, 1 H) 8.31 (br. s., 1 H) 8.35 (br. s., 1 H) 8.65 (s, 1 H) 9.01 (br. s., 1 H) 9.05 (s, 1 H) 1 1 .92 (br. s., 1 H). LCMS (ES+) m/e 633 [M+H] ⁺ .

Example 88

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

(trifluoromethyl)phenyl)amino)benzoic acid

To a suspension of ethyl 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin- 4-yl)amino)-5-((3-(trifluoromethyl)phenyl)amino)benzoate (92 mg, 0.145 mmol) in methanol (10 mL) was added sodium hydroxide (6. ON) (0.135 mL, 0.808 mmol). The reaction was kept stirring overnight, then acidified to pH 6.0. The precipitate was collected, washed with water and dried under reduced pressure to afford 3-((3-carbamoyl- 7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-((3-

(trifluoromethyl)phenyl)amino)benzoic acid (80 mg, 0.132 mmol, 82 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.01 (s, 3 H) 7.13 - 7.20 (m, 1 H) 7.31 (br. s., 1 H) 7.33 -7.37 (m, 2 H) 7.38 - 7.44 (m, 2 H) 7.58 (s, 1 H) 7.85 (br. s., 1 H) 7.89 (d, J=9.09 Hz, 1 H) 8.30 (d, J=9.09 Hz, 1 H) 8.42 (s, 1 H) 8.46 - 8.55 (m, 1 H) 8.64 (s, 1 H) 9.10 - 9.16 (m, 2 H) 12.19 (br. s., 1 H) 13.14 (br. s., 1 H). LCMS (ES+) m/e 605 [M+H] ⁺ .

Example 89

4-((3-(3-carbamoylphenoxy)phenyl)amino)-7-(2,4-dimethoxypyri midin-5-yl)quinoline carboxamide

a) 3-(3-nitrophenoxy)benzamide. A mixture of anhydrous copper(ll) 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 ) 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, =Q.2^ 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 ) 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) 4-((3-(3-carbamoylphenoxy)phenyl)amino)-7-(2,4-dimethoxypyri midin-5- yl)quinoline-3-carboxamide. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-carboxamide (0.088 g, 0.255 mmol) and 3-(3- aminophenoxy)benzamide (0.076 g, 0.333 mmol) in acetic acid (1 mL) was stirred at 50 °C for 18 h, then cooled. The solvent was removed under reduced pressure and the residue azeotroped three times with toluene. The mixture was

chromatographed (silica gel, 1 -10% methanol/dichloromethane) to give the title compound (0.1 13 g, 83%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 3.98 (s, 3 H) 3.99 (s, 3 H) 6.60 (t, J=2.15 Hz, 1 H) 6.68 (dd, J=8.08, 1.77 Hz, 1 H) 6.79 (dd, J=7.83, 1 .77 Hz, 1 H) 7.14 (ddd, J=8.15, 2.46, 0.76 Hz, 1 H) 7.29 (t, J=8.08 Hz, 1 H) 7.37 (t, J=7.96 Hz, 1 H) 7.42 (s, 1 H) 7.48 - 7.53 (m, 1 H) 7.60 (dt, J=7.89, 1 .1 1 Hz, 1 H) 7.66 (dd, J=8.84, 1.77 Hz, 1 H) 7.74 (br. s., 1 H) 7.87 (d, J=8.84 Hz, 1 H) 8.00 (s, 1 H) 8.13 (d, J=1 .77 Hz, 1 H) 8.29 (br. s., 1 H) 8.57 (s, 1 H) 9.00 (s, 1 H) 10.44 (s, 1 H).

