FIELD OF THE INVENTION

The present invention relates to substituted benzothiadiazine derivatives that are inhibitors of the activity of CD73. The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes and other diseases associated with CD73 inhibition, such as AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia- reperfusion injury.

BACKGROUND OF THE INVENTION

Local levels of extracellular adenosine triphosphate (ATP) are acutely elevated as a consequence of infection, tissue injury, ischaemia or intervention-induced tumor cell death. Elevated extracellular ATP is recognized by the immune system as a danger signal to initiate multiple pro-inflammatory events, including the recruitment of macrophages and dendritic cells. (1) Successive processing of extracellular ATP by the extracellular ectonucleotidases CD73 and CD39 lowers extracellular ATP levels and can rapidly elevate extracellular adenosine from a low homeostatic level (20-200 nM) to as much as 1 ,000- 10,000 nM. (2) These elevated adenosine concentrations engage the immunosuppressive actions of adenosine A2A and A2B receptors on the infiltrating lymphocytes, shielding cells from an excessive inflammatory response and thereby providing a self-limiting mechanism to resolve the immune response. Within the context of a solid tumor, hypoxia has been shown to increase adenosine levels by 10-20-fold compared with normal levels. (3) It has been proposed that adenosine elevation is sufficient to maintain a chronic suppression of the innate immune response, resulting in immune tolerance and, subsequently, uncontrolled malignant growth.

CD73 is a glycophosphatidylinositol-anchored di-Zn ²⁺ metallo-phosphatase specific for the dephosphorylation of purine and pyrimidine ribo- and deoxyribonucleoside monophosphates to the corresponding nucleoside, with adenosine monophosphate (AMP) being the preferred substrate of CD73. CD73-catalyzed conversion of AMP to adenosine is thought to be the major contributor to extracellular adenosine in the tumor microenvironment. Its expression is directly regulated by HIF1 a, consistent with the observed increase in extracellular adenosine under hypoxic conditions. (4) CD73 is overexpressed in multiple solid tumor types and leukaemias, including aggressive and difficult to treat tumours, such as glioblastoma and ovarian tumours. (5) In patients with head and neck squamous cell carcinoma (HNSCC), T-regulatory cells (T _Reg ) (both circulating and tumor associated) express both CD73 and CD39, thus providing a mechanism for the conversion of ATP to adenosine that only depends on T _Reg cells. (6) There are multiple reports using small-interfering ribonucleic acids (siRNA), transgenic knockouts and overexpression models to confirm the involvement of CD73 in the generation of adenosine and promotion of immune tolerance. (5)

Thus, small-molecule inhibitors of CD73 are expected to have the ability to relieve the adenosine-mediated immunosuppression of the tumor microenvironment and alone, or incombination with other agents, provide a treatment for cancer.

Because inhibiton of CD73 results in decreased extracellular adenosine, CD73 inhibitors are also expected to be useful for other diseases mediated by adenosine and its action on adenosine receptors. Thus, CD73 inhibitors could be used for enhancing immune responses, enhancing immunization, and increasing inflammatory responses, as well as treating a wide range of conditions including neurological, neurodegenerative and CNS diseases, including depression, Parkinson's disease, cerebral and cardiac ischemic diseases, sleep disorders, and fibrosis. (7-10)

Certain selected benzothiadiazine compounds have been shown to inhibit the activity of lnterleukin-8/CXCR2. (1 1 , 12) However, these compounds are not indicated as inhibitors of CD73.

References

1 . Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1 p-dependent adaptive immunity against tumors. Nat. Med. 15, 1 170— 1 178 (2009).

2. Chen, J. F., Eltzschig, H. K. & Fredholm, B. B. Adenosine receptors as drug targets — what are the challenges? Nat. Rev. Drug Discov. 12, 265-286 (2013).

3. Blay, J., White, T. D. & Hoskin, D. W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57, 2602- 2605 (1997).

4. Synnestvedt, K. et al. Ecto-5 ^' -nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.

5. Stagg, J. & Smyth, M. J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346-5358 (2010).

6. Mandapathil, M. et al. Adenosine and prostaglandin e2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J. Biol.

Chem. 285, 27571 -27580 (2010).

7. Antonioli, L. et al. Immunity, inflammation and cancer: a leading role for adenosine.

Nature Rev. Cancer 13, 842-857 (2013).

8. Regateiro, F. S. et al. CD73 and adenosine generation in the creation of regulatory microenvironments. Clin. Exp. Immunol. 171 , 1 -7 (2013). 9. Sorrentino, R. et al. The adenosinergic system in cancer. Oncol mmunology 2, e22448 (2013).

10. Allard, B. et al. CD73-Generated Adenosine: Orchestrating the Tumor-Stroma Interplay to Promote Cancer Growth. J. Biomed. Biotech. 2012, Article ID 485156, 8 pages, doi:10.1155/2012/485156.

11 . International Application No. PCT/US2004/017892, having an International Filing Date of June 4, 2004, an International Publication No. WO 2005/000231 and an International Publication Date of January 6, 2005.

12. Wang, Y. et al., (2007) Bioorg. Med. Chem. Lett. 17: 3864-3867.

It is an object of the present invention to provide novel compounds that are inhibitors of CD73. It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds of Formula (I).

It is also an object of the present invention to provide a method for treating cancer, pre-cancerous syndromes, AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury that comprises administering novel inhibitors of CD73 activity.

SUMMARY OF THE INVENTION

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

wherein R, R1 , R2, R3, R4 _an( R5 _{are as} defined below; or a pharmaceutically acceptable salt thereof. The present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of CD73.

This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating pre-cancerous syndromes, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating AIDS, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating autoimmune diseases, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof. This invention also relates to a method of treating infections, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating atherosclerosis, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating ischemia-reperfusion injury, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of pre-cancerous syndromes.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of AIDS.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of autoimmune diseases.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of infections.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of atherosclerosis. The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemia-reperfusion injury.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer. The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of pre-cancerous syndromes. The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of AIDS.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of autoimmune diseases.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of infections.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of atherosclerosis.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of ischemia-reperfusion injury. The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias. Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition as defined above for use in therapy. Also included in the present invention are methods of co-administering the presently invented CD73 inhibiting compounds with a further anti-neoplastic agent or agents. The invention also relates to a combination for use in therapy which comprises a therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (ii) at least one anti-neoplastic agent.

DETAILED DESCRIPTION OF THE INVENTION

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

R is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy, Ci -4alkoxy substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-N02,

-NH2,

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl -4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl -4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro, bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl, -N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2, -NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

cycolalkyi, and

cycolalkyi substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

0X0,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2;

lected from:

hydrogen,

Cl-4alkyl, and

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, and -NH2; R ² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN, Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

R ³ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN,

Cl-4alkyloxy, Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

lected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl; and

lected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN, Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

and pharmaceutically acceptable salts thereof;

provided the compound is not:

7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-methoxy-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((3-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-methoxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-methoxy-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-morpholinophenyl)amino)-4H-benzo [e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 -(2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

1 - (2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

2- ((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid; 2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid; 3-((2-bromophenyl)amino)-7-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-5-hydroxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-5-methoxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-methoxy-1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 -dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H-1, 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H- 1, 2, 4-benzothiadiazin-5-methoxy-1 , 1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1- dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1 -dioxide; 3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 - dioxide;

3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; or

3-[(2-chlorophenyl)amino]-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide. Included in the methods of the invention are compounds of Formula (IX):

R is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH, -Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl, Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro, chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl, -N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

cycolalkyi, and

cycolalkyi substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2, -NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl) ₂ ,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl -4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2;

R is selected from:

hydrogen,

Cl-4alkyl, and

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, and -NH2; is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN, Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

lected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

lected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH, -CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci -4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl; and

R ⁵ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Cl -4alkyl, Cl -4alkyloxy,

-OH, -COOH, -CF3, -Cl-4alkylOCl -4alkyl, -NO2, -NH2 and -CN, Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

and pharmaceutically acceptable salts thereof. Included in the presently invented compounds of Formula (I) are compounds of la (II):

wherein:

is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl, -C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH, -COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2,

cycolalkyi, and

cycolalkyi substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and -N(Cl-4alkyl)2;

elected from: hydrogen, and

Cl-4alkyl;

R ² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

R ³ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and -OC(0)Cl -4alkyl;

R ⁴ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl; and

R ⁵ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and -OC(0)Cl -4alkyl;

and pharmaceutically acceptable salts thereof;

provided the compound is not:

7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-methoxy-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((3-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-methoxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-methoxy-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-methoxyphenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethoxy)phenyl)amino)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 - (2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

1 -(2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

2- ((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

2- ((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

3- ((2-bromophenyl)amino)-7-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-bromo-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-5-hydroxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-5-methoxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 -dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H-1, 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H- 1, 2, 4-benzothiadiazin-5-methoxy-1 , 1-dioxide; 7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1- dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1 -dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 - dioxide;

3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; or

3-[(2-chlorophenyl)amino]-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide.

Included in the methods of the invention are compounds of Formula (NX):

(I IX) elected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl -6alkyl,

Ci -6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl -4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl -4alkoxy,

Ci -4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl -4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH, -COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2,

cycolalkyl, and cycolalkyi substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2;

R is selected from:

hydrogen, and

Cl-4alkyl;

R ² is selected from:

hydrogen,

fluoro,

chloro,

bromo, iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

R ³ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

R ⁴ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH, -CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and -OC(0)Cl -4alkyl; and

R ⁵ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and -OC(0)Cl -4alkyl;

and pharmaceutically acceptable salts thereof.

Included in the methods of the invention are compounds of Formula (IIX):

elected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl, -N0 ₂ ,

-NH2,

-N(H)Cl -4alkyl, -N(Cl -4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl -4alkyl,

-N(H)C(0)Cl -4alkyl,

-N(H)S(0)2Cl -4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl -6alkyl,

Ci -6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl -4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl -4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-Νθ2,

-NH2,

-N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2, -N(H)Cl-4alkyl, and

-N(Cl-4alkyl)2,

cycolalkyi, and

cycolalkyi substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, Cl-4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2,

-N(H)Cl-4alkyl, and -N(Cl-4alkyl)2;

R is selected from:

hydrogen, and

Cl-4alkyl;

R ² is selected from: hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

R ³ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

R ⁴ is selected from:

hydrogen,

fluoro, chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and -OC(0)Cl -4alkyl; and

R ⁵ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-OH,

-CN,

Cl-6alkyl,

Ci-4alkyl substituted with from one to five substituents independently selected from: fluoro, chloro and bromo,

Cl-4alkyloxy,

Ci-4alkyloxy substituted with from one to five substituents independently selected from: fluoro, chloro and bromo, and

-OC(0)Cl -4alkyl;

and pharmaceutically acceptable salts thereof,

provided the compound is not:

7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-3-((2-fluorophenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((4-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((4-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-hydroxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-methoxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-methoxy-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 7-chloro-5-hydroxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethyl)phenyl)amino)-4 H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-morpholinophenyl)amino)-4H-benzo [e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 -(2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

1 - (2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

2- ((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

2- ((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

3- ((2-bromophenyl)amino)-7-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-bromo-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-5-hydroxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-5-methoxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-8-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-8-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-8-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 , 1 -dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 , 1 -dioxide; 7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-methoxy-1 ,1-dioxide; 3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 -dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H-1, 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H- 1, 2, 4-benzothiadiazin-5-methoxy-1 , 1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; 7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1- dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1 -dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 - dioxide;

3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; or

3-[(2-chlorophenyl)amino]-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide.

Included in the compounds of Formula (I) are compounds of Formula (III):

wherein:

R is selected from:

phenyl,

phenyl substituted with from one to five substituents independently

selected from:

fluoro, chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl, -N(H)S(0)2Cl -4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl -6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)CH3, -N(CH3)2 and -CN,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-NH2,

-N(H)CH3, and

-N(CH3)2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro, chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)CH3, -N(CH3)2 and -CN,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-NH2,

-N(H)CH3, and

-N(CH3)2;

R ² is selected from:

hydrogen, and

Cl-4alkyl;

R ²² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-OH,

-CN,

Cl-4alkyl,

Cl-4alkyloxy, and

-OC(0)Cl -4alkyl; Fc ^J is selected from:

hydrogen, fluoro,

chloro,

bromo,

-OH,

-CN,

Cl-4alkyl,

Cl-4alkyloxy, and

-OC(0)Cl -4alkyl;

R ²⁴ is selected from:

hydrogen, fluoro,

chloro,

bromo,

-OH,

-CN,

Cl-4alkyl,

Cl-4alkyloxy, and

-OC(0)Cl -4alkyl; and

R ²⁵ is selected from:

hydrogen, fluoro,

chloro,

bromo,

-OH,

-CN,

Cl-4alkyl,

Cl-4alkyloxy, and -OC(0)Cl -4alkyl; and pharmaceutically acceptable salts thereof;

provided the compound is not:

7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-3-((2-fluorophenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((4-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((4-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-hydroxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 7-chloro-5-hydroxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethoxy)phenyl)amino)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 -(2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

1 - (2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

2- ((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

3- ((2-bromophenyl)amino)-7-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-5-hydroxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-5-methoxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-8-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-8-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1-dioxide; 7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-methoxy-1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 -dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H-1, 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H- 1, 2, 4-benzothiadiazin-5-methoxy-1 , 1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1- dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1 -dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 - dioxide;

3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; or

3-[(2-chlorophenyl)amino]-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide.

Included in the methods of the invention are compounds of Formula (MIX):

wherein:

on

R is selected from: phenyl,

phenyl substituted with from one to five substituents independently

selected from:

fluoro,

chloro,

bromo,

iodo,

Cl -6alkyl,

Ci -6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl -4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl -4alkoxy,

Ci -4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl -4alkyl, -N(Cl -4alkyl)2,

-Cl -4alkylNHBoc, -N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)CH3, -N(CH3)2 and -CN,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-NH2,

-N(H)CH3, and

-N(CH3)2, bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

chloro,

bromo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, C1 -4alkyloxy, -OH, -COOH, -NH2

-N(H)CH3, -N(CH3)2 and -CN,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

oxo,

-OH,

-NH2,

-N(H)CH3, and

-N(CH3)2;

R ² is selected from:

hydrogen, and

Cl-4alkyl;

R ²² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-OH,

-CN, Cl-4alkyl,

Ci-4alkyloxy, and

-OC(0)Cl -4alkyl;

R ²³ is selected from:

hydrogen, fluoro,

chloro,

bromo,

-OH,

-CN,

Cl-4alkyl,

Ci-4alkyloxy, and

-OC(0)Cl -4alkyl;

R ²⁴ is selected from:

hydrogen, fluoro,

chloro,

bromo,

-OH,

-CN,

Cl-4alkyl,

Cl-4alkyloxy, and

-OC(0)Cl -4alkyl; and

R ²⁵ is selected from:

hydrogen, fluoro,

chloro,

bromo,

-OH,

-CN, Cl-4alkyl,

Cl-4alkyloxy, and

-OC(0)Cl -4alkyl;

and pharmaceutically acceptable salts thereof.

Included in the compounds of Formula (I) are compounds of Formula (IV):

wherein:

R is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH3)3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl -4alkyl, -N(Cl -4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl -4alkyl,

-N(H)C(0)Cl -4alkyl,

-N(H)S(0)2Cl -4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo, -C(0)C(CH3)NH2,

-C(0)OC(CH3), and

-OCH3,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo,

-C(0)C(CH3)NH2,

-C(0)OC(CH3), and

-OCH3,

R ³¹ is selected from:

hydrogen, and

-CH3;

R ³² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-OH, and

-OCH3;

R ³³ is selected from:

hydrogen,

fluoro,

chloro, and

bromo;

R ³⁴ is selected from:

hydrogen,

fluoro, chloro,

bromo,

-CN,

-OCH3; and

R is selected from:

hydrogen,

fluoro,

chloro, and

bromo;

and pharmaceutically acceptable salts thereof;

provided the compound is not:

7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-3-((2-fluorophenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((3-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((3-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((4-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-methoxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethoxy)phenyl)amino)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 -(2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

1 -(2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid; 2- ((7- chloro-5-methoxy-1 , 1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid;

3- ((2- bromophenyl)amino )-7-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-7-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-7-bromo-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3- ((2- bromophenyl)amino )-7-bromo-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-5-hydroxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-5-methoxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-8-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-8-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

3- ((2- bromophenyl)amino )-8-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3- ((2- bromophenyl)amino )-8-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1-dioxide; 7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-methoxy-1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 -dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H-1, 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H- 1, 2, 4-benzothiadiazin-5-methoxy-1 , 1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1- dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1 -dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 - dioxide;

3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; or

3-[(2-chlorophenyl)amino]-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide. Included in the compounds of Formula (I) are compounds of Formula (IVa):

is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH, -Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo,

-C(0)C(CH3)NH2,

-C(0)OC(CH3), and

-OCH3, bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo,

-C(0)C(CH3)NH2,

-C(0)OC(CH3), and

-OCH3,

R ³ is selected from:

hydrogen, and

-CH3;

R ³² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-OH, and

-OCH3;

R ³³ is selected from:

hydrogen,

fluoro,

chloro, and

bromo;

R ³⁴ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-CN, -OCH3; and

R is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-CN; and;

and pharmaceutically acceptable salts thereof;

provided the compound is not:

7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-((2-fluorophenyl)amino)-5-methoxy-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((3-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((3-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-bromophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-hydroxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2-chloro-3-fluorophenyl)amino)-5-methoxy-4H-ben zo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-4-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-5-fluorophenyl)amino)-7-chloro-5-methoxy-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 3-((2-bromo-6-fluorophenyl)amino)-7-chloro-5-methoxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-(o-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-([1 ,1 '-biphenyl]-2-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-phenoxyphenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethyl)phenyl)amino)-4H-b enzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-methoxy-3-((2-(trifluoromethoxy)phenyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-((2-morpholinophenyl)amino)-4H-benzo [e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-5-methoxy-3-((2-morpholinophenyl)amino)-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 -(2-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

1 - (2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

2- ((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid; 2-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzoic acid; 3-((2-bromophenyl)amino)-7-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-7-bromo-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-5-hydroxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-5-methoxy-7-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-fluoro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-bromophenyl)amino)-8-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-(cyclopentylamino)-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-chloro-3-[(2,3-dichlorophenyl)amino]-4H-1 , 2, 4- benzothiadiazin-5-methoxy-1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-chlorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 -dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H-1, 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

3-[(2-bromophenyl)amino]-7-nitro-4H- 1, 2, 4-benzothiadiazin-5-methoxy-1 , 1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide;

7-nitro-3-{[2-(phenyloxy)phenyl]amino}-4H-1 , 2, 4-benzothiadiazin-5-methoxy-1 ,1- dioxide;

3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-ol1 ,1 -dioxide; 3-[(2-chloro-3-fluorophenyl)amino]-7-nitro-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1 - dioxide;

3-[(2-chlorophenyl)amino]-4H-1 , 2, 4-benzothiadiazin-5-ol1 ,1-dioxide; or

3-[(2-chlorophenyl)amino]-4H-1 ,2,4-benzothiadiazin-5-methoxy-1 ,1-dioxide.

Included in the methods of the invention are compounds of Formula (IVX): elected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN,

oxo,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl, -NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo,

-C(0)C(CH3)NH2,

-C(0)OC(CH3), and

-OCH3,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

-CH3, -C(0)CH3,

0X0,

-C(0)C(CH3)NH2, -C(0)OC(CH3), and -OCH3,

R ³ is selected from:

hydrogen, and

-CH3;

R ³² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-OH, and

-OCH3;

R ³³ is selected from:

hydrogen,

fluoro,

chloro, and

bromo;

R ³⁴ is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-CN,

-OCH3; and

R ³⁵ is selected from:

hydrogen,

fluoro,

chloro, and bromo;

and pharmaceutically acceptable salts thereof.

Included in the methods of the invention are compounds of Formula (IVX):

is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NH2

-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,

-CN, 0X0,

-OH,

-Oaryl,

-C(0)OC(CH ₃ )3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(Cl-4alkyl)2,

-Cl -4alkylNHBoc,

-N(H)aryl,

-N(H)C(0)aryl,

-N(H)OC(0)Cl-4alkyl,

-N(H)C(0)Cl-4alkyl,

-N(H)S(0)2Cl-4alkyl,

-N(H)S(0)2aryl,

-N(H)S(0)2cycloalkyl,

-N(H)S(0)2CH2aryl, and

SO2NH2,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo,

-C(0)C(CH3)NH2,

-C(0)OC(CH3), and -OCH3,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents independently selected from:

fluoro,

-CH3,

-C(0)CH3,

oxo,

-C(0)C(CH3)NH2,

-C(0)OC(CH3), and

-OCH3,

R ³ is selected from:

hydrogen, and

-CH3;

R ³² is selected from:

hydrogen,

fluoro,

chloro,

bromo,

-OH, and

-OCH3;

R ³³ is selected from:

hydrogen,

fluoro,

chloro, and

bromo;

R ³⁴ is selected from:

hydrogen,

fluoro,

chloro,

bromo, -CN,

-OCH3; and

R is selected from:

hydrogen,

fluoro,

chloro,

bromo, and

-CN;

pharmaceutically acceptable salts thereof.

on

Suitably, in the compounds of Formula (IV), R is selected from:

Suitably, in the compounds of Formula (IV), R is selected from: hydrogen and -CH3; suitably hydrogen.

Suitably, in the compounds of Formula (IV), R ³² is selected from: hydrogen, -OH, - OCH3, and F; suitably -OH.

Suitably, in the compounds of Formula (IV), R is selected from: hydrogen, CI, F and Br; suitably hydrogen.

Suitably, in the compounds of Formula (IV), R ³⁴ is selected from: hydrogen, CI, F, Br, -CN, and -OCH3; suitably selected from: CI and F.

Suitably, in the compounds of Formula (IV), R is selected from: hydrogen, CI, F, and Br; suitably hydrogen.

Suitably, in the compounds of Formula (IV), R ³² is -OH, and R ³⁴ is CI.

Suitably, in the compounds of Formula (IV), R is -OH, and R is F.

Suitably, in the compounds of Formula (IV), R is -OH, and R is Br.

Suitably, in the compounds of Formula (IV), R ³² is -OCH3, and R ³⁴ is CI.

Suitably, in the compounds of Formula (IV), R is -OCH3, and R is hydrogen.

Suitably, in the compounds of Formula (IV), R is hydrogen, and R is hydrogen.

Suitably, in the compounds of Formula (IV), R is CI, and R is hydrogen.

Suitably, in the compounds of Formula (IV), R is F, and R is hydrogen.

Suitably, in the compounds of Formula (IV), R is Br, and R is hydrogen.

Suitably, in the compounds of Formula (IV), R is hydrogen, and R is F.

Suitably, in the compounds of Formula (IV), R is hydrogen, and R is F. In each of the above suitable embodiments, R together with R may be combined with R ³² together with R ³⁴ .

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

4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile;

7-Chloro-5-hydroxy-3-((4-hydroxyphenyl)amino)-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile; 7-Chloro-3-((3-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((4-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-(m-tolylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-5-hydroxy-3-(p-tolylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-3-((3-cyclopropylphenyl)amino)-5-hydroxy-2H-benzo[e ][1 ,2,4]thiadiazine

1 ,1 -dioxide;

7-Chloro-3-((4-cyclopropylphenyl)amino)-5-hydroxy-2H-benz o[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((4-Aminophenyl)amino)-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzamide;

7-Chloro-5-hydroxy-3-((3-hydroxyphenyl)amino)-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((4-(dimethylamino)phenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 1 -(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone; 7-Chloro-5-hydroxy-3-((3-methoxyphenyl)amino)-2H-benzo[e][1 ,2,4]thiadiazine

1 ,1 -dioxide;

7-Chloro-5-hydroxy-3-((1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-5-hydroxy-3-((1 ,2,3,4-tetrahydroisoquinolin-6-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((3-ethylphenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-((4-(methylamino)phenyl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-Aminophenyl)amino)-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-(Benzo[d]thiazol-6-ylamino)-7-chloro-5-hydroxy-4H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-5-hydroxy-3-(quinolin-6-ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-3-((3,4-dihydroxyphenyl)amino)-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-Benzo[d]imidazol-6-yl)amino)-7-chloro-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 1 -(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone;

7-Chloro-5-hydroxy-3-(quinoxalin-6-ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-chloro-3-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 2-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile; 2-(3-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetic acid;

2- (3-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetamide;

7-chloro-5-methoxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-chloro-3-[(2-chlorophenyl)amino]-5-methoxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

1 - (7-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)- 3,4-dihydroisoquinolin-2(1 H)-yl)ethanone;

3- (Benzo[b]thiophen-5-ylamino)-7-chloro-5-hydroxy-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-(Benzo[b]thiophen-6-ylamino)-7-chloro-5-hydroxy-4H-benz o[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-3-((3,4-dichlorophenyl)amino)-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine

1 ,1 -dioxide;

7-Chloro-3-((3,5-dichlorophenyl)amino)-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((3,4-difluorophenyl)amino)-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

2- (3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)-N,N-dimethylacetamide;

7-Chloro-5-hydroxy-3-((2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)- 4Hbenzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 5-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)isoindolin-1 -one; (S)-2-Amino-1 -(7-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)-3,4-dihydroisoquinolin-2(1 H)-yl)propan-1 -one;

2- (3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)-N-methylacetamide;

7-Chloro-3-((2,4-dichlorophenyl)amino)-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-3-((2,5-dichlorophenyl)amino)-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine

1 ,1 -dioxide;

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)methanesulfonamide;

7-Chloro-3-((2,4-difluorophenyl)amino)-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((2,6-difluorophenyl)amino)-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)cyclopropanesulfonamide; 3-((1 H-lndol-6-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3- ((1 H-lndol-5-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-3-((4-fluoro-1 H-indol-6-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndol-4-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((1 H-lndol-7-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)benzenesulfonamide; N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)cyclopropanesulfonamide;

4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)-3- fluorobenzonitrile;

3-(Benzofuran-5-ylamino)-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 7-Chloro-5-hydroxy-3-((4-(phenylamino)phenyl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)benzamide;

N-(4-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)benzamide;

7-Chloro-3-((2,3-dihydro-1 H-inden-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-5-hydroxy-3-((2,4,6-trifluorophenyl)amino)-2H-be nzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-5-hydroxy-3-((6-methoxypyridin-3-yl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)-4- fluorobenzonitrile;

7-Chloro-3-((3-((dimethylamino)methyl)phenyl)amino)-5-hyd roxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-Benzo[d]imidazol-7-yl)amino)-7-chloro-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)methanesulfonamide;

7-Chloro-5-hydroxy-3-((3-phenoxyphenyl)amino)-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-5-hydroxy-3-((3-(phenylamino)phenyl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((3,5-difluorophenyl)amino)-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-5-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-(quinolin-8-ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-((3-methyl-1 H-indazol-6-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-(Benzo[d]thiazol-2-ylamino)-7-chloro-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine

1 ,1 -dioxide;

3-((1 H-lndazol-6-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-((4-methyl-1 H-indol-5-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetamide;

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetamide; 7-Chloro-3-((2,5-difluorophenyl)amino)-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine

1 ,1 -dioxide;

7-Chloro-3-((2-chloro-4-hydroxyphenyl)amino)-5-hydroxy-2H - benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((2-fluoro-4-hydroxyphenyl)amino)-5-hydroxy-2H - benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((2-fluoro-5-methylphenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-3-(cyclohexylamino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-((1 -methyl-1 H-indol-4-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)indolin-2-one; 3-((1 H-lndazol-7-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-3-((4-fluoro-2-methyl-1 H-indol-5-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-5-hydroxy-3-((3-methyl-1 H-indazol-5-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-4-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)-5- fluoro-2-hydroxyphenyl)acetamide; 7-Chloro-3-((4-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-(naphthalen-1 -ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Chloro-5-hydroxy-3-(naphthalen-2-ylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-fluoro-5-hydroxy-3-((3-hydroxyphenyl)amino)-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Fluoro-5-hydroxy-3-((4-hydroxyphenyl)amino)-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 - dioxide; 7-Fluoro-5-hydroxy-3-((4-methoxyphenyl)amino)-2H-benzo[e][1 ,2,4]thiadiazine

1 ,1 -dioxide; 7-Fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((4-Chlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Fluoro-5-hydroxy-3-(m-tolylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Fluoro-5-hydroxy-3-(p-tolylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Fluoro-5-hydroxy-3-((3-methoxyphenyl)amino)-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Fluoro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Fluoro-3-((4-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide; 3-((1 H-Benzo[d]imidazol-5-yl)amino)-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Fluoro-5-hydroxy-3-(o-tolylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-Chlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((2-Chlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((1 H-lndol-6-yl)amino)-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; tert-Butyl 7-((7-fluoro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)-3,4-dihydroisoquinoline-2(1 H)-carboxylate;

7-Fluoro-5-hydroxy-3-((1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-indol-5-yl)amino)-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 6,7-Dichloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7-Dichloro-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7-Dichloro-5-hydroxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-((1 H-Benzo[d]imidazol-6-yl)amino)-6,7-dichloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7-dichloro-3-((4-fluoro-1 H-indol-6-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 6,7-Dichloro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzo[e] [1 ,2,4]thiadiazine

1 ,1 -dioxide;

3-((1 H-lndol-5-yl)amino)-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((1 H-lndazol-6-yl)amino)-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-5-yl)amino)-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7-Dichloro-3-((3,4-dichloro-2-fluorophenyl)amino)-5-hyd roxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 6-Chloro-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

6-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

6-Fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

6-Fluoro-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide; 7-Bromo-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7- Bromo-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

8- Fluoro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 6-bromo-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

7-Bromo-6-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Bromo-6-chloro-3-((2-chlorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((2-chlorophenyl)amino)-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-6-fluoro-5-hydroxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 6-Chloro-8-fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-6-fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,8-Dichloro-5-hydroxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6-Chloro-3-((2-chlorophenyl)amino)-8-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7,8-Trichloro-5-hydroxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

8-Bromo-7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 3-((2-Fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine-7-carbonitrile 1 ,1 -dioxide;

7-Methoxy-3-((2-chlorophenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((2-chlorophenyl)amino)-5-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

5-Bromo-7-chloro-3-((2-chlorophenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

5,7-Dichloro-3-((2-chlorophenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7- Chloro-3-((2-chlorophenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

5-Hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2-Chlorophenyl)amino)-5-hydroxy-4-methyl-4H-benzo[e][ 1 ,2,4]thiadiazine 1 ,1 - dioxide;

5-Hydroxy-4-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

8- Bromo-7-chloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-Pyrrolo[2,3-b]pyridin-5-yl)amino)-7-chloro-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7-Dichloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-Chloro-3-((6-fluoro-1 H-indazol-4-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((6-chloro-1 H-indazol-4-yl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-(Benzo[d]thiazol-5-ylamino)-7-chloro-5-hydroxy-4H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7-chloro-5-hydroxy-8-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide; 7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine-8-carbonitrile

1 ,1 -dioxide;

3-((1 H-lndazol-4-yl)amino)-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

6,7-Dichloro-3-((2,5-dichlorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-4-yl)amino)-6-chloro-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-4-yl)amino)-6-chloro-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((1 H-lndazol-4-yl)amino)-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((1 H-lndazol-4-yl)amino)-8-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((1 H-lndazol-6-yl)amino)-6,7-difluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndol-5-yl)amino)-6,7-difluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

3-((1 H-lndazol-4-yl)amino)-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((1 H-lndazol-5-yl)amino)-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-6-fluoro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-4-yl)amino)-6,7-difluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 6,7-Difluoro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 6,7-Difluoro-3-((4-fluoro-1 H-indol-6-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((2,5-Dichlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzo [e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7- Chloro-3-((5-chloro-2-fluorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-lndazol-4-yl)amino)-8-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide;

8- Fluoro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 7,8-Dichloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-5-hydroxy-3-((7-methyl-1 H-indazol-4-yl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((7-fluoro-1 H-indazol-4-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((6-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((7-chloro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((3-(Aminomethyl)phenyl)amino)-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

3-((1 H-indazol-4-yl)amino)-7,8-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

7-Chloro-3-((7-chloro-1 H-indazol-4-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; 3-((2-Amino-1 H-benzo[d]imidazol-5-yl)amino)-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; and 3-((1 H-Benzo[d][1 ,2,3]triazol-7-yl)amino)-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; and pharmaceutically acceptable salts thereof. The skilled artisan will appreciate that pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention pharmaceutically acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to pharmaceutically acceptable salts, of the compounds according to Formula (I). The invention is further directed to free or unsalted compounds of Formula (I).

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 be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of 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 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. Accordingly, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may exist in solvated and unsolvated forms.

The skilled artisan will further appreciate that certain compounds of Formula (I) or 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." 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. Accordingly, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may exist in a single crystalline form or in different polymorphic forms.

DEFINITIONS

"Alkyl" refers to a hydrocarbon chain having the specified number of "member atoms". For example, C<\ -CQ 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. Alkyl includes but is not limited to: methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl. "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 carbon member atoms.

Examples of such groups include but is not limited to: methoxy, ethoxy, propoxy, butoxy, and t-butoxy.

"Aryl" refers to an aromatic hydrocarbon ring system. Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as but no limited to: phenyl, naphthalene, tetrahydronaphthalene and biphenyl. Suitably aryl is phenyl or naphthalene.

"Bicycloheteroaryl" refers to two fused ring syatems, wherein at least one ring system is aromatic, containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. Bicycloheteroaryl rings have from 6 to 1 1 member atoms. Bicycloheteroaryl includes but is not limited to: 1 /-/-pyrrolo[3,2-c]pyridine, 1 /-/-pyrazolo[4,3-c]pyridine, 1 H-pyrazolo[3,4- d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2- c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3-d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridine, imidazo[4.5-b]pyridine, furopyridinyl, napthyridinyl, tetrahydroisoquinoline, dihydroisoquinoline, benzothiazole, benzoimidazole, benzothiophene, benzofurane, benzodiazole, quinoline, quinoxaline, dihydrobenzodioxine, isoindoline, indole, indazole and indoline.

Suitably "Bicycloheteroaryl" includes: tetrahydroisoquinoline, dihydroisoquinoline, benzothiazole, benzoimidazole, benzothiophene, benzofurane, benzodiazole, quinoline, quinoxaline, dihydrobenzodioxine, isoindoline, indole, indazole and indoline. "Cycloalkyl", unless otherwise defined, refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl.

"Heteroaryl" refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl includes but is not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl. Suitably, "heteroaryl" includes: pyrazole, pyrrole, isoxazole, pyridine, pyrimidine, pyridazine, and imidazole.

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

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-fe/f-butyl dicarbonate);

BOP (Benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate);

CAN (cerric ammonium nitrate);

Cbz (benzyloxycarbonyl);

CSI (chlorosulfonyl isocyanate);

CSF (cesium fluoride);

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);

DIEA (diisopropylethylamine);

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

Dioxane (1 ,4-dioxane);

DMAP (4-dimethylaminopyridine); DME (1 ,2-dimethoxyethane);

DMEDA (Λ/,Λ/'-dimethylethylenediamine);

DMF (/V,/V-dimethylformamide);

DMSO (dimethylsulfoxide);

DPPA (diphenyl phosphoryl azide);

EDC (A/-(3-dimethylaminopropyl)-/V'ethylcarbodiimide) hydrochloride salt;

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)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate);

HOAt (1 -hydroxy-7-azabenzotriazole);

HOBt (1 -hydroxybenzotriazole);

HOAc (acetic acid);

HPLC (high pressure liquid chromatography);

HMDS (hexamethyldisilazide);

Hunig's Base (Λ/,/V-Diisopropylethylamine);

IPA (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);

NCS (N-chlorosuccinimide);

NBS (/V-bromosuccinimide);

PE (petroleum ether);

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

Pd(dppf)CI ₂ .DCM Complex([1 ,1 '-

Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).dic hloromethane complex);

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

PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);

RPHPLC (reverse phase high pressure liquid chromatography);

RT (room temperature);

Sat. (saturated)

SFC (supercritical fluid chromatography);

SGC (silica gel chromatography);

SM (starting material);

TCL (thin layer 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 compounds according to Formula I are prepared using conventional organic synthetic methods. Suitable synthetic routes are depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art. 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. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

As used in the Schemes, r ^2"5 represents all combinations of R ² , R ³ , R ⁴ , and R ⁵ disclosed herein. As used in the Schemes, R represents all values for R as used in Formulas I to IV.

General procedure for preparing 3-bromo-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxides (A2)

The general procedure for preparation of the key 3-bromo-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide intermediate A2 is shown in Scheme 1 . An aniline is treated with chlorosulfonyl isocyanate in 1 -nitropropane at -40 °C, allowed to warm to 0 °C, and AICI ₃ is then added. The reaction mixture is then stirred at 1 10 °C for 20-60 minutes until LCMS indicates the reaction has proceeded to completion. The reaction mixture is allowed to cool to room temperature and is then poured into ice water and stirred vigorously for 10-15 minutes. The precipitate is collected by filtration, washed with water and dried to afford the intermediate 2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one1 ,1 dioxide A1 , which is used without further purification.

The benzo[e][1 ,2,4]thiadiazin-3(4H)-one1 ,1 dioxide A1 is treated with phosphorus oxybromide in acetonitrile at 100 °C for 24 hours or in propionitrile at 1 15 °C. The crude product is isolated by partitioning between EtOAc and water, separating the EtOAc layer, drying it over sodium sulfate, filtering and evaporating to dryness. Alternatively, the crude product is isolated from the reaction mixture by removal of the solvent under reduced pressure. The crude product is purified by flash silica gel chromatography (EtOAc/DCM or MeOH/DCM) to afford the key 3-bromo-2H-benzo[e][1 ,2,4]thiadiazine-1 ,1 -dioxide A2.

SCHEME 1

It should be noted that 3-substituted benzothiadiazines such as A2 can exist in one of two tautomeric forms as shown below. When X = NHR, a third tautomeric form is also available. One skilled in the art will understand that any of these representations refers to the same compound. In the following Examples, the tautomeric forms are used interchangeably.

2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

X = Br, NHR

3-imino-3,4-dihydro-2/-/-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide General procedure for preparation of 3-anilino-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxides (A3)

The general procedure for preparation of the 3-anilino-2/-/- benzo[e][1 ,2,4]thiadiazine1 ,1 -dioxides (A3) is shown in Scheme 2 below. A 3-bromo-2H- benzo[e][1 ,2, 4]thiadiazine1 ,1 -dioxide (A2) and aniline are stirred in t-BuOH at 80 °C in the presence of potassium hydrogen phosphate (K ₂ HP0 ₄ ) or potassium dihyrdogen phosphate (KH ₂ PO ₄ ) for 1 -18 hrs. The crude product is conveniently precipitated from the reaction mixture by pouring it into cold water with vigorous stirring, collected by filtration, and purified by silica gel flash chromatography or preparative reversed phase HPLC.

SCHEME 2

A2 80 °C A3

Methods of Use The compounds according to Formula (I) and pharmaceutically acceptable salts thereof are inhibitors of CD73. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to CD73, for example, cancer and pre-cancerous syndromes. Accordingly, in another aspect the invention is directed to methods of treating such conditions.

The compounds of Formulas (IX), (MX), (MIX) and (IVX), and pharmaceutically acceptable salts thereof are inhibitors of CD73 and are useful in the methods of the invention, particularly in treatment of cancer and pre-cancerous syndromes. Suitably, the present invention relates to a method for treating breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating colon cancer. Suitably the present invention relates to a method for treating pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.

Suitably the present invention relates to a method for treating skin cancer, including melanoma, including metastatic melanoma. Suitably the present invention relates to a method for treating 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 cancers selected from the group consisting of: cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid glad, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemagioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; neoplasms of the CNS; spinal axis tumours; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hanlartoma; inesothelioma; and Hodgkin's Disease.

Suitably the present invention relates to a method for treating cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, 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, 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), neuroendocrine cancers and testicular cancer.

Suitably the present invention relates to a method for treating pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

In some embodiments, the compounds of the invention can be used to overcome Tcell tolerance.

Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viarl vaccines, and cancer vaccines such as GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).

In one embodiment, compounds of the invention are used to enhance the immune response in an immunosuppressed subject, such as a subject infected with an immunodeficiency virus (e.g., HIV-1 or HIV-2). In another embodiment, compounds of the invention are used to enhance the immune response in a subject infected with a pathogen such as a bacterial, viral, or fungal pathogen, to facilitate destruction of the pathogen in the subject.

Immune deficiencies associated with immune deficiency diseases, immune suppressive medical treatment, acute and/or chronic infection, and aging can be treated using the compounds disclosed herein. Compounds of the invention can be used to stimulate the immune system of patients suffering from medical treatment or iatrogenically induced immune suppression, including those who have undergone bone marrow transplants, chemotherapy, and/or radiotherapy.

In other embodiments, compounds of the invention are used to increase or enhance an immune response to an antigen by providing adjuvant activity. In one embodiment, at least one antigen or vaccine is administered to a subject in conjunction with at least one compound of the invention to prolong an immune response to the antigen or vaccine. Therapeutic compositions are also provided which include at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with a compound of the invention.

Compounds of the invention can be used as antidepressants, to stimulate cognitive functions, and to improve motor impairment due to neurodegenerative diseases such as Parkinson's disease.

Compounds of the present invention can be used to treat infections, in particular infections caused by pathogens that exploit extonucleotidases in order to generate adenosine-rich environments to escape immune surveillance and infections associated with inflammation. Diseases and disorders treatable with compounds of the invention include infections, including but not limited to, parasitic, fungal, bacterial, and viral infections, including, but not limited to, Leishmania, Trypanosoma, Toxoplasma, Trichomonas, Giardia, Candida, Legionellapneumophila, Staphylococcus aureus, Bacillus anthracis, Streptococcus sanguinis, Pseudomonas aeruginosa, and AIDS. Compounds of the invention can be used to treat sepsis, decrease or inhibit bacterial growth, reduce inflammatory cytokine levels, and lessen organ injury.

Further diseases and disorders treatable with compounds of the invention include, but are not limited to, neurological, CNS, respiratory, neurodegenerative, inflammatory, cardiovascular, gastrointestinal, ophthalmologic, connective tissue, and renal diseases and disorders.

