FIELD OF THE INVENTION

The present invention relates to substituted macrocycle 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, the treatment of HIV, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury.

BACKGROUND OF THE INVENTION

Local levels of extracel^Lar adenosine triphosphate (ATP) are acutely elevated as a consequence of infection, tissue injury, ischaemia or intervention-induced tumor cell death. Elevated extracel^Lar ATP is recognized by the immune system as a danger signal to initiate Γτιμίίίρΐβ pro-inflammatory events, including the recruitment of macrophages and dendritic cells. (1) Successive processing of extracel^Lar ATP by the extracel^Lar ectonucleotidases CD73 and CD39 lowers extracel^Lar ATP levels and can rapidly elevate extracel^Lar 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, 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 extracel^Lar adenosine in the tumor microenvironment. Its expression is directly regμLated by HIF1 , consistent with the observed increase in extracel^Lar adenosine under hypoxic conditions. (4) CD73 is overexpressed in Γτιμίίίρΐβ solid tumor types and leukaemias, including aggressive and diff^Lt to treat tumours, such as glioblastoma and ovarian tumours. (5) In patients with head and neck squamous cell carcinoma (HNSCC), cells (T _Reg ) (both cir- 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 Γτιμυίρΐβ 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, 5ΓΤΊ3ΐΙ-η"ΐοΙβομΙ_β inhibitors of CD73 are expected to have the ability to relieve the adenosine-mediated immunosuppression of the tumor microenvironment and alone, or in combination with other agents, provide a treatment for cancer.

Because inhibition of CD73 Γβεμίίε in decreased extracel^Lar adenosine, CD73 inhibitors are also expected to be υεβίμί. for other diseases mediated by adenosine and its action on adenosine receptors. Thus, CD73 inhibitors οομί^ 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)

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 extracel^Lar fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57, 2602- 2605 (1997).

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

5. Stagg, J. & Smyth, M. J. Extracel^Lar 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 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

microenvironments. Clin. Exp. Immunol. 171 , 1 -7 (2013).

9. Sorrentino, R. et al. The adenosinergic system in cancer. Oncolmmunology 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:10.1 155/2012/485156. 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 a pharmaceutical composition that comprises a pharmaceutical carrier and a compound of Forrr^La (I), or a pharmaceutically acceptable salt thereof.

It is also an object of the present invention to provide a method for treating cancer, pre-cancerous syndromes, AIDS, HIV, 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 salicylamide derivatives. Specifically, the invention is directed to compounds according to Forrr^La (I):

wherein R, R1 , P , X, Y, and Z are as defined below; or a pharmaceutically acceptable salt thereof.

The present invention also relates to the discovery that the compounds of Forrr^La (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 Forrr^La (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 Forrr^La (I); or a pharmaceutically acceptable salt thereof.

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

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

The invention also relates to a compound of Forrr^La (I) or a pharmaceutically acceptable salt thereof for use in therapy. The invention also relates to a compound of Forrr^La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

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

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

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

The invention also relates to a compound of Forrr^La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of atherosclerosis.

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

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

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

The invention also relates to the use of a compound of Forrr^La (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 Forrr^La (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 Forrr^La (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 Forrr^La (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 Forrr^La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease state selected from: myocardial infarction, disease, atherosclerosis, οομί,βΓ diseases, and arrhythmias. Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Forrr^La (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 Forrr^La (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 Forrr^La (I) and to the use of compounds of Forrr^La (I) in the methods of the invention:

wherein:

R is selected from:

hydrogen,

fluoro,

chloro,

bromo,

iodo,

-CN,

-N02,

Cl -6alkyl, and

Ci -6alkyl substituted with from 1 to 5 substituents

independently selected from: fluoro, chloro, oxo, Ci -4alkoxy, -OH, -NH2, -NR ⁵ R ⁶ , and -CN;

P is selected from: Ci -3alkyl and Ci -3alkyl substituted from 1 to 4 times by fluoro;

X is selected from:

aryl,

aryl substituted with from one to five substituents independently selected fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl-4alkoxy, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, cycloalkyl,

heteroaryl,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

-CN,

oxo,

-OH,

-OcycloalkyI,

-OcycloalkyI substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-3alkyl, Cl-4alkoxy, -CF3,

heterocycloalkyl, substituted heterocycloalkyl,

-NR ⁵ R ⁶ , and -CN,

-OheterocycloalkyI,

-OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, -CN, Cl-3alkyl, and Cl-3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -4alkoxy, -OH, -NH2, and -CN,

-NO2,

-NR ⁵ R ⁶ ,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

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

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

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

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

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

-SCl -6alkyl,

-SCi -6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, 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 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkoxy, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, 5 cycloalkyl,

heteroaryl,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, 10 oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , -N(H)Cl -4alkyl,

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

-CN,

oxo,

15 -OH,

-OcycloalkyI,

-OcycloalkyI substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-3alkyl, Cl-4alkoxy, -CF3,

20 heterocycloalkyl, substituted heterocycloalkyl,

-NR ⁵ R ⁶ , and -CN,

-OheterocycloalkyI,

-OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo,

25 oxo, -OH, Cl-4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,

Cl-3alkyl, and Cl-3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN, -NO2,

-NR ⁵ R ⁶ ,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

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

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

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

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

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

-SCl -6alkyl,

-SCi -6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, and

-SO2NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents

independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkoxy, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, cycloalkyl,

heteroaryl,

Cl -6alkoxy,

Ci -6alkoxy substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

-CN,

oxo,

-OH,

-Ocycloalkyl,

-Ocycloalkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, Cl -3alkyl, -CF3, heterocycloalkyl, substituted heterocycloalkyl,

-NR ⁵ R ⁶ , and -CN,

-OheterocycloalkyI,

-OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,

Cl -3alkyl, and Cl -3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,

-NO2,

-NR ⁵ R ⁶ ,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, -N(H)C(0)OCl-4alkyl,

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

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

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

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

-SCl -6alkyl,

-SCi -6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, and

-SO2NH2,

Z is absent or 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 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl-4alkoxy, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, cycloalkyl,

heteroaryl,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

-CN,

oxo,

-OH,

-Ocycloalkyl,

-Ocycloalkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -3alkyl, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, -OheterocycloalkyI,

-OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,

Cl -3alkyl, and Cl -3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,

-NO2,

-NR ⁵ R ⁶ ,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , -N(H)Cl -4alkyl,

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

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

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

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

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

-SCl -6alkyl,

-SCi -6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, 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 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkoxy, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, cycloalkyl,

heteroaryl,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , -N(H)Cl -4alkyl,

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

0X0,

-OH,

-Ocycloalkyl,

-Ocycloalkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -3alkyl, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, -OheterocycloalkyI,

-OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, -CN, Cl -3alkyl, and Cl -3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,

-NO2,

-NR ⁵ R ⁶ ,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

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

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

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

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

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

-SCl -6alkyl, -SCi -6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR^RS, and -CN, 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 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkoxy, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, cycloalkyl,

heteroaryl,

Cl -6alkoxy,

Ci -6alkoxy substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁵ R ⁶ , and -CN,

-CN,

oxo,

-OH,

-OcycloalkyI,

-OcycloalkyI substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, Cl -4alkoxy, Cl -3alkyl, -CF3, heterocycloalkyl, substituted heterocycloalkyl,

-NR ⁵ R ⁶ , and -CN,

-OheterocycloalkyI,

-OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,

Cl-3alkyl, and Cl-3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,

-NO2,

-NR ⁵ R ⁶ ,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN,

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

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

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

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

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

-SCl -6alkyl,

-SCi -6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN, and -SO2NH2,

cycloalkyi,

cycloalkyi substituted with one or two substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 9 substituents

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

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

heteroaryl,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 9 substituents

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

-CN,

oxo,

-OH,

-Ocycloalkyl,

-Ophenyl,

-C(0)OC(CH3)3,

-COOH,

-Cl -4alkylOCl -4alkyl,

-NO2,

-NH2,

-N(H)Cl-4alkyl, -N(H)Cl-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,

-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)2cycloalkyl,

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

-SCl -6alkyl,

-SCi -6alkyl substituted with from 1 to 9 substituents

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

-SO2NH2,

heterocycloalkyi, and

heterocycloalkyi substituted with from one to four substituents independently selected from:

fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

C-| -6alkyl substituted with from 1 to 9 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -IMH2, and -CN, Cl -4alkoxy,

-CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2, and

SO2NH2;

Y is a 2 to 18 atom saturated or unsaturated alkylene chain, optionally containing one ring selected from: aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, and optionally containing from 1 to 7 additional heteroatoms independently selected from: O, S, B, P, N ⁺ (Cl -4alkyl)(Cl -4alkyl), and N-R ⁷ , where:

R ⁷ is H, Cl -6alkyl, C3-6cycloalkyl, or -C(0)-R ⁸ ,

wherein R ⁸ is Cl -6alkyl, C3-6cycloalkyl, or aryl; and

R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any εμίΛΐΓ atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, or one or two substituents at any boron atom of said chain Y, or one or two substituents at any phosphorus atom of said chain Y,

wherein said substituents are independently selected from the group consisting of: fluoro, chloro, bromo, iodo, cyano, -NR^RS, Cl -6alkoxy, -OH, oxo, thio, Cl -6thioalkyl, Cl -6alkyl, and

Ci -6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -IMH2, Cl -4alkoxy, -NR ⁵ R ⁶ , and -CN;

where,

R5 and R6 are independently selected from hydrogen and C-| -C4alkyl, or R5 and R6 are taken together with the nitrogen to which they are attached to form a 5 to 6 member heterocyclic ring containing up to one other heteroatom selected from oxygen and nitrogen; or a pharmaceutically acceptable salt thereof.

Suitably, R is selected from:

hydrogen,

fluoro,

chloro,

-CN,

Cl-2alkyl,

Ci-2alkyl substituted from 1 to 3 times by fluoro,

Cl-2alkoxy, and

Ci-2alkoxy substituted from 1 to 3 times by fluoro.

Suitably, X is selected from:

aryl,

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

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH, -Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-Oheterocycloalkyl substituted by -CH2CH3,

-COOH,

-NH2,

-N(H)Cl -4alkyl,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl -4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl -4alkyl,

Cl -4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl -4alkyl,

Ci -4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2, Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-NH2.

Suitably, P is selected from: Ci-2alkyl and Ci -2alkyl substituted one or two times by fluoro.

Suitably, Y is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O,

N ⁺ (CH3)(CH3), and N-R ²⁵ , wherein R ²⁵ is H or Ci-4alkyl.

Suitably, Z is absent or selected from:

aryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3, -COOH, -NH2,

-N(H)Cl-4alkyl,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl-4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-NH2.

Suitably, R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, wherein said substituents are independently selected from the group consisting of: Cl -3alkyl, Cl -3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and

-CN, Cl -3alkoxy, -OH, amino, and oxo.

Suitably, R is hydrogen or chloro. Part^Larly suitably, R is hydrogen. Suitably, P is Ci-3alkyl. Part^Larly suitably, P is Ci-2alkyl.

Suitably, X is selected from:

aryl,

aryl substituted with one or two substituents independently selected from:

chloro,

Ci- ₆ alkyl substituted with from 1 to 4 substituents independently selected from: oxo, d- ₄ alkoxy, -OH and -NR ⁵ R ⁶ ,

Ci_ ₆ alkoxy,

Ci- ₆ alkoxy substituted with -NR ⁵ R ⁶ ,

-OheterocycloalkyI,

-OheterocycloalkyI substituted with Ci_ ₃ alkyl substituted with from 1 or 2 substituents selected from oxo and Ci- ₄ alkoxy,

heteroaryl,

bicycloheteroaryl, and

bicycloheteroaryl substituted with Ci_ ₆ alkyl.

Suitably, X is selected from:

phenyl, nyl substituted with one or two substituents independently selected from: chloro,

Ci- ₆ alkyl substituted with from 1 to 4 substituents independently selected from: oxo, Ci- ₄ alkoxy, -OH and -NR ⁵ R ⁶ ,

Ci_ ₆ alkoxy,

Ci- ₆ alkoxy substituted with -NR ⁵ R ⁶ ,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted with Ci_ ₃ alkyl substituted with from 1 or 2 substituents selected from oxo and Ci- ₄ alkoxy,

6-membered heteroaryl,

bicycloheteroaryl, and

bicycloheteroaryl substituted with Ci_ ₆ alkyl.

Suitably, Z is absent, aryl or heteroaryl. Part^Larly suitably, Z is absent, phenyl, 5- membered heteroaryl or 6-membered heteroaryl.

Suitably, Y is a 2 to 8 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 heteroatoms independently selected from O, N ⁺ (Ci -4alkyl)(Ci -4alkyl) and N-R ⁷ , wherein R ⁷ is H.

Suitably, R ¹ is H, or a substituent which is oxo.

Included in the compounds of the invention and used in the methods of the invention compounds of Forrr^La (II):

wherein:

R ⁰ is selected from:

hydrogen;

fluoro, chloro,

-CN,

-N02,

Cl-3alkyl, and

Ci-3alkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro,

oxo, Cl-4alkoxy, -OH, -NH2, and -CN,

P is selected from: Ci -2alkyl and Ci -2alkyl substituted one or two times by fluoro;

X ¹ is selected from:

aryl,

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

fluoro,

chloro,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -IMH2,

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

-CN,

oxo,

-OH,

-Ocycloalkyl,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3, -Oheterocycloalkyl substituted by -CH2CH3,

-COOH,

-NH2,

-NO2,

-N(H)Cl -4alkyl,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl -4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl -4alkyl,

Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -IMH2, and -CN,

Cl -4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl -6alkyl, Ci-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, 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,

-NO2, and

-NH2,

sent or selected from:

aryl,

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

fluoro,

chloro,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

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

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

heteroaryl,

Cl-6alkoxy,

Ci-6alkoxy substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, oxo, -OH, heterocycloalkyl, substituted heterocycloalkyl, -NH2, -N(H)Cl -4alkyl,

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

-CN,

oxo,

-OH,

-Ocycloalkyl,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-NO2,

-NH2,

-N(H)Cl-4alkyl,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, -IMH2, -N(H)Cl-4alkyl, -N(Cl -4alkyl)2, and -CN, and

-N(Cl-4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, and -CN,

Cl-4alkoxy,

-CN,

oxo,

-OH, -NO2, and

-NH2,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, and -CN, cycloalkyi,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 5 substituents

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

-CN,

oxo,

-OH,

-NO2, and

-NH2,

cycloalkyi,

cycloalkyi substituted with from one to three substituents independently selected from:

fluoro,

chloro,

Cl-3alkyl,

Ci-3alkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, chloro, iodo, oxo, Cl -4alkoxy, -OH, -NH2, and -CN, Cl-3alkoxy,

Ci-3alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, and -CN,

-CN,

oxo,

-OH,

-COOH,

-NO2,

-NH2,

-N(H)Cl-2alkyl,

-N(H)Ci-2alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, -OH, and -CN, and

-N(Cl-2alkyl)2,

heterocycloalkyi, and

heterocycloalkyi substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-3alkyl,

Ci-3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, iodo, oxo, -OH, -NH2, and -CN,

Cl-4alkoxy,

-CN,

oxo,

-OH,

-COOH,

-NO2, and -NH2;

Y is a 2 to 14 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O, S, B, P, N ⁺ (Cl-4alkyl)(Cl-4alkyl), and N-R ⁷ ,

where:

R ⁷ is H, Cl-6alkyl, C3-6cycloalkyl, or -C(0)-R ¹⁸ ,

wherein R ⁸ is Cl-6alkyl, C3-6cycloalkyl, or aryl; and

R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any εμίΛΐΓ atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y,

wherein said substituents are independently selected from the group consisting of: Ci-6alkyl, Ci-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -IMH2, and -CN, Cl-6alkoxy, -OH, amino, oxo, thio, and Ci -6thioalkyl; or a pharmaceutically acceptable salt thereof.

Suitably, R ⁰ is selected from:

hydrogen,

fluoro,

chloro,

-CN,

Cl-2alkyl,

Ci-2alkyl substituted from 1 to 3 times by fluoro,

Cl-2alkoxy, and

Ci-2alkoxy substituted from 1 to 3 times by fluoro. selected from:

aryl,

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

fluoro,

chloro,

Cl -4alkyl,

Ci -4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2,

Cl -4alkoxy,

Ci -4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-Oheterocycloalkyl substituted by -CH2CH3,

-COOH,

-NH2,

-N(H)Cl -4alkyl,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl -4alkyl)2,

heteroaryl,

heteroaryl substituted with from one to three substituents independently selected from: fluoro,

chloro,

Cl-4alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, and -CN,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-IMH2.

Suitably, P is selected from: Ci-2alkyl and Ci-2alkyl substituted one ortwo times by fluoro. Suitably, Y is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O,

N ⁺ (CH3)(CH3), and N-R ²⁵ , wherein R ²⁵ is H or Ci-4alkyl. is absent or selected from:

aryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-COOH,

-NH2,

-N(H)Cl-4alkyl,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl-4alkyl)2,

heteroaryl,

heteroaryl substituted with from one to three substituents independently selected from: fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-IMH2.

Suitably, R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, wherein said substituents are independently selected from the group consisting of: Cl-3alkyl, Cl-3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and -CN, Cl -3alkoxy, -OH, amino, and oxo.

Suitably, R ¹⁰ is hydrogen or chloro. Part^Larly suitably, R ¹⁰ is hydrogen. Suitably, P ¹ is Ci-3alkyl. Part^Larly suitably, P ¹ is Ci-2alkyl.

Suitably, X ¹ is selected from:

aryl,

aryl substituted with one or two substituents independently selected from:

chloro,

Ci- ₆ alkyl substituted with from 1 to 4 substituents independently selected from: oxo, d- ₄ alkoxy, -OH and -NR ⁵ R ⁶ ,

Ci_ ₆ alkoxy,

Ci- ₆ alkoxy substituted with -NR ⁵ R ⁶ ,

-Oheterocycloalkyl,

heteroaryl,

bicycloheteroaryl, and

bicycloheteroaryl substituted with Ci_ ₆ alkyl. Suitably, X ¹ is selected from:

phenyl,

phenyl substituted with one or two substituents independently selected from: chloro,

Ci- ₆ alkyl substituted with from 1 to 4 substituents independently selected from: oxo, Ci- ₄ alkoxy, -OH and -NR ⁵ R ⁶ ,

Ci_ ₆ alkoxy,

Ci- ₆ alkoxy substituted with -NR ⁵ R ⁶ ,

-Oheterocycloalkyl,

6-membered heteroaryl,

bicycloheteroaryl, and

bicycloheteroaryl substituted with Ci_ ₆ alkyl.

Suitably, Z ¹ is absent, aryl or heteroaryl. Part^Larly suitably, Z ¹ is absent, phenyl, 5- membered heteroaryl or 6-membered heteroaryl. Suitably, Y ¹ is a 2 to 8 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 heteroatoms independently selected from O, N ⁺ (Ci-4alkyl)(Ci-4alkyl) and N-R ¹⁷ , wherein R ¹⁷ is H.

Suitably, R ¹¹ is H, or a substituent which is oxo.

Included in the compounds of the invention and used in the methods of the invention are compounds of Forrr^La (III):

wherein:

R is selected from:

hydrogen,

fluoro,

chloro,

-CN,

Cl-2alkyl,

Ci-2alkyl substituted from 1 to 3 times by fluoro,

Cl-2alkoxy, and

Ci-2alkoxy substituted from 1 to 3 times by fluoro;

selected from: Ci -2alkyl and Ci -2alkyl substituted one or two times by fluoro; selected from:

aryl,

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

fluoro,

chloro, Cl -4alkyl,

Ci -4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2,

Cl -4alkoxy,

Ci -4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-Oheterocycloalkyl substituted by -CH2CH3,

-COOH,

-NH2,

-N(H)Cl -4alkyl,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl -4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl -4alkyl,

Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, and -CN,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-NH2;

sent or selected from:

aryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy, Ci-4alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-COOH,

-NH2,

-N(H)Cl-4alkyl,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and

-N(Cl-4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro, Cl -4alkyl,

Ci -4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl -4alkoxy,

Ci -4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-NH2;

Y ² is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O, N ⁺ (CH3)(CH3), and N-R ²⁵ , wherein R ²⁵ is H or Ci -4alkyl;

R ² is H, or one or two substituents at any carbon atom of said chain Y ² , or one or two substituents at any nitrogen atom of said chain Y ² ,

wherein said substituents are independently selected from the group consisting of: Ci -3alkyl, Ci -3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and -CN, Cl -3alkoxy, -OH, amino, and oxo; or a pharmaceutically acceptable salt thereof.

Suitably, R' is selected from:

hydrogen,

fluoro,

chloro,

-CN,

Cl -2alkyl, Ci -2alkyl substituted from 1 to 3 times by fluoro,

Cl -2alkoxy, and

Ci -2alkoxy substituted from 1 to 3 times by fluoro.

Suitably, X ² is selected from:

aryl,

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

fluoro,

chloro,

Cl -4alkyl,

Ci -4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, Cl -4alkoxy,

Ci -4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3,

-Oheterocycloalkyl substituted by -CH2CH3,

-COOH,

-IMH2,

-N(H)Cl -4alkyl,

-N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and -N(Cl-4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl-4alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, and -CN,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo, -OH, and

-NH2.

Suitably, P ² is selected from: Ci-2alkyl and Ci-2alkyl substituted one ortwo times by fluoro.

Suitably, Y is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O, N ⁺ (CH3)(CH3), and N-R ²⁵ , wherein R ²⁵ is H or Ci-4alkyl. Suitably, Z ² is absent or selected from:

aryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, oxo,

-OH,

-Oheterocycloalkyl,

-Oheterocycloalkyl substituted by -C(0)OC(CH3)3, -COOH,

-NH2,

-N(H)Cl-4alkyl,

-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and -N(Cl-4alkyl)2,

heteroaryl,

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

fluoro,

chloro,

Cl-4alkyl,

Cl-4alkoxy,

oxo,

-OH,

-COOH, and

-NH2,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to three substituents

independently selected from:

fluoro,

chloro,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 3 substituents

independently selected from: fluoro, chloro, oxo, -OH, and -IMH2,

Cl-4alkoxy,

Ci-4alkoxy substituted with from 1 to 3 substituents

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

oxo,

-OH, and

-IMH2. Suitably, R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, wherein said substituents are independently selected from the group consisting of: Cl -3alkyl, Cl -3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and

-CN, Cl -3alkoxy, -OH, amino, and oxo.

Suitably, R ²⁰ is hydrogen or chloro. Part^Larly suitably, R ²⁰ is hydrogen. Suitably, P ² is d- ₃ alkyl. Part^Larly suitably, P ² is Ci_ ₂ alkyl.

Suitably, X ² is selected from:

aryl,

aryl substituted with one or two substituents independently selected from:

chloro,

Ci- ₄ alkyl substituted with from 1 to 4 substituents independently selected from: oxo, Ci_ ₄ alkoxy, -OH and -NR ⁵ R ⁶ ,

Ci- ₄ alkoxy,

Ci. ₄ alkoxy substituted with -NR ⁵ R ⁶ ,

-Oheterocycloalkyl,

heteroaryl,

bicycloheteroaryl, and

bicycloheteroaryl substituted with Ci_ ₄ alkyl. Suitably, X ² is selected from:

phenyl,

phenyl substituted with one or two substituents independently selected from: chloro,

Ci- ₄ alkyl substituted with from 1 to 4 substituents independently selected from: oxo, Ci- ₄ alkoxy, -OH and -NR ⁵ R ⁶ ,

Ci_ ₄ alkoxy,

Ci_ ₄ alkoxy substituted with -NR ⁵ R ⁶ ,

-Oheterocycloalkyl, 6-membered heteroaryl,

bicycloheteroaryl, and

bicycloheteroaryl substituted with Ci_ ₄ alkyl.

Suitably, Z ² is absent, aryl or heteroaryl. Part^Larly suitably, Z ² is absent, phenyl, 5- membered heteroaryl or 6-membered heteroaryl.

Suitably, Y ² is a 2 to 8 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 heteroatoms independently selected from O, N ⁺ (Ci -4alkyl)(Ci -4alkyl) and N-R ¹⁷ , wherein R ¹⁷ is H.

Suitably, R ²¹ is H, or a substituent which is oxo.

Included in the compounds of the invention and used in the methods of the invention compounds of Forrr^La (IV):

wherein:

X ³ is selected from:

phenyl,

phenyl substituted by chloro,

phenyl substituted by methoxy,

phenyl substituted by -C(0)NH2,

phenyl substituted by -OCH(CH3)2,

phenyl substituted by -Opyrrolidine,

phenyl substituted by -OCH2CH2NH2,

phenyl substituted by -OCH2CH2N(CH3)2, phenyl substituted by -OpyrrolidineC(0)OC(CH3)3, indolyl, and

indolyl substituted by -CH2CH3,

Z ³ is absent or selected from:

phenyl, and

thiophenyl;

Y ³ is a 2 to 7 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 additional heteroatoms independently selected from: O, N ⁺ (CH3)(CH3), and N-H,

R ³ is H, or one or two substituents at any carbon atom of said chain Y ³ , or one or two substituents at any nitrogen atom of said chain Y ³ ,

wherein said substituents are independently selected from the group consisting of: -CH3, and oxo; or a pharmaceutically acceptable salt thereof.

Suitably, X ³ is selected from:

phenyl,

phenyl substituted by chloro,

phenyl substituted by methoxy,

phenyl substituted by -C(0)NH2,

phenyl substituted by -OCH(CH3)2,

phenyl substituted by -Opyrrolidine,

phenyl substituted by -OCH2CH2NH2, phenyl substituted by -OCH2CH2N(CH3)2,

phenyl substituted by -OpyrrolidineC(0)OC(CH3)3,

indolyl, and

indolyl substituted by -CH2CH3, Suitably, Z ³ is absent or selected from:

phenyl, and

thiophenyl. Suitably, Y is a 2 to 7 atom saturated or unsaturated alkylene chain optionally containing

1 or 2 additional heteroatoms independently selected from:

O, N ⁺ (CH3)(CH3), and N-H.

Suitably, R ³ is H, or one or two substituents at any carbon atom of said chain Y ³ , or one or two substituents at any nitrogen atom of said chain Y ³ , wherein said substituents are independently selected from the group consisting of: -CH3, and oxo.

While aspects for each variable have generally been listed above separately for each variable, this invention includes those compounds in which several of each aspect in Forrr^La (I) is selected from each of the aspects listed above. Therefore, this invention is intended to include all combinations of aspects for each variable.

Included in the presently invented compounds of Forrr^La (I) are:

(18E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4(9),5,7, 12, 14, 16(26), 18,21 ,23-decaene- 6-carboxamide;

7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa- 1 (25),4(9),5,7,12,14,16(26),21 ,23-nonaene-6-carboxamide;

7-hydroxy-3,3-dioxo-18-oxa-3A ⁶ -thia-2,10- diazatetracyclo[18.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]pentacosa-1 (24),4(9),5,7, 12,14, 16(25),20,22-nonaene-6- carboxamide;

7-hyd roxy-3 , 3 , 18-trioxo-3A ⁶ -th ia-2 , 10 , 19- triazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8, 12,14, 16(26),21 , 23-nonaene-6- carboxamide; 7-hydroxy-3,3-dioxo-18-oxa-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa-1 (25),4(9),5,7, 12,14, 16(26),21 , 23-nonaene-6- carboxamide;

(17E)-7-hydroxy-3,3-dioxo-3A ⁶ ,13-dithia-2,10- diazatetracyclo[18.3.1 .1 ¹² , ^l5 .0 ⁴ , ⁹ ]pentacosa-1 (24), 4(9), 5, 7,12(25), 14,17,20,22-nonaene-6- carboxamide;

(18E)-24-ethyl-7-hyd roxy-3,3-d ioxo-3A ⁶ -th ia-2, 10,25- triazapentacyclo[19.6.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ .0 ²² , ²⁶ ]nonacosa-1 (28),4,6, 8, 12(29), 13, 15, 18,21 , 23,26- undecaene-6-carboxamide;

(19E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[20.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]heptacosa-1 (26),4(9),5,7, 12, 14, 16(27), 19,22,24- decaene-6-carboxamide;

(18E)-7-hydroxy-3,3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (24),4,6,8, 12,14,16(26), 18,21 (25),22- decaene-6-carboxamide;

(18Z)-7-hydroxy-3,3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (24),4,6,8, 12,14,16(26), 18,21 (25),22- decaene-6-carboxamide;

7-hydroxy-3,3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8,12,14,16(26),21 ,23-nonaene-6- carboxamide;

(18Z)-7-hydroxy-22-methoxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8,12,14,16(26),18,21 ,23-decaene-6- carboxamide;

(18E)-7-hydroxy-22-methoxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8,12,14,16(26),18,21 ,23-decaene-6- carboxamide;

(18E)-22-chloro-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8,12,14,16(26),18,21 ,23-decaene-6- carboxamide;

(16E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide; (16Z)-7-hydroxy-3, 3-d ioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide;

(18E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10,23- triazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8, 12, 14, 16(26), 18,21 ,23-decaene-6- carboxamide;

(18E)-22-[2-(dimethylamino)ethoxy]-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6,8,12,14,16(26),18,21 ,23-decaene-6- carboxamide;

(18E)-7-hyd roxy-3 , 3-d ioxo-3A ⁶ -th ia-2 , 10 , 14- triazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (25),4(9),5,7,12,14,16(26),18,21 ,23-decaene- 6-carboxamide;

7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10,13,15,25- pentaazatetracyclo[18.3.1 .1 ¹² , ¹⁵ .0 ⁴ , ⁹ ]pentacosa-1 (24),4(9),5,7,12(25), 13,17,20,22- nonaene-6-carboxamide; (E and Z forms)

(16E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-

1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide;

(16Z)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide;

(16E)-7-hydroxy-3,3-dioxo-14-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide;

(16Z)-7-hydroxy-3, 3-d ioxo-14-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide;

6-carbamoyl-7-hydroxy-18,18-dimethyl-3, 3-dioxo-3A ⁶ -thia-2, 10,18-triazatetracyclo- [19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa-1 (24), 4, 6, 8,12(26), 13,15,21 (25),22-nonaen-18-ium;

(E)-14-(2-(dimethylamino)ethoxy)-44-hydroxy-8-oxa-3-thia-2,5 -diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-45-carboxamide 3,3-dioxide;

(15Z)-7-hydroxy-3,3-dioxo-13,18-dioxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (23),4,6,8,15,19,21 -heptaene-6-carboxamide;

(15E)-7-hydroxy-3,3-dioxo-13,18-dioxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (23),4,6,8,15,19,21 -heptaene-6-carboxamide; 7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[16.3.1 .0 ⁴ , ⁹ ]docosa- 1 (22),4,6,8,15,18,20-heptaene-6-carboxamide; (E and Z forms)

14-(2-(dimethylamino)ethoxy)-44-hydroxy-8-oxa-3-thia-2,5-dia za-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphane-45-carboxamide 3,3-dioxide;

(16E)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,23- triazatetracyclo[17.6.1 .0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4,6,8, 16, 19,21 ,24-octaene-6- carboxamide;

7-hydroxy-3,3-dioxo-13,18-dioxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (23),4,6,8,19,21 -hexaene-6-carboxamide;

(16E)-7-hydroxy-3,3-dioxo-14-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-

1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide;

7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,19(23),20-hexaene-6-carboxamide;

7-hydroxy-3,3,18-trioxo-13-oxa-3A ⁶ -thia-2,10,17,23- tetraazatetracyclo[17.6.1 .0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4(9),5,7,19,21 ,24-heptaene-6- carboxamide;

7-hyd roxy-3 , 3 , 17-trioxo- 13-oxa-3A ⁶ -th ia-2 , 10 , 16 ,22- tetraazatetracyclo[16.6.1 .0 ⁴ , ⁹ .0 ^l9 , ²³ ]pentacosa-1 (25),4(9), 5,7,18,20,23-heptaene-6- carboxamide;

(E)-14-(2-aminoethoxy)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-t1 1 -ene-45-carboxamide 3,3-dioxide;

tert-butyl (E)-3-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2,5 -diaza- 1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1 -en-14-yl)oxy)pyrrolidine-1 -carboxylate; tert-butyl 3-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2,5-dia za- 1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphane-14-yl)oxy)pyrrolidine-1 -carboxylate;

(E)-44-hydroxy-14-(pyrrolidin-3-yloxy)-8-oxa-3-thia-2,5-diaz a-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-45-carboxamide 3,3-dioxide;

14-(2-aminoethoxy)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphane-45-carboxamide 3,3-dioxide;

44-hydroxy-14-(pyrrolidin-3-yloxy)-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphane-45-carboxamide 3,3-dioxide; 7-hyd roxy-3 , 3-d ioxo- 13-oxa-3A ⁶ -th ia-2 ,10,18- triazatetracyclo[16.5.2.0 ⁴ , ⁹ .0 ²¹ , ^2S ]pentacosa-1 (24),4,6,8, 19,21 (25),22-heptaene-6- carboxamide;

(15E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18- triazatetracyclo[16.5.2.0 ⁴ ' ⁹ .0 ²¹ ' ²⁵ ]pentacosa-1 (24),4,6,8,15,19,21 (25),22-octaene-6- carboxamide;

(15Z)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -th ia-2, 10,18- triazatetracyclo[16.5.2.0 ⁴ , ⁹ .0 ^{21 <} 25]pentacosa-1 (24),4,6,8, 15, 19,21 (25),22-octaene-6- carboxamide;

7-hydroxy-3,3-dioxo-13,17-dioxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-

1 (23),4(9),5,7,19,21 -hexaene-6-carboxamide;

(E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotetradecaphan-1 1 -ene-45-carboxamide 3,3-dioxide;

44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotetradecaphane- 45-carboxamide 3,3-dioxide;

44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphane- 15,45-dicarboxamide 3,3-dioxide;

(16E)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,23- triazatetracyclo[17.6.1 .0 ⁴ ' ⁹ .0 ²⁰ ' ²⁴ ]hexacosa-1 (26),4,6,8,16,19,21 ,24-octaene-6- carboxamide;

(16Z)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,23- triazatetracyclo[17.6.1 .0 ⁴ ' ⁹ .0 ²⁰ ' ²⁴ ]hexacosa-1 (26),4,6,8,16,19,21 ,24-octaene-6- carboxamide;

22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2, 10,23- triazatetracyclo[17.6.1 .0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4,6,8, 19,21 , 24-heptaene-6- carboxamide;

7-hydroxy-3,3-dioxo-13,16-dioxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (23),4(9),5,7,19,21 -hexaene-6-carboxamide; 7-hyd roxy-3 , 3-d ioxo- 13-oxa-3A ⁶ -th ia-2 ,10,18- triazatetracyclo[16.5.2.0 ⁴ , ⁹ .0 ²¹ , ²⁵ ]pentacosa-1 (23),4(9),5,7,19,21 ,24-heptaene-6- carboxamide; trifluoroacetic acid;

(15E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18- triazatetracyclo[16.5.2.0 ⁴ , ⁹ .0 ²¹ , ²⁵ ]pentacosa-1 (23),4(9),5,7,15,19,21 ,24-octaene-6- carboxamide; trifluoroacetic acid;

(16Z)- and (16E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[18.3.1 .0 ⁴ , ⁹ ]tetracosa-1 (24),4(9),5,7,16,20,22-heptaene-6-carboxamide;

(16Z)- and (16E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,16,19(23),20-heptaene-6,21 -dicarboxamide; methyl (16Z)- and (16E)-6-carbamoyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,16,19(23),20-heptaene-21 -carboxylate;

(16Z)- and (16E)-6-carbamoyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2, 10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4(9),5,7,16,19(23),20-heptaene-21 -carboxylic acid; methyl 6-carbamoyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6, 8, 19(23),20-hexaene-21 -carboxylate;

6- carbamoyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4(9),5,7,19(23),20-hexaene-21 -carboxylic acid;

7- hydroxy-N21 -methyl-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,19(23),20-hexaene-6,21 -dicarboxamide; and

7-hydroxy-21 -(hydroxymethyl)-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (23),4(9),5,7,19,21 -hexaene-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

The skilled artisan will appreciate that pharmaceutically acceptable salts, of the compounds according to Forrr^La (I) may be prepared. Indeed, in certain embodiments of the invention pharmaceutically acceptable salts of the compounds according to Forrr^La (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 Forrr^La (I). The invention is further directed to free or unsalted compounds of Forrr^La (I). The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art. Typically, the salts of the present invention are pharmaceutically acceptable salts.

Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, οβηζβηβεμί-ίοηβίβ (besylate), benzoate, bitartrate, butyrate, calcium edetate, camphorate, campho^Lfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecy^Lfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl εμίίβίβ), ethane-1 (edisylate), βίηβηβεμΙ-ίοηβίβ (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (A/,A/'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, ηΊβίΐΊβηβεμΙ-ίοηβίβ (mesylate), (napadisylate), naphthalene-2^Lfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p- aminobenzenesμLfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, pe^Lfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, -ίοΐυβηβεμίίοηβίβ (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, εμΙ-ίβΓΤΐβίβ, εμίίβίβ, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate. Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (/V-benzylphenethylamine), benzathine (Λ/,Λ/'- dibenzylethylenediamine), Jb; ^' s-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl-2-pyrrolildine-1 '-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (/V-methylglucamine), piperazine, piperidinyl, potassium, procaine, quinine, quinoline, sodium, strontium, t- butylamine, and zinc.

The compounds according to Forrr^La (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 Forrr^La (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 Forrr^La (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically or diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers.

The compounds according to Forrr^La (I) and pharmaceutically acceptable salts thereof may contain isotopically-labelled compounds, which are identical to those recited in Forrr^La (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, εμί-ρΐΊυΓ, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251. Isotopically-labelled compounds, for example those into which radioactive isotopes such as 3H or 14C are incorporated, are υεβίμί. in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are part^Larly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are part^Larly υεβίμί. in PET (positron emission tomography), and 1251 isotopes are part^Larly υεβίμί. in SPECT (single photon emission computerized tomography), both are υεβίμί. in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds according to Forrr^La (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Forrr^La (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 Forrr^La (I) whether such tautomers exist in equilibrium or predominately in one form.

The compounds of the invention may exist in solid or liquid form. In solid form, compound of the invention may exist in a continuum of solid states ranging from fyUy amorphous to fyUy crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the ΓηοΙβομΙ-βΓ level and, depending upon the temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a ordered internal structure at the ΓηοΙβομΙ-βΓ level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid , but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').

The compounds of the invention may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism ("polymorphs"). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also Γβεμί-ί from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility and melting point. The compounds of Forrr^La (I) may exist in solvated and unsolvated forms. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Forrr^La (I) or a salt) and a solvent. Such solvents, for the purpose of the invention, may not interfere with the biological activity of the solute. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent ΊθΙβομΙ-βε are incorporated into the crystalline lattice during crystallization . The incorporated solvent ΊθΙβομΙ-βε may be water ΊθΙβομΙ-βε or non-aqueous such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate ΊθΙβομΙ-βε. Crystalline lattice incorporated with water ΊθΙβομΙ-βε are typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

It is also noted that the compounds of Forrr^La (I) may form tautomers. Tautomers' refer to compounds that are interchangeable forms of a part^Lar compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention are included within the scope of the compounds of the present invention.

While aspects for each variable have generally been listed above separately for each variable this invention includes those compounds in which several or each aspect in Forrr^La (I) is selected from each of the aspects listed above. Therefore, this invention is intended to include all combinations of aspects for each variable.

DEFINITIONS

"Alkyl" refers to a hydrocarbon chain having the specified number of "member atoms". For example, C-1 -C5 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, ethylenyl, propyl (n-propyl and isopropyl), butenyl, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl, heptenyl. "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, t-butoxy, butoxypropanyl, propoxyethyl, butoxyethyl, ethoxyethyl,

but-3-enyloxyethyl, isopentyloxyethyl, isobutoxyethyl, propoxypropyl, methoxyethyl, allyloxyethyl, allyloxypropyl, pentyloxyethyl, prop-2-enyloxypropyl, prop-2-enyloxyethyl.

"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, dihydroindene, naphthalene, tetrahydronaphthalene. Suitably aryl is phenyl. "Bicycloheteroaryl" refers to two fused ring systems, 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]pyridinyl, 1 /-/-pyrrolo[2,3-Jb]pyridinyl, 1 H-pyrazolo[4,3- c]pyridinyl, 1 H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, furo[2,3- d]pyrimidinyl, 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]pyridinyl, imidazo[1 ,2-a]pyridinyl, furopyridinyl, napthyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, benzothiazolyl, benzoimidazolyl, benzodiazolyl, quinolinyl, quinoxalinyl, dihydrobenzodioxinyl, dihydrobenzodioxol, isoindolinyl, indazolyl and indolinyl.

Suitably "Bicycloheteroaryl" includes: 1 /-/-pyrrolo[2,3-Jb]pyridine, benzimidazolyl, benzothienyl, imidazo[1 ,2-a]pyridinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydrobenzodioxol, indazolyl and indolinyl. Suitably "Bicycloheteroaryl" includes indolinyl, indazolyl, benzimidazolyl, and benzothienyl.

"Cycloalkyi", unless otherwise defined, refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyi groups are monocyclic ring systems. For example, C3-C7 cycloalkyi refers to a cycloalkyi group having from 3 to 7 member atoms. Examples of cycloalkyi as used herein include but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitably cycloalkyi is selected from: cyclopropyl, cyclopentyl and cyclohexyl.

"Heterocycloalkyl", unless otherwise defined, refers to a saturated or unsaturated non- aromatic monocyclic ring system containing 4 to 8 member atoms, of which 1 to 7 are carbon atoms and from 1 to 4 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, and azetidinyl. Suitably, "Heterocycloalkyl" includes: pyrrolidinyl, tetrahydropyranyl, oxazolidinyl, piperidinyl, and azetidinyl. Suitably, "Heterocycloalkyl" is: pyrrolidinyl.

"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 is pyrazolyl. "Heteroatom" refers to a nitrogen, εμίρΐιυτ or oxygen atom.

"Substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has from one to six substituents, suitably from one to three substituents, suitably from one or two substituents, selected from the group consisting of: fluoro, chloro, bromo, iodo, Cl -6alkoxy, -CN, oxo, -OH, Cl -6alky, -COOH, -NO2, -NH2, CH2F, -CHF2, trifluoromethyl, C-| -C4alkylamino, and diC-| -C4alkylamino.

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);

AC2O (acetic anhydride);

ACN (acetonitrile);

AIBN (azobis(isobutyronitrile));

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

BMS (borane - dimethyl complex);

Bn (benzyl);

Boc (tert-Butoxycarbonyl);

B0C2O (di-fe/ -butyl dicarbonate);

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

CAN (cerric ammonium nitrate);

Cbz (benzyloxycarbonyl);

CSI (οηΙοηοεμϋΐ^Ι isocyanate); CSF (cesium fluoride);

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

DAST (Diethylamino)spLfur 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 (dimethylspLfoxide);

DPPA (diphenyl phosphoryl azide);

EDC (A/-(3-dimethylaminopropyl)-A/'ethylcarbodiimide) hydrochloride salt;

EDTA (ethylenediaminetetraacetic acid);

EtOAc (ethyl acetate); EtOH (ethanol);

Et ₂ 0 (diethyl ether);

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

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

HOBt (1 -hydroxybenzotriazole);

HOAc (acetic acid);

HPLC (high pressure liquid chromatography);

HMDS (hexamethyldisilazide);

Hunig's Base (/V,/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 liguid 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 agueous solution of NaCI.

COMPOUND PREPARATION

The compounds according to Forrr^La (I) are prepared using conventional organic synthetic methods. A suitable synthetic route is depicted below in the following general reaction scheme. 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 seguence 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 υεβίμί. as an intermediate compound or is a desired substituent in a target compound.

As used in Scheme 1 below, r, r , r ² , r ³ , r ⁴ and r ⁵ represents all corresponding positional combinations on all of the Forrr^Las disclosed herein. For example, r, r , r ² , r ³ , r ⁴ and r ⁵ represent R, R ¹ , P, X, Y and Z of Forrr^La (I).

General procedure for the preparation of salicylamide spLfonamides (A3)

The general procedure for preparation of salicylamide (A3) is shown in Scheme 1 below. Salicylamide-5^Lfonyl chlorides (A1) are conveniently prepared by chlorosμLfonylation of salicylamides with οηΙθΓοεμΙ-ίοηίο acid. Salicylamides are either dissolved in a mixture of οηΙθΓοεμΙ-ίοηίο acid and thionyl chloride at 0 °C, allowed to warm to RT and stirred overnight, or dissolved in excess οηΙθΓοεμΙ-ίοηίο acid at RT and stirred at 55 °C overnight. Quenching the reaction by οβΓβίμί. addition of the reaction mixture to ice water affords the sμLfonyl chloride as a solid, which can be collected by filtration, washed, dried, and used without further purification.

The salicylamide chloride

(A1) with an appropriate arylamine in pyridine, DCM, a mixture of DCM and pyridine, or a mixture of pyridine in a non-reactive alcohol (n-butanol or fe/ -butanol). Extractive workup followed by precipitation from water or dilute HCI solution affords the crude salicylamide

(A2) which can be collected by filtration, washed, dried, and used without further purification. Alternatively, an extractive workup followed by silica gel column chromatography or preparative HPLC as necessary affords the purified salicylamide

The salicylamide (A3) can be prepared by displacement of Xi , where Xi is a halogen, by treating the salicylamide (A2) with an appropriate amine in ethanol, 1 -butanol, a mixture of 1 -butanol and TEA, or a mixture of 1 -butanol and DIEA followed by heating under microwave irradiation. Alternatively, salicylamide

(A3) can be prepared through metal-mediated cross-coupling, where Xi is a halogen, by treating the salicylamide (A2) with an appropriate amine in DMSO with L- proline, copper(l) iodide and K ₃ P0 ₄ under microwave irradiation. Extractive workup of the displacement products followed by silica gel column chromatography or preparative HPLC as necessary affords the desired salicylamide (A3).

General procedures for the preparation of macrocycles (A4) Macrocycles (A4) can be prepared by the ring-closing metathesis reaction of terminal olefin-containing r an r1 groups within compounds (A3). These bis-olefins (A3) are dissolved in a solvent, such as DCM, ethyl acetate, isopropanol and treated with a catalyst such as (1 ,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylp hosphine)ruthenium or [1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 - oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (also known as GreenCat) and stirred at room temperature or with heating. Extractive workup of the ring-closed products followed by silica gel column chromatography or preparative HPLC as necessary affords the desired macrocycles (A4).

Unsaturated macrocycles so produced can be optionally reduced by hydrogenation with hydrogen gas over an appropriate catalyst such as Pd-on-C in a suitable solvent such as ethanol, methanol, AcOH or ethyl acetate. Filtration to remove catalyst followed by silica gel column chromatography or preparative HPLC as necessary affords the desired saturated macrocycles (A4).

cyclization

A4

Alternatively, Scheme 2, a salicylamide sμLfonamide (A5) containing a protected primary amine can be deprotected, for example when P = BOC by treatment with an appropriate acid such as HCI or TFA in a solvent such as DCM or 1 ,4-dioxane. Alternatively, when P = phthalimide by treatment with hydrazine hydrate in ethanol. The primary amine is then dissolved in ethanol, 1 -butanol, a mixture of 1 -butanol and TEA, or a mixture of 1 -butanol and DIEA followed by heating under microwave irradiation. Extractive workup of the ring-closed products followed by silica gel column chromatography or preparative HPLC as necessary affords the desired macrocycles (A6).

Alternatively, Scheme 3, macrocycles (A9) can be prepared by the amide bond formation reaction of r an r1 groups within compounds (A7) or (A8), one of which is a primary or secondary amine and the other containing a carboxylic acid. These amino acids (A3) are dissolved in a solvent, typically DMSO, DCM or DMF and treated with a coupling agent such as DCC, EDC, HATU and a base such as DIEA and stirred at room temperature. Extractive workup of the coupled products followed by silica gel column chromatography or preparative HPLC as necessary affords the desired macrocyclic amides (A4).

Scheme 3

Methods of Use

The compounds according to Forrr^La (I) and pharmaceutically acceptable salts thereof are inhibitors of CD73. These compounds are potentially υεβίμί. 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.

Suitably, the present invention relates to a method for treating breast cancer, including inflammatory breast cancer, ductal carcinoma, and 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 ίηεμϋηοηιβε, 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 gland, 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, νμΙ-va, 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 rr^Ltiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma,

head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, ίηεμϋηοηιβ, 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, ηιμυίρΐβ myeloma, megakaryoblastic leukemia, ηιμυίρΐβ myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non- Hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, foll^Lar lymphoma, neuroblastoma, bladder cancer, urothelial cancer, νμΙ-val cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocel^Lar cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and test^Lar 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 intraepithelial (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 viral vaccines, and cancer vaccines such as GV AX® 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 stirr^Late 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 stirr^Late 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 part^Lar infections caused by pathogens that exploit ectonucleotidases 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, 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, ηιμυίρΐβ sclerosis, diabetes, type II diabetes, diabetes mellitus, ίηεμϋη resistance, risk of diabetes, epilepsy, asthma, chronic obstructive ρμΙ-ΓΤΐοηβίγ disease (COPD), fibrosis, dermal fibrosis, hepatic fibrosis, liver fibrosis, ρμΙ-ΓΤΐοηβίγ fibrosis, idiopathic ρμΙ-ΓΤΐοηβίγ 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 οβρεμϋίίε, 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 ίηεμϋη resistance, diabetes and risk of diabetes. In some embodiments, compounds of the invention are used to reduce ίηεμϋη 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, stirr^Lating, enhancing, promoting, inducing or activating in the subject ίηεμϋη 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 a safe and effective amount of a compound of Forrr^La (I), or a pharmaceutically acceptable salt thereof to a mammal, suitably a human, in need thereof. As used herein, "treat", and derivatives thereof, in reference to a condition means:

(1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The term "treating" and derivatives thereof refers to therapeutic therapy. Therapeutic therapy is appropriate to alleviate symptoms or to treat at early signs of disease or its progression.

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.

The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "safe and effective amount" in reference to a compound of Forrr^La (I), or a pharmaceutically acceptable salt thereof, means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of the compound will vary with the part^Lar route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan. As used herein, "subject", "patient", and derivatives thereof refers to a human or other mammal, suitably a human.

The subject to be treated in the methods of the invention is typically a mammal in need of such treatment, preferably a human in need of such treatment.

The compounds of Forrr^La (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, ίηίΓβΓηυεομΙ-βΓ, and subcutaneous injection or infusion.

The compounds of Forrr^La (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. Typical daily dosages may vary depending upon the part^Lar route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose. Preferred dosages are 1 - 500 mg once daily or twice a day per person.

Additionally, the compounds of Forrr^La (I) or pharmaceutically-acceptable salts thereof may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other diff^Lty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, ethers, esters, carbonates, and carbamates, are well known to those skilled in the art. 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 Forrr^La (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be υεβίμί. in the treatment of cancer or pre-cancerous syndromes.

By the term "co-administration" as used herein is meant either sirr^Ltaneous 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 υεβίμί. 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 sirr^Ltaneous, 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 υεβίμί. in the present invention include, but are not limited to, anti-micro ^Le agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alky^Lfonates, 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.

"Chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostirr^Lants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc. ), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti- VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc. ), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to In, ⁹⁰ Y, or ³ 1, etc. ). In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as ⁴⁷ Sc, ⁶⁴ C ⁶⁷ C, ⁸⁹ Sr, ⁸⁶ Y, ⁸⁷ Y, and ^{2 2} Bi, optionally conjugated to antibodies directed against tumor antigens.

Anti-microti^Le or anti-mitotic agents are phase specific agents active against the microti^Les of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microti^Le 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-^μϋη subunit of the microti^Les, 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 1 3-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 ^Lin. Consequently, the bound ^Lin ηιοΙβομΙ_β is unable to polymerize into 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 εμίίβίβ, 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 test^Lar 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-οχο-, εμίίβίβ, 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 myelosuppression 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, part^Larly 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 test^Lar 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 ηιοΙβομΙ_β such as phosphate, amino, εμί-ίΙ^ΓγΙ, 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 εμίίοηβίβε such as busμLfan; 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, ηιμυίρΐβ 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 ηιμυίρΐβ 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 foll^Lar lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.

Βυεμί-ίβη, 1 ,4-butanediol dimethanesμLfonate, is commercially available as MYLERAN® TABLETS. Βυεμίίβη is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busμLfan.

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, ηιμΙ_ίίρΙβ 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 Γβεμίίε 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, anthracyclines such as daunorubicin and doxorubicin; and bleomycins. Dactinomycin, also known as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin. Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,1 1 -trihydroxy-1 -methoxy-5,12

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

Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy] -8- glycoloyl, 7,8,9,10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a υεβίμί. 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 test^Lar carcinomas. Ρμΐ-Γτιοηβίγ 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 accurr^Late 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 οβρεμίβε 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 test^Lar and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leukopenia 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 leukopenia 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 Γβεμίί 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 leukopenia, 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 υεβίμί. 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 leukopenia, 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 leukopenia, 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 (leukopenia, 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 Γβεμίί of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.

Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA η·ΊθΙβομΙ_β. 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 Forrr^La 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 υεβίμί. 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 υεβίμί. in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are υεβίμί. in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane υεβίμί. in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate υεβίμί. 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, υεβίμί. 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 (SERMS) such those described in U.S. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, usefyL in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stirr^Late the release of leutinizing hormone (LH) and/or follicle stirr^Lating 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 intracel^Lar change. As used herein this change is cell proliferation or differentiation. Signal transduction inhibitors υεβίμί. 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 tyrosinyl residues in various proteins involved in the 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 extracel^Lar ligand binding domain, a transmembrane domain , and a tyrosine kinase domain . Receptor tyrosine kinases are involved in the 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 Γβεμίί in uncontrolled cell growth . Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases a^Ld provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, νβεομίβΓ endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobμLin-like and epidermal growth factor homology domains (TIE-2), ίηεμϋη growth factor -I (IGFI) receptor, macrophage colony stirr^Lating 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):803-81 8; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Mo\ec Lar Targets for Cancer Chemotherapy, ed . Workman , Pa L and Kerr, David, CRC press 1 994, 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-methylbenzenesμLfona mide, 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 1 9, 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-pyrimidi nyl]amino]-2- 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- 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- 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 oc Lar diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and oc Lar diseases/angiogenesis, suitably age-related ΓηβομΙ-βΓ degeneration , which method comprises the administration of a compound of Forrr^La (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. , (1 999) 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 ΊθΙβομΙ-βε (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 Extracel^Lar RegμLated Kinase (MEKs), and Extracel^Lar RegμLated 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 ΜοΙβομίβΓ 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 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, A/-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesμLfona mide, 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. A/-{3-[5-(2-Amino-4- pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesμLfonamide 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, A/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. 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 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, 201 0.

Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be υεβίμί. 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 1 7 (25) 3301 -3308; Jackson, S.P. (1 997), 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., (1 994) New ΜοΙβομίβΓ Targets for Cancer Chemotherapy ed. , Pa L 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 extracel^Lar 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 υεβίμί. 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 ηιοΙβομΙ_β inhibitors of integrin (alpha _v beta ₃ ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove υεβίμί. 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 υεβίμί. in combination with the compounds of Forrr^La (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 ηιοΙβομΙ_β 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. of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stirr^Lates anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to οΙο πΓβςμίΒίβ 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 ΐΎΐοΙβομΙ-βε 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:

A/-hydroxy-/V'-phenyl-octanediamide

2. Romidepsin, including pharmaceutically acceptable salts thereof.

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

Romidepsin, has the following che ame:

(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:

(2E)-/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:

2-propylpentanoic acid

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

Mocetinostat, has the foll

A/-(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, part^Larly the compounds of table 3 therein as indicated below.

Proteasome inhibitors are drugs that block the action of proteasomes, cel^Lar 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 R)-3-methyl-1 -({(2S)-3-phenyl-2-[(pyrazin-2- ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid

2. □ίεμί.ΐΊΓβιτι, including pharmaceutically acceptable salts thereof.

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

□ίεμΙ-ίίΓβιτι has the following chemical structure and name.

1 ,1 ',1 ",1 "'-[disμLfanediylbis(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(71-1,14H)-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 upregμLated 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 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 ηιοΙβομΙ_β 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 υεβίμί 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 υεβίμί. 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 υεβίμί. 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 υεβίμί. 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 extracel^Lar or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobμLin ηιοΙβομΙ_β. Examples of immunoadhesion mo^Les that specifically bind to PD-1 are described in WO2010/027827 and WO201 1 /066342. Specific fusion proteins υεβίμί. 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 υεβίμί. 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 υεβίμί. 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 fpLly human monoclonal antibody marketed by Bristol Myers Squibb directed against the Eiegative immunoregpLatory human ceil surface receptor PD- 1 (programmed death-1 or programmed cell death-1/PCD-1 ) with immunopotentiation activity. Nivoiumab binds to and blocks the activation of PD-1 , an !g superiamiiy transmembrane protein, by its ligands PD-L1 and PD-L2, respiting in the activation oi l- cells and cell-mediated immune responses against tumor ceils or pathogens. Activated PD-1 negatively regplates T-cell activation and effector function through the suppression of P13k/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-modpLators.

As used herein "immuno-modpLators" refer to any substance including monoclonal antibodies that affects the immune system. The ICOS binding proteins of the present invention can be considered immune-modpLators. Immuno-modpLators can be used as anti-neoplastic agents for the treatment of cancer. For example, immune-modpLators 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- modpLators 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 fpLly 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 costimpLatory molecpLe, 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 fpLI 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 υεβίμί. as vaccine adjuvants and immunostirr^Latory agents for stirr^Lating 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 immunorrK^Lating 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 Forrr^La (I) are STING moc^Lating 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 Forrr^La (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-microti^Le 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 υεβίμί. as CD73 inhibitors in mammals, part^Larly humans, in need thereof.

The present invention provides a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Forrr^La (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 Forrr^La (I) as described above or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Forrr^La (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 Forrr^La (I) or a pharmaceutically acceptable salt thereof. The compounds of Forrr^La (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, ίηίΓβΓηυεομΙ-βΓ, oral, topical, subcutaneous, intradermal, ίηίΓβοομίβτ and parenteral.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as οβρεμίβε, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium εμίίβίβ 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, err^Lsion, soft gelatin οβρεμίβ, sterile injectable liquid such as an βηΊρομΙ-β, or an aqueous or nonaqueous liquid suspension.

When referring to a pharmaceutical compositions, the term carrier and excipient are used interchangeably herein.

As used herein the terms "disease" and "disease state" are considered to refer to the same condition. These terms are used interchangeably herein. The pharmaceutical compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granμLating, 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 part^Lar 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 part^Lar patient being treated will Γβεμίί 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 Forrr^La (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 Forrr^La (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The invention also provides a compound of Forrr^La (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 Forrr^La (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 Forrr^La (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 Forrr^La (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.

The invention also provides novel processes and novel intermediates υεβίμί. in preparing the presently invented compounds. The invention also provides a pharmaceutical composition comprising from 0.5 to 1 ,000 mg of a compound of Forrr^La (I) or pharmaceutically acceptable salt thereof and from 0.5 to 1 ,000 mg of a pharmaceutically acceptable excipient. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its ίμίΐβεί 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 part^Lar 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.

Example 1

(18E)-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracycloM 9.3.1.1 ¹² , ¹⁶ .0 ⁴ , ⁹ 1hexacosa- 1 (25>.4(9>.5.7.12.1 e-6-carboxamide

a) fe/f-Butyl 3-bromobenzylcarbamate

A solution of (3-bromophenyl)methanamine (1 g, 5.37 mmol) in dichloromethane (10 mL) at 10 °C. was treated with triethylamine (1 .498 mL, 10.75 mmol) then fe/ -butyl dicarbonate (1 .498 mL, 6.45 mmol) and stirred at 10 °C for 4 h. Water (10 mL) was added then the mixture extracted with DCM (2 x 10 mL), washed with brine, dried and evaporated and the residue purified by chromatography (silica gel, 10:1 hexanes/ethyl acetate) to afford the desired product (1 .5 g; 93%) as a colorless solid. Ή NMR (500 MHz, CDCI ₃ ) δ ppm 7.43 (s, 1 H), 7.39 (d, J = 6.8 Hz, 1 H), 7.20 (d, J = 6.8 Hz, 2H), 4.89 (s, 1 H), 4.29 (d, J = 5.7 Hz, 2H), 1 .46 (s, 9H).

b) fe/f-Butyl 3-allylbenzylcarbamate

A solution of te f-butyl 3-bromobenzylcarbamate (1 .5 g, 5.24 mmol), allyltributylstannane (2.60 g, 7.86 mmol) and Pd(Ph ₃ P) ₄ (0.303 g, 0.262 mmol) in 1 ,4-dioxane (15 mL) was stirred and heated at 130 °C for 16 h. The reaction mixture was then cooled to 10 °C and poured into a solution of KF (0.5 g) in water (50 mL) and stirred at 10 °C for 10 min. then extracted with EtOAc (3 x 50 mL). The combined extracts were filtered through celite, the celite washed with EtOAc (50 mL) then the combined organics dried, evaporated and the residue purified by chromatography (silica gel, 10:1 hexanes/ethyl acetate) to afford the desired product (700 mg; 41 .6%) as a yellow oil. ¹ H NMR (500 MHz, CDCI ₃ ) δ ppm 7.31 - 7.19 (m, 2H), 7.16 - 7.06 (m, 2H), 6.02 - 5.86 (m, 1 H), 5.12 - 5.02 (m, 2H), 4.30 (d, J = 5.4 Hz, 2H), 3.38 (d, J = 6.7 Hz, 2H), 1 .46 (s, 9H).

c) (3-Allylphenyl)methanamine hydrochloride

A solution of fe/ -butyl 3-allylbenzylcarbamate (1 1 .6 g; 46.9 mmol.) in HCI (4M in 1 ,4-dioxane) (1 1 .73 mL) was stirred at 10 °C for 16 h. The mixture was evaporated and the residue purified by chromatography (C-18 silica, gradient 5-95% MeOH in water (0.05% TFA)) to afford the desired product (5.3 g; 61 .5%) as a colorless solid. ¹ H NMR (500 MHz, d ₆ - DMSO) δ ppm 8.30 (s, 3H), 7.37 - 7.29 (m, 3H), 7.21 (d, J = 7.3 Hz, 1 H), 5.96 (dd, J = 17.0, 10.1 Hz, 1 H), 5.18 - 5.01 (m, 2H), 3.99 (s, 2H), 3.38 (d, J = 6.2 Hz, 2H).

d) 4-Fluoro-2-hvdroxybenzamide

A solution of 4-fluoro-2-hydroxybenzoic acid (50g, 320 mmol)) in thionyl chloride (150 mL) was stirred and heated at 70 °C for 4h. The mixture was cooled and evaporated then the residue dissolved in THF (150 mL) and added dropwise to a precooled (-40 °C) solution of ammonia (109 g) in THF (750 mL) then the mixture stirred and allowed to warm to room temperature overnight. This procedure was repeated a further two times utilizing 50 g and 22 g of 4-fluoro- 2-hydroxybenzamide starting material. The combined reaction mixtures were then filtered, washed with THF (2 x 50 mL) then the solids dissolved in THF (1 L) and acidified to pH = 5 with HCI (33% ethanolic solution). The mixture was evaporated and the residue purified by chromatography (silica gel, gradient 10-25% petroleum ether in EtOAc)to afford the desired product (29.9 g; 54.2%) as a yellow solid. LCMS (ES) m/z = 154.0 (M-H) ^" .

e) 5-Carbamoyl-2-fluoro-4-hvdroxybenzene-1 -suLfonyl chloride

A solution of 4-fluoro-2-hydroxybenzamide (35.5 g; 229 mmol) in οηΐοηοεμίίοηίο acid (62.3 mL) was stirred and heated at 60 °C overnight. This was combined with a second batch prepared in the identical manner and poured slowly into ice-water (1 .5 L) then filtered and washed twice with cold water to afford the desired product (43.5 g; 71 .2%) as a yellow solid. LCMS (ES) m/z = 251 .8 (M-H)-.

f) 5-(N-(3-allylphenyl)suLfamoyl)-4-fluoro-2-hvdroxybenzamide

A solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (667 mg, 2.63 mmol) in DCM (12 mL) was treated with 3-allylaniline (350 mg, 2.63 mmol) and pyridine (0.213 mL, 2.63 mmol) at 0 °C, and the mixture was stirred at room temperature for 2h. The mixture was evaporated and the residue purified by chromatography (silica gel, gradient 0 to 60% EtOAc/hexanes) to give the desired product (730 mg) as a pale brown solid. LCMS (ES) m/z = 351 .1 [M+H] ⁺ . Ή NMR (400 MHz, CD ₃ OD) δ ppm 3.28 (d, J = 6.34 Hz, 2H), 4.99 (m, 2 H), 5.86 (m, 1 H), 6.71 - 6.77 (m, 1 H), 6.89 (d, J = 7.60 Hz, 1 H), 6.95 - 7.01 (m, 2H), 7.1 1 - 7.19 (m, 1 H), 8.34 (d, J=8.1 1 Hz, 1 H).

g) 4-((3-allylbenzyl)amino)-5-(N-(3-allylphenyl)s Lfamoyl)-2-hvdroxybenzamide

A mixture of 5-(N-(3-allylphenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (320 mg, 0.913 mmol), 1 -butanol (6 mL), (3-allylphenyl)methanamine hydrochloride (503 mg, 2.74 mmol), and DIEA (0.479 mL, 2.74 mmol) was stirred and heated at 120 °C for 1 h under microwave irradiation. The mixture was cooled, evaporated and the residue was washed with water to afford the desired product (310 mg) as a pale brown solid. LCMS (ES) m/z = 478.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.27 (d, J = 6.84 Hz, 2H), 3.35 (m, 2H), 4.42 (s, 2H), 4.95 - 5.08 (m, 4H), 5.78 - 6.03 (m, 3H), 6.86 - 6.97 (m, 3H), 7.07 - 7.18 (m, 4H), 7.21 - 7.29 (m, 1 H), 8.17 (s, 1 H).

h) (18E)-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ lhexacosa- 1 (25V4(9V5.7.12.14.16(26V18.21 .23-decaene-6-carboxamide

A solution of 4-((3-allylbenzyl)amino)-5-(N-(3-allylphenyl)sμLfamoyl)-2-h ydroxybenzamide (240 mg, 0.503 mmol) and (1 ,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylp hosphine)ruthenium (55.5 mg, 0.065 mmol) in DCM (18 mL) under a nitrogen atmosphere was stirred at room temperature for 6h. The mixture was evaporated and the residue was washed with hexanes to give a mixture of 5:1 trans/cis macrocycle products (190 mg) as a brown solid. A portion of the mixture (80 mg) was further purified using chromatography [C-18 silica, 30x100 mm, 5 micron, gradient 40% acetonitrile/H ₂ 0 (0.1 % formic acid) to 85% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (19 mg) as a brown solid. LCMS (ES) m/z = 450.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.28 (d, J = 5.83 Hz, 2H), 3.41 (m, 2H), 4.56 (s, 2H), 5.53 - 5.67 (m, 2H), 5.87 (s, 1 H), 6.90 - 6.97 (m, 2H), 7.1 1 (d, J = 7.35 Hz, 1 H), 7.15 - 7.25 (m, 2H), 7.27 - 7.40 (m, 3H), 8.05 (s, 1 H). Example 2

7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracycloM 9.3.1.1 ¹² , ^l6 .0 ⁴ , ⁹ 1hexacosa- 1 (25).4(9).5.7.1 -carboxamide

A solution of the 5:1 mixture of cis/trans 16-membered macrocycles from Example 1 (100 mg, 0.222 mmol) in methanol (6.0 mL) was hydrogenated at room temperature and atmospheric pressure with hydrogen gas over Pd-C (10%, 50 mg, 0.470 mmol) for 18h. The mixture was filtered through a short pad of Celite and the filtrate was evaporated. The residue was purified by chromatography [C-18 silica, 30x100 mm, 5 micron, gradient 40% acetonitrile/H ₂ 0 (0.1 % formic acid) to 85% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (21 mg) as an off-white solid. LCMS (ES) m/z = 452.2 [M+H] ⁺ . Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .08 (br. s., 2H), 1 .53 (br. s., 2H), 2.40 (t, J = 7.22 Hz, 2H), 2.63 (t, J = 6.08 Hz, 3H), 4.48 (d, J = 5.58 Hz, 2H), 5.73 (s, 1 H), 6.78 (d, J = 7.60 Hz, 1 H), 6.88 - 7.05 (m, 4H), 7.05 - 7.17 (m, 2H), 7.18 - 7.33 (m, 4H), 8.28 (s, 1 H), 10.45 (s, 1 H), 13.70 (s, 1 H).