Example 90

-butoxy-4-((3-cvclopentyl-5-(hvdroxymethyl)phenyl)amino)- 7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide

a) 4,7-dichloro-6-methoxyquinolin-3-amine. To a solution of 7-chloro-4-hydroxy-6- methoxyquinoline-3-carboxylic acid (254 mg , 1 mmol) in thionyl chloride (50 mL) was added a drop of Ν,Ν-dimethylformamide. The mixture was heated under reflux for 3 h, then cooled and concentrated in vacuo. The residue was dissolved in dry tetrahydrofuran (50 mL), then added dropwise to sodium azide (104 mg, 1.5 mmol) dissolved in water (5 mL). The precipitate was filtered off and dissolved in toluene. The solution was heated under reflux for 30 min. Water (10 mL) was added. The reaction mixture was refluxed for another 30 min, then cooled and concentrated in vacuo. The residue was further purified by column

chromatography to give the title compound (85 mg, 35%) as yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 4.02 (s, 3 H), 6.17 (s, 2 H), 7.29 (s, 1 H), 7.93 (s, 1 H), 8.45 (s, 1 H). LCMS (ES+) m/e 243 [M+H] ⁺ .

b) 4,7-dichloro-6-methoxyquinoline-3-sulfonamide. 4,7-Dichloro-6-methoxyquinolin- 3-amine (243 mg, 1 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and the resulting solution cooled to -5 °C. A solution of sodium nitrite (69 mg, 1 mmol) in distilled water (5 mL) was added in portions with stirring, while

maintaining the temperature below 0 °C. The mixture was stirred for 10 min. In a second flask, thionyl chloride (1 mL) was added dropwise to distilled water (2 mL), which had been pre-cooled to -5 °C. The resulting solution was allowed to warm to room temperature, and copper(ll) chloride (40 mg, 0.3 mmol) was added. The reaction mixture was re-cooled to -5 °C. The diazonium salt mixture was added in portions to the second flask, and the resulting mixture stirred for 30 min, during which time a precipitate formed. The mixture was extracted with ethyl acetate (50 mL x 3). Purification by column chromatography afforded 4,7-dichloro-6- methoxyquinoline-3-sulfonyl chloride (62 mg, 19%) as a white solid. A solution of the sulfonyl chloride in tetrahydrofuran (2 mL) was added dropwise to ammonium hydroxide (0.5 mL). The reaction mixture was concentrated in vacuo to give the title compound (41 mg, 71 %) as a white solid. ¹ H NMR (300 MHz, DMSO-c/ ₆ ) ppm 4.1 1 (s, 3 H), 7.48 (s, 2 H), 7.74 (s, 1 H), 8.32 (s, 1 H), 9.16 (s, 1 H). LCMS (ES+) m/e 307 [M+H] ⁺ .

c) 4,7-dichloro-6-hvdroxyquinoline-3-sulfonamide. A solution of 4,7-dichloro-6- methoxyquinoline-3-sulfonamide in 1 ,2-dichloroethane (25 mL) was stirred at 0 °C. Boron tribromide dissolved in 1 ,2-dichloroethane (10 mL) was added to the mixture dropwise, then the reaction mixture heated to 60 °C for 12 h. TLC showed no 4, 7-dichloro-6-methoxyquinoline-3-sulfonamide left. The reaction mixture was quenched with methanol (5 mL) and water (50 mL), and extracted with ethyl acetate (100 mL x 2). The extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the crude product. Further purification by column chromatography afforded the title compound (134 mg, 46%) as an off-white solid. LCMS (ES+) m/e 293 [M+H] ⁺ .

d) 6-butoxy-4,7-dichloroquinoline-3-sulfonamide. A solution of 4,7-dichloro-6- hydroxyquinoline-3-sulfonamide (132 mg, 0.45 mmol), potassium carbonate (62 mg, 0.45 mmol), 1-bromobutane (62 mg, 0.45 mmol), sodium iodide (20 mg, 0.14 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50 °C for 1.5 h. TLC showed no starting material left. The reaction mixture was diluted with water (5 mL), neutralized with sodium bicarbonate to pH 7, then extracted with ethyl acetate (25 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to give the crude product. Further purification by column chromatography afforded the title compound (78 mg, 43%) as a white solid.