Diseases and disorders treatable with compounds of the invention also include, but are not limited to, AIDS, HIV infection, extra pyramidal syndrome (EPS), dystonia, primary (idiopathic) dystonia, akathisia, pseudoparkinsonism, tardive dyskinesia, restless leg syndrome (RLS), periodic limb movement in sleep (PLMS), attention deficit disorders, including attention deficit hyperactivity disorder (ADHD), depression, anxiety, cognitive function diseases, cognitive decline, Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's disease, Wilson's disease, psychiatric disorders, Hallervorden-Spatz disease, progressive pallidal atrophy, cerebral ischemia, hemorrhagic stroke, neonatal ischemia and hypoxia, subarachnoid hemorrhage, traumatic brain injury, cardiac arrest, multiple sclerosis, diabetes, type II diabetes, diabetes mellitus, insulin resistance, risk of diabetes, epilepsy, asthma, chronic obstructive pulmonary disease (COPD), fibrosis, dermal fibrosis, hepatic fibrosis, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, interstitial fibrosis, cystic fibrosis, emphysema, peritoneal fibrosis, cardiac fibrosis, myocardial fibrosis, endomyocardial fibrosis, atrial fibrosis, alcoholic fatty liver disease, fatty liver, hepatic steatosis, cirrhosis, hepatic cirrhosis, nonalcoholic fatty liver disease (NAFLD), non-alcoholic hepatosteatosis (NASH), mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloids, hypertrophic scars, scleroderma, systemic sclerosis, arthrofibrosis, Peyronie's disease, priapism, Dupuytren's contracture, adhesive capsulitis, stroke, psychosis, psychoses of organic origin, dry eye disease, keratoconjunctivitis sicca, keratitis sicca, glaucoma, diabetic retinopathy, retinal ischemia, kidney disease, renal failure, and acute renal failure.

In some embodiments, diseases and disorders treatable with compounds of the invention are insulin resistance, diabetes and risk of diabetes. In some embodiments, compounds of the invention are used to reduce insulin resistance, reduce the risk of diabetes, decrease or inhibit statin-induced adenosine production, or reduce or decrease increases in blood glucose caused by a statin in a subject taking a statin. In some embodiments, compounds of the invention are used to treat diabetes in a subject taking a statin or to prevent diabetes in a subject taking a statin. Methods of the invention include decreasing, reducing, inhibiting, suppressing, limiting or controlling in the subject elevated blood glucose levels. In further aspects, methods of the invention include increasing, stimulating, enhancing, promoting, inducing or activating in the subject insulin sensitivity. Statins include, but are not limited to atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rousuvastatin and simvastatin.

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.

By the term "treating" and derivatives thereof as used herein, is meant therapeutic therapy. Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise 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 or 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 agent known to be useful in the treatment of cancer or pre-cancerous syndromes. By the term "co-administration" as used herein is meant either simultaneous administration or any manner of separate sequential administration of a CD73 inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active agent or agents, 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 & Wlkins Publishers. 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; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented combinations 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 anti-cancer 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,1 0β,1 3a-hexa-hydroxytax-1 1 -en-9-one 4,1 0- 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. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian and breast cancer in the United States.

Docetaxel, (2R.3S)- N-carboxy-3-phenylisoserine,N-fe/?-butyl ester, 13-ester with δβ-20-epoxy-l ,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 know 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 and is also incorporated 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 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) methyljmethylamino] 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(41-1, 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 l - DNA complex and prevents religation of singles 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; and 5,491 ,237.

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; progestrins 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 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 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, myo-inositol 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.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonam ide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonam ide can be prepared as described in International Application No. PCT/US01/49367.

Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidi nyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 .

5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrim idinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient ^® .

Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib.

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 nonreceptor 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.

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-dimethyl-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-dimethyl-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. /V-{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, /V-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 /-/-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. Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4- chloro-1 -methyl-1 /-/-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.

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 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 cancenerbB 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.

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.

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, p21 WAF1/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 in combination 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:

/V-hydroxy-/V'-phenyl-octanediamide

2. Romidepsin, including pharmaceutically acceptable salts thereof.

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

Romidepsin, has the following chemical structure and name:

(1 S,4S,7Z,10S,16E,21 R)-7-ethylidene-4,21 -di(propan-2-yl)-2-oxa-12,13-dithia-5, 8,20,23- tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-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:

(2£)-/V-hydroxy-3-[4-({[2-(2-methyl-1 /-/-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

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:

,.0

CH¾— CH;>— CM;.. ^'

2-propylpentanoic acid

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

Mocetinostat, has the fol

/V-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]m ethyl] 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 in combination 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 f?)-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 chemical structure and name.

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 1 18 (6): 1369-74.

Epigallocatechin gallate has t and name.

[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-y l]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 chemical structure and name.

(4R,5S)-4-(2-chloroethyl)-1 -((1 S)-cyclohex-2-enyl(hydroxy)methyl) -5-methyl-6-oxa-2- azabicyclo3.2.0heptane-3,7-dione 5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn DJ, et al, Blood, 2007, 1 10:3281 -3290.

Carfilzomib has the following chemical structure and name.

(S)-4-methyl-N-((S)-1 -(((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1 -oxopentan-2-yl)amino)-

1 -oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 - phenylbutanamido)pentanamide

The 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins (Hsp90s) are a family of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include:

1 . 17-AAG(Geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood. 2003 Sep 1 ;102(5):1824-32.

17-AAG(Geldanamycin) has the following chemical structure and name.

17-(Allylamino)-17-demethoxygeldanamycin

2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al.,

Mol Cell Endocrinol. 2002, 188,47-54)

Radicicol has the following chemical structure and name.

(1 aR,2Z,4E,14R,15aR)-8-chloro-9,1 1 -dihydroxy-14-methyl-15,15a-dihydro-1 aH- benzo[c]oxireno[2,3-k][1 ]oxacyclotetradecine-6,12(7H,14H)-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. al., Nature Reviews, 2010, 267.

P. Leder, et. al., Cancer Cell, 2006, 9, 425. High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance. Alii et al. Oncogene (2005) 24, 39-46. doi:10.1038

Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitable for use in combination with the compounds of this invention. Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are anti-PD-L1 agents.

Anti-PD-L1 antibodies and methods of making the same are known in the art. Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized.

Exemplary PD-L1 antibodies are disclosed in:

US Patent No. 8,217,149; 12/633,339;

US Patent No. 8,383,796; 13/091 ,936;

US Patent No 8,552,154; 13/120,406;

US patent publication No. 201 10280877; 13/068337;

US Patent Publication No. 20130309250; 13/892671 ;

WO2013019906;

WO2013079174;

US Application No. 13/51 1 ,538 (filed August 7, 2012), which is the US National Phase of International Application No. PCT/US10/58007 (filed 2010);

and

US Application No. 13/478,51 1 (filed May 23, 2012).

Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and methods for use are disclosed in US Patent No. 7,943,743; US20130034559, WO2014055897, US Patent No. 8,168,179; and US Patent No. 7,595,048. PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer.

In one embodiment, the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the antibody to PD-L1 is an antibody disclosed in US Application No. 13/51 1 ,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No. 13/51 1 ,538.

In another embodiment, the antibody to PD-L1 is an antibody disclosed in Application No. 13/478,51 1 . In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No. 13/478,51 1 .

In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1 105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another embodiment, the anti-PD-L1 antibody is MEDI4736.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are PD-1 antagonist.

"PD-1 antagonist" means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1 . Alternative names or synonyms for PD- 1 and its ligands include: PDCD1 , PD1 , CD279 and SLEB2 for PD-1 ; PDCD1 L1 , PDL1 , B7H1 , B7-4, CD274 and B7-H for PD-L1 ; and PDCD1 L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present invention in which a human individual is to be treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1 , and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1 . Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 , and preferably specifically binds to human PD-1 or human PD-L1 . The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of lgG1 , lgG2, lgG3 and lgG4 constant regions, and in preferred embodiments, the human constant region is an lgG1 or lgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.

Examples of mAbs that bind to human PD-1 , and useful in the vario us aspects and embodiments of the present invention, are described in US7488802, US7521051 , US8008449, US8354509, US8168757, WO2004/004771 , WO2004/072286, WO2004/056875, and US201 1/0271358.

Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161 -162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1 , pages 68-69 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 7; the humanized antibodies h409A1 1 , h409A16 and h409A17, which are described in WO2008/156712, and AMP-514, which is being developed by Medimmune.

Other PD-1 antagonists useful in the any of the aspects and embodiments of the present invention include an immunoadhesin that specifically binds to PD-1 , and preferably specifically binds to human PD-1 , e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO201 1 /066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1 . Other examples of mAbs that bind to human PD-L1 , and useful in the treatment method, medicaments and uses of the present invention, are described in WO2013/019906, W02010/077634 A1 and US8383796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C. KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No. 8,168,757. Opdivo/nivolumab is a fu M human monoclonal antibody marketed by Bristol Myers Squibb directed against, the negative immunoreguiatory human cell surface receptor PD-1 (programmed death-1 or programmed ceil death- 1 /PCD-1) with immunopotentiation activity. Nivo!umab binds to and blocks the activation of PD-1 , an ig superfamiiy transmembrane protein, by its ligands PD-L1 and PD-L2 resulting in the activation of T- celis and cell-mediated immune responses against tumor ceils or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P1 3k/Akt pathway activation. Other names for nivoiumab include: B S-936558, DX- 1 106, and ONO-4538. The amino acid sequence for nivoiumab and methods of using and making are disclosed in US Patent No. US 8,008,449.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are immuno-modulators.

As used herein "immuno-modulators" refer to any substance including monoclonal antibodies that affects the immune system. The ICOS binding proteins of the present invention can be considered immune-modulators. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer. For example, immune-modulators include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab). Other immuno- modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41 BB antibodies and GITR antibodies.

Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods are using are described in US Patent Nos. 6,984,720 and 7,605,238. CD134, also known as OX40, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naive T cells, unlike CD28. OX40 is a secondary costimulatory molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels. OX-40 antibodies, OX- 40 fusion proteins and methods of using them are disclosed in US Patent Nos: US 7,504,101 ; US 7,758,852; US 7,858,765; US 7,550,140; US 7,960,515; WO2012027328; WO2013028231 .

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are Toll-like Receptor 4 (TLR4) antagonists.

Aminoalkyl glucosaminide phosphates (AGPs) are known to be useful as vaccine adjuvants and immunostimulatory agents for stimulating cytokine production, activating macrophages, promoting innate immune response, and augmenting antibody production in immunized animals. Aminoalkyl glucosaminide phosphates (AGPs) are synthetic ligands of the Toll-like Receptor 4 (TLR4). AGPs and their immunomodulating effects via TLR4 are disclosed in patent publications such as WO 2006/016997, WO 2001 /090129, and/or U.S. Patent No. 6,1 13,918 and have been reported in the literature. Additional AGP derivatives are disclosed in U.S. Patent No. 7,129,219, U.S. Patent No. 6,525,028 and U.S. Patent No 6,91 1 ,434. Certain AGPs act as agonists of TLR4, while others are recognized as TLR4 antagonists.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are antibodies to ICOS.

CDRs for murine antibodies to human ICOS having agonist activity are shown in PCT/EP2012/055735 (WO 2012/131004). Antibodies to ICOS are also disclosed in WO 2008/137915, WO 2010/056804, EP 1374902, EP1374901 , and EP1 125585.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented compound of Formula (I) are STING modulating compounds, CD39 inhibitors and A2a and A2a adenosine antagonists.

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, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism. Compositions

The pharmaceutically active compounds within the scope of this invention are useful as CD73 inhibitors in mammals, particularly humans, in need thereof. The present invention provides a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof.

The present invention provides a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (I) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.

The present invention therefore provides a method of treating cancer, precancerous syndromes and other conditions requiring CD73 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 CD73 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, topical, subcutaneous, intradermal, intraocular 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 compositions 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 - 500 mg/kg of active compound, preferably 0.01 - 100 mg/kg. When treating a human patient in need of a CD73 inhibitor, the selected dose is administered preferably from 1 -6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.5 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 CD73 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 CD73 inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective CD73 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 CD73 inhibitor. The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer and pre-cancerous syndromes.

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

The invention also provides for a pharmaceutical composition for use as a CD73 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 CD73 inhibitor.

Contemplated Equivalents: - It will be appreciated by the person of ordinary skill in the art that the compounds of Formulas (I) to (IV) may exist in tautomeric forms. For example, when R1 = H, three tautomeric forms of the Formulas are available: (la), (lb) and (lc), where the "R" groups are as defined above. Similarly, when R1≠ H, two tautomeric forms of the Formulas are available: (Id) and (le), where the "R" groups are as defined above. It should be understood that the various tautomeric froms describe the same compound and that all such compounds are included in the scope of the invention and inherently included in the definition of the compounds of Formulas (I) to (IV). The tautomeric forms are used interchangeably in the Examples.

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.

Intermediates

7-Chloro-5-methoxy-2H-benzorein ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-1)

To a vigorously stirred solution of 4-chloro-2-methoxyaniline (4.8 g) in 1 -nitropropane (10 ml_) at -40 °C was added chlorosulfonyl isocyanate (3.5 ml_) in 1 -nitropropane (40 ml_) dropwise. The reaction mixture was allowed to warm to 0 °C and aluminum chloride (5.5 g) was added in portions. The reaction mixture was then allowed to stir at 1 10 °C for 30 minutes. The reaction mixture was allowed to cool to room temperature and was then poured into ice water (250 mL) and stirred for 10 minutes. The resulting precipitate was collected by filtration, washed with water, air-dried and then dried in vacuum for 24 hours, affording the titled compound (3.6 g) as a brown solid, which was used without further purification. LCMS m/z 263.0 (M+H).

Alternatively, to a stirred solution of chlorosulfonyl isocyanate (35.8 mL) in 1 -nitropropane (400 mL) at -40 °C was added dropwise a solution of 4-chloro-2-methoxyaniline (50 g) in 1 -nitropropane (100 mL). The reaction mixture was warmed to 0 °C. After 1 h, aluminum chloride (55.0 g) was added to the reaction mixture. The reaction mixture was warmed to 1 10 °C for 1 h. The reaction mixture was poured into ice-water (1 .5 L). The solids were filtered and dried under high vacuum to afford the titled compound (45 g) as a brown solid. LCMS m/z 260.97 (M-H).

3-Bromo-7-chloro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-2)

A solution of 7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (Int- 1 , 4.5 g) and phosphorus oxybromide (25.0 g) in acetonitrile (130 mL) was stirred at 1 10 °C for 24 hours. The reaction mixture was allowed to cool to room temperature and a few ice chips were added. The reaction mixture was allowed to stir for 3-4 minutes, then was diluted with EtOAc and washed with water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction product was purified by silica gel flash chromatography, eluting with a 0-40% gradient of EtOAc in DCM to afford the titled compound (2.9 g) as a tan solid. LCMS m/z 324.9 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 3.97 (s, 3 H) 7.45 (d, J=2.02 Hz, 1 H) 7.41 (d, J=2.02 Hz, 1 H).

Alternatively, to a stirred solution of 7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin- 3(4H)-one 1 ,1 -dioxide (lnt-1 , 45 g) in propionitrile (700 mL) at room temperature was added phosphorus oxybromide (246 g). The reaction mixture was heated to 1 15 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with cold water (1 .5 L). The solids were filtered and dried under vacuum to afford the titled compound (40 g) as an ash- colored solid. LCMS m/z 323.10 (M-H). 3-Bromo-7-chloro-5-hvdroxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-3)

To a stirred solution of 3-bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-2, 12.0 g) in DCE (150 mL) was added BBr ₃ (13.94 mL) at RT. The reaction mixture was then stirred at 80 °C for 16 hr. The reaction mixture was allowed to cool to RT and poured into ice water (500 mL). The resulting precipitate was collected by filtration and air-dried to afford the titled compound (1 1 .0 g), which was used without further purification. LCMS m/z 310.86 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.75 (br. s., 1 H) 7.1 1 (d, J=2.19 Hz, 1 H) 7.28 (d, J=2.19 Hz, 1 H) 1 1 .71 (br. s., 1 H).

Alternatively, to a stirred solution of 3-bromo-7-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 1 1 g) in 1 ,2-dichloroethane (150 mL) in a sealed tube at 0 °C was added BBr ₃ (12.78 mL). The reaction mixture was warmed to 80 °C. After 16h, the reaction mixture was cooled to room temperature and diluted with cold water (500 mL). The solids were filtered and dried under vacuum to afford the titled compound (10.5 g) as an off-white solid. LCMS m/z 310.96 (M+H).

6-Chloro-5-methoxy-2H-benzoreiri ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-4)

A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (6.93 ml) in nitropropane (86 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 3-chloro-2-methoxyaniline (10.22 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 1 h, aluminum chloride (10.81 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 °C. After 60 min, the reaction mixture was checked by LCMS and showed a peak matching the expected product. The reaction was poured into ice/water (400 mL) and stirred. The solids were filtered and washed with water, and dried in a vacuum oven at 50 °C to afford the titled compound (5.8 g). LCMS m/z 262.9 (M+H).

3-Bromo-6-chloro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-5)

A 250 mL round-bottomed flask was charged with 6-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-4, 5.8 g) and phosphorus oxybromide (31 .7 g) in acetonitrile (200 ml) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred to 90 °C. After 2 days, the reaction mixture was checked by LCMS and showed a peak matching the expected product as well as some residual starting material. An additional aliquot of phosphorus oxybromide (1 g) was added to the reaction mixture. The reaction mixture was stirred to 100 °C. After 4 days, the reaction mixture was checked by LMCS and showed a peak matching the expected product. The reaction was concentrated under reduced pressure, diluted with ice/water and stirred for 1 h. The solids were filtered and washed with water and hexane to afford the titled compound (6.1 g). LCMS m/z 325.0 (M+H).

3-Bromo-6,7-dichloro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-6)

A 20 mL microwave tube was charged with 3-bromo-6-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-5, 574 mg) in N,N-dimethylformamide (10 mL) to give a brown solution at 0 °C under nitrogen. NCS (706 mg) in DMF (2.5 mL) was added to the reaction mixture. After 10 min, the reaction was stirred to room temperature. After 2 days, the reaction mixture was pouring into water and stirred for 30 min. The solids were filtered and washed with water and hexanes to obtain to afford the titled compound (477 mg). LCMS m/z 358.9 (M+H).

Alternatively, to a stirred solution of 3-bromo-6-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-5, 10 g) in Λ/,/V-dimethylformamide (270 mL) at 0 °C was added a solution of NCS (12.30 g) in Λ/,/V-dimethylformamide (60 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with cold water. The solids were filtered, washed with water (2 x 100 mL), and dried under vacuum to afford the titled compound (8 g). LCMS m/z 356.76 (M-H).

3-Bromo-6.7-dichloro-5-hvdroxy-2H-benzorein ,2.41thiadiazine 1.1 -dioxide (lnt-7)

A 25 mL microwave tube was charged with 3,6-dibromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-6, 650 mg) in dichloromethane (10 mL) to give a white suspension at 0 °C under nitrogen. Boron tribromide (5.27 mL, 1 N in dichloromethane) was added to the reaction mixture. The reaction was stirred to 50 °C. After 2h, the reaction mixture was checked by LCMS and showed a new peak matching the expected product. The reaction mixture was poured in ice/water and stirred. The solids were filtered washed with water and hexanes to obtain to afford the titled compound (240 mg). LCMS m/z 344.9 (M+H). Alternatively, to a stirred solution of 3-bromo-6,7-dichloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-6, 8 g) in 1 ,2-dichloroethane (150 mL) in a sealed tube at room temperature was added BBr ₃ (8.40 mL). The reaction mixture was heated to 80 °C. After 16 h, the reaction mixture was cooled to room temperature and diluted with cold water (100 mL). The solids were filtered, washed with water (100 mL), and dried under vacuum to afford the titled compound (3.4 g) as brown solid. LCMS m/z 343.12 (M-H).

6-Fluoro-5-methoxy-2H-benzorein ,2.41thiadiazin-3(4H)-one 1.1 -dioxide (lnt-8)

A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (1 .476 ml) in nitropropane (50.1 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 3-fluoro-2-methoxyaniline (2 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 1 h, aluminum chloride (2.362 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 °C. After 30 min, the reaction was poured into ice/ water (400 mL) and stirred. The solids were filtered and washed with water and hexanes and the solids were dried in a vacuum oven at 50 °C to obtain 6-fluoro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (2.6 g). LCMS m/z 247.0 (M+H).

3-Bromo-6-fluoro-5-methoxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-9)

A 250 mL round-bottomed flask was charged with 6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-8, 1 .35 g) and phosphorus oxybromide (7.86 g) in acetonitrile (50 mL) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred to 80 °C. After overnight, phosphorus oxybromide (1 g) was added to the reaction mixture. The reaction was stirred to 100 °C for 3 days. The reaction was concentrated under reduced pressure, diluted with water and extracted with EtOAc (3 times). The ethyl acetate layers were dried over Na ₂ S0 ₄ , filtered through pad of silica gel, and concentrated to obtain 3-bromo-6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (1 .67 g). LCMS m/z 309.0 (M+H). 7-Bromo-5-methoxy-2H-benzore1M ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-10)

A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (1 .031 ml) in nitropropane (45 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 4-bromo-2-methoxyaniline (2 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 20min, aluminum chloride (1 .650 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 °C. After 30 min, the reaction was poured into ice/ water (400 mL) and stirred. The solids were filtered and washed with water and hexanes. The solids were placed in vacuum over at 50 °C the titled compound (2.6 g). LCMS m/z 307.1 (M+H). Alternatively, to a stirred solution of chlorosulfonyl isocyanate (27.9 mL) in 1 -nitropropane (400 mL) at -40 °C was added a solution of 4-bromo-2-methoxyaniline (50 g) in 1 - nitropropane (100 mL). The reaction mixture was warmed to 0 °C for 1 hr. Aluminum chloride (42.9 g) was added to the reaction mixture. The reaction mixture was heated to 1 10 °C for 30 min. The reaction mixture was cooled to room temperature and poured into ice water (1 .5 L). The solids were filtered and dried under vacuum to afford the titled compound (50 g) as a brown solid. LCMS 304.93 m/z (M-H).

3,7-Dibromo-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-11 )

A 250 mL round-bottomed flask was charged with 7-bromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-10, 1 .24 g) and phosphorus oxybromide (5.79 g) in acetonitrile (50 mL) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred to 90 °C. After 3 days, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc (2x). The ethyl acetate layers were dried over Na ₂ S0 ₄ , filtered through a pad of silca gel, and concentrated to obtain 3,7-dibromo-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (1 .27 g), which was used without further purification. LCMS m/z 371 .0 (M+H).

Alternatively, to a stirred solution of 7-bromo-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin- 3(4H)-one 1 ,1 -dioxide (lnt-10, 60 g) in propionitrile (1 L) at room temperature was added phosphorus oxybromide (280 g). The reaction mixture was heated to 120 °C for 36 h. The reaction mixture was cooled to room temperature and diluted with ice water (3 L). The solids were filtered, washed with water (500 mL), and dried under vacuum to afford the titled compound (53 g) as a brown solid. LCMS m/z 368.71 (M+H). 8-Fluoro-5-methoxy-2H-benzoreiri ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-12)

A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (2.058 ml) in nitropropane (20 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 5-fluoro-2-methoxyaniline (2.72 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 1 h, aluminum chloride (3.21 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 °C. After 30 min, the reaction mixture was poured in ice/water (400 mL) and stirred for 1 h. The solids were filtered and washed with water. The solids were placed in drying oven overnight at 50 °C to obtain the titled compound (2.3 g). LCMS m/z 247.1 (M+H).

3-Bromo-8-fluoro-5-methoxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-13)

A 125 mL round-bottomed flask was charged with 8-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-12, 500 mg) and phosphorus oxybromide (291 1 mg) in acetonitrile (15 mL) to give a white suspension at room temperature under argon. The reaction mixture was heated to 90 °C. After overnight reaction, the reaction mixture was concentrated. The reaction mixture was diluted with and the pH adjusted with Na ₂ C0 ₃ (sat'd) to pH 8 and then extracted with DCM. The aqueous layer was acidified with HCI to pH 1 . The reaction mixture was extracted then with EtOAc (3x). The ethyl acetate layer was dried over Na ₂ S0 ₄ , filtered, and concentrated to obtain the titled compound (250 mg), which was used without further purification. LCMS m/z 309.0 (M+H).

6-Bromo-5-methoxy-2H-benzorein ,2.41thiadiazin-3(4H)-one 1.1 -dioxide (lnt-14)

A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (2.57 ml) in nitropropane (40.2 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 3-bromo-2-methoxyaniline (4.87 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 1 h, aluminum chloride (4.02 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 °C. After 30 min, the reaction mixture was poured into ice/ water (400 mL) and stirred. The reaction mixture was extracted with DCM (3x). The dichloromethane layers were dried over Na ₂ S0 ₄ , filtered, and concentrated. The crude solid was stirred with EtOAc (10 mL). The solids were filtered and washed with hexanes to obtain the titled compound (1 .6 g), which was used without further purification. LCMS m/z 306.9 (M+H). Alternatively, to a solution of chlorosulfonyl isocyanate (0.645 mL) in 1 -nitropropane (15 mL) at -40 °C was added a solution of 2-bromo-3-methoxyaniline (1 .00 g) in 1 -nitropropane (5 mL) dropwise. The reaction mixture stirred at -40 °C for 20 minutes, then warmed to 0 °C over 1 hour. Then, aluminum chloride (0.858 g) was added. The reaction mixture was stirred at 1 10 °C for 2 hours. After cooling to RT, the reaction mixture was poured on an ice-water mixture and stirred for 10 minutes. The precipitate was filtered via vacuum filtration, washed with water, and dried in vacuo to afford the titled compound (1 .12 g) as a tan solid. LCMS m/z 307.1 , 309.1 (M+H). 3,6-Dibromo-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-15)

A 250 mL round-bottomed flask was charged with 6-bromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-14, 1 .6 g) and phosphorus oxybromide (7.47 g) in acetonitrile (52.1 ml) to give a white/yellow suspension at room temperature under nitrogen. The reaction mixture was stirred at 90 °C. After 2 days, the reaction was concentrated under reduced pressure, diluted with ice/water, and stirred for 30 min. The solids were filtered and washed with water followed by hexanes to obtain the titled compound (1 .4 g). LCMS m/z 370.9 (M+H).

3,6-Dibromo-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-16)

A 25 mL microwave tube was charged with 3,6-dibromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-15, 650 mg) in dichloromethane (10 mL) to give a white suspension at 0 °C under nitrogen. Boron tribromide (1 N in DCM, 5.27 mL) was added to the reaction mixture. After 2h, the reaction mixture was poured in ice/water and stirred. The solids were collected by filtration. The solids were dissolved into methanol and concentrated. The solid was stirred with EtOAc for 1 h. The solids were filtered and washed with hexanes to obtain the titled compound (371 mg), which was used without further purification. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.53 (d, J=8.59 Hz, 1 H) 7.17 (d, J=8.84 Hz, 1 H) 7-Bromo-6-chloro-5-methoxy-2H-benzore1M ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (Int- 17)

A 20 mL microwave tube was charged with 7-bromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-10, 600 mg) in N,N- dimethylformamide (15 mL) to give a brown solution at 0 °C under nitrogen. NCS (783 mg) in DMF (0.5 mL) was added to the reaction mixture. The reaction was stirred to room temperature. After 7 days, the reaction was poured in water and filtered. The filtrate was extracted with DCM (3x). The dichloromethane layers were dried over Na2S04, filtered, and concentrated to obtain 551 mg of a mixture of 7-bromo-6-chloro-3-hydroxy-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide [LCMS m/z 341 .1 (M+H)] and 7-bromo-8-chloro-3- hydroxy-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide [LCMS m/z 341 .1 (M+H)] and residual starting material, which was carried on without purification.

3,7-Dibromo-6-chloro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-18) A 250 mL round-bottomed flask was charged with the above mixture of 7-bromo-6-chloro- 3-hydroxy-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide and 7-bromo-8-chloro-3- hydroxy-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-17, 551 mg) and phosphorus oxybromide (2312 mg) in acetonitrile (100 ml) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred to 100 °C. After 3 days, the reaction was concentrated. The reaction was diluted with ice/water and stirred for 1 h. The solids were filtered and washed with water and hexanes. The solid was chromatographed on silica gel column and eluted with a 5-75% gradient of ethyl acetate in hexanes, and the clean fractions were concentrated to obtain 3,7-dibromo-6-chloro-5- methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (130 mg). LCMS m/z (M+H)].

3.7-Dibromo-6-chloro-5-hvdroxy-2H-benzorein ,2.41thiadiazine 1.1 -dioxide (lnt-19)

A 20 mL microwave tube was charged with 3,7-dibromo-6-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-18, 130 mg) in dichloromethane (5 mL) to give a brown suspension at room temperature under nitrogen. Boron tribromide (1 M in DCM, 0.964 mL) was added to the reaction mixture. The sealed reaction mixture was stirred at 50 °C. After overnight reaction, the reaction mixture was concentrated, quenched with ice/water, and stirred for 20 min. The solids were filtered and dried in a vacuum oven to obtain 3,7-dibromo-6-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (88 mg). LCMS m/z 390.9 (M+H).

3-Bromo-7-chloro-6-fluoro-5-methoxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (Int- 20)

A 20 mL microwave tube was charged with 3-bromo-6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-9, 1000 mg) in N,N-dimethylformamide (15 mL) to give a yellow solution at 0 °C under nitrogen. NCS (1296 mg) in DMF (4 mL) was added to the reaction mixture. After 10 min, the reaction allowed to warm to room temperature and stirred at RT for 2 days. The reaction mixture was poured into water and stirred for 30 min. The solids were filtered and washed with water and hexanes to obtain the titled compound (824 mg). LCMS m/z 345.0 (M+H).

3-Bromo-7-chloro-6-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (Int- 21)

A 20 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-20, 610 mg) in dichloromethane (10 mL) to give a brown suspension at room temperature under nitrogen. Boron tribromide (1 M in DCM, 5.33 mL) was added to the reaction mixture. The sealed reaction mixture was stirred at 50 °C. After 5 h, the reaction was allowed to cool to room temperature overnight. The reaction mixture was then concentrated, diluted with ice/water and stirred for 20 min. The solids were filtered and dried in a vacuum oven to obtain the titled compound (470 mg). LCMS m/z 295.1 (M+H). 3-Bromo-6-chloro-8-fluoro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (Int- 22)

A 20 mL microwave tube was charged with 3-bromo-8-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (A13, 459 mg) in N,N-dimethylformamide (10 mL) to give a brown solution at 0 °C under nitrogen. NCS (595 mg) in 2 mL of DMF was added to the reaction mixture. The reaction was stirred at room temperature for 2 days. The reaction mixture was then poured into water and stirred for 30 min. The solids were filtered and washed with water. The solids were dissolved into DCM/MeOH (1 :1) and filtered again. The filtrate was dried over Na ₂ S0 ₄ , filtered and concentrated to obtain the titled compound. (289 mg). LCMS m/z 342.9 (M+H).

3-Bromo-6-chloro-8-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (Int- 23)

A 20 mL microwave tube was charged with 3-bromo-6-chloro-8-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-22, 289 mg) in dichloromethane (5 mL) to give a white suspension at room temperature under nitrogen. Boron tribromide (1 M in DCM, 2.52 mL) was added to the reaction mixture. The sealed reaction was stirred to 50 ^° C overnight. The reaction mixture was then concentrated, diluted with ice/water and stirred for 30 min. The solids were collected by filtration and dried in a vacuum oven to obtain the titled compound (98 mg). LCMS m/z 329.0 (M+H).

6,8-Dichloro-5-methoxy-2H-benzorein ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-24) A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (0.717 ml) in nitropropane (40 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 3,5-dichloro-2-methoxyaniline (1220 mg) in nitropropane (20 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 30 min, aluminum chloride (1 101 mg) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 100 °C. After 45 min, the reaction mixture was poured in ice/water (400 mL) and stirred for 1 h. The solids were filtered and washed with water and hexanes, and dried in a vacuum oven overnight to obtain the titled compound (391 mg). LCMS m/z 297.1 (M+H).

3-Bromo-6.8-dichloro-5-methoxy-2H-benzorein ,2.41thiadiazine 1.1 -dioxide (lnt-25) A 200 mL round-bottomed flask was charged with 6,8-dichloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-24, 391 mg) in propionitrile (15 mL) to give a brown suspension at room temperature under nitrogen. Phosphorus oxybromide (1886 mgl) was added to the reaction mixture. The reaction mixture was stirred to 1 10 °C for 2 da. The reaction was then concentrated and diluted with ice/water and stirred for 30 min. The solids were filtered and washed with water and hexanes. The solids were placed in vacuum oven overnight at 50 °C to obtain the titled compound (307 mg). LCMS m/z 359.1 (M+H). 3-Bromo-6,8-dichloro-5-hvdroxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-26)

A 20 mL round-bottomed flask was charged with 3-bromo-6,8-dichloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-24, 207 mg) in dichloromethane (4 mL) to give a brown suspension at 0 °C under nitrogen. Boron tribromide (1 M in DCM, 1 .725 mL) was added to the reaction mixture. The reaction mixture was stirred to 40 °C. After 3 h, the reaction mixture was concentrated, then diluted with ice/water and stirred for 30 min. The solids were filtered and washed with water and hexanes. The solids were dried in vacuum oven overnight at 50 °C to obtain the titled compound (133 mg). LCMS m/z 345.0 (M+H).

3-Bromo-6,7,8-trichloro-5-methoxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-27)

A 20 mL microwave tube was charged with 3-bromo-6,8-dichloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-25, 100 mg) in Ν,Ν-dimethylformamide (DMF) (3 mL) to give a brown solution at 0 °C under nitrogen. NCS (74.2 mg) in 2 mL of DMF was added to the reaction mixture. The reaction was stirred at o room temperature overnight. The reaction mixture was then poured into ice/water and stirred for 30 min. The solids were filtered, washed with water and hexanes. The solids were dried in vacuum oven overnight to obtain the titled compound (50 mg). LCMS m/z 395.0 (M+H). 3-Bromo-6,7,8-trichloro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-28)

A 20 mL round-bottomed flask was charged with 3-bromo-6,7,8-trichloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-27, 50 mg) in dichloromethane (2 mL) to give a brown suspension at 0 °C under nitrogen. Boron tribromide (1 M in DCM, 0.380 mL) was added to the reaction mixture. The reaction was stirred to 40 °C. After 3 h, the reaction mixture was concentrated, diluted with ice/water and stirred for 30 min.The solids were filtered and washed with water and hexanes. The solids were dried in vacuum oven overnight at 50 °C to afford the titled compound (40 mg). LCMS m/z 381 .0 (M+H).

7-Methoxy-2H-benzorein ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-29)

A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (2.75 ml) in nitropropane (40.6 ml) to give a colorless solution at -40 °C under nitrogen. After 10 min, a solution of 4-methoxyaniline (3 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 1 h, aluminum chloride (4.22 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 °C. After 30 min, the reaction mixture was poured in ice/water (400 mL) and stirred for 1 h. The solid was filtered and washed with water and hexanes, and was placed in drying oven overnight at 50 °C to obtain the titled compound (4.02 g). LCMS m/z 229.1 (M+H).

3-Bromo-7-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-30)

A 250 mL round-bottomed flask was charged with 7-methoxy-2H-benzo[e][1 ,2,4]thiadiazin- 3(4H)-one 1 ,1 -dioxide (lnt-29, 1 .53 g) in acetonitrile (100 ml) to give a yellow suspension at room temperature under nitrogen. Phosphorus oxybromide (9.61 g, 33.5 mmol) was added to the reaction mixture. The reaction was stirred to 100 °C overnight. The reaction mixture was concentrated and then stirred with ice/water for 1 h. The solids were filtered and washed with hexanes to obtain the titled compound (1 .68 g). LCMS m/z 290.9 (M+H).

5-Bromo-7-chloro-2H-benzorein ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-31)

To a solution of chlorosulfonyl isocyanate (1 .6 mL) in 1 -nitropropane (15 mL) at -40 °C was added a solution of 2-bromo-4-chloroaniline (3.0 g) in 1 -nitropropane (10 mL) dropwise. The reaction mixture was allowed to warm up to 0 °C over 10 minutes and aluminum chloride (2.5 g) was added at once, and the reaction mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was poured on an ice-water mixture and stirred for 10 minutes. The resulting precipitate collected by filtration, washed with water, and dried in vacuo overnight to a brown solid. The solid was purified using reversed phase HPLC (15-35% acetonitrile (with 0.1 % TFA modifier): water (with 0.1 % TFA modifier), C18 50x30 mm Luna column, 47 mL/min). The desired fractions were combined and evacuated in vacuo to afford the titled compound (757 mg) as a white. LCMS m/z 310.9 (M+H).

Alternatively, to a stirred solution of chlorosulfonyl isocyanate (31 .5 mL) in 1 -nitropropane (400 mL) at -40 °C was added a solution of 2-bromo-4-chloroaniline (50 g) in 1 -nitropropane (150 mL). The reaction mixture temperature was raised to 0 °C. After 2 hr, aluminum chloride (42.0 g) was added to the reaction mixture. The reaction mixture was warmed to 100 °C for 2 hr. The reaction mixture was cooled to room temperature and diluted with ice water (1000 mL). The solids were filtered, washed with water (500 mL), and dried under vacuum to afford the titled compound (30 g) as a white solid. LCMS m/z 31 1 .54 (M-H).

3,5-Dibromo-7-chloro-4H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-32)

To a solution of 5-bromo-7-chloro-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (Int- 31 , 750 mg) in acetonitrile (12 mL) at room temperature was added phosphorus oxybromide (3451 mg) in one charge. The mixture was warmed to 90 °C and stirred for 12 days, during which time additional acetonitrile was added as needed to replenish evaporated solvent and wash solids down the sides of the flask. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and acidic water. The aqueous layer was further extracted with EtOAc (2 x 30 mL). The aqueous layer was then made basic and extracted with EtOAc (1 x 30 mL). Finally, the aqueous layer was adjusted to pH = 5 and extracted with EtOAc (1 x 30 mL), and the combined organic layers were washed with brine, dried (Na2S04), filtered and evaporated in vacuo to afford the titled compound (732 mg) as an off-white solid. LCMS m/z 372.9 (M+H).

Alternatively, to a stirred solution of 5-bromo-7-chloro-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)- one 1 ,1 -dioxide (lnt-31 , 30 g) in propionitrile (600 mL) at room temperature was carefully added phosphorus oxybromide (138 g). The reaction mixture was heated to 1 15 °C for 16 hr. The reaction mixture was cooled to room temperature and diluted with ice water (700 mL). The solids were filtered, washed with water (2 x 300 mL), and dried under vacuum to afford the titled compound (15 g) as a brown solid. LCMS m/z 372.95 (M-H).

5,7-Dichloro-2H-benzorein ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-33)

To a solution of chlorosulfonyl isocyanate (1 .9 mL) in 1 -nitropropane (20 mL) at -40 °C was added a solution of 2,4-dichloroaniline (3.0 g) in 1 -nitropropane (10 mL) in one portion. The reaction mixture was allowed to warm up to 0 °C over 1 hour. Then, aluminum chloride (2.9 g) was added at once, and the reaction mixture was stirred at 100 °C for 3 hours. After cooling to room temperature, the reaction mixture was poured on an ice-water mixture and stirred for 30 minutes. The precipitate was filtered, washed with water, and dried in vacuo overnight to afford a tan solid. The solid was absorbed onto silica and purified on a standard pre-packed silica column (AnaLogix SuperFlash, 150 g silica) eluted with a gradient of 0- 100% EtOAc in hexanes. The desired fractions were combined and evaporated in vacuo, then triturated in methanol and filtered via vacuum filtration to afford the titled compound (360 mg) as an off-white solid. LCMS m/z 267.1 (M+H). 3-Bromo-5,7-dichloro-4H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-34)

To a 20 mL microwave reaction vial was added 5,7-dichloro-2H-benzo[e][1 ,2,4]thiadiazin- 3(4H)-one 1 ,1 -dioxide (lnt-33, 350 mg) in acetonitrile (3 mL) at room temperature, followed by phosphorus oxybromide (1503 mg) in one charge. The reaction vial was sealed and the mixture was stirred at 80 °C overnight in a standard reaction block. The sides of the vial were washed down with acetonitrile (2 mL) and an additional portion (0.5 mg) of POBr ₃ was added. The reaction stirred at 80 °C for 6 hours, then at room temperature for 2 days. Water was slowly added and the reaction mixture was extracted with EtOAc (2 x 30 mL). The aqueous layer was adjusted to pH = 5 and further extracted with EtOAc (1 x 30 mL). The combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated in vacuo to afford an off-white solid. The solid was purified on a standard pre-packed silica column (Biotage ZIP, 45 g silica) eluted with a gradient of 0-100% EtOAc in hexanes. The desired fractions were combined and evaporated in vacuo to afford the titled compound (222 mg) as a white solid. LCMS m/z 329.1 (M+H).

8-Bromo-7-chloro-5-methoxy-2H-benzore1M ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (Int- 35)

To a solution of chlorosulfonyl isocyanate (1 .7 ml) in 1 -nitropropane (100 ml) cooled to -40 °C was slowly added a solution of 5-bromo-4-chloro-2-methoxyaniline (3.6 g) in 1 - nitropropane (35 ml). The resulting suspension was warmed to 0 °C and stirred for 1 hour at that temperature. To the reaction was added aluminum chloride (2.64 g) and the resulting dark red solution was heated at 100 °C for 18 hours. The suspension was concentrated to about 50 ml then poured into ice water. The solids were collected by filtration and rinsed with water. The filtrate was extracted with EtOAc then the extracts were dried (sodium sulfate) and concentrated to a dark residue. The crude product residue and the previously filtered solids were combined, dissolved in acetone then treated with decolorizing charcoal. The suspension was filtered through celite and concentrated to a residue that was triturated from DCM to afford 8-bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (1 .3 g) as an off-white solid. LCMS m/z 341 .1 (M+H).