Example 3

7-hydroxy-3.3-dioxo-18-oxa-3A ⁶ -thia-2.10-diazatetracycloM 8.3.1.1 ¹² , ^l6 .0 , ⁹ 1pentacosa-

a) 3-(((3-nitrobenzyl)oxy)methyl)benzonitrile

A solution of (3-nitrophenyl)methanol (1 .3 g, 8.49 mmol) in DMF (40 mL) was treated with sodium hydride (95%, 0.257 g, 10.19 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. 3-(Bromomethyl)benzonitrile (1 .664 g, 8.49 mmol) was then added and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, quenched with saturated NH ₄ CI aqueous solution, and extracted with EtOAc (3x). The extract was dried (Na2S04) and evaporated. The residue was purified by chromatography (silica gel, 0 to 50% EtOAc/hexanes) to give the desired product (2.1 g) as a pale brown solid. LCMS (ES) m/z =

291 .1 [M+Na] ⁺ ._ ¹ H NMR (400 MHz, CDCI3) δ ppm 4.68 (s, 2H), 4.72 (s, 2H), 7.48 - 7.69 (m, 4H), 7.70 - 7.78 (m, 2H), 8.19 - 8.31 (m, 2H).

b) tert-butyl 3-(((3-nitrobenzyl)oxy)methyl)benzylcarbamate

A solution of 3-(((3-nitrobenzyl)oxy)methyl)benzonitrile (1 .3 g, 4.85 mmol) in tetrahydrofuran (32 mL) was treated with BH ₃ THF (1 M, 14.54 mL, 14.54 mmol) at 0 °C, and the mixture was warmed to room temperature and stirred for 3h. The reaction was then cooled to -30 °C and MeOH was added dropwise until gas evolution ceased. The mixture was evaporated and the residue dissolved in DCM (32.0 mL)then treated with di-fe/ -butyl dicarbonate (1 .35 mL, 5.82 mmol) and TEA (0.878 mL, 6.30 mmol), and the mixture was stirred at room temperature for 2h. The reaction was quenched with 10% NaHC03 and extracted with DCM (3x). The extract was dried (Na ₂ S0 ₄ ), evaporated and the residue was purified by chromatography (silica gel, gradient 0 to 50% EtOAc/hexanes) to give to give the desired product (1 .3g) as a colorless oil. LCMS (ES) m/z = 395.2 [M+Na] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ ppm 1 .50 (s, 9H), 4.38 (d, J = 5.83 Hz, 2H), 4.65 (s, 2H), 4.68 (s, 2H), 7.25 - 7.43 (m, 4H), 7.53 - 7.61 (m, 1 H), 7.74 (d, J = 7.86 Hz, 1 H), 8.20 (dd, J = 8.1 1 , 1 .27 Hz, 1 H), 8.27 (s, 1 H).

c) tert-butyl 3-(((3-aminobenzyl)oxy)methyl)benzylcarbamate

A solution of tert-butyl 3-(((3-nitrobenzyl)oxy)methyl)benzylcarbamate (1 .01 g, 2.71 mmol) and NiCI ₂ -6H ₂ 0 (1 .615 g, 6.78 mmol) in methanol (15 mL) was treated with sodium borohydride (513 mg, 13.56 mmol) in portions over 20 min. at 0 °C with stirring. The reaction mixture was then stirred at room temperature for 30 min. The mixture was evaporated and the residue was treated with concentrated NH ₄ OH and extracted with DCM (3x). The extract was dried (Na ₂ S0 ₄ ) and evaporated to give the desired product (890 mg) as a pale brown oil. LCMS (ES) m/z =

365.2 [M+Na] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ ppm 1 .50 (s, 9 H), 4.36 (d, J = 5.58 Hz, 2H), 4.52 (s, 2H), 4.57 (s, 2H), 4.92 (br. s., 1 H), 6.75 - 6.88 (m, 2H), 7.15 - 7.42 (m, 6H).

d) tert-butyl-3-(((3-(5-carbamoyl-2-fluoro-4-hvdroxyphenyls Lfonamido)benzyl)oxy)

methyl) benzylcarbamate

A solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (300 mg, 1 .183 mmol) in DCM (6 mL) was treated with fe/ -butyl 3-(((3- aminobenzyl)oxy)methyl) benzylcarbamate (405 mg, 1 .183 mmol) and pyridine (0.096 mL, 1 .183 mmol) at 0 °C, and the mixture was stirred at room temperature for 3h. The mixture was evaporated and the residue washed with water to give the desired product (630 mg) as a pale brown solid. LCMS (ES) m/z = 460.2 [M-Boc] ⁺ . Ή NMR (400 MHz, CD ₃ OD) δ ppm 1 .46 (s, 9H), 4.25 (s, 2H), 4.46 (m, 4H), 5.52 (s, 1 H), 6.73 (d, J = 1 1 .66 Hz, 1 H), 7.05 (d, J = 7.60 Hz, 1 H), 7.12 (s, 1 H), 7.17 - 7.38 (m, 6H), 8.36 (d, J = 8.1 1 Hz, 1 H). e) 5-(N-(3-(((3-(aminomethyl)benzyl)oxy)methyl)phenyl)suLfam

hvdroxybenzamide, hydrochloride

A solution of tert-butyl 3-(((3-(5-carbamoyl-2-fluoro-4- hydroxypheny^Lfonamido) benzyl)oxy)methyl)benzylcarbamate (100 mg, 0.179 mmol) in DCM (5 mL) was treated with TFA (0.23 mL, 2.99 mmol) and the mixture was stirred at room temperature for 4h. The mixture was evaporated and the residue was treated with MeOH and 1 M aqu. HCI and evaporated to afford the desired product (92 mg) as a pale brown solid. LCMS (ES) m/z = 460.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.15 (s, 2 H), 4.49 - 4.53 (m, 4 H), 6.73 (d, J = 1 1 .41 Hz, 1 H), 7.05 - 7.12 (m, 2H), 7.20 - 7.29 (m, 2H), 7.36 - 7.51 (m, 4H), 8.37 (d, J = 8.1 1 Hz, 1 H).

f) 7-hvdroxy-3,3-dioxo-18-oxa-3A ⁶ -thia-2,10-diazatetracvclo[18.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ lpentacosa- 1 (24),4(9),5,7,12,14,16(25),20,22-nonaene-6-carboxamide

A solution of 5-(N-(3-(((3-(aminomethyl)benzyl)oxy)methyl) phenyl^Lfamoyl)-4-fluoro-2- hydroxybenzamide hydrochloride (95 mg, 0.192 mmol), 1 -butanol (4 mL) and DIEA (0.067 mL, 0.383 mmol) was stirred and heated at 120 °C for 1 h under microwave irradiation. The mixture was evaporated and the residue was purified by reverse-phase chromatography [ODS silica, 30x100 mm, 5 micron, gradient 38% acetonitrile/H ₂ 0 (0.1 % formic acid) to 75% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (18 mg) as a pale brown solid. LCMS (ES) m/z = 440.4 [M+H] ⁺ . Ή NMR (400 MHz, CD ₃ OD) δ ppm 4.36 (s, 2H), 4.50 (s, 2H), 4.60 (d, J = 5.32 Hz, 2H), 5.83 (s, 1 H), 6.97 (d, J = 7.35 Hz, 1 H), 7.03 (s, 1 H), 7.1 1 - 7.16 (m, 2H), 7.18 - 7.38 (m, 5H), 8.30 (s, 1 H).

Example 4

7-hydroxy-3,3,18-trioxo-3A ⁶ -thia-2,10,19-triazatetracycloH 9.3.1.1 ¹² , ^l6 .0 ⁴ , ⁹ 1hexacosa- 1 (25).4.6.8.12.1 -6-carboxamide

a) tert-butyl 3-(5-carbamoyl-2-fluoro-4-hvdroxyphenyls Lfonamido)benzylcarbamate A solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (700 mg, 2.76 mmol) in DCM (15 mL) was treated with fe/ -butyl 3-aminobenzylcarbamate (613 mg, 2.76 mmol) and pyridine (0.223 mL, 2.76 mmol) at 0 °C and the mixture was stirred at room temperature for 3h. The mixture was evaporated and the residue was washed with water to afford the desired product (880 mg) as a pale brown solid. LCMS (ES) m/z =462.2 [M+Na] ⁺ . Ή NMR (400 MHz, CD ₃ OD) δ ppm 1 .48 (s, 9H), 4.15 (s, 2H), 6.74 (d, J = 1 1 .66 Hz, 1 H), 6.92 - 7.06 (m, 2H), 7.12 - 7.25 (m, 2H), 8.32 (d, J = 8.1 1 Hz, 1 H)

b) 2-(3-(((2-(N-(3-(((tert-butoxycarbo

hvdroxyphenyl)amino)methyl)phenyr)acetic acid

A mixture of fe/f-butyl 3-(5-carbamoyl-2-fluoro-4-hydroxyphenylsμLfonamido)benzylca rbamate (150 mg, 0.341 mmol), 2-(3-(aminomethyl)phenyl)acetic acid (169 mg, 1 .024 mmol), 1 -butanol (3 mL) and DIEA (0.179 mL, 1 .024 mmol was heated at 120 °C with stirring for 1 h under microwave irradiation. The reaction mixture was evaporated and the residue treated with water (5 mL), acidified using 2N aqu. HCI, and extracted with EtOAc (3x). The combined organic layers was dried (Na ₂ S0 ₄ ), evaporated and the residue purified using by chromatography (silica gel, gradient 0 to 70% EtOAc/DCM) to give the desired product (1 10 mg) as a pale brown solid. LCMS (ES) m/z =585.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1 .47 (br. s., 9H), 3.59 (s, 2H), 4.15 (s, 2H), 4.43 (s, 2H), 5.51 (s, 2H), 5.98 (s, 1 H), 6.96 (d, J = 7.10 Hz, 2H), 7.1 1 - 7.35 (m, 8H), 8.18 (s, 1 H).

c) 7-hvdroxy-3, 3,18-trioxo-3A ⁶ -thia-2, 10,19-triazatetracvclo[19.3.1 .1 ¹² , ¹⁶ . OVlhexacosa-

1 (25),4,6,8,12,14,16(26),21 ,23-nonaene-6-carboxamide

A solution of 2-(3-(((2-(N-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)s μLfamoyl)-4- carbamoyl-5-hydroxyphenyl)amino)methyl)phenyl)acetic acid (1 10 mg, 0.188 mmol) in DCM (2.0 mL) was treated with TFA (0.5 mL, 6.49 mmol) and the mixture was stirred at room temperature for 4h. The reaction mixture was evaporated and the residue was treated with MeOH (1 mL) and 1 M aqu. HCI and evaporated. The residue was dissolved in DMSO (2 mL) then treated with N-methylmorpholine (0.145 mL, 1 .317 mmol), EDC (72.1 mg, 0.376 mmol), and 1 -hydroxy-7-azabenzotriazole (51 .2 mg, 0.376 mmol) and the mixture stirred at room temperature for 5h. The reaction mixture was quenched with water (10 mL) and the precipitate was collected and washed with ether and to afford the desired product (68 mg) as a pale brown solid. LCMS (ES) m/z =467.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.49 (s, 2H), 4.19 (d, J = 5.07 Hz, 2H), 4.44 (d, J = 5.32 Hz, 2H), 5.85 (s, 1 H), 6.82 - 6.94 (m, 2H), 7.01 (s, 1 H), 7.06 - 7.18 (m, 2H), 7.24 - 7.40 (m, 4H), 8.1 1 (s, 1 H), 8.62 (t, J = 6.21 Hz, 1 H).

Example 5

7-hvdroxy-3,3-dioxo-18-oxa-3A ⁶ -thia-2,10-diazatetracycloM 9.3.1.1 ¹² , ^l6 .0Vlhexacosa-

1 (25).4(9).5.7.12. e-6-carboxamide

a) 3-((3-nitrophenethoxy) methyl ^' ) benzonitrile

A solution of 2-(3-nitrophenyl)ethanol (1 .3 g, 7.78 mmol) in DMF (40 mL) was treated with sodium hydride (95%, 0.236 g, 9.33 mmol) at 0 °C and the mixture stirred at 0 °C for 30 min. 3- (Bromomethyl)benzonitrile (1 .525 g, 7.78 mmol) was then added and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH ₄ CI aqueous, and extracted with EtOAc (3x). The extract was dried (Na ₂ S0 ₄ ), evaporated and the residue was purified by chromatography (silica gel, gradient 0 to 50% EtOAc/hexanes) to give the desired product (1 .41 g) as a pale brown oil. ¹ H NMR (400 MHz, CDCI3) δ ppm 3.08 (t, J = 6.46 Hz, 2H), 3.80 (t, J = 6.46 Hz, 2H), 4.58 (s, 2H), 7.42 - 7.66 (m, 6H), 8.10 - 8.20 (m, 2H).

b) tert-butyl 3-((3-nitrophenethoxy)methyl)benzylcarbamate

A solution of 3-((3-nitrophenethoxy)methyl)benzonitrile (1 .3 g, 4.61 mmol) in THF (30 mL) was treated with BH ₃ -THF (1 M, 13.82 mL, 13.82 mmol) at 0 °C and the mixture warmed to room temperature and stirred for 3h. The reaction was then cooled to -30 °C and MeOH was added dropwise until gas evolution ceased. The mixture was evaporated and the residue dissolved in DCM (30.0 mL) then treated with di-te/ -butyl dicarbonate (1 .390 mL, 5.99 mmol) and TEA (0.834 mL, 5.99 mmol) and the mixture stirred at room temperature for 2h. The reaction was quenched with 10% NaHC0 ₃ and extracted with DCM (3x). The extract was dried (Na ₂ S0 ₄ ), evaporated and the residue was purified by chromatography (silica gel, gradient 0 to 50% EtOAc/hexanes) to give the desired product (985 mg ) as a colorless oil. LCMS (ES) m/z =409.2 [M+Na] ⁺ . Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .50 (s, 9H), 3.06 (t, J = 6.46 Hz, 2 H), 3.74 - 3.81 (m, 2 H), 4.34 (br. s., 2 H), 4.55 (s, 2 H), 7.18 - 7.28 (m, 3 H), 7.28 - 7.39 (m, 1 H), 7.50 (t, J = 7.86 Hz, 1 H), 7.61 (d, J = 7.60 Hz, 1 H), 8.09 - 8.23 (m, 2 H).

c) tert-butyl3-((3-(5-carbamoyl-2-fluoro-4- hvdroxyphenylsuLfonamido)phenethoxy)methyl) benzylcarbamate A solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (570 mg, 2.247 mmol) in DCM (12 mL) was treated with fe/ -butyl 3-((3 aminophenethoxy) methyl)benzylcarbamate (801 mg, 2.247 mmol) and pyridine (0.182 mL, 2.247 mmol) at 0 °C and the mixture stirred at room temperature for 3h. The reaction was evaporated and the residue was washed with water to afford the desired product (910 mg) as a pale brown solid. LCMS (ES) m/z =596.4 [M+Na] ⁺ .

d) 7-hvdroxy-3,3-dioxo-18-oxa-3A ⁶ -thia-2,10-diazatetracvclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ lhexacosa- 1 (25),4(9),5,7,12,14,16(26),21 ,23-nonaene-6-carboxamide

A solution of fe/ -butyl 3-((3-(5-carbamoyl-2-fluoro-4- hydroxypheny^Lfonamido) phenethoxy)methyl)benzylcarbamate (200 mg, 0.349 mmol) in DCM (4.0 mL) was treated with TFA (0.5 mL, 6.49 mmol) and the mixture stirred at room temperature for 6h. The mixture was evaporated and the residue was treated with MeOH and 1 M aqu. HCI and evaporated. The residue was then dissolved in 1 -butanol (5mL), treated with DIEA (0.122 mL, 0.697 mmol) and stirred and heated at 120 °C for 1 h under microwave irradiation. The mixture was cooled, evaporated and the residue purified by chromatography [C-18 silica, 30x100 mm, 5 micron, gradient 40% acetonitrile/H ₂ 0 (0.1 % formic acid) to 85% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (45 mg) as a pale brown solid. LCMS (ES) m/z =454.4 [M+H] ⁺ . Ή NMR (400 MHz, CD ₃ OD) δ ppm 2.83 (t, J = 5.32 Hz, 2H), 3.68 - 3.75 (m, 2H), 4.41 (s, 2 H), 4.58 (s, 2H), 5.77 (s, 1 H), 6.90 (d, J = 7.60 Hz, 1 H), 7.00 (t, J = 1 .77 Hz, 1 H), 7.05 - 7.23 (m, 3H), 7.24 - 7.41 (m, 4H), 8.29 (s, 1 H).

Example 6

(17E)-7-hvdroxy-3,3-dioxo-3A ⁶ ,13-dithia-2,10-diazatetracycloM 8.3.1.1 ¹² , ^lS .0 ⁴ . ⁹ lpentacosa- 1 (24).4(9).5.7.1 -carboxamide

a) tert-butyl ((4-allylthiophen-2-yl)methyl)carbamate

A solution of tert-butyl ((4-bromothiophen-2-yl)methyl)carbamate (1 g, 3.42 mmol) in toluene (18 mL) under an inert atmosphere was treated with allyltributylstannane (1 .592 mL, 5.13 mmol) and lithium chloride (0.508 g, 1 1 .98 mmol) and stirred at room temperature for10 min. Tetrakis(triphenylphosphino)palladium (0.198 g, 0.171 mmol) was added and the mixture was stirred and heated under reflux for 18h. The reaction mixture was cooled and diluted with EtOAc. Potassium fluoride (1 .988 g, 34.2 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was evaporated and the residue was purified by chromatography (silica gel, gradient 0 to 40% EtOAc/hexanes) to give the desired product (540 mg) as a pale brown oil. LCMS (ES) m/z =254.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ ppm 1 .50 (s, 9 H) 3.35 (dd, J = 6.59, 1 .01 Hz, 2H), 4.46 (br. s., 2 H), 5.07 - 5.17 (m, 2H), 5.98 (m, 1 H), 6.82 (s, 1 H), 6.86 - 6.90 (m, 1 H). b) (4-allylthiophen-2-yl)methanamine, hydrochloride

A solution of tert-butyl ((4-allylthiophen-2-yl)methyl)carbamate (520 mg, 2.052 mmol) in DCM (10 ml_) was treated with TFA (1 ml_, 12.98 mmol) and the reaction mixture stirred at room temperature for 6h. The reaction mixture was evaporated, treated with MeOH (5 ml) and 6N aqu. HCI and evaporated to afford the desired product (420 mg) as a pale brown solid. LCMS (ES) m/z =136.9 [M-NH ₂ ] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.39 (dd, J = 6.72, 1 .14 Hz, 2H), 4.30 (s, 2H), 5.04 - 5.16 (m, 2H), 5.99 (m, 1 H), 7.10 (s, 1 H), 7.16 (s, 1 H).

c) 5-(N-(3-allylphenyl)suLfamoyl)-4-(((4-allylthiophen-2-yl)met hyl)amino)-2- hydroxybenzamide

A mixture of 5-(N-(3-allylphenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (200 mg, 0.571 mmol), (4-allylthiophen-2-yl)methanamine, hydrochloride (194 mg, 0.856 mmol), 1 -butanol (4 ml_), and DIEA (0.199 ml_, 1 .142 mmol) was heated at 120 °C for 1 h with stirring under microwave irradiation. The mixture was evaporated and the residue was purified by chromatography (silica gel, gradient 0 to 80% EtOAc/DCM) to give the desired product (170 mg) as a pale brown solid. LCMS (ES) m/z =484.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ ppm 3.30 (d, J = 6.59 Hz, 2H), 3.37 (dd, J = 6.59, 1 .01 Hz, 2H), 4.53 (s, 2H), 4.93 - 5.20 (m, 4H), 5.85 (m, 1 H), 5.99 (m, 1 H), 6.26 - 6.30 (m, 1 H), 6.69 - 6.81 (m, 1 H), 6.85 - 6.95 (m, 4H), 6.98 - 7.05 (m, 1 H), 7.16 - 7.23 (m, 1 H), 7.68 (s, 1 H).

d) (17E)-7-hvdroxy-3.3-dioxo-3A ⁶ .13-dithia-2.10- diazatetracvclo[18.3.1 .1 ¹² . ^l5 .0 ⁴ . ⁹ lpentacosa-1 (24).4(9).5.7.12(25).14.17.20.22- nonaene-6-carboxamide

A solution of 5-(N-(3-allylphenyl)sμLfamoyl)-4-(((4-allylthiophen-2-yl)me thyl)amino)-2- hydroxybenzamide (160 mg, 0.331 mmol) in DCM (15 mL) under an inert atmosphere was treated with (1 ,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylp hosphine)ruthenium (36.5 mg, 0.043 mmol) and the reaction mixture stirred at room temperature for 6h. The mixture was evaporated and the residue was washed with hexanes/DCM (1 :1) to give a mixture of trans/cis macrocycle products (130 mg). A portion of the mixture (80 mg) was purified by chromatography [C-18 silica, 30x100 mm, 5 micron, gradient 40% acetonitrile/H ₂ 0 (0.1 % formic acid) to 85% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (12 mg) as an off- white solid. LCMS (ES) m/z = 456.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.16 - 3.26 (m, 4H), 4.63 (d, J = 5.32 Hz, 2H), 5.49 - 5.57 (m, 2H), 5.92 (s, 1 H), 6.69 (s, 1 H), 6.76 (s, 1 H), 6.85 - 6.97 (m, 2H), 7.03 - 7.10 (m, 1 H), 7.15 (t, J = 7.86 Hz, 1 H), 7.36 (d, J = 8.36 Hz, 1 H), 8.15 (s, 1 H), 10.20 (s, 1 H), 13.74 (s, 1 H).

Example 7

(18E)-24-ethyl-7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10.25-

a) 4-allyl-2-ethyl-1 H-indol-6-amine

A solution of tert-butyl (4-allyl-2-ethyl-1 H-indol-6-yl)carbamate (390 mg, 1 .298 mmol) in DCM (8 mL) was treated with TFA (800 μΙ, 10.38 mmol), and the mixture was stirred at room temperature for 18h. The mixture was evaporated and the residue treated with saturated aqueous Na ₂ C0 ₃ solution and extracted with DCM (3x). The extract was dried (Na ₂ S0 ₄ ) and evaporated to give the desired product (250 mg) as a pale brown solid. LCMS (ES) m/z =201 .1 [M+H] ⁺ . Ή NMR (400 MHz, CDCI3) δ ppm 1 .32 - 1 .40 (m, 3H), 2.71 - 2.84 (m, 2H), 3.58 (m, 3H), 5.07 - 5.24 (m, 2H), 6.09 (m, 1 H), 6.18 (dd, J = 2.03, 1 .01 Hz, 1 H), 6.39 - 6.44 (m, 1 H), 6.50 - 6.59 (m, 1 H), 7.68 (br. s., 1 H).

b) 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl)s Lfamoyl)-4-fluoro-2-hvdroxybenzamide

A solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (310 mg, 1 .222 mmol) in DCM (8 mL) was treated with 4-allyl-2-ethyl-1 H-indol-6-amine (245 mg, 1 .222 mmol) and pyridine (0.109 mL, 1 .344 mmol), and the mixture stirred at room temperature for 3h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3x). The extract was dried (Na ₂ S0 ₄ ) and evaporated and the residue purified by chromatography (silica gel, gradient 0 to 90% EtOAc/DCM) to give the desired product (460 mg) as a brown solid. LCMS (ES) m/z =418.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1 .27 - 1 .36 (m, 3H), 2.68 - 2.80 (m, 2H), 3.45 (d, J = 6.59 Hz, 2H), 4.95 - 5.03 (m, 2H), 5.84 - 5.99 (m, 1 H), 6.52 (d, J = 1 .77 Hz, 1 H), 6.76 (d, J = 1 1 .41 Hz, 1 H), 7.00 (d, J = 1 .77 Hz, 1 H), 8.07 - 8.22 (m, 3H), 8.70 (tt, J = 7.86, 1 .52 Hz, 1 H), 8.91 (d, J = 5.07 Hz, 2H).

c) 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl)s LfamoylV4-((3-allylbenzyl)amino)-2- hvdroxybenzamide

A mixture of 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (220 mg, 0.527 mmol), (3-allylphenyl)methanamine hydrochloride (194 mg, 1 .054 mmol), 1 -butanol (3 mL), and DIEA (0.184 mL, 1 .054 mmol), was stirred and heated at 120 °C for 1 h under microwave irradiation. The mixture was cooled, evaporated and the residue purified by chromatography (silica gel, gradient 0 to 80% EtOAc/DCM) to give the desired product (270 mg) as a brown solid. LCMS (ES) m/z =545.3 [M+H] ⁺ . Ή NMR (400 MHz, CDCI3) δ ppm 1 .36 (t, J = 7.60 Hz, 3H), 2.79 (q, J = 7.44 Hz, 2H), 3.39 (d, J = 6.59 Hz, 2H), 3.49 (d, J = 6.59 Hz, 2H), 4.30 (br. s., 2H), 4.99 - 5.16 (m, 4H), 5.82 - 6.04 (m, 2H), 6.15 - 6.20 (m, 1 H), 6.24 (br. s., 1 H), 6.47 (s, 1 H), 6.58 - 6.73 (m, 2H), 6.95 (s, 1 H), 7.03 (d, J = 7.35 Hz, 1 H), 7.1 1 - 7.18 (m, 2H), 7.22 - 7.29 (m, 1 H), 7.63 (s, 1 H), 7.98 (br. s., 1 H).

d) (18E)-24-ethyl-7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10.25- triazapentacvcloH 9.6.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ .0 ²² , ²⁶ lnonacosa- 1 (28),4,6,8, 12(29), 13, 15,18,21 ,23,26-undecaene-6-carboxamide

A solution of 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl)sμLfamoyl)-4-((3-allylbenzyl)amino)-2- hydroxybenzamide (260 mg, 0.477 mmol) in DCM (15 mL) under an inert atmosphere was treated with (1 ,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylp hosphine)ruthenium (60.8 mg, 0.072 mmol) and the mixture was stirred at room temperature for 6h. The reaction mixture was diluted with hexanes (15 mL) and the precipitate collected and washed with hexanes to give a mixture of trans/cis macrocycle products as a black solid. A portion of this mixture (80 mg) was purified by chromatography [C-18 silica, 30x100 mm, 5 micron, gradient 40% acetonitrile/H ₂ 0 (0.1 % formic acid) to 85% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (15 mg) as a brown solid. LCMS (ES) m/z = 517.3 [M+H] ⁺ . Ή NMR (400 MHz, DMSO- d ₆ ) δ ppm 1 .20 - 1 .27 (m, 3H), 2.69 (q, J = 7.52 Hz, 2H), 3.39 (d, J = 5.58 Hz, 4H), 4.47 (br. s., 2H), 5.52 - 5.68 (m, 2H), 5.79 (s, 1 H), 6.09 - 6.14 (m, 1 H), 6.55 (s, 1 H), 6.96 (d, J = 2.79 Hz, 1 H), 7.13 (t, J = 3.55 Hz, 1 H), 7.21 (s, 1 H), 7.25 - 7.35 (m, 2H), 7.42 (s, 1 H), 7.98 (s, 1 H), 9.81 (s, 1 H). Example 8

(19E)-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracvclor20.3.1.1 ¹² , ^l6 .0 ⁴ , ⁹ 1heptacosa- 1 (26).4(9).5.7.12.1 e-6-carboxamide

a) (3-(but-3-en-1 -yl)phenyl)methanamine

A solution of 3-(but-3-en-1 -yl)benzonitrile (1 g, 6.36 mmol) in diethyl ether (30 mL) was treated with lithium aluminum hydride (12.72 mL, 12.72 mmol) at 0 °C and the mixture was slowly warmed to room temperature and stirred for 3h. The mixture was cooled in an ice-batch and quenched with a minimum amount of water until gas evolution ceased. The mixture was diluted with DCM, filtered, the precipitate washed with DCM and the combined organic filtrates were evaporated. The residue was purified by chromatography (silica gel, gradient 0 to 13% MeOH/DCM) to give the desired product (960 mg) as a colorless oil. LCMS (ES) m/z =162.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ ppm 2.37 - 2.48 (m, 2H), 2.71 - 2.84 (m, 2H), 3.86 - 3.92 (m, 2H), 4.99 - 5.16 (m, 2H), 5.91 (m, 1 H) 7.09 - 7.21 (m, 3H) 7.26 - 7.35 (m, 1 H).

b) 5-(N-(3-allylphenyl)s Lfamoyl)-4-((3-(but-3-en-1 -yl)benzyl)amino)-2-hvdroxybenzamide

A mixture of 5-(N-(3-allylphenyl^Lfamoyl)-4-fluoro-2-hydroxybenzamide (120 mg, 0.343 mmol), (3-(but-3-en-1 -yl)phenyl)methanamine (99 mg, 0.617 mmol) in 1 -butanol (3 mL) was stirred and heated at 120 °C for 1 h under microwave irradiation. The mixture was evaporated and the residue purified by chromatography (silica gel, gradient 0 to 50% EtOAc/DCM) to give the desired product (153 mg) as an off-white solid. LCMS (ES) m/z =492.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ ppm 2.36 - 2.44 (m, 2H), 2.70 - 2.77 (m, 2H), 3.30 (d, J = 6.59 Hz, 2H), 4.36 (s, 2H), 4.94 - 5.13 (m, 4H), 5.75 - 5.95 (m, 2H), 6.16 - 6.21 (m, 1 H), 6.76 (br. s., 1 H), 6.83 - 6.94 (m, 2H), 7.03 (d, J = 7.60 Hz, 1 H), 7.07 - 7.28 (m, 5H), 7.73 (s, 1 H).

c) (19E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracvclo[20.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ lheptacosa- 1 (26).4(9).5.7.12.14.16(27).19.22.24-decaene-6-carboxamide

A solution of 5-(N-(3-allylphenyl)sμLfamoyl)-4-((3-(but-3-en-1 -yl)benzyl)amino)-2- hydroxybenzamide (150 mg, 0.305 mmol) in DCM (12 mL) under an inert atmosphere was treated with (1 ,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylp hosphine)ruthenium (33.7 mg, 0.040 mmol) and stirred at room temperature for 6h. The mixture was evaporated and the precipitate was washed with hexanes to give a mixture of ~3:1 trans/cis macrocycle products (1 10 mg) as a brown solid. A portion of this mixture (50 mg) was purified by chromatography [C-18 silica, 30x100 mm, 5 micron, gradient 35% acetonitrile/H ₂ 0 (0.1 % formic acid) to 75% acetonitrile/H ₂ 0, (0.1 % formic acid) over 10 min.] to give the desired product (1 1 mg) as a brown solid. LCMS (ES) m/z =464.2 [M+H] ⁺ . Ή NMR (400 MHz, CD ₃ OD) δ ppm 2.35 - 2.42 (m, 2H), 2.71 - 2.78 (m, 2H), 2.98 (d, J = 6.59 Hz, 2H), 4.43 (s, 2H), 5.20 (dt, J = 15.02, 7.32 Hz, 1 H), 5.34 - 5.47 (m, 1 H), 6.13 (s, 1 H), 6.47 (s, 1 H), 6.91 (t, J = 3.55 Hz, 1 H), 7.14 - 7.29 (m, 5H), 7.32 - 7.40 (m, 2H), 7.82 (s, 1 H).