LCMS (ES+) m/e 349 [M+H] ⁺ .

6-butoxy-7-chloro-4-(3-cvclopentyl-5-(hvdroxymethyl)pheny lamino)quinoline-3- sulfonamide. A solution of 6-butoxy-4,7-dichloroquinoline-3-sulfonamide (271 mg, 0.78 mmol), and (3-amino-5-cyclopentylphenyl)methanol (179 mg, 0.94 mmol) in ethanol (20 mL) was stirred at reflux for 1 h. TLC showed no starting materials left. The mixture was purified by column chromatography to give the title compound (310 mg, 79%) as a yellow solid. LCMS (ES+) m/e 504 [M+H] ⁺ .

6-butoxy-4-(3-cvclopentyl-5-(hvdroxymethyl)phenylamino)-7 -(2,4- dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide. To a solution of 6-butoxy-7- chloro-4-(3-cyclopentyl-5-(hydroxymethyl)phenylamino)quinoli ne-3-sulfonamide (75 mg, 0.15 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (41 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0075 mmol) in 1 ,4-dioxane (4 mL) was added a solution of potassium carbonate (62 mg, 0.45 mmol) in water (2 mL) dropwise. The reaction mixture was stirred at 80 °C for 2.5 h. TLC showed no starting material left. The mixture was cooled. Water (20 mL) was added and the mixture stirred for 10 min. The precipitate was filtered, washed with water and dried to give the title compound (65 mg, 71 %) as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) ppm 0.76 (t, J = 7.2 Hz, 3 H), 1.07-1 .95 (m, 12 H), 2.85-2.96 (m, 1 H), 3.39 (t, J = 6.3 Hz, 2 H), 3.85 (s, 3 H), 3.95 (s, 3 H), 4.43 (d, J = 5.7 Hz, 2 H), 5.17 (t, J = 5.7 Hz, 1 H), 6.73 (s, 1 H), 6.86 (s, 1 H), 6.90 (s, 1 H), 6.96 (s, 1 H), 7.84 (s, 1 H), 7.85 (s, 2 H), 8.29 (s, 1 H), 8.33 (s, 1 H), 8.91 (s, 1 H). LCMS (ES+) m/e 608 [M+H] ⁺ .

Example 91

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(m- 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-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(m- tolylamino)benzoic acid. To a suspension of 10% palladium on carbon (26.6 mg, 0.025 mmol) in acetic acid (10 mL) was added ethyl 3-nitro-5-(m- tolylamino)benzoate (75 mg, 0.250 mmol). The reaction mixture was

hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (77 mg, 0.225 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 (6.0 N) (0.208 mL, 1 .249 mmol) was added. The reaction was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-(m-tolylamino)benzoic acid, trifluoroacetic acid salt (17 mg, 0.026 mmol, 10.24 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 3 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 6.70 (d, J=7.58 Hz, 1 H) 6.83 -6.90 (m, 2 H) 7.08 (t, J=7.7^ Hz, 1 H) 7.12 (br. S., 1 H) 7.22 (s, 1 H) 7.49 (s, 1 H) 7.82 - 7.93 (m, 2 H) 8.13 (d,J=8.84 Hz, 1 H) 8.23 (d, J=1.77 Hz, 1 H) 8.31 (br. S., 1 H) 8.48 (br. S., 1 H) 8.65 (s, 1 H) 9.02 (s, 1 H) 1 1.87 (br. S., 1 H) 13.07 (br. S., 1 H). LCMS (ES+) m/e 551 [M+H] ⁺ .