3,8-Dibromo-7-chloro-5-methoxy-4H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-36)

A 25 ml microwave reaction vial with stir bar was charged with a suspension of 8-bromo-7- chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-35, 280 mg) in propionitrile (8.0 ml) then phosphorus oxybromide (940 mg) was added in one portion. The vessel was sealed then heated on an aluminum block at 100 °C for 4 days. The reaction was cooled, diluted with water then extracted with EtOAc. The dried extracts (sodium sulfate) were concentrated to a residue that was triturated from ethyl ether to afford 3,8- dibromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (237 mg) as a pale orange solid. LCMS m/z 405.0 (M+H). ¹ H NMR (400 MHz, DMSO-cfe) L ppm 7.62 (s, 1 H) 3.95 (s, 3 H).

7-Fluoro-5-methoxy-2H-benzore1M ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-37)

To a stirred solution of chlorosulfonyl isocyanate (31 .5 mL) in 1 -nitropropane (350 mL) was added a solution of 4-fluoro-2-methoxyaniline (44 g) in 1 -nitropropane (150 mL) at -40 °C. Then the reaction mixture temperature was raised to 0 °C and stirred for 1 hr. Aluminium chloride (48.3 g) was the added at 0 °C. Then the reaction mixture temperature was warmed to 1 10 °C and stirred for 1 hr. The reaction mixture was then poured in to ice-water (200 mL), and the resulting solid was filtered and dried under vacuum to afford the titled compound (22.5 g) which was used without further purification. LCMS m/z 245.15 (M-H) ^~ .

3-Bromo-7-fluoro-5-methoxy-4H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide (lnt-38)

To a stirred solution of 7-fluoro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (lnt-37, 25 g) was added phosphorus oxybromide (146 g) at RT. The reaction mixture temperature was raised to 1 10 °C and the reaction mixture was stirred for 16 hr. The reaction mixture was then poured into ice water and extracted with EtOAc (3 x 350 mL). The combined EtOAc extracts were washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with 5% MeOH/DCM and dried under vacuum to afford the titled compound (13 g), which was used without further purification. LCMS m/z 309.07(M+H).

3-Bromo-7-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-39)

To a stirred solution of 3-bromo-7-fluoro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-38, 5 g) in 1 ,2-Dichloroethane (DCE) (100 mL) was added BBr ₃ (12.23 mL) at RT. The reaction mixture was warmed to 80 °C and stirred for for 16 hr. The reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (4.5 g), which was used without further purification. LCMS m/z 294.84 (M+H). 7-Chloro-5-fluoro-2H-benzorein ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide (lnt-40)

To a stirred solution of chlorosulfonyl isocyanate (3.64 mL) in n-nitropropane (80 mL) was added a solution of 4-chloro-2-fluoroaniline (5.0 g) in n-nitropropane dropwise at -45 °C. The reaction mixture was allowed to warm to 0 °C and aluminum chloride (5.73 g) was added in portion. The reaction mixture was then stirred at RT for 1 hr and for 1 hr at 1 10 °C. The reaction mixture was cooled to RT, decanted in ice water (60ml) and filtered, and the filtrate was concentrated under reduced pressure to afford the crude product (7 g) as brown gummy oil. The crude product was purified by column chromatography using neutral alumina (25g), eluting with 10% ammonia in 10% MeOH/DCM. The desired fractions were concentrated under reduced pressure and the resulting solid was washed with 5% MeOH in DCM to afford the titled compound (900 mg). LCMS m/z 249.0 (M-H)-.

3,7-Dichloro-5-fluoro-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide (lnt-41)

To a stirred solution of 7-chloro-5-fluoro-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (lnt-40, 500 mg) in POCI ₃ (5.0 mL) was added N,N-diethylaniline (744 mg) dropwise at 5 °C. The reaction mixture was allowed to warm to RT and was then stirred at 80 °C for 8 hr. The reaction mixture was allowed to cool to RT and then quenched with saturated aq sodium bicarbonate solution. The reaction mixture was then extracted with EtOAc (3 x 105 mL). The combined EtOAc extracts were washed with brine solution (10 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure and the resulting solid washed with EtOAc to afford the titled compound (300 mg) as an off-white solid, which was used without further purification. LCMS m/z 266.8 (M-H) ^" .

Example 1

4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)benzonitrile

(a) 4-((7-Chloro-5-methoxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 50 mg), 4- aminobenzonitrile (21 .8 mg) and KH ₂ P0 ₄ (25.1 mg) were suspended in n-BuOH (5 mL) and stirred at 80 °C for 16 hr. The reaction was allowed to cool to RT, diluted with water and extracted with DCM (2 x 30 ml_). The combined DCM extracts were washed with saturated brine, dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure to afford the crude product (129 mg). The crude product was purified by silica gel flash chromatography (10 g column) eluting sequentially with DCM (100 ml_), 1 % MeOH/DCM (100 ml_), 2% MeOH/DCM (100 ml_), and 3% MeOH/DCM (100 mL) to afford the titled compound (18 mg). LCMS 362.97 (M+H). The above procedure was repeated using 3-bromo-7-chloro-5- methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 250 mg), 4-aminobenzonitrile (109 mg) and KH ₂ P0 ₄ (125 mg) in n-BuOH (10 mL), and the crude product was purified as described to yield the titled compound (137 mg). LCMS m/z 362.75 (M+H).

(b) 4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile

To a suspension of the combined 4-((7-Chloro-5-methoxy-1 ,1 -dioxido-2H- benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzonitrile from Example 1 (a) above (155 mg) in DCM (5 mL) at 0 °C was added BBr ₃ (2.14 mL). The reaction mixture was then stirred at 50 °C for 16 hr. Solvent was removed under reduced pressure to afford the crude product (289 mg). The crude product was purified by silica gel flash chromatography (20 g column) eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL), 4% MeOH/DCM (100 mL) and 6% MeOH/DCM (100 mL) followed by preparative reversed phase HPLC (Sunfire C18 19 x 150 mm) using a 10-50% gradient of 0.1 % formic acid/water in acetonitrile, to afford the titled compound (42 mg). LCMS m/z 348.95 (M+H); ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.05 (d, J=2.19 Hz, 1 H) 7.16 (d, J=2.19 Hz, 1 H) 7.72 - 7.77 (m, 2 H) 7.80 - 7.85 (m, 2 H). Example 2

7-Chloro-5-hvdroxy-3-((4-hvdroxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 7-Chloro-3-((4-hydroxyphenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 100 mg), 4- methoxyaniline (45.4 mg) and KH ₂ P0 ₄ (50.2 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 a. The crude product (100 mg) was used without further purification. LCMS m/z 367.8 (M+H).

The above procedure was repeated using 3-bromo-7-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 300 mg), 4-methoxyaniline (136 mg) and KH2PO4 (150 mg) in n-BuOH (5 mL). The crude product (280 mg) was used without further purification. LCMS m/z 367.92 (M+H).

(b) 7-Chloro-5-hydroxy-3-((4-hydroxyphenyl)amino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

The combined 7-Chloro-3-((4-hydroxyphenyl)amino)-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide from Example 2(a) (380 mg) was reacted with BBr ₃ (5.17 mL) as in Example 1 (b) for 10 hr. The crude product was purified by silica gel flash chromatography (20 g column) eluting with DCM (200 mL), 1 % MeOH/DCM (200 mL), 2% MeOH/DCM (200 mL), and 3% MeOH/DCM (200 mL) to afford the titled compound (170 mg). LCMS m/z 339.93 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-cf ₆ ) δ ppm 6.71 - 6.88 (m, 2 H) 7.06 (d, J=2.19 Hz, 1 H) 7.15 (d, J=1 .97 Hz, 1 H) 7.27 (d, J=8.77 Hz, 2 H).

Example 3

3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3-

(a) 3-((7-Chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 500 mg), 3- aminobenzonitrile (218 mg) and KH2PO4 (251 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a). The crude product (360 mg) was used without further purification. LCMS m/z 361 .33 (M-H ).

(b) 3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile

3-((7-Chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzonitrile was reacted with BBr3 (4.96 mL) in DCM (15 mL) as in Example 1 (b). Removal of solvent under reduced pressure afforded the crude product (350 mg) which was purified by silica gel flash chromatography (20 g column) eluting with DCM (200 mL), 1 % MeOH/DCM (200 mL), 2% MeOH/DCM (200 mL) and 3% MeOH/DCM (200 mL), followed by preparative reversed phase HPLC (Atlantis T3 19x250 mm) using 35% (0.1 % formic acid/water) to afford the titled compound (49 mg). LCMS m/z 348.95 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 1 .23 (br. s., 1 H) 7.00 (s, 1 H) 7.10 (s, 1 H) 7.53 - 7.61 (m, 2 H) 7.78 (d, J=7.67 Hz, 1 H) 8.04 (s, 1 H). Example 4

7-Chloro-3-((3-chlorophenyl)amino)-5-hydroxy-2H-benzoreir i ,2,41thiadiazine 1 ,1 -

(a) 7-Chloro-3-((3-chlorophenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 100 mg), 3- chloroaniline (47 mg) and KH ₂ P0 ₄ (50.2 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a). The crude product (179 mg) was purified by silica gel flash chromatography (10 g column) eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL) and 3% MeOH/DCM (100 mL) to afford the titled compound (41 mg). LCMS m/z 370.21 (M-H ).

The above procedure was repeated using 3-bromo-7-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg), 3-chloroaniline (188 mg) and KH2PO4 (201 mg) in n-BuOH (10 mL). Purification of the crude produce as described above afforded the titled compound (246 mg). LCMS m/z 371 .95 (M+H). (b) 7-Chloro-3-((3-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

The combined 7-chloro-3-((3-chlorophenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide from Example 4(a) (280 mg) was reacted with BBr ₃ (3.76 mL) in DCM (10 mL) as in Example 1 (b). Removal of solvent under reduced pressure gave the crude product (489 mg) which was purified by silica gel flash chromatography (20 g column) eluting with hexane (200 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL), 4% MeOH/DCM (100 mL) and 6% MeOH/DCM), followed by preparative reversed phase HPLC (X-Bridge C18 19x50 mm) using a gradient of 0-100% 5 mM ammonium formate/water in acetonitrile to afford the titled compound (126 mg). LCMS m/z 357.91 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.03 - 7.06 (m, 1 H) 7.13 - 7.21 (m, 2 H) 7.35 - 7.44 (m, 2 H) 7.76 (s, 1 H).

Example 5

7-chloro-3-((4-chlorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 7-Chloro-3-((4-chlorophenyl)amino)-5-methoxy-3,4-dihydro-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 100 mg), 4- chloroaniline (47 mg) and KH ₂ P0 ₄ (50 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (60 mg) which was used without further purification. LCMS m/z 372.03 (M+H).

The above reaction was repeated using 3-bromo-7-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg), 4-chloroaniline (187 mg) and KH2PO4 (199 mg) in n-BuOH (20 mL) to afford the crude product (320 mg) which was used without further purification. LCMS m/z 372.29 (M+H). (b) 7-chloro-3-((4-chlorophenyl)amino)-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

The combined 7-Chloro-3-((4-chlorophenyl)amino)-5-methoxy-3,4-dihydro-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (380 mg) was reacted with BBr ₃ (5.1 mL) in DCM (15mL) as in Example 1 (b). The reaction mixture was diluted with water and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product (430 mg), which was purified by silica gel flash chromatography (20 g column) eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL) and 4% MeOH/DCM (100 mL) to afford the titled compound (134 mg). LCMS m/z 357.83 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.09 (d, J=2.19 Hz, 1 H) 7.19 (d, J=2.19 Hz, 1 H) 7.45 (d, J=8.99 Hz, 2 H) 7.55 (d, J=8.99 Hz, 2 H).

Example 6

7-Chloro-5-hvdroxy-3-(m-tolylamino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

(a) 7-Chloro-5-methoxy-3-(m-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 300 mg), m- toluidine (1 18 mg) and KH ₂ P0 ₄ (150 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a) to give the crude product (280 mg) which was used without further purification. LCMS m/z 350.31 (M-H ).

(b) 7-Chloro-5-hydroxy-3-(m-tolylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

7-Chloro-5-methoxy-3-(m-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (280 mg) was reacted with BBr ₃ (3.98 mL) in DCM (10 mL) as in Example 1 (b). Removal of solvent under reduced pressure gave the crude product (290 mg) which was purified by silica gel flash chromatography (20 g column) eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL) and 4% MeOH/DCM (100 mL) to afford the titled compound (168 mg). LCMS m/z 337.97 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.30 - 2.36 (m, 3 H) 7.00 (d, J=7.02 Hz, 1 H) 7.10 (d, J=2.19 Hz, 1 H) 7.19 (d, J=2.19 Hz, 1 H) 7.26 - 7.37 (m, 3 H).

Example 7

7-chloro-5-hvdroxy-3-(p-tolylamino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

(a) 7-Chloro-5-methoxy-3-(p-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 100 mg), p- toluidine (39.5 mg) and KH ₂ P0 ₄ (50.2 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (70 mg) which was used without further purification. LCMS m/z 351 .80 (M+H).

The above reaction was repeated using 3-bromo-7-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg), p-toluidine (158 mg) and KH ₂ P0 ₄ (201 mg) in n-BuOH (5 mL) to afford the crude product (320 mg) which was used without further purification. LCMS m/z 351 .94 (M+H).

(b) 7-Chloro-5-hydroxy-3-(p-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

The combined 7-chloro-5-methoxy-3-(p-tolylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide from Example 7(a) (390 mg) was reacted with BBr ₃ (4.27 mL) in DCM (15 mL) as in Example 1 (b). Removal of solvent under reduced pressure gave the crude product (500 mg). The crude product was purified by silica gel flash chromatography (50 g column) eluting with DCM (200 mL), 1 % MeOH/DCM (200 mL), 2% MeOH/DCM (200 mL) and 3% MeOH/DCM (200 mL) followed by preparative reversed phase HPLC (Xbridge C18 4.6 x 150 mm) using a gradient of 5-95% 0.01 ammonium bicarbonate/water in acetonitrile. The desired fractions were evaporated to dryness, dissolved in EtOAc (100 mL), washed with water (2 x 10 mL), dried over sodium sulfate, filtered and evaporated to dryness to afford the titled compound (28 mg). LCMS m/z 337.95 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 2.30 (s, 3 H) 7.1 1 (d, J=2.19 Hz, 1 H) 7.17 - 7.26 (m, 3 H) 7.38 (d, J=8.33 Hz, 2 H).

Example 8

7-Chloro-3-((3-cvclopropylphenyl)amino)-5-hvdroxy-2H-benzore iri ,2,41thiadiazine

1 ,1 -dioxide

(a) 7-Chloro-3-((3-cyclopropylphenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 500 mg), 3- cyclopropylaniline (245 mg) and KH ₂ P0 ₄ (251 mg) in n-BuOH (10 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (678 mg), which was purified by silica gel flash chromatography (10 g column) eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL) and 3% MeOH/DCM (100 mL) which afforded the titled compound (321 mg). LCMS m/z 378.0 (M+H).

(b) 7-Chloro-3-((3-cyclopropylphenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To 7-chloro-3-((3-cyclopropylphenyl)amino)-5-methoxy-4H-benzo[e ][1 ,2,4]thiadiazine 1 ,1 - dioxide (250 mg) in DMSO (10 mL) was added LiCI (140 mg) and the reaction mixture was stirred at 150 °C for 10 hr. The reaction mixture was allowed to cool to RT and was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with saturated brine (20 mL), dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product (356 mg). The crude product was purified by silica gel flash chromatography (20 g column) eluting with DCM (500 mL), 2% MeOH/DCM (500 mL), 4% MeOH/DCM (500 mL) and 6% MeOH/DCM (500 mL), followed by preparative reversed phase HPLC (25 x 150 mm Kromosil phenyl) using a gradient of 10-40% 5 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were combined and lyophilized to afford the titled compound (107 mg). LCMS m/z 364.03 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-cfe) δ ppm 0.64 - 0.70 (m, 2 H) 0.99 (dd, ^8.44, 2.19 Hz, 2 H) 1 .86 - 2.01 (m, 1 H) 6.87 (s, 1 H) 7.08 (d, J=2.14 Hz, 1 H) 7.16 - 7.20 (m, 2 H) 7.24 - 7.31 (m, 2 H).

Example 9

7-Chloro-3-((4-cvclopropylphenyl)amino)-5-hvdroxy-2H-benzore in .2.41thiadiazine

1 ,1 -dioxide

(a) 7-chloro-3-((4-cyclopropylphenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 500 mg), 4- cyanoaniline (245 mg) and KH ₂ P0 ₄ (251 mg) in n-BuOH (10 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (689 mg). The crude product was purified by silica gel flash chromatography (10 g column), eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL) and 3% MeOH/DCM (100 mL) to afford the titled compound (367 mg). LCMS m/z 377.8 (M+H).

(b) 7-chloro-3-((4-cyclopropylphenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To 7-chloro-3-((4-cyclopropylphenyl)amino)-5-methoxy-4H-benzo[e ][1 ,2,4]thiadiazine 1 ,1 - dioxide (300 mg) in DMSO (10 mL) was added LiCI (168 mg) and the reaction mixture was stirred at 150 °C for 10 hr. The reaction mixture was allowed to cool to RT and was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product (326 mg). The crude product was purified by silica gel column chromatography (20 g column) eluting with DCM (500 mL), 2% MeOH/DCM (500 mL), 4% MeOH/DCM (500 mL) and 6% MeOH/DCM (500 mL) followed by preparative reversed phase HPLC (25 x 150 mm Kromosil phenyl) using a gradient of 0-40% 5 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were combined and lyophilized to afford the titled compound (34 mg). LCMS 364.03 (M+H). ¹ H NMR after D20 exchange (400 MHz, DMSO-cfe) δ ppm 0.65 (dd, J=5.04, 2.08 Hz, 2 H) 0.94 (dd, J=8.30, 2.06 Hz, 2 H) 1 .83 - 1 .98 (m, 1 H) 7.07 - 7.13 (m, 3 H) 7.17 (d, J=2.19 Hz, 1 H) 7.35 - 7.40 (m, 2 H).

Example 10

3-((4-Aminophenyl)amino)-7-chloro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 3-((4-aminophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg), benzene-1 ,4-diamine (159 mg) and KH2PO4 (201 mg) in n-BuOH (15 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (689 mg). The crude product was purified by silica gel flash chromatography (10 g column) eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL) and 3% MeOH/DCM (100 mL) to afford the titled compound (213 mg). LCMS m/z 353.1 (M+H).

(b) 3-((4-Aminophenyl)amino)-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

7-Chloro-3-((4-aminophenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (180 mg) was reacted with BBr ₃ (2.55 mL) in DCM (10 mL) as in Example 1 (b). Removal of solvent under reduced pressure afforded the crude product (267 mg). The crude product was purified by silica gel flash chromatography (20 g column) eluting with DCM (300 mL), 2% MeOH/DCM (300 mL), 4% MeOH/DCM (300 mL) and 6% MeOH/DCM (300 mL) followed by preparative reversed phase HPLC (25 x 150 mm Kromosil phenyl) using a gradient of 0-40% 5 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were combined and lyophilized to afford the titled compound (57 mg). LCMS m/z 338.94 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.55 - 6.63 (m, 2 H) 7.03 (d, J=2.19 Hz, 1 H) 7.08 - 7.13 (m, 3 H).

Example 11

3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)benzamide

(a) 3-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzamide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg), 3- aminobenzamide (201 mg) and KH ₂ P0 ₄ (201 mg) in n-BuOH (5 ml_) were reacted and worked up as in Example 1 (a) to afford the crude product (330 mg) which was used without further purification. LCMS m/z 380.96 (M+H).

(b) 3-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzamide

3-((7-chloro-5-methoxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzamide (330 mg) was reacted with BBr ₃ (0.41 ml_) in DCM (15 ml_) as in Example 1 (b). The reaction mixture was quenched with water (15 ml_) and extracted with DCM (2 x 50 ml_). The combined DCM extracts were washed with saturated brine (50 ml_), dried over sodium sulfate, filtered and evaporated to afford the crude product (270 mg). The crude product was purified by preparative reversed phase HPLC (X-Bridge C18, 4.6 x 75 mm) using a gradient of 5-50% 5 mM ammonium bicarbonate/water in acetonitrile to afford the titled compound (76 mg). LCMS m/z 367.00 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.08 (d, J=2.19 Hz, 1 H) 7.17 (d, J=2.14 Hz, 1 H) 7.48 (t, J=7.89 Hz, 1 H) 7.63 (ddd, J=7.92, 1 .40, 1 .21 Hz, 1 H) 7.72 (dd, J=2.38, 1 .12 Hz, 1 H) 7.73 - 7.76 (m, 1 H) 7.89 (t, J=1 .95 Hz, 1 H). Example 12

7-Chloro-5-hvdroxy-3-((3-hvdroxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 7-chloro-5-methoxy-3-((3-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg), 3- methoxyaniline (182 mg) and KH ₂ P0 ₄ (201 mg) in n-BuOH (15 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (350 mg), which was used without further purification. LCMS m/z 367.8 (M+H).

(b) 7-Chloro-5-hydroxy-3-((3-hydroxyphenyl)amino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

7-Chloro-5-methoxy-3-((3-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (140 mg) was reacted with BBr ₃ (1 M in DCM, 1 .465 mL) as in Example 1 (b). Removal of solvent under reduced pressure afforded the crude product (400 mg). The crude product was purified by preparative reversed phase HPLC (X-Bridge C18 4.6 x 75 mm) using a gradient of 5-50% 5 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were combined, concentrated, dissolved in EtOAc (100 mL), washed with water (2 x 10 mL), dried over sodium sulfate, filtered and evaporated to dryness to afford the purified product (55 mg). LCMS m/z 339.97 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 6.57 (ddd, J=8.1 1 , 2.30, 0.77 Hz, 1 H) 6.85 - 6.92 (m, 1 H) 7.05 (d, J=1 .97 Hz, 1 H) 7.08 (t, J=2.19 Hz, 1 H) 7.13 (d, J=2.19 Hz, 1 H) 7.18 (t, J=8.1 1 Hz, 1 H)

Example 13

7-chloro-3-((4-(dimethylamino)phenyl)amino)-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

(a) 7-Chloro-3-((4-(dimethylamino)phenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 350mg), N1 ,N1 -dimethylbenzene-1 ,4-diamine (176 mg) and KH ₂ P0 ₄ (176 mg) in n-BuOH (5 mL) were reacted as in Example 1 (a). The reaction mixture was filtered to afford the crude product (340 mg), which was used without further purification. LCMS m/z 381 .1 (M+H).

(b) 7-chloro-3-((4-(dimethylamino)phenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

A suspension of 7-chloro-3-((4-(dimethylamino)phenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (340 mg) in DCM (5 mL) was reacted with BBr ₃ (0.174 mL) in DCM as in Example 1 (b). After removal of solvent under reduced pressure, the residue was quenched with saturated NaHC0 ₃ (aq) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were dried over sodium sulfate and evaporated to afford the crude product (400 mg). The crude product was purified by silica gel flash chromatography (15 g column) eluting with DCM (300 mL) and then 5% MeOH/DCM (300 mL), followed by preparative reversed phase HPLC (X-Bridge C18, 30 x 250 mm) using 50% 10 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were combined and lyophilized to afford the titled compound (108 mg). LCMS 366.99 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.88 (s, 6 H) 6.64 - 6.88 (m, 2 H) 7.02 (d, J=1 .97 Hz, 1 H) 7.10 (d, J=1 .97 Hz, 1 H) 7.18 - 7.37 (m, 2 H). Example 14

1 -(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)ethanone

(a) 1 -(3-((7-Chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 500mg), 1 - (3-aminophenyl)ethanone (249 mg) and KH ₂ P0 ₄ (251 mg) in n-BuOH (5 mL) were reacted as in Example 1 (a). The reaction mixture was filtered to afford the crude product (350 mg), which was used without further purification. LCMS m/z 378.33 (M-H) ^" .

(b) 1 -(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone

1 -(3-((7-Chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone (250 mg) was reacted with BBr ₃ (3.29 mL) in DCM (4 mL) as in Example 1 (b). The reaction mixture was diluted with water (5 mL) and filtered to obtain the crude product (180 mg). The crude product was purified by silica gel flash chromatography (15 g column) eluting with 5% MeOH/DCM, followed by preparative reversed phase HPLC (X-Bridge C18, 19 x 150 mm) using a gradient of 10-50% 10 mM ammonium bicarbonate/water in acetonitrile to afford the titled compound (20 mg). LCMS m/z 366.12 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.60 (s, 3 H) 7.01 (d, J=2.19 Hz, 1 H) 7.10 (d, J=1 .97 Hz, 1 H) 7.52 - 7.59 (m, 1 H) 7.70 - 7.82 (m, 2 H) 8.07 (t, J=1 .86 Hz, 1 H).

Example 15

7-Chloro-5-hvdroxy-3-((3-methoxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To 7-chloro-5-methoxy-3-((3-methoxyphenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (Example 12(a), 100 mg) in DCM (5 mL) was added BBr ₃ (1 .047 mL) at 0 °C and the reaction was then stirred at 40 °C for 10 hr. Removal of solvent under reduced pressure afforded the crude product which was purified by silica gel flash chromatography (100 g column), eluting with 5% MeOH/DCM (500 mL) to afford the partially purified product (50 mg).

The above procedure was repeated on the same scale to afford an additional 60 mg of partially purified product.

The combined partially purified products (1 10 mg) were then purified by preparative reversed phase HPLC (XBridge C18, 4.6 x 75 mm) using a gradient of 5-50% 10 mM ammonium bicarbonate/water in acetonitrile. The appropriated fractions were concentrated, dissolved in EtOAc (100 mL), washed with water (2 x 10 mL), dried over sodium sulfate, filtered and evaporated to obtain the titled compound (39 mg). LCMS m/z 353.95 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 3.72 (s, 3 H) 6.70 (dd, J=8.1 1 , 2.19 Hz, 1 H) 6.96 - 7.04 (m, 2 H) 7.05 - 7.18 (m, 2 H) 7.26 (t, J=8.22 Hz, 1 H).

Example 16

7-Chloro-5-hvdroxy-3-((1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-4H- benzorein .2.41thiadiazine 1.1 -dioxide. Trifluoroacetic acid salt

(a) 7-Chloro-5-methoxy-3-((1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 200 mg), tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1 H)-carboxylate (200 mg), potassium dihydrogen phosphate (1 10 mg), and tert-Butanol (3 mL) were stirred at 80 °C for 16 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in DMSO (2.5 mL). The clear yellow solution was decanted from the insoluble potassium phosphate with a pipette, and was then purified via injection onto a Biotage Isolera One, 25 gram Biotage KP-C18-HS column, using a 0-100% IPA:H ₂ 0 (0.1 % formic acid in the water) gradient to afford the titled compound (69 mg) as a white solid. LCMS m/z 393.1 (M+H).

(b) 7-Chloro-5-hydroxy-3-((1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

7-Chloro-5-methoxy-3-((1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (69 mg) was stirred in Dichloromethane (DCM) (5 mL) at 0°C as 1 M BBr ₃ in DCM (900 μί) was added dropwise via syringe. After the addition, the ice bath was removed and the reaction stirred at 50 °C. After 6 hours, the reaction was cooled to room temperature. An ice bath was placed under the reaction flask and MeOH (~ 10 mL) was added to decompose the remaining BBr ₃ . The reaction was returned to room temperature and concentrated in vacuo. The residue was taken up in MeOH and filtered over Celite, rinsing the Celite with MeOH. The filtrate was concentrated in vacuo, and was purified via reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (26 mg) as a white solid. LCMS m/z 379.1 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 2.98 (t, J=6.19 Hz, 2 H) 3.39 (t, J=6.19 Hz, 2 H) 4.32 (s, 2 H) 7.07 (d, J=2.27 Hz, 1 H) 7.17 (d, J=2.02 Hz, 1 H) 7.26 (d, J=8.34 Hz, 1 H) 7.37 (d, J=2.27 Hz, 1 H) 7.39 (s, 1 H) 9.03 (br. s., 1 H) 9.57 (s, 1 H) 10.22 (br. s., 1 H) 1 1 .75 (br. s., 1 H).

Example 17

7-Chloro-5-hvdroxy-3-((1 ,2,3,4-tetrahvdroisoquinolin-6-yl)amino)-4H- benzoreiri ,2,41thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

(a) tert-Butyl 6-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)-3,4-dihydroisoquinoline-2(1 H)-carboxylate, Formic acid salt

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 170 mg), tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1 H)-carboxylate (170 mg), potassium dihydrogen phosphate (95 mg,), and tert-Butanol (3 mL) were reacted and purified as in Example 16(a) to afford the titled compound (1 10 mg) as a white solid. LCMS m/z 493.3 (M+H).

(b) 7-Chloro-5-hydroxy-3-((1 ,2,3,4-tetrahydroisoquinolin-6-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

tert-Butyl 6-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)- 3,4-dihydroisoquinoline-2(1 H)-carboxylate, Formic acid salt (1 10 mg), 1 M BBr ₃ in DCM (1 .0 ml), and Dichloromethane (DCM) (5 mL) were reacted and purified as in Example 16(b) to afford the titled compound (36 mg) as a white solid. LCMS m/z 379.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 3.02 (t, J=6.32 Hz, 2 H) 3.40 (t, J=6.32 Hz, 2 H) 4.26 (s, 2 H) 7.07 (d, J=2.27 Hz, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.24 (d, J=9.09 Hz, 1 H) 7.32 - 7.45 (m, 2 H) 9.02 (br. s., 1 H) 9.60 (s, 1 H) 10.24 (s, 1 H) 1 1 .80 (br. s., 1 H).

Example 18

7-Chloro-3-((3-ethylphenyl)amino)-5-hvdroxy-2H-benzorein ,2.41thiadiazine 1.1 - dioxide

(a) 7-Chloro-3-((3-ethylphenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 300mg), 3- ethylaniline (134 mg) and KH ₂ P0 ₄ (150 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (225 mg), which was used without further purification. LCMS m/z 365.85 (M+H).

(b) 7-Chloro-3-((3-ethylphenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

7-Chloro-3-((3-ethylphenyl)amino)-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (200 mg) was reacted with BBr ₃ (2.73 mL) in DCM (10 mL) for 10 hr as in Example 1 (b). Removal of solvent under reduced pressure afforded the crude product (220 mg), which was purified by silica gel flash chromatography (20 g column), eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (150 mL), 4% MeOH/DCM (200 mL) and 8% MeOH/DCM (300 mL) to afford the titled compound (39 mg). LCMS m/z 351 .97 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 1 .20 (t, J=7.67 Hz, 3 H) 2.63 (q, J=7.38 Hz, 2 H) 7.03 (d, J=7.23 Hz, 1 H) 7.1 1 (d, J=1 .97 Hz, 1 H) 7.19 (d, J=1 .97 Hz, 1 H) 7.27 - 7.39 (m, 3 H).

Example 19

7-Chloro-5-hvdroxy-3-((4-(methylamino)phenyl)amino)-2H- benzorelH ,2.41thiadiazine 1.1 -dioxide

(a) tert-Butyl methyl(2-nitrophenyl)carbamate

N-Methy-2-nitroaniline (4 g), di-tert-butyl dicarbonate (9.16 mL) and DMAP (0.161 g) were combined in THF (40 mL) at RT and then heated at 65 °C for 2 hr. Solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography (100 g column), eluting with 20% EtOAc/hexane (500 mL) to afford the titled compound (4 g). LCMS m/z 152.99 (M+H-Boc). (b) tert-Butyl methyl(2-nitrophenyl)carbamate

To a solution of tert-butyl methyl(2-nitrophenyl)carbamate (2 g) in EtOH (30 mL) at RT was added ammonium chloride (4.24 g) in water (6 mL) in one portion. The reaction mixture was heated to 80 °C and iron (2.214 g) was added. The reaction mixture was stirred at 80 °C for 2 hr. Solvent was then removed under reduced pressure and the residue was dissolved in water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by silica gel flash chromatography (100 g column), eluting with 25% EtOAc/hexane (500 mL) to afford the titled compound (1 .7 g). LCMS m/z 223.21 (M+H).

(c) tert-Butyl (4-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)(methyl)carbamate and 7-chloro-5-methoxy-3-((2-

(methylamino)phenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400mg), tert-Butyl methyl(2-nitrophenyl)carbamate (328 mg) and KH ₂ P0 ₄ (201 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a) to afford a mixture (260 mg) containing both the Boc product (LCMS m/z 467.13 (M+H)) and the des-Boc product (LCMS m/z 367.09 (M+H)), which was carried on to the next step without further purification.

(d) 7-Chloro-5-hydroxy-3-((4-(methylamino)phenyl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

The mixture of Boc and des-Boc products from Example 19(c) (260 mg) was reacted with BBr ₃ (1 M in DCM, 2.784 mL) as in Example 1 (b). Removal of the solvent under reduced pressure afforded the crude product, which was purified by silica gel flash chromatography (20 g column), eluting with 10% MeOH/DCM (200 mL) followed by preparative reversed phase HPLC (XBridge C18, 4.6 x 250 mm) using a 10-50% gradient of 5 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were concentrated and dissolved in EtOAc (100 mL), washed with water (2 x 10 mL) and evaporated to dryness to afford the titled compound (104 mg). LCMS m/z 353.02 (M+H). Ή NMR after D20 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.68 (s, 3 H) 6.56 - 6.61 (m, 2 H) 7.07 (d, J=2.19 Hz, 1 H) 7.14 (d, J=2.19 Hz, 1 H) 7.15 - 7.21 (m, 2 H). Example 20

3-((3-Aminophenyl)amino)-7-chloro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 3-((3-Aminophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 500mg), benzene-1 ,3-diamine (199 mg) and KH ₂ P0 ₄ (201 mg) in n-BuOH (5 mL) were reacted and worked up as in Example 1 (a) to afford the crude product (679 mg). The crude product was purified by silica gel flash chromatography (30 g column), eluting with DCM (500 mL), 1 % MeOH/DCM (500 mL), 2% MeOH/DCM (500 mL), 4% MeOH/DCM (500 mL) and 6% MeOH/DCM (500 mL) to afford the titled compound (312 mg). LCMS m/z 352.91 (M+H).

(b) 3-((3-Aminophenyl)amino)-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-((3-Aminophenyl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (300 mg) was reacted with BBr ₃ (3.32 mL) in DCM (10 mL) for 16 hr as in Example 1 (b). Removal of solvent under reduced pressure afforded the crude product (527 mg), which was purified by silica gel flash chromatography (30 g column), eluting with DCM (500 mL), 1 % MeOH/DCM (500 mL), 2% MeOH/DCM (500 mL), 4% MeOH/DCM (500 mL) and 6% MeOH/DCM (500 mL) followed by preparative reversed phase HPLC (XBridge C18 30 x 250 mm) using a gradient of 25-57% 10 mM ammonium bicarbonate/water in acetonitrile. The appropriate fractions were combined and lyophilized to afford the titled compound (54 mg). LCMS m/z 338.94 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.37 (dd, J=8.00, 1 .43 Hz, 1 H) 6.68 (dd, J=7.56, 1 .64 Hz, 1 H) 6.73 (t, J=2.08 Hz, 1 H) 7.01 (t, J=8.00 Hz, 1 H) 7.07 (d, J=2.19 Hz, 1 H) 7.16 (d, J=2.19 Hz, 1 H). Example 21

3-(Benzord1thiazol-6-ylamino)-7-chloro-5-hvdroxy-4H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

(a) 3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 500 mg) was stirred in dichloromethane (DCM) (30 mL) at 0 °C as 1 M BBr ₃ in DCM (7.0 mL, 7.00 mmol) was added dropwise via syringe. After the addition, the ice bath was removed and the reaction stirred at 50 °C. After 5 hours, the reaction was cooled to room temperature. The flask was placed in an ice bath and MeOH (~ 20 mL) was added to decompose the remaining BBr3. The solution was concentrated in vacuo and the residue taken up in EtOAc and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the titled compound (255 mg) as a black solid, which was used without further purification. LCMS m/z 31 1 .0, 313.0 (M+H).

(b) 3-(benzo[d]thiazol-6-ylamino)-7-chloro-5-hydroxy-4H-benzo[e] [1 ,2,4]thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (100 mg), benzo[d]thiazol-6-amine (65 mg), potassium dihydrogen phosphate (60 mg), and tert- Butanol (2 mL) were reacted as in Example 16(a). The crude product was purified via reversed phase HPLC, using a 10-90% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (19 mg) as a white solid, TFA salt. LCMS m/z 381 .1 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 7.08 (d, J=2.27 Hz, 1 H) 7.20 (d, J=2.02 Hz, 1 H) 7.60 (dd, J=8.84, 2.02 Hz, 1 H) 8.10 (d, J=8.84 Hz, 1 H) 8.39 (d, J=2.27 Hz, 1 H) 9.33 (s, 1 H) 9.80 (s, 1 H) 10.29 (s, 1 H) 1 1 .70 (s, 1 H). Example 22

7-Chloro-5-hvdroxy-3-(quinolin-6-ylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

(a) 7-chloro-5-methoxy-3-(quinolin-6-ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 200 mg), quinolin-6-amine (120 mg) potassium dihydrogen phosphate (1 15 mg), and tert-Butanol (3 ml_) were reacted and purified as in Example 16(a) to afford the titled compound (135 mg) as a yellow solid. LCMS m/z 389.1 (M+H).

(b) 7-Chloro-5-hydroxy-3-(quinolin-6-ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

7-Chloro-5-methoxy-3-(quinolin-6-ylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (135 mg), 1 M BBr ₃ in DCM (1 .7 ml_), and Dichloromethane (DCM) (10 mL) were reacted as in Example 16(b). The solid residue was taken up in a slurry with MeOH & Acetonitrile. The slurry was filtered. Desired product was observed in both the filtered solid and filtrate by LCMS. The filtrate was concentrated in vacuo. The solid was dried under house vacuum. Both were taken up in DMSO, combined and purified via preparative reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (22 mg) as a yellow solid, TFA salt. LCMS m/z 375.0 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.09 (d, J=2.27 Hz, 1 H) 7.23 (d, J=2.02 Hz, 1 H) 7.64 (dd, J=8.21 , 4.42 Hz, 1 H) 7.89 (dd, J=9.09, 2.53 Hz, 1 H) 8.10 (d, J=9.09 Hz, 1 H) 8.26 (d, J=2.27 Hz, 1 H) 8.54 (d, J=8.08 Hz, 1 H) 8.92 (dd, J=4.29, 1 .52 Hz, 1 H) 9.95 (s, 1 H) 10.35 (s, 1 H) 1 1 .73 (s, 1 H).

Example 23

7-Chloro-3-((3^-dihvdroxyphenyl)amino)-5-hvdroxy-4H-benzorei ri ,2,41thiadiazine

1 ,1 -dioxide

(a) 3-(benzo[d][1 ,3]dioxol-5-ylamino)-7-chloro-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 200 mg), benzo[d][1 ,3]dioxol-5-amine (1 1 0 mg), potassium dihydrogen phosphate (1 15 mg,) , and tert-Butanol (3 mL) were reacted and purified as in Example 16(a) to afford the titled compound (138 mg) as a purple solid. LCMS m/z 382.1 (M+H).

(b) 7-Chloro-3-((3,4-dihydroxyphenyl)amino)-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-(Benzo[d][1 ,3]dioxol-5-ylamino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (138 mg) 1 M BBr ₃ in DCM (1 .8 mL), and Dichloromethane (DCM) (1 0 mL) were reacted as in Example 16(b). The crude product was purified by flash silica gel chromatography, 1 0 gram column, using a 0-20% MeOH :EtOAc gradient followed by reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (44 mg) as a grey solid . LCMS m/z 356.0 (M+H). ¹ H NMR (400 MHz, DMSO-cf ₆ ) δ ppm 6.62 - 6.70 (m, 1 H) 6.70 - 6.76 (m, 1 H) 6.97 - 7.07 (m, 2 H) 7.15 (d, J=2.27 Hz, 1 H) 8.82 (s, 1 H) 9.18 (d, J=9.85 Hz, 2 H) 9.98 (br. s. , 1 H) 1 1 .57 (s, 1 H).

Example 24

3-((1 H-Benzorcnimidazol-6-yl)amino)-7-chloro-5-hydroxy-4H- benzoreiri ,2,41thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 H-benzo[d]imidazol-6-amine (80mg), potassium dihydrogen phosphate (85 mg), and tert- Butanol (3 ml_) were reacted as in Example 16(a). The crude product was purified via reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (1 10 mg) as a white solid. LCMS m/z 364.0 (M+H). Ή NMR (400 MHz, DMSO- de) δ ppm 7.08 (d, J=2.27 Hz, 1 H) 7.20 (d, J=2.02 Hz, 1 H) 7.36 (dd, J=8.84, 2.02 Hz, 1 H) 7.80 (d, J=8.84 Hz, 1 H) 8.28 (d, J=2.02 Hz, 1 H) 9.19 (s, 1 H) 9.85 (s, 1 H) 10.28 (s, 1 H) 1 1 .77 (br. s., 1 H).