Examples 9 and 10

(18E)-7-hvdroxy-3,3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2,10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ 1hexacosa-1 (241.4.6.8.12.14.16(26).18.21 (25).22-decaene-

6-carboxamide and

(18Z)-7-hvdroxy-3.3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2.10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ 1hexacosa-1 (24U.6.8.12.14.16(26).18.21 (25).22-decaene-

6-carboxamide

.a) N-(4-(allyloxy)phenyl)acetamide

A mixture of N-(4-hydroxyphenyl)acetamide (7.5 g, 49.6 mmol), 3-bromoprop-1 -ene (6.48 g, 53.6 mmol), and solid K ₂ C0 ₃ (7.13 g, 51 .6 mmol) in 2-butanone (30 ml_) was

heated under reflux with stirring for 16h. The reaction was cooled, filtered, and the solid residue was washed with diethyl ether. The filtrate was concentrated in vacuo to give a colorless solid, 9.73 grams. The solid was recrystallized from 100 ml of 1 :1 EtOAc:hexanes to give the desired product (6.21 g, 66%) as a colorless solid. LC-MS (ES) m/z = 192.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ ppm 2.00 (s, 3 H) 4.51 (dt, J=5.14, 1 .47 Hz, 2 H) 5.25 (dd, J=10.51 , 1 .71 Hz, 1 H) 5.38 (dd, J=17.36, 1 .71 Hz, 1 H) 5.91 - 6.13 (m, 1 H) 6.88 (d, J=9.05 Hz, 2 H) 7.33 - 7.58 (m, 2 H) 9.76 (s, 1 H) .b) N-(3-allyl-4-hvdroxyphenvDacetamide

Diphenyl ether (30 ml) was heated to 235 °C in a sand bath then N-(4- (allyloxy)phenyl)acetamide (6.18 g, 32.3 mmol) was added portionwise over 5 min. The reaction was heated for 95 min at 240-250 °C and allowed to cool to room temperature. The cooled reaction was diluted with diethyl ether and extracted with 2M NaOH (100 ml). The basic aqueous layer was cooled to 0 °C and acidified to pH 1 with concentrated HCI (18 ml). The suspension was extracted with diethyl ether and the ether layer was separated and concentrated in vacuo to give a brown solid. The solid was triturated with 100 ml of hexanes and stirred vigorously. The suspension was filtered and the process was repeated. The solid was filtered and dried to give the desired product (4.6 g, 74%) as a light tan solid. LC- MS (ES) m/z = 192.1 [M+H] ^{+ 1} H NMR (400 MHz, CDCI3) δ ppm 2.17 (s, 3 H) 3.40 (d, J=6.27 Hz, 2 H) 5.12 - 5.22 (m, 2 H) 5.30 (s, 1 H) 5.95 - 6.08 (m, 1 H) 6.74 - 6.80 (m, 1 H) 7.1 1 (br. s., 1 H) 7.20 - 7.26 (m, 2 H)

.c) N-(3-allyl-4-isopropoxyphenyl)acetamide

A mixture of N-(3-allyl-4-hydroxyphenyl)acetamide (802.4 mg, 4.20 mmol), 2-iodopropane (713 mg, 4.20 mmol), and potassium carbonate (580 mg, 4.20 mmol) in 2-butanone (5 ml_) was stirred at room temperature for 90 min then heated under reflux for 2h. Additional 2- iodopropane was added (1 .426 g, 2 eq) and the reaction was heated under reflux for 15h. The reaction was cooled and additional (713 mgs, 1 eq) 2-iodopropane was added. The reaction was stirred for 3h at room temperature. Additional potassium carbonate (1 .16g, 2 eq) was added and the reaction was stirred at room temperature for 1 hour and heated at 48 °C for 1 hour. Additional potassium carbonate (1 eq) was added and the reaction was heated at 50 °C for 1 .5h. The reaction was cooled to room temperature and stirred for 15h. The reaction was diluted with 6 ml_ of MEK and the suspension was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in a mixture of diethyl ether and 2M NaOH. The layers were separated and the ether layer was washed with sat. aq. NaCI, dried over sodium εμί-ίβίβ, filtered, and concentrated to give the desired product (813.4 mg, 83%) as a light tan solid. LC-MS (ES) m/z = 234.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .24 (d, J=5.87 Hz, 6 H) 1 .99 (s, 3 H) 3.26 (d, J=6.85 Hz, 2 H) 4.51 (dt, J=12.04, 6.08 Hz, 1 H) 4.95 - 5.15 (m, 2 H) 5.80 - 6.01 (m, 1 H) 6.89 (d, J=9.05 Hz, 1 H) 7.28 (d, J=2.45 Hz, 1 H) 7.38 (dd, J=8.80, 2.69 Hz, 1 H) 9.70 (s, 1 H)

d) 3-allyl-4-isopropoxyaniline

A mixture of N-(3-allyl-4-isopropoxyphenyl)acetamide (0.807 g, 3.46 mmol) and sodium hydroxide (1 .802 ml_, 34.6 mmol) in Ethanol (10 ml_) was stirred and heated under reflux for 3 hours. The reaction was cooled to room temperature and stirred for 15h followed by an additional 30min at reflux. The reaction was concentrated in vacuo and the residue was suspended in water. The oily suspension was treated with 6N HCI until pH 8. The suspension was extracted with DCM (2X) and the DCM layers were washed with sat.aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated to give the desired product (597.5 mg, 90%) as a brown oil. LC-MS (ES) m/z = 192.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .19 (d, J=6.02 Hz, 6 H) 3.19 (d, J=6.78 Hz, 2 H) 4.17 - 4.33 (m, 1 H) 4.58 (br. s., 2 H) 4.88 - 5.1 1 (m, 2 H) 5.88 (ddt, J=17.00, 10.10, 6.78, 6.78 Hz, 1 H) 6.31 - 6.43 (m, 2 H) 6.57 - 6.73 (m, 1 H)

e) S^N-O-allyl^-isopropoxyphenvOs LfamovD^-fluoro^-hvdroxybenzamide

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (783.0 mg, 3.09 mmol), 3-allyl-4-isopropoxyaniline (590 mg, 3.09 mmol) and pyridine (0.250 ml_, 3.09 mmol) in dichloromethane (12 ml_) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo and the residue was triturated with water, filtered, and dried. The solid was purified via silica gel chromatography (Biotage Isolera, 100% EtOAc over 20 min, 120 g column, loaded as a solution in EtOAc) and the desired fractions were combined and concentrated to give the desired product (783.3 mg, 62%) as a light tan solid. LC-MS (ES) m/z = 409.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .08 - 1 .28 (m, 6 H) 3.16 (d, J=6.60 Hz, 2 H) 4.47 (dt, J=12.10, 5.93 Hz, 1 H) 4.82 - 5.05 (m, 2 H) 5.69 - 5.91 (m, 1 H) 6.72 - 7.01 (m, 4 H) 8.09 (br. s., 1 H) 8.32 (d, J=8.31 Hz, 1 H) 8.65 (br. s., 1 H) 10.03 (s, 1 H) 14.13 (br. s., 1 H)

f) 5-(N-(3-allyl-4-isopropoxyphenyl)suLfamoyl)-4-((3-allylbenzy l)amino)-2- hydroxybenzamide

A mixture of 5-(N-(3-allyl-4-isopropoxyphenyl)sμLfamoyl)-4-fluoro-2-hydr oxybenzamide (264.8 mg, 0.648 mmol), (3-allylphenyl)methanamine, hydrochloride (125 mg, 0.681 mmol), and DIEA (0.459 ml_, 2.63 mmol) in 1 -butanol (4 ml_) was heated at 120 °C under microwave irradiation for 5h followed by further heating at 150 °C for 3h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc/satu rated ammonium chloride solution. The layers were separated and the EtOAc layer was washed with water and sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated to give a gum. The gum was purified via silica gel chromatography (Biotage Isolera, 5-50% EtOAc:hexanes over 20 min, 40 g column, loaded as a solution in DCM) and the desired fractions were combined and evaporated to afford the desired product (144 mg, 42%) as a colorless solid. LC-MS (ES) m/z = 536.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-cfe) δ ppm 1 .20 (d, J=6.1 1 Hz, 6 H) 3.16 (d, J=6.60 Hz, 2 H) 3.30 (s, 1 H) 4.38 - 4.51 (m, 3 H) 4.86 - 5.09 (m, 4 H) 5.71 - 5.84 (m, 2 H) 5.86 - 5.99 (m, 2 H) 6.73 - 6.88 (m, 4 H) 7.03 - 7.26 (m, 4 H) 7.58 (br. s., 1 H) 8.14 (s, 1 H) 8.27 (br. s., 1 H) 9.87 (s, 1 H) 13.72 (s, 1 H)

g) (18E)-7-hvdroxy-3,3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2,10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ lhexacosa-1 (24V4.6.8.12.14.16(26V18.21 (25V22-decaene-6- carboxamide

5-(N-(3-Allyl-4-isopropoxyphenyl^Lfamo

(129.1 mg, 0.241 mmol) was dissolved in dichloromethane (20 ml_) with stirring and purged with nitrogen for 15 min. [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1- (methoxy(methyl)amino)-1-oxopropan-2-yl]oxy]benzylidene}ruth enium(ll) dichloride (18.89 mg, 0.024 mmol) was quickly added and the green homogeneous reaction was stirred at room temperature for 23h. The reaction was filtered while washing with DCM and dried to give a colorless solid (76 mg) as a 5:1 mixture of E:Z isomers. The solid was purified via preparative SFC (DEAP column, 30% MeOH co-solvent) to give the pure isomers as follows: E isomer: 39.8 mg LC-MS (ES) m/z = 508.3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-cfe) δ ppm 1.22 (d, J=5.87 Hz, 6 H) 3.13 (d, J=5.14 Hz, 2 H) 3.37 (d, J=4.65 Hz, 2 H) 4.47 (d, J=6.11 Hz, 3 H) 5.36 - 5.61 (m, 2 H) 5.79 (s, 1 H) 6.80 - 6.94 (m, 3 H) 7.12 (t, J=3.55 Hz, 1 H) 7.22 (dd, J=8.68, 2.57 Hz, 1 H) 7.30 (d, J=4.89 Hz, 2 H) 7.38 (s, 1 H) 7.51 (d, J=8.07 Hz, 1 H) 7.99 (s, 1 H) 8.19 (br. s., 1 H) 9.83 (s, 1 H) 13.58 (s, 1 H);

Z isomer: 7.84 mg. LC-MS (ES) m/z = 508.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (d, J=6.11 Hz, 6H) 3.28 (d, J=6.60 Hz, 4 H) 4.38 - 4.52 (m, 3 H) 5.55 - 5.64 (m, 2 H) 5.70 (br. s., 1 H) 6.76 - 6.89 (m, 3 H) 7.01 (d, J=2.45 Hz, 1 H) 7.09 - 7.22 (m, 2 H) 7.23 - 7.30 (m, 2 H) 7.47 (br. s., 1 H) 8.12 (s, 1 H) 8.32 (br. s., 1 H) 9.95 (br. s., 1 H) 13.61 (br. s., 1 H).

Example 11

7-hvdroxy-3.3-dioxo-22-(propan-2-yloxy)- 3A ⁶ -thia-2.10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ 1hexacosa-1 (25).4.6.8.12.14.16(26).21 ,23-nonaene-6-

A solution of (18E)-7-hydroxy-3,3-dioxo-22-(propan-2-yloxy)-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-1 (24),4,6,8,12,14,16(26),18,21 (25),22-decaene-6- carboxamide (20.0 mg, 0.039 mmol) in methanol (8 ml_) was hydrogenated over 5% Pd-C (0.419 mg, 3.94 μηιοΙ) for 20h at room temperature and 1 atmosphere pressure. The reaction mixture was diluted with MeOH, filtered through celite and evaporated to afford the desired product (19.1 mg, 95%) as an off-white solid. LC-MS (ES) m/z = 510.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-c/e) δ ppm 1 .19 (d, J=6.1 1 Hz, 10 H) 1 .24 (s, 1 H) 2.39 - 2.47 (m, 3 H) 2.58 (br. s., 2 H) 4.39 - 4.53 (m, 4 H) 5.68 (br. s., 1 H) 6.77 (d, J=9.05 Hz, 1 H) 6.86 (d, J=2.69 Hz, 1 H) 7.00 (d, J=5.38 Hz, 1 H) 7.07 - 7.30 (m, 4 H) 8.21 (s, 1 H) 10.08 (br. s., 1 H) 13.64 (br. s., 1 H).

Examples 12 and 13

(18Z)-7-hvdroxy-22-methoxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ 1hexacosa-1 (25 .6.8.12.14.16(26>.18.21.23-decaene-6- carboxamide and

(18E)-7-hvdroxy-22-methoxy-3.3-dioxo-3A ⁶ -thia-2.10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ 1hexacosa-1 (25).4.6.8.12.14.16(26).18.21 ,23-decaene-6-

a) N-(3-allyl-4-methoxyphenyl)acetamide

A mixture of N-(3-allyl-4-hydroxyphenyl)acetamide (519.1 mg, 2.71 mmol), iodomethane (385 mg, 2.71 mmol), and potassium carbonate (375 mg, 2.71 mmol) in 2-butanone (4 ml_) was heated at 70 °C for 3h and then at 80 °C for 16h. Additional iodomethane (385 mg, 1 eq) was added and the reaction was heated under reflux for 2.5h. Additional iodomethane was added (385 mg, 1 eq) and the reaction was heated under reflux for 60 min. The reaction was cooled, diluted with 2-butanone, filtered, and concentrated in vacuo. The residue was dissolved in diethyl ether/2M NaOH, the layers were separated and the ether layer was washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated to give the desired product (452.6 mg, 81 % ) as a pale yellow solid. LC-MS (ES) m/z = 206.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .99 (s, 3 H) 3.28 (d, J=6.60 Hz, 2 H) 3.75 (s, 3 H) 4.92 - 5.14 (m, 2 H) 5.84 - 6.00 (m, 1 H) 6.89 (d, J=8.80 Hz, 1 H) 7.28 (d, J=2.69 Hz, 1 H) 7.42 (dd, J=8.80, 2.69 Hz, 1 H) 9.71 (s, 1 H)

b) 3-allyl-4-methoxyaniline

... A mixture of N-(3-allyl-4-methoxyphenyl)acetamide (450.6 mg, 2.195 mmol) and sodium ethyoxide (1 .143 mL, 21 .95 mmol) in ethanol (10 mL) was stirred and heated under reflux for 5h. The reaction was concentrated in vacuo and the residue was suspended in water and treated with 6N HCI until pH 8-9. The suspension was extracted with DCM (2X) and the DCM layers were washed with saturated NaCI, dried over sodium εμίίβίβ, filtered, and concentrated to give the desired product (295 mg, 82%) as a brown oil. LC-MS (ES) m/z = 164.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.19 (d, J=6.60 Hz, 2 H) 3.59 - 3.68 (m, 3 H) 4.55 (br. s., 2 H) 4.92 - 5.07 (m, 2 H) 5.80 - 5.97 (m, 1 H) 6.31 - 6.44 (m, 2 H) 6.67 (d, J=8.31 Hz, 1 H)

c) 5-(N-(3-allyl-4-methoxyphenyl)sμLfamoyl)-4-fluoro-2-hydroxy benzamide

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (449 mg, 1 .769 mmol), 3-allyl-4-methoxyaniline (288.7 mg, 1 .769 mmol) and pyridine (0.143 mL, 1 .769 mmol) in dichloromethane (12 mL) was stirred at room temperature for 23h. The reaction was concentrated in vacuo and the residue was triturated with water and filtered. The solid was triturated with DCM, filtered, dried and the solid was purified via silica gel chromatography (Biotage Isolera, 100% EtOAc over 20 min,, 40 g column, loaded as a solution in EtOAc) to give a light tan solid. The solid was triturated with DCM and the

suspension was filtered and dried to afford the desired product (375.1 mg, 56%) as an off-white solid. LC-MS (ES) m/z = 381 .0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.19 (d, J=6.60 Hz, 2 H) 3.60 - 3.83 (m, 3 H) 4.71 - 5.12 (m, 2 H) 5.80 (ddt, J=16.93, 10.21 , 6.60, 6.60 Hz, 1 H) 6.83 (dd, J=5.75, 3.06 Hz, 2 H) 6.88 - 6.94 (m, 2 H) 8.09 (br. s., 1 H) 8.32 (d, J=8.07 Hz, 1 H) 8.65 (br. s., 1 H) 10.05 (s, 1 H) 14.13 (br. s., 1 H)

d) 5-(N-(3-allyl-4-methoxyphenyl)sμLfamoyl)-4-((3-allylbenzyl) amino)-2-hydroxybenzamide A mixture of 5-(N-(3-allyl-4-methoxyphenyl)sμLfamoyl)-4-fluoro-2-hydroxy benzamide (362.4 mg, 0.953 mmol), (3-allylphenyl)methanamine, hydrochloride (184 mg, 1 .000 mmol), and DIEA (0.674 mL, 3.86 mmol) in 1 -butanol (5 mL) was heated at 150 °C under microwave irradiation for 3h. The reaction was concentrated in vacuo and the residue was dissolved in a mixture of EtOAc and saturated ammonium chloride. The layers were separated and the organic layer was washed with saturated sodium chloride, dried over sodium εμίίβίβ, filtered, and concentrated to give a semi-solid which was purified via silica gel chromatography (Biotage Isolera, 10-60% EtOAc:hexanes, 24 g column, loaded as a solution in DCM) to give the desired product (270 mg, 56%) as a colorless solid. LC-MS (ES) m/z = 508.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.18 (d, J=6.36 Hz, 2 H) 3.30 (br. s., 2 H) 3.66 - 3.73 (m, 3 H) 4.43 (d, J=5.62 Hz, 2 H) 4.83 - 5.12 (m, 4 H) 5.79 (ddt, J=16.93, 10.21 , 6.60, 6.60 Hz, 1 H) 5.88 - 6.02 (m, 2 H) 6.73 - 6.93 (m, 4 H) 7.02 - 7.28 (m, 4 H) 7.59 (br. s., 1 H) 8.15 (s, 1 H) 8.28 (br. s., 1 H) 9.89 (s, 1 H) 13.71 (s, 1 H)

e) (18Z)-7-hydroxy-22-methoxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6, 8, 12, 14, 16(26), 18,21 , 23-decaene-6- carboxamide and (18E)-7-hydroxy-22-methoxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa-1 (25),4,6, 8, 12, 14, 16(26), 18,21 , 23-decaene-6- carboxamide

5-(N-(3-allyl-4-methoxyphenyl)sμLfamoyl)-4-((3-allylbenzyl) amino)-2-hydroxybenzamide

(252.2 mg, 0.497 mmol) was dissolved in dichloromethane (20 ml_) with stirring. Nitrogen was bubbled directly into the solution for 15 min. [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2- ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (19.47 mg, 0.025 mmol) was added and the solution was stirred at room

temperature for 16h. The reaction was filtered while washing with DCM and dried to afford a colorless solid (153.1 mg) as a 5:1 mixture of E:Z isomers. The solid was purified via reverse- phase HPLC (Column: XBridge C18, 30x 150mm, 5u, mobile phase: A: Water + 0.1 %

NH40H; B: MeCN Flow rate: 35ml/min Gradient: 10%B to 50% B in 8 min, then hold at 50%B for 10min) to give the following:

Z isomer: minor isomer as a colorless solid (1 1 .6 mg). LC-MS (ES) m/z = 480.3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.10-3.60 (m, 4 H) 3.71 (s, 3 H) 4.41 (d, J=5.14 Hz, 2 H) 5.53 - 5.73 (m, 3 H) 6.78 (d, J=9.05 Hz, 2 H) 7.03 (d, J=2.45 Hz, 1 H) 7.08 - 7.30 (m, 5 H) 7.38 (br. s., 1 H) 8.15 (m, 1 H) 8.30 (s, 1 H) 8.60 (br. s., 1 H) 9.91 (br. s., 1 H);

E isomer: major isomer as a colorless solid (27.9 mg). LC-MS (ES) m/z = 480.3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.15 (d, J=3.67 Hz, 2 H) 3.37 (d, J=3.18 Hz, 3 H) 3.66 - 3.76 (m, 3 H) 4.43 (d, J=5.14 Hz, 2 H) 5.47 - 5.57 (m, 2 H) 5.72 (s, 1 H) 6.74 - 6.92 (m, 3 H) 7.10 (d, J=3.67 Hz, 1 H) 7.18 - 7.33 (m, 3 H) 7.38 (s, 1 H) 7.99 (s, 1 H) 8.31 (s, 1 H) 8.53 (br. s., 1 H) 9.79 (br. s., 1 H).

Example 14

(18E)-22-chloro-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10-

a) N-(3-bromo-4-chlorophenyr)acetamide

A solution of 3-bromo-4-chloroaniline (4.6 g, 22.28 mmol) and 4-methylmorpholine (2.254 g, 22.28 mmol) in DCM (20 ml) was cooled to 0 °C. A solution of acetyl chloride (1 .749 g, 22.28 mmol) in DCM (10 ml) was added dropwise over 10 min and the suspension was stirred and allowed to warm to room temperature over 24h. The cloudy reaction was diluted with 1 N HCI and DCM and the suspension was filtered and dried to afford the desired product (3.87 g, 70%) as a colorless solid. LC-MS (ES) m/z = 248.0 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ ppm 2.06 (s, 3 H) 7.41 - 7.65 (m, 2 H) 8.12 (d, J=2.26 Hz, 1 H) 10.22 (s, 1 H).

b) N-(3-allyl-4-chlorophenyl)acetamide

A mixture of N-(3-bromo-4-chlorophenyl)acetamide (3.78 g, 15.21 mmol) and

tetrakis(triphenylphosphine)palladium(0) (1 .758 g, 1 .521 mmol) in toluene (60 mL) was stirred at room temperature while nitrogen was bubbled directly into the reaction for 15 min.

Allyltributylstannane (4.72 mL, 15.21 mmol) was then added and the reaction was stirred and heated under reflux for 6h under an inert atmosphere. The reaction was cooled, concentrated, and the residue was purified by chromatography (silica gel, gradient elution 10- 60% EtOAc:hexanes over 45 min, 120 g column, loaded as a solution in DCM) to afford the desired product (2.4 g, 75%) as a pale yellow solid. LC-MS (ES) m/z = 210.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .94 - 2.08 (m, 3 H) 3.42 (d, J=6.60 Hz, 2 H) 4.90 - 5.19 (m, 2 H) 5.93 (ddt, J=16.90, 10.24, 6.48, 6.48 Hz, 1 H) 7.34 (d, J=8.56 Hz, 1 H) 7.45 - 7.57 (m, 2 H) 10.02 (s, 1 H).

c) 3-allyl-4-chloroaniline

A mixture of N-(3-allyl-4-chlorophenyl)acetamide (2.32 g, 1 1 .06 mmol) and 50% aq. NaOH (5.76 mL, 1 1 1 mmol) in ethanol (30 mL) was stirred and heated under reflux for 3h. The reaction was concentrated in vacuo and the residue was suspended in water and treated with 6N HCI until pH 8-9. The suspension was extracted with DCM (2X) and the DCM layers were washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, concentrated, and purified via silica gel chromatography (Biotage Isolera, 0-35% EtOAc:hexanes, 120 g column, loaded as a solution in DCM:hexanes) to give a reddish oil. The oil was further purified via silica gel chromatography (Biotage Isolera, 0-20% EtOAc:hexanes, 40 g column, loaded as a solution in hexanes) to give the desired product (572.1 mg, 31 %) as a yellow liquid. LC-MS (ES) m/z = 168.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.18 - 3.31 (m, 2 H) 5.01 - 5.1 1 (m, 2 H) 5.17 (s, 2 H) 5.81 - 5.97 (m, 1 H) 6.35 - 6.52 (m, 2 H) 7.01 (d, J=8.31 Hz, 1 H) d) 5-(N-(3-allyl-4-chlorophenyl ^' )s Lfamoyl ^' )-4-fluoro-2-hvdroxybenzamide

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (860 mg, 3.39 mmol), 3-allyl-4-chloroaniline (568.1 mg, 3.39 mmol) and pyridine (0.274 ml_, 3.39 mmol) in dichloromethane (20 ml_) was stirred at room temperature for 24h. The reaction was concentrated in vacuo and the residue was triturated with water. The filtered solid was triturated with 50 ml of 3% MeOH:DCM and suspension was filtered and purified via chromatography on silica gel (Biotage Isolera, 0-40% EtOAc:hexanes, 40 g column, loaded as a solution in 12 ml of 1 :1 EtOAc:hexanes) then further purified via reverse phase HPLC (C-18 silica gel, 37-67% MeCN:water with 0.1 % TFA, 1 1 x 1000 μΙ_ injections, loaded as a solution in DMSO) and the product fractions were combined and concentrated afford the desired product (441 .1 mg, 34%) as a colorless solid. LC-MS (ES) m/z = 385.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ ppm 3.35 (s, 2 H) 4.83 - 5.06 (m, 2 H) 5.82 (ddt, J=16.90, 10.24, 6.36, 6.36 Hz, 1 H) 6.79 - 7.13 (m, 3 H) 7.30 (d, J=8.80 Hz, 1 H) 8.14 (br. s., 1 H) 8.46 (d, J=8.31 Hz, 1 H) 8.73 (br. s., 1 H) 10.64 (s, 1 H) 14.22 (br. s., 1 H).

e) 5-(N-(3-allyl-4-chlorophenyl)suLfamoyl)-4-((3-allylbenzyl)am ino)-2-hvdroxybenzamide A mixture of 5-(N-(3-allyl-4-chlorophenyl)sμLfamoyl)-4-fluoro-2-hydroxyb enzamide (214 mg, 0.556 mmol), (3-allylphenyl)methanamine, hydrochloride (102.1 mg, 0.556 mmol), and DIEA (0.388 mL, 2.223 mmol) in 1 -butanol (3 mL) was heated at 150 °C for 4h under microwave irradiation. The reaction was concentrated to give a pale yellow gum which was dissolved in ethenwater and the layers were separated. The ether layer was dried over sodium εμίίβίβ, filtered, concentrated, and the solid was purified via reverse phase HPLC (C-18 silica gel, 55-85% MeCN:water with 0.1 % TFA, loaded as a solution in DMSO, 3 x 1000 μΐ injections). The desired fractions were combined to afford the desired product (156.6 mg, 55%) as a colorless solid. LC-MS (ES) m/z = 512.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.29 (d, J=6.85 Hz, 2 H) 3.34 (d, J=6.36 Hz, 2 H) 4.44 (d, J=5.87 Hz, 2 H) 4.89 - 5.09 (m, 4 H) 5.89 (s, 2 H) 6.75 (br. s., 1 H) 6.95 (dd, J=8.56, 2.69 Hz, 1 H) 7.01 - 7.15 (m, 4 H) 7.18 - 7.31 (m, 2 H) 7.64 (br. s., 1 H) 8.28 (s, 1 H) 8.39 (br. s., 1 H) 10.47 (br. s., 1 H) 13.79 (br. s., 1 H).

f) (18EV22-chloro-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracvclo[19.3.1 .1 ¹² . ¹⁶ .0 ⁴ . ⁹ lhexacosa-1 (25).4.6.8.12.14.16(26).18.21 .23-decaene-6- carboxamide.

5-(N-(3-allyl-4-chlorophenyl^Lfamoyl)-4-((3-allylbenzyl)am (143.0 mg, 0.279 mmol) was suspended in dichloromethane (50 ml_) with stirring. Nitrogen was bubbled directly into the solution for 15 min. [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2- ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (10.95 mg, 0.014 mmol) was quickly added and the reaction was stirred at room temperature for 18h then heated under reflux for 3. Oh. Additional [1 ,3-Bis(2,6-di-i- propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (10.95 mg, 0.014 mmol) was added and the reaction was heated under reflux for 2h. The reaction was cooled and stirred for 3 days at room temperature. The DCM was removed in vacuo and the solid was dissolved in EtOAc (50 ml) and nitrogen was bubbled into the solution for 15 min. The degassed mixture was stirred for 10 min at which time the mixture became green and homogeneous. The reaction was stirred at room temperature for 24h and concentrated in vacuo. The residue was purified via chromatography (C-18 silica gel, 40-70% MeCN:water with 0.1 % TFA, 2 x 1000 μΙ_ injections, loaded as a solution in 2 ml DMSO) and the collected fractions were allowed to stand for 3 days at room temperature in a suspension which was filtered to afford the desired product (50.1 mg, 37%) as a colorless solid. LC-MS (ES) m/z = 484.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.27 - 3.34 (m, 2 H) 3.39 (d, J=5.62 Hz, 2 H) 4.46 (d, J=5.14 Hz, 2 H) 5.47 - 5.67 (m, 2 H) 5.81 (s, 1 H) 6.89 (br. s., 1 H) 6.99 (d, J=1 .96 Hz, 1 H) 7.08 - 7.19 (m, 1 H) 7.24 - 7.37 (m, 5 H) 7.58 (br. s., 1 H) 8.08 (s, 1 H) 8.27 (br. s., 1 H) 10.35 (br. s., 1 H) 13.64 (br. s., 1 H).

Example 15a and 15b

(16E)-7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricycloH 7.3.1.0 ⁴ , ⁹ 1tricosa-

1 (22).4.6.8.16.19(23).20-heptaene-6-carboxamide and

(16Z)-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10-diazatricvclon 7.3.1.0 ⁴ . ⁹ 1tricosa-

a) 4-{[2-(but-3-en-1 -yloxy)ethyl]amino}-2-hydroxy-5-{[3-(prop-2-en- 1 yl)phenyl]sμLfamoyl}benzamide.

A solution of 5-(N-(3-allylphenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (150 mg, 0.428 mmol), 2-(but-3-en-1 -yloxy)ethanamine (59.2 mg, 0.514 mmol), and DIEA (0.090 mL, 0.514 mmol) in n-BuOH (3 mL) was heated at 155 °C under microwave irradiation for 1 h. The mixture was evaporated then dissolved in EtOAc (10 mL), washed with 1 M HCI solution (2 x 5 mL), and the organics were dried over Na ₂ S0 ₄ , filtered, and evaporated. The crude product was dissolved in refluxing DCM/MeOH (~1 mL), treated dropwise with EtOAc (~3mL) and allowed to cool to room temperature overnight. The supernatant was decanted and the precipitate dried under vacuum to afford the desired product (99 mg; 50%) as a beige solid. LCMS (ES) m/z = 446.1 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d6) δ ppm 13.81 (br. s., 1 H), 10.12 (br. s., 1 H), 8.35 (br. s., 1 H), 8.22 (s, 1 H), 7.62 (br. s., 1 H), 7.17 - 7.07 (m, 1 H), 6.95 - 6.86 (m, 2H), 6.81 (d, J=7.6 Hz, 1 H), 6.33 (t, J=5.3 Hz, 1 H), 6.08 (s, 1 H), 5.91 - 5.71 (m, 2H), 5.15 - 4.89 (m, 4H), 3.55 (t, J=5.5 Hz, 2H), 3.47 (t, J=6.7 Hz, 2H), 3.25 (d, J=6.6 Hz, 2H), 2.26 (ddt, J=1 .3, 5.5, 6.7 Hz, 2H).

b) (16E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ⁱ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide and (16Z)-7-hydroxy-3,3-dioxo-13- oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ^{4 9} tricosa-1 (22),4,6, 8, 16,19(23),20-heptaene-6- carboxamide

A solution of 4-{[2-(but-3-en-1 -yloxy)ethyl]amino}-2-hydroxy-5-{[3-(prop-2-en-1 - yl)phenyl^Lfamoyl}benzamide (125 mg, 0.281 mmol.) in EtOAc (3 mL) was treated with [1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (5 mg) and the solution was stirred at room temperature for 5 h, then left unstirred at room temperature overnight. The mixture was filtered, the filtrate evaporated and the residue purified by chromatography (silica gel, gradient 0-100% EtOAc/hexanes) to afford the desired product (15 mg; 13%) as a mixture of (E) and (Z)-isomers. LCMS (ES) m/z = 418.3 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d6) δ ppm 13.52 (br. s., 1 H), 9.90 - 9.67 (m, 1 H), 8.18 - 8.05 (m, 2H), 7.58 (br. s., 1 H), 7.17 - 7.09 (m, 1 H), 7.08 - 6.98 (m, 1 H), 6.96 - 6.84 (m, 2H), 6.45 -6.30 (m, 1 H), 6.13 - 6.04 (m, 1 H), 5.55 - 5.38 (m, 2H), 3.62 - 3.47 (m, 5H), 3.28 - 3.15 (m, 3H), 2.37 - 2.16 (m, 2H).