Example 92

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4- yl)amino)-5-(methyl(3-

(trifluoromethyl)phenyl)amino)benzoic acid

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-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amin

(trifluoromethyl)phenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (21.67 mg, 0.020 mmol) in acetic acid (10 ml.) was added 3-(methyl(3- (trifluoromethyl)phenyl)amino)-5-nitrobenzoic acid (75 mg, 0.221 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (63.2 mg, 0.183 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 (6.0 N) (0.170 ml_, 1 .018 mmol) was added. The reaction was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4- dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)-5-(methyl(3- (trifluoromethyl)phenyl)amino)benzoic acid, trifluoroacetic acid salt (35 mg, 0.048 mmol, 23.46 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 3.33 (s, 3 H) 4.00 (s, 3 H) 4.02 (s, 3 H) 7.20 (s, 1 H) 7.27 - 7.38 (m, 3 H) 7.42 - 7.49 (m, 3 H) 7.85 (br. s., 1 H) 7.91 (dd, J=9.09, 1 .52 Hz, 1 H) 8.20 - 8.26 (m, 2 H) 8.29 (br. s., 1 H) 8.66 (s, 1 H) 8.98 (s, 1 H) 1 1.69 (br. s., 1 H) 13.19 (br. s., 1 H). LCMS (ES+) m/e 619 [M+H] ⁺ .

Example 93

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-((3- 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, 0.970 mmol, 53 % 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] ⁺ .

3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4 -yl)amino)-5-((3- isopropylphenyl)amino)benzoic acid. To a suspension of 10% palladium on carbon (33.9 mg, 0.0318 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (99 mg, 0.286 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 (6.0 N) (0.265 mL, 1 .591 mmol) was added. The mixture was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5- yl)quinolin-4-yl)amino)-5-((3-isopropylphenyl)amino)benzoic acid, trifluoroacetic acid salt (42 mg, 0.061 mmol, 19.06 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 .10 (d, J=7.07 Hz, 6 H) 2.69 (spt, J=7.07 Hz, 1 H) 3.99 (s, 3 H) 4.02 (s, 3 H) 6.77 (d, J=7.58 Hz, 1 H) 6.84- 6.91 (m, 2 H) 7.04 - 7.14 (m, 2 H) 7.20 (s, 1 H) 7.49 (s, 1 H) 7.82 - 7.94 (m, 2 H) 8.1 1 (d, J=9.09 Hz, 1 H) 8.23 (d, J=1.77 Hz, 1 H) 8.33 (br. s., 1 H) 8.50 (s, 1 H) 8.65 (s, 1 H) 9.02 (s, 1 H) 1 1.75 (br. s., 1 H) 13.03 (br. s., 1 H). LCMS (ES+) m/e 579 [M+H] ⁺ . Example 94

3-((7-(2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl )amino)-5-((3- isopropylphenyl)amino)benzoic acid

To a suspension of 10% palladium on carbon (33.9 mg, 0.0318 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- sulfonamide (109 mg, 0.286 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature, then the organic solvent was removed under reduced pressure. The residue was dissolved in methanol (10.00 ml_), to which sodium hydroxide (6.0 N) (0.265 ml_, 1 .591 mmol) was added. The mixture was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 3-((7- (2,4-dimethoxypyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino )-5-((3- isopropylphenyl)amino)benzoic acid, trifluoroacetic acid salt (18 mg, 0.025 mmol, 7.76 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.82 Hz, 6 H) 2.56 (spt, J=6.82 Hz, 1 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 6.61 - 6.72 (m, 4 H) 6.88 -6.96 (m, 1 H) 7.12 (s, 1 H) 7.31 (s, 1 H) 7.76 - 7.86 (m, 2 H) 7.86 - 7.91 (m, 2 H) 8.29 (d, J=1.01 Hz, 1 H) 8.37 (s, 1 H) 8.43 (br. s., 1 H) 8.63 (s, 1 H) 9.10 (s, 1 H). LCMS (ES+) m/e 615

[M+H] ⁺ .