Example 25

1 -(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)ethanone

(a) 1 -(4-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 300mg), 1 - (4-aminphenyl)ethanone (149 mg) and KH ₂ P0 ₄ (150 mg) in n-BuOH (15 ml_) were reacted for 12 hr and worked up as in Example 1 (a) to afford the crude product (330 mg), which was used without further purification. LCMS m/z 379.98 (M+H). (b) 1 -(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)ethanone

To a stirred solution of 1 -(4-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin- 3-yl)amino)phenyl)ethanone (210 mg) in DCM (2 mL) was added BBr ₃ (2.76 mL) at RT. The reaction was allowed to stir at RT for 12 hr and then was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product (220 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18 4.6 x 75 mm) using a gradient of 5-50% 5 mM ammonium bicarbonate/water in acetonitrile to afford the titled compound (43 mg). LCMS m/z 365.94 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.56 (s, 3 H) 7.1 1 (d, J=2.19 Hz, 1 H) 7.21 (d, J=2.19 Hz, 1 H) 7.52 - 7.80 (m, 2 H) 7.85 - 8.10 (m, 2 H). Example 26

7-Chloro-5-hydroxy-3-(quinoxalin-6-ylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 100 mg), quinoxalin-6-amine (60 mg), potassium dihydrogen phosphate (55 mg), and tert-Butanol (2 mL) were reacted as in Example 16(a). The crude product was purified via reversed phase HPLC, using a 10-40% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (15 mg) as a white solid. LCMS m/z 376.0 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.09 (d, J=2.27 Hz, 1 H) 7.24 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=9.09, 2.53 Hz, 1 H) 8.12 (d, J=9.09 Hz, 1 H) 8.49 (d, J=2.53 Hz, 1 H) 8.86 (d, J=1 .77 Hz, 1 H) 8.93 (d, J=1 .77 Hz, 1 H) 10.07 (s, 1 H) 10.41 (s, 1 H) 1 1 .76 (s, 1 H). Example 27

7-chloro-3-((2,3-dihvdrobenzorbiri ,41dioxin-6-yl)amino)-5-hydroxy-4H-

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 100 mg), 2,3-dihydrobenzo[b][1 ,4]dioxin-6-amine (60 mg, 0.397 mmol), potassium dihydrogen phosphate (55 mg, 0.404 mmol), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 20-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (61 mg) as a white solid. LCMS m/z 382.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 4.25 (td, J=5.05, 3.79 Hz, 4 H) 6.77 - 6.91 (m, 2 H) 7.04 (d, J=2.27 Hz, 1 H) 7.12 (d, J=1 .77 Hz, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 9.33 (s, 1 H) 10.10 (br. s., 1 H) 1 1 .62 (br. s., 1 H). Example 28

2-((7-Chloro-5-hvdroxy-1.1 -dioxido-2H-benzorein ,2.41thiadiazin-3- yl)amino)benzonitrile

(a) 2-((7-Chloro-5-methoxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile

To a solution of 2-aminobenzonitrile (174 mg) in THF (15 mL) at -78 °C was added lithium bis(trimethylsilyl)amide (1 M in THF, 1 .843 mL) dropwise and the reaction mixture was allowed to stir 1 hr at -78 °C. The reaction mixture was allowed to warm to RT and then stirred at 50 °C for 6 hr. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the crude product (742 mg). The crude product was purified by silica gel flash chromatography (50 g column), eluting with DCM (600 mL), 1 % MeOH/DCM (600 mL), 2% MeOH/DCM (600 mL), 4% DCM/MeOH (600 mL) and 6% MeOH/DCM (600 mL)to afford the titled compound (286 mg). LCMS m/z 362.95 (M+H).

(b) 2-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile

A solution of 2-((7-chloro-5-methoxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzonitrile (120 mg) and lithium chloride (168 mg) in DMSO (3 mL) was heated in a microwave reactor at 150 °C for 4 hr. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were washed with saturated brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the crude product (356 mg). The crude product was purified by silica gel flash chromatography (10 g column) eluting with DCM (200 mL), 1 % MeOH/DCM (200 mL), 2% MeOH/DCM (200 mL), and 3% MeOH/DCM, followed by preparative reversed phase HPLC (XBridge C18 30 x 250 mm) using a gradient of 50-100% 0.1 % formic acid/water and acetonitrile to afford the titled compound (52 mg). LCMS m/z 348.95 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.1 1 (d, J=2.19 Hz, 1 H) 7.18 (d, J=2.19 Hz, 1 H) 7.41 (td, J=7.67, 1 .10 Hz, 1 H) 7.75 - 7.81 (m, 1 H) 7.86 (dd, J=7.78, 1 .21 Hz, 1 H) 7.92 (dd, J=8.33, 0.66 Hz, 1 H).

Example 29

2-(3-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzoreiri ,2,41thiadiazin-3- yl)amino)phenyl)acetic acid, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 100 mg), 2- (3-aminophenyl)acetic acid (70 mg), potassium dihydrogen phosphate (62 mg), and tert- Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-45% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (78 mg) as a white solid. LCMS m/z 382.0 (M+H). Ή NMR (400 MHz, DMSO- cfe) δ ppm 3.59 (s, 2 H) 6.95 - 7.09 (m, 2 H) 7.18 (d, J=2.27 Hz, 1 H) 7.27 - 7.38 (m, 2 H) 7.48 (d, J=1 .52 Hz, 1 H) 9.55 (s, 1 H) 10.16 (s, 1 H) 1 1 .64 (s, 1 H) 12.38 (s, 1 H).

Example 30

2-(3-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)acetamide, Trifluoroacetic acid salt

2-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetic acid, Trifluoroacetic acid salt (Example 29, 58 mg), EDC (30 mg), HOBt (25 mg), and DIEA (70 μΙ_) were stirred in Ν,Ν-Dimethylformamide (DMF) (2 mL) at room temperature for 15 minutes, followed by the addition of ammonium chloride (15 mg, 0.280 mmol). After 6 hours, LCMS analysis displayed complete conversion to the carboxamide. The reaction mixture was purified via direct injection onto reversed phase HPLC, eluting with 10-45% ACN:H ₂ 0 (0.1 % TFA) to afford the titled compound (34 mg) as a white solid, TFA salt. LCMS m/z 381 .1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.40 (s, 2 H) 6.91 (br. s., 1 H) 7.02 - 7.07 (m, 2 H) 7.18 (d, J=2.27 Hz, 1 H) 7.29 - 7.34 (m, 2 H) 7.44 - 7.55 (m, 2 H) 9.54 (s, 1 H) 10.14 (s, 1 H) 1 1 .64 (s, 1 H).

Example 31

7-Chloro-5-methoxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

a) 7-Chloro-5-methoxy-2-methyl-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide

To a suspension of 7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (lnt-1 , 0.40 g) in MeOH (10 mL) was added ammonia (7N in MeOH, 2.18 mL) and the mixture was stirred for 20 h. The volatiles were removed and Λ/,/V-dimethylformamide (5 mL) was added, followed by Mel (0.143 mL). The mixture was stirred at RT for 40 h. The volatiles were removed and the residue was combined with the product from a smaller scale preparation (starting with 7-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (15 mg)). The combined residues were redissolved in EtOAc and washed sequentially with water and brine. The organic phase was dried over Na ₂ S0 ₄ , filtered, and concentrated to give the titled compound (210 mg) as a brown solid. LCMS m/z 277.0 (M+H); Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 3.39 (s, 3H), 4.00 (s, 3H), 7.09 (d, J=1 .77 Hz, 1 H), 7.46 (d, J=1 .77 Hz, 1 H), 7.88 (br. s., 1 H).

b) 3,7-Dichloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred suspension of 7-chloro-5-methoxy-2-methyl-2H-benzo[e][1 ,2,4]thiadiazin- 3(4H)-one 1 ,1 -dioxide (100 mg) in phosphorus oxychloride (0.34 mL) at 0 °C was added dropwise 2,6-lutidine (0.084 mL). After addition, the mixture was allowed to stir at 1 10 °C for 16 h. The mixture was cooled to RT and concentrated. To the residue was added 10 mL of ice-water. After stirring for 20 min, the product was extracted with EtOAc, washed sequentially with saturated aqueous NaHC03 solution and brine, and dried over Na ₂ S0 ₄ . The volatiles were removed to give the titled compound (65 mg) which was used without further purification. LCMS m/z 281 .0 (M+H).

c) 7-Chloro-5-methoxy-3-(phenylamino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a solution of 3,7-dichloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (30 mg) in DCM (1 .0 mL) was added aniline (0.097 mL) and the reaction mixture was stirred at RT for 3 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (10 g column) eluting with 0-100% EtOAc/hexanes to afford the titled compound (20 mg) as an off-white solid. LCMS m/z 338.1 (M+H); ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 4.03 (s, 3H), 7.15 (br t, J=7.4 Hz, 1 H), 7.32 (d, J=1 .9 Hz, 1 H), 7.38-7.41 (m, 2H), 7.41 (d, J=2.3 Hz, 1 H), 7.52 (br d, J=7.6 Hz, 2H), 9.59 (s, 1 H), 10.25 (br s, 1 H).

Example 32

7-Chloro-3-((2-chlorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a solution of 3,7-dichloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 31 b, 34 mg) in DCM (1 .0 ml_) was added 2-chloroaniline (0.13 ml_). The reaction mixture was stirred at RT for 1 h, at 50 °C for 3 h and at 70 °C for 7 h. The mixture was cooled to RT and concentrated. The residue was purified by silica gel flash chromatography (10 g column) eluting with 0-100% EtOAc/hexanes to give the titled compound (19 mg) as an off-white solid. LCMS m/z 372.1 (M+H); ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 4.05 (s, 3H), 7.24 (dt, J=1 .52, 7.71 Hz, 1 H), 7.33 (d, J=2.02 Hz, 1 H), 7.39-7.46 (m, 2H), 7.56 (dd, J=1 .52, 8.08 Hz, 1 H ), 7.93 (dd, J=1 .39, 8.21 Hz, 1 H), 9.29 (br s, 1 H), 10.85 (br s, 1 H).

Example 33

1 -(7-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzoreiri ,2,41thiadiazin-3-yl)amino)-3,4- dihydroisoquinolin-2(1 H)-yl)ethanone

(a) 1 -(7-Nitro-3,4-dihydroisoquinolin-2(1 H)-yl)ethanone

7-Nitro-1 ,2,3,4-tetrahydroisoquinoline, Hydrochloride (0.7 g) and pyridine (0.8 ml_) were stirred in Dichloromethane (DCM) (10 ml_) at 0°C as acetic anhydride (0.4 ml_) was added dropwise. The reaction mixture was stirred under nitrogen for 1 hour, allowing it to slowly warm to room temperature. With LCMS confirming complete conversion, the reaction was diluted with DCM (~ 10 mL) and washed with saturated aq. sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography, 25 gram column, using a 0-10% MeOH:EtOAc gradient to afford the titled compound (530 mg) as a light yellow solid. LCMS m/z 221 .0 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.10 (s, 3 H) 2.89 (t, J=5.94 Hz, 1 H) 3.00 (t, J=5.94 Hz, 1 H) 3.65 - 3.73 (m, 2 H) 4.72 (s, 1 H) 4.79 (s, 1 H) 7.48 (d, J=8.34 Hz, 1 H) 8.02 - 8.08 (m, 1 H) 8.14 (s, 1 H).

(b) 1 -(7-Amino-3,4-dihydroisoquinolin-2(1 H)-yl)ethanone

1 -(7-Nitro-3,4-dihydroisoquinolin-2(1 H)-yl)ethanone (530 mg, 2.407 mmol) was taken up in ethanol (30 mL). Under a stream of nitrogen, 10% Pd/C (100 mgmol) was added to the vessel. A hydrogen balloon was attached to the vessel. Hydrogen and house vacuum were cycled through the system (4X). The reaction was stirred at room temperature under an atmosphere of hydrogen. After 1 hour, LCMS confirmed complete reduction. The reaction was filtered over celite, rinsing the celite with EtOH (~ 20 mL). The filtrate was concentrated in vacuo to afford the titled compound (379 mg) as a waxy white solid which was used without further purification. LCMS m/z 191 .1 (M+H). ¹ H NMR (400 MHz, DMSO-cf ₆ ) δ ppm 2.06 (d, J=1 .00 Hz, 3 H) 2.56 (t, J=5.81 Hz, 1 H) 2.67 (t, J=5.94 Hz, 1 H) 3.58 (td, J=5.94, 3.28 Hz, 2 H) 4.46 (s, 1 H) 4.42 (s, 1 H) 4.89 (br. s., 2 H) 6.34 (dd, J=5.05, 2.02 Hz, 1 H) 6.37 - 6.45 (m, 1 H) 6.81 (d, J=8.08 Hz, 1 H).

(c) 1 -(7-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)- 3,4-dihydroisoquinolin-2(1 H)-yl)ethanone

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 161 mg), 1 - (7-amino-3,4-dihydroisoquinolin-2(1 H)-yl)ethanone (120 mg), potassium dihydrogen phosphate (90 mg), and tert-Butanol (3 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (101 mg) as a white solid. LCMS m/z 421 .2 (M+H).

Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.08 (d, J=1 .00 Hz, 3 H) 2.73 (t, J=5.81 Hz, 1 H) 2.84 (t, J=5.81 Hz, 1 H) 3.66 (t, J=5.94 Hz, 2 H) 4.60 (s, 1 H) 4.67 (s, 1 H) 7.01 - 7.09 (m, 1 H)

7.14 - 7.22 (m, 2 H) 7.23 - 7.33 (m, 1 H) 7.33 - 7.42 (m, 1 H) 9.47 (d, J=7.58 Hz, 1 H) 10.19

(br. s., 1 H) 1 1 .65 (br. s., 1 H).

Example 34

3-(Benzorb1thiophen-5-ylamino)-7-chloro-5-hvdroxy-4H-benzore iri ,2,41thiadiazine

1 ,1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and benzo[b]thiophen-5-amine (1 15 mg) in t-BuOH (10 mL) was added KH2PO4 (105 mg) in one portion. The reaction mixture was stirred at 80 °C for 24 hr. Solvent was removed under reduced pressure and water (15 mL) was added to the reaction mixture, stirred for 15 min, and the precipitate was collected by filtration. The precipitate was washed with water (2 x 5 mL) and diethyl ether (3 x 15 mL) and air-dried to afford the titled compound (195 mg). LCMS m/z 379.98 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.1 1 (d, J=2.19 Hz, 1 H) 7.20 (d, J=2.19 Hz, 1 H) 7.43 (dd, J=8.77, 2.19 Hz, 1 H) 7.49 (d, J=5.26 Hz, 1 H) 7.80 (d, J=5.48 Hz, 1 H) 8.01 (d, J=8.55 Hz, 1 H) 8.10 (d, J=2.19 Hz, 1 H).

Example 35

3-(Benzorb1thiophen-6-ylamino)-7-chloro-5-hydroxy-4H-benzore iri ,2,41thiadiazine

1 ,1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and benzo[b]thiophen-6-amine (1 15 mg) in t-BuOH (10 mL) was added KH2PO4 (105 mg) in one portion. The reaction mixture was stirred at 80 °C for 24 hr. Solvent was removed under reduced pressure and water (15 mL) was added to the reaction mixture, stirred for 15 min, and the precipitate was collected by filtration. The precipitate was washed with water (2 x 5 mL) and diethyl ether (3 x 15 mL) and air-dried to afford the titled compound (236 mg). LCMS m/z 379.95 (M+H). ¹ H NMR after D20 exchange (400 MHz, DMSO-c/e) δ ppm 7.10 (d, J=1 .97 Hz, 1 H) 7.21 (d, J=2.19 Hz, 1 H) 7.39 - 7.47 (m, 2 H) 7.70 (d, J=5.26 Hz, 1 H) 7.90 (d, J=8.55 Hz, 1 H) 8.25 (d, J=1 .97 Hz, 1 H).

Example 36

7-Chloro-3-((3,4-dichlorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 3,4-dichloroaniline (125 mg), KH ₂ P0 ₄ (105 mg) in 2-BuOH (10 mL) at 0 °C was added 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in portions. The reaction mixture was then stirred at 80 °C for 16 hr, cooled to RT, and diluted with water. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to afford the titled compound (155 mg). LCMS m/z 391 .94 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.12 (d, J=1 .97 Hz, 1 H) 7.22 (d, J=1 .97 Hz, 1 H) 7.40 (dd, J=8.77, 2.41 Hz, 1 H) 7.62 (d, J=8.77 Hz, 1 H) 7.91 (d, J=2.41 Hz, 1 H).

Example 37

7-Chloro-3-((3,5-dichlorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 3,5-dichloroaniline (125 mg), KH ₂ P0 ₄ (105 mg) in 2-BuOH (10 mL) at 0 °C was added 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in portions. The reaction mixture was then stirred at 80 °C for 16 hr, cooled to RT, and diluted with water. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to afford the titled compound (105 mg). LCMS m/z 391 .97 (M+H) . Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.1 1 (d, J=2.19 Hz, 1 H) 7.22 (d, J=2.19 Hz, 1 H) 7.34 (t, J=1 .75 Hz, 1 H) 7.58 (d, J=1 .75 Hz, 2 H).

Example 38

7-Chloro-3-((3.4-difluorophenyl)amino)-5-hvdroxy-2H-benzorei n .2.41thiadiazine 1.1 - dioxide

A solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg), 3,4-difluoroaniline (0.076 mL) and KH ₂ P0 ₄ (105 mg) in t-BuOH (10 mL) was stirred at 1 10 °C for 16 hr. The reaction mixture was allowed to cool to RT and was diluted with water. The resulting solid was collected by filtration and dried under vacuum to afford the titled compound (104 mg). LCMS m/z 359.97 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.09 (d, J=2.19 Hz, 1 H) 7.20 (d, J=1 .97 Hz, 1 H) 7.22 - 7.28 (m, 1 H) 7.46 (dt, J=10.41 , 9.15 Hz, 1 H) 7.69 (ddd, J=12.72, 7.24, 2.63 Hz, 1 H).

Example 39

2-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)-N,N-dimethylacetamide, Trifluoroacetic acid salt

2-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetic acid (Example 29, 103 mg) was stirred in N,N-Dimethylformamide (DMF) (2 mL) as DIEA (100 μί) was added. After 5 minutes of stirring, HOBt (65 mg) and EDC (80 mg) were added as solids. Dimethylamine (2M in MeOH, 200 μΙ_) was added. The reaction mixture was stirred under nitrogen at room temperature. After 1 hour, LCMS analysis confirmed complete conversion to the desired product. The reaction mixture was purified via reversed phase HPLC, using a 10-40% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient and a 10-40% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (27 mg) as a white solid. LCMS m/z 409.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.85 (s, 3 H) 3.03 (s, 3 H) 3.71 (s, 2 H) 6.99 (d, J=7.58 Hz, 1 H) 7.06 (d, J=2.02 Hz, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.27 - 7.37 (m, 2 H) 7.44 (d, J=8.08 Hz, 1 H) 9.55 (s, 1 H) 10.15 (s, 1 H) 1 1 .66 (s, 1 H).

Example 40

7-Chloro-5-hvdroxy-3-((2-methyl-1 ,2,3,4-tetrahvdroisoquinolin-7-yl)amino)- 4Hbenzoreiri ,2,41thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

(a) 2-methyl-7-nitro-1 ,2,3,4-tetrahydroisoquinoline

7-Nitro-1 ,2,3,4-tetrahydroisoquinoline, Hydrochloride (490 mg) and TEA (350 μΙ) were stirred in 1 ,2-Dichloroethane (DCE) (15 ml_) at room temperature for 5 minutes. Formaldehyde (38% solution in water, 250 μΙ) was then added dropwise. The reaction mixture stirred for 20 minutes, then was cooled to 0°C. Sodium triacetoxyborohydride (1 .0 g) was then added. The reaction mixture was stirred at 0°C for 30 minutes. The ice bath was removed and a reflux condenser was attached to the flask. The reaction stirred at 80 °C for 16 hours. The reaction was cooled to room temperature, diluted with DCM, and washed with saturated aq. sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography, 25 gram column, using a 0-10% MeOH:2-MeTHF gradient to afford the titled compound (405 mg) as a brown gel. LCMS m/z 193.0 (M+H).

(b) 2-Methyl-1 ,2,3,4-tetrahydroisoquinolin-7 -amine

2-Methyl-7-nitro-1 ,2,3,4-tetrahydroisoquinoline (396 mg) was taken up in ethanol (30 mL). Under a stream of nitrogen, 10% Pd/C (100 mg) was added to the vessel. A hydrogen balloon was attached to the vessel. Hydrogen and house vacuum were cycled through the system (4X). The reaction stirred at room temperature under an atmosphere of hydrogen. After 3 hours, LCMS confirmed complete reduction. The reaction was filtered over celite, rinsing the celite with EtOH (~ 20 ml_). The filtrate was concentrated in vacuo to afford the titled compound (330 mg) as a brown gel, which was used without further purification. LCMS m/z 163.0 (M+H).

(c) 7-Chloro-5-hydroxy-3-((2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)- 4Hbenzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 100 mg), 2- methyl-1 ,2,3,4-tetrahydroisoquinolin-7-amine (70 mg), potassium dihydrogen phosphate (60 mg), and tert-Butanol (2 ml_) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient and a 10-40% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (28 mg) as a white solid. LCMS m/z 393.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.95 (br. s., 3 H) 2.99 - 3.14 (m, 2 H) 3.34 - 3.67 (m, 2 H) 4.34 (br. s., 1 H) 4.56 (d, J=1 .02 Hz, 1 H) 7.07 (d, J=2.02 Hz, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.28 (d, J=8.34 Hz, 1 H) 7.36 (dd, J=8.34, 2.02 Hz, 1 H) 7.43 (d, J=2.02 Hz, 1 H) 9.61 (s, 1 H) 10.24 (s, 1 H) 1 1 .76 (s, 1 H).

Example 41

5-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzoreiri ,2,41thiadiazin-3- yl)amino)isoindolin-1 -one. Trifluoroacetic acid salt

(a) 5-((7-Chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)isoindolin-1 -one

3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 150 mg), 5- aminoisoindolin-1 -one (85 mg), potassium dihydrogen phosphate (80 mg), and tert-Butanol (3 mL) were reacted as in Example 16 (a). The crude material was not soluble in DMSO (4 mL) with heat. Upon cooling to room temperature, the resulting white precipitate was filtered, washed with water, and lyophilized to afford the titled compound (90 mg) as a white solid. LCMS m/z 393.1 (M+H). (b) 5-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)isoindolin-1 -one, Trifluoroacetic acid salt

5-((7-chloro-5-methoxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)isoindolin-1 - one (90 mg,), BBr ₃ (1 M in DCM, 1 .0 ml_), and Dichloromethane (DCM) (10 mL) were reacted and purified as in Example 16 (b) to afford the titled compound (5 mg) as a white solid, TFA salt. LCMS m/z 379.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 4.41 (s, 2 H) 7.08 (d, J=2.02 Hz, 1 H) 7.21 (d, J=2.02 Hz, 1 H) 7.49 (dd, J=8.21 , 1 .89 Hz, 1 H) 7.67 (d, J=8.34 Hz, 1 H) 7.90 (s, 1 H) 8.48 (s, 1 H) 9.88 (s, 1 H) 10.32 (s, 1 H) 1 1 .74 (s, 1 H). Example 42

(S)-2-Amino-1 -(7-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzore1H ,2,41thiadiazin-3- yl)amino)-3,4-dihvdroisoquinolin-2(1 H)-yl)propan-1 -one, Trifluoroacetic acid salt

(a) (S)-tert-Butyl (1 -(7-nitro-3,4-dihydroisoquinolin-2(1 H)-yl)-1 -oxopropan-2- yl)carbamate

7-Nitro-1 ,2,3,4-tetrahydroisoquinoline, Hydrochloride (500 mg) was stirred in N,N- Dimethylformamide (DMF) (10 mL) as DIEA (1 .0 mL) was added. The reaction mixture was stirred at room temperature for 5 minutes. (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (500 mg), HOBt (800 mg), and EDC (1 .0 g) were added. The reaction mixture was stirred under nitrogen at room temperature for 16 hours. The reaction mixture was poured into EtOAc. The organic solution was separated, washed with 0.1 M HCI, sat. aq sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified over flash silica, 25 gram column, eluting with 40-80% EtOAc:Hexane to afford the titled compound (620 mg) as a white foamy solid. LCMS m/z 294.1 (M+H-Boc).

(b) (S)-tert-Butyl (1 -(7-amino-3,4-dihydroisoquinolin-2(1 H)-yl)-1 -oxopropan-2- yl)carbamate (S)-tert-butyl (1 -(7-nitro-3,4-dihydroisoquinolin-2(1 H)-yl)-1 -oxopropan-2-yl)carbamate (200 mg) was taken up Ethyl acetate (12 ml_). Under a stream of nitrogen, 10% Pd/C (50 mg) was added. A hydrogen balloon was attached to the vessel. After cycling house vacuum and hydrogen through the system (4X), the reaction was stirred at room temperature under an atmosphere of hydrogen for 16 hours. With LCMS analysis confirming complete reduction, the reaction was filtered over celite, rinsing the celite with EtOAc. The filtrate was concentrated in vacuo to afford the titled compound (170 mg) as a foamy light pink solid, which was used without further purification. LCMS m/z 320.2 (M+H).

(c) (S)-2-Amino-1 -(7-((7-chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)-3,4-dihydroisoquinolin-2(1 H)-yl)propan-1 -one, Trif luoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 100 mg), (S)-tert-butyl (1 -(7-amino-3,4-dihydroisoquinolin-2(1 H)-yl)-1 -oxopropan-2-yl)carbamate (125 mg), potassium dihydrogen phosphate (60 mg), and tert-Butanol (2 ml_) were reacted as in Example 16 (a) to afford a mixture of Boc and des-Boc products. The crude product was purified via reversed phase HPLC, using a 5-35% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient and a 5-40% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (45 mg) as a white solid, TFA salt. LCMS m/z 450.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 .35 (dd, J=12.63, 6.82 Hz, 3 H) 2.69 - 2.83 (m, 1 H) 2.88 (br. s., 1 H) 3.57 (dt, J=12.88, 6.44 Hz, 1 H) 3.70 (dt, J=12.95, 6.28 Hz, 1 H) 3.74 - 3.84 (m, 1 H) 3.86 - 3.98 (m, 1 H) 4.60 - 4.89 (m, 2 H) 7.07 (t, J=2.02 Hz, 1 H) 7.13 - 7.19 (m, 1 H) 7.19 - 7.30 (m, 1 H) 7.32 - 7.40 (m, 1 H) 7.46 (s, 1 H) 8.1 1 (br. s., 2 H) 9.54 (d, J=1 .00 Hz, 1 H) 10.22 (d, J=6.32 Hz, 1 H) 1 1 .79 (d, J=8.84 Hz, 1 H).

Example 43

2-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)-N-methylacetamide, Trifluoroacetic acid salt

2-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetic acid (Example 29, 130 mg), DIEA (130 μΙ_), HOBt (75 mg), EDC (95 mg), methanamine (33% in EtOH) (150 μΙ_), and N,N-Dimethylformamide (2 mL) were reacted and purified as in Example 39 to afford the titled compound (16 mg) as a white solid. LCMS m/z 395.2 (M+H). ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 2.59 (d, J=4.80 Hz, 3 H) 3.41 (s, 2 H) 7.03 (d, J=7.83 Hz, 1 H) 7.06 (d, J=2.02 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.25 - 7.36 (m, 2 H) 7.41 - 7.51 (m, 1 H) 8.01 (q, J=4.00 Hz, 1 H) 9.55 (s, 1 H) 10.15 (s, 1 H) 1 1 .65 (s, 1 H).

Example 44

7-Chloro-3-((2,4-dichlorophenyl)amino)-5-hydroxy-2H-benzo reiri ,2,41thiadiazine 1 ,1 - dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 2,4-dichloroaniline (0.076 mL) in t-BuOH (3 mL) under nitrogen at RT was added KH ₂ P0 ₄ (105 mg) portionwise. The reaction mixture was then stirred at 100 °C for 16 hr under nitrogen, then allowed to cool to RT and diluted with cold water (3 mL). The resulting solid was collected by filtration, washed with pentane and diethyl ether, and dried under vacuum to afford the titled compound (60 mg). LCMS m/z 391 .90 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.12 (d, J=2.19 Hz, 1 H) 7.19 (d, J=1 .97 Hz, 1 H) 7.51 (dd, J=8.77, 2.41 Hz, 1 H) 7.72 (d, J=2.41 Hz, 1 H) 7.95 (d, J=8.99 Hz, 1 H).

Example 45

7-Chloro-3-((2,5-dichlorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 2,5-dichloroaniline (125 mg), KH ₂ P0 ₄ (105 mg) in t-BuOH (10 mL) at 0 °C was added 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in portions. The reaction mixture was then stirred at 80 °C for 16 hr, cooled to RT, and diluted with cold water. The resulting solid was collected by filtration, washed with diethyl ether and dried to afford the crude product (180 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18 19 x 50 mm) using a gradient of 10-35% 10 mM ammonium bicarbonate/water in acetonitrile to afford the titled compound (35.6 mg). LCMS m/z 391 .94 (M+H). ¹ H NMR after D20 exchange (400 MHz, DMSO-c/e) δ ppm 7.10 (d, J=2.19 Hz, 1 H) 7.22 (d, J=2.19 Hz, 1 H) 7.30 (dd, J=8.66, 2.52 Hz, 1 H) 7.59 (d, J=8.55 Hz, 1 H) 8.12 (d, J=2.63 Hz, 1 H).

Example 46

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)methanesulfonamide

To a stirred solution of N-(4-aminophenyl)methanesulfonamide (143 mg), KH ₂ P0 ₄ (105 mg) in t-BuOH (10 mL) at 0 °C was added 3-bromo-7-chloro-5-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in portions. The reaction mixture was then stirred at 80 °C for 16 hr, cooled to RT, and diluted with cold water. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to afford the titled compound (177.7 mg). LCMS m/z 416.92 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 2.97 (s, 3 H) 7.09 (d, J=1 .97 Hz, 1 H) 7.18 (d, J=2.19 Hz, 1 H) 7.25 (d, J=8.77 Hz, 2 H) 7.48 (d, J=8.77 Hz, 2 H).

Example 47

7-Chloro-3-((2,4-difluorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 2,4-difluoroaniline (99 mg) in t-BuOH (3 ml_) under nitrogen at RT was added KH ₂ P0 ₄ (105 mg) portionwise. The reaction mixture was then stirred at 100 °C for 16 hr under nitrogen, allowed to cool to RT, and diluted with cold water (3 ml_). The resulting solid was collected by filtration, washed with pentane and diethyl ether, and dried under vacuum to afford the titled compound (90 mg). LCMS m/z 359.89 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-cfe) δ ppm 7.1 1 (d, J=2.19 Hz, 1 H) 7.13 - 7.23 (m, 2 H) 7.38 (ddd, J=1 1 .07, 8.66, 2.85 Hz, 1 H) 7.95 (td, J=9.04, 6.03 Hz, 1 H).

Example 48

7-Chloro-3-((2,6-difluorophenyl)amino)-5-hydroxy-2H-benzo reiri ,2,41thiadiazine 1 ,1 - dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 2,6-difluoroaniline (99 mg) in n-BuOH (5 ml_) under nitrogen at RT was added KH ₂ P0 ₄ (105 mg) portionwise. The reaction mixture was then stirred at 1 10 °C for 16 hr under nitrogen. The reaction mixture was allowed to cool to RT and was then diluted with cold water. The resulting precipitate was collected by filtration and dried to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18 19 x 150 mm) using a 23% 10 mM ammonium acetate/water in acetonitrile to afford the titled compound (50 mg). LCMS m/z 359.89 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.09 (d, J=2.19 Hz, 1 H) 7.15 (d, J=1 .97 Hz, 1 H) 7.20 - 7.28 (m, 2 H) 7.40 - 7.50 (m, 1 H).

Example 49

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)cyclopropanesulfonamide

(a) tert-Butyl (4-(cyclopropanesulfonamido)phenyl)carbamate

To a solution of tert-butyl (4-aminophenyl)carbamate (2.0 g) and pyridine (3.88 mL) in DCM (50 mL) under nitrogen at 0 °C was added cyclopropanesulfonyl chloride (1 .62 g) dropwise over 5 min. The reaction was allowed to warm to RT and was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure, and diluted with 20 mL cold water. The resulting precipitate was collected by filtration to afford the titled compound (2.5 g). LCMS m/z 31 1 .20 (M-H)-.

(b) N-(4-aminophenyl)cyclopropanesulfonamide Hydrochloride

To a solution of tert-Butyl (4-(cyclopropanesulfonamido)phenyl)carbamate (500 mg) in 1 ,4- dioxane (10 mL) stirred under nitrogen was added HCI (4 M in 1 ,4 dioxane, 4.0 mL) dropwise. The reaction was stirred at RT for 16 hr. Solvent was removed under reduced pressure and the residue evaporated twice from toluene. The resulting solid was washed with n-pentane (3 x 15 mL) and dried under vacuum to afford the titled compound (350 mg). LCMS m/z 213.02 (M+H).

(c) N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)cyclopropanesulfonamide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and N-(4-aminophenyl)cycloprpoanesulfonamide hydrochloride (240 mg) in t-BuOH (10 mL) under nitrogen at RT was added KH ₂ P0 ₄ (175 mg) in one portion. The reaction mixture was then stirred at 1 10 °C for 16 hr under nitrogen. The reaction mixture was concentrated under reduced pressure and then diluted with deionized water (15 mL) and stirred for 15 min. The resulting solid was collected by filtration, washed with water (2 x 5 mL), diethyl ether (2 x 15 mL) and n-pentane (3 x 15 mL) and dried under vacuum to afford the titled compound (161 mg). LCMS m/z 442.99 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 0.90 - 0.98 (m, 4 H) 2.56 - 2.62 (m, 1 H) 7.09 (d, J=2.19 Hz, 1 H) 7.18 (d, J=1 .97 Hz, 1 H) 7.27 (m, J=8.77 Hz, 2 H) 7.47 (m, J=8.77 Hz, 2 H).

Example 50

3-((1 H-lndol-6-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 H-indol-6-amine (80 mg), potassium dihydrogen phosphate (90 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (80 mg) as a white solid, TFA salt. LCMS m/z 363.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.40 - 6.41 (m, 1 H) 6.90 (dd, J=8.34, 2.02 Hz, 1 H) 7.06 (d, J=2.02 Hz, 1 H) 7.17 (d, J=2.27 Hz, 1 H) 7.33 (t, J=2.80 Hz, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 7.88 (s, 1 H) 9.49 (s, 1 H) 10.1 1 (s, 1 H) 1 1 .17 (s, 1 H) 1 1 .63 (s, 1 H). Example 51

3-((1 H-lndol-5-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 H-indol-5-amine (80 mg), potassium dihydrogen phosphate (90 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (80 mg) as a white solid, TFA salt. LCMS m/z 363.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 6.45-6.46 (m, 1 H) 7.05 (d, J=2.27 Hz, 1 H) 7.1 1 (dd, J=8.72, 2.15 Hz, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 7.33 - 7.45 (m, 2 H) 7.72 (d, J=2.02 Hz, 1 H) 9.36 (s, 1 H) 10.08 (br. s., 1 H) 1 1 .14 (br. s., 1 H) 1 1 .60 (s, 1 H). Example 52

7-Chloro-3-((4-fluoro-1 H-indol-6-yl)amino)-5-hvdroxy-4H-benzoreiri ,2,41thiadiazine

1 ,1 -dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 4- fluoro-1 H-indol-6-amine (90 mg), potassium dihydrogen phosphate (90 mg), and tert- Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (32 mg) as a white solid, TFA salt. LCMS m/z 381 .1 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 6.62-6.63 (m, 1 H) 7.00 (dd, J=9.35, 1 .52 Hz, 1 H) 7.09 (d, J=2.27 Hz, 1 H) 7.22 (d, J=2.02 Hz, 1 H) 7.38 (t, J=2.80 Hz, 1 H) 7.67 (dd, J=12.30, 2.30 Hz, 1 H) 9.55 (s, 1 H) 10.62 (s, 1 H) 1 1 .36 (br. s., 1 H) 1 1 .75 (s, 1 H).

Example 53

3-((1 H-lndol-4-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 160 mg), 1 H-indol-4-amine (85 mg), potassium dihydrogen phosphate (90 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 20-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (71 mg) as a white solid, TFA salt. LCMS m/z 363.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.56 - 6.67 (m, 1 H) 7.02 - 7.10 (m, 1 H) 7.12 (d, J=7.83 Hz, 1 H) 7.19 (d, J=2.02 Hz, 1 H) 7.23 (d, J=8.08 Hz, 1 H) 7.39 (t, J=2.78 Hz, 1 H) 7.63 (d, J=7.58 Hz, 1 H) 9.41 (s, 1 H) 10.49 (s, 1 H) 1 1 .29 (br. s., 1 H) 1 1 .68 (s, 1 H).

Example 54

3-((1 H-lndol-7-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 170 mg), 1 H-indol-7-amine (88 mg), potassium dihydrogen phosphate (90 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 20-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (43 mg) as a white solid, TFA salt. LCMS m/z 363.1 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.50-6.51 (m, 1 H) 6.98 - 7.05 (m, 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.08 - 7.13 (m, 1 H) 7.15 (d, J=2.02 Hz, 1 H) 7.38 (t, J=2.78 Hz, 1 H) 7.50 (d, J=7.83 Hz, 1 H) 9.15 (s, 1 H) 10.21 (br. s., 1 H) 1 1 .03 (br. s., 1 H) 1 1 .61 (s, 1 H). Example 55

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)benzenesulfonamide

(a) tert-Butyl (3-(phenylsulfonamido)phenyl)carbamate

To a solution of tert-butyl (3-aminophenyl)carbamate (0.5 g) and pyridine (0.971 mL) in DCM (10 mL) stirred under nitrogen at 0 °C was added benzenesulfonyl chloride (0.381 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure and then diluted with cold water (10 mL). The resulting solid was collected by filtration to afford the titled compound (700 mg). LCMS m/z 347.07 (M-H) ^" .

(b) N-(3-Aminophenyl)benzenesulfonamide hydrochloride

To a stirred solution of tert-butyl (3-(phenylsulfonamido)phenyl)carbamate (700 mg) in 1 ,4- dioxane (10 mL) under nitrogen at 0 °C was added HCI (4 M in 1 ,4-dioxane, 5.02 mL) dropwise over 3 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was evaporated under reduced pressure and the resulting solid washed with pentane (20 mL) to afford the titled compound (650 mg). LCMS m/z 249.1 (M+H).

(c) N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)benzenesulfonamide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) N-(3-aminophenyl)benzenesulfonamide hydrochloride (191 mg) in t-BuOH (5 mL) under nitrogen at RT was added KH ₂ P0 ₄ (175 mg) portionwise. The reaction mixture was then stirred at 100 °C for 16 hr under nitrogen. The reaction mixture was allowed to cool to RT, solvent was removed under reduced pressure and the reaction mixture was diluted with cold water (5 mL). The resulting solid was collected by filtration to afford the crude product (350 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil Phenyl 25 x 150 mm) using a gradient of 10-70% 10 mM ammonium bicarbonate/water in acetonitrile. The appropriate fraction was lyophilized to afford the titled compound. LCMS m/z 479.02 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) 5 ppm 6.81 (dt, J=7.62, 1 .78 Hz, 1 H) 7.03 (d, J=2.19 Hz, 1 H) 7.13 (d, J=2.19 Hz, 1 H) 7.16 - 7.25 (m, 2 H) 7.43 (t, J=1 .86 Hz, 1 H) 7.54 - 7.65 (m, 3 H) 7.83 - 7.89 (m, 2 H).

Example 56

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)cyclopropanesulfonamide

(a) tert-Butyl (3-(cyclopropanesulfonamido)phenyl)carbamate

To a solution of tert-butyl (3-aminophenyl)carbamate (2.0 g) and pyridine (3.88 mL) in DCM (50 mL) at 0 °C under nitrogen was added cyclopropanesulfonyl chloride (1 .62 g) dropwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. Solvent was removed under reduced pressure and the reaction mixture was diluted with cold water (10 mL). The resulting precipitate was collected by filtration to afford the titled compound (1 .8 g), which was used without further purification. LCMS m/z 625.13 (2M+H).

(b) N-(3-Aminophenyl)cyclopropanesulfonamide hydrochloride

To a solution of tert-butyl (3-(cyclopropanesulfonamido)phenyl)carbamate (600 mg) in 1 ,4- dioxane (10 mL) at 0 °C under nitrogen was added HCI (4 M in 1 ,4-dioxane, 4.80 mL) over 1 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. Solvent was removed under reduced pressure and the resulting solid was washed with pentane (20 mL) to afford the titled compound (350 mg), which was used without further purification. LCMS m/z 213.0 (M+H).

(c) N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)cyclopropanesulfonamide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) N-(3-aminophenyl)cyclopropanesulfonamide hydrochloride (164 mg) in t- BuOH (5 ml_) under nitrogen at RT was added KH ₂ P0 ₄ (105 mg) portionwise. The reaction mixture was stirred at 100 °C for 16 hr. The reaction mixture was then concentrated under reduced pressure and diluted with cold water (3 ml_). The resulting precipitate was collected by filtration to afford the crude product (1 15 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-55% 0.1 % formic acid/water in acetonitrile. The appropriate fraction was lyophilized to afford the titled compound (71 mg). LCMS m/z 442.95 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 0.91 - 1 .04 (m, 4 H) 2.60 - 2.71 (m, 1 H) 6.96 - 7.03 (m, 1 H) 7.08 (d, J=1 .97 Hz, 1 H) 7.18 (d, J=2.19 Hz, 1 H) 7.30 - 7.37 (m, 2 H) 7.41 (s, 1 H).

Example 57

4-((7-Chloro-5-hvdroxy-1 ,1 -dioxido-2H-benzoreiri ,2,41thiadiazin-3-yl)amino)-3- fluorobenzonitrile

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in t-BuOH (5 ml_) were added 4-amino-3-fluorobenzonitrile (105 mg) and KH2PO4 (105 mg). The reaction mixture was stirred at 1 10 °C for 16 hr under nitrogen. The reaction mixture was allowed to cool to RT and was diluted with cold water. The resulting precipitate was collected by filtration and dried under vacuum to afford the crude product (150 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% 0.1 % formic acid/water in acetonitrile. The appropriate fractions were pooled and evaporated under reduced pressure to afford the titled compound (12 mg). LCMS m/z 366.85 (M+H). ¹ H NMR after D20 exchange (400 MHz, DMSO-c/e) δ ppm 7.12 (d, J=2.19 Hz, 1 H) 7.24 (d, J=2.19 Hz, 1 H) 7.76 (d, J=8.55 Hz, 1 H) 7.92 (dd, J=1 1 .18, 1 .75 Hz, 1 H) 8.43 (t, J=8.33 Hz, 1 H). Example 58

3-(Benzofuran-5-ylamino)-7-chloro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) and benzofuran-5-amine (103 mg) in t-BuOH (10 mL) stirred under nitrogen was added KH ₂ P0 ₄ (105 mg) in one portion. The reaction mixture was stirred at 80 °C for 24 hr. The reaction mixture was allowed to cool to RT, then was concentrated under reduced pressure, diluted with deionized water (15 mL) and allowed to stir for 15 min. The resulting precipitate was collected by filtration and washed with water (2 x 5 mL) and diethyl ether (3 x 5 mL), and dried to afford the titled compound (160 mg). LCMS m/z 364.00 (M+H). ¹ H NMR after D ₂ 0 exchange(400 MHz, DMSO-c/ ₆ ) δ ppm 7.02 (d, J=1 .53 Hz, 1 H) 7.10 (d, J=2.19 Hz, 1 H) 7.19 (d, J=1 .97 Hz, 1 H) 7.33 (dd, J=8.77, 2.19 Hz, 1 H) 7.63 (d, J=8.77 Hz, 1 H) 7.87 (d, J=2.19 Hz, 1 H) 8.00 (d, J=2.19 Hz, 1 H).