Example 16

(18E)-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10,23-triazatetracvclon 9.3.1.1 ¹² , ¹⁶ .0 ⁴ , ⁹ 1hexacosa- 1 (25) ,4,6, 8.12.14.16(26).18.21 ,23-decaene-6-carboxamide trifluoroacetate

a) 5-allylpyridin-3-amine

A mixture of tert-butyl (5-bromopyridin-3-yl)carbamate (3.0 g, 10.98 mmol) and allyltributylstannane (3.41 mL, 10.98 mmol) in toluene (40 mL) was stirred at room temperature while nitrogen was bubbled directly into the reaction for 15 min. A condenser with a nitrogen inlet was added to the flask and solid tetrakis(triphenylphosphine)palladium(0) (1 .269 g, 1 .098 mmol) was added in one portion. The reaction was heated at 90 °C for 20h, concentrated in vacuo, and the residue was triturated with DCM. The suspension was filtered and the filtrate was concentrated and purified via silica gel chromatography (Biotage Isolera, 0-7% MeOH:DCM, 120 g column, loaded as a solution in DCM) to give a yellow viscous oil which was dissolved in 1 ,4-dioxane (7 ml) with stirring. 4M HCI in 1 ,4-dioxane was added (14 mL, 56 mmol) and the solution was stirred at room temperature for 2h. The suspension was concentrated in vacuo and the residue was triturated with diethyl ether. The suspension was filtered and dried to afford the desired product (671 .0 mg, 46%) as a pale yellow solid. LC-MS (ES) m/z = 135.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.44 (d, J=6.85 Hz, 2 H) 5.13 - 5.20 (m, 2 H) 5.91 - 6.01 (m, 1 H) 7.45 (d, J=1 .71 Hz, 1 H) 7.87 - 7.93 (m, 2 H). b) 5-(N-(5-allylpyridin-3-yl)s Lfamoyl)-4-fluoro-2-hvdroxybenzamide

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 -sμLfonyl chloride (429 mg, 1 .692 mmol), 5-allylpyridin-3-amine, hydrochloride (288.7 mg, 1 .692 mmol), and pyridine (1 .368 ml_, 16.92 mmol) was stirred at room temperature for 1 h. Additional 5-carbamoyl-2-fluoro-4- hydroxybenzene-I ^Lfonyl chloride (429 mg, 1 .692 mmol) was added and the reaction was stirred for 20h at room temperature. The reaction was concentrated in vacuo and the residue was purified via reverse-phase chromatography (C-18 silica, 5-35% MeCN:water with 0.1 % TFA, loaded as a solution in DMSO, 1 .2 g dissolved up to 1 .6 ml in DMSO, 16 x 1000 μΙ_ injections) to give the desired product (220.6 mg, 37%) as a pale yellow solid. LC-MS (ES) m/z = 352.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ ppm 3.34 (d, J=6.36 Hz, 2 H) 4.80 - 5.14 (m, 2 H) 5.86 (ddt, J=16.93, 10.21 , 6.60, 6.60 Hz, 1 H) 6.95 (d, J=1 1 .74 Hz, 1 H) 7.42 (t, J=1 .96 Hz, 1 H) 8.04 - 8.30 (m, 3 H) 8.49 (d, J=8.31 Hz, 1 H) 8.74 (br. s., 1 H) 10.94 (br. s., 1 H) 14.30 (br. s., 1 H).

c) 4-((3-allylbenzyl)amino)-5-(N-(5-allylpyridin-3-yl)s Lfamoyl)-2-hvdroxybenzamide

A mixture of 5-(N-(5-allylpyridin-3-yl)sμLfamoyl)-4-fluoro-2-hydroxybenz amide (103.0mg, 0.293 mmol), (3-allylphenyl)methanamine, hydrochloride (53.8 mg, 0.293 mmol), and DIEA (0.205 ml_, 1 .173 mmol) in 1 -butanol (3 ml_) was heated at 150 °C under microwave irradiation for 60 min, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in EtOAc/water and the layers were separated and the EtOAc layer was washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated. The residue was purified via chromatography on silica gel (Biotage Isolera, 0-5% MeOH:DCM over 15 CV, 12 g column, loaded as a solution in DCM with a couple drops of MeOH) to give the desired product (25.2 mg, 18%) as a colorless solid. LC-MS (ES) m/z = 479.4 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.18 (d, J=5.14 Hz, 2 H) 4.00 - 4.13 (m, 1 H) 4.45 (d, J=5.62 Hz, 2 H) 4.92 - 5.10 (m, 4 H) 5.79 - 5.98 (m, 3 H) 6.79 (br. s., 1 H) 7.03 - 7.26 (m, 4 H) 7.33 (s, 1 H) 7.65 (br. s., 1 H) 8.05 (s, 1 H) 8.16 (d, J=2.45 Hz, 1 H) 8.29 (s, 1 H) 8.42 (br. s., 1 H) 10.63 (br. s., 1 H) 13.83 (br. s., 1 H).

d) (18EV7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10.23-triazatetracvclo[19.3.1 .1 ¹² . ¹⁶ .0 ⁴ . ⁹ lhexacosa- 1 (25),4,6,8,12,14,16(26),18,21 ,23-decaene-6-carboxamide trifluoroacetate

4-((3-allylbenzyl)amino)-5-(N-(5-allylpyridin-3-yl)sμLfamoy l)-2-hydroxybenzamide (23.2 mg, 0.048 mmol) was dissolved in ethyl acetate (14 ml_) with stirring and nitrogen was bubbled directly into the solution for 15 min. [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 - (methoxy(methyl)amino)-1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (3.80 mg, 4.85 μηιοΙ) was added and the reaction was stirred at room temperature for 18h. The reaction was heated at 55 °C for 20h and then heated under reflux for 2h. Additional [1 ,3-Bis(2,6-di-i- propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (3.80 mg, 4.85 μηιοΙ) was added and the reaction was heated under reflux for a further 5h. The reaction was cooled and concentrated in vacuo. The solid was purified via reverse-phase chromatography (C-18 silica gel, 25-55% MeCN:water with 0.1 % TFA, single injection in 1000 μΙ_ of DMSO) to give the desired product (6.3 mg, 23%, 5:1 mixture of E:Z isomers) as a colorless solid. LC-MS (ES) m/z = 451 .3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.29 (d, J=6.36 Hz, 4 H) 3.41 - 3.49 (m, 1 H) 4.45 - 4.52 (m, 2 H) 5.45 - 5.65 (m, 2 H) 5.78 - 5.82 (m, 1 H) 6.92 (t, J=5.75 Hz, 1 H) 6.97 - 7.03 (m, 1 H) 7.10 (s, 2 H) 7.13 (s, 1 H) 7.24 - 7.31 (m, 4 H) 7.62 (br. s., 1 H) 8.15 (d, J=1 .71 Hz, 1 H) 8.19 (s, 1 H) 8.23 - 8.38 (m, 1 H) 8.49 (d, J=2.20 Hz, 1 H) 10.46 (s, 1 H) 13.62 - 13.76 (m, 1 H).

Example 17

(18E)-22-r2-(dimethylamino)ethoxy1-7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10- diazatetracvcloM 9.3.1.1 ¹² . ¹⁶ .0 ⁴ . ⁹ 1hexacosa-1 (25).4.6.8.12.14.16(26).18.21 ,23-decaene-6- carboxamide

a) N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)acetamide

60% NaH (0.215 g, 5.39 mmol) was suspended in DMF (4 ml) and the suspension was stirred at room temperature under nitrogen. A solution of N-(3-allyl-4-hydroxyphenyl)acetamide (1 .03 g, 5.39 mmol) in DMF (5 ml) was added and the brown mixture was stirred for 15 min. 2-bromo- Ν,Ν-dimethylethanamine, hydrobromide (0.627 g, 2.69mmol) was added as a solid and the mixture was stirred at room temperature for 48h. Additional 60% NaH (0.215 g, 5.39 mmol) was added followed by addition of 2-bromo-N,N-dimethylethanamine, hydrobromide (0.627 g, 2.69mmol) and the reaction was stirred for 18h at room temperature. Added an additional 1 .0 eq of NaH (215 mg) and stirred 1 hour at room temperature. The reaction was poured into ice- water and stirred until the ice had melted. The solution was transferred to a separatory funnel and the pH was adjusted to 8 using 2M HCI. The solution was extracted with ether and the ether was washed with 2M NaOH, water, dried over sodium εμίίβίβ, filtered, and concentrated. The ΓΘεμΙ-ίΐΓ^ solid was purified via silica gel chromatography (Biotage Isolera, 24 g column, 0-15% MeOH:DCM over 45 min, loaded as a solution in DCM) to give the desired product (88.0 mg, 6%) as a pale yellow solid. LC-MS (ES) m/z = 263.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .99 (s, 3 H) 2.22 (s, 6 H) 2.62 (t, J=5.75 Hz, 2 H) 3.28 (d, J=6.85 Hz, 2 H) 4.01 (t, J=5.87 Hz, 2 H) 4.97 - 5.10 (m, 2 H) 5.92 (ddt, J=16.93, 10.09, 6.79, 6.79 Hz, 1 H) 6.89 (d, J=8.80 Hz, 1 H) 7.28 (d, J=2.45 Hz, 1 H) 7.40 (dd, J=8.80, 2.69 Hz, 1 H) 9.71 (s, 1 H).

b) 3-allyl-4-(2-(dimethylamino)ethoxy)aniline

N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)acetamide (87.0 mg, 0.332 mmol) was dissolved in ethanol (2 ml_) with stirring. Aqueous sodium hydroxide (0.173 ml_, 3.32 mmol, 19.2 M) was added and the solution was heated under reflux for 7h and cooled to room temperature. The reaction was neutralized with 6N HCI and the mixture was concentrated. The residue was dissolved in a mixture of DCM and water. The layers were separated and the aqueous layer was extracted twice with DCM The combined DCM layers were washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated to give the desired product (68.5 mg, 94%) as a reddish oil as a mixture of isomers (70% allyl and 30% styryl). LC-MS (ES) m/z = 221 .2 [M+H] ⁺ Ή NMR (400 MHz, CDCI3-tf) δ ppm 2.29 - 2.41 (m, 6 H) 2.68 - 2.80 (m, 2 H) 3.35 (d, J=6.60 Hz, 2 H) 3.97 - 4.06 (m, 2 H) 5.00 - 5.13 (m, 2 H) 5.89 - 6.25 (m, 1 H) 6.48 - 6.82 (m, 3 H).

c) 5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)suLfamoyl)-4 -fluoro-2-hvdroxybenzamide

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (69.1 mg, 0.272 mmol), 3-allyl-4-(2-(dimethylamino)ethoxy)aniline (60.0 mg, 0.272 mmol), and pyridine (0.022 ml_, 0.272 mmol) in dichloromethane (12 ml_) was stirred for 2h at room temperature. The reaction was concentrated in vacuo and purified via reverse-phase chromatography (C-18 silica gel, 3 x 1000 μΙ_ injections, loaded as a solution in 3 ml of DMSO, 5-35% MeCN:water with 0.1 %TFA) to give the desired product (20.4 mg, 17%) as a pale yellow oil. LC-MS (ES) m/z = 438.3 [M+H] ^{+ 1} H NMR (400 MHz, METHANOL-d,) δ ppm 2.95 - 3.02 (m, 6 H) 3.24 - 3.40 (m, 2 H) 3.54 - 3.63 (m, 2 H) 4.23 - 4.33 (m, 2 H) 4.78 - 4.92 (m, 1 H) 5.03 (dd, J=10.03, 1 .71 Hz, 1 H) 5.90 (ddt, J=16.93, 10.33, 6.17, 6.17 Hz, 1 H) 6.74 (d, J=1 1 .49 Hz, 1 H) 6.90 (d, J=8.80 Hz, 1 H) 6.96 (d, J=2.45 Hz, 1 H) 7.01 - 7.08 (m, 1 H) 8.25 (d, J=8.07 Hz, 1 H).

d) 5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)sμLfamoyl)- 4-((3-allylbenzyl)amino)-2- hydroxybenzamide

A mixture of 5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)sμLfamoyl)- 4-fluoro-2- hydroxybenzamide (17.0 mg, 0.039 mmol), (3-allylphenyl)methanamine, hydrochloride (7.14 mg, 0.039 mmol), and DIEA (0.027 mL, 0.155 mmol) in 1 -butanol (1 .5 mL) was heated at 150 °C under microwave irradiation for 90 min. The reaction was concentrated in vacuo to afford the desired product (28.2 mg) as a colorless oil. The crude product was carried on to the next step without further purification. LC-MS (ES) m/z = 565.5 [M+H] ⁺ .

e) 18EV22-[2-(dimethylamino)ethoxyl-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatetracycloH 9.3.1 .1 ■0 ⁴ , ⁹ lhexacosa-

1 (25),4,6, 8,12,14,16(26), 18,21 ,23-decaene-6-carboxamide, hydrochloride

5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)sμLfamoy l)-4-((3-allylbenzyl)amino)-2- hydroxybenzamide (27.7 mg, 0.049 mmol) was dissolved in dichloromethane (10 ml_) with stirring. Nitrogen was bubbled directly into the solution for 15 min. [1 ,3-Bis(2,6-di-i- propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (3.84 mg, 4.91 μηιοΙ) was quickly added and the green homogeneous reaction was stirred at

room temperature for 44h. The reaction was concentrated in vacuo and purified via reverse- phase chromatography (C-18 silica gel, 23-53% MeCN:water with 0.1 % TFA, sample in DMSO, single 850 μΙ_ injection). The product fractions were combined and neutralized by addition of 1 N NaOH. The neutralized solution was concentrated and the residue was triturated with EtOAc and filtered.

The filtrate was concentrated in vacuo to give a colorless oil. The oil was dissolved in 0.3 ml of 1 ,4-dioxane and 4M HCI in 1 ,4-dioxane (0.3 ml) was added. The solution was stirred until a suspension appeared. The suspension was concentrated to give the desired product (9.7 mg, 35%) as a colorless solid as a 9:1 mixture of E:Z isomers. LC-MS (ES) m/z = 537.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.78 - 2.85 (m, 6 H) 3.23 (d, J=5.14 Hz, 2 H) 3.37 (d, J=4.65 Hz, 3 H) 3.57 (s, 1 H) 3.65 - 3.75 (m, 2 H) 4.25 - 4.32 (m, 2 H) 4.46 (d, J=5.14 Hz, 2 H) 5.50 - 5.57 (m, 2 H) 5.81 (s, 1 H) 6.89 (d, J=9.05 Hz, 1 H) 6.95 (d, J=2.45 Hz, 1 H) 7.01 (t, J=5.62 Hz, 1 H) 7.08 - 7.47 (m, 2 H) 7.51 (br. s., 1 H) 8.09 (s, 1 H) 8.20 (s, 1 H) 10.13 (s, 1 H) 10.51 (br. s., 1 H) 13.54 (br. s., 1 H).

Example 18

(18E)-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10,14-triazatetracycloH 9.3.1.1 ¹² , ¹⁶ .0 ⁴ , ⁹ 1hexacosa-

a) fe/ -Butyl ((5-allylpyridin-3-yl)methyl)carbamate

A mixture of tert-butyl ((5-bromopyridin-3-yl)methyl)carbamate (0.228 g, 0.794 mmol), allyltributylstannane (0.369 mL, 1 .191 mmol), palladiumtetrakis (0.092 g, 0.079 mmol) and lithium chloride (0.168 g, 3.97 mmol) in toluene (5 mL) was degassed by vacuum-nitrogen backfilling and then heated at 1 10 °C overnight (gentle reflux). The reaction mixture was cooled, directly loaded on a 24g silica gel column and eluted with 10-80% EtOAc/hexanes to afford the title compound as a colorless liquid. MS (ES) m/z = 249.3 [M+H] ⁺ . 1 H NMR (400 MHz, CDC ) δ ppm 8.40 (d, J=10 Hz, 2 H), 7.49 (s, 1 H), 5.86 - 6.04 (m, 1 H), 5.06 - 5.22 (m, 2 H), 4.34 (d, J=5 Hz, 2 H), 3.42 (d, J=7 Hz, 2 H), 1 .48 (s, 9 H).

b) (5-allylpyridin-3-yl)methanamine, bis-trifluoroacetic acid salt

A solution of tert-butyl ((5-allylpyridin-3-yl)methyl)carbamate (0.15 g, 0.604 mmol), and TFA (0.5 mL, 6.49 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction was incomplete so was evaporated then the residue was dissolved neat TFA (2ml) and stirred for 3h. The mixture was evaporated and triturated with diethyl ether to afford the desired product (232 mg; quant.) as a solid. MS (ES) m/z = 149.2 [M+H] ⁺ .

c) 5-(N-(3-allylphenyl)s Lfamoyl)-4-(((5-allylpyridin-3-yl)methyl)amino)-2-hvdroxyben zamide, Trifluoroacetic acid salt

A mixture of 5-(N-(3-allylphenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (80 mg, 0.228 mmol), (5-allylpyridin-3-yl)methanamine, bis-trifluoroacetic acid salt (0.1 18 g, 0.314 mmol) and N,N-diisopropylethylamine (0.160 mL, 0.913 mmol) in 1 -Butanol (2 mL) was heated at 150 °C for 2h under microwave irradiation then concentrated in vacuo. The residue was dissolved in 1 .2mL of MeOH

and purified by chromatography (C-18 silica, 15-45% MeCN/0.1 % TFA aqueous solution, 13.4min) to afford the title compound (32.8 mg; 18%) as a brown solid. LC-MS (ES) m/z = 479.1 [M+H] ⁺ .

d) (18E)-7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10.14-triazatetracvclo[19.3.1 .1 ¹² . ¹⁶ .0 ⁴ . ⁹ lhexa cosa- 1 (25).4(9).5.7.12.14.16(26).18.21 ,23-decaene-6-carboxamide

5-(N-(3-allylphenyl)sμLfamoyl)-4-(((5-allylpyridin-3-yl)met hyl)amino)-2-hydroxybenzamide, trifluoroacetic acid salt (32mg, 0.041 mmol) was dissolved in ethyl acetate (10 mL) and degassed

by vacuum-nitrogen backfilling cycles. GreenCat (14 mg, 0.018 mmol) was added. The homogeneous reaction mixture was heated under gentle reflux for 1 .5h and concentrated in vacuo. The residue was purified by chromatography (silica gel, 12g column, 50-100% EtOAc/hexanes) to afford the title compound (1 1 mg; 60%) as a gray solid as a (~1 :5) mixture of cis:trans isomers. LC-MS (ES) m/z = 451 .2 [M+H] ⁺ . Example 19

7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10,13,15,25- pentaazatetracvcloM 8.3.1.1 ¹² . ¹⁵ .0 ⁴ . ⁹ 1pentacosa-1 (24).4(9).5.7.12(25),13,17,20,22- nonaene-6-carboxamide (E and Z forms)

a) 1 -allyl-1 H-1 ,2,4-triazole-3-carbonitrile

To a mixture of 1 H-1 ,2,4-triazole-3-carbonitrile (0.8935 g, 9.50 mmol) and potassium carbonate (3.46 g, 25.04 mmol) in acetone (100 ml_) was added allyl bromide (1 .027 ml_, 1 1 .87 mmol). The Γβεμίίβηί mixture was stirred at room temperature overnight then stirred at 50 °C for 2h. The solids were removed by filtration and washed with acetone. The filtrate was concentrated in vacuo to afford the title product as a brown oil (1 .2 g; 80%) that was directly used for the next step without further purification. LC/MS: m/z 135.1 (M+H) ⁺ .

b) (1 -allyl-1 H-1 ,2,4-triazol-3-yl)methanamine

To the solution of 1 -allyl-1 H-1 ,2,4-triazole-3-carbonitrile (1 .2 g, 8.95 mmol) in THF (10 mL) at ~ 0 °C was added lithium aluminum hydride (0.5 g, 13.17 mmol) slowly. The Γβεμίίβηί mixture was stirred at ~ 0 °C for 0.5h, quenched with water (0.5ml_) slowly, followed by MeOH (10ml_) upon cooling, filtered through a Celite pad and washed with MeOH. The filtrate was concentrated and the residue was dissolved in EtOAc (75ml_), stirred and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (0.96g; 47%) as a brown liquid which was used without further purification.

c) 4-(((1 -allyl-1 H-1 , 2,4-triazol-3-yl)methyl)amino)-5-(N-(3-allylphenyl)s Lfamoyl)-2- hvdroxybenzamide, trifluoroacetic acid salt

A mixture of 5-(N-(3-allylphenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (1 10 mg, 0.188 mmol), (1 -allyl-1 H-1 ,2,4-triazol-3-yl)methanamine (0.3 g, 1 .086 mmol) and

N.Ndiisopropylethylamine (0.5 mL, 2.86 mmol) in 1 -butanol (4 mL) was heated at 150 °C for 2h under microwave irradiation and concentrated in vacuo. The residue was dissolved in 4mL of MeOH and purified by chromatography (C-18 silica, 25-55% MeCN/0.1 % TFA aqueous solution, 13.4 min gradient) to afford the title compound (96.5 mg; 79%) as a brown solid. LCMS (ES) m/z = 469.1 [M+H] ⁺ .

d) 7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10.13.15.25- pentaazatetracvclo[18.3.1 .1 ¹² . ¹⁵ .0 ⁴ . ⁹ lpentacosa-1 (24).4(9).5.7.12(25).13.17.20.22- nonaene-6-carboxamide

4-(((1 -allyl-1 H-1 ,2,4-triazol-3-yl)methyl)amino)-5-(N-(3-allylphenyl)sμLfamo yl)-2- hydroxybenzamide, trifluoroacetic acid salt (95 mg, 0.163 mmol) was dissolved in ethyl acetate (10 mL) and degassed by vacuum-nitrogen backfilling cycles. GreenCat (22.2 mg, 0.028 mmol) was added. The homogeneous reaction mixture was heated under gentle reflux for 1 .5h and concentrated in vacuo. The residue was purified by chromatography (silica gel, 100% EtOAc) to afford the title compound (19.1 mg; 25%) as a gray solid. NMR and LCMS indicated an inseparable mixture of cis and trans isomers (ratio = 1 :2). LC/MS: two peaks at RT = 0.66 and 0.67 min, both presented m/z = 441 .1 (M+H) ⁺ .

Example 20

(16E)-7-hvdroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatricvclon 7.3.1.OVltricosa-

1 (22),4,6,8,16,19(23), 20-heptaene-6-carboxamide and

(16Z)-7-hvdroxy-3.3-dioxo-3A ⁶ -thia-2.10-diazatricvclon 7.3.1.OVltricosa-

a) 4-[(hept-6-en-1 -yl)amino]-2-hydroxy-5-{[3-(prop-2-en-1 - yl)phenyl^Lfamoyl}benzamide.

A solution of 4-fluoro-2-hydroxy-5-{[3-(prop-2-en-1 -yl)phenyl]sμLfamoyl}benzamide (150 mg, 0.428 mmol), hept-6-en-1 -amine (48.5 mg, 0.428 mmol), and DIEA (0.075 mL, 0.428 mmol) in n-BuOH (4 mL) was stirred and heated under microwave irradiation at 155 °C for 1 h. The solution was evaporated, treated with EtOAc (10 mL) and washed with 1 M aq. HCI (2 x 5 mL). The organics were dried over Na ₂ S0 ₄ , filtered, evaporated and the crude product purified by chromatography (silica gel, gradient elution 0-100% EtOAc in hexanes) to afford the desired product (1 18 mg) as a solid. A crop of impure product was also obtained which was re-purified by chromatography [C-18 silica gel, 30 x 50 mm, 5 micron, gradient elution 5-100 % ACN in water (0.1 % TFA)] to afford a second crop of the desired product (20 mg) as a tan solid. LCMS (ES) m/z = 444.4 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d6) δ = 13.81 (s, 1 H), 10.18 (s, 1 H), 8.48 - 8.27 (m, 1 H), 8.23 (s, 1 H), 7.61 (br. s., 1 H), 7.16 - 7.06 (m, 1 H), 6.92 - 6.86 (m, 2H), 6.80 (d, J=7.3 Hz, 1 H), 6.1 1 (t, J=5.4 Hz, 1 H), 6.01 (s, 1 H), 5.89 - 5.75 (m, 2H), 5.06 - 4.90 (m, 4H), 3.25 (d, J=6.8 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.03 (q, J=6.8 Hz, 2H), 1 .54 (quin, J=7.1 Hz, 2H), 1 .44 -1 .28 (m, 4H).

b) (16E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ ' ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide and (16Z)-7-hydroxy-3,3-dioxo-3A ⁶ - thia-2,10-diazatricyclo[17.3.1 .0 ^{4 9} ]tricosa-1 (22),4,6, 8, 16,19(23),20-heptaene-6- carboxamide

A solution of 4-[(hept-6-en-1 -yl)amino]-2-hydroxy-5-{[3-(prop-2-en-1 - yl)phenyl^Lfamoyl}benzamide (1 15 mg, 0.259 mmol) in DCM (4 ml_) was treated with [1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (5.0 mg, 6.38 μηιοΙ) and the mixture was stirred at room temperature for 22 h. (After ~5 h, further catalyst (~ 5 mg) was added). The mixture was filtered and washed with DCM to afford the desired product (75 mg) as a mixture of (16E)-7- hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,16,19(23),20- heptaene-6-carboxamide and (16Z)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10- diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide. LCMS (ES) m/z = 416.3 [M+H] ⁺ .

The filtrate from the above was evaporated and the residue was purified by chromatography [C-18 silica gel, 30 x 50 mm, 5 micron, gradient elution 10-65 % ACN in water (0.1 % TFA) then 100% ACN] to afford a second crop of the desired product as a mixture of (E) and (Z)-isomers (9 mg; 8%). LCMS (ES) m/z = 416.2 [M+H] ⁺ . Ή NMR (400MHz, DMSO-d6) δ = 13.63 (br. s., 1 H), 10.16 (br. s., 1 H), 8.19 (s,2H), 7.56 (br. s., 1 H), 7.17 - 7.07 (m, 2H), 6.89 - 6.77 (m, 2H), 6.12 (br. s., 1 H), 6.02 (s, 1 H), 5.41 (br. s., 2H), 3.26 - 3.16 (m, 4H), 2.05 (br. s., 2H), 1 .53 (br. s., 2H), 1 .41 (br. s., 2H), 1 .33 (d, J=6.0 Hz, 2H).

Example 21

(16E)-7-hvdroxy-3,3-dioxo-14-oxa-3A ⁶ -thia-2,10-diazatricvclon 7.3.1.OVltricosa-

1 (22).4.6.8.16.19(23).20-heptaene-6-carboxamide and

(16Z)-7-hvdroxy-3.3-dioxo-14-oxa-3A ⁶ -thia-2.10-diazatricvclon 7.3.1.0 ⁴ . ⁹ 1tricosa-

a) a) 2-hydroxy-5-{[3-(prop-2-en-1 -γΙ)ρΐΊβηγΙ]5μίί3ΓΤΊογΙ}-4-{[3-(ρΓορ-2 -βη-1 - yloxy)propyl]amino}benzamide.

A solution of 5-(N-(3-allylphenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide (120 mg, 0.343 mmol)], 3-(allyloxy)propan-1 -amine (47.3 mg, 0.41 1 mmol), and DIEA (0.072 ml_, 0.41 1 mmol) in n-BuOH (3 ml_) was heated at 155 °C under microwave irradiation for 1 h. The solution was cooled, poured into EtOAc (20 ml_), Et ₂ 0 (5 ml_), and water (8 ml_). The aqueous phase was extracted with EtOAc (5 ml_) and the combined organics were dried over Na ₂ S0 ₄ , filtered, and evaporated. The residue was azeotroped with DCM (2 x 20 ml_) then suspended in DCM (10 ml_) and left to slowly evaporated until the volume was approximately 2 ml_. The supernatant was decanted and the precipitate dried to afford the desired product (60 mg, 37% yield) as a tan solid. LCMS (ES) m/z = 446.3 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d6) δ ppm 13.80 (br. s., 1 H), 10.15 (br. s., 1 H), 8.34 (br. s., 1 H), 8.23 (s, 1 H), 7.60 (br. s., 1 H), 7.12 (t, J=7.5 Hz, 1 H), 6.94 - 6.85 (m, 2H), 6.81 (d, J=7.3 Hz, 1 H), 6.17 (br. s., 1 H), 6.04 (s, 1 H), 5.97 - 5.72 (m, 2H), 5.26 (d, J=17.3 Hz, 1 H), 5.14 (d, J=10.3 Hz, 1 H), 5.04 - 4.93 (m, 2H), 3.93 (d, J=4.8 Hz, 2H), 3.44 (t, J=5.8 Hz, 2H), 3.27 - 3.18 (m, 4H),1 .79 (t, J=6.3 Hz, 2H).

b) b) (16E)-7-hydroxy-3,3-dioxo-14-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ ' ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide and (16Z)-7-hydroxy-3,3-dioxo-14- oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ^{4 9} ]tricosa-1 (22),4,6, 8, 16,19(23),20-heptaene-6- carboxamide.

To a solution of 2-hydroxy-5-{[3-(prop-2-en-1 -yl)phenyl]sμLfamoyl}-4-{[3-(prop-2-en-1 - yloxy)propyl]amino}benzamide (88 mg, 0.198 mmol) in DCM (4 ml_) was treated with[1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (9.0 mg, 0.01 1 mmol) and the mixture stirred at room temperature for 4 h. The mixture was filtered and evaporated and the residue purified by chromatography [C-18 silica gel, 5 micron, 30 x 50 mm, gradient elution 5-70% ACN in water (0.1 % TFA)] to afford the desired product (10 mg, 12% yield) as a colorless solid as a mixture of (E) and (Z)-isomers. LCMS (ES) m/z = 418.3 [M+H] ^{+ 1} H NMR: (400MHz, DMSO-d6) δ ppm 13.57 (br. s., 1 H), 10.08 (br. s., 1 H), 8.53 - 7.91 (m, 2H), 7.56 (br. s., 1 H), 7.19 - 7.08 (m, 2H), 6.95 - 6.80 (m, 2H), 6.15 (br. s., 1 H), 6.06 - 5.98 (m, 1 H), 5.70 (td, J=7.3, 15.1 Hz, 1 H), 5.58 - 5.42 (m, 1 H), 4.09 - 3.89 (m, 2H), 3.44 (t, J=7.3 Hz, 2H), 3.29 - 3.15 (m, 4H), 1 .82 (br. s., 2H).

Example 22

6-carbamoyl-7-hydroxy-18,18-dimethyl-3,3-dioxo-3A ⁶ -thia-2,10,18-triazatetracyclo- Γ19.3.1.1 ¹² , ^l6 .0 ⁴ , ⁹ 1hexacosa-1 (24).4.6.8.12(26),13,15,21 (25).22-nonaen-18-ium.

trifluoroacetate

c) N-(3-(((tert-butoxycarbonyl)amino)methyl)benzyl)-N,N-dimethy l-2-(3- nitrophenyl)ethanaminium

A solution of fe/ -butyl 3-(aminomethyl)benzylcarbamate (1 .027 g, 4.35 mmol) in DCM (10 mL) was treated with a solution of 1 -(2-bromoethyl)-3-nitrobenzene (1 g, 4.35 mmol) in DCM (5 mL) and the mixture was evaporated under reduced pressure maintaining the temperature below 35 °C. The residue was then heated at 35 °C for 90 min., then raised to 45 °C overnight and then to 60 °C for an additional 2d. The solid reaction mixture was treated with ethanol (10 mL), sonicated, then the suspension filtered to afford a bright yellow solid. This was then treated with acetone (7.5 mL), saturated aqu. NaHC03 (7.56 mL, 8.69 mmol) (~6 equivalents) then iodomethane (0.272 mL, 4.35 mmol) an the mixture stirred at room temperature over the weekend.

The mixture was filtered through a pad of celite, diluted up to ~30 mL total volume with acetone, filtered again through a pad of celite, and the filtrate evaporated. The residue was then diluted up to ~ 25 mL total volume with EtOAc and the organic layer separated. The aqueous layer was further extracted with EtOAc and the combined organic layers dried over sodium εμίίβίβ, evaporated and the residue purified by chromatography [C-18 silica, 25 g, gradient 10% acetonitrile/H ₂ 0 (0.2% ammonium acetate) to 90% acetonitrile/H ₂ 0, (0.2% ammonium acetate) over 16 column volumes] to afford the crude product (612 mg) which was used without further purification. LCMS m/z 414.3 M ⁺ . d) 6-carbamoyl-7-hvdroxy-18 8-dimethyl-3,3-dioxo-3A ⁶ -thia-2, 10, 18-triazatetracyclo- [19.3.1 .1 ¹² . ^l6 .0 ⁴ . ⁹ lhexacosa-1 (24).4.6.8.12(26).1 3.1 5.21 (25).22-nonaen-18-ium trifluoroacetate

A solution of N-(3-(((tert-butoxycarbonyl)amino)methyl)benzyl)-N,N-dimethy l-2-(3- nitrophenyl)ethanaminium (612 mg) in ethanol (10 mL) was heated to 60 °C then treated with a solution of ammonium chloride (605 mg) in water (2 mL). The clear yellow solution was then treated portionwise with iron dust (316 mg, 5.65 mmol) and the mixture stirred and heated at 60 °C for 2h . The mixture was diluted to 30 mL with ethanol and the suspension filtered through a pad of celite to remove iron residues. The filtrate was evaporated then diluted to 30 mL with EtOAc and filtered through a pad of sodium εμίίβίβ to remove the ammonium chloride. The filtrate was evaporated then treated with pyridine (0.1 01 mL, 1 .243 mmol) and DCM (5.0 mL). A mixture of 5-carbamoyl-2-fluoro-4- hydroxybenzene-I ^Lfonyl chloride (287 mg , 1 .130 mmol) in DCM (5.0 mL) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was decanted to remove the supernatant liquid then the residual oil washed with DCM (2 x 10 mL), 1 M aqu . HCI (1 0 mL), and water (10 mL). The residue was treated with ethanol and the suspension filtered. The filtrate was evaporated to afford the crude intermediate N-(3-(((tert-butoxycarbonyl)amino)methyl)benzyl)-2-(3-(5-car bamoyl-2-fluoro- 4-hydroxyphenylsμLfonamido)phenyl)-N,N-dimethylethanaminium used without further purification .