Example 95

-((3-(tert-butyl)phenyl)amino)-5-((3-carbam

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-carbamoyl-7-(2,4-dimet hoxypyrimidin-5- yl)quinolin-4-yl)amino)benzoic acid. To a suspension of 10% palladium on carbon (32.4 mg, 0.0305 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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (94 mg, 0.274 mmol) was added to the filtrate. The mixture was kept stirring at room temperture 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 at room temperature overnight and was purified via reverse-phase preparative HPLC (YMC 20X50 mm column, acetonitrile/water + 0.1 %

trifluoroacetic acid) to afford 3-((3-(tert-butyl)phenyl)amino)-5-((3-carbamoyl-7- (2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)benzoic acid, trifluoroacetic acid salt (55 mg, 0.078 mmol, 25.6 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 9 H) 3.99 (s, 3 H) 4.01 (s, 3 H) 6.87 - 6.96 (m, 2 H) 7.06 (br. s., 2 H) 7.08 - 7.14 (m, 1 H) 7.19 (s, 1 H) 7.50 (s, 1 H) 7.83 - 7.88 (m, 1 H) 7.91 (br. s., 1 H) 8.10 (d, J=9.09 Hz, 1 H) 8.22 (d, J=1.77 Hz, 1 H) 8.33 (br. s., 1 H) 8.51 (s, 1 H) 8.64 (s, 1 H) 9.02 (s, 1 H) 1 1 .77 (br. s., 1 H). LCMS (ES+) m/e 593 [M+H] ⁺ .

Example 96

-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluorophenyl)ami no)-5-(2H-tetrazol-5- yl)phenyl)amino)quinoline-3-sulfonamide

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) 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) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluorophenyl)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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- sulfonamide (91 mg, 0.240 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4- fluorophenyl)amino)-5-(2H-tetrazol-5-yl)phenyl)amino)quinoli ne-3-sulfonamide (40 mg, 0.065 mmol, 24.43 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.98 (s, 3 H) 3.98 (s, 3 H) 6.55 (s, 1 H) 6.93 (s, 2 H) 6.94 (s, 2 H) 7.20 (s, 1 H) 7.36 (s, 1 H) 7.78 (dd, J=8.97, 1 .64 Hz, 1 H) 7.86 - 7.94 (m, 3 H) 8.29 (d, J=1.52 Hz, 1 H) 8.45 (s, 1 H) 8.52 (br. s., 1 H) 8.62 (s, 1 H) 9.13 (s, 1 H). LCMS (ES+) m/e 615 [M+H] ⁺ .

Example 97

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluorophenyl)amino )-5-(2H-tetrazol-5- yl)phenyl)amino)quinoline-3-carboxamide

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-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (83 mg, 0.240 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-((4-fluorophenyl)amino )-5-(2H-tetrazol-5- yl)phenyl)amino)quinoline-3-carboxamide (22 mg, 0.038 mmol, 14.27 % yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) ppm 3.98 (s, 3 H) 3.99 (s, 3 H) 6.71 (br. s., 1 H) 6.96 - 7.06 (m, 4 H) 7.20 (s, 1 H) 7.39 (s, 1 H) 7.75 - 7.80 (m, 1 H) 7.83 (br. s., 1 H) 8.04 (d, J=9.09 Hz, 1 H) 8.21 (d, J=1.52 Hz, 1 H) 8.30(br. s., 1 H) 8.47 (s, 1 H) 8.61 (s, 1 H) 9.06 (s, 1 H) 10.89 (br. s., 1 H). LCMS (ES+) m/e 579 [M+H] ⁺ .