Example 59

7-Chloro-5-hvdroxy-3-((4-(phenylamino)phenyl)amino)-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of N1 -phenylbenzene-1 ,4-diamine (142 mg) in t-BuOH (10 mL) was added KH ₂ P0 ₄ (105 mg). The solution was cooled to 0 °C and 3-bromo-7-chloro-5-hydroxy- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) was added portionwise. The reaction mixture was heated to 80 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to afford the crude product (190 mg). The crude product was washed with diethyl ether and dried under vacuum to afford the titled compound (162 mg). LCMS m/z 415.01 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.82 (t, J=7.34 Hz, 1 H) 7.03 - 7.13 (m, 5 H) 7.15 - 7.18 (m, 1 H) 7.20 - 7.27 (m, 2 H) 7.33 - 7.39 (m, 2 H).

Example 60

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)benzamide

(a) tert-Butyl (3-benzamidophenyl)carbamate

To a solution of tert-butyl (3-aminophenyl)carbamate (1 .0 g) in DCM (20 mL) at 0 °C was added Et ₃ N (2.008 mL) followed by benzoyl chloride (0.877 g). The reaction mixture was allowed to warm to RT and stirred for 2 hr. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc. The EtOAc layer was separated, dried over sodium sulfate and concentrated under vacuum to afford the crude product (1 .5 g). The crude product was triturated with n-pentane and dried under vacuum to afford the titled compound (1 .1 g) which was used without further purification. LCMS m/z 313.06 (M+H), 625.23 (2M+H).

(b) N-(3-Aminophenyl)benzamide

To a solution of tert-butyl (3-benzamidophenyl)carbamate (1 .1 g) in DCM (30 mL was added HCI (4 M in 1 ,4 dioxane, 5 mL) at 0 °C.The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was quenched with saturated NaHC03 (aq) until the pH was > 8 and then extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated to afford the crude product (620 mg). The crude product was triturated with n-pentane and dried under vacuum to afford the titled compound (500 mg), which was used without further purification. LCMS m/z 213.0 (M+H).

(c) N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)benzamide To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in t-BuOH (10 mL) was added KH ₂ P0 ₄ (105 mg) at RT followed by N-(3- aminophenyl)benzamide (164 mg). The reaction mixture was stirred at 1 10 °C for 16 hr. The reaction mixture was allowed to cool to RT and then quenched with water. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the titled compound (158 mg). LCMS m/z 443.02 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.10 (d, J=2.19 Hz, 1 H) 7.20 (d, J=2.19 Hz, 1 H) 7.34 - 7.46 (m, 2 H) 7.48 - 7.64 (m, 4 H) 7.85 - 8.10 (m, 3 H).

Example 61

N-(4-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H-benzoreiri ,2,41thiadiazin-3- yl)amino)phenyl)benzamide

(a) tert-Butyl (4-benzamidophenyl)carbamate

To a stirred solution of tert-butyl (4-aminophenyl)carbamate (1 .0 g) in DCM (10 mL) at 0 °C was added Et ₃ N (2.008 mL) followed by benzoyl chloride (0.669 mL). The reaction mixture was allowed to warm to RT and stirred for 1 hr. The reaction mixture was then diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (1 .0 g), which was used without further purification. LCMS m/z 313.06 (M+H).

(b) N-(4-aminophenyl)benzamide hydrochloride

To a stirred solution of tert-butyl (4-benzamidophenyl)carbamate (1 .0 g) in 1 ,4-dioxane (10 mL) was added HCI (4 M in 1 ,4-dioxane, 10 mL) and the reaction mixture was allowed to stir overnight at RT. The reaction mixture was concentrated under reduced pressure and the resulting solid was washed with diethyl ether (10 mL) and dried under vacuum to afford the titled compound (500 mg), which was used without further purification. (c) N-(4-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)benzamide

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) and N-(4-aminophenyl)benzamide hydrochloride (164 mg) in t- BuOH (10 mL) was added KH2PO4 (105 mg) at RT and the reaction was then stirred at 1 10 °C for 16 hr. The reaction mixture was allowed to cool to RT and then was quenched with ice water (10 mL). The resulting solid was collected by filtration to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 5 u, 19 x 50 mm) using a gradient of 10-50% 10 mM ammonium bicarbonate/water in acetonitrile. The appropriate fraction was concentrated under reduced pressure and the resulting solid collected by filtration, washed with water (10 mL) and dried under vacuum to afford the titled compound (73 mg). LCMS m/z 442.90 (M+H). ¹ H NMR after D2O exchange (400 MHz, DMSO-c/e) δ ppm 7.10 (d, J=1 .97 Hz, 1 H) 7.19 (d, J=2.19 Hz, 1 H) 7.45 - 7.66 (m, 5 H) 7.78 (d, J=8.77 Hz, 2 H) 7.96 (d, J=7.23 Hz, 2 H).

Example 62

7-Chloro-3-((2.3-dihvdro-1 H-inden-5-yl)amino)-5-hvdroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 2,3-dihydro-1 H-inden-5-amine (103 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one charge. The reaction mixture was stirred at 80 °C for 24 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 mL) was added to the reaction mixture, which was stirred for 15 min and then filtered with a buchner funnel. The precipitate was washed with water (2 X 5 mL) followed by diethyl ether ( 3 X 15 mL) and dried to obtain 7-chloro-3-((2,3-dihydro-1 H-inden-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (170 mg) as an off white solid. LCMS m/z 364.00 (M+H). ¹ H NMR after D2O exchange (400 MHz, DMSO-c/e) δ ppm 1 .97 - 2.09 (m, 2 H) 2.86 (dt, J=18.80, 7.37 Hz, 4 H) 7.08 (d, J=1 .97 Hz, 1 H) 7.14 - 7.27 (m, 3 H) 7.36 - 7.45 (m, 1 H).

Example 63

7-Chloro-5-hvdroxy-3-((2^,6-trifluorophenyl)amino)-2H-benzor eiri ,2,41thiadiazine

1 ,1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 2,4,6-trifluoroaniline (1 13 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one charge. The reaction mixture was stirred at 80 °C for 24 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 mL) was added to reaction mixture, which was stirred for 15 min and filtered on buchner funnel to give the crude producte (500 mg), which was purified by preparative reversed phase HPLC (Kromosil C18, 25 x 150 mm) using a gradient of 45-100% acetonitrile in 0.1 % formic acid/water. The appropriate fractions were combined and concentrated under reduced pressure, and the resulting solid was collected by filtration and air-dried to afford the titled compound (73 mg). LCMS m/z 377.97 (M+H). ¹ H NMR after D20 exchange (400 MHz, DMSO-cfe) δ ppm 7.1 1 (d, J=2.19 Hz, 1 H) 7.17 (d, J=2.19 Hz, 1 H) 7.28 - 7.37 (m, 2 H).

Example 64

7-Chloro-5-hvdroxy-3-((6-methoxypyridin-3-yl)amino)-2H-benzo reiri ,2,41thiadiazine

1 ,1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 6-methoxypyridin-3-amine (96 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one portion. The reaction mixture was stirred at 1 10 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 mL) was added to reaction mixture, which was stirred for 15 min and filtered on a Buchner funnel. The solid was washed with water (2 x 5 mL) followed by diethyl ether (2 x 10 mL) and then with n-pentane (3 x 10 mL), dried under high vacuo to obtain the crude product as grey colored solid. The crude product was purified by silica gel column chromatography (100-200 mesh silica), eluting with 9:1 :90 v/v MeOH: Aq. NH ₄ OH: DCM. The pure fractions were concentrated under reduced pressure to afford the titled compound(25 mg) as a grey solid. LCMS m/z 354.96 (M+H). Ή NMR after D ₂ 0 exhcange (400 MHz, DMSO-c/ ₆ ) δ ppm 3.86 (s, 3 H) 6.79 - 6.99 (m, 1 H) 7.09 (d, J=2.19 Hz, 1 H) 7.17 (d, J=2.19 Hz, 1 H) 7.84 (dd, J=8.88, 2.74 Hz, 1 H) 8.21 (d, J=2.63 Hz, 1 H).

Example 65

3-((7-Chloro-5-hvdroxy-1 ,1 -dioxido-2H-benzoreiri ,2,41thiadiazin-3-yl)amino)-4- fluorobenzonitrile

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) in tert-butanol (5 mL), were added 3-amino-4-fluorobenzonitrile (105 mg) and potassium dihydrogen phosphate (105 mg) at RT in a sealed tube. The reaction mixture was warmed to 1 10 °C and this temperature reaction was maintained for 16 hr. The reaction mixture was cooled to RT, diluted with cold water, and the resulting solid was collected by filtration and dried under reduced pressure to obtained solid, then was triturated with diethyl ether and pentane and dried to afford the crude product (200 mg) as an ash color solid. The crude product was purified by preparative reversed phase HPLC (Kinetix C8, 30 x 250 mm) using a 10-40% gradient of 10 mM ammonium acetate (aq) in 1 :1 acetonitrile/MeOH. The appropriate fractions were combined and concentrated under reduced pressure to afford the titled compound (20 mg). LCMS m/z 366.91 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.12 (d, J=2.19 Hz, 1 H) 7.23 (d, J=2.19 Hz, 1 H) 7.57 (dd, J=10.74, 8.55 Hz, 1 H) 7.71 (ddd, J=8.50, 4.66, 1 .97 Hz, 1 H) 8.52 (dd, J=7.24, 1 .97 Hz, 1 H).

Example 66

7-Chloro-3-((3-((dimethylamino)methyl)phenyl)amino)-5-hvdrox y-4H- benzorelH ,2.41thiadiazine 1.1 -dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 3- ((dimethylamino)methyl)aniline (90 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The reaction mixture was purified via injection onto a Biotage Isolera One, 25 gram Biotage KP-C18-HS column, using a 0- 100% ΙΡΑ:Η2θ (0.1 % formic acid in the water) gradient to afford the titled compound (19 mg) as a white solid. LCMS m/z 381 .2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.26 (s, 6 H) 3.54 (s, 2 H) 6.98 (d, J=2.02 Hz, 1 H) 7.03 - 7.15 (m, 3 H) 7.35 (t, J=7.83 Hz, 1 H) 7.44 (s, 1 H) 7.49 (d, J=7.83 Hz, 1 H) 8.15 (s, 1 H) 9.66 (br. s., 1 H).

Example 67

3-((1 H-Benzord1imidazol-7-yl)amino)-7-chloro-5-hydroxy-4H- benzoreiri ,2,41thiadiazine 1 ,1 -dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 H-benzo[d]imidazol-7-amine (80 mg), potassium dihydrogen phosphate (85 mg), and tert- Butanol (2 mL) were reacted as in Example 16a. The reaction mixture was purified via injection onto a Biotage Isolera One, 25 gram Biotage KP-C18-HS column, using a 0-100% ΙΡΑ:Η ₂ 0 (0.1 % formic acid in the water) gradient and via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (23 mg) as a white solid, TFA salt. LCMS m/z 364.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 4.54 (br. s., 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.35 (t, J=7.96 Hz, 1 H) 7.45 (d, J=8.08 Hz, 1 H) 7.82 (d, J=7.58 Hz, 1 H) 8.69 (br. s., 1 H) 9.95 (br. s., 1 H) 10.99 (br. s., 1 H) 1 1 .63 (s, 1 H).

Example 68

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)methanesulfonamide

To a stirred solution of N-(3-aminophenyl)methanesulfonamide (143 mg) in tert-butanol (10 ml_) was added potassium dihydrogen phosphate (105 m). The reaction mixture was cooled to 0 °C and 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg, 0.642 mmol) was added slowly. The reaction mixture was then heated to 80 °C and stirred for 16 hr. The reaction mixture was cooled to RT, diluted with cold water, and the resulting solid was collected by filtration to afford the crude product (200 mg), which was washed with diethyl ether (4ml_) and dried under reduced pressure. The crude product was purified by preparative reversed phase HPLC (Xterra C18 19 x 250 mm) using a gradient of 10-50% 10 mM ammonium bicarbonate (aq) in acetonitrile. The appropriate fractions were concentrated under reduced pressure to afford the final product (80 mg). LCMS m/z 417.03 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 3.03 (s, 3 H) 6.98 (dt, J=6.85, 2.17 Hz, 1 H) 7.08 (d, J=2.19 Hz, 1 H) 7.19 (d, J=2.19 Hz, 1 H) 7.28 - 7.47 (m, 3 H). Example 69

7-Chloro-5-hvdroxy-3-((3-phenoxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 3-phenoxyaniline (143 mg) in tert-butanol (10 mL) were added potassium dihydrogen phosphate (105 mg) and 3-bromo-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and the reaction mixture was heated to 80 °C and stirred for 16 hr. The reaction mixture was cooled to RT, diluted with water, and the resulting solid was collected by filtration and dried under reduced pressure which afforded the crude product (190 mg), which was washed with diethyl ether and dried under reduced pressure to afford the titled compound(140 mg) as a brown solid. LCMS m/z 416.02 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.61 - 6.86 (m, 1 H) 7.03 - 7.12 (m, 2 H) 7.13 - 7.22 (m, 2 H) 7.22 - 7.30 (m, 2 H) 7.31 - 7.49 (m, 3 H) 9.61 (s, 1 H) 10.14 (br. s., 1 H) 1 1 .62 (br. s., 1 H).

Example 70

7-Chloro-5-hvdroxy-3-((3-(phenylamino)phenyl)amino)-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg), in tert-butanol (10 mL) were added potassium dihydrogen phosphate (105 mg) followed by N1 -phenylbenzene-1 ,3-diamine (142 mg) at RT.The reaction mixture was sealed with cap and stirred for 16 hr at 1 10 °C. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to afford the crude product (260 mg). The crude product was added to a silica gel (100-200) mesh column and was eluted with 55% EtOAc in Hexanes. The appropriate fractions were concentrated under reduced pressure to afford a partially purified product. The partially purified product was further purified by preparative reversed phase HPLC (Kromosil C18, 25 x 150 mm) using a gradient of 10-55% acetonitrile in 10 mM ammonium bicarbonate (aq). The appropriate fractions were concentrated under reduced pressure to afford 7-chloro-5-hydroxy-3-((3- (phenylamino)phenyl)amino)-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (83 mg) as brown solid. LCMS m/z 415.05 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.73 - 6.99 (m, 3 H) 7.05 (d, J=2.19 Hz, 1 H) 7.1 1 - 7.29 (m, 5 H) 7.33 (s, 1 H) 8.29 (s, 1 H) 9.45 (s, 1 H) 10.10 (br. s., 1 H) 1 1 .60 (br. s., 1 H).

Example 72

7-Chloro-3-((3,5-difluorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 3,5-difluoroaniline (99 mg) in tert-butanol (10 ml_) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one portion. The reaction mixture was stirred at 1 10 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 ml_) was added to reaction mixture, stirred for 15 min and filtered with a Buchner funnel. The precipitate was washed with water (2 x 5 ml_) followed by diethyl ether (3 x 15 ml_) and then n-pentane (3 x 10 ml_), and dried under vacuum to afford the crude product (210 mg) as an off white solid. The crude product was purified by column chromatography (100-200 mesh silica), eluting with 1 % MeOH in DCM followed by a 2-2.5% MeOH in DCM gradient. The desired fractions were concentated under reduced pressure to afford 7-chloro-3-((3,5-difluorophenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (34.3 mg as an off-white solid. LCMS m/z 360.0 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .69 (br s, 1 H), 10.34 (br s, 1 H), 9.84 (s, 1 H), 7.27 (br d, J = 7.0 Hz, 2H), 7.23 - 7.19 (m, 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 7.03 - 6.95 (m, 1 H). Example 73

3-((1 H-lndazol-5-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 220 mg), 1 H-indazol-5-amine (1 10 mg), potassium dihydrogen phosphate (1 15 mg), and tert-Butanol (3 ml_) were reacted as in Example 16a. The reaction mixture was purified via injection onto a Biotage Isolera One, 25 gram Biotage KP-C18-HS column, using a 0-100% IPA:H ₂ 0 (0.1 % formic acid in the water) gradient and via reversed phase HPLC, using a 20-60% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (13 mg) as a light brown solid, TFA salt. LCMS m/z 364.1 (M+H). ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 7.06 (d, J=2.27 Hz, 1 H) 7.17 (d, J=2.02 Hz, 1 H) 7.35 (dd, J=8.84, 2.02 Hz, 1 H) 7.57 (d, J=8.84 Hz, 1 H) 7.97 (d, J=1 .26 Hz, 1 H) 8.1 1 (d, J=1 .01 Hz, 1 H) 9.50 (s, 1 H) 10.17 (s, 1 H) 1 1 .63 (s, 1 H) 13.10 (br. s., 1 H).

Example 74

7-Chloro-5-hydroxy-3-(quinolin-8-ylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg), quinolin-8-amine (1 15 mg), potassium dihydrogen phosphate (1 15 mg), and tert-Butanol (3 ml_) were reacted as in Example 16a. The crude product was purified via reversed phase HPLC, using a 10-60% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (60 mg) as a white solid. LCMS m/z 375.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.08 (d, J=2.02 Hz, 1 H) 7.21 (d, J=2.27 Hz, 1 H) 7.55 - 7.78 (m, 3 H) 8.45 (dd, J=8.34, 1 .77 Hz, 1 H) 8.69 (dd, J=7.58, 1 .52 Hz, 1 H) 8.99 (dd, J=4.17, 1 .64 Hz, 1 H) 10.76 (s, 1 H) 1 1 .58 (br. s., 2 H).

Example 75

7-Chloro-5-hvdroxy-3-((3-methyl-1 H-indazol-6-yl)amino)-4H- benzorelH ,2.41thiadiazine 1.1 -dioxide

(a) 7-Chloro-5-methoxy-3-((3-methyl-1 H-indazol-6-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

3-bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 150 mg), 3- methyl-1 H-indazol-6-amine (85 mg), potassium dihydrogen phosphate (85 mg), and tert- Butanol (2 mL) were reacted as in Example 16a. The reaction mixture was purified via injection onto a Biotage Isolera One, 25 gram Biotage KP-C18-HS column, using a 0-100% IPA:H ₂ 0 (0.1 % formic acid in the water) gradient to afford the titled compound (98 mg) as a white solid. LCMS m/z 392.2 (M+H).

(b) 7-Chloro-5-hydroxy-3-((3-methyl-1 H-indazol-6-yl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

7-Chloro-5-methoxy-3-((3-methyl-1 H-indazol-6-yl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (98 mg), BBr ₃ (1 M in DCM, 1 .0 mL), and Dichloromethane (DCM) (10 mL) were reacted as in Example 16b. The crude product was purified via reversed phase HPLC, using a 10-60% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (13 mg) as a white solid. LCMS m/z 378.2 (M+H). 1 H NMR (400 MHz, DMSO-c/6) δ ppm 2.44 (s, 3 H) 6.91 (dd, J=8.59, 1 .77 Hz, 1 H) 7.06 (d, J=2.27 Hz, 1 H) 7.19 (d, J=2.27 Hz, 1 H) 7.67 (d, J=8.59 Hz, 1 H) 8.02 (d, J=1 .01 Hz, 1 H) 9.70 (s, 1 H) 10.22 (br. s., 1 H) 1 1 .71 (br. s., 1 H) 12.59 (s, 1 H). Example 76

3-(Benzord1thiazol-2-ylamino)-7-chloro-5-hvdroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and benzo[d]thiazol-2-amine (1 16 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one charge. The reaction mixture was stirred at 1 10 °C for 24 hr. The reaction mixture was concentrated and quenched with demineralized water (15 ml_).The resulting precipitate was isolated by filtration to afford the crude product (380 mg). The crude product was purified by preparative reversed phase HPLC ( KINETEX C-8, 150 X4.6 mm) using a 50-90% gradient of 1 :1 acetonitrile/MeOH in 0.1 % TFA/water. The desired fractions were concentrated under reduced pressure, and the resultant precipitate was collected by filtration and air dried to affored 3-(benzo[d]thiazol-2-ylamino)-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (23 mg) as an off-white solid. LCMS m/z 380.96 (M+H). Ή NMR after D ₂ 0 exchange(400 MHz, DMSO-c/ ₆ ) δ ppm 7.13 (s, 1 H) 7.25 (s, 1 H) 7.34 (t, J=7.89 Hz, 1 H) 7.48 (t, J=7.13 Hz, 1 H) 7.63 (br. s., 1 H) 7.98 (d, J=7.45 Hz, 1 H).

Example 77

3-((1 H-lndazol-6-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 3-((1 H-lndazol-6-yl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide 3-Bromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 150 mg), 1 H-indazol-6-amine (80 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 ml_) were reacted as in Example 16 (a). The reaction mixture was purified via injection onto a Biotage Isolera One, 25 gram Biotage KP-C18-HS column, using a 0-100% IPA:H ₂ 0 (0.1 % formic acid in the water) gradient to afford the titled compound (88 mg) as a yellow solid. LCMS m/z 378.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 4.05 (s, 3 H) 6.96 (dd, J=8.59, 1 .77 Hz, 1 H) 7.35 (d, J=2.02 Hz, 1 H) 7.43 (d, J=2.02 Hz, 1 H) 7.75 (d, J=8.59 Hz, 1 H) 8.03 (s, 1 H) 8.12 (s, 1 H) 9.77 (s, 1 H) 10.28 (s, 1 H) 13.03 (s, 1 H).

(b) 3-((1 H-lndazol-6-yl)amino)-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

3-((1 H-lndazol-6-yl)amino)-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (88 mg, 0.233 mmol), BBr ₃ (1 M in DCM, 1 .0 ml_), and Dichloromethane (DCM) (10 mL) were reacted as in Example 16 (b). The crude product was purified via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (50 mg) as a white solid. LCMS m/z 364.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.95 (dd, J=8.30, 2.10 Hz, 1 H) 7.07 (d, J=2.02 Hz, 1 H) 7.20 (d, J=2.27 Hz, 1 H) 7.74 (d, J=8.59 Hz, 1 H) 8.02 (s, 1 H) 8.12 (s, 1 H) 9.72 (s, 1 H) 10.23 (br. s., 1 H) 1 1 .70 (br. s., 1 H) 13.02 (s, 1 H). Example 78

7-Chloro-5-hvdroxy-3-((4-methyl-1 H-indol-5-yl)amino)-4H-benzoreiri .2.41thiadiazine

1 ,1 -dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 4- methyl-1 H-indol-5-amine (90 mg), potassium dihydrogen phosphate (85 mg), and tert- Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-60% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (93 mg) as a light pink solid. LCMS m/z 377.1 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 2.39 (s, 3 H) 6.51 (s, 1 H) 7.01 - 7.16 (m, 4 H) 7.26 (d, J=8.59 Hz, 1 H) 7.37 (t, J=2.78 Hz, 1 H) 8.88 (br. s., 1 H) 10.25 (br. s., 1 H) 1 1 .16 (br. s., 1 H).

Example 79

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)acetamide

(a) tert-Butyl (4-acetamidophenyl)carbamate

To a solution of tert-butyl (4-aminophenyl)carbamate (1 .8 g) and triethylamine (6.02 mL) in Dichloromethane (DCM) (25 mL) stirred under nitrogen at 0 °C was added neat acetyl chloride (1 .234 mL) dropwise over 5 min. The reaction mixture was stirred at 25 °C for 6 hr. The reaction mixture was concentrated under reduced presure, quenched with cold water (20 mL) and the resulting precipitate was collected by filtration and air dried to give tert- butyl (4-acetamidophenyl)carbamate (2.5 g) as a yellow solid. LCMS m/z 249.34 (M+H). (b) N-(4-aminophenyl)acetamide

To a solution of tert-butyl (4-acetamidophenyl)carbamate (2.45 g) in Dichloromethane (DCM) (2.5 mL) stirred under nitrogen at 0 °C was added neat TFA (2.262 mL) dropwise over 5 min. The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure and co-evoporated using toluene (2 X 15 mL). The reaction mixture was then treated with 5% NaHC03 until a pH of ~7 was reached, and the reaction mixture was extracted using EtOAc (2 X 50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain N-(4-aminophenyl)acetamide (1 .5 g,) as brown gummy liquid, which was used without further purification. LCMS m/z 151 .0 (M+H).

(c) N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetamide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and N-(4-aminophenyl)acetamide (1 14 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one charge. The reaction mixture was stirred at 1 10 °C for 24 hr. The reaction mixture was then concentrated under reduced pressure, and demineralized watenacetonitrile (9:1 , 15 mL) was added to the reaction mixture, stirred for 15 min and filtered with a Buchner funnel. The precipitate was washed with water 2 X 5 mL followed by diethyl ether (3 X 15 mL) and dried to obtain N-(4-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H- benzo[e][1 ,2,4]thiadiazin-3-yl)amino)phenyl)acetamide (190 mg) as an off white-solid. LCMS m/z 379.28 (M-H) ^" . ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.05 (s, 3 H) 7.09 (d, J=1 .97 Hz, 1 H) 7.18 (d, J=2.19 Hz, 1 H) 7.32 - 7.50 (m, 2 H) 7.51 - 7.71 (m, 2 H).

Example 80

N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzore1H ,2,41thiadiazin-3- yl)amino)phenyl)acetamide

(a) tert-Butyl (3-acetamidophenyl)carbamate

To a solution of tert-butyl (3-aminophenyl)carbamate (1 .8 g) and triethylamine (6.02 mL) in Dichloromethane (DCM) (25 mL) stirred under nitrogen at 0 °C was added neat acetyl chloride (0.617 mL) dropwise over 5 min. The reaction mixture was stirred at 25 °C for 6 hr. The reaction mixture was concentrated under reduced presure, quenched with cold water (50 mL), and the resulting precipitate was filtered and air dried to give tert-butyl (3- acetamidophenyl)carbamate (2 g) as a yellow solid. LCMS m/z 268.2 (M+NH ₄ ).

(b) N-(3-Aminophenyl)acetamide trifluoroacetate

To a solution of tert-butyl (3-acetamidophenyl)carbamate (2 g) in Dichloromethane (DCM) (2.5 mL) stirred under nitrogen at 0 °C was added neat TFA (0.708 mL) dropwise over 1 min. The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure and co-evaporated using toluene (2 X 50 mL), and then quenched by ice/water (30 mL). The resulting precipitate was collected by filtration, washed with pentane (10 mL) and air dried to afford N-(3-aminophenyl)acetamide (1 .7 g) as yellow solid. LCMS m/z 151 .1 (M+H). (c) N-(3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)phenyl)acetamide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 300 mg) and N-(3-aminophenyl)acetamide trifluoroacetate (153 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (655 mg) in one charge. The reaction mixture was stirred at 1 10 °C for 24 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 mL) was added to reaction mixture, which was stirred for 15 min and the filtered on a Buchner funnel. The precipitate was washed with water (2 X 5 mL) followed by diethyl ether ( 3 X 15 mL) and dried to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Xbridge C18, 4.6 x 250 mm) using a gradient of 10- 60% acetonitrile/MeOH 1 :1 in 0.1 % formic acid/water. The desired fractions were concentrated under reduced pressure and the resulting solid was collected by filtration and dried under vacuum to afford the titled compound (90 mg). LCMS m/z 380.96 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-cfe) δ ppm 2.07 (s, 3 H) 7.10 (d, J=1 .97 Hz, 1 H) 7.19 (d, J=2.19 Hz, 1 H) 7.23 - 7.40 (m, 3 H) 7.66 - 7.86 (m, 1 H).

Example 81

7-Chloro-3-((2,5-difluorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 2,5-difluoroaniline (99 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg) in one charge. The reaction mixture was stirred at 1 10 °C for 24 hr. The reaction mixture was then concentrated under reduced pressure. Demineralized water (15 mL) was added to reaction mixture, stirred for 15 min and the resulting precipitate was collected by filtration with a Buchner funnel. The precipitate was washed with water (2 X 5 mL) followed by diethyl ether (3 X 15 mL) and dried to obtain the crude product (120 mg). The crude product was purified by preparative reversed phase HPLC (Xbridge C18, 4.6 x 250 mm) using a gradient of 10- 60% acetonitrile in 10 mM ammonium bicarbonate/water. The appropriate fractions were pooled and lyophilized to afford the titled compound (45 mg). LCMS m/z 359.93 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.97 - 7.06 (m, 1 H) 7.08 (d, J=2.19 Hz, 1 H) 7.20 (d, J=1 .97 Hz, 1 H) 7.39 (dd, J=10.63, 9.10 Hz, 1 H) 7.38 (dd, J=10.74, 9.21 Hz, 1 H) 7.95 - 8.08 (m, 1 H).

Example 82

7-Chloro-3-((2-chloro-4-hydroxyphenyl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) in tert-butanol (5 mL), were added 4-amino-3-chlorophenol (1 1 1 mg) and potassium dihydrogen phosphate (105 mg) at RT. The reaction mixture was warmed to 100 °C and reaction was maintained at this temperature for 16 hr. The reaction mixture was poured in ice water (50 mL), extracted with EtOAc (3x50 mL) and the combined EtOAc extracts washed with brine solution (50 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether and pentane to afford the crude product (165 mg) as ash colored solid. This solid was triturated with DCM (100 mL) and dried to obtained a partially purified product (135 mg) as a brown solid, which was further purified by preparative reversed phase HPLC (Kromosil Phenyl, 25 x 150 mm) using 50 % acetonitrile in 0.1 % formic acid/water. The desired fractions were concentrated under reduced pressure to afford the titled compound (75 mg) as a pale violet solid. LCMS m/z 373.93 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.99 (d, J=8.77 Hz, 1 H) 7.08 (d, J=2.19 Hz, 1 H) 7.13 - 7.21 (m, 2 H) 7.57 (d, J=2.63 Hz, 1 H). Example 83

7-Chloro-3-((2-fluoro-4-hvdroxyphenyl)amino)-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 4-amino-3-fluorophenol (98 mg) in tert-butanol (10 mL) were added potassium dihydrogen phosphate (105 mg) and 3-bromo-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg), and the reaction mixture was heated to 80 °C and stirred for 16 hr. The reaction mixture was cooled to RT and diluted with cold water. The resulting was collected by filtration and dried under reduced pressure to afford the crude product (350 mg). The crude product was purified by by preparative reversed phase HPLC (XBridge C18, 30 x 250 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (89 mg) as an ash-colored solid. LCMS m/z 355.93 (M-H)-. ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.63 - 6.74 (m, 2 H) 7.06 (d, J=2.19 Hz, 1 H) 7.14 (d, J=2.19 Hz, 1 H) 7.56 (t, J=9.10 Hz, 1 H).

Example 84

7-Chloro-3-((2-fluoro-5-methylphenyl)amino)-5-hydroxy-2H- benzorelH ,2.41thiadiazine 1.1 -dioxide

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) in tert-butanol (10 mL) were added potassium dihydrogen phosphate (105 mg) and 2-fluoro-5-methylaniline (96 mg) at RT.The reaction mixture was sealed with a cap and stirred for 16 hr at 1 10 °C. The reaction mixture was quenched with water (10 mL), and the resulting solid was collected by filtration and dried under vacuum to afford the titled compound (65 mg) as off- white solid. LCMS m/z 353.88 (M-H)-. ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.32 (s, 3 H) 7.00 - 7.06 (m, 1 H) 7.10 (d, J=1 .97 Hz, 1 H) 7.16 - 7.24 (m, 2 H) 7.80 (dd, J=7.56, 1 .86 Hz, 1 H). Example 85

7-Chloro-3-(cvclohexylamino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy -2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and cyclohexylamine (88 uL) in tert-BuOH (10 mL) stirred under nitrogen at RT was added potassium dihydrogen phosphate (105 mg) in one portion. The reaction mixture was stirred at 80 °C for 24 hr. The reaction mixture concentrated under reduced pressure. Demineralized water (15 mL) was added and the reaction mixture was stirred for 15 min and the resulting solid collected by filttration on a Buchner funnel. The solid was washed with 0.5 N HCI (2 x 10 mL) and diethyl ether (3 x 15 mL) and then dried to afford the titled compound (170 mg) as an off-white solid. LCMS m/z 329.98 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 1 .16 - 1 .45 (m, 5 H) 1 .48 - 1 .59 (m, 1 H) 1 .66 (dd, J=8.88, 3.84 Hz, 2 H) 1 .80 - 1 .92 (m, 2 H) 3.57 - 3.69 (m, 1 H) 6.99 (d, J=2.19 Hz, 1 H) 7.08 (d, J=2.19 Hz, 1 H) 7.32 (d, J=7.45 Hz, 1 H) 9.81 (s, 1 H) 1 1 .41 (s, 1 H). Example 86

7-Chloro-5-hydroxy-3-((1 -methyl-1 H-indol-4-yl)amino)-4H-benzore1M ,2,41thiadiazine

1 ,1 -dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 - methyl-1 H-indol-4-amine (85 mg), potassium dihydrogen phosphate (85 mg), and tert- Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (71 mg) as a white solid. LCMS m/z 377.2 (M+H). ¹ H NMR (400 MHz, DMSO- d _e ) δ ppm 3.81 (s, 3 H) 6.59 (dd, J=3.28, 0.76 Hz, 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.12 - 7.22 (m, 2 H) 7.27 (d, J=8.00 Hz, 1 H) 7.37 (d, J=3.03 Hz, 1 H) 7.68 (d, J=7.33 Hz, 1 H) 9.42 (s, 1 H) 10.48 (br. s., 1 H) 1 1 .71 (br. s., 1 H). Example 87

4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzoreiri ,2,41thiadiazin-3-yl)amino)indolin-

2-one

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 4- aminoindolin-2-one (90 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-50% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (105 mg) as a light pink solid. LCMS m/z 379.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.50 (s, 2 H) 6.66 (d, J=7.58 Hz, 1 H) 7.05 (d, J=2.02 Hz, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 7.22 (t, J=7.96 Hz, 1 H) 7.43 (d, J=7.83 Hz, 1 H) 9.1 1 (s, 1 H) 10.50 (s, 1 H) 1 1 .76 (br. s., 1 H).

Example 88

3-((1 H-lndazol-7-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 H-indazol-7-amine (80 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-40% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (53 mg) as a white solid. LCMS m/z 364.2 (M+H). ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 7.05 (d, J=2.27 Hz, 1 H) 7.08 - 7.20 (m, 2 H) 7.35 (br. s., 1 H) 7.68 (br. s., 1 H) 8.15 (br. s., 1 H) 9.26 (br. s., 1 H) 1 1 .16 (br. s., 1 H) 13.04 (br. s., 1 H).

Example 89

7-Chloro-3-((4-fluoro-2-methyl-1 H-indol-5-yl)amino)-5-hvdroxy-4H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 4- fluoro-2-methyl-1 H-indol-5-amine (100 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 5-40% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (99 mg) as a light pink solid. LCMS m/z 395.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 2.40 (s, 3 H) 6.23 (s, 1 H) 7.04 (d, J=2.27 Hz, 1 H) 7.09 - 7.17 (m, 2 H) 7.26 (t, J=8.00 Hz, 1 H) 9.08 (s, 1 H) 10.36 (br. s., 1 H) 1 1 .30 (br. s., 1 H) 1 1 .65 (br. s., 1 H).

Example 90

7-Chloro-5-hvdroxy-3-((3-methyl-1 H-indazol-5-yl)amino)-4H- benzorelH ,2.41thiadiazine 1.1 -dioxide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 3- methyl-1 H-indazol-5-amine (90 mg), potassium dihydrogen phosphate (85 mg), and tert- Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 10-60% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (103 mg) as a white solid. LCMS m/z 378.2 (M+H). ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 2.49 (s, 3 H) 7.05 (d, J=2.27 Hz, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 7.36 (dd, J=8.84, 1 .77 Hz, 1 H) 7.49 (d, J=8.84 Hz, 1 H) 7.79 (d, J=1 .52 Hz, 1 H) 9.44 (s, 1 H) 10.17 (br. s., 1 H) 1 1 .63 (br. s., 1 H) 12.68 (s, 1 H).

Example 91

3-((1 H-lndazol-4-yl)amino)-7-chloro-5-hydroxy-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 1 H-indazol-4-amine (80 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 5-40% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient and a 10-40% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (23 mg) as a white solid, TFA salt. LCMS m/z 364.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.09 (d, J=2.02 Hz, 1 H) 7.21 (d, J=2.27 Hz, 1 H) 7.28 - 7.43 (m, 2 H) 7.67 (dd, J=7.50, 0.70 Hz, 1 H) 8.17 (d, J=0.76 Hz, 1 H) 9.71 (s, 1 H) 10.49 (s, 1 H) 1 1 .76 (s, 1 H) 13.26 (br. s., 1 H).

Example 92

N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzoreiri ,2,41thiadiazin-3-yl)amino)-5- fluoro-2-hvdroxyphenyl)acetamide

(a) 5-Fluoro-2-methylbenzo[d]oxazole

To a solution of 2-amino-4-fluorophenol (2.72 g) and triethyl orthoacetate (7.89 ml) in ethanol (100 ml) was added ytterbium(lll) trifluoromethanesulfonate (310 mg, 0.500 mmol). The reaction was heated at reflux for 2 hours whereupon LCMS indicated complete conversion. The resulting dark solution was cooled, concentrated to a dark residue, then purified directly on a pre-packed silica column (SF40-150g), using a gradient of 0-100% ethyl acetate in hexanes to afford the titled compound(1 .65 g) as an orange oil, which was used without further purification. LCMS m/z 151 .9 [M+H]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.61 (s, 3H), 7.19 (td, J=9.35, 2.53 Hz, 1 H), 7.52 (dd, J=8.84, 2.53 Hz, 1 H), 7.68 (dd, J=8.84, 4.29 Hz, 1 H).

(b) 5-Fluoro-2-methyl-6-nitrobenzo[d]oxazole

To a solution of 5-fluoro-2-methylbenzo[d]oxazole (1 .65 g) in sulfuric acid (10 ml) was added a mixture of nitric acid (2.5 m) and sulfuric acid (2.5 ml) at 0 °C. The reaction was allowed to stir at room temperature for 30 minutes whereupon LCMS indicated complete conversion. After 1 hour, the reaction was slowly poured onto crushed ice then diluted with water. After stirring 20 minutes, the solids were collected, rinsed well with water, and suction dried to afford the titled compound (1 .85 g) as a pink solid. LCMS m/z = 196.9 [M+H]. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.71 (s, 3H), 7.97 (d, J=1 1 .12 Hz, 1 H), 8.64 (d, J=6.32 Hz, 1 H).

(c) 5-Fluoro-2-methylbenzo[d]oxazol-6-amine

In a 100 ml round bottom flask, 5-fluoro-2-methyl-6-nitrobenzo[d]oxazole (200 mg) was taken up in Ethyl acetate (20 mL). Under a stream of nitrogen, 10% Pd/C (50 mg, 0.047 mmol) was added to the solution. A hydrogen balloon was attached to the vessel. After cycling house vacuum and hydrogen through the system (5X), The reaction mixture was allowed to stir at room temperature under an atmosphere of hydrogen for 1 hour. LCMS analysis confirmed reduction complete. Under a light blowing stream of nitrogen, the reaction solution was filtered over celite, rinsing the celite with EtOAc (~ 20 ml_). The filtrate was concentrated in vacuo to afford the titled compound (170 mg) as a light pink solid, which was used without further purification. LCMS m/z 166.9 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 2.50 (s, 3 H) 5.25 (s, 2 H) 6.94 (d, J=7.58 Hz, 1 H) 7.31 (d, J=1 1 .00 Hz, 1 H).

(d) N-(4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)- 5-fluoro-2-hydroxyphenyl)acetamide

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), 5- fluoro-2-methylbenzo[d]oxazol-6-amine (100 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 ml_) were reacted as in Example 16 (a). The oxazole ring was hydrolyzed under these conditions. The crude product was purified via reversed phase HPLC, using a 10-40% ACN:H ₂ 0 (0.1 % NH ₄ OH) gradient to afford the titled compound (15 mg) as a light pink solid. LCMS m/z 415.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2.10 (s, 3 H) 7.05 (d, J=2.27 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.72 (d, J=8.08 Hz, 1 H) 7.88 (d, J=13.30 Hz, 1 H) 9.28 (s, 1 H) 9.35 (s, 1 H) 10.1 1 (br. s., 1 H) 10.56 (br. s., 1 H) 1 1 .66 (br. s., 1 H).

Example 93

7-Chloro-3-((4-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 7-Chloro-3-((4-fluorophenyl)amino)-5-methoxy-3,4-dihydro-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7-chloro-5-methoxy-3,4-dihydro-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 400 mg) in 1 -butanol (20 ml_) added 4- fluoroaniline (163 m) and potassium dihydrogen phosphate (199 mg) portion wise at 0 °C. After completion of addition reaction mixture was heated to 80 °C and stirred for 12 hr. The reaction mixture was then quenched with water, extracted with DCM (50ml x 2), and the combined organic layers were washed with brine solution (50 ml), dried over Na ₂ S0 ₄ and concentrated under reduced pressure to afford the crude product (330 mg).

The identical procedure was performed using 3-bromo-7-chloro-5-methoxy-3,4-dihydro- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-2, 100 mg), 4-fluoroaniline (40.7 mg) and potassium dihydrogen phosphate (49.9 mg) to afford the crude product (65 mg).

(b) 7-Chloro-3-((4-fluorophenyl)amino)-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

The combined 7-chloro-3-((4-fluorophenyl)amino)-5-methoxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide from Example 93a (395 mg) and boron tribromide (5.55 mL) in DCM (20 mL) were heated at 50 °C for 12 hr. The reaction mixture was quenched with water and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate and evaporated at reduced pressure to afford the crude product (460 mg). The crude product was purified by silica gel flash chromatography (20 g column), eluting with DCM (100 mL), 1 % MeOH/DCM (100 mL), 2% MeOH/DCM (100 mL), 4% MeOH/DCM (100 mL), and 10% MeOH/DCM (1000 mL). The desired fractions were evaporated under reduced pressure to afford the titled compound (179 mg) as a white solid. LCMS 339.93 (M-H) ^~ . ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.08 (d, J=2.19 Hz, 1 H) 7.18 (d, J=2.19 Hz, 1 H) 7.21 - 7.29 (m, 2 H) 7.48 - 7.56 (m, 2 H).