A solution of this intermediate in ethanol (2.0 mL) was treated with HCI (4M in 1 ,4-dioxane) (2.83 mL, 1 1 .30 mmol), and the mixture stirred at 45 °C for 30 min. The reaction mixture was evaporated then treated with isopropanol (1 0.00 mL) and diisopropylethylamine (0.790 mL, 4.52 mmol) and the mixture stirred and heated at 120 °C 2h under microwave irradiation (incomplete conversion to product) then at 150 °C for a further 3h under microwave irradiation. The mixture was cooled , evaporated, partitioned between 1 M aqu. NaOH and EtOAc. The organic layer was separated and the aqueous washed twice more with EtOAc. The aqueous layer was then acidified by addition of 6N aqu . HCI until pH ~1 . The mixture was sonicated , the aqueous supernatant decanted and the solid residue triturated twice with 1 M aqu . HCI. The solid residue was was purified by reverse-phase chromatography [C-1 8 silica, 25 g , gradient 10% acetonitrile/H ₂ 0 (0.2% ammonium acetate) to 90% acetonitrile/H ₂ 0, (0.2% ammonium acetate) over 16 column volumes] to afford the titled compound as a bright colorless solid (9 mg). LCMS m/z 481 .2 (M) ⁺ . 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .29 (s, 2 H) 2.97 - 3.07 (m, 6 H) 3.1 1 - 3.1 9 (m, 2 H) 4.50 (d , J=6.08 Hz, 2 H) 4.55 (s, 2 H) 5.89 (s, 1 H) 6.91 - 6.98 (m, 1 H) 7.02 - 7.08 (m, 1 H) 7.1 1 (m, 1 H) 7.23 (t, J=7.80 Hz, 1 H) 7.36 (t, J=5.70 Hz, 1 H) 7.42 - 7.51 (m, 2 H) 7.55 (t, J=7.48 Hz, 1 H) 7.61 - 7.74 (m, 2 H) 8.08 (br. s., 1 H) 8.18 (s, 1 H) 10.24 (s, 1 H) 13.30 (br. s., 1 H).

Example 23

(E)-14-(2-(dimethylamino)ethoxy)-44-hvdroxy-8-oxa-3-thia-2,5 -diaza-1 (1 ,3),4(1 ,2)- dibenzenacvclotridecaphan-11 -ene-45-carboxamide 3,3-dioxide, Trifluoroacetic acid

salt

a) N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)acetamide

A mixture of N-(3-allyl-4-hydroxyphenyl)acetamide (1 .62 g, 8.47 mmol), triphenylphosphine (3.33 g, 12.71 mmol), and 2-(dimethylamino)ethanol (0.906 g, 10.17 mmol) in anhydrous THF (45 ml) was stirred at room temperature. A solution of (E)-diethyl diazene-1 ,2-dicarboxylate (5.53 g, 12.71 mmol, 40% in toluene) was added followed by addition of dry THF (5 ml). The reaction was stirred for 15h at room temperature then concentrated in vacuo, and purified via silica gel chromatography (Biotage Isolera, 0-15% MeOH:DCM over 15 CV, loaded as a solution in 30 ml DCM) to give the desired product (1 .02 g, 46%) as a tan solid. LC-MS (ES) m/z = 263.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 .99 (s, 3 H) 2.22 (s, 6 H) 2.62 (t, J=5.77 Hz, 2 H) 3.28 (d, J=6.53 Hz, 2 H) 4.01 (t, J=5.77 Hz, 2 H) 4.95 - 5.1 1 (m, 2 H) 5.92 (ddt, J=17.00, 10.10, 6.78, 6.78 Hz, 1 H) 6.90 (d, J=8.78 Hz, 1 H) 7.28 (d, J=2.51 Hz, 1 H) 7.40 (dd, J=8.78, 2.51 Hz, 1 H) 9.73 (s, 1 H).

b) 3-allyl-4-(2-(dimethylamino)ethoxy)aniline

N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)acetamide (1 .00 g, 3.81 mmol) was dissolved in ethanol (20 ml_) with stirring. Aqueous sodium hydroxide (1 .985 ml_, 38.1 mmol, 19.2 M) was added and the solution was heated under reflux for 8h. The reaction was cooled, neutralized to pH 7 with 6N HCI, and concentrated in vacuo. The residue was dissolved in a mixture of DCM and water and the layers were separated. The aqueous layer was extracted with DCM and the combined organics were washed with water and sat. aq. NaCI, dried over sodium εμί-ίβίβ, filtered, and concentrated to give the desired product (721 .0 mg, 86%) as a reddish oil as a mixture of isomers (80% allyl and 20% styryl). LC-MS (ES) m/z = 221 .3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ ppm 2.14 - 2.25 (m, 6 H) 2.54 - 2.62 (m, 2 H) 3.20 (d, J=6.53 Hz, 2 H) 3.89 (t, J=5.90 Hz, 2 H) 4.57 (br. s., 2 H) 4.95 - 5.07 (m, 2 H) 5.90 (ddt, J=16.94, 10.10, 6.68, 6.68 Hz, 1 H) 6.34 - 6.41 (m, 2 H) 6.65 - 6.70 (m, 1 H).

c) 5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)s Lfamoyl ^' )-4-fluoro-2- hvdroxybenzamide, trifluoroacetic acid salt

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (827 mg, 3.26 mmol), 3- allyl-4-(2-(dimethylamino)ethoxy)aniline (718.4 mg, 3.26 mmol), and pyridine (0.264 mL, 3.26 mmol) in dry DMF (7 mL) was stirred at room temperature for 30 min and heated at 60 °C for 30 min. The reaction was cooled and stirred at room temperature for 3 days. The reaction was diluted with water and concentrated in vacuo. The residue was purified via silica gel chromatography (Biotage Isolera, 0-30% MeOH:DCM over 20 CV, 120 gm gold column, loaded as a solution in 10% MeOH:DCM) followed by purification via reverse-phase chromatography (C-18 silica gel, 13 x 1000 μί injections, loaded as a solution in 13 ml of DMSO, 5-35% MeCN:water with 0.1 % TFA) to give the desired product (312.0 mg, 17%) as a white foam. LC- MS (ES) m/z = 438.4 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-cfe) δ ppm 2.85 (d, J=3.42 Hz, 6 H) 3.26 (d, J=6.36 Hz, 2 H) 3.48 (d, J=3.91 Hz, 2 H) 4.13 - 4.28 (m, 2 H) 4.84 - 5.07 (m, 2 H) 5.66 - 5.91 (m, 1 H) 6.77 - 7.00 (m, 4 H) 8.12 (br. s., 1 H) 8.35 (d, J=8.31 Hz, 1 H) 8.65 (br. s., 1 H) 9.53 (br. s., 1 H) 10.18 (s, 1 H).

Impure fractions from the above purification were combined and purified via reverse-phase chromatography (C-18 silica gel, Sunfire C18 column, 30 x100mm, 5u: mobile phase: A: Water + 0.1 % TFA ; B: MeCN + 0.1 % TFA, Flow rate: 35ml/min, Gradient: 2%B to 25% B in 15 min, hold at 25% B for 10 min) to give a second crop of the desired product (272.6 mg, 15%) as a colorless solid. LC-MS (ES) m/z = 438.4 [M+H] ⁺ .

d) 5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)s Lfamoyl)-4-((2-(but-3-en-1 - yloxy)ethyl)amino)-2-hvdroxybenzamide, trifluoroacetic acid salt

A suspension of 5-(N-(3-allyl-4-(2-(dimethylamino)ethoxy)phenyl)sμLfamoyl)- 4-fluoro-2- hydroxybenzamide, trifluoroacetic acid salt (153.1 mg, 0.278 mmol), 2-(but-3-en-1 -yloxy)ethan- 1 -amine (63.9 mg, 0.555 mmol), and DIEA (0.242 mL, 1 .388 mmol) in 1 -butanol (3 mL) was heated at 150 °C for 30 min under microwave irradiation. The reaction was concentrated in vacuo and the residue was purified via reverse-phase chromatography (C-18 silica gel, 15- 45% MeCN:water with 0.1 % TFA, 3 x 1000 μΐ injections, loaded as a solution in DMSO) to give the desired product (126.3 mg, 70%) as a pale yellow solid. LC-MS (ES) m/z = 533.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .23 - 1 .30 (m, 2 H) 2.27 (q, J=6.78 Hz, 2 H) 2.85 (d, J=4.52 Hz, 6 H) 3.23 - 3.35 (m, 4 H) 3.44 - 3.60 (m, 4 H) 4.17 - 4.24 (m, 2 H) 4.88 - 5.20 (m, 4 H) 5.70 - 5.96 (m, 2 H) 6.09 (s, 1 H) 6.33 (t, J=5.27 Hz, 1 H) 6.74 - 6.99 (m, 3 H) 7.62 (br. s., 1 H) 8.12 (s, 1 H) 8.30 (br. s., 1 H) 9.58 (br. s., 1 H) 9.88 (s, 1 H) 13.77 (br. s., 1 H).

e) (E)-14-(2-(dimethylamino)ethoxy)-44-hydroxy-8-oxa-3-thia-2,5 -diaza-1 (1 ,3),4(1 ,2V

dibenzen

acyclotridecaphan-1 1 -ene-45-carboxamide 3,3-dioxide, trifluoroacetic acid salt

5-(N-(3-Allyl-4-(2-(dimethylamino)ethoxy)phenyl)sμLfamoy l)-4-((2-(but-3-en

yloxy)ethyl)amino)-2-hydroxybenzamide, trifluoroacetic acid salt (107.8 mg, 0.167 mmol) was dissolved in dichloromethane (14 ml_) with stirring. Nitrogen was bubbled directly into the solution for 15 min. [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 - (methoxy(methyl)amino)-1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (7.84 mg, 10.00 μηιοΙ) was quickly added and the green homogeneous reaction was stirred at room temperature for 1 hour. Additional [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 - (methoxy(methyl)amino)-1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride GreenCat (5.2 mg) was added and the reaction was stirred for 3.5h. The reaction was concentrated in vacuo and purified via reverse-phase chromatography (C-18 silica gel, 4-34% MeCN:water with 0.1 % TFA, loaded as a solution in DMSO, 2 x 1000 μΙ_ injections) to give the desired product (42.7 mg, 41 %) as a colorless solid. NMR suggested that 15% Z isomer is be present. LC- MS (ES) m/z = 505.1 [M+H] ⁺ . Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.25 (d, J=4.89 Hz, 2 H) 2.86 (d, J=4.65 Hz, 6 H) 3.20 (d, J=5.87 Hz, 2 H) 3.39 (d, J=4.65 Hz, 2 H) 3.46 - 3.66 (m, 6 H) 4.21 - 4.27 (m, 2 H) 5.37 - 5.56 (m, 2 H) 6.17 (s, 1 H) 6.35 - 6.44 (m, 1 H) 6.83 - 6.92 (m, 2 H) 7.04 (dd, J=8.68, 2.57 Hz, 1 H) 7.56 (br. s., 1 H) 8.01 (s, 1 H) 8.10 (s, 1 H) 9.46 (br. s., 1 H) 9.61 (s, 1 H) 13.50 (br. s., 1 H).

Example 24

(15Z) and (15E)-7-hvdroxy-3.3-dioxo-13.18-dioxa-3A ⁶ -thia-2.10- diazatricycloH 7.3.1.0 ⁴ , ⁹ 1tricosa-1 (23),4,6,8,15,19,21 -heptaene-6-carboxamide

a) 1 -(allyloxy)-3-nitrobenzene

A solution of 3-nitrophenol (9.5g, 68.3 mmol) and 3-bromoprop-1 -ene (8.86 ml, 102 mmol) in acetone (222 ml) was treated with potassium carbonate (18.88 g, 137 mmol) and stirred at room temperature for 12h. The reaction mixture was then filtered through celite and the filtrate was evaporated to provide an orange oil. The oil was diluted with hexane and cooled and the precipitate washed several times with hexane to afford 1 -(allyloxy)-3-nitrobenzene (9.6g, 53.6 mmol, 78 % yield) as a pale yellow solid. LCMS m/z 180.2 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-c/6) δ ppm 7.83 (dd, J=8.16, 1 .38 Hz, 1 H), 7.73 (t, J=2.26 Hz, 1 H), 7.59 (t, J=8.28 Hz, 1 H), 7.45 (dd, J=8.03, 2.26 Hz, 1 H), 6.06 (ddt, J=17.32,10.54, 5.27, 5.27 Hz, 1 H), 5.44 (dq, J=17.32, 1 .67 Hz, 1 H), 5.28 - 5.33 (m, 1 H), 4.72 (dt, J=5.14, 1 .32 Hz, 2 H).

b) 3-(allyloxy)aniline

A solution of 1 -(allyloxy)-3-nitrobenzene ( 500mg, 2.79 mmol) in ethanol (3.751 mL) was treated with iron powder (468 mg, 8.37 mmol) then a solution of ammonium chloride (851 mg, 15.91 mmol) in water (3.75 mL) was then added and the reaction mixture was stirred and heated for 12h at 80 °C. After cooling, the reaction mixture was filtered and evaporated. Sat.NaHC03 solution was added and the mixture was extracted with DCM, dried (sodium εμίίβίβ) and evaporated to afford 3-(allyloxy)aniline (251 mg, 1 .682 mmol, 60.3 % yield) as a brown oil. LCMS m/z 150.2 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-c/6) δ ppm 6.85 - 6.93 (m, 1 H) 6.13 - 6.18 (m, 2 H) 5.96 - 6.12 (m, 2 H) 5.37 (dq, J=17.32, 1 .76 Hz, 1 H) 5.23 (dq, J=10.54, 1 .51 Hz, 1 H) 5.05 (s, 2 H) 4.44 (dt, J=5.14, 1 .44 Hz, 2 H).

c) 5-(N-(3-(allyloxy)phenyl)s Lfamoyl)-4-fluoro-2-hvdroxybenzamide

A solution of 3-(allyloxy)aniline (294 mg, 1 .971 mmol) in dichloromethane (6 mL) was treated with 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (500 mg, 1 .971 mmol) then with pyridine (0.159 mL, 1 .971 mmol) and the mixture was stirred at room temperature for 4h. The mixture was filtered and the precipitate washed several times with DCM to afford 5-(N-(3- (allyloxy)phenyl^Lfamoyl)-4-fluoro-2-hydroxybenzamide (438 mg, 1 .196 mmol, 60.6 % yield) as a colorless solid. LCMS m/z 367.1 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-c/6) δ ppm 14.21 (br. s., 1 H), 10.55 (s, 1 H), 8.73 (br. s., 1 H), 8.48 (d, J=8.28 Hz, 1 H), 8.17 (br. s., 1 H), 7.06 - 7.17 (m, 1 H), 6.93 (d, J=1 1 .80 Hz, 1 H), 6.66 - 6.71 (m, 2 H), 6.60 (dd, J=8.28, 1 .51 Hz, 1 H), 5.98 (ddt, J=17.25, 10.54, 5.18, 5.18 Hz, 1 H), 5.33 (dd, J=17.32, 1 .51 Hz, 1 H), 5.22 (dd, J=10.54, 1 .51 Hz, 1 H), 4.41 - 4.48 (m, 2 H).

d) 4-((2-(allyloxy)ethyl)amino)-5-(N-(3-(allyloxy)phenyl)suLfam oyl)-2-hvdroxybenzamide A solution of 2-(allyloxy)ethan-1 -amine (41 .4 mg, 0.409 mmol) in 1 -butanol (3 mL) was treated with 5-(N-(3-(allyloxy)phenyl)sμLfamoyl)-4-fluoro-2-hydroxybenza mide (150 mg, 0.409 mmol) then with DIEA (0.072 mL, 0.409 mmol) and the mixture stirred and heated at 150 °C for 1 .5 h under microwave irradiation. The reaction mixture was quenched with sat. aqueous ammonium chloride and then extracted with DCM. The organic layer was dried and evaporated then the residue was treated with DCM to give a small amount of the desired product which was combined with a second crop obtained by evaporation of the filtrate and purification of the residue by chromatography ( silica gel, gradient elution 0 - 100% ethyl acetate in hexanes) to afford 4-((2-(allyloxy)ethyl)amino)-5-(N-(3-(allyloxy)phenyl)sμLfa moyl)-2-hydroxybenzamide (64 mg, 0.143 mmol, 34.9 % yield) as a colorless solid. LCMS m/z 448.1 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-c/6) δ ppm 13.86 (br. s., 1 H), 10.25 (s, 1 H), 8.43 - 8.62 (m, 1 H), 8.16 - 8.30 (m, 1 H), 7.59 (br. s., 1 H), 7.08 (t, J=7.83 Hz, 1 H), 6.60 - 6.64 (m, 2 H), 6.55 (d, J=6.36 Hz, 1 H), 6.30 (br. s., 1 H), 5.93 - 6.08 (m, 2 H), 5.80 - 5.92 (m, 1 H), 5.11 - 5.39 (m, 4 H), 4.44 (d, J=5.14 Hz, 2 H), 3.98 (dt, J=5.32, 1.50 Hz, 2 H), 3.56 (t, J=5.50 Hz, 2 H), 3.28 - 3.32 (m, 2 H).

e) (15E) and 15(Z)-7-hvdroxy-3.3-dioxo-13.18-dioxa-3A ⁶ -thia-2.10- diazatricycloH 7.3.1 .OVltricosa-

1 (23),4,6,8,15,19,21 -heptaene-6-carboxamide

A solution of 4-((2-(allyloxy)ethyl)amino)-5-(N-(3-(allyloxy)phenyl^Lfamoy l)-2- hydroxybenzamide (60 mg, 0.134 mmol) in dichloromethane (30 ml_) was treated with [1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene](2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene)ruthenium(vi) dichloride (5.25 mg, 6.70 μηιοΙ) and stirred at room temperature for 6h. The mixture was evaporated and the residue dissolved in DMSO and purified by chromatography (C-18 silica gel, gradient elution 0-100% acetonitrile in water (1 .2 TFA)) to afford the desired product (24.3 mg, 0.058 mmol, 43.2 % yield; mixture of E/Z olefin isomers) as a colorless solid. LCMS m/z 420.2 (M+H)M H NMR (400 MHz, DMSO-c/6) δ ppm 13.63 (s, 1 H), 9.91 - 10.09 (m, 1 H), 8.22 (s, 2 H), 7.62(br. s., 1 H), 7.06 (t, J=8.07 Hz, 1 H), 6.72 - 6.76 (m, 1 H), 6.68 (t, J=2.08 Hz, 1 H), 6.56 (dd, J=8.31 , 1.71 Hz, 1 H), 6.26 (t, J=5.62 Hz, 1 H), 6.10 (s, 1 H), 5.52 - 5.80 (m, 2 H), 4.66 (d, J=4.40 Hz, 2 H), 3.87 (d, J=5.87 Hz, 2 H), 3.35 - 3.38 (m, 2 H), 3.25 - 3.30 (m, 2 H).

Example 25

7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricycloH 6.3.1.OVldocosa- forms)

a) 4-((2-(allyloxy)ethyl)amino)-5-(N-(3-allylphenyl)sμLfamoyl) -2-hydroxybenzamide A solution of the compound from Example 1 f), 5-(N-(3-allylphenyl^Lfamoyl)-4-fluoro-2- hydroxybenzamide (50 mg, 0.143 mmol), in 1-butanol (2 mL) was treated with Et ₃ N (0.020 mL, 0.143 mmol) then with 2-(allyloxy)ethan-1 -amine (14.43 mg; 0.143 mmol.) and the mixture stirred and heated at 110 °C for 50 min. The reaction mixture cooled and quenched with sat. aqu ammonium chloride and the mixture directly purified by chromatography (C-18 silica gel, gradient elution 0-100% acetonitrile in water (0.2% formic acid)) to afford 4-((2- (allyloxy)ethyl)amino)-5-(N-(3-allylphenyl)sμLfamoyl)-2-hyd roxybenzamide as a colorless solid. LCMS m/z 432.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 13.76-13.91 (m, 1 H), 10.16 (s, 1 H), 8.04-8.42 (m, 2H), 7.54 (s, 1 H), 7.00-7.21 (m, 1 H), 6.66-6.94 (m, 2H), 6.34 (t, J=5.40, Hz, 1 H), 5.99-6.16 (m, 1 H), 5.75-5.99 (m, 2H), 5.08-5.49 (m, 3H), 4.90-5.05 (m, 1 H), 3.93-4.08 (m, 2H), 3.74-3.93 (m, 1 H), 3.41-3.65 (m, 3H), 3.25 (d,J=6.78 Hz, 2H), 2.91 (d, J=6.02 Hz, 1 H). b) 7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[16.3.1. OVldocosa- 1 (22),4,6,8,15,18,20-heptaene-6-carboxamide

A solution of 4-((2-(allyloxy)ethyl)amino)-5-(N-(3-allylphenyl)sμLfamoyl) -2-hydroxybenzamide in isopropanol (50.0 ml_) was treated with [1 ,3-bis(2,6-di-i-propylphenyl)imidazolidin-2- ylidene]{2-[[1-(methoxy(methyl)amino)-1-oxopropan-2-yl]oxy]b enzylidene}ruthenium(ll) dichloride (5.59 mg, 7.14 μηιοΙ) and the mixture was stirred under an inert atmosphere at room temperature for 12h. The mixture was evaporated and the residue purified by chromatography (C-18 silica gel, gradient elution 0-100% acetonitrile in water (0.2% formic acid)) to afford the desired product (15 mg; 26%; mixture of E/Z isomers) as a colorless solid. LCMS m/z 404.1 (M+H) ⁺ . Ή NMR (400 MHz, DMSO-d6) δ ppm 9.81 -9.95 (m, 1 H), 8.10-8.21 (m, 1 H), 7.51-7.69 (m, 1 H), 7.09-7.19 (m, 2H), 7.03 (s, 1 H), 6.81-6.98 (m, 2H),6.54-6.77 (m, 1 H), 5.72-5.88 (m, 2H), 5.18-5.41 (m, 1 H), 3.97 (d, J=6.60 Hz, 2H), 3.86 (d, J=6.60 Hz, 3H), 3.19-3.38 (m, 4H).

Example 26

14-(2-(dimethylamino)ethoxy)-44-hvdroxy-8-oxa-3-thia-2.5-dia za-1 (1.3).4(1.2)-dibenzen acyclotridecaphane-45-carboxamide 3,3-dioxide, Trifluoroacetic acid salt

A solution of (E)-14-(2-(dimethylamino)ethoxy)-44-hydroxy-8-oxa-3-thia-2,5 -diaza- 1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1-ene-45-carboxamide 3,3-dioxide, trifluoroacetic acid salt (20.04 mg, 0.032 mmol) in methanol (3 ml_) was hydrogenated over wet 10% Pd-C (0.689 mg, 6.48 μηιοΙ) at room temperature and atmospheric pressure for 4h. The reaction was filtered through celite using methanol to wash the celite. The filtrate was concentrated to give the product (15.1 mg, 75%) as an off-white solid. LC-MS (ES) m/z = 507.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-c/e) δ ppm 1 .24 (s, 2 H) 1 .38 - 1 .66 (m, 4 H) 2.54 - 2.62 (m, 2 H) 2.73 (br. s., 6 H) 3.14 - 3.56 (m, 8 H) 4.17 (t, J=4.89 Hz, 2 H) 6.07 (s, 1 H) 6.46 (t, J=5.01 Hz, 1 H) 6.80 - 6.92 (m, 2 H) 6.97 (d, J=2.20 Hz, 1 H) 7.66 (br. s., 1 H) 7.99 - 8.19 (m, 1 H) 8.24 (s, 1 H) 9.59 (br. s., 1 H) 13.44 (br. s., 1 H).

Example 27

(16E)-22-ethyl-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.23- triazatetracyclon 7.6.1.0 ⁴ , ⁹ .0 ² °, ² 1hexacosa-1 (26) ,4,6,8,16,19,21 ,24-octaene-6-

a) 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl)s Lfamoyl)-4-((2-(but-3-en-1 -yloxy)ethyl)amino)-2- hvdroxybenzamide

A solution of the compound from Example 7b), 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl^Lfamoyl)-4- fluoro-2-hydroxybenzamide (90 mg, 0.216 mmol, 28.8 % yield), in 1 -butanol (3 mL) was treated with triethylamine (0.104 mL, 0.749 mmol) and 2-(but-3-en-1 -yloxy)ethan-1 -amine (129 mg, 1 .123 mmol) and stirred and heated at 135 °C for 50 min. under microwave irradiation. The reaction mixture was cooled and treated with sat.NH ₄ CI (1 mL). The crude mixture was purified by chromatography (C-18 silica gel, gradient elution 0-100% acetonitrile in water ) to afford 5- (N-(4-allyl-2-ethyl-1 H-indol-6-yl)sμLfamoyl)-4-((2-(but-3-en-1 -yloxy)ethyl)amino)-2- hydroxybenzamide (45 mg, 0.088 mmol, 1 1 .72 % yield) as a light brown solid. LCMS m/z 513.1 (M+H) ⁺ .

b) (16E)-22-ethyl-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.23- triazatetracvclo[17.6.1 .0 ⁴ . ⁹ .0 ²⁰ . ²⁴ lhexacosa-1 (26).4.6.8.16.19.21 .24-octaene-6- carboxamide

A solution of 5-(N-(4-allyl-2-ethyl-1 H-indol-6-yl^Lfamoyl)-4-((2-(but-3-en-1 - yloxy)ethyl)amino)-2-hydroxybenzamide (45 mg, 0.088 mmol) in isopropanol (5 mL) was treated with [1 ,3-bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -

(methoxy(methyl)amino)-1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (3.44 mg, 4.39 μηιοΙ) and the reaction mixture was stirred at room temperature for 12 h. The mixture was evaporated and the residue purified by chromatography (C-18 silica gel, gradient elution 0- 100% acetonitrile in water (0.2% formic acid)) to afford the desired product (5.1 mg, 10.52 μηιοΙ, 1 1 .99 % yield; mixture of olefin E/Z isomers) as a colorless solid. LCMS m/z 485.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 9.34-9.65 (m, 1 H), 8.39 (s, 1 H), 8.07 (s, 1 H), 6.95 (s, 1 H), 6.59 (s, 1 H), 6.34 (br. s., 1 H), 6.08 (s,1 H), 5.97 (br. s., 1 H), 5.42-5.63 (m, 2H), 3.56 (td, J=4.86, 13.75 Hz, 6H), 3.10-3.28 (m, 5H), 2.67 (q, J=7.42 Hz, 2H), 2.25 (d, J=4.89 Hz, 1 H), 1 .24 (t, J=7.58 Hz, 3H). Example 28

7-hvdroxy-3.3-dioxo-13.18-dioxa-3A ⁶ -thia-2.10-diazatricvcloM 7.3.1.OVltricosa-

A solution of the compound from Example 26e), 44-hydroxy-8,13-dioxa-3-thia-2,5-diaza- 1 (1 ,3),4(1 ,2)-dibenzenacyclotridecaphan-10-ene-45-carboxamide 3,3-dioxide (15 mg, 0.036 mmol) in ethanol (5 mL) was hydrogenated over 10 Pd on C (3.81 mg, 0.036 mmol at room temperature and 1 atm. pressure for 12 h. The reaction mixture was filtered through celite and evaporated to afford the desired product (10 mg, 0.024 mmol, 66.3 % yield) as a colorless solid. LCMS m/z 422.2 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-c/6) δ ppm 13.43 (s, 1 H), 9.91 (s, 1 H), 8.15 (s, 2 H), 7.58 (s, 1 H), 7.08 (t, J=8.03 Hz, 1 H), 6.78 (s, 1 H), 6.56 (d, J=6.78 Hz, 2 H), 6.40 (br. s., 1 H) ,6.02 (br. s., 1 H), 4.07 (t, J=6.65 Hz, 2 H), 3.47 (t, J=5.02Hz, 2 H), 3.40 (br. s., 2 H), 3.19 (d, J=4.02 Hz, 2 H), 1 .77 (d, J=6.78 Hz, 2 H), 1 .63 (d, J=5.52 Hz, 2 H).

Example 29

(16E)-7-hvdroxy-3.3-dioxo-14-oxa-3A ⁶ -thia-2.10-diazatricvclon 7.3.1.OVltricosa- 1 (22).4.6.8. rboxamide

a) 4-fluoro-2-hvdroxy-5-f[3-(prop-2-en-1 -yl)phenylls Lfamoyl>benzamide

A mixture of 3-allylaniline, hydrochloride (488 mg, 2.88 mmol) in DCM (10 mL) at 0 °C was treated with pyridine (0.465 mL, 5.75 mmol) and stirred for 10 min. A fine suspension of 5- carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (583 mg, 2.3 mmol) in DCM (5 mL) was added dropwise over five min (rinse with 5 mL additional DCM). The mixture was stirred and allowed to warm to room temperature for 60 min. The reaction was evaporated, treated with EtOH (3.5 mL), and 1 M aq. HCI (20 mL), sonicated, then the suspension stirred for 10 min. then filtered to afford the desired product (743 mg, 92%) as a tan solid. LCMS m/z 351 .2 (M+H) ⁺ . 1 H NMR (400MHz, DMSO-d6) G = 14.18 (br. s., 1 H), 10.46 (s, 1 H), 8.71 (br. s., 1 H), 8.45 (d, J=8.3 Hz, 1 H), 8.14 (br. s., 1 H), 7.29 - 7.03 (m, 1 H), 6.97 - 6.88 (m, 3H), 6.84 (d, J=7.8 Hz, 1 H), 5.90 - 5.75 (m, 1 H), 5.04 - 4.90 (m, 2H), 3.25 (d, J=6.6 Hz, 2H).

b) 4-f[2-(but-3-en-1 -yloxy)ethyllamino>-2-hydroxy-5-f[3-(prop-2-en-1 - vDphenvnsuLfamovDbenzamide

A solution of 4-fluoro-2-hydroxy-5-{[3-(prop-2-en-1 -yl)phenyl]sμLfamoyl}benzamide (150 mg, 0.428 mmol)], 2-(but-3-en-1 -yloxy)ethanamine (59.2 mg, 0.514 mmol), and DIEA

(0.090 mL, 0.514 mmol) in n-BuOH (3 mL) was stirred and heated at 155 °C under microwave irradiation for 60 min. The reaction mixture was cooled and poured into EtOAc (2 mL), Et20 (5 mL) and water (8 mL). The aqueous phase was extracted with EtOAc (5 mL) and the combined organics were dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was azeotroped with DCM (2 x 20 mL) then suspended in DCM (10 mL) and left to slowly evaporated until the volume was approximately 2 mL. The supernatant was decanted and the precipitate was purified by chromatography (silica gel, gradient elution 0-100% EtOAc in hexanes) to afford the desired product (1 10 mg, 57% yield) as a solid. LCMS m/z 446.1 (M+H) ⁺ . 1 H NMR (400MHz, DMSO- d6) δ = 13.78 (br. s., 1 H), 10.05 (br. s., 1 H), 8.35 (br. s., 1 H), 8.22 (s, 1 H), 7.59 (br. s., 1 H), 7.16 - 7.08 (m, 1 H), 6.90 (br. s., 2H), 6.81 (d, J=7.5 Hz, 1 H), 6.33 (br.s., 1 H), 6.07 (s, 1 H), 5.91 - 5.77 (m, 2H), 5.13 - 4.93 (m, 4H), 3.56 (t, J=4.9 Hz, 2H), 3.47 (t, J=6.7 Hz, 2H), 3.25 (d, J=6.8 Hz, 2H), 2.27 (q, J=6.4 Hz, 2H).

c) c) (16E)-7-hvdroxy-3,3-dioxo-14-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ^{4 9} ltricosa-

1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide

A solution of 4-{[2-(but-3-en-1 -yloxy)ethyl]amino}-2-hydroxy-5-{[3-(prop-2-en-1 - yl)phenyl^Lfamoyl}benzamide (1 10 mg, 0.247 mmol) in EtOAc (6 mL) was treated with [1 ,3- Bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan- 2-yl]oxy]benzylidene}ruthenium(ll) dichloride (9.67 mg, 0.012 mmol) and the mixture stored at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was triturated in DCM (2 mL) with cooling to 0 °C for 15 min. The mixture was filtered and the crude product (100 mg) was purified by chromatography (Chiral SFC, Column: 2-EP, 20 x150 mm, 5μ, Co-Solvent: 30% MeOH, total flow rate: 50 g/min, pressure: 100 Bar). Injected sample over 10 injections. The desired product fractions from the major eluting peak were collected and dried under reduced pressure. The sample was concentrated from MeOH under N.2 stream at 40°C isolating 16.4 mg of the major olefin isomer as (16E)-7-hydroxy-3,3-dioxo- 14-oxa-3A hia-2 0-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,16,19(23),20-heptaene-6- carboxamide (15 mg; 15%) as a colorless solid. LCMS m/z 418.1 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ = 13.53 (br. s., 1 H), 9.86 (s, 1 H), 8.12 (s, 2H), 7.60 (br. s., 1 H), 7.18 - 7.08 (m, 1 H), 7.02 (d, J=8.3 Hz, 1 H), 6.91 (s, 1 H), 6.87 (d, J=7.3 Hz, 1 H), 6.40 (t, J=5.3 Hz, 1 H), 6.1 1 (s, 1 H), 5.54 - 5.37 (m, 2H), 3.63 - 3.50 (m, 4H), 3.38 - 3.29 (m, 2H), 3.24 - 3.18 (m, 2H), 2.22 (d, J=4.9 Hz, 2H). Example 30

7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricycloH 7.3.1.OVltricosa- 1 (22) ,4,6 oxamide

A solution of 4-{[2-(but-3-en-1 -yloxy)ethyl]amino}-2-hydroxy-5-{[3-(prop-2-en-1 - yl)phenyl^Lfamoyl}benzamide (150 mg, 0.337 mmol) in EtOAc (5 mL) was treated with [1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (10 mg, 0.013 mmol) and the mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated to ~1 mL volume then further EtOAc (4 mL) was added and the mixture was stirred and heated at 50 °C for 5 h. The reaction mixture was filtered while warm and the filtrate was cooled to 0 °C. The precipitate was washed with DCM to afford a crude mixture of (16E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia- 2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa-1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide and (16Z)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (22),4,6,8,16,19(23),20-heptaene-6-carboxamide (78 mg, 0.187 mmol) as a beige solid. A solution of this mixture in EtOAc (4 mL) and MeOH (2 mL) was hydrogenated over 10% Pd/C (Degussa Type) (10 mg) at room temperature and 1 atm. pressure overnight. The catalyst was removed by filtration, the filtrate evaporated and the residue purified by chromatography [C-18 silica gel, 5 micron, 30 x 50 mm, gradient elution 5-60% ACN in water (0.5% TFA) then 100% ACN)] to afford the desired product (20 mg, 25% yield). LCMS m/z 420.1 (M+H) ⁺ . Ή NMR (400MHz, DMSO-d6) δ = 13.48 (s, 1 H), 9.81 (s, 1 H), 8.27 - 8.22 (m, 1 H), 8.1 1 (br. s., 1 H), 7.64 (br. s., 1 H), 7.15 - 7.07 (m, 1 H), 6.96 (s, 1 H), 6.93 - 6.82 (m, 2H), 6.39 (t, J=5.3 Hz, 1 H), 6.10 - .04 (m, 1 H), 3.49 - 3.42 (m, 2H), 3.39 (t, J=5.3 Hz, 2H), 3.23 (q, J=4.9 Hz, 2H), 2.63 - 2.54 (m,H), 1 .66 - 1 .51 (m, 2H), 1 .50 - 1 .38 (m, 2H), 1 .19 (quin, J=7.3 Hz, 2H).