Example 98

-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl) amin

carbonvDbenzoic 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) 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 ) 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-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl )amino)-5-(pyrrolidine-

1 -carbonvDbenzoic acid. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-carboxamide (0.080 g, 0.232 mmol) and methyl 3-amino-5- (pyrrolidine-l-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 and the residue azeotroped three times with toluene. The mixture was chromatographed (silica gel, 1 -10% 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 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 (0.060 g, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 1.66 - 1.77 (m, 2 H) 1.78 - 1 .87 (m, 2 H) 3.24 (t, J=6.44 Hz, 2 H) 3.40 (t, J=6.82 Hz, 2 H) 3.98 (s, 3 H) 3.99 (s, 3 H) 7.18 - 7.27 (m, 1 H) 7.55 - 7.60 (m, 1 H) 7.62 (t, J=1.39 Hz, 1 H) 7.68 (dd, J=8.84, 2.02 Hz, 1 H) 7.70 (br. s., 1 H) 7.90 (d, J=8.84 Hz, 1 H) 8.19 (d, J=1.77 Hz, 1 H) 8.26 (br. s., 1 H) 8.58 (s, 1 H) 9.02 (s, 1 H) 10.26

(s, 1 H) 13.15 (br. s., 1 H).

Example 99

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrrolidine-1 -carbonyl)phenyl)amino)qui

carboxamide

A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxam ide (0.080 g, 0.232 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 h, then cooled. The mixture was chromatographed directly (silica gel, 2-10% methanol/dichloromethane) to give the title compound (0.073 g, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 1.63 - 1.75 (m, 2 H) 1 .75 - 1 .85 (m, 2 H) 3.22 (t, J=6.44 Hz, 2 H) 3.38 (t, J=6.98 Hz, 2 H) 3.97 (s, 3 H) 3.99 (s, 3 H) 7.02 (s, 1 H) 7.10 (dd, J=7.96, 1 .64 Hz, 1 H) 7.15 (d, J=7.58 Hz, 1 H) 7.34 (t, J=7.83 Hz, 1 H) 7.60 (dd, J=8.84, 1.77 Hz, 1 H) 7.74 (br. s., 1 H) 7.79 (d, J=8.84 Hz, 1 H) 8.15 (d, J=1.77 Hz, 1 H) 8.32 (br. s., 1 H) 8.56 (s, 1 H) 9.05 (s, 1 H) 10.54 (s, 1 H).

Example 100

-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-((2,6-difluo rophenyl)am acid a) ethyl 3-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-((2,6- difluorophenyl)amino)benzoate. To a suspension of 7-bromo-4-chloroquinoline-3- carboxamide (80 mg, 0.279 mmol) in acetic acid (10 ml.) was added ethyl 3-((2,6- difluorophenyl)amino)-5-nitrobenzoate (100 mg, 0.310 mmol). The reaction mixture was kept stirring at room temperature overnight. The precipitate was collected, washed with ether and water and dried under reduced pressure to afford ethyl 3-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-((2,6- difluorophenyl)amino)benzoate (105mg, 0.194 mmol, 62.5 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) ppm 1 .27 (t, J=7.07 Hz, 3 H) 4.27 (q, J=7.07 Hz, 2 H) 6.79 (s, 1 H) 7.13 -7.31 (m, 5 H) 7.80 (dd, J=9.09, 2.02 Hz, 1 H) 7.88 (br. s., 1 H) 8.03 (d, J=9.35 Hz, 1 H) 8.31 (d, J=1 .77 Hz, 1 H) 8.38 (s, 1 H) 8.41 (br. s., 1 H) 9.07 (s, 1 H) 12.08 (br. s., 1 H). LCMS (ES+) m/e 541/543

[M+H] ⁺ .

b) 3-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-((2,6-difluoro phenyl)amino)benzoic acid. To a suspension of ethyl 3-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5- ((2,6-difluorophenyl)amino)benzoate (90 mg, 0.166 mmol) in methanol (10 ml.) was added sodium hydroxide (6.0 N) (0.154 ml_, 0.924 mmol). The reaction was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 %