Example 94

7-Chloro-5-hydroxy-3-(naphthalen-1 -ylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide, Trifluoroacetic acid salt

3-Bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg), naphthalen-1 -amine (85 mg), potassium dihydrogen phosphate (85 mg), and tert-Butanol (2 mL) were reacted as in Example 16 (a). The crude product was purified via reversed phase HPLC, using a 20-60% ACN:H ₂ 0 (0.1 % TFA) gradient to afford the titled compound (95 mg) as a grey solid, TFA salt. LCMS m/z 374.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.09 (d, J=2.27 Hz, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.47 - 7.68 (m, 3 H) 7.80 - 7.90 (m, 2 H) 7.98 - 8.04 (m, 1 H) 8.1 1 (d, J=8.34 Hz, 1 H) 9.55 (s, 1 H) 10.62 (s, 1 H) 1 1 .69 (s, 1 H).

Example 95

7-Chloro-5-hydroxy-3-(naphthalen-2-ylamino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and naphthalen-2-amine (1 10 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg ) in one charge. The reaction mixture was stirred at 80 °C for 24 hr. The reaction mixture was then concentrated under reduced pressure. Demineralized water (15 mL) was added to reaction mixture, which was stirred for 15 min and filtered on a Buchner funnel to give the crude product ( 350 mg) as a brown solid. The crude product was purified by preparative reversed phase HPLC (Xbridge C18, 4.6 x 250 mm) using a gradited of 10-50% acetonitrile in 0.1 % formic acid/water. The desired fractions were combined and concentrated under reduced pressure. The resultant solid was collected by filtration and air dried to afford the titled compound (95 mg) as an off-white solid. LCMS m/z 374.01 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 7.07 (d, J=2.19 Hz, 1 H) 7.20 (d, J=2.19 Hz, 1 H) 7.42 - 7.49 (m, 1 H) 7.49 - 7.56 (m, 1 H) 7.59 (dd, J=8.88, 2.08 Hz, 1 H) 7.89 (dd, J=8.00, 2.96 Hz, 2 H) 7.95 (d, J=8.77 Hz, 1 H) 8.03 - 8.24 (m, 1 H) 9.74 (s, 1 H) 10.26 (br. s., 1 H) 1 1 .65 (br. s., 1 H).

Example 96

7-fluoro-5-hvdroxy-3-((3-hvdroxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 150 mg) and 3-aminophenol (66.6 mg) in tert-butanol (10 ml_) stirred under nitrogen at room temp was added potassium dihydrogen phosphate (83 mg) in one charge. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was then concentrated under reduced pressure. Demineralized water (15 ml_) was added to reaction mixture, which was then stitrred for 15 min and filtered on a Buchner funnel. The precipitate was washed with water (2 x 5 ml_) and diethyl ether (3 X 15 ml_) and dried in vacuo to obtain the titled compound (101 mg) as brown solid. LCMS m/z 324.04 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.54 (dd, J=8.1 1 , 1 .53 Hz, 1 H) 6.87 (dd, J=8.00, 1 .21 Hz, 1 H) 6.92 (dd, J=10.09, 2.63 Hz, 1 H) 6.99 (dd, J=7.67, 2.63 Hz, 1 H) 7.10 (t, J=2.08 Hz, 1 H) 7.16 (t, J=8.00 Hz, 1 H).

Example 97

7-Fluoro-5-hvdroxy-3-((4-hvdroxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 200 mg) and 4-aminophenol (89 mg) in tert-butanol (10 ml_) stirred under nitrogen at room temp was added potassium dihydrogen phosphate (1 1 1 mg) in one charge. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 ml_) was added to the reaction mixture, which was stirred for 15 min and filtered on a Buchner funnel. The precipitate was washed with diethyl ether (2 X 5 mL) and air dried to afford the titled compound (95 mg) as brown solid. LCMS m/z 324.00 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.77 - 6.82 (m, 2 H) 6.91 (dd, J=10.08, 2.63 Hz, 1 H) 6.96 (dd, J=7.56, 2.74 Hz, 1 H) 7.24 - 7.29 (m, 2 H).

Example 98

7-Fluoro-5-hvdroxy-3-((4-methoxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 200 mg) and 4-methoxyaniline (100 mg) in tert-butanol (10 mL) stirred under nitrogen at room temp was added potassium dihydrogen phosphate (1 1 1 mg) in one charge. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 mL) was added to the reaction mixture, which was stirred for 15 min and filtered on a Buchner funnel. The precipitate was washed with diethyl ether (2 X 5 mL) and dried under vacuum to afford the titled compound (145 mg) as a black solid. LCMS m/z 338.01 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 3.76 (s, 3 H) 6.91 (dd, J=10.09, 2.63 Hz, 1 H) 6.94 - 7.01 (m, 3 H) 7.33 - 7.51 (m, 2 H).

Example 99

7-Fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Int- 39, 150 mg) and 2-fluoroaniline (67.8 mg) in tert-butanol (3 ml_) stirred under nitrogen at RT was added potassium dihydrogen orthophosphate (83 mg) was added portionwise over 1 min. The reaction mixture was then stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure and cold water (3 ml_) was added. The supernatant was decanted from the resulting precipitate to afford the crude product (1 10 mg). The crude product was purified by preparative reverse phase HPLC (Xbridge C18, 19 x 150 mm), using a gradient of 0-50% acetonitrile in 5 mM aq ammonium bicarbonate. The desired fraction was lyophilized to afford the titled compound (83 mg) as an off-white solid. LCMS m/z 326.02 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.93 (dd, J=10.09, 2.63 Hz, 1 H) 6.98 (dd, J=7.67, 2.63 Hz, 1 H) 7.18 - 7.37 (m, 3 H) 8.01 (td, J=7.95, 2.08 Hz, 1 H).

Example 100

3-((4-Chlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 4-chloroaniline (78 mg) in 2-Butanol (5 ml_) were added potassium dihydrogen phosphate (83 mg) and 3-bromo-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 150 mg) at RT. The reaction mixture was heated to 80 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT, then was diluted with water and the resulting solid was collected by filtratoin and dried under vacuum to afford the titled compound (127 mg) as an off-white solid. LCMS m/z 341 .97 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.95 (dd, J=10.09, 2.63 Hz, 1 H) 7.01 (dd, J=7.45, 2.63 Hz, 1 H) 7.42 - 7.49 (m, 2 H) 7.51 - 7.58 (m, 2 H). Example 101

7-Fluoro-5-hvdroxy-3-(m-tolylamino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-39, 150 mg) in 2-butanol (5 ml_), were added m-toluidine (65.4 mg) and potassium dihydrogen phosphate (83 ml) at RT. The reaction mixture was warmed to 80 °C and stirred for 16 hr under nitrogen. The reaction mixture was allowed to cool to RT, the diluted with cold water. The resulting solid was collected by filtration and dried under reduced pressure to afford the titled compound (120 mg) as an ash-colored solid. LCMS m/z 322.02 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.33 (s, 3 H) 6.89 - 7.02 (m, 3 H) 7.24 - 7.36 (m, 3 H).

Example 102

7-Fluoro-5-hvdroxy-3-(p-tolylamino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-39, 150 mg) in 2-butanol (5 ml_), were added p-toluidine (65.4 mg) and potassium dihydrogen phosphate (83 mg) at RT. The reaction mixture was warmed to 80 °C and stirred for 16 hr under nitrogen. The reaction mixture was allowed to cool to RT and then diluted with cold water. The resulting solid was collected by filtration and dried in vacuum to afford the titled compound (120 mg) as an ash-colored solid. LCMS m/z 322,02 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 2.29 (s, 3 H) 6.92 (dd, J=10.09, 2.63 Hz, 1 H) 6.98 (dd, J=7.67, 2.63 Hz, 1 H) 7.17 - 7.23 (m, 2 H) 7.36 - 7.42 (m, 2 H). Example 103

7-Fluoro-5-hvdroxy-3-((3-methoxyphenyl)amino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 200 mg) and 3-methoxyaniline (100 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (1 1 1 mg) in one charge. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure and demineralized water (15 mL) was added to reaction mixture, which was then stirred for 15 min and filtered on a Buchner funnel. The solid was washed with diethyl ether 2 X 5 mL and dried in vacuo to obtain the titled compound (150 mg) as a brown solid. LCMS m/z 338.04 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 3.77 (s, 3 H) 6.74 (dd, J=8.00, 2.30 Hz, 1 H) 6.93 (dd, J=10.09, 2.63 Hz, 1 H) 7.00 (dd, J=7.45, 2.63 Hz, 1 H) 7.04 (dd, J=7.67, 1 .75 Hz, 1 H) 7.18 (t, J=2.30 Hz, 1 H) 7.31 (t, J=8.1 1 Hz, 1 H).

Example 104

7-Fluoro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt- 39, 150 mg) and 3-fluoroaniline (67.8 mg) in tert-butanol (3 mL) stirred under nitrogen at RT was added potassium dihydrogen phosphate (83 mg) portionwise over 1 min. The reaction mixture was then stirred at 80 °C 16 hr. The reaction mixture was concentrated under reduced presure, quenched with cold water (3 mL) and water layer was decanted to afford the crude product (120 mg) as an ash-coloured solid. The crude product was purified by preparative reversed phase HPLC (Xbridge C18, 19 x 50 mm) using a 5-30% gradient of acetonitrile in 10 mM aq ammonium bicarbonate. The desired fraction was lyophilized to afford the titled compound (73 mg) as an off-white solid. LCMS m/z 325.98 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.91 (dd, J=10.30, 2.63 Hz, 1 H) 6.93 - 7.02 (m, 2 H) 7.23 (ddd, J=8.17, 2.03, 0.77 Hz, 1 H) 7.42 (td, J=8.22, 7.02 Hz, 1 H) 7.54 (dt, J=1 1 .40, 2.19 Hz, 1 H).

Example 105

7-Fluoro-3-((4-fluorophenyl)amino)-5-hvdroxy-2H-benzorein .2.41thiadiazine 1.1 - dioxide

To a solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Int- 39, 150 mg) and 4-fluoroaniline (67.8 mg) in tert-butanol (3 mL) stirred under nitrogen at RT was added potassium dihydrogen phosphate (83 mg) was added portionwise over 1 min. The reaction mixture was then stirred at 80 °C 16 hr. The reaction mixture was concentrated under reduced presure, quenched with cold water (3 mL) and the water layer was decanted to give the crude product (85 mg) as an ash-coloured solid. The crude product was purified by preparative reversed phase HPLC (XTerra C18, 19 x 250 mm) using a 10-40% gradient of acetonitrile in ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (45 mg) as an off-white solid. LCMS m/z 326.02 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.86 - 6.97 (m, 2 H) 7.20 - 7.28 (m, 2 H) 7.47 - 7.55 (m, 2 H).

Example 106

3-((1 H-Benzorcnimidazol-5-yl)amino)-7-fluoro-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Int- 39, 200 mg) and 1 H-benzo[d]imidazol-5-amine (108 mg) in tert-butanol (3 mL) stirred under nitrogen at RT was added potassium dihydrogen phosphate (1 1 1 mg) portionwise over 1 min. The reaction mixture was stirred at 80 °C 16 hr. The reaction mixture was concentrated under reduced presure, quenched cold water ( 5 mL) and the water layer was decanted to give the crude product (200 mg) as an ash-coloured solid. The crude product was purified by preparative reversed phase HPLC (Xbridge C-18, 19 x 150 mm) using a gradient of 5- 25% acetonitrile in 10 mM ammonium acetate (aq). The desired fraction was lyophilized to afford the titled compound (80 mg) as a pink solid. LCMS m/z 345.91 (M-H)-. ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.89 (dd, J=10.19, 2.74 Hz, 1 H) 6.95 (dd, J=7.67, 2.63 Hz, 1 H) 7.15 (br. s., 1 H) 7.60 (d, J=8.55 Hz, 1 H) 7.96 (br. s., 1 H) 8.21 (s, 1 H).

Example 107

7-Fluoro-5-hvdroxy-3-(o-tolylamino)-2H-benzorein ,2.41thiadiazine 1.1 -dioxide

To a stirred solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-39, 150 mg) in 2-butanol (5 mL) were added o-toluidine (65.4 mg) and potassium dihydrogenphosphate (83 mg) at RT. The reaction mixture stirred at 80 °C for 16 hr under nitrogen. The reaction mixture was cooled to RT and diluted with cold water. The resulting solid was collected by filtration and dried under reduced pressure to obtaine the crude product (100 mg) as an ash-colored solid. The solid was suspended in water and evaporated to dryness to remove residual 2-butanol, affording the titled compound (30 mg) as an ash-coloured solid. LCMS m/z 321 .98 (M+H). ¹ H NMR after D ² 0 exchange (400 MHz, DMSO-c/e) δ ppm 2.28 (s, 3 H) 6.81 - 7.04 (m, 2 H) 7.06 - 7.20 (m, 1 H) 7.20 - 7.42 (m, 2 H) 7.59 (dd, J=8.00, 1 .21 Hz, 1 H).

Example 108

3-((3-Chlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 3-chloroaniline (78 mg) in 2-butanol (10 mL) was added potassium dihydrogen phosphate (83 mg). The reaction mixture was cooled to 0 °C and 3-bromo-7- fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 150 mg) was added protionwise. The reaction mixture was stirred at 80 °C for 16h. The reaction mixture was cooled to RT and diluted with cold water. The resulting solid was collected by filtration and triutrated with pentane to afford the crude product (150 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 50 mm) using a gradient of 10- 55% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to affor d the titled compound (1 15 mg) as an off- white solid. LCMS m/z 341 .97 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.96 (dd, J=10.09, 2.63 Hz, 1 H) 7.02 (dd, J=7.45, 2.63 Hz, 1 H) 7.22 (dt, J=7.95, 0.96 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.39 - 7.47 (m, 1 H) 7.75 (t, J=2.08 Hz, 1 H).

Example 109

3-((2-Chlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 2-chloroaniline (78 mg) in 2-butanol (10 mL) was added potassium dihydrogen phosphate (83 mg). The reaction mixture was cooled to 0 °C and 3-bromo-7- fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 150 mg) was added portionwise. The reaction mixture was stirred at 80 °C for 16 hr. Reaction mixture was cooled to RT and diluted with cold water. The resulting solid was collected by filtration and triutrated with pentane to afford the crude product (96 mg). The crude product was purificed by preparative reversed phase HPLC (XTerra C18, 19 x 50 mm) using a gradient of 10- 55% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound, (52.3 mg) as an off- white solid. LCMS m/z 342.00 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.93 (dd, J=10.19, 2.74 Hz, 1 H) 6.98 (dd, J=7.45, 2.63 Hz, 1 H) 7.24 (td, J=7.78, 1 .53 Hz, 1 H) 7.38 - 7.45 (m, 1 H) 7.56 (dd, J=8.00, 1 .43 Hz, 1 H) 7.93 (dd, J=8.33, 1 .53 Hz, 1 H).

Example 110

3-((1 H-lndol-6-yl)amino)-7-fluoro-5-hvdroxy-2H-benzorein ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-39, 200 mg) in tert-butanol (5 mL, were added 1 H-indol-6-amine (107 mg) and potassium dihydrogen phosphate (1 1 1 mg) at RT. The reaction mixture was warmed to 80 °C and stirred for 16 hr under nitrogen. The reaction mixture was cooled to RT and diluted with cold water. The resulting solid was collected by filtration and dried under reduced pressure and triturated with diethyl ether and pentane to afford the titled compound (165 mg). LCMS m/z 347.04 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.44 (dd, J=3.07, 0.88 Hz, 1 H) 6.89 - 6.96 (m, 2 H) 6.98 (dd, J=7.56, 2.74 Hz, 1 H) 7.33 (d, J=3.07 Hz, 1 H) 7.55 (d, J=8.55 Hz, 1 H) 7.79 - 7.84 (m, 1 H).

Example 111

tert-Butyl 7-((7-fluoro-5-hydroxy-1 ,1 -dioxido-2H-benzoreiri ,2,41thiadiazin-3- yl)amino)-3.4-dihvdroisoquinoline-2(1 H)-carboxylate

To a stirred solution of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-39, 300 mg) in tert-butanol (10 ml_) were added tert-butyl 7-amino-3,4- dihydroisoquinoline-2(1 H)-carboxylate (303 mg,) and potassium dihydrogen phosphate (166 mg) at RT. The reaction mixture was warmed to 80 °C and stirred for 16 hr. The reaction mixture was cooled to RT and diluted with cold water. The resulting solid was collected by filtration and dried under reduced pressure. The solid was triturated with diethyl ether and pentane to afford the titled compound (52 mg) as a white solid. LCMS m/z 463.07 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 1 .44 (s, 9 H) 2.76 (t, J=5.81 Hz, 2 H) 3.56 (t, J=5.81 Hz, 2 H) 4.50 (br. s., 2 H) 6.93 (dd, J=10.09, 2.63 Hz, 1 H) 6.99 (dd, J=7.67, 2.63 Hz, 1 H) 7.20 (d, J=8.33 Hz, 1 H) 7.24 - 7.41 (m, 2 H).

Example 112

7-Fluoro-5-hvdroxy-3-((1 ,2,3,4-tetrahvdroisoquinolin-7-yl)amino)-2H- benzoreiri ,2,41thiadiazine 1 ,1 -dioxide, Hydrochloride

To a stirred solution of tert-butyl 7-((7-fluoro-5-hydroxy-1 ,1 -dioxido-2H- benzo[e][1 ,2,4]thiadiazin-3-yl)amino)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (Example 111 , 150 mg) in 1 ,4-dioxane (5 mL) was added hydrogen chloride (4 M in 1 ,4-dioxane, 2 mL) at 0 °C under nitrogen. The reaction mixture was stirred at RT under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a solid which was triturated with EtOAc followed by pentane, and then dried under vacuum to afford the titled compound (1 18 mg) as a white solid. LCMS m/z 363.06 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 3.00 (t, J=6.14 Hz, 2 H) 3.36 - 3.42 (m, 2 H) 4.30 (s, 2 H) 6.95 (dd, J=10.09, 2.63 Hz, 1 H) 6.99 (dd, J=7.67, 2.63 Hz, 1 H) 7.28 (d, J=8.55 Hz, 1 H) 7.33 - 7.52 (m, 2 H).

Example 113

3-((1 H-indol-5-yl)amino)-7-fluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-fluoro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 200 mg) and 1 H-indol-5-amine (107 mg) in tert-butanol (10 mL) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (1 1 1 mg) in one charge. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. Demineralized water (15 mL) was added to the reaction mixture, which was stirred for 15 min and filtered with a Buchner funnel. The solid was washed with diethyl ether (2 x 5 mL) and acetonitrile:water( 1 : 9) 2 X 5 mL and was then air dried to obtain the titled compound (1 10 mg) as an off-white solid. LCMS m/z 347.04 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 6.46 (dd, J=3.07, 0.88 Hz, 1 H) 6.91 (dd, J=10.09, 2.63 Hz, 1 H) 6.97 (dd, J=7.67, 2.63 Hz, 1 H) 7.1 1 (dd, J=8.66, 2.08 Hz, 1 H) 7.35 - 7.45 (m, 2 H) 7.71 (d, J=2.19 Hz, 1 H).

Example 114

6,7-Dichloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 -

A 20 mL microwave tube was charged with 3-bromo-6,7-dichloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Int 4, 120 mg) and 2-fluoroaniline (0.040 mL) and potassium dihydrogen phosphate (70.8 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C. After overnight reaction, the reaction mixture was concentrated to dryness. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 20- 70% acetonitrile/0.1 % TFA in water/0.1 %TFA to obtain the titled compound (35 mg). LCMS m/z 376.0 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .55 (br. s., 1 H) 10.73 (br. s., 1 H) 9.58 (br. s., 1 H) 8.06 (t, J=7.58 Hz, 1 H) 7.43 (br. s., 1 H) 7.30 - 7.38 (m, 1 H) 7.15 - 7.30 (m, 3 H).

Example 115

6,7-Dichloro-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 -

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 120 mg) was reacted with 2-chloroaniline (0.044 mL) and potassium dihydrogen phosphate (70.8 mg) in tert-butanol (5 ml_) as in Example 114. The reaction mixture was diluted with water. The solids were filtered and washed with water. The crude product (solid) was purified by Pre-HPLC C18 column and was eluted with a gradient of 20-70% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (36 mg). LCMS m/z 392.0 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 1 1 .55 (br. s., 1 H) 10.94 (br. s., 1 H) 9.40 (s, 1 H) 7.93 (dd, J=8.21 , 1 .39 Hz, 1 H) 7.57 (dd, J=8.08, 1 .52 Hz, 1 H) 7.36 - 7.52 (m, 2 H) 7.25 (td, J=7.77, 1 .64 Hz, 1 H).

Example 116

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with aniline (0.019 ml_) and potassium dihydrogen phosphate (30.7 mg) in tert- butanol (2 ml_) as in Example 114. The reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre-HPLC C18 column and was eluted with a gradient of 20-70% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (25 mg). LCMS m/z 358.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 1 1 .56 (br. s., 1 H) 10.31 (br. s., 1 H) 9.68 (s, 1 H) 7.49 - 7.62 (m, 2 H) 7.46 (s, 1 H) 7.33 - 7.44 (m, 2 H) 6.98 - 7.21 (m, 1 H).

Example 117

3-((1 H-Benzord1imidazol-6-yl)amino)-6,7-dichloro-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide 3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with 1 H-benzo[d]imidazol-6-amine (27.7 mg) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 mL) as in Example 114. The reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre-HPLC C18 column and was eluted with a gradient of 20-70% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (23 mg). LCMS m/z 398.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 10.29 (br. s., 1 H) 9.75 (s, 1 H) 8.46 (s, 1 H) 8.05 (d, J=2.02 Hz, 1 H) 7.65 (d, J=8.84 Hz, 1 H) 7.44 (s, 1 H) 7.19 (dd, J=8.59, 2.02 Hz, 1 H).

Example 118

6,7-dichloro-3-((4-fluoro-1 H-indol-6-yl)amino)-5-hydroxy-2H-

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with 4-fluoro-1 H-indol-6-amine (31 .2 mg) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 mL) as in Example 114. The reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre-HPLC C18 column and was eluted with water with a gradient of 20-70% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (10 mg). LCMS m/z 415.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .62 (br. s., 1 H) 1 1 .37 (br. s., 1 H) 10.72 (br. s., 1 H) 9.69 (s, 1 H) 7.66 (dd, J=12.13, 2.27 Hz, 1 H) 7.50 (s, 1 H) 7.29 - 7.45 (m, 1 H) 7.01 (dd, J=9.35, 1 .52 Hz, 1 H) 6.63 (br. s., 1 H).

Example 119

6,7-Dichloro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzorei ri ,2,41thiadiazine 1 ,1 -

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with 3-fluoroaniline (0.020 mL) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 mL) as in Example 114. After 4h the reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre-HPLC C18 column and was eluted with water with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (27 mg). LCMS m/z 376.1 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 1 1 .63 (br. s., 1 H) 10.39 (br. s., 1 H) 9.86 (s, 1 H) 7.54 (dt, J=1 1 .18, 2.24 Hz, 1 H) 7.49 (s, 1 H) 7.38 - 7.48 (m, 1 H) 7.14 - 7.30 (m, 1 H) 6.99 (td, J=8.53, 2.65 Hz, 1 H).

Example 120

3-((1 H-lndol-5-yl)amino)-6.7-dichloro-5-hvdroxy-2H-benzorein ,2.41thiadiazine 1.1 -

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with 1 H-indol-5-amine (27.5 mg) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 ml_) as in Example 114. After 4h the reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (31 mg). LCMS m/z 397.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 1 1 .47 (br. s., 1 H) 1 1 .15 (br. s., 1 H) 10.19 (br. s., 1 H) 9.49 (s, 1 H) 7.72 (d, J=2.02 Hz, 1 H) 7.32 - 7.49 (m, 3 H) 7.1 1 (dd, J=8.59, 2.02 Hz, 1 H) 6.46 (t, J=2.02 Hz, 1 H).

Example 121

3-((1 H-lndazol-6-yl)amino)-6,7-dichloro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with and 1 H-indazol-6-amine (27.7 mg) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 mL) as in Example 114. After 4h the reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre- HPLC C18 column and was eluted with water with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (20 mg). LCMS m/z 398.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 13.04 (br. s., 1 H) 1 1 .60 (br s, 1 H) 10.36 (s, 1 H) 9.86 (s, 1 H) 8.12 (s, 1 H) 8.03 (s, 1 H) 7.75 (d, J=8.59 Hz, 1 H) 7.51 (s, 1 H) 6.96 (dd, J=8.72, 1 .89 Hz, 1 H).

Example 122

3-((1 H-lndazol-5-yl)amino)-6.7-dichloro-5-hvdroxy-2H-benzoreiri .2.41thiadiazine 1.1 -

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with and 1 H-indazol-5-amine (27.7 mg) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 ml_) as in Example 114. After 4h the reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre- HPLC C18 column and was eluted with water with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (10 mg). LCMS m/z 398.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 13.10 (br. s., 1 H) 1 1 .54 (br. s., 1 H) 10.29 (br. s., 1 H) 9.64 (s, 1 H) 8.12 (s, 1 H) 7.98 (d, J=1 .77 Hz, 1 H) 7.58 (d, J=8.84 Hz, 1 H) 7.47 (s, 1 H) 7.36 (dd, J=8.84, 1 .77 Hz, 1 H)

Example 123

6,7-Dichloro-3-((3,4-dichloro-2-fluorophenyl)amino)-5-hydrox y-2H- be -dioxide

3-Bromo-6,7-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg) was reacted with and 3,4-dichloro-2-fluoroaniline (37.5 mg) and potassium dihydrogen phosphate (30.7 mg) in tert-butanol (2 ml_) as in Example 114. After overnight, the reaction was concentrated. The solids were filtered and washed with water. The crude product was purified by Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (10 mg). LCMS m/z 444.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .61 (br. s., 1 H) 10.84 (br. s., 1 H) 9.75 (s, 1 H) 8.10 (t, J=8.59 Hz, 1 H) 7.60 (dd, J=9.09, 1 .77 Hz, 1 H) 7.49 (s, 1 H).

Example 124

6-Chloro-3-((2-chlorophenyl)amino)-5-hvdroxy-2H-benzorein .2.41thiadiazine 1.1 -

(a) 6-chloro-3-((2-chlorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3-bromo-6-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-5, 100 mg) and 2-chloroaniline (41 .1 mg) and potassium dihydrogen phosphate (41 .8 mg) in 1 -butanol to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C. After overnight, the reaction was concentrated. The crude product was chromatographed on silica gel column and eluted with a gradient of 5-100% EtOAc in hexanes to afford the titled compound (50 mg). LCMS m/z 372.1 (M+H).

(b) 6-Chloro-3-((2-chlorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 250 mL round-bottomed flask was charged with 6-chloro-3-((2-chlorophenyl)amino)-5- methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (50 mg) in dichloromethane (5 mL) to give a yellow suspension at 0 °C under nitrogen. After 10 min, BBr ₃ (1 M in DCM, 0.403 mL) was added to the reaction mixture. The reaction was stirred to 40 °C. After 3 h, the reaction mixture was poured into ice/water and extracted with DCM (3x). The dichloromethane layers were dried over Na2S04, filtered, and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 5-50% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (1 1 mg). LCMS m/z 358.1 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 10.97 (br. m., 2 H) 9.35 (br. s., 1 H) 7.95 (d, J=8.34 Hz, 1 H) 7.56 (dd, J=8.08, 1 .26 Hz, 1 H) 7.38 - 7.49 (m, 1 H) 7.32 (d, J=8.08 Hz, 1 H) 7.1 1 - 7.28 (m, 2 H). Example 125

6-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

(a) 6-Chloro-3-((2-fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3-bromo-6-chloro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-5, 250 mg) and 2-fluoroaniline (0.078 mL) and potassium dihydrogen phosphate (105 mg) in N-methyl-2-pyrrolidone (4 mL) to give a light brown solution at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C. After overnight reaction, 2-fluoroaniline (0.078 mL) was added to the reaction mixture. The sealed reaction mixture was stirred to 80 °C. After overnight reaction, the reaction mixture was poured into water then extracted with DCM (3x). The dichloromethane layers were dried over Na ₂ S0 ₄ , filtered, and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound which was carried on to the next step without additional purification. LCMS m/z 356.1 (M+H).

(b) 6-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 6-chloro-3-((2-fluorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (from Example 125 a) in DCM (5 mL) to give a yellow suspension at 0 °C under nitrogen. BBr ₃ (1 N in DCM, 2.304 mL) was added to the reaction mixture. The reaction was stirred to 40 °C. After 1 h, the reaction was poured into ice/water and extracted with DCM. The DCM layer was dried over Na ₂ S04, filtered, and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA to afford the titled compound (15 mg). LCMS m/z 342.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 10.98 (br. s., 1 H) 10.68 (br. s., 1 H) 9.55 (s, 1 H) 7.99 - 8.19 (m, 1 H) 7.14 - 7.43 (m, 5 H).

Example 126

6-Fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -

(a) 6-Fluoro-3-((2-fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3-bromo-6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-9, 250 mg) and 2-fluoroaniline (0.094 mL) and potassium dihydrogen phosphate (138 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C. After overnight reaction, the reaction mixture was concentrated onto celite. The residue was chromatographed on silica gel column and eluted with hexanes and ethyl acetate with 10% methanol (5% to 100%) and the clean fractions were concentrated to dryness to obtain 6- fluoro-3-((2-fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (261 mg). LCMS m/z 340.1 (M+H).

(b) 6-Fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 6-fluoro-3-((2-fluorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (261 mg) in DCM (5 mL) to give a yellow suspension at 0 °C under nitrogen. BBr ₃ (1 N in DCM, 2.3 mL) was added to the reaction mixture. The reaction was stirred at 40 °C. After 3h, the reaction mixture was quenched with water and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA and the clean fractions were concentrated and dried under vacuum overnight to obtain 6-fluoro-3- ((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (123 mg) as white solid. LCMS m/z 326.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .27 (s, 1 H) 10.71 (s, 1 H) 9.47 (s, 1 H) 8.09 (m, 1 H) 7.16 - 7.37 (m, 5 H). Example 127

6-Fluoro-3-((2-chlorophenyl)amino)-5-hvdroxy-2H-benzorein .2.41thiadiazine 1.1 -

(a) 6-Fluoro-3-((2-chlorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3-bromo-6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-9, 250 mg) and 2-chloroaniline (0.102 mL) and potassium dihydrogen phosphate (138 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C. After overnight reaction, the reaction mixture was concentrated onto celite. The residue was chromatographed on silica gel column and eluted with hexanes and ethyl acetate with 10% methanol (5% to 100%) and the clean fractions were concentrated to dryness to obtain 6- fluoro-3-((2-chlorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (221 mg). LCMS m/z 356.1 (M+H).

(b) 6-Fluoro-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 6-fluoro-3-((2-chlorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (221 mg) in DCM (5 mL) to give a yellow suspension at 0 °C under nitrogen. BBr ₃ (1 N in DCM, 2.3 mL) was added to the reaction mixture. The reaction was stirred to 40 °C. After 3h, the reaction mixture was quenched with water and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA and the clean fractions were concentrated and dried under vacuum overnight to obtain 6-fluoro-3- ((2-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (148 mg) as white solid. LCMS m/z 342.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.13 - 7.27 (m, 3 H) 7.36 - 7.42 (m, 1 H) 7.53 (dd, J=7.96, 1 .39 Hz, 1 H) 7.86 (dd, J=8.08, 1 .52 Hz, 1 H) 9.18 - 9.42 (br. s, 1 H). Example 128

7-Bromo-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

(a) 7-Bromo-3-((2-fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3,7-dibromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-11 , 550 mg) and 2-fluoroaniline (0.158 mL) and potassium dihydrogen phosphate (233 mg) in tert-butanol (10 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C. After overnight, the reaction was concentrated onto celite. The residue was chromatographed on silica gel column and eluted with a gradient of 5-100% EtOAc/10% MeOH in hexanes and the clean fraction were concentrated to dryness to obtain 7-bromo- 3-((2-fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (482 mg). LCMS m/z 400.1 (M+H).

(b) 7-Bromo-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 7-bromo-3-((2-fluorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (100 mg) in DCM (5 mL) to give a yellow suspension at 0 °C under nitrogen. BBr ₃ (1 N in DCM, 0.744 mL) was added to the reaction mixture. The reaction was stirred to 40 °C. After 3h, the reaction mixture was quenched with water and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated and dried under vacuum overnight to obtain 7-bromo-3- ((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (27 mg) as white solid. LCMS m/z 386.0 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .64 (s, 1 H) 10.63 (br. s., 1 H) 9.46 (s, 1 H) 8.06 (td, J=8.08, 1 .77 Hz, 1 H) 7.14 - 7.37 (m, 5 H). Example 129

7-Bromo-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 7-Bromo-3-((2-chlorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3,7-dibromo-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-11 , 550 mg, 1 .486 mmol) and 2-chloroaniline (0.172 mL, 1 .635 mmol) and potassium dihydrogen phosphate (233 mg, 1 .709 mmol) in Tert-Butanol (10 mL) to give a white suspension at room temperature under nitrogen. The seal reaction mixture was stirred to 80 oC. After overnight, the reaction mixture was checked by LCMS and showed a peak matching the expected product. The reaction was concentrated onto celite, which was chromatographed on silica gel column and eluted with a gradient of 5-100% EtOAc/10% MeOH in hexanes. The desired fractions were concentrated to dryness to obtain the titled compound (241 mg). LCMS m/z 416.1 (M+H).

(b) 7-Bromo-3-((2-chlorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 7-bromo-3-((2-chlorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (161 mg) in DCM (5 mL) to give a yellow suspension at 0 °C under nitrogen. BBr ₃ (1 N in DCM, 1 .080 mL) was added to the reaction mixture. The reaction was stirred at 40 °C. After 3h, the reaction mixture was checked by LCMS and showed product. The reaction mixture wa quenched with water and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with water with 0.1 % TFA with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concnentrated and dried under vacuum overnight to obtainthe titled compound (71 mg) as white solid. LCMS m/z 402.0 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.20 (d, J=2.02 Hz, 1 H) 7.24 (td, J=7.71 , 1 .52 Hz, 1 H) 7.29 (d, J=1 .77 Hz, 1 H) 7.40 - 7.46 (m, 1 H) 7.56 (dd, J=8.08, 1 .52 Hz, 1 H) 7.95 (dd, J=8.21 , 1 .39 Hz, 1 H) 9.26 - 9.31 (m, 1 H) 10.84 (s, 1 H) 1 1 .65 (s, 1 H). Example 130

8-Fluoro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

(a) 8-Fluoro-3-((3-fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3-bromo-8-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-13, 250 mg) and 3-fluoroaniline (0.082 mL) and potassium dihydrogen phosphate (1 16 mg) in N-methyl-2-pyrrolidone (NMP, 4 mL) to give a light brown solution at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C. After overnight, the reaction mixture was poured into cold water and stirred. The solids were filtered and washed with water and hexanes. The solids were dissolved into EtOAc and small amount of MeOH. The EtOAc layer was dried over Na ₂ S0 ₄ , filtered, and concentrated to obtain the titled comound (258 mg). LCMS m/z 340.2 (M+H).

(b) 8-fluoro-3-((3-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 8-fluoro-3-((3-fluorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide in DCM (5 mL) to give a yellow suspension at 0 °C under nitrogen. BBr ₃ ( 1 N in DCM, 2.42 mL) was added to the reaction mixture. The reaction was stirred to 40 °C. After 4h, the reaction mixture was coold to rt. After 1 day, the reaction was poured in ice/water and extracted with DCM. The dichloromethane layer was dried over Na ₂ S0 ₄ , filtered, and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-95% acetonitrile/0.1 % TFA in water/0.1 %TFA and the clean fractions were concentrated. The solid was dried under vacuum overnight to obtain the titled compound (40 mg) as white solid. LCMS m/z 326.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.88 - 7.05 (m, 3 H) 7.24 (dd, J=8.34, 1 .26 Hz, 1 H) 7.38 - 7.47 (m, 1 H) 7.54 (dt, J=1 1 .37, 2.15 Hz, 1 H) 9.68 (s, 1 H) 10.21 (br. s., 1 H) 1 1 .73 (br. s., 1 H). Example 131

6-bromo-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

A 20 mL microwave tube was charged with 3,6-dibromo-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-16, 185 mg) and 2-fluoroaniline (0.060 mL) and potassium dihydrogen phosphate (106 mg) in tert-butanol (5 mL) to give a brown suspension at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C. After overnight reaction, the reaction mixture was concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with water with 0.1 % TFA with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (77 mg). LCMS m/z 386.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 10.71 (br. s., 2 H) 9.58 (s, 1 H) 8.06 - 8.14 (m, 1 H) 7.47 (d, J=8.59 Hz, 1 H) 7.12 - 7.38 (m, 4 H).

Example 132

7-Bromo-6-chloro-3-((2-fluorophenyl)amino)-5-hydroxy-2H- ben -dioxide

A 20 mL microwave tube was charged with 3,7-dibromo-6-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-19, 44 mg) and 2-fluoroaniline (0.013 mL and potassium dihydrogen phosphate (23.00 mg) in tert-butanol (4 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C. After overnight reaction, the reaction mixture was concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (18 mg). LCMS m/z 420.1 (M+H). ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 1 1 .78 (s, 1 H) 10.59 - 10.66 (m, 1 H) 9.50 (s, 1 H) 8.04 - 8.10 (m, 1 H) 7.17 - 7.43 (m, 4 H).

Example 133

7-Bromo-6-chloro-3-((2-chlorophenyl)amino)-5-hvdroxy-2H- ben -dioxide

A 20 mL microwave tube was charged with 3,7-dibromo-6-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-19, 44 mg) and 2-chloroaniline (0.014 mL) and potassium dihydrogen phosphate (23.00 mg) in tert-butanol (4 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C. After overnight reaction, the reaction mixture was checked by LCMS and showed a new peak matching product. The reaction was concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled comound (20 mg). LCMS m/z 436.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.24 (t, J=7.07 Hz, 1 H) 7.32 - 7.39 (m, 1 H) 7.43 (t, J=7.20 Hz, 1 H) 7.51 - 7.62 (m, 1 H) 7.95 (d, J=8.08 Hz, 1 H) 9.31 (s, 1 H) 10.72 - 10.96 (m, 1 H) 1 1 .80 (br. s., 1 H).

Example 134

-Chloro-3-((2-chlorophenyl)amino)-6-fluoro-5-hydroxy

ben -dioxide

A 20 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-21 , 150 mg), 2-chloroaniline (0.044 mL) and potassium dihydrogen phosphate (93 mg) in tert-butanol (10 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C overnight. The reaction was then concentrated. The crude product was added to a Pre- HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (90 mg). LCMS m/z 376.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .94 (br. s., 1 H) 1 1 .01 (br. s., 1 H) 9.31 (s, 1 H) 7.94 (dd, J=8.08, 1 .52 Hz, 1 H) 7.57 (dd, J=8.08, 1 .52 Hz, 1 H) 7.34 - 7.51 (m, 2 H) 7.24 (td, J=7.77, 1 .64 Hz, 1 H).

Example 135

7-Chloro-6-fluoro-5-hvdroxy-3-(phenylamino)-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

A 20 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-21 , 150 mg) aniline (0.050 mL) and potassium dihydrogen phosphate (93 mg) in tert-butanol (10 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C overnight. The reaction mixture was checked by LCMS and showed new peak matching product. The reaction mixture was concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentratedto obtain the titled compound (100 mg). LCMS m/z 342.1 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.16 (t, J=7.45 Hz, 1 H), 7.35 - 7.46 (m, 2 H), 7.49 - 7.58 (m, 2 H), 9.58 (s, 1 H), 10.37 (br. s., 1 H), 1 1 .92 (br. s., 1 H).

Example 136

6-Chloro-8-fluoro-3-((2-fluorophenyl)amino)-5-hydroxy-2H- benz -dioxide

A 20 mL microwave tube was charged with 3-bromo-6-chloro-8-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-23, 50 mg), 2-fluoroaniline (0.018 mL) and potassium dihydrogen phosphate (31 .0 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C overnight. The reaction mixture was then concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (19 mg). LCMS m/z 360.2 (M+H). ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 1 1 .94 (s, 1 H) 10.60 (s, 1 H) 9.46 (s, 1 H) 8.06 (td, J=8.15, 1 .64 Hz, 1 H) 7.13 - 7.43 (m, 3 H) 7.08 (d, J=10.1 1 Hz, 1 H).

Example 137

-Chloro-6-fluoro-3-((2-fluorophenyl)amino)-5-hydroxy

ben -dioxide

A 20 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-21 , 150 mg), 2-fluoroaniline (0.053 mL) and potassium dihydrogen phosphate (93 mg) in tert-butanol (10 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred at 80 °C overnight. The reaction mixture was the checked by LCMS and showed new peak matching product. The reaction mixture was concentrated. The crude product was added to a Pre- HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (70 mg). LCMS m/z 360.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.18 - 7.37 (m, 3 H) 7.41 (d, J=6.82 Hz, 1 H) 8.06 (td, J=8.15, 1 .64 Hz, 1 H) 9.50 (s, 1 H) 10.80 (br. s., 1 H) 1 1 .93 (br. s., 1 H). Example 138

A 20 mL microwave tube was charged with 3-bromo-6,8-dichloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-26, 133 mg), aniline (0.042 mL) and potassium dihydrogen phosphate (108 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred at 90 °C overnight. The reaction was then concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-60% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtainthe titled compound (50 mg). LCMS m/z 358.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .27 (br. s., 1 H) 10.25 (br. s., 1 H) 9.70 (s, 1 H) 7.49 - 7.60 (m, 2 H) 7.46 (s, 1 H) 7.41 (t, J=7.96 Hz, 2 H) 7.05 - 7.23 (m, 1 H).