Example 31

7-hydroxy-3,3,18-trioxo-13-oxa-3A ⁶ -thia-2,10,17,23- tetraazatetracycloM 7.6.1.0 ⁴ , ⁹ .0 ² °, ² 1hexacosa-1 (26),4(9),5,7,19,21 ,24-heptaene-6-

a) Methyl 6-((5-carbamoyl-2-fluoro-4-hvdroxyphenyl)suLfonamido)-1 H-indole-4- carboxylate

A solution of methyl 6-amino-1 H-indole-4-carboxylate (500 mg, 2.63 mmol) in dichloromethane (5 ml_) and pyridine (0.213 ml_, 2.63 mmol) was stirred for 10 min 0 °C, then 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (667 mg, 2.63 mmol) was added and stirred at room temperature for 12h. Sat. NH ₄ CI (1 ml) was added, the organic layer separated and evaporated and the residue purified by chromatography (silica gel, gradient elution 0-100% ethyl acetate in hexanes) to afford methyl 6-((5-carbamoyl-2-fluoro-4- hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylate (420 mg, 1 .031 mmol, 39.2 % yield) as light yellow solid. LCMS m/z 408.2 (M+H) ⁺ 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.60- 14.35 (m, 1 H), 1 1 .39 (br. s., 1 H), 10.35 (s, 1 H), 8.66 (br. s., 1 H), 8.34 (d, J=8.28 Hz, 1 H), 7.36-7.63 (m, 3H), 6.65-6.98 (m, 2H), 3.82-3.97 (m, 4H).

b) 6-((5-Carbamoyl-2-fluoro-4-hvdroxyphenyl)suLfonamido)-1 H-indole-4-carboxylic acid A solution of methyl 6-((5-carbamoyl-2-fluoro-4-hydroxyphenyl^Lfonamido)-1 H-indole-4- carboxylate (300 mg, 0.736 mmol) in tetrahydrofuran (3 ml_) was treated with LiOH (70.5 mg, 2.95 mmol) in water (1 ml_) and the reaction was stirred for 12h at room temperature. The mixture was evaporated and treated with 1 M HCI and filtered to afford 6-((5-carbamoyl- 2-fluoro-4-hydroxyphenyl)sμLfonamido)-1 H-indole-4-carboxylic acid (220 mg; 59%) which was used without further purification. LCMS m/z 394.0 (M+H) ⁺

c) 6-((2-((2-(3-((Tert-butoxycarbonyl)amino)propoxy)ethyl)amino )-5-carbamoyl-4- hvdroxyphenyl)suLfonamido)-1 H-indole-4-carboxylic acid

A solution of 6-((5-carbamoyl-2-fluoro-4-hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylic acid (100 mg, 0.254 mmol) in 1 -butanol (1 ml_) was treated with fe/ -butyl (3-(2- aminoethoxy)propyl)carbamate (55.5 mg, 0.254 mmol) and the reaction mixture was stirred and heated for 50 min. at 135 °C under microwave irradiation. Sat.NH ₄ CI (0.2ml_) was added, and the crude mixture was purified directly by chromatography (C-18 silica gel, gradient elution 0-100% acetonitrile in water (0.2% formic acid)) to afford the desired product (75 mg, 0.127 mmol, 49.9 % yield) as light brown solid. LCMS m/z 491 .1 (M+H-100) ⁺ , 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .25 (br. s., 1 H), 9.71 -9.94 (m, 1 H), 8.04-8.25 (m, 2H), 7.41 -7.49 (m, 2H), 7.32-7.38 (m, 1 H), 6.84 (t, J=2.08 Hz, 1 H), 6.70-6.81 (m, 2H), 6.29 (s, 1 H), 6.05 (s, 1 H), 3.13- 3.24 (m, 3H), 2.83-3.06 (m, 5H), 1 .55-1 .64 (m, 4H), 1 .37-1 .43 (m, 9H).

d) 6-((2-((2-(3-Aminopropoxy)ethyl)amino)-5-carbamoyl-4-hvdroxy phenyl)s Lfonamido)- 1 H-indole-4-carboxylic acid, trifluoroacetate

A solution of 6-((2-((2-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)amino )-5-carbamoyl-4- hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylic acid (75 mg, 0.127 mmol, 49.9 % yield) in dichloromethane (1 .0 mL) was treated with TFA (0.196 mL, 2.54 mmol) and the mixture was stirred at room temperature for 18h. The mixture was evaporated and azeotroped with toluene to afford the desired product (35 mg, 0.058 mmol, 22.77 % yield) as a dark brown solid and was used without further purification. LCMS m/z 491 .4 (M+H) ⁺ .

e) 7-hydroxy-3,3,18-trioxo-13-oxa-3A ⁶ -thia-2,10,17,23- tetraazatetracvclon 7.6.1 .0 ⁴ . ⁹ .0 ² °. ²⁴ lhexacosa-1 (26).4(9).5.7.19.21 ,24-heptaene-6- carboxamide

A solution of 6-((2-((2-(3-aminopropoxy)ethyl)amino)-5-carbamoyl-4- hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylic acid (30 mg, 0.061 mmol) in N,N- Dimethylformamide (DMF) (1 mL) was treated with HATU (23.21 mg, 0.061 mmol) and DIEA (10.66 μΙ, 0.061 mmol) and the reaction was stirred at room temperature for 12h. Sat.NaHC03 (0.5ml) was added followed by ethyl acetate and layers were separated, the organic layers dried and evaporated and the residue purified by chromatography (C-18 silica gel, gradient elution 0- 100% acetonitrile in water (0.1 % formic acid)) to provide the title compound (5 mg, 10.56 μηιοΙ, 17.30 % yield) as a colorless solid. LCMS m/z 474.1 (M+H) ⁺ Η NMR (400 MHz, DMSO-d6) δ ppm 1 1 .21 (br. s., 1 H), 9.60-9.81 (m, 1 H), 8.16 (s, 1 H), 8.04 (s, 1 H), 7.28-7.41 (m, 3H), 7.15- 7.26 (m, 2H), 6.73 (d, J=2.20 Hz, 2H), 6.54 (s, 1 H), 6.09 (s, 1 H), 3.63-3.83 (m, 4H), 3.41 (d, J=5.14 Hz, 4H), 1 .83 (br. s., 2H).

Example 32

7-hydroxy-3,3,17-trioxo-13-oxa-3A ⁶ -thia-2,10,16,22- tetraazatetracycloM 6.6.1.0 ⁴ , ⁹ .0 ^l9 , ²³ 1pentacosa-1 (25),4(9),5,7,18,20,23-heptaene-6- carboxamide

a) Methyl 6-((2-((2-(2-((te/ -butoxycarbonyl)amino)ethoxy)ethyl)aminoV5-carbamoyl-4- hydroxyphenvDsuLfonamidoVI H-indole-4-carboxylate

A solution of methyl 6-((5-carbamoyl-2-fluoro-4-hydroxyphenyl^Lfonamido)-1 H-indole-4- carboxylate (420 mg, 1 .031 mmol) in 1 -butanol (5.00 mL) was treated with fe/ -butyl (2-(2- aminoethoxy)ethyl)carbamate (537 mg, 2.63 mmol) and DIEA (0.459 mL, 2.63 mmol) and the reaction mixture was stirred and heated at 135 °C for 50 min. under microwave irradiation. After cooling, sat. NH ₄ CI (0.5ml) was added and the mixture directly purified by chromatography (C- 18 silica gel, gradient elution 0-100% acetonitrile in water (0.2% formic acid)) to provide the desired product (210 mg, 0.355 mmol, 13.50 % yield) as colorless solid. LCMS m/z 492.2 (M+H- 100) ⁺ ; Ή NMR (400 MHz, DMSO-d6) δ ppm 13.68 (s, 1 H), 1 1 .33 (br. s., 1 H), 9.98 (s, 1 H), 8.12 (s, 1 H), 7.42-7.68 (m, 3H), 7.38 (d, J=1 .00 Hz, 1 H), 6.63-6.91 (m, 2H), 6.29 (s, 1 H), 6.06 (s, 1 H), 3.86 (s, 3H), 3.36-3.53 (m, 4H), 3.23 (d, J=5.52 Hz, 2H), 3.08 (d, J=5.77 Hz, 2H), 1 .37 (s, 9H).

b) Methyl 6-((2-((2-(2-aminoethoxy)ethyl)amino)-5-carbamoyl-4- hvdroxyphenyl)suLfonamido)-1 H-indole-4-carboxylate, trifluoroacetate

A solution of methyl 6-((2-((2-(2-((fe/ -butoxycarbonyl)amino)ethoxy)ethyl)amino)-5-carbamoyl- 4-hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylate (150 mg, 0.254 mmol) in DCM (3.0 mL) was treated with TFA (0.195 mL, 2.54 mmol) and the reaction mixture was stirred at room temperature for 12h. The mixture was evaporated to afford the desired product (95 mg, 0.157 mmol, 62.0 % yield) as yellow solid. LCMS m/z 492.3 (M+H) ⁺ Ή NMR (400 MHz, DMSO-d6) δ ppm 1 1 .15-1 1 .40 (m, 1 H), 8.51 -8.70 (m, 1 H), 8.36 (s, 1 H), 8.12 (s, 1 H), 7.46 (d, J=1 .76 Hz, 1 H), 7.21 -7.39 (m, 3H), 6.77 (d, J=3.01 Hz, 1 H), 6.59-6.71 (m, 1 H), 5.93 (s, 1 H), 3.83-3.95 (m, 3H), 3.58 (td, J=5.08, 17.44 Hz, 4H), 3.22 (br. s., 4H), 2.95 (t, J=5.02 Hz,3H).

c) 6-((2-((2-(2-aminoethoxy)ethyl)amino)-5-carbamoyl-4-hvdroxyp henyl)s Lfonamido)- 1 H-indole-4-carboxylic acid

A solution of methyl 6-((2-((2-(2-aminoethoxy)ethyl)amino)-5-carbamoyl-4- hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylate, trifluoroacetate (95 mg, 0.157 mmol, 62.0 % yield) in tetrahydrofuran (3 mL) was treated with LiOH (30.4 mg, 1 .268 mmol) in water (1 .0 mL) and the reaction mixture was stirred at room temperature for 12h. The reaction mixture was evaporated and treated with 1 M aqu. HCI then filtered to afford 6-((2-((2-(2- aminoethoxy)ethyl)amino)-5-carbamoyl-4-hydroxyphenyl)sμLfon amido)-1 H-indole-4- carboxylic acid (65 mg, 0.136 mmol, 53.7 % yield). LCMS m/z 478.2 (M+H) ^{+ ; 1} H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .21 (br. s., 1 H), 8.25 (s, 1 H), 8.14 (s, 1 H), 7.32-7.44 (m, 3H), 6.86 (br. s., 1 H), 6.34 (br. s., 1 H), 6.06 (s, 1 H), 3.57 (t, J=5.01 Hz, 4H), 3.48 (t, J=5.50 Hz, 4H), 3.25 (d, J=5.14 Hz, 4H), 2.97 (t, J=5.01 Hz, 2H).

d) 7-hvdroxy-3,3,17-trioxo-13-oxa-3A ⁶ -thia-2, 10,16,22- tetraazatetracvcloM 6.6.1 .0 ⁴ . ⁹ .0 ^l9 . ²³ lpentacosa-1 (251.4(9 ^' ).5.7.18.20.23-heptaene-6- carboxamide

A solution of 6-((2-((2-(2-aminoethoxy)ethyl)amino)-5-carbamoyl-4- hydroxyphenyl^Lfonamido)-1 H-indole-4-carboxylic acid (55 mg, 0.1 15 mmol) in N,N- Dimethylformamide (2.0 mL) was treated with HATU (43.8 mg, 0.1 15 mmol) and DIEA (0.020 mL, 0.1 15 mmol) and the reaction was stirred at room temperature for 12h. Sat.NaHC0 ₃ was added , the organic layer separated, dried and evaporated and the residue was purified by chromatography (silica gel, gradient elution 0-100% ethyl acetate in hexanes) to afford the desired product (4 mg; 8%) as tan solid. LCMS m/z 460.1 (M+H) ⁺ ; Ή NMR (400 MHz, DMSO- d6) δ ppm 12.47-12.93 (m, 1 H), 1 1 .13 (br. s., 1 H), 10.06 (s, 1 H), 8.17 (s, 1 H), 7.73 (t, J=5.26 Hz, 2H), 7.22-7.39 (m, 3H), 7.14 (s, 2H), 6.59 (br. s., 1 H), 6.09 (s, 1 H), 3.49-3.78 (m, 8H).

Example 33

(E)-14-(2-aminoethoxy)-44-hvdroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)-

a) tert-butyl (2-(4-acetamido-2-allylphenoxy)ethyl)carbamate

A solution of N-(3-allyl-4-hydroxyphenyl)acetamide (1 .2 g, 6.28 mmol), fe/ -butyl (2- hydroxyethyl)carbamate (1 .214 g, 7.53 mmol), and triphenylphosphane (2.469 g, 9.41 mmol) in THF (40 ml) was stirred under nitrogen and cooled to 0 °C. Diethyl (E)-diazene-l ,2- dicarboxylate (4.10 g, 9.41 mmol, 40% in toluene) was added dropwise via syringe over 10 min. Additional THF (5 ml) was added and the reaction was stirred for 5 min at 0 °C. The ice- bath was removed and the reaction was stirred for 21 h at room temperature, concentrated in vacuo, and purified via silica gel chromatography (Biotage Isolera, 0-15% MeOH:DCM, 120 gm column, loaded crude as a solution in DCM) to give an orange oil. The oil was dissolved in diethyl ether and washed sequentially with sat. aq. sodium bicarbonate (2X), water, and sat. aq. NaCI. The ether layer was dried over sodium εμίίβίβ, filtered, and concentrated to give a white foam. The foam was purified via silica gel chromatography (Biotage Isolera, 10-90% EtOAc:hexanes , 120 g column, loaded as a sample in DCM) to give a colorless solid. The solid was dissolved in DCM and extracted twice with 2N NaOH , dried over sodium εμίίβίβ, filtered, and concentrated to give the desired product (580.3 mg, 28%) as a colorless solid. LC- MS (ES) m/z = 335.3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .39 (s, 9 H) 1 .99 (s, 3 H) 3.30 (d, J=5.62 Hz, 4 H) 3.90 (t, J=5.62 Hz, 2 H) 4.95 - 5.14 (m, 2 H) 5.91 (ddt, J=17.06, 10.09, 6.85, 6.85 Hz, 1 H) 6.86 (d, J=8.80 Hz, 1 H) 6.96 (t, J=5.62 Hz, 1 H) 7.28 (d, J=2.45 Hz, 1 H) 7.39 (dd, J=8.80, 2.45 Hz, 1 H) 9.72 (s, 1 H)

b) tert-butyl (2-(2-allyl-4-aminophenoxy)ethyl)carbamate

fe/ -Butyl (2-(4-acetamido-2-allylphenoxy)ethyl)carbamate (566.9 mg, 1 .695 mmol) was dissolved in ethanol (7 ml_) with stirring. Aqueous sodium hydroxide (0.883 ml_, 16.95 mmol, 19.2 M) was added dropwise and the clear solution was heated under reflux for 4h. The reaction was cooled to room temperature, neutralized with 6N HCI, and concentrated in vacuo. The residue was dissolved in DCM/water and the layers were separated. The aqueous layer was extracted with DCM and the combined DCM layers were washed with water, dried over sodium εμί-ίβίβ, filtered, and concentrated to give a reddish oil. The oil was purified via silica gel chromatography (Biotage Isolera, 30% 3:1 EtOAc:EtOH/hexanes to 100% 3:1 EtOAc:EtOH/hexanes, 40 g column) to give the desired product (232.0 mg, 47%) as pale yellow oil. NMR indicated ca. 90% desired and ca. 10% isomerized product. LC-MS (ES) m/z = 293.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .31 - 1 .43 (m, 9 H) 3.16 - 3.28 (m, 4 H) 3.78 (t, J=5.75 Hz, 2 H) 4.58 (br. s., 2 H) 4.92 - 5.10 (m, 2 H) 5.89 (ddt, J=16.99, 10.09, 6.76, 6.76 Hz, 1 H) 6.31 - 6.41 (m, 2 H) 6.59 - 6.70 (m, 1 H) 6.91 (t, J=5.38 Hz, 1 H).

c) tert-butyl (2-(2-allyl-4-((5-carbamoyl-2-fluoro-4- hvdroxyphenyl)suLfonamido)phenoxy)ethyl)carbamate

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (201 mg, 0.793 mmol), fe/ -butyl (2-(2-allyl-4-aminophenoxy)ethyl)carbamate (232.0 mg, 0.793 mmol), and pyridine (0.064 ml_, 0.793 mmol) in dichloromethane (8 ml_) was stirred at room temperature for 75 min. The suspension was concentrated in vacuo and the residue was triturated with water. The ΓΘεμΙ-ίΐΓ^ suspension was filtered and dried to afford the desired product (405.0 mg, 100%) as a tan solid. LC-MS (ES) m/z = 510.3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-cfe) δ ppm 1 .26 - 1 .44 (m, 9 H) 3.09 - 3.32 (m, 4 H) 3.84 (t, J=5.40 Hz, 2 H) 4.84 - 5.04 (m, 2 H) 5.68 - 5.89 (m, 1 H) 6.73 - 7.01 (m, 5 H) 8.13 (br. s., 1 H) 8.33 (d, J=8.28 Hz, 1 H) 8.66 (br. s., 1 H) 10.09 (s, 1 H) 14.16 (br. s., 1 H).

d) tert-butyl (2-(2-allyl-4-((2-((2-(but-3-en-1 -yloxy)ethyl)amino)-5-carbamoyl-4- hvdroxyphenyl)suLfonamido)phenoxy)ethyr) carbamate

A mixture of fe/ -butyl (2-(2-allyl-4-((5-carbamoyl-2-fluoro-4- hydroxyphenyl^Lfonamido)phenoxy)ethyl)carbamate (398.1 mg, 0.781 mmol), 2-(but-3-en-1 - yloxy)ethan-1 -amine (99 mg, 0.859 mmol), and N-ethyl-N-isopropylpropan-2-amine (303 mg, 2.344 mmol) in 1 -butanol (8 ml_) was heated at 150 °C for 30 min under microwave irradiation. The solvent was removed in vacuo and the residue was dissolved in EtOAc/water. The layers were separated and the EtOAc was washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated. The residue was purified via silica gel chromatography (Biotage Isolera, 24 g column, 20-75% EtOAc:hexanes over 15 CV, loaded as a solution in 4 ml DCM) to give the desired product (234.4 mg, 50%) a pale yellow solid. LC-MS (ES) m/z = 605.6 [M+H] ⁺ Ή NMR (400 MHz, DMSO-cfe) δ ppm 1 .32 - 1 .42 (m, 9 H) 2.22 - 2.31 (m, 2 H) 3.18 - 3.31 (m, 6 H) 3.43 - 3.50 (m, 2 H) 3.53 (t, J=5.50 Hz, 2 H) 3.85 (t, J=5.50 Hz, 2 H) 4.89 - 5.13 (m, 4 H) 5.71 - 5.90 (m, 2 H) 6.02 - 6.13 (m, 1 H) 6.31 (t, J=5.26 Hz, 1 H) 6.73 - 6.96 (m, 4 H) 7.59 (br. s., 1 H) 8.10 (s, 1 H) 8.30 (d, J=8.31 Hz, 1 H) 9.71 (s, 1 H) 13.77 (br. s., 1 H).

e) tert-butyl (E)-(2-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2, 5-diaza- 1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1 -en-14-yl)oxy)ethyl)carbamate

te/ -butyl (2-(2-allyl-4-((2-((2-(but-3-en-1 -yloxy)ethyl)amino)-5-carbamoyl-4- hydroxyphenyl^Lfonamido)phenoxy)ethyl)carbamate (232.0 mg, 0.384 mmol) was dissolved in DCM (16 ml_) with stirring. Nitrogen was bubbled into the solution for 5 min. [1 ,3-Bis(2,6-di- i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (18.04 mg, 0.023 mmol) was added and the reaction was stirred for 3 days at room temperature. The reaction was concentrated in vacuo and the residue was purified via reverse-phase chromatography (C-18 silica gel, acidic Luna column, 3 x 1000 μΐ injections, 35-65% MeCN:water with 0.1 % TFA, loaded as a solution in 3 ml DMSO) to give the desired product (81 .2 mg, 37%) as a colorless solid as a 5:1 mixture of E:Z isomers. LC-MS (ES) m/z = 577.5 [M+H] ⁺ Ή NMR for E -isomer (400 MHz, DMSO-c/ ₆ ) δ ppm 1 .37 (s, 9 H) 2.24 (d, J=4.89 Hz, 2 H) 3.14 (d, J=5.38 Hz, 2 H) 3.24 - 3.31 (m, 2 H) 3.37 (d, J=4.65 Hz, 2 H) 3.43 - 3.66 (m, 4 H) 3.87 (t, J=5.38 Hz, 2 H) 5.32 - 5.50 (m, 2 H) 6.16 (s, 1 H) 6.40 (t, J=5.38 Hz, 1 H) 6.73 - 6.87 (m, 2 H) 6.90 - 7.08 (m, 2 H) 7.56 (br. s., 1 H) 8.00 (s, 1 H) 8.10 (s, 1 H) 9.49 (s, 1 H) 13.53 (br. s., 1 H).

f) (EV14-(2-aminoethoxyV44-hvdroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2V

dibenzenacvclotridecaphan-1 1 -ene-45-carboxamide 3,3-dioxide, trifluoroacetic acid salt te/ -Butyl (E)-(2-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2, 5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -en-14-yl)oxy)ethyl)carbamate (79.1 mg, 0.137 mmol) was dissolved in 1 ,4-dioxane (3 ml). A solution of 4M HCI (3.0 mL, 12.00 mmol) in dioxane was added and the mixture was stirred for 2h at room temperature. The reaction was concentrated in vacuo and the residue was purified via reverse-phase chromatography (C-18 silica gel, 3 x 600 μΙ_ injections, acidic Luna column, 4-34% MeCN:water with 0.1 % TFA, loaded as a solution in 1 .8 ml of DMSO) to give the desired product (56.3 mg, 70%) as a colorless solid as a 5:1 E:Z mixture. LC-MS (ES) m/z = 477.4 [M+H] ⁺ . ¹ H NMR for E-isomer (400 MHz, DMSO-d ₆ ) δ ppm 2.26 (d, J=5.14 Hz, 2 H) 3.15 - 3.27 (m, 4 H) 3.30 - 3.71 (m, 6 H) 4.08 (t, J=4.89 Hz, 2 H) 5.31 - 5.57 (m, 2 H) 6.19 (s, 1 H) 6.40 (t, J=5.50 Hz, 1 H) 6.76 - 6.91 (m, 2 H) 7.03 (dd, J=8.56, 2.69

Hz, 1 H) 7.55 (br. s., 1 H) 7.87 (br. s., 2 H) 7.98 (s, 1 H) 8.08 (s, 1 H) 9.58 (s, 1 H) 13.50 (s, 1 H).

Example 34

tert-butyl (E)-3-((45-carbamoyl-44-hvdroxy-3,3-dioxido-8-oxa-3-thia-2,5 -diaza- 1 (1 ,3),4(1 ,2)-dibenzenacvclotridecaphan-11 -en-14-yl)oxy)pyrrolidine-1 -carboxylate

a) fe/f-butyl 3-(4-acetamido-2-allylphenoxy)pyrrolidine-1 -carboxylate

A stirred mixture of N-(3-allyl-4-hydroxyphenyl)acetamide (2.0 g, 10.46 mmol), fe/f-butyl 3- hydroxypyrrolidine-1 -carboxylate (2.350 g, 12.55 mmol), and triphenylphosphane (4.1 1 g, 15.69 mmol) in THF (90 ml) was placed under nitrogen and cooled to 0 °C. A solution of diethyl (E)- diazene-1 ,2-dicarboxylate (7.14 mL, 15.69 mmol, 40% in toluene) was added dropwise via syringe over 10 min. Additional THF (10 ml) was added and the reaction was stirred for 5 min at 0 °C. The ice-bath was removed and the reaction was stirred at room temperature under nitrogen for 39h. The reaction was concentrated in vacuo and the residue was dissolved in DCM. The DCM layer was washed with 2N aqueous NaOH (2 X), sat. aq. NaCI, dried over sodium εμί-ίβίβ, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (25% to 100% EtOAc/hexanes) to give the desired product (2.09 g, 37%) as a pale yellow syrup. Sample was ca. 67% pure (contains ca. 33% PPh30). LC-MS (ES) m/z = 361 .3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 .39 (d, J=10.03 Hz, 9 H) 1 .98 - 2.01 (m, 3 H) 2.05 (br. s., 2 H) 3.05 - 3.52 (m, 6 H) 4.89 - 5.07 (m, 3 H) 5.85 (dd, J=16.87, 7.34 Hz, 1 H) 6.93 (d, J=9.05 Hz, 1 H) 7.31 (d, J=2.45 Hz, 1 H) 7.41 (dd, J=8.56, 2.45 Hz, 1 H) 9.75 (s, 1 H). b) tert-butyl 3-(2-allyl-4-aminophenoxy)pyrrolidine-1 -carboxylate fe/ -Butyl 3-(4-acetamido-2- allylphenoxy)pyrrolidine-1 -carboxylate (2.09 g, 5.80 mmol) was dissolved in ethanol (27 mL) with stirring. Aqueous sodium hydroxide (3.02 mL, 58.0 mmol, 19.2M) was added and the solution was heated under reflux for 9.5h. The reaction was diluted with EtOH (20 ml) and cooled in an ice bath. The cooled and stirred solution was slowly acidified to pH 7 with 6N HCI. The suspension was concentrated in vacuo and the residue was dissolved in a mixture of DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined DCM layers were washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (20-90% 3:1 EtOAc/EtOH: hexanes, 120 g column) to give the desired product (643.0 mg, 35%) as an orange oil. LC-MS (ES) m/z = 319.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .39 (d, J=8.56 Hz, 9 H) 2.00 (d, J=6.1 1 Hz, 2 H)

3.13 (d, J=6.1 1 Hz, 2 H) 3.27 - 3.41 (m, 4 H) 4.60 - 4.82 (m, 3 H) 4.92 - 5.06 (m, 2 H) 5.83 (dd, J=16.87, 8.07 Hz, 1 H) 6.34 - 6.43 (m, 2 H) 6.70 (d, J=8.31 Hz, 1 H).

c) fe/f-butyl 3-(2-allyl-4-((5-carbamoyl-2-fluoro-4- hvdroxyphenyl)suLfonamido)phenoxy)pyrrolidine-1 -carboxylate

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (512 mg, 2.019 mmol), fe/f-butyl 3-(2-allyl-4-aminophenoxy)pyrrolidine-1 -carboxylate (643.0 mg, 2.019 mmol), and pyridine (0.163 mL, 2.019 mmol) in dichloromethane (24 mL) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, triturated with water, and filtered. The filtered solid was triturated with hexanes and the suspension was filtered and dried to afford the desired product (1 .08 g, 100%) as a light purple solid. LC-MS (ES) m/z = 536.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .22 - 1 .30 (m, 2 H) 1 .37 (d, J=19.56 Hz, 9 H) 1 .94 - 2.12 (m, 2 H) 3.14 (d, J=6.36 Hz, 2 H) 3.30-3.40 (m, 2H) 4.69 - 4.98 (m, 3 H) 5.63 - 5.87 (m, 1 H) 6.78 - 7.01 (m, 4 H) 8.1 1 (br. s., 1 H) 8.34 (d, J=8.07 Hz, 1 H) 8.66 (br. s., 1 H) 10.12 (s, 1 H) 14.16 (br. s., 1 H). d) fe/f-butyl 3-(2-allyl-4-((2-((2-(but-3-en-1 -yloxy)ethyl)aminoV5-carbamoyl-4-hvdro xyphenyl)suLfonamido)phenoxy)pyrrolidine-1 -carboxylate

A mixture of fe/f-butyl 3-(2-allyl-4-((5-carbamoyl-2-fluoro-4- hydroxyphenyl)sμLfonamido)phenoxy)pyrrolidine-1 -carboxylate (1 .08 g, 2.016 mmol), 2-(but-3- en-1 -yloxy)ethan-1 -amine (0.255 g, 2.218 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.782 g, 6.05 mmol) in 1 -butanol (9 ml_) was heated for 45 min at 150 °C under microwave irradiation. The reaction was concentrated in vacuo and the residue was dissolved in a mixture of EtOAc and water. The layers were separated and the EtOAc layer was washed with sat. aq. NaCI, dried over sodium εμίίβίβ, filtered, and concentrated. The residue was purified via silica gel chromatography (Biotage Isolera, 10-60% EtOAc:hexanes over 15 CV, loaded as a solution in 4 ml of DCM, 80 g column) to give the desired product (637.5 mg, 50%) as a colorless solid. LC-MS (ES) m/z = 631 .6 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .38 (d, J=14.31 Hz, 9 H) 1 .97 - 2.1 1 (m, 2 H) 2.22 - 2.30 (m, 2 H) 3.10 - 3.19 (m, 3 H) 3.28 (d, J=10.54 Hz, 3 H) 3.37 - 3.43 (m, 2 H) 3.46 (t, J=6.65 Hz, 2 H) 3.50 - 3.55 (m, 2 H) 4.85 - 4.96 (m, 3 H) 4.98 - 5.12 (m, 2 H) 5.65 - 5.91 (m, 2 H) 6.08 (s, 1 H) 6.27 - 6.38 (m, 1 H) 6.75 - 6.94 (m, 3 H) 7.61 (br. s., 1 H) 8.12 (s, 1 H) 8.28 (br. s., 1 H) 9.78 (d, J=6.78 Hz, 1 H) 13.81 (s, 1 H).

e) fe/f-butyl (E)-3-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2,5 -diaza-1 (

1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1 -en-14-yl)oxy)pyrrolidine-1 -carboxylate fe/f-butyl 3-(2-allyl-4-((2-((2-(but-3-en-1 -yloxy)ethyl)amino)-5-carbamoyl-4- hydroxyphenyl^Lfonamido)phenoxy)pyrrolidine-1 -carboxylate (628.2 mg, 0.996 mmol) was dissolved in dichloromethane (50 ml_) with stirring. Nitrogen was bubbled into the clear solution for 5 min. [1 ,3-Bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)- 1 -oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (39.0 mg, 0.050 mmol) was added as a solid and the reaction was stirred for 15h at room temperature. The reaction was concentrated and the residue was purified via silica gel chromatography (Biotage Isolera, 20- 70% EtOAc:hexanes over 15 CV, 40 g column, loaded as a solution in 4 ml of DCM) to give an impure solid. The solid was further purified by chromatography on silica gel (Biotage Isolera, 40 g column, 0-5% MeOH:DCM over 18 CV, loaded as a solution in DCM) to give the desired product (372.0 mg, 62%, 5:1 mixture of E:Z isomers) as a tan solid. LC-MS (ES) m/z = 603.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .38 (d, J=13.94 Hz, 9 H) 1 .94 - 2.14 (m, 2 H) 2.23 (d, J=4.40 Hz, 2 H) 3.02 - 3.19 (m, 2 H) 3.24 - 3.63 (m, 9 H) 4.92 (br. s., 1 H) 5.32 - 5.52 (m, 2 H) 5.76 (s, 1 H) 6.15 (s, 1 H) 6.39 (t, J=5.38 Hz, 1 H) 6.81 - 6.92 (m, 2 H) 6.97 (br. s., 1 H) 7.55 (br. s., 1 H) 8.01 (s, 1 H) 8.06 - 8.16 (m, 1 H) 9.51 (d, J=3.42 Hz, 1 H) 13.40 - 13.66 (m, 1 H).