trifluoroacetic acid) to afford 3-((7-bromo-3-carbamoylquinolin-4-yl)amino)-5-((2,6- difluorophenyl)amino)benzoic acid, trifluoroacetic acid salt (70 mg, 0.1 12 mmol, 60.4 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (s, 1 H) 7.09 (d, J=8.84 Hz, 2 H) 7.14 - 7.31 (m, 3 H) 7.75 (dd,J=9.22, 1.89 Hz, 1 H) 7.85 (br. s., 1 H) 7.96 (d, J=9.09 Hz, 1 H) 8.16 (d, J=2.02 Hz, 1 H) 8.25 (s, 1 H) 8.29 (br. s., 1 H) 8.98 (s, 1 H) 1 1 .46 (br. s., 1 H) 13.00 (br. s., 1 H). LCMS (ES+) m/e 513/515 [M+H] ⁺ . Example 101

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N-hvdroxycarbamimidoy l)-5-((3- (trifluoromethyl)phenyl)amino)phenyl)amino)quinoline-3-carbo xamide

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

(trifluoromethyl)phenyl)amino)phenyl)amino)quinoline-3-carbo xam To a suspension of 10% palladium on carbon (23.46 mg, 0.022 mmol) in acetic acid (10 ml.) was added N-hydroxy-3-nitro-5-((3-

(trifluoromethyl)phenyl)amino)benzimidamide (75 mg, 0.220 mmol). The reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 hours and filtered. 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (68.4 mg, 0.198 mmol) was added to the filtrate. The reaction was kept stirring overnight at room temperature and was purified via reverse-phase preparative HPLC (YMC 75 X 30 mm column, acetonitrile/water + 0.1 % trifluoroacetic acid) to afford 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(N- hydroxycarbamimidoyl)-5-((3-

(trifluoromethyl)phenyl)amino)phenyl)amino)quinoline-3-ca rboxamide,

trifluoroacetic acid salt (15 mg, 0.020 mmol, 9.29 % yield) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-^) δ ppm 4.10 (s, 3 H) 4.13 (s, 3 H) 7.16 (t, J=1 .64 Hz, 1 H) 7.22 - 7.27(m, 2 H) 7.31 (t, J=1 .77 Hz, 1 H) 7.32 (br. s., 1 H) 7.39 - 7.42 (m, 2 H) 7.88 (dd, J=8.97, 1 .64 Hz, 1 H) 8.18 (d, J=9.09 Hz, 1 H) 8.23 (d, J=1 .77 Hz, 1 H) 8.56 (s, 1 H) 9.02 (s, 1 H). LCMS (ES+) m/e 619 [M+H] ⁺ .

Example 102

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrrolidine-1-carbony l)-5- sulfamoylphenyl)amino)quinoline-3-carboxamide

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 ) 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 ) 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) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(pyrrolidine-1-carbony l)-5- sulfamoylphenyl)amino)quinoline-3-carboxamide. A mixture of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (0.080 g, 0.232 mmol) and 3- amino-5-(pyrrolidine-1-carbonyl)benzenesulfonamide (0.078 g, 0.290 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, 2-10% methanol/dichloromethane) to give the title compound (0.1 1 1 g, 83%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 1.67 - 1.88 (m, 4 H) 3.21 (t, J=6.32 Hz, 2 H) 3.39 (t, J=6.82 Hz, 2 H) 3.98 (s, 3 H) 4.00 (s, 3 H) 7.13 (t, J=1 .64 Hz, 1 H) 7.39 (s, 2 H) 7.47 - 7.52 (m, 2 H) 7.70 (dd, J=8.84, 1.77 Hz, 1 H) 7.73 (br. s., 1 H) 7.89 (d, J=8.84 Hz, 1 H) 8.21 (d, J=1.52 Hz, 1 H) 8.29 (br. s., 1 H) 8.59 (s, 1 H) 9.05 (s, 1 H) 10.33 (s, 1 H). Example 103

-(2,4-dimethoxypyrimidin-5-yl)-4-((3-methoxy-5-sulfamoylp henyl)amino)quino

carboxamide

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 ) 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 ) 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) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-methoxy-5-sulfamoylphe nyl)am