Example 139

6-Chloro-3-((2-chlorophenyl)amino)-8-fluoro-5-hydroxy-2H- benz -dioxide

A 20 mL microwave tube was charged with 3-bromo-6-chloro-8-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-23, 50 mg), 2-chloroaniline (0.019 mL) and potassium dihydrogen phosphate (31 .0 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The seaedl reaction mixture was stirred at 80 °C overnight. The reaction mixture was checked by LCMS and showed new peak matching product. The reaction was then concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-60% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (25 mg). LCMS m/z 376.1 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.08 (d, J=10.10 Hz, 1 H) 7.22 - 7.27 (m, 1 H) 7.41 - 7.46 (m, 1 H) 7.56 (dd, J=8.08, 1 .26 Hz, 1 H) 7.94 (dd, J=8.21 , 1 .39 Hz, 1 H) 9.26 (s, 1 H) 10.80 (s, 1 H) 1 1 .93 (s, 1 H).

Example 140

A 20 mL microwave tube was charged with 3-bromo-6,7,8-trichloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-28, 40 mg), aniline (0.012 mL) and potassium dihydrogen phosphate (18.60 mg) in tert-butanol (5 mL) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred at 90 °C overnight. The reaction was then concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-70% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (15 mg). LCMS m/z 392.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 10.31 (br. s., 1 H) 9.74 (s, 1 H) 7.53 (d, J=7.58 Hz, 2 H) 7.41 (t, J=8.08 Hz, 2 H) 7.03 - 7.24 (m, 1 H).

Example 141

8-Bromo-7-chloro-5-hvdroxy-3-(phenylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

a) 8-Bromo-7-chloro-5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a solution of 3,8-dibromo-7-chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-36, 231 mg) in t-butanol (6.0 ml) at 80 °C was added aniline (78 μΙ) and K ₂ HP0 ₄ (149 mg). The reaction was stirred at 80 °C for 1 hour then poured into cold water. The solids were collected and dried, then triturated with EtOH to afford 8-bromo-7-chloro-5-methoxy- 3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (200 mg) as a white solid. LCMS m/z 416.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 10.19 (s, 1 H) 9.60 (s, 1 H) 7.59 (s, 1 H) 7.52 (d, J = 7.6 Hz, 2 H) 7.34 - 7.46 (m, 2 H) 7.08 - 7.23 (m, 1 H) 4.03 (s, 3 H).

b) 8-Bromo-7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a suspension of 8-bromo-7-chloro-5-methoxy-3-(phenylamino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 141 a, 76 mg) in anhydrous DCM (1 .0 ml) was added 1 .0 M boron tribromide in DCM (2.0 ml). The reaction was heated at 40 °C for 4 days then quenched with MeOH and concentrated to a residue. The crude product was purified by flash chromatography on S1O2 (eluent: 0-80% [3:1 EtOAc/EtOH mixture containing 1 % NH ₄ OH] in EtOAc) to give a residue that was recrystallized from MeOH/water to afford 8-bromo-7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (18 mg) as an off-white solid. LCMS m/z 402.1 (M+H). ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 1 1 .72 - 1 1 .95 (m, 1 H) 10.06 - 10.24 (m, 1 H) 9.57 (s, 1 H) 7.52 (d, J = 7.6 Hz, 2 H) 7.40 (t, J = 8.0 Hz, 2 H) 7.21 (s, 1 H) 7.15 (t, J = 7.3 Hz, 1 H).

Example 142

3-((2-Fluorophenyl)amino)-5-hydroxy-2H-benzoreiri,2,41thiadi azine-7-carbonitrile

(a) 3-((2-Fluorophenyl)amino)-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine-7- carbonitrile 1 ,1 -dioxide

A 5 mL microwave tube was charged with 7-bromo-3-((2-fluorophenyl)amino)-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 128a, 286 mg) in N,N- dimethylacetamide (6 mL) to give a brown solution at room temperature under nitrogen. The reaction was bubbled with Ar for 2 min. PdCl2(dppf)-CH ₂ Cl2 adduct (58.4 mg), zinc (9.34 mg), and zinc cyanide (58.7 mg) were added to the reaction mixture. The sealed reaction was stirred to 100 °C. After 5h, the reaction mixture was poured into water. The solids were filtered and washed with water. The solids were dissloved in DCM with a small amount of methanol and filtered, and the filtrate was concentrated. The resulting solids were stirred with ether then filtered and washed with hexanes to obtain the titled compound (168 mg). LCMS m/z 347.2 (M+H).

(b) 3-((2-Fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine-7- carbonitrile 1 ,1 -dioxide

A 20 mL microwave tube was charged with 3-((2-fluorophenyl)amino)-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine-7-carbonitrile 1 ,1 -dioxide (Example 142a, 56 mg) in dichloromethane (2 mL) to give a brown suspension at 0 °C under nitrogen. BBr ₃ (0.046 mL) was added to the reaction mixture. The reaction was stirred to 50 °C for 6 h, then allowed to cool to to room temperature and stirred overnight. The reaction mixture was the quenched with a couple drops of water and concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-60% acetonitrile/0.1 % TFA in water/0.1 % TFA, and the clean fractions were were concentrated to obtain the titled compound (20 mg). LCMS m/z 333.0 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .97 (br. s., 1 H) 10.89 (br. s., 1 H) 9.58 (br. s., 1 H) 8.06 (t, J=7.20 Hz, 1 H) 7.72 (s, 1 H) 7.14 - 7.44 (m, 4 H).

Example 143

A 20 mL microwave tube was charged with 3-bromo-7-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-30, 250 mg), 2-chloroaniline (0.083 mL) and potassium dihyrdrogen phosphate (175 mg) in tert-butanol (10 mL) to give a white suspension at room temperature under nitrogen. The sealed reaction mixture was stirred to 80 °C overnight. The sealed reaction mixture was the stirred at 100 °C for 2 days. The reaction was then concentrated. The crude product was added to a Pre-HPLC C18 column and was eluted with a gradient of 10-75% acetonitrile/0.1 % TFA in water/0.1 %TFA, and the clean fractions were concentrated to obtain the titled compound (100 mg). LCMS m/z 338.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .02 (s, 1 H) 8.97 (s, 1 H) 7.78 (dd, J=8.21 , 1 .39 Hz, 1 H) 7.57 (dd, J=7.96, 1 .39 Hz, 1 H) 7.42 (td, J=7.71 , 1 .52 Hz, 1 H) 7.19 - 7.33 (m, 3 H) 7.18 (d, J=1 .77 Hz, 1 H) 3.84 ( m, 3 H).

Example 144

7-Chloro-3-((2-chlorophenyl)amino)-5-fluoro-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

To a stirred solution of 3,7-dichloro-5-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Int- 41 , 300 mg) in 1 -butanol (1 .5 ml_) was added 2-chloroaniline (142 mg) and potassium dihydrogen phosphate (152 mg) at RT. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with MeOH and the MeOH evaporated to afford the crude product (250 mg). The crude product was purified by column chromatography using neutral alumina (150 g column) and eluting with MeOH, followed by preparative reversed phase HPLC (XBridge C18, 30 x 250 mm), eluting with a gradient of 50-95% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were lyophilized to afford the titled compound (62 mg) as an off-white solid. LCMS 359.86 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/e) δ ppm 7.28 (td, J=7.67, 1 .53 Hz, 1 H) 7.36 - 7.50 (m, 1 H) 7.58 (dd, J=8.00, 1 .43 Hz, 1 H) 7.62 - 7.71 (m, 1 H) 7.81 - 8.04 (m, 2 H).

Example 145

5-Bromo-7-chloro-3-((2-chlorophenyl)amino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 -

To a solution of 3,5-dibromo-7-chloro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-32, 300 mg) in t-butanol (4 ml_) at 80 °C was added 2-chloroaniline (0.126 ml_) and potassium phosphate, dibasic (209 mg). The mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, the solvent was removed in vacuo, and the resulting off-white solid was partitioned between EtOAc and water. Brine was added, and the aqueous layer was further extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated in vacuo to an off-white solid. The solid was purified on a standard pre-packed silica column (Grace Reveleris, 40 g silica) eluted with a gradient of 20-100% EtOAc in hexanes. The desired fractions were combined and evaporated in vacuo to afford the titled compound (160 mg) as a white solid. LCMS m/z 420.0 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.24 - 7.34 (m, 1 H) 7.43 (t, J=7.58 Hz, 1 H) 7.58 (d, J=8.08 Hz, 1 H) 7.80 (d, J=7.33 Hz, 1 H) 7.84 (s, 1 H) 8.17 (s, 1 H) 9.87 (br. s., 1 H) 10.41 (s, 1 H).

Example 146

To a solution of 3-bromo-5,7-dichloro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-34, 220 mg) in t-butanol (3 ml_) at 80 °C was added 2-chloroaniline (0.105 ml_) and potassium phosphate, dibasic (174 mg). The mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the solvent was removed in vacuo, and the resulting off-white solid was partitioned between EtOAc and water. Brine was added, and the aqueous layer was further extracted with EtOAc (2 x 30 ml_). The combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated in vacuo to a tan solid. The solid was triturated with DCM, filtered via vacuum filtration, washed with DCM and dried to afford the titled compound (176 mg) as an off-white solid. LCMS m/z 376.0 (M+H). Ή NMR (400 MHz, DMSO-c/e) δ ppm 7.23 - 7.32 (m, 1 H) 7.39 - 7.48 (m, 1 H) 7.58 (dd, J=7.96, 1 .39 Hz, 1 H) 7.80 - 7.88 (m, 2 H) 8.06 (d, J=2.27 Hz, 1 H) 9.65 (br. s., 1 H) 10.75 (s, 1 H). Example 147

7-Chloro-3-((2-chlorophenyl)amino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

(a) 7-Chloro-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide

To a solution of 4-chloroaniline (5 g) in nitropropane(I Oml) at -40 °C was added a solution of chlorosulfonyl isocyanate (4.15 ml) in nitropropane(30ml) dropwise over 5 min. The reaction mixture was allowed to warm up to 0 °C. Aluminium chloride (6.53 g) was added in one portion. The reaction mixture then stirred at 1 10 °C for 30 min. The reaction mixture was allowed to cool to RT and then was poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to afford the titled compound (2.5 g), which was used without further purification. LCMS m/z 230.95 (M-H) ^~ .

(b) 7-Chloro-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3-yl trifluoromethanesulfonate To a solution of 7-chloro-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (1 .5 g) and pyridine (1 .825 ml) in dichloromethane (DCM) (25 ml) at -78 °C was added triflic anhydride (10.89 ml). The reaction mixture was allowed to warm to RT and was stirred 12 hr. The reaction mixture was quenched by the addition of saturated ammonium chloride (aq) (75 ml_) and then extracted with DCM (2 x 100 ml_). The combined DCM extracts were dried over sodium sulfate and then concentrated under reduced pressure to afford the titled compound (2 g), which was used without further characterization or purification.

(c) 7-Chloro-3-((2-chlorophenyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a solution of 7-chloro-1 ,1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-3-yl trifluoromethanesulfonate (1 .5 g) in dichloromethane (DCM) (25 ml) at -78 °C was added 2-chloroaniline (1 .298 ml_). The reaction mixture was allowed to warm to RT and was stirred for 12 hr. The reaction mixture was diluted with DCM (80 ml_) and was washed with saturated aq sodium bicarbonate (100 ml_). The aqueous phase was back extracted with DCM (2 x 100 ml_) and the combined DCM layers were dried over sodium sulfate and then concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel flash chromatograpy using a gradient of EtOAc in petroleum ether, followed by preparative reversed phase HPLC (XBridge C18, 30 x 150 mm), eluting with a gradient of 30-90% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were lyophilized to afford the titled compound (171 mg) as an off-white solid. LCMS m/z 341 .89 (M+H). Ή NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.27 - 7.36 (m, 2 H) 7.43 (td, J=7.78, 1 .53 Hz, 1 H) 7.58 (dd, J=8.1 1 , 1 .32 Hz, 1 H) 7.68 (dd, J=8.77, 2.41 Hz, 1 H) 7.71 - 7.77 (m, 2 H).

Example 148

(a) 5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide

To a solution of chlorosulfonyl isocyanate (1 .402 g) in nitropropane (20 mL) under nitrogen at -40 °C was added 2-methoxyaniline (1 .0 g).The reaction mixture was allowed to warm to 0 °C, and aluminum trichloride (1 .353 g) was added. The reaction mixture was heated under reflux for 1 hr. The reaction mixture was allowed to cool to room temperature, and poured into crushed ice. The reaction mixture was extracted with DCM (2 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the crude product (400 mg). The crude product was purified by silica gel flash chromatography (10 g column) using a gradient of 0-5% MeOH in 2% NH ₄ OH/DCM to afford the titled compound (150 mg). LCMS m/z 227.43 (M-H) ^" .

(b) 3-Chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a solution of 5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (300 mg)and N,N-diethylaniline (490 mg) under nitrogen was added POCI ₃ (613 μΙ) and the reaction mixture was stirred at 100 °C for 8 hr. The reaction mixture was poured into ice cold water (5 mL) and made basic with saturated NaHC0 ₃ (aq),and extracted with ethyl acetate (2 x 20 mL). The combined EtOAc extracts were dried over anhydrous sodium sulfate, concentrated to get crude (600 mg) as clear liquid and stirred with 5% MeOH in DCM. The resulting solid was isolated by decanting the solvent and dried to obtain the titled compound (100 mg). LCMS m/z 247.13 (M+H).

(c) 5-Methoxy-3-(phenylamino)-4H-benzo[b][1 ,4]thiazine 1 ,1 -dioxide

A solution of 3-chloro-5-methoxy-4H-benzo[b][1 ,4]thiazine 1 ,1 -dioxide (600 mg), aniline (227 mg) and KH ₂ P0 ₄ (332 mg) in 1 -butanol (10 mL) wa stirred under nitrogen at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (25 mL) and extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (800 mg). The crude product was purified by silica gel flash chromatography (10 g column) using DCM followed by 1 % MeOH DCM to afford the titled compound (400 mg) as an off- white solid. LCMS m/z 303.91 (M+H).

(d) 5-Hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a solution of 5-methoxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (400 mg) in dichloromethane (DCM) (8 mL) was added BBr ₃ (0.374 mL). The reaction mixture was stirred at 40 °C for 16 hr. The reaction mixture was then poured into ice cold water (20 mL), made basic by the addition of saturated NaHC03 (aq), and extracted with DCM (2x50 mL). The combined DCM extracts were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product (500 mg) as gummy solid. The crude product was purified by silica gel flash chromatography (10 g column) using DCM followed by 1 % MeOH/DCM to afford the titled compound (1 10 mg) as an off-white solid. LCMS m/z 289.98 (M+H). ¹ H NMR after D ₂ 0 exchange (400 MHz, DMSO-c/ ₆ ) δ ppm 7.06 - 7.22 (m, 4 H) 7.36 - 7.44 (m, 2 H) 7.49 - 7.57 (m, 2 H).36787 Example 149

3-((2-Chlorophenyl)amino)-5-hvdroxy-4-methyl-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 5-Methoxy-4-methyl-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide

To a vigorously stirred solution of chlorosulfonyl isocyanate (1 .52 mL) in 1 -nitropropane (20 mL) at -40 °C, under nitrogen, was slowly added over 10 min a solution of 2-methoxy-N- methylaniline (2.0 g) in 1 -nitropropane (10 mL). The mixture was then allowed to warm to RT and stirred for 60 min. Anhydrous aluminum chloride (2.53 g) was added and the mixture was then allowed to stir at 120 °C for 2 h. The hot solution was poured onto ice (~40 g) and, after stirring and complete melting of ice, the resulting precipitate was collected by filtration and rinsed with water (5 mL). The insoluble crude material was suspended in an aqueous solution of NaHC0 ₃ (1 .5 g/30 mL) and heated until most of the precipitate was dissolved. The suspension was filtered, and the filtrate was adjusted to pH ~1 with 6 N HCI. The resulting solid was collected by filtration, rinsed with water, and dried to give the titled compound (0.79 g) as a yellowish solid. LCMS m/z 242.9 (M+H); ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 3.40 (s, 3H), 3.92 (s, 3H), 7.38-7.50 (m, 3H).

(b) 3-Chloro-5-methoxy-4-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred suspension of 5-methoxy-4-methyl-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (200 mg) in phosphorus oxychloride (0.77 ml) at 0 °C was added dropwise 2,6- lutidine (0.19 ml). The reaction mixture was allowed to stir at 1 10 °C for 16 h. The mixture was concentrated and to the residue was added 10 mL of ice-water. After stirring for 20 min, the product was extracted with EtOAc, washed sequentially with saturated aqueous NaHC0 ₃ solution and brine, and dried over Na ₂ S0 ₄ . The volatiles were removed under reduced pressure to give the titled compound (150 mg) as a brownish solid. LCMS m/z 260.9 (M+H).

(c) 3-((2-Chlorophenyl)amino)-5-methoxy-4-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a solution of 3-chloro-5-methoxy-4-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (50 mg) in DCM (1 .0 mL) was added 2-chloroaniline (0.20 mL). The mixture was stirred at RT for 40 h and then heated at 50 °C for 2 h and at 60 °C for 16 h. The mixture was allowed to cool to RT and concentrated. The residue was purified by silica gel flash chromatography (10 g column) eluting with 0-100% EtOAc/hexane to afford the titled compound (43 mg). LCMS m/z 352.1 (M+H).

(d) 3-((2-Chlorophenyl)amino)-5-hydroxy-4-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a mixture of 3-((2-chlorophenyl)amino)-5-methoxy-4-methyl-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (32 mg) in DCM (1 .0 mL) at 0 °C was added tribromoborane (1 M in DCM, 0.27 mL). The mixture was allowed to stir at 50 °C for 2 h. The reaction was allowed to cool to RT and quenched with water, and the volatiles were removed. The product was dissolved in EtOAc (20 mL) and washed sequentially with water and brine, dried with Na ₂ S0 ₄ and concentrated. The product was then crystallized from MeOH/DCM/EtOAc (1 :10:20) and dried to afford the titled compound (26 mg) as a light gray solid. LCMS m/z 338.0 (M+H); Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.71 (s, 3H), 7.12-7.19 (m, 2H), 7.23-7.30 (m, 1 H), 7.33-7.39 (m, 1 H), 7.40-7.44 (m, 2H), 7.59 (d, J=7.83 Hz, 1 H), 9.68 (s, 1 H), 10.71 (br s, 1 H).

Example 150

5-Hvdroxy-4-methyl-3-(phenylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

(a) 5-Methoxy-4-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a solution of 3-chloro-5-methoxy-4-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 149(b), 50 mg) in DCM (1 .0 ml_) was added aniline (0.18 ml_). The mixture was stirred at RT for 42 h and then heated at 50 °C for 4 h. The mixture was allowed to cool to RT and concentrated. The residue was purified by silica gel flash chromatography (10 g column) eluting with 0-100% EtOAc/hexane to afford the titled compound (49 mg). LCMS m/z 318.1 (M+H); ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.64 (s, 3H), 3.96 (s, 3H), 7.12- 7.22 (m, 1 H), 7.29-7.35 (m, 1 H), 7.36-7.52 (m, 6H), 9.80 (br s, 1 H).

(b) 5-Hydroxy-4-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a mixture of 5-methoxy-4-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (37 mg) in DCM (1 mL) at 0 °C was added tribromoborane (1 M in DCM, 0.35 ml_). The mixture was then heated at 50 °C for 2 h. The reaction was quenched with MeOH and the volatiles were removed. The residue was purified by silica gel flash chromatography (10 g column) eluting with 0-100% EtOAc/hexane to afford the product the titled compound (12 mg) as an off white solid. LCMS m/z 304.0 (M+H); ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.67 (s, 3H), 7.13-7.20 (m, 3H), 7.24-7.31 (m, 1 H), 7.36-7.42 (m, 2H), 7.43-7.49 (m, 2H), 9.72 (s, 1 H), 10.72 (br s, 1 H). Example 151

8-Bromo-7-chloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H-benzor eiri,2,41thiadiazine 1 ,1 -dioxide

(a) 3,8-Dibromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

A 25 mL microwave vial with stir bar was charged with a suspension of 3,8-dibromo-7- chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-36, 936 mg) in anhydrous DCM (5.0 mL) then treated with 1 .0 M boron tribromide in DCM (7.0 mL). The vessel was sealed with a standard aluminum crimp cap then heated on an aluminum block at 50 °C for 3 days. The reaction was chilled on ice, slowly quenched with MeOH (5 mL) then concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and water then further extracted with EtOAc. The combined extracts were dried over Na ₂ S0 ₄ , filtered, and were concentrated to a residue that was triturated from DCM/ethyl ether to afford the titled compound (850 mg) as a cream solid. LC-MS m/z 391 .0, 393.1 [M+H]. 1 H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .70 (br. s, 1 H) 7.26 (s, 1 H) 4.87 (br. s, 1 H).

(b) 8-Bromo-7-chloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H-benzo[ e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a suspension of 3,8-dibromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (463 mg) and 7-fluoro-1 H-indol-5-amine (196 mg) in f-butanol (10 mL) was added potassium dihydrogen phosphate (310 mg). The reaction was heated at 50 °C for 18 h and then poured into water, adjusted to pH 12 with 2N aq NaOH, and partitioned with DCM. The organic phase was discarded and the aqueous phase was acidified with 1 N aq HCI to pH 2 and extracted with EtOAc. The combined extracts were dried over Na ₂ S0 ₄ , filtered, and were concentrated to a residue that was purified by reverse phase HPLC (C-18: 30x50 mm column; 10-90% acetonitrile w/ 0.1 % TFA/water w/ 0.1 % TFA) to afford the titled compound (154 mg) as a grey solid. LC-MS m/z 459.0, 461 .0 [M+H]. ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 1 1 .83 (br. s., 1 H) 1 1 .67 (br. s., 1 H) 10.13 (br. s., 1 H) 9.47 (s, 1 H) 7.48 (d, J=1 .27 Hz, 1 H) 7.45 (t, J=2.66 Hz, 1 H) 7.21 (s, 1 H) 7.1 1 (dd, J=12.55, 1 .65 Hz, 1 H) 6.51 - 6.61 (m, 1 H).

Example 152

3-((1 H-Pyrrolor2,3-blpyridin-5-yl)amino)-7-chloro-5-hvdroxy-4H-be nzorein ,2,4

Ithiadiazine 1.1 -dioxide

To a suspension of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 125 mg) in f-butanol (4.0 ml_) was added 1 H-pyrrolo[2,3-b]pyridin-5-amine (59 mg) and potassium dihydrogen phosphate (105 mg). The reaction was heated at 50 °C for 18 h and then poured into water and acidified with 1 N aq HCI to pH 2. The resulting solids were collected by filtration, rinsed with water and ethyl ether, and then dried using air suction to afford a crude solid that was purified by reverse phase HPLC (C-18: 30x50 mm column; 20-60% acetonitrile w/ 0.1 % TFA/water w/ 0.1 % TFA) to afford the titled compound (61 mg) as a white solid. LC-MS m/z 364.0 [M+H]. Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .74 (br. s., 1 H) 1 1 .65 (br. s., 1 H) 10.26 (br. s., 1 H) 9.41 (s, 1 H) 8.18 (d, J=2.28 Hz, 1 H) 8.12 (d, J=2.28 Hz, 1 H) 7.52 (t, J=2.80 Hz, 1 H) 7.17 (d, J=2.28 Hz, 1 H) 7.05 (d, J=2.28 Hz, 1 H) 6.50 (dd, J=3.42, 1 .90 Hz, 1 H).

Example 153

7-Chloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H-benzoreiri ,2,41thiadiazine

1 ,1 -dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg) in fe/ -butanol (3 mL) at 80 °C was added 7-fluoro-1 H-indol-5-amine (87 mg) and potassium phosphate, dibasic (126 mg). The mixture was stirred at 80 °C for 3 h. After cooling to RT, the reaction mixture was poured onto water and acidified to pH = 4 with 2M aq HCI. The precipitate was collected via vacuum filtration, and then the collected solids were triturated with DCM, filtered via vacuum filtration, washed with DCM and dried to afford the titled compound (155 mg) as a gray solid. LCMS m/z 381 .2, 383.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/e) δ 6.52 - 6.58 (m, 1 H) 7.05 (d, J=2.02 Hz, 1 H) 7.12 (dd, J=1 .52, 12.63 Hz, 1 H) 7.17 (d, J=2.02 Hz, 1 H) 7.45 (t, J=2.65 Hz, 1 H) 7.48 (d, J=1 .26 Hz, 1 H) 9.44 (s, 1 H) 10.15 (s, 1 H) 1 1 .59 - 1 1 .70 (m, 2 H).

Example 154

6,7-Dichloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-4H- benzorelH ,2.41thiadiazine 1.1 -dioxide

To a solution of 3-bromo-6,7-dichloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 70 mg) in fe/f-butanol (1 mL) at RT was added 7-fluoro-1 H-indol-5-amine (39.5 mg) and potassium phosphate, dibasic (71 mg). The mixture was stirred at 80 °C overnight. After cooling to RT, the reaction mixture was poured onto water and acidified to pH = 4 with 2M aq HCI. The precipitate was collected via vacuum filtration, and then the collected solids were triturated with DCM, filtered via vacuum filtration, and washed with DCM. The residue was purified using reverse phase HPLC (10-75% ACN (with 0.1 % TFA):water (with 0.1 % TFA), C18 50x30 mm Luna column, 47 mL/min) to afford the titled compound (16 mg) as a gray solid. LCMS m/z 415.2, 417.2 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 6.56 (d, J=1 .77 Hz, 1 H) 7.12 (dd, J=12.51 , 1 .39 Hz, 1 H) 7.41 - 7.52 (m, 3 H) 9.58 (s, 1 H) 10.27 (br. s., 1 H) 1 1 .55 (br. s., 1 H) 1 1 .67 (br. s., 1 H). Example 155

7-Chloro-3-((6-fluoro-1 H-indazol-4-yl)amino)-5-hydroxy-4H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 100 mg) in fe/ -butanol (3 ml_) at RT was added 6-fluoro-1 H-indazol-4-amine (58.2 mg) and potassium phosphate, dibasic (84 mg). The mixture was stirred at 80 °C for 1 day. After cooling to RT, the reaction mixture was poured onto water and acidified to pH = 4 with 2M aq HCI. The solids were collected via vacuum filtration and then purified using reverse phase HPLC (20-60% ACN (with 0.1 % TFA):water (with 0.1 % TFA), C18 100x30 mm Luna column, 47 mL/min) to afford the titled compound (8 mg) as a yellow solid. LCMS m/z 382.3, 384.3 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.00 - 7.15 (m, 2 H) 7.24 (d, J=2.27 Hz, 1 H) 7.69 (dd, J=12.00, 1 .89 Hz, 1 H) 8.17 (s, 1 H) 9.89 (s, 1 H) 10.59 (br. s., 1 H) 1 1 .83 (br. s., 1 H) 13.33 (s, 1 H).

Example 156

7-Chloro-3-((6-chloro-1 H-indazol-4-yl)amino)-5-hydroxy-4H- benzorelH ,2.41thiadiazine 1.1 -dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 150 mg) in fe/ -butanol (3 ml_) at RT was added 6-chloro-1 H-indazol-4-amine (81 mg) and potassium phosphate, dibasic (151 mg). The mixture was stirred at 80 °C overnight. After cooling to RT, the reaction mixture was poured onto water and acidified to pH = 3 with 2M aq HCI. The solids were collected via vacuum filtration, then taken into methanol and DMSO. The solids were precipitated out using water and the material was extracted into EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (Na ₂ S04), filtered and evaporated in vacuo to a yellow oil. The oil was purified using reverse phase HPLC (20-60% ACN (with 0.1 % TFA):water (with 0.1 % TFA), C18 50x30 mm Luna column, 47 mL/min) to afford the titled compound (17 mg) as a light pink solid. LCMS m/z 398.3, 400.3 (M+H). Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.10 (d, J=2.02 Hz, 1 H) 7.24 (d, J=2.02 Hz, 1 H) 7.39 (s, 1 H) 7.83 (d, J=1 .26 Hz, 1 H) 8.18 (s, 1 H) 9.86 (s, 1 H) 10.60 (br. s., 1 H) 1 1 .83 (br. s., 1 H) 13.39 (s, 1 H).

Example 157

3-(Benzord1thiazol-5-ylamino)-7-chloro-5-hvdroxy-4H-benzo reiri ,2,41thiadiazine 1 ,1 - dioxide

To a solution of 3-bromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) in fe/ -butanol (4 mL) at RT was added benzo[d]thiazol-5-amine (125 mg) and potassium phosphate, dibasic (224 mg). The mixture was stirred at 80 °C overnight. After cooling to RT, the reaction mixture was poured onto water and acidifed to pH = 2 with aq 2M HCI solution. The precipitate was collected via vacuum filtration, washed with water and dried. The solid was taken into water (10 mL), then basified to pH = 12 using concentrated ammonium hydroxide (7 mL). The insoluble solids were collected via vacuum filtration and discarded. The filtrate was washed with dichloromethane (20 mL), and the organic layer was discarded. The pH of the aqueous layer was adjusted to pH = 7 using an aqueous 2 M HCI solution, and the formed precipitate was collected via vacuum filtration, washed with water and dried to afford the titled compound (1 19 mg) as a tan solid. LCMS m/z 381 .2, 383.2 (M+H). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 7.06 (d, J=2.27 Hz, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.50 (dd, J=8.59, 2.02 Hz, 1 H) 8.16 (d, J=8.59 Hz, 1 H) 8.42 (d, J=1 .77 Hz, 1 H) 9.44 (s, 1 H) 9.81 (br. s., 1 H) 10.10 - 10.76 (m, 1 H) 1 1 .35 - 12.07 (m, 1 H). Example 158

7-chloro-5-hvdroxy-8-methyl-3-(phenylamino)-4H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

(a) 7-chloro-5-methoxy-8-methyl-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide

To a solution of chlorosulfonyl isocyanate (1 .31 ml_) in 1 -nitropropane (75 ml_) cooled to - 40 °C was slowly added a solution of 4-chloro-2-methoxy-5-methylaniline (2.0 g) in 1 - nitropropane (35 ml_). The resulting suspension was warmed to 0 °C and stirred for 30 min at that temperature. To the reaction was added aluminum chloride (2.00 g) and the resulting dark solution was heated at 100 °C for 3 h. The reaction was cooled slightly and then poured into ice-water and allowed to stir overnight. The solids were collected, rinsed with water and briefly suction dried before being taken into acetone/methanol and decolorized with activated charcoal. The suspension was filtered through celite and the filtrate was evaporated to a residue that was triturated from DCM to afford the titled compound (1 .68 g) as an off-white solid. LC-MS m/z 277.1 , 279.1 [M+H].

(b) 3-bromo-7-chloro-5-methoxy-8-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide A 25 mL microwave reaction vial with stir bar was charged with a suspension of 7-chloro- 5-methoxy-8-methyl-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (500 mg) in propionitrile (10 mL) and then phosphorus oxybromide (2.0 g) was added in one portion. The vessel was sealed with a standard aluminum crimp cap and heated on an aluminum block at 100 °C for 20 h. The reaction mixture was cooled, poured into iced water, and extracted with EtOAc. The combined extracts were dried over Na ₂ S0 ₄ , filtered, and were concentrated to a residue that was triturated from ethyl ether/DCM to afford the titled compound (348 mg) as an off-white solid. LC-MS m/z 339.1 , 341 .1 [M+H].

(c) 7-chloro-5-methoxy-8-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a suspension of 3-bromo-7-chloro-5-methoxy-8-methyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (338 mg) in f-butanol (6.0 mL) at 80 °C was added aniline (100 μί) and potassium dihydrogen phosphate (260 mg). The reaction was stirred at 80 °C for 3 h and then poured into cold water and adjusted to pH 5 with 2N aq HCI. The resulting solids were collected, rinsed with water and suction dried before trituration from EtOH to afford the titled compound (265 mg) as a light cream solid. LC-MS m/z 352.2, 354.2 [M+H]. ¹ H NMR (400 MHz, DMSO-c/e) δ ppm 10.06 (s, 1 H) 9.57 (s, 1 H) 7.52 (d, J=7.6 Hz, 2 H) 7.33 - 7.45 (m, 3 H) 7.14 (t, J=7.3 Hz, 1 H) 4.00 (s, 3 H) 2.54 (s, 3 H).

(d) 7-chloro-5-hydroxy-8-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

A 25 mL microwave vial with stir bar was charged with a suspension of 7-chloro-5-methoxy- 8-methyl-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (260 mg) in anhydrous DCM (2.0 mL) and treated with 1 .0 M boron tribromide in DCM (3.0 mL). The vessel was sealed with a standard aluminum crimp cap then heated on an aluminum block at 40 °C for 3 h. The reaction was cooled, slowly quenched with methanol (5 mL), and then concentrated to dryness. The resulting residue was purified by flash chromatography on silica eluting with 0-80% [3:1 ethyl acetate/ethanol mixture containing 1 % NH ₄ OH] in ethyl acetate to give a residue that was recystallized from EtOH/water to afford the titled compound (52 mg) as a white solid. LC-MS m/z 338.2 [M+H]. Ή NMR (400 MHz, DMSO- d _e ) δ ppm 1 1 .25 - 1 1 .47 (m, 1 H) 9.90 - 10.12 (m, 1 H) 9.53 (s, 1 H) 7.52 (d, J=7.58 Hz, 2 H) 7.39 (t, J=7.96 Hz, 2 H) 7.13 (t, J=7.33 Hz, 1 H) 7.08 (s, 1 H) 2.51 - 2.52 (m, 3 H).

Example 159

7-chloro-5-hvdroxy-3-(phenylamino)-4H-benzoreiri,2,41thia diazine-8-carbonitrile

1 ,1 -dioxide

(a) 3,8-Dibromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

A 25 mL microwave vial with stir bar was charged with a suspension of 3,8-dibromo-7- chloro-5-methoxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-36, 936 mg) in anhydrous DCM (5.0 mL) and treated with 1 .0 M boron tribromide in DCM (7.0 ml_). The vessel was sealed with a standard aluminum crimp cap then heated on an aluminum block at 50 °C for 3 days. The reaction was chilled on ice, slowly quenched with MeOH (5 mL), and then concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and water and then further extracted with EtOAc. The combined extracts were dried over Na ₂ S0 ₄ , filtered, and were concentrated to a residue that was triturated from DCM/ethyl ether to afford the titled compound (850 mg) as a cream solid. LC-MS m/z 391 .0, 393.1 [M+H]. 1 H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 1 .70 (br. s, 1 H) 7.26 (s, 1 H) 4.87 (br. s, 1 H).

(b) 8-bromo-7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide

To a suspension of 3,8-dibromo-7-chloro-5-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (253 mg) in f-butanol (3.0 mL) was added aniline (59 μί) and potassium dihydrogen phosphate (169 mg). The reaction was heated at 50 °C for 1 h and then poured into water that was adjusted to pH 2 with 2N aq HCI. The resulting solids were collected, rinsed with water and briefly suction dried before trituration from MeOH to afford the titled compound (145 mg) as a cream solid. LC-MS m/z 402.2, 404.3 [M+H].

(c) 7-chloro-5-hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine-8-carbonitrile 1 ,1 -dioxide

A 25 mL microwave reaction vial was charged with a suspension of 8-bromo-7-chloro-5- hydroxy-3-(phenylamino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (136 mg), dicyanozinc (39.7 mg), copper(l) iodide (64.3 mg), and tetrakis(triphenylphosphine)palladium(0) (39.0 mg) in anhydrous /V-methyl-2-pyrrolidone (4.0 mL). The vessel was sealed with a standard aluminum crimp cap then purged via needles with nitrogen. The reaction was heated at 1 15 °C overnight and the resutling suspension was cooled, filtered to remove palladium, and diluted with 1 N aq HCI (5 mL). The resulting solids were collected and purified by flash chromatography on silica eluting with 0-100% [3:1 ethyl acetate/ethanol mixture containing 1 % NH4OH] in ethyl acetate. Concentration afforded the desired product as an ammonia salt. The solids were taken into hot water/methanol (10:1) and the solution was treated with 5 drops 2N aq HCI to precipitate the product. The solids were collected, rinsed with water, and vacuum dried to afford the titled compound (13 mg) as an off-white solid. LC- MS m/z 349.2 [M+H]. Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 10.40 (br. s., 1 H) 9.65 (s, 1 H) 7.51 (d, J=7.83 Hz, 2 H) 7.41 (t, J=7.96 Hz, 2 H) 7.10 - 7.23 (m, 2 H). Example 160

3-((1 H-lndazol-4-yl)amino)-6,7-dichloro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

A 5 mL microwave tube was charged with 3-bromo-6,7-dichloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg), 1 H-indazol-4-amine (27.7 mg), and potassium phosphate (30.7 mg) in fe/ -butanol (2 mL) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred at 90 °C. After overnight, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (10 mg) as a white solid. LCMS m/z 398.2 (M+H); Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.28 - 7.42 (m, 2 H), 7.47 (br. s., 1 H), 7.67 (d, J=7.33 Hz, 1 H), 8.18 (s, 1 H), 9.86 (s, 1 H), 10.61 (br. s., 1 H), 1 1 .66 (br. s., 1 H), 13.26 (s, 1 H).

Example 161

6,7-Dichloro-3-((2,5-dichlorophenyl)amino)-5-hydroxy-2H-b enzoreiri ,2,41thiadiazine

1.1 -dioxide

A 5 mL microwave tube was charged with 3-bromo-6,7-dichloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-7, 60 mg), 2,5-dichloroaniline (33.7 mg), and potassium phosphate (30.7 mg) in fe/ -butanol (2 mL) to give a white suspension at room temperature under nitrogen. The reaction mixture was stirred at 90 °C. After overnight, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (10 mg) as a white solid. LCMS 426.2 m/z (M+H); Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.32 (dd, J=8.59, 2.53 Hz, 1 H), 7.48 (br. s., 1 H), 7.61 (d, J=8.59 Hz, 1 H), 8.1 1 (d, J=2.53 Hz, 1 H), 9.50 (s, 1 H), 1 1 .08 (br. s., 1 H), 1 1 .62 (br. s., 1 H).

Example 162

3-((1 H-lndazol-4-yl)amino)-6-chloro-7-fluoro-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

a) 3-Bromo-6-chloro-7-fluoro-5-methoxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

A 500 mL round-bottomed flask was charged with 3-bromo-6-fluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-9, 2.05 g) in Λ/,/V-dimethylformamide (60 mL) to give a brown solution at 0 °C under nitrogen. NCS (1 .328 g) in DMF (10 mL) was added to the reaction mixture. After 10 min, the reaction mixture was stirred at room temperature. After overnight, the reaction mixture was cooled to 0 °C. NCS (1 .328 g) in DMF (10 mL) was added to the reaction mixture. After 10 min, the reaction mixture was stirred at room temperature. After 3 days, NCS (1000 mg) was added to the reaction mixture. After 4 days, the reaction mixture was diluted with water (400 mL). The solids were filtered and washed with water and hexanes to afford the titled compound (1 .1 g). LCMS m/z 343.0 (M+H).

b) 3-Bromo-6-chloro-7-fluoro-5-hvdroxy-2H-benzorein ,2.41thiadiazine 1.1 -dioxide

A 200 mL round-bottomed flask was charged with 3-bromo-6-chloro-7-fluoro-5-methoxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (1 .4 g) in dichloromethane (30 mL) at 0 °C under nitrogen to give a white/yellow suspension. Boron tribromide (1 M in DCM, 12.23 mL) was added to the reaction mixture. The sealed reaction was stirred at 50 °C. After overnight, the reaction mixture was concentrated. The reaction mixture was diluted with ice/water and stirred for 20 min. The solids were filtered and washed with water and hexanes. The solids were dried in a vacuum oven to afford the titled compound (1 .12 g). LCMS m/z 329.0 (M+H).

c) 3-((1 H-lndazol-4-yl)amino)-6-chloro-7-fluoro-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide A 5 mL microwave tube was charged with 3-bromo-6-chloro-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (70 mg), 1 H-indazol-4-amine (33.9 mg), and potassium phosphate (57.8 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 5h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 20-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (30 mg) as a white solid. LCMS 382.2 m/z (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.10 (d, J=10.1 1 Hz, 1 H), 7.32 (d, J=8.34 Hz, 1 H), 7.38 (t, J=7.96 Hz, 1 H), 7.68 (d, J=7.07 Hz, 1 H), 8.17 (s, 1 H), 9.71 (s, 1 H), 10.45 (s, 1 H), 12.03 (s, 1 H), 13.26 (s, 1 H).

Example 163

3-((1 H-lndazol-4-yl)amino)-6-chloro-7-fluoro-5-hydroxy-2H- benzor ,1 -dioxide

A 5 mL microwave tube was charged with 3-bromo-6-chloro-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 162b, 70 mg), 2,5-difluoroaniline (0.026 mL), and potassium phosphate (57.8 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After overnight, the reaction mixture was concentrated. The crude product was purified by prep- HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 % TFA to obtain the titled compound (30 mg) as a white solid. LCMS 378.2 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.00 - 7.10 (m, 2 H), 7.40 (ddd, J=10.61 , 9.09, 5.05 Hz, 1 H), 7.99 - 8.06 (m, 1 H), 9.64 (br. s., 1 H), 10.70 (br. s., 1 H), 12.01 (br. s., 1 H).

Example 164

3-((1 H-lndazol-4-yl)amino)-7-fluoro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

A 5 mL microwave tube was charged with 3-bromo-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 60 mg), 1 H-indazol-4-amine (32.5 mg), and potassium phosphate (36.0 mg) in fe/ -butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After overnight, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using an X-Bridge column (30 x 70 mm) and eluting with 5-50% acetonitrile to waterwith 0.1 %TFA to obtain the titled compound (21 mg) as a white solid. LCMS 347.9 m/z (M+H); 1 H NMR (400 MHz, DMSO-de) δ ppm 6.94 (dd, J=9.98, 2.65 Hz, 1 H), 7.03 (dd, J=7.58, 2.53 Hz, 1 H), 7.24 - 7.53 (m, 2 H), 7.67 (d, J=6.82 Hz, 1 H), 8.17 (s, 1 H), 9.68 (s, 1 H), 10.44 (s, 1 H), 1 1 .80 (s, 1 H), 13.25 (s, 1 H).

Example 165 3-((1 H-lndazol-4-yl)amino)-8-chloro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

a) 8-Chloro-5-methoxy-2H-benzore1M ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide

To a stirred solution of chlorosulfonyl isocyanate (17.91 mL) in 1 -nitropropane (200 mL) at -40 °C was added a solution of 5-chloro-2-methoxyaniline (25 g) in 1 -nitropropane (50 mL). The reaction mixture was warmed to 0 °C. After 1 h, aluminium chloride (27.5 g) was added. The reaction mixture temperature was warmed to 1 10 °C for 20 min. The reaction mixture was poured into ice/water (1000 mL). The solids were filtered and dried at high vacuum to afford the titled compound (15 g). LCMS 262.94 m/z (M+H). b) 3-Bromo-8-chloro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of (8-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (15 g) in propionitrile (450 mL) at room temperature was added phosphorus oxybromide (82 g). The reaction mixture temperature was heated to 1 10 °C. After 16 h, the reaction mixture was poured into ice/water (500 mL). The solids were filtered and dried under high vacuum to afford the titled compound (8 g). LCMS 324.9 m/z (M+H).

c) 3-Bromo-8-chloro-5-hvdroxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-8-chloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (7 g) in 1 ,2 dichloroethane (80 mL) in a sealed tube at room temperature was added BBr ₃ (21 .50 mL). The reaction mixture was warmed to 80 °C. After 16 h, the reaction mixture was poured into ice/water (200 mL). The solids were filtered and dried under high vacuum to afford the titled compound (5 g). LCMS 312.84 m/z (M+H).

d) 3-((1 H-lndazol-4-yl)amino)-8-chloro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

A 5 mL microwave tube was charged with 3-bromo-8-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (60 mg), 1 H-indazol-4-amine (30.8 mg), and potassium phosphate (34.1 mg) in fe/ -butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 4h, the reaction was concentrated. The crude product was purified by prep-HPLC using an X-Bridge column (30 x 70mm) and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (9.7 mg) as a white solid. LCMS 363.9 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.08 (d, J=8.59 Hz, 1 H), 7.20 (d, J=8.59 Hz, 1 H), 7.32 (d, J=8.08 Hz, 1 H), 7.38 (t, J=7.96 Hz, 1 H), 7.71 (d, J=7.07 Hz, 1 H), 8.18 (s, 1 H), 9.72 (s, 1 H), 10.41 (s, 1 H), 1 1 .43 (s, 1 H), 13.25 (s, 1 H).

Example 166

3-((1 H-lndazol-6-yl)amino)-6,7-difluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

a) 6,7-Difluoro-5-methoxy-2H-benzoreiri ,2,41thiadiazin-3(4H)-one 1 ,1 -dioxide A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (3.51 mL) in nitropropane (60 mL) at -40 °C under nitrogen to give a clear solution. After 10 min, a solution of 3,4-difluoro-2-methoxyaniline (4.95 g) in nitropropane (10 mL) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 °C. After 1 h, aluminium chloride (5.81 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 120 °C. After 1 h, the reaction mixture was poured into ice/water (400 mL) and stirred. The solids were filtered and washed with water to afford the titled compound (1 .93 g). LCMS 265.1 m/z (M+H).

b) 3-Bromo-6,7-difluoro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide

A 250 mL round-bottomed flask was charged with 6,7-difluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (1 .95 g) in acetonitrile (100 mL) at room temperature under nitrogen to give a brown solution. Phosphorus oxybromide (10.58 g) was added to the reaction mixture. The reaction mixture was stirred to 100 °C. After 2 days, the reaction mixture was concentrated. The reaction mixture was stirred with ice/water for 1 h. The solids were filtered and washed with hexanes to afford the titled compound (1 .7 g). LCMS 327.0 m/z (M+H).

c) 3-Bromo-6,7-difluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine

A 20 mL microwave tube was charged with 3-bromo-6,7-difluoro-5-methoxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (700 mg) in dichloromethane (10 mL) at 0 °C under nitrogen to give a white/gray suspension. Boron tribromide (1 M, DCM, 6.42 mL) was added to the reaction mixture. The sealed reaction was heated to 50 °C. After 5 h, the reaction mixture was cooled to room temperature. After overnight, the reaction mixture was concentrated. The reaction was diluted with ice/water and stirred for 20 min. The solids were filtered and washed with water and hexanes. The solids were dried in a vacuum oven to afford the titled compound (666 mg). LCMS 312.9 m/z (M+H).

d) 3-((1 H-lndazol-6-yl)amino)-6,7-difluoro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -dioxide

A 5 mL microwave tube was charged with 3-bromo-6,7-difluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (70 mg), 1 H-indazol-5-amine (44.7 mg), and potassium phosphate (60.9 mg) in fe/ -butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound as the trifluoroacetate salt (8 mg) as a white solid. LCMS 366.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.24 - 7.45 (m, 2 H), 7.58 (d, J=8.84 Hz, 1 H), 7.91 - 8.04 (m, 1 H), 8.12 (s, 1 H), 9.50 (s, 1 H), 10.28 (br. s., 1 H), 12.02 (br. s., 1 H), 13.1 1 (br. s., 1 H).

Example 167

3-((1 H-lndol-5-yl)amino)-6,7-difluoro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

A 5 mL microwave tube was charged with 3-bromo-6,7-difluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 166c, 70 mg), 1 H-indol-5-amine (44.3 mg), and potassium phosphate (60.9 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (25 mg) as a white solid. LCMS 365.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.46 (br. s., 1 H), 7.10 (dd, J=8.59, 2.02 Hz, 1 H), 7.20 - 7.35 (m, 1 H), 7.35 - 7.52 (m, 2 H), 7.72 (s, 1 H), 9.35 (s, 1 H), 10.18 (br. s., 1 H), 1 1 .16 (br. s., 1 H), 1 1 .97 (br. s., 1 H).

Example 168

3-((1 H-lndazol-4-yl)amino)-7-chloro-6-fluoro-5-hydroxy-2H- benz -dioxide

A 5 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-21 , 52 mg), 1 H-indazol-4-amine (31 .5 mg), and potassium phosphate (53.7 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (25 mg) as a white solid. LCMS 382.3 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.28 - 7.47 (m, 3 H), 7.67 (d, J=7.07 Hz, 1 H), 8.17 (s, 1 H), 9.77 (s, 1 H), 10.66 (br. s., 1 H), 12.03 (br. s., 1 H), 13.26 (s, 1 H).

Example 169

3-((1 H-lndazol-5-yl)amino)-7-chloro-6-fluoro-5-hydroxy-2H- ben -dioxide

A 5 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-21 , 52 mg), 1 H-indazol-5-amine (31 .5 mg), and potassium phosphate (53.7 mg) in fe/ -butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (8 mg) as a white solid. LCMS 382.3 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.33 - 7.41 (m, 2 H), 7.58 (d, J=8.84 Hz, 1 H), 7.98 (s, 1 H), 8.12 (s, 1 H), 9.55 (s, 1 H), 10.36 (br. s., 1 H), 1 1 .91 (br. s., 1 H), 13.12 (s, 1 H).

Example 170

7-Chloro-6-fluoro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benz -dioxide

A 5 mL microwave tube was charged with 3-bromo-7-chloro-6-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-21 , 52 mg), 7-fluoro-1 H-indol-5-amine (28.4 mg), and potassium phosphate (53.7 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound as the trifluoroacetate salt (13 mg) as a white solid. LCMS 399.0 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.56 (d, J=2.02 Hz, 1 H), 7.07 - 7.16 (m, 1 H), 7.35 - 7.55 (m, 3 H), 9.49 (s, 1 H), 10.34 (br. s., 1 H), 1 1 .67 (br. s., 1 H), 1 1 .90 (br. s., 1 H). Example 171

3-((1 H-lndazol-4-yl)amino)-6,7-difluoro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 - dioxide

A 5 mL microwave tube was charged with 3-bromo-6,7-difluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 166c, 54 mg), 1 H-indazol-4-amine (34.4 mg), and potassium phosphate (58.7 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound as the trifluoroacetate salt (25 mg) as a white solid. LCMS 366.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.27 - 7.41 (m, 3 H), 7.66 (d, J=7.07 Hz, 1 H), 8.17 (s, 1 H), 9.73 (s, 1 H), 10.59 (br. s., 1 H), 12.16 (br. s., 1 H), 13.26 (s, 1 H).

Example 172

6,7-Difluoro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benz -dioxide

A 5 mL microwave tube was charged with 3-bromo-6,7-difluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 166c, 54 mg), 7-fluoro-1 H-indol-5-amine (38.8 mg), and potassium phosphate (58.7 mg) in fe/ -butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (16 mg) as a white solid. LCMS 383.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.46 - 6.65 (m, 1 H), 7.12 (dd, J=12.63, 1 .52 Hz, 1 H), 7.29 (t, J=8.21 Hz, 1 H), 7.39 - 7.59 (m, 2 H), 9.45 (s, 1 H), 10.25 (br. s., 1 H), 1 1 .67 (br. s., 1 H), 12.02 (br. s., 1 H).

Example 173

6,7-Difluoro-3-((4-fluoro-1 H-indol-6-yl)amino)-5-hydroxy-2H- benzo ,1 -dioxide

A 5 mL microwave tube was charged with 3-bromo-6,7-difluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 166c, 54 mg), 4-fluoro-1 H-indol-6-amine (38.8 mg), and potassium phosphate (58.7 mg) in fe/ -butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After 3h, the reaction mixture was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-75% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (10 mg) as a white solid. LCMS 383.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.62 (t, J=2.15 Hz, 1 H), 7.00 (dd, J=9.35, 1 .52 Hz, 1 H), 7.24 - 7.53 (m, 2 H), 7.66 (dd, J=12.38, 2.27 Hz, 1 H), 9.56 (s, 1 H), 10.70 (br. s., 1 H), 1 1 .38 (br. s., 1 H), 12.14 (br. s., 1 H).

Example 174

3-((2,5-Dichlorophenyl)amino)-7-fluoro-5-hydroxy-2H-benzo reiri ,2,41thiadiazine 1 ,1 -

A 5 mL microwave tube was charged with 3-bromo-7-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-39, 60 mg), 2,5-dichloroaniline (39.5 mg), and potassium phosphate (36.0 mg) in fe/f-butanol (2 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After overnight, the reaction was concentrated. The crude product was purified by prep-HPLC using an X- Bridge C18 (30 x 70 mm) and eluting with 10-60% acetonitrile to water with 0.1 %TFA to obtain the titled compound as a trifluoroacetate salt (14 mg) as a white solid. LCMS 375.9 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.93 (dd, J=10.1 1 , 2.53 Hz, 1 H), 7.04 (dd, J=7.58, 2.53 Hz, 1 H), 7.30 (dd, J=8.59, 2.53 Hz, 1 H), 7.60 (d, J=8.59 Hz, 1 H), 8.14 (d, J=2.53 Hz, 1 H), 9.33 (s, 1 H), 10.95 (br. s., 1 H), 1 1 .79 (br. s., 1 H).

Example 175

7-Chloro-3-((5-chloro-2-fluorophenyl)amino)-5-hydroxy-2H- benzor ,1 -dioxide

A 5 mL microwave tube was charged with 3-bromo-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 60 mg), 5-chloro-2-fluoroaniline (0.026 mL), and potassium phosphate (34.1 mg) in fe/f-butanol (5 mL) at room temperature under nitrogen to give a white suspension. The reaction mixture was stirred at 90 °C. After overnight, the reaction was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10-50% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound as a trifluoroacetate salt (15 mg) as a white solid. LCMS 376.2 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.94 - 7.18 (m, 2 H), 7.22 (d, J=2.02 Hz, 1 H), 7.62 (dd, J=8.97, 5.94 Hz, 1 H), 7.95 (dd, J=10.86, 3.03 Hz, 1 H), 9.39 (s, 1 H), 1 1 .05 (s, 1 H), 1 1 .75 (s, 1 H).

Example 176

3-((1 H-lndazol-4-yl)amino)-8-fluoro-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

a) 3-Bromo-8-fluoro-5-hvdroxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-8-fluoro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-13, 10 g) in 1 ,2-dichloroethane (200 ml_) at room temperature was added BBr ₃ (3.36 ml_). The reaction mixture was heated to 80 °C for 16 h. The reaction mixture was poured in ice water (3000 ml_). The solids were collected by filtration and washed with (500 mL) and dried to the titled compound (6.6 g). LCMS 294.95 m/z (M+H).

b) 3-((1 H-lndazol-4-yl)amino)-8-fluoro-5-hvdroxy-2H-benzorein ,2,41thiadiazine 1 ,1 - dioxide

A 20 mL microwave tube was charged with 3-bromo-8-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (100 mg) and potassium phosphate (64.6 mg) in tert- butanol (3 mL) at room temperature under nitrogen to give a white suspension. 1 H-lndazol- 4-amine (54.1 mg) was added to the reaction mixture. The reaction mixture was stirred at 90 °C. After 3h, the mixture reaction was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 15-40% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (30 mg) as a white solid. LCMS 348.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.99 (t, J=9.25 Hz, 1 H), 7.08 (dd, J=8.87, 4.82 Hz, 1 H), 7.23 - 7.50 (m, 2 H), 7.70 (d, J=7.10 Hz, 1 H), 8.18 (s, 1 H), 9.71 (br. s., 1 H), 10.47 (br. s., 1 H), 1 1 .08 (br. s., 1 H), 13.26 (s, 1 H). Example 177

8-Fluoro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine

-dioxide

A 20 mL microwave tube was charged with 3-bromo-8-fluoro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Example 176a, 100 mg) and potassium phosphate (64.6 mg) in fe/ -butanol (3 mL) at room temperature under nitrogen to give a white suspension. 1 H-lndol-5-amine (53.7 mg) was added to the reaction mixture. The reaction mixture was stirred at 90 °C. After 3h, the mixture reaction was concentrated. The crude product was purified by prep-HPLC using a C18 column and eluting with a gradient of 10- 50% acetonitrile with 0.1 % TFA to water with 0.1 %TFA to obtain the titled compound (25 mg) as a white solid. LCMS 365.1 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.56 (d, J=2.02 Hz, 1 H), 6.94 (t, J=9.09 Hz, 1 H), 7.03 (dd, J=8.84, 4.55 Hz, 1 H), 7.09 - 7.18 (m, 1 H), 7.45 (t, J=2.65 Hz, 1 H), 7.49 (d, J=1 .26 Hz, 1 H), 9.43 (br. s., 1 H), 10.1 1 (br. s., 1 H), 10.94 (br. s., 1 H), 1 1 .66 (br. s., 1 H).

Example 178

7,8-Dichloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benz -dioxide

a) 7.8-Dichloro-5-methoxy-2H-benzoreiri ,2.41thiadiazin-3(4H)-one 1.1 -dioxide

To a stirred solution of chlorosulfonyl isocyanate (5.88 mL) in 1 -nitropropane (80 mL) at - 40 °C was added a solution of 4,5-dichloro-2-methoxyaniline (10 g) in 1 -nitropropane (20 mL). The reaction mixture was warmed to 0 °C. After 1 h, aluminium chloride (9.03 g) was added to the reaction mixture. The reaction mixture was warmed to 100 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with cold water. The solids were collected by filtration and dried under vacuum to afford the titled compound (5.8 g) as off white solid. LCMS 295.16 m/z (M-H).

b) 3-Bromo-7,8-dichloro-5-methoxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 7,8-dichloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 - dioxide (6.2 g) in propionitrile (120 mL) at room temperature was added phosphorus oxybromide (29.9 g). The reaction mixture was warmed to 1 15 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with cold water. The solids were collected by filtration and dried under reduced pressure to obtain the titled compound (5.3 g) as an off-white solid. LCMS 358.99 m/z (M+H).

c) 3-Bromo-7,8-dichloro-5-hvdroxy-2H-benzore1M ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7,8-dichloro-5-methoxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (5.3 g) in 1 ,2-dichloroethane (100 mL) in a sealed tube at room temperature was added BBr ₃ (5.57 mL). The reaction mixture was warmed to 80 °C. After 16 h, the reaction mixture was cooled to room temperature and diluted with cold water. The solids were filtered and dried under vacuum to afford the titled compound (4.8 g). LCMS 345.06 m/z (M+H).

d) 7,8-Dichloro-3-((7-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7,8-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (150 mg) in fe/f-butanol (10 mL) at room temperature was added potassium dihydrogenphosphate (1 18 mg)) and 7-fluoro-1 H-indol-5-amine (65.1 mg). The reaction mixture was sealed and stirred at 1 10 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The solids were filtered, washed with n- pentane, and dried under vacuum to afford the titled compound (102 mg) as a grey solid. LCMS 415.12 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 1 .75 (br s, 1 H), 1 1 .63 (br s, 1 H), 10.12 (br s, 1 H), 9.46 (s, 1 H), 7.48 (d, J=1 .47 Hz, 1 H), 7.44 (t, J=2.69 Hz, 1 H), 7.20 (s, 1 H), 7.1 1 (dd, J=1 .59, 12.59 Hz, 1 H), 6.53-6.59 (m, 1 H).

Example 179

7-Chloro-5-hvdroxy-3-((7-methyl-1 H-indazol-4-yl)amino)-2H- benzor ,1 -dioxide

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) in fe/f-butanol (10 mL) at room temperature were added potassium dihydrogen phosphate (175 mg) and 7-methyl-1 H-indazol-4-amine (1 13 mg). The reaction mixture was sealed and heated to 1 10 °C. After 16 h, the reaction mixture was cooled to room temperature and diluted with water (20 mL). The reaction mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified by prep-HPLC using a Kinetex C18 column and eluting with a gradient of 10-100% acetonitrile with 0.1 % HCOOH to water with 0.1 % HCOOH to obtain the titled compound (36 mg) as an off-white solid. LCMS 378.14 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.28 (br s, 1 H), 1 1 .94 - 1 1 .75 (m, 1 H), 10.85 (br s, 1 H), 9.61 (s, 1 H), 8.15 (s, 1 H), 7.51 (d, J=7.7 Hz, 1 H), 7.17 - 7.10 (m, 2H), 7.06 (d, J=2.2 Hz, 1 H), 3.60 (s, 3H).

Example 180

7-Chloro-3-((7-fluoro-1 H-indazol-4-yl)amino)-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 200 mg) and 7-fluoro-1 H-indazol-4-amine (1 16 mg) in fe/f-butanol (10 mL) was added potassium dihydrogen phosphate (105 mg). The reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was then concentrated. Water (20 mL) was added to reaction mixture, which was then stirred for 20 min. The solids were filtered. The crude product was purified by prep-HPLC using an XBRIDGE C-18 column and eluting with a gradient of 10-100% acetonitrile to 10 mM aq ammonium bicarbonate to obtain the titled compound (95 mg) as an off-white solid. LCMS 379.97 m/z (M-H); 1 H NMR (400 MHz, DMSO-de) δ ppm 13.80 (br s, 1 H), 1 1 .71 (br s, 1 H), 10.42 (br s, 1 H), 9.66 (s, 1 H), 8.23 (br s, 1 H), 7.52 (br dd, J=3.18, 8.07 Hz, 1 H), 7.14-7.29 (m, 2H), 7.08 (d, J=1 .96 Hz, 1 H).

Example 181

7-Chloro-3-((6-fluoro-1 H-indol-5-yl)amino)-5-hvdroxy-2H-benzoreiri ,2,41thiadiazine

-dioxide

a) 5-Bromo-6-fluoro-1 -(triisopropylsilyl)-l H-indole

LiHMDS (16.26 mL) was slowly added to a solution of 5-bromo-6-fluoro-1 H-indole (2.9 g) in tetrahydrofuran (30 mL) at -78° C under nitrogen atmosphere. After 20 min, chlorotriisopropylsilane (2.59 mL) was added to the reaction mixture. After 20 min, the reaction mixture was warmed to room temperature over a period of 1 hour. The reaction mixture was quenched by addition of saturated aqueous NH ₄ CI (40 mL), diluted with water (80 mL), and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered, and concentrated. The crude product was purified by column chromatography using silica 100-200 mesh and eluting with hexanes to afford the titled compound (3.5 g) as liquid. LCMS 372.08 m/z (M+2H).

b) 6-Fluoro-N-(4-methoxybenzyl)-1 -(triisopropylsilyl)-1 H-indol-5 -amine

To a stirred solution of 5-bromo-6-fluoro-1 -(triisopropylsilyl)-l H-indole (1 .5 g) in toluene (15 mL) in a sealed tube were added (4-methoxyphenyl)methanamine (0.833 g) and sodium fe/ -butoxide (1 .168 g). The reaction mixture was purged with argon for 20 min. Dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphine (0.217 g) and Pd ₂ (dba) ₃ (0.371 g) was added to reaction mixture. The reaction mixture was heated to 1 15 °C for 20 h. The reaction mixture was cooled to room temperature and filtered through pad of celite. The filtrate was concentrated to obtain 2.1 g of crude product. The above procedure was repeated using 5-bromo-6-fluoro-1 -(triisopropylsilyl)-1 H-indole (500 mg), (4-methoxyphenyl)methanamine (278 mg), dicyclohexyl(2',4',6'-triisopropyl-3,6- dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphine (72 mg), Pd ₂ (dba) ₃ (124 mg), and sodium tert- butoxide (389 mg) in toluene (10 mL) to obtain 550 mg of crude product. The combined solids (2.65 g) were purified by column chromatography using silica gel (100-200 mesh) and eluting with 4% EtOAc in hexanes to obtain the titled compound (800 mg) as an off- white solid. LCMS 427.26 m/z (M-H).

c) 6-Fluoro-1 -(triisopropylsilvD-1 H-indol-5-amine

To a stirred solution of 6-fluoro-N-(4-methoxybenzyl)-1 -(triisopropylsilyl)-1 H-indol-5-amine (700 mg) in ethyl acetate (12 mL) was added Pd/C (10%) (349 mg) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 16 h under a hydrogen balloon atmosphere at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to afford the titled compound (380 mg) as an off-white solid. LCMS 307.18 m/z (M+H).

d) 7-Chloro-3-((6-fluoro-1 -(triisopropylsilyl)-l H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred solution of 6-fluoro-1 -(triisopropylsilyl)-1 H-indol-5-amine (150 mg) in tert- butanol (10 mL) were added potassium dihydrogenphosphate (233 mg) and 3-bromo-7- chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 152 mg) at room temperature. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 25 mL), and washed with brine (30 mL). The combined organic layers were separated, dried over anhydrous Na ₂ S0 ₄ , filtered, and concentrated to afford the titled compound (250 mg) as an off-white solid. LCMS 537.18 m/z (M+H).

e) 7-Chloro-3-((6-fluoro-1 H-indol-5-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a solution of 7-chloro-3-((6-fluoro-1 -(triisopropylsilyl)-1 H-indol-5-yl)amino)-5-hydroxy- 2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (200 mg) in tetrahydrofuran (8 mL) at room temperature was added TBAF (1 .0 M solution in THF, 1 .489 mL). After 3 h, the reaction mixture was diluted with water (20 mL), extracted with EtOAc (3 x 35 mL), and washed with brine (60 mL). The combined organic layers were separated, dried over anhydrous Na ₂ S0 ₄ , filtered, and concentrated. The crude product was purified by prep-HPLC using an XBRIDGE C-18 column and eluting with a gradient of 10-40% acetonitrile in 10 mM aq ammonium bicarbonate to obtain the titled compound (82 mg) as an off-white solid. LCMS 381 .04 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 1 .58 (br s, 1 H), 1 1 .18 (br s, 1 H), 10.44 (br s, 1 H), 9.16 (s, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.37 (t, J = 2.7 Hz, 1 H), 7.31 (d, J = 1 1 .2 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 7.05 (d, J = 2.2 Hz, 1 H), 6.49 (d, J = 2.0 Hz, 1 H).

Example 182

7-Chloro-3-((7-chloro-1 H-indol-5-yl)amino)-5-hvdroxy-2H-benzoreiri .2.41thiadiazine

-dioxide

To a solution of 7-chloro-1 H-indol-5-amine (150 mg) in fe/f-butanol (10 mL) at room temperature were added potassium dihydrogenphosphate (368 mg) and 3-bromo-7-chloro- 5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 280 mg). The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with water (15 mL). The solids were collected by filtration and dried under reduced pressure. The solid was suspended in water (15 mL) and stirred for 16 h. The solids were collected by filtration and dried under reduced pressure to afford the titled compound (120 mg) as a gray solid. LCMS 394.91 m/z (M-H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 1 .63 - 1 1 .46 (m, 2H), 10.13 (br s, 1 H), 9.41 (s, 1 H), 7.62 (d, J = 1 .5 Hz, 1 H), 7.45 (t, J = 2.7 Hz, 1 H), 7.32 (d, J = 1 .8 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 7.05 (d, J = 2.2 Hz, 1 H), 6.57 (dd, J = 1 .9, 2.7 Hz, 1 H).

Example 183

3-((3-(Aminomethyl)phenyl)amino)-7-chloro-5-hydroxy-2H- be -dioxide

a) fert-Butyl 3-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3- yl)amino)benzylcarbamate

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 400 mg) in fe/f-butanol (15 mL) at room temperature in a sealed tube were added fe/ -butyl 3-aminobenzylcarbamate (342 mg) and potassium dihydrogenphosphate (210 mg). The reaction mixture was warmed to 100 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with cold water. The solids were collected by filtration and dried under reduced pressure. The solids were triturated with diethyl ether and pentane to afford titled compound (250 mg) as an off-white solid. LCMS 396.98 m/z (M+H).

b) 3-((3-(Aminomethyl)phenyl)amino)-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred solution of fe/ -butyl 3-((7-chloro-5-hydroxy-1 ,1 -dioxido-2H- benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzylcarbamate (250 mg) in 1 ,4-dioxane (10 mL) at 0 °C under nitrogen was added hydrogen chloride (4M solution in 1 ,4-dioxane, 4 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated. The solids were triturated with EtOAc and pentane. The solids were dried under reduced pressure. The solids were sonicated with diethyl ether and filtered to afford the titled compound (160 mg) as the hydrochloride salt as an off-white solid. LCMS 353.04 m/z (M+H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 1 .76 (br s, 1 H), 10.41 (br s, 1 H), 10.04 (s, 1 H), 8.29 (br s, 3H), 7.57-7.70 (m, 1 H), 7.54 (s, 1 H), 7.45 (t, J=7.9 Hz, 1 H), 7.25 (d, J=7.7 Hz, 1 H), 7.05-7.21 (m, 2H), 4.04 ppm (s, 2H).

Example 184

3-((1 H-indazol-4-yl)amino)-7,8-dichloro-5-hydroxy-2H-benzoreiri ,2,41thiadiazine 1 ,1 -

To a stirred solution 3-bromo-7,8-dichloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (Int-x9, 500 mg) in fe/ -butanol (30 mL) at room temperature in a sealed tube were added potassium dihydrogenphosphate (236 mg) and 1 H-indazol-4-amine (231 mg). The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with cold water (20 mL). The solids were collected by filtration. The solids were triturated with diethyl ether (20 mL) and pentane (20 mL). The crude product was purified by prep-SFC with a Chiralpak AS-H column, eluting with a gradient of 5% CO in methanol with 5% DEA to obtain crude product. The crude product was then purified by prep-HPLC using an XBRIDGE C-18 column and eluting with a gradient of 10- 35% acetonitrile in 10 mM aq ammonium bicarbonate to obtain the titled compound (14 mg) as an off-white solid. LCMS 397.96 m/z (M-H); 1 H NMR (400 MHz, DMSO-d ₆ -D ₂ 0) δ ppm 8.21 (s, 1 H), 7.69 (d, J=7.5 Hz, 1 H), 7.37 - 7.32 (m, 1 H), 7.26 (d, J=7.9 Hz, 1 H), 7.01 (b s, 1 H).

Example 185

7-Chloro-3-((7-chloro-1 H-indazol-4-yl)amino)-5-hydroxy-2H- benzorelM ,2,41thiadiazine 1 ,1 -dioxide

a) fert-Butyl 4-nitro-1 H-indazole-1 -carboxylate

To a stirred solution of 4-nitro-1 H-indazole (30 g) in dichloromethane (500 mL) at room temperature were added triethylamine (77 mL) and Boc ₂ 0 (51 .2 mL). The reaction mixture was stirred for 16 h. The reaction mixture was diluted with water (500 mL), extracted with DCM (3 x 200 mL), and washed with brine (100 mL). The combined organic layers were separated, dried over anhydrous Na2S04, filtered, and concentrated to obtain the titled compound (30 g) as an off-white solid. LCMS 264.22 m/z (M+H).

b) tert-Butyl 4-amino-1 H-indazole-1 -carboxylate

To a stirred solution of fe/f-butyl 4-nitro-1 H-indazole-1 -carboxylate (30 g) in a mixture of methanol (100 mL) and ethyl acetate (250 mL) was added Pd/C (4 g). The reaction mixture was purged with nitrogen and stirred under a hydrogen balloon for 16 h. The reaction mixture was filtered through celite and washed with EtOAc (200 mL). The filtrate was concentrated to obtain the titled compound (26 g) as an off-white solid. LCMS 234.22 m/z (M+H).

c) tert-Butyl 4-amino-7-chloro-1 H-indazole-1 -carboxylate

To a stirred solution of fe/f-butyl 4-amino-1 H-indazole-1 -carboxylate (26 g) in N,N- dimethylformamide (250 mL) at 0 °C was added NCS (17.86 g). The reaction mixture was warmed to room temperature for 16 h. The reaction mixture was diluted with ice cold water (500 mL), extracted with EtOAc (3 x 300 mL), and washed with chilled brine (3 x 200 mL). The combined organic layers were separated, dried over anhydrous Na ₂ S0 ₄ , filtered, and concentrated. The solids were purified by column chromatography using silica gel 100-200 mesh, eluting with 20% to 40% EtOAc in hexanes to obtain the titled compound (14 g) as pale brown solid. LCMS 268.1 1 m/z (M+H).

d) 7-Chloro-3-((7-chloro-1 H-indazol-4-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

To a stirred solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 - dioxide (lnt-3, 10 g) in fe/ -butanol (250 mL) at room temperature under argon were added potassium dihydrogenphosphate (10.92 g) and fe/ -butyl 4-amino-7-chloro-1 H-indazole-1 - carboxylate (10.31 g). The reaction mixture was heated to 100 °C. After 30 h, the reaction mixture was cooled to room temperature and diluted with cold water (300 mL). The solids were collected by filtration and dried under vacuum. The solids were triturated with diethyl ether (200 mL) to afford a 1 :3.5 crude mixture of fe/Y-butyl 7-chloro-4-((7-chloro-5-hydroxy- 1 ,1 -dioxido-2H-benzo[e][1 ,2,4]thiadiazin-3-yl)amino)-1 H-indazole-1 -carboxylate [LCMS 495.79 m/z (M-H)] and 7-chloro-3-((7-chloro-1 H-indazol-4-yl)amino)-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide [LCMS 395.58 m/z (M-H)] as brown solid (10 g).

To the above crude mixture (10 g) in 1 ,4-dioxane (100 mL) at 0 °C under nitrogen was added hydrogen chloride (4M in 1 ,4-dioxane, 80 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure. The solids were triturated with EtOAc (100 mL) and filtered. The crude product was purified by prep-HPLC using a Sunfire column (250 x 30 mm,10u) and eluting with a gradient of 10-60% acetonitrile in water with 0.2% HCOOH. The product fractions were concentrated under reduced pressure. The solids were washed with water (200 mL) to afford 4 g of titled product as a brown solid. LCMS 397.97 m/z (M+H).

The above sequences were repeated using 7 g of 3-bromo-7-chloro-5-hydroxy-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3) to obtain 2.6 g of 7-chloro-3-((7-chloro-1 H- indazol-4-yl)amino)-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide. LCMS 398.04 m/z (M+H). The combined product batches (6.6 g) were dissolved in ethanol (500 mL) and ethanolic ammonia (~5 M, 150 mL). To the solution were added activated charcoal (DARCO-100 mesh, 4 g) and sili-thiol (3.5 g) and the mixture was stirred under reflux for 2 h. The hot mixture was filtered through a pad of celite and washed with hot ethanol (2 L). The filtrate was concentrated. The solids were suspended in water (200 mL), and the pH was adjusted to ~4 with 0.1 M aq HCI. After stirring for 30 min, the solid was filtered and washed with water (400 mL) to afford the titled compound (5.8 g) as a white solid. LCMS 395.95 m/z (M-H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.73 (s, 1 H), 1 1 .72 (s, 1 H), 10.48 (br s, 1 H), 9.76 (s, 1 H), 8.26 (d, J=1 .3 Hz, 1 H), 7.69 (d, J=8.3 Hz, 1 H), 7.47 (d, J=8.1 Hz, 1 H), 7.21 (d, J=2.2 Hz, 1 H), 7.09 (d, J=2.2 Hz, 1 H).

Example 186

3-((2-Amino-1 H-benzorcnimidazol-5-yl)amino)-7-chloro-5-hydroxy-2H-

To a solution of 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 200 mg) and 1 H-benzo[d]imidazole-2,5-diamine (1 14 mg) in fe/ -butanol (10 ml_) stirred under nitrogen at room temperature was added potassium dihydrogen phosphate (105 mg). The reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was concentrated. Water (15 ml_) was added to reaction mixture and stirred for 15 min. The solids were filtered. The crude product was purified by prep-HPLC with a Kromasil Phenyl column and was eluted with a gradient of 10-100% acetonitrile in water with 0.1 % formic acid to obtain the titled compound (53 mg) as a formic acid salt as an off-white solid. LCMS 379.06 m/z (M+H); 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (br s, 1 H), 8.16 (s, 1 H), 7.42 (d, J=1 .8 Hz, 1 H), 7.02-7.24 (m, 2H), 6.98 (d, J=2.0 Hz, 1 H), 6.87 (s, 1 H), 6.34 (br s, 2H).

Example 187

3-((1 H-Benzordiri ,2,31triazol-7-yl)amino)-7-chloro-5-hydroxy-2H- benz ,1 -dioxide

To a stirred solution of 1 H-benzo[d][1 ,2,3]triazol-7-amine (129 mg) in fe/ -butanol (10 ml_) were added 3-bromo-7-chloro-5-hydroxy-2H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (lnt-3, 250 mg) and potassium dihydrogen phosphate (131 mg). The reaction mixture was stirred under nitrogen at 1 10 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The solids were triturated with water (15 mL), filtered, washed with water (3 x 10 mL), and and dried under high vacuum. The crude product was purified by prep- HPLC with an XBRIDGE C-18 column, eluting with a gradient of 10-35% acetonitrile in 10 mM aq ammonium bicarbonate to obtain the titled compound (121 mg) as an off-white solid. LCMS 362.81 m/z (M-H); 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 15.77 (bs, 1 H), 1 1 .62-10.38 (m, 3H), 8.1 1 (bs, 1 H), 7.57-7.43 (m, 2H), 7.21 (d, J=1 .88 Hz, 1 H), 7.08 (d, J=2.15 Hz, 1 H).

Table 1. LCMS Data for Examples

34 379.99 379.98 377.98

35 379.99 379.95 377.98

36 391.94 391.94 389.93

37 391.94 391.97 389.93 389.79

38 360.00 359.97 357.99

39 409.07 409.2 407.06

40 393.08 393.2 391.06

41 379.03 379.2 377.01

42 450.10 450.2 448.08

43 395.06 395.2 393.04

44 391.94 391.9 389.93

45 391.94 391.94 389.93

46 417.01 416.92 414.99

47 360.00 359.89 357.99

48 360.00 359.89 357.99

49 443.03 442.99 441.01

50 363.03 363.2 361.02

51 363.03 363.1 361.02

52 381.02 381.1 379.01

53 363.03 363.1 361.02

54 363.03 363.1 361.02

55 479.03 479.02 477.01

56 443.03 442.95 441.01

57 367.01 366.85 364.99

58 364.02 364.0 362.00

59 415.06 415.01 413.05

60 443.06 443.02 441.04

61 443.06 442.9 441.04

62 364.05 364.0 362.04

63 377.99 377.97 375.98

64 355.03 354.96 353.01

65 367.01 366.91 364.99

66 381.08 381.0 379.06

67 364.03 364.1 362.01

68 417.01 417.03 414.99

69 416.05 416.02 414.03

70 415.06 415.05 413.05

72 360.00 360.0 357.99

73 364.03 364.1 362.01

74 375.03 375.1 373.02

75 378.04 378.2 376.03

76 380.99 380.96 378.97 77 364.03 364.1 362.01

78 377.05 377.1 375.03

79 381 .04 379.03 379.28

80 381 .04 380.96 379.03

81 360.00 359.93 357.99

82 373.98 373.93 371 .96

83 358.01 355.99 355.93

84 356.03 354.01 353.88

85 330.07 329.97 328.05 327.93

86 377.05 377.2 375.03

87 379.03 379.2 377.01

88 364.03 364.2 362.01

89 395.04 395.2 393.02

90 378.04 378.2 376.03

91 364.03 364.2 362.01

92 415.03 415.2 413.01

93 342.01 340.00 339.93

94 374.04 374.2 372.02

95 374.04 374.01 372.02

96 324.05 324.04 322.03

97 324.05 324.0 322.03

98 338.06 338.01 336.05

99 326.04 326.02 324.03

100 342.01 314.97 340.00

101 322.07 322.02 320.05

102 322.07 322.02 320.05

103 338.06 338.04 336.05

104 326.04 325.98 324.03

105 326.04 326.02 324.03

106 348.06 346.04 345.91

107 322.07 321 .98 320.05

108 342.01 341 .97 340.00

109 342.01 342.0 340.00

1 10 347.06 347.04 345.05

1 1 1 463.15 463.07 461 .13

1 12 363.09 363.06 361 .08

1 13 347.06 347.04 345.05

1 14 375.97 376.0 373.96

1 15 391 .94 392.0 389.93

1 16 357.98 358.1 355.97

1 17 397.99 398.2 395.97

1 18 414.98 415.2 412.97 1 19 375.97 376.1 373.96

120 396.99 397.2 394.98

121 397.99 398.2 395.97

122 397.99 398.2 395.97

123 443.90 444.1 441 .88

124 357.98 358.1 355.97

125 342.01 342.1 340.00

126 326.04 326.1 324.03

127 342.01 342.1 340.00

128 385.96 386.0 383.95

129 401 .93 402.0 399.92

130 326.04 326.1 324.03

131 385.96 386.1 383.95

132 419.92 420.1 417.91

133 435.89 436.1 433.88

134 375.97 376.2 373.96

135 342.01 342.1 340.00

136 360.00 360.2 357.99

137 360.00 360.2 357.99

138 357.98 358.1 355.97

139 375.97 376.1 373.96

140 391 .94 392.2 389.93

141 401 .93 402.1 399.92

142 333.05 333.0 331 .03

143 338.04 338.2 336.02

144 359.98 359.86 357.96

145 419.90 420.0 417.88

146 375.95 376.0 373.93

147 341 .99 341 .89 339.97

148 290.06 289.98 288.04

149 338.04 338.0 336.02

150 304.08 304.0 302.06

Example 188 - CD73 Assay Compounds of the invention were assayed for CD73 enzyme inhibitory activity.

Human CD73 catalyzes the conversion of AMP to adenosine. A RapidFire mass spectrometry assay is used to directly measure the formation of adenosine from CD73. Typically 15uL of human flag-CD73 (1 -552, Thr376Ala) in assay buffer (20mM Tris pH 7.5, 25mM NaCI, 1 mM MgCI2, 0.002% Tween-20, 0.5mM DTT, 0.01 mg/ml_ BSA) is added to a 384 well plate containing 300nl_ of test compound in DMSO, serially diluted 1 :3 in an 1 1 point titration. The compound and enzyme are incubated for 10 minutes at room temperature. Next 15uL of AMP in assay buffer is added to the plate. The final concentration of CD73 and AMP in the reaction are 50pM and 20uM respectively. Following a 30 minute reaction at room temperature, the reaction is quenched with 20uL of 0.1 % TFA in water with 2.5uM C13-adenosine internal standard at 2.5 times their final concentration. Adenosine is then detected using a RapidFire/Sciex 4000 Q-Trap RF-MS. The adenosine generated is normalized to the C13-adenosine internal standard. Test compound inhibition is expressed as percent inhibition of internal assay controls and a four parameter curve fit is applied in Activity Base XE to determine the potency of the test compound.

Example 189 - Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table 2, below.

Table 2

INGREDIENTS AMOUNTS

4-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H- 7 mg

benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzonitrile

(Compound of Example 1 )

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg Example 190 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1 .7% by weight of 7-Chloro-5-hydroxy-3-((4-hydroxyphenyl)amino)-2H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Compound of Example 2) in 10% by volume propylene glycol in water.

Example 191 - Tablet Composition

The sucrose, calcium sulfate dihydrate and a CD73 inhibitor as shown in Table 3 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 3

INGREDIENTS AMOUNTS

3-((7-Chloro-5-hydroxy-1 ,1 -dioxido-2H- 12 mg

benzo[e][1 ,2,4]thiadiazin-3-yl)amino)benzonitrile

(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

Those of skill in the art will recognise that the above assay is subject to experimental variability. Accordingly, it is to be understood that the values given below are exemplary only.

Compounds of the invention are tested for activity against CD73 generally according above assay.

All the compounds of the Examples were tested generally according to the above CD73 enzyme assay and in at least one experimental run exhibited a plC50 value from 5 to 8.4 against CD73.

The compounds of Examples 45, 53, 73, 82, 84, 88, 96, 99, 108, 1 15, 1 17, 120, 125, 135, 137, 151 , 155, 168, 172, 177, and 184 were tested generally according to the above CD73 assay and in at least one set of experimental runs exhibited an average plC50 value to≥ 6.5.

The compound of Example 7 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 6.0 against CD73. The compound of Example 39 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 5.5 against CD73. The compound of Example 96 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 7.0 against CD73.

The compound of Example 151 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 7.2 against CD73.

The compound of Example 168 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 7.8 against CD73.

The compound of Example 177 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 7.0 against CD73.

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.