3-carboxamide. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3- carboxamide (0.075 g, 0.218 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 (2 mL). The precipitate was filtered off, washed with acetic acid and dried to give the title compound (0.073 g, 66%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 3.81 (s, 3 H) 4.00 (s, 3 H) 4.03 (s, 3 H) 7.09 (br. s., 1 H) 7.25 (s, 1 H) 7.30 (s, 1 H) 7.43 (s, 2 H) 7.84 (br. s., 1 H) 7.88 - 7.94 (m, 1 H) 8.24 (d, J=8.84 Hz, 1 H) 8.32 (d, J=1.52 Hz, 1 H) 8.41 (br. s., 1 H) 8.67 (s, 1 H) 9.07 (s, 1 H) 1 1.79 (br. s., 1 H).

Example 104

7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(dimethylcarbamoyl)-5- sulfamoylphenyl)amino)quinoline-3-carboxamide

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 ) 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) 7-(2,4-dimethoxypyrimidin-5-yl)-4-((3-(dimethylcarbamoyl)-5- sulfamoylphenyl)amino)quinoline-3-carboxamide. A mixture of 4-chloro-7-(2,4- dimethoxypyrimidin-5-yl)quinoline-3-carboxamide (0.074 g, 0.215 mmol) and 3- amino-N,N-dimethyl-5-sulfamoylbenzamide (60% pure, 0.139 g, 0.343 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, 2-10% methanol/dichloromethane) to give the title compound (0.028 g, 24%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 2.84 (s, 3 H) 2.92 (s, 3 H) 3.98 (s, 3 H) 4.00 (s, 3 H) 7.02 (br. s., 1 H) 7.31 - 7.43 (m, 3 H) 7.48 (s, 1 H) 7.56 - 7.79 (m, 2 H) 7.90 (d, J=8.84 Hz, 1 H) 8.20 (br. s., 1 H) 8.30 (br. s., 1 H) 8.58 (s, 1 H) 9.04 (s, 1 H) 10.34 (br. s., 1 H).

Example 105

4-((3-carbamoyl-5-(4-fluorophenoxy)phenyl)amino)-7-(2,4-dime thoxypyrimidin-5- yl)quinoline-3-carboxamide

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- d ₆ ) 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 ) 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) 4-((3-carbamoyl-5-(4-fluorophenoxy)phenyl)amino)-7-(2,4-dime thoxypyrimidin-5- yl)quinoline-3-carboxamide. A mixture of 4-chloro-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-carboxamide (0.074 g, 0.215 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 (0.098 g, 82%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ppm 4.00 (s, 3 H) 4.03 (s, 3 H) 7.06 (br. s., 1 H) 7.10 - 7.17 (m, 2 H) 7.18 - 7.26 (m, 2 H) 7.40 (s, 1 H) 7.54 (s, 1 H) 7.58 (s, 1 H) 7.85 - 7.94 (m, 2 H) 7.99 (s, 1 H) 8.20 (d, J=9.09 Hz, 1 H) 8.29 (d, J=1 .52 Hz, 1 H) 8.37 (br. s., 1 H) 8.66 (s, 1 H) 9.05 (s, 1 H) 1 1 .86 (br. s., 1 H).

Example 106 - Capsule Composition

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

Table I, below.

Table I

INGREDIENTS AMOUNTS

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

yl)amino)-5-(cyclohexylamino)benzoic acid

(Compound of Example 1 )

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg

Example 107 - Injectable Parenteral Composition

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

Example 108 - 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

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

fluorophenylsulfonamido)phenyl)amino)quinoline-3- carboxamide (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

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.

Compounds of the invention are tested for activity against lactate dehydrogenase A generally according to the above assay or in an analogous assay. The compounds of Examples 1 to 106 were tested generally according to either the above Enzymatic Assay or the above Cell-based Assay 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 9 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 5.3 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.