Example 35

tert-butyl 3-((45-carbamoyl-44-hvdroxy-3,3-dioxido-8-oxa-3-thia-2,5-dia za-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphane-14-yl)oxy)pyrrolidine-1 -carboxylate

A solution of fe/ -butyl (E)-3-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2,5 -diaza-

1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1 -en-14-yl)oxy)pyrrolidine-1 -carboxylate (40.7 mg, 0.068 mmol) in methanol (6 mL) was hydrogenated over and 10% wet Pd-C (7.19 mg, 0.068 mmol) at room temperature and atmospheric pressure 90 min. The mixture was filtered through two 0.2 micron filters and then through a prepacked celite funnel. The filtrate was concentrated to afford the desired product (29.5 mg, 72%) as an off-white solid. (NMR indicated rotational isomers at Boc amine.) LC-MS (ES) m/z = 605.6 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .19 - 1 .30 (m, 3 H) 1 .38 (d, J=1 1 .98 Hz, 9 H) 1 .51 (br. s., 2 H) 1 .92 - 2.18 (m, 2 H) 3.13 (br. s.,

2 H) 3.22 - 3.53 (m, 10 H) 4.93 (br. s., 1 H) 5.76 (s, 1 H) 6.02 (s, 1 H) 6.36 (br. s., 1 H) 6.67 - 6.90 (m, 2 H) 6.97 (s, 1 H) 7.62 (br. s., 1 H) 8.05 - 8.36 (m, 2 H) 9.44 (br. s., 1 H) 13.47 (br. s., 1 H).

Example 36

(E)-44-hvdroxy-14-(pyrrolidin-3-yloxy)-8-oxa-3-thia-2,5-diaz a-1 (1 ,3),4(1 ,2)- dibenzenacvclotridecaphan-11 -ene-45-carboxamide 3,3-dioxide, Trifluoroacetic acid

salt

te/ -Butyl (E)-3-((45-carbamoyl-44-hydroxy-3,3-dioxido-8-oxa-3-thia-2,5 -diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -en-14-yl)oxy)pyrrolidine-1 -carboxylate (310.09 mg, 0.514 mmol) was dissolved in dry 1 ,4-dioxane (3 ml) with stirring. A solution of 4M HCI in 1 ,4-dioxane (3 mL, 12.00 mmol) was added and the solution was stirred at room temperature for 90 min. The reaction was concentrated in vacuo and purified via reverse-phase chromatography (C-18 silica gel, 4-34% MeCN:water with 0.1 % TFA, acidic Luna column, loaded as a solution in 4.8 mL DMSO, 6 x 800 μί injections) to give the desired product (269.8 mg, 85%, 5:1 mixture of E:Z isomers) as colorless solid. LC-MS (ES) m/z = 503.4 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- cfe) δ ppm 2.00 - 2.37 (m, 3 H) 3.06 - 3.69 (m, 1 1 H) 5.06 (br. s., 1 H) 5.32 - 5.58 (m, 2 H) 6.18 (s, 1 H) 6.42 (t, J=5.38 Hz, 1 H) 6.80 - 6.94 (m, 2 H) 6.99 - 7.10 (m, 1 H) 7.57 (br. s., 1 H) 7.99 (s, 1 H) 8.10 (s, 2 H) 8.81 - 9.10 (m, 2 H) 9.58 (s, 1 H) 13.51 (br. s., 1 H).

Example 37

14-(2-aminoethoxy)-44-hvdroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphane-45-carboxamide 3,3-dioxide, trifluoroacetic acid salt

A solution of (E)-14-(2-aminoethoxy)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-45-carboxamide 3,3-dioxide, trifluoroacetic acid salt (47.3 mg, 0.080 mmol) in methanol (4 mL) was hydrogenated over 10% wet Pd-C (1 .705 mg, 0.016 mmol) at room temperature and atmospheric pressure for 4h. The reaction was filtered through celite and the filtrate was concentrated in vacuo to give the desired product (38.6 mg, 81 %) as light tan solid. LC-MS (ES) m/z = 479.4 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 .24 (br. s., 3 H) 1 .43 - 1 .61 (m, 4 H) 2.62 (br. s., 2 H) 3.16 - 3.26 (m, 5 H) 3.42 (t, J=5.01 Hz, 2 H) 3.46 - 3.51 (m, 2 H) 4.06 (t, J=5.01 Hz, 2 H) 6.08 (s, 1 H) 6.47 (t, J=5.14 Hz, 1 H) 6.79 - 6.84 (m, 1 H) 6.86 - 6.91 (m, 1 H) 6.96 (d, J=2.45 Hz, 1 H) 7.65 (br. s., 1 H) 8.07 (br. s., 2 H) 8.22 (s, 1 H) 13.29 (br. s., 1 H). Example 38

44-hvdroxy-14-(pyrrolidin-3-yloxy)-8-oxa-3-thia-2.5-diaza-1 (1.3).4(1.2)- dibenzenacyclotridecaphane-45-carboxamide 3,3-dioxide, Trifluoroacetic acid salt

A solution of (E)-44-hydroxy-14-(pyrrolidin-3-yloxy)-8-oxa-3-thia-2,5-diaz a-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-45-carboxamide 3,3-dioxide, trifluoroacetic acid salt (232.9 mg, 0.378 mmol) in methanol (10 mL) was hydrogenated over 10% wet Pd-C (20.10 mg, 0.189 mmol) at room temperature and atmospheric pressure for 5h. The reaction was filtered through celite, and the filtrate was concentrated in vacuo to give the desired product (200.6 mg, 86%) as an off-white solid. LC-MS (ES) m/z = 505.4 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-cfe) δ ppm 1 .17 - 1 .30 (m, 2 H) 1 .42 - 1 .61 (m, 4 H) 2.02 - 2.23 (m, 2 H) 3.16 - 3.50 (m, 10 H) 5.04 (br. s., 1 H) 5.76 (s, 1 H) 6.08 (s, 1 H) 6.45 (t, J=4.89 Hz, 1 H) 6.77 - 6.91 (m, 2 H) 6.98 (s, 1 H) 7.66 (br. s., 1 H) 8.07 (br. s., 1 H) 8.23 (s, 1 H) 8.88 (br. s., 1 H) 9.02 (br. s., 1 H) 9.58 (s, 1 H) 13.44 (br. s., 1 H).

Example 39

7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18-triazatetracyclori 6.5.2.0 ⁴ , ⁹ .0 ²¹ , ^2S lpentacosa-

1 (24),4,6, boxamide

A suspension of a mixture of cis/trans isomers, (15E)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia- 2,10,18-triazatetracyclo[16.5.2.0 ⁴ ' ⁹ .0 ²¹ ' ²⁵ ]pentacosa-1 (24),4,6,8,15,19,21 (25),22-octaene-6- carboxamide and (15Z)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18- triazatetracyclo[16.5.2.0 ⁴ ' ⁹ .0 ²¹ ' ²⁵ ]pentacosa-1 (24),4,6,8,15,19,21 (25),22-octaene-6- carboxamide (87 mg, 0.197 mmol) in MeOH (10 mL) and EtOAc (3 mL) (warming to dissolve) was hydrogenated over Pd/C (10% Degussa) (10 mg) at 1 atm. pressure and room temperature overnight. The mixture was filtered through celite and evaporated to afford the desired product (40 mg; 42%) as a grey solid. LCMS m/z = 445.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 13.46 (br. s., 1 H), 9.63 (s, 1 H), 8.17 - 8.02 (m, 2H), 7.57 (br. s., 1 H), 7.42 - 7.34 (m, 1 H), 7.29 (d, J=3.2 Hz, 1 H), 7.25 (s, 1 H), 6.74 (dd, J=1 .7, 8.3 Hz,_1 H), 6.35 - 6.23 (m, 2H), 6.06 - 5.98 (m, 1 H), 4.14 (t, J=7.0 Hz, 2H), 3.23 (t, J=5.4 Hz, 2H), 3.13 (br. s., 4H), 1 .87 - 1 .72 (m, 2H), 1 .56 - 1 .43 (m, 2H).

Example 40

(15E)-7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18- triazatetracvcloM 6.5.2.0 ⁴ ' ⁹ .0 ²¹ ' ²⁵ 1pentacosa-1 (24 .6.8.15.19.21 (25>.22-octaene-6- carboxamide and

(15Z)-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18- triazatetracvclori 6.5.2.0 ⁴ . ⁹ .0 ²¹ 25lpentacosa-1 (24).4.6.8.15.19.21 (25).22-octaene-6-

a) 6-bromo-1 -(prop-2-en-1 -yl)-1 H-indole

A solution of 6-bromo-1 H-indole (5.00 g, 25.5 mmol) in DMF (25 mL) was treated with NaH (60% in mineral oil, 1 ,5 g, 38.3 mmol) and the mixture was stirred at room temperature for 1 h. 3-Bromoprop-1 -ene (2.204 mL, 25.5 mmol) was then added dropwise and the mixture stirred at room temperature for 45 min before the reaction contents were poured into sat. aq. NaHC0 ₃ (100 mL) and extracted with EtOAc (3 x 50 mL). The organics were washed with brine (30 mL), dried over Na ₂ S0 ₄ , filtered, and evaporated and the residue purified by chromatography (silica gel, gradient elution 0-100% EtOAc in hexanes) to afford the desired product (3.2 g; ) as an orange oil. LCMS m/z = 237.07 (M+H) ⁺ . Ή NMR (400MHz, DMSO-d6) δ = 7.69 (s, 1 H), 7.52 (d, J=8.5 Hz, 1 H), 7.38 (d, J=2.5 Hz, 1 H), 7.15 (d, J=8.3 Hz, 1 H), 6.49 (d, J=2.5 Hz, 1 H), 6.08 - 5.93 (m, 1 H), 5.15 (d, J=10.0 Hz, 1 H), 5.00 (d, J=17.1 Hz, 1 H), 4.84 (d, J=4.5 Hz, 2H).

b) 1 -(prop-2-en-1 -yl)-1 H-indol-6-amine

A solution of 1 -allyl-6-bromo-1 H-indole (1 .180 g, 5.00 mmol) in toluene (5 mL) was treated with diphenylmethanimine (1 .087 g, 6.00 mmol), 2,2'-bis(diphenylphosphanyl)-1 ,1 '-binaphthalene (0.187 g, 0.300 mmol), Pd ₂ (dba) ₃ (0.137 g, 0.150 mmol) and sodium tert-butoxide (0.673 g, 7.00 mmol) and the mixture was stirred at room temperature under an inert atmosphere overnight. The reaction mixture was cooled and poured into a mixture of EtOAc (100 ml_) and sat. aq. NH ₄ CI (30 ml_). The layers were separated and the aqueous phase was extracted once with EtOAc (20 ml_) and the combined organics were dried over Na ₂ S0 ₄ , filtered and evaporated and the residue purified by chromatography (silica gel, 0-100% EtOAc in hexanes) to afford a dark orange oil (1 .5 g). This oil was dissolved in DCM (10ml_), treated with TFA (3 ml_) and stirred at room temperature for 4 d. The mixture was evaporated and treated with EtOAc (50 ml_) and sat. aq. NH ₄ CI (20 ml_). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 20 ml_) and the combined organics were dried over Na ₂ S0 ₄ . filtered and evaporated and the residue purified by chromatography (silica gel, 0-100% EtOAc in hexanes) to afford the desired product (280 mg; 27%). LCMS m/z = 172.9 (M+H) ⁺ . Ή NMR (400MHz, DMSO-d6) δ = 7.19 (d, J=8.3 Hz, 1 H), 6.96 (d, J=3.2 Hz, 1 H), 6.50 (s, 1 H), 6.42 (dd, J=1 .7, 8.3 Hz, 1 H), 6.21 (d, J=2.7 Hz, 1 H), 5.97 (tdd, J=5.1 , 10.3, 17.1 Hz, 1 H), 5.17 - 5.10 (m, 1 H), 4.96 (qd, J=1 .7, 17.0 Hz, 1 H), 4.83 (br. s., 2H), 4.62 (td, J=1 .5, 5.1 Hz, 2H).

c) 2-hvdroxy-5-f[1 -(prop-2-en-1 -yl)-1 H-indol-6-yllsuLfamoyl>-4-f[2-(prop-2-en-1 - yloxy)ethyllamino>benzamide

A solution of 1 -(prop-2-en-1 -yl)-1 H-indol-6-amine (277 mg, 1 .609 mmol) and pyridine (0.141 ml_, 1 .743 mmol) in DCM (5 ml_) at 0°C was added dropwise to a suspension (sonicated for 2 min to a fine milky appearance) of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (340 mg, 1 .341 mmol) in DCM (5 ml_). The mixture was stirred at 0 °C for 60 min then poured into EtOAc (50 ml_), water (10 ml_) and 1 M aq. HCI (1 ml_). The aqueous phase was extracted with EtOAc (30 ml_) and the combined organics were dried over Na ₂ S0 ₄ , filtered and evaporated to afford the crude desired product (550 mg) as a brown foam which was used without further purification. An analytical sample was prepared by taking a portion of the crude material (50 mg) and triturating with DCM-MeOH (1 :1) (2 mL) to afford 4-fluoro-2-hydroxy-5-{[1 - (prop-2-en-1 -yl)-1 H-indol-6-yl^Lfamoyl}benzamide (16 mg) as a colorless solid. LCMS m/z = 390.3 (M+H) ⁺ . Ή NMR (400MHz, DMSO-d6) δ = 10.25 (s, 1 H), 8.65 (br. s., 1 H), 8.39 (d, J=8.3 Hz, 1 H), 8.10 (br. s., 1 H), 7.39 (d, J=8.6 Hz, 1 H), 7.25 (d, J=3.2 Hz, 1 H), 7.09 (s, 1 H), 6.89 (d, J=1 1 .7 Hz, 1 H), 6.80 (dd, J=1 .8, 8.4 Hz, 1 H), 6.35 (d, J=3.2 Hz, 1 H), 5.96 - 5.81 (m, 1 H), 5.05 (dd, J=1 .2, 10.3 Hz, 1 H), 4.82 (dd, J=1 .5, 17.1 Hz, 1 H), 4.69 (d, J=5.4 Hz, 2H).

A solution of the crude 4-fluoro-2-hydroxy-5-{[1 -(prop-2-en-1 -yl)-1 H-indol-6- yl^Lfamoyl}benzamide (500 mg) in warm n-BuOH (4 mL) was treated with 2-(allyloxy)ethan- 1 -amine (195 mg, 1 .926 mmol) and DIEA (0.336 mL, 1 .926 mmol) and stirred and heated in a sealed vessel at 160 °C for 1 .5 hr. After cooling, the reaction mixture was poured into EtOAc (50 mL), water (10 mL) and 1 M aq. HCI (1 mL), the layers separated and the aqueous phase was extracted with EtOAc (3 x 10mL). The combined organics were dried over Na ₂ S0 ₄ , filtered, and evaporated and the residue purified by chromatography (silica gel, 0-100% EtOAc in hexanes) to afford a viscous oil which was azeotroped with DCM (2 x 10 ml_) to afford the desired product (200 mg, 62.2 % yield) as a colorless solid. LCMS m/z = 471 .3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ = 13.74 (s, 1 H), 9.92 (s, 1 H), 8.55 - 8.07 (m, 2H), 7.59 (br. s., 1 H), 7.37 (d, J=8.3 Hz, 1 H), 7.24 (d, J=3.2 Hz, 1 H), 7.05 (s, 1 H), 6.73 (dd,J=1 .8, 8.4 Hz, 1 H), 6.40 - 6.29 (m, 2H), 6.06 (s, 1 H), 5.98 - 5.81 (m, 2H), 5.27 (qd, J=1 .7, 17.4 Hz, 1 H), 5.18 - 5.03 (m, 2H), 4.86 (dd, J=1 .5, 17.1 Hz, 1 H), 4.69 (d, J=5.4 Hz, 2H), 3.96 (td, J=1 .5, 5.4 Hz, 2H), 3.54 - 3.46 (m, 2H), 3.32 - 3.25 (m, 2H).

d) (15E)-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.18- triazatetracvclo[16.5.2.0 ^{4 9} .0 ^{21 25} lpentacosa-1 (24).4.6.8.15.19.21 (25).22-octaene-6- carboxamide and (15Z)-7-hvdroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,18- triazatetracvclon 6.5.2.0 ^{4 9} .0 ²¹ ' ²⁵ lpentacosa-1 (24).4.6.8.15.19.21 (25).22-octaene-6- carboxamide

A mixture of 2-hydroxy-5-{[1 -(prop-2-en-1 -yl)-1 H-indol-6-yl]sμLfamoyl}-4-{[2-(prop-2-en-1 - yloxy)ethyl]amino}benzamide (180 mg, 0.383 mmol) in EtOAc (8 ml_) was treated with

[1 ,3-bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 - oxopropan-2-yl]oxy]benzylidene}ruthenium(ll) dichloride (15 mg) and the mixture gently warmed to allow complete dissolution then stirred at room temperature for 6 h. The reaction mixture was filtered to afford a grey solid (155 mg). A portion of this solid (68 mg) was purified via triturated in warm MeOH/EtOAc (~1 /1 ratio, 6 ml_) to afford the desired product (26 mg; 15%) as a colorless solid.

A second crop was obtained by warming the filtrate from the above trituration and allowing to cool over 3 d before filtration to afford the desired product (16 mg; 9%) as a colorless solid. A third crop was obtained by evaporation of the trituration filtrate from the second crop and purification of the residue by chromatography [C-18 silica gel, gradient elution 20-100% ACN in water (0.5% TFA)] to afford the desired product (8 mg; 4%) as a colorless solid as an approximately 93:7 mixture of (E) to (Z)-isomers. LCMS m/z = 443.32 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ = 13.48 (s, 1 H), 9.80 (s, 1 H), 8.29 - 8.07 (m, 2H), 7.89 - 7.46 (m, 1 H), 7.39 - 7.33 (m, 1 H), 7.29 (d, J=2.9 Hz, 1 H), 7.13 (s, 1 H), 6.96 (dd, J=1 .8, 8.4 Hz, 1 H), 6.44 (t, J=5.5 Hz, 1 H), 6.31 (d, J=2.4 Hz, 1 H), 6.03 (s, 1 H), 5.72 (td, J=5.5, 15.4 Hz, 1 H), 5.52 - 5.39 (m, 1 H), 4.77 (d, J=5.1 Hz, 2H), 3.86 (d, J=6.8 Hz, 2H), 3.32 - 3.20 (m, 4H). (one methylene partially hidden by water peak). Example 41

7-hvdroxy-3,3-dioxo-13,17-dioxa-3A ⁶ -thia-2,10-diazatricyclon 7.3.1.OVltricosa-

a) 3-((3-nitrobenzvDoxy)propan-1 -ol

A solution of propane-1 ,3-diol (20 g, 263 mmol) in DMF (100 ml_) was treated with sodium hydride (2.8 g, 1 17 mmol) at room temperature. The solution was stirred for 30 min. then 1 - (bromomethyl)-3-nitrobenzene (10 g, 46.3 mmol) was added to the solution portionwise. The mixture was stirred at 25 °C for 16 hr. Methanol (1 ml_) was slowly added then the mixture was evaporated and the residue purified by chromatography (silica gel, gradient elution 0- 30% EtOAc in pet.ether) to afford the desired product (8.0 g; 82%) as a yellow oil. LCMS m/z = 21 1 .9 (M+H) ⁺ .

b) 1 -((3-bromopropoxy)methyl)-3-nitrobenzene

A solution of 3-((3-nitrobenzyl)oxy)propan-1 -ol (5 g, 23.67 mmol) in DCM (200 mL) was treated with triphenylphosphine (15 g, 57.2 mmol) and stirred at room temperature for 30 min. Carbon tetrabromide (10 g, 30.2 mmol) was added to the solution portionwise over 60 min. and the mixture was stirred at 20 °C for 6 hr. The reaction mixture was evaporated and the residue purified by chromatography (silica gel, gradient elution 0-20% EtOAc in pet.ether) to afford the desired product (4.2 g; 65%) as a yellow oil. ¹ H NMR (400 MHz, CDCI3) δ ppm 8.23 (s, 1 H), 8.18 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 4.64 (s, 2H), 3.69 (t, J = 5.8 Hz, 2H), 3.58 (t, J = 6.4 Hz, 2H), 2.20 (p, J = 6.1 Hz, 2H).

c) fe/ -butyl (2-(3-((3-nitrobenzyl)oxy)propoxy)ethyl)carbamate

A solution of fe/ -butyl (2-hydroxyethyl)carbamate (8 g, 49.6 mmol) in THF (100 mL) was treated with potassium fe/ -butoxide (3 g, 26.7 mmol) and stirred at room temperature for 30 min. 1 -((3-bromopropoxy)methyl)-3-nitrobenzene (4 g, 14.59 mmol) was then added to the solution dropwise and the mixture was stirred at 20 °C for 16 h. The reaction mixture was evaporated and the residue purified by chromatography (silica gel, gradient elution 0-40% EtOAc in pet.ether) to afford the desired product (1 .0 g; 19%) as a yellow solid. LCMS m/z = 376.9 (M+Na) ⁺ .

d) fe/ -butyl (2-(3-((3-aminobenzyl)oxy)propoxy)ethyl)carbamate

A solution of fe/ -butyl (2-(3-((3-nitrobenzyl)oxy)propoxy)ethyl)carbamate (1 g, 2.82 mmol) in ethanol (30 mL) was hydrogenated over Pd/C (100 mg) at 60 °C and 4 atm. for 16 h. The reaction solution was cooled to room temperature, filtered to remove catalyst, evaporated and the residue purified by chromatography (silica gel, gradient elution 0-10% MeOH in DCM) to afford the desired product (600 mg; 66%) a yellow solid. LCMS m/z = 346.9 (M+Na) ⁺ .

e) tert-butyl (2-(3-((3-(5-carbamoyl-2-fluoro-4- hydroxyphenylsμLfonamido)benzyl)oxy)propoxy)ethyl)carbamate

A solution of fe/ -butyl (2-(3-((3-aminobenzyl)oxy)propoxy)ethyl)carbamate (300 mg, 0.925 mmol) in THF (50 mL), was added 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (235 mg, 0.925 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and the residue purified by chromatography (silica gel, gradient elution 0-20% EtOAc in pet. ether) to afford the desired product (400 g; 68%) as a yellow solid. LCMS m/z = 563.7 (M+Na) ⁺ .

f) 5-(N-(3-((3-(2-aminoethoxy)propoxy)methyl)phenyl)sμLfamoyl) -4-fluoro-2- hydroxybenzamide, hydrochloride

A solution of tert-butyl (2-(3-((3-(5-carbamoyl-2-fluoro-4- hydroxypheny^Lfonamido)benzyl)oxy)propoxy)ethyl)carbamate (400 mg, 0.739 mmol) in methanol (20 mL), was treated 6M aq. HCL (1 .23 mL) and the mixture was stirred at 20 °C for 16 h. The mixture was evaporated to afford the desired product (320 mg; 83%). LCMS m/z = 441 .8 (M+H) ⁺ .

g) 7-hydroxy-3,3-dioxo-13,17-dioxa-3A ⁶ -thia-2,10-diazatricyclo[17.3.1 .0 ⁴ , ⁹ ]tricosa- 1 (23),4(9),5,7,19,21 -hexaene-6-carboxamide

A solution of 5-(N-(3-((3-(2-aminoethoxy)propoxy)methyl)phenyl)sμLfamoyl) -4-fluoro-2- hydroxybenzamide (200 mg, 0.453 mmol) in 1 -butanol (10 mL) was treated with N-ethyl-N- isopropylpropan-2-amine (500 mg, 3.87 mmol) and the mixture was stirred and heated at 100 °C under microwave irradiation for 1 hr. The reaction mixture was evaporated and the residue purified by chromatography (silica gel, gradient elution 0-10% MeOH in DCM) to afford the desired product (20 mg; 9%) a a yellow solid. LCMS m/z = 419.1 (M-H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 13.59 (s, 1 H), 10.08 (s, 1 H), 8.24 (s, 1 H), 8.1 1 (s, 1 H), 7.57 (s, 1 H), 7.22 - 7.12 (m, 2H), 7.00 (s, 1 H), 6.89 (d, J = 7.1 Hz, 1 H), 6.24 (d, J = 5.6 Hz, 1 H), 6.13 (s, 1 H), 4.44 (s, 2H), 3.56 - 3.51 (m, 2H), 3.47 (t, J = 5.2 Hz, 2H), 3.33 - 3.31 (m, 1 H), 3.25 - 3.15 (m, 3H), 1 .70 - 1 .61 (m, 2H). Example 42

(E)-44-hvdroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)-dibenzenacyclotetradecaphan-11 -

a) 3-(but-3-en-1 -yl)aniline

A solution of te/ -butyl (3-(but-3-en-1 -yl)phenyl)carbamate (840 mg) (Org. Lett. , 2005, 7 (2), 315) in DCM (6 mL) under an inert atmosphere was treated with TFA (2 mL) and stirred at room temperature for 3h. The mixture was evaporated and the residue treated with 1 M HCI (25 mL) and extracted with EtOAc (25 mL). The acidic aqueous layer was basified with NaOH (6N) and further extracted with EtOAc (25 mL). The combined organic layers was dried over Na ₂ S0 ₄ and evaporated to afford 3-(but-3-en-1 -yl)aniline (61 1 mg). LCMS m/z 148.1 (M+H) ⁺ .

b) 5-(N-(3-(but-3-en-1 -yl)phenyl)sμLfamoyl)-4-fluoro-2-hydroxybenzamide

A mixture of 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (1 .053 g), 3-(but-3-en- 1 -yl)aniline (61 1 mg), and pyridine (1 .007 mL) in DCM (12 mL) was stirred at room temperature for 18h. The mixture was evaporated then diluted with water (25 ml) and stirred at room temperature for 1 h. The precipitate was washed with water then hexanes to afford 5-(N-(3-(but- 3-en-1 -yl)phenyl^Lfamoyl)-4-fluoro-2-hydroxybenzamide (1 .3 g). LCMS m/z 363.2 (M-H) ^" . c) 5-(N-(3-(but-3-en-1 -yl)phenyr^Lfamoyl)-4-((2-(but-3-en-1 -yloxy)ethyl)amino)-2- hydroxybenzamide

A mixture of 2-(but-3-en-1 -yloxy)ethan-1 -amine (322 mg), 5-(N-(3-(but-3-en-1 - yl)phenyl^Lfamoyl)-4-fluoro-2-hydroxybenzamide (680 mg), and DIEA (0.978 mL) in 1 - butanol (10 mL) was stirred and heated to 80 °C for 3 d (incomplete conversion) then heated at 150 °C under microwave irradiation for 45 min. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with 1 N HCI (50 mL) then dried over Na ₂ S0 ₄ , filtered, and evaporated. The crude product was purified by chromatography (silica gel, gradient 5-40% EtOAc in heptanes) to afford 5-(N-(3-(but-3-en-1 - yl)phenyl)sμLfamoyl)-4-((2-(but-3-en-1 -yloxy)ethyl)amino)-2-hydroxybenzamide (469 mg) as colorless solid. LCMS m/z 460.2 (M+H) ⁺ ; Ή NMR (400 MHz, DMSO-d ₆ J δ ppm 13.86 (s, 1 H), 10.14 (s, 1 H), 8.39 (br. s., 1 H), 8.25 (s, 1 H), 7.64 (br. s., 1 H), 7.03 - 7.16 (m, 1 H), 6.92 (s, 1 H), 6.75 - 6.89 (m, 2 H), 6.33 (t, J = 5.32 Hz, 1 H), 6.08 (s, 1 H), 5.63 - 5.92 (m, 2 H), 4.86 - 5.1 1 (m, 4 H), 3.51 - 3.62 (m, 2 H), 3.47 (t, J = 6.72 Hz, 2 H), 3.26 - 3.33 (m, 2 H), 2.53 - 2.58 (m, 2 H), 2.23 - 2.32 (m, 2 H), 2.08 - 2.23 (m, 2 H).

d) (E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotetradecaphan-1 1 - ene-45-carboxamide 3,3-dioxide

A degassed solution of 5-(N-(3-(but-3-en-1 -yl)phenyl^Lfamoyl)-4-((2-(but-3-en-1 - yloxy)ethyl)amino)-2-hydroxybenzamide (426 mg) in DCM (46 mL) was treated with [1 ,3- bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy] benzylidene}ruthenium(ll) dichloride (36.3 mg) and stirred at room temperature for 18h under an inert atmosphere. The mixture was filtered and the precipitate washed with DCM then methanol then purified by chromatography [C-18 silica, gradient 10% acetonitrile/H ₂ 0 (0.1 % NH4OH) to 35% acetonitrile/H ₂ 0, (0.1 % NH4OH)] to afford a mixture of (E)-44-hydroxy-8-oxa- 3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotetradecaphan-1 1 -ene-45-carboxamide 3,3- dioxide and (Z)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotetradecaphan-1 1 -ene-45-carboxamide 3,3-dioxide (140 mg) in an approximate 2.3:1 ratio, along with pure (E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotetradecaphan-1 1 -ene-45-carboxamide 3,3-dioxide (58 mg) as colorless solid. LCMS m/z 432.1 (M+H) ⁺ ; Ή NMR (400 MHz, DMSO-d ₆ J δ ppm 13.43-14.00 (m, 1 H), 9.68- 10.31 (m, 1 H), 8.87 (br d, J = 3.7 Hz, 1 H), 8.31 -8.49 (m, 1 H), 8.28 (br s, 1 H), 7.17 - 7.77 (m, 1 H), 7.04 (t, J = 7.3 Hz, 1 H), 6.83 (br d, J = 7.7 Hz, 1 H), 6.70 (br s, 1 H), 6.61 - 6.68 (m, 1 H), 5.86 - 6.20 (m, 1 H), 5.13 - 5.21 (m, 1 H), 4.93 (br dd, J = 5.3, 4.0 Hz, 1 H), 3.42 - 3.47 (m, 2 H), 3.24 - 3.31 (m, 2 H), 3.13 (br s, 2H), 2.55 (s, 2 H), 2.1 1 - 2.14 (m, 2 H), 1 .90 - 2.03 (m, 2 H).

Example 43

44-hvdroxy-8-oxa-3-thia-2.5-diaza-1 (1 ,3).4(1.2)-dibenzenacvclotetradecaphane-45-

A mixture of (E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotetradecaphan-1 1 -ene-45-carboxamide 3,3-dioxide and (Z)-44-hydroxy-8-oxa- 3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotetradecaphan-1 1 -ene-45-carboxamide 3,3- dioxide (2.3:1 ratio; 78 mg) from Example 47 in methanol (9 mL) and EtOAc (4 mL) was hydrogenated over Pd/C (5%, 1 mg) at room temperature and 1 atm. of hydrogen gas for 20 min. The mixture was filtered through celite, evaporated and the residue treated with EtOAc (5 ml_), stirred for 1 h, filtered and the precipitate washed with EtOAc to afford 44-hydroxy-8-oxa- 3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)-dibenzenacyclotetradecaphane-45-carboxamide 3,3-dioxide (40 mg) as colorless solid. LCMS m/z 434.1 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 13.62 (br s, 1 H), 9.98 (br s, 1 H), 8.45-8.87 (m, 1 H), 8.14 - 8.32 (m, 1 H), 7.45 (br s, 1 H), 7.01 - 7.20 (m, 1 H), 6.89 (d, J=7.86 Hz, 1 H), 6.84 (s, 1 H), 6.79 (d, J=7.60 Hz, 1 H), 6.39 (br s, 1 H), 6.03 (br s, 1 H), 3.47 (t, J=4.44 Hz, 2 H), 3.25 - 3.287 (m , 4 H), 2.47 (br s, 2 H), 1 .48 - 1 .58 (m, 2 H), 1 .44 (dt, J=12.17, 6.08 Hz, 2 H), 1 .19 - 1 .31 (m, 2 H), 1 .00 - 1 .17 (m, 2 H). Example 44

44-hvdroxy-8-oxa-3-thia-2.5-diaza-1 (1.3).4(1.2)-dibenzenacvclotridecaphane-15.45- dicarboxamide 3,3-dioxide

a) 3-allyl-5-nitrobenzoic acid

A degassed solution of methyl 3-bromo-5-nitrobenzoate (1 .0 g, 3.85 mmol) and

allyltributylstannane (1 .24 ml_, 4.0 mmol) in THF (38 mL) was treated with Pd(Ph ₃ P) ₄ (222 mg, 0.192 mmol) and stirred and heated at 1 10 °C for 3h under an inert atmosphere. The mixture was evaporated and purified by chromatography (silica gel, gradient elution 3-20% EtOAc/hexanes) to afford methyl 3-allyl-5-nitrobenzoate (150 mg) followed by 3-allyl-5- nitrobenzoic acid (870 mg). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.58 (d, J=6.84 Hz, 2 H) 5.09 - 5.20 (m, 2 H) 6.00 (ddt, J=16.95, 10.1 1 , 6.75, 6.75 Hz, 1 H) 8.06 - 8.27 (m, 2 H) 8.45 (s, 1 H) 13.7 (br s, 1 H).

b) 3-allyl-5-nitrobenzamide

A solution of 3-allyl-5-nitrobenzoic acid (829 mg, 4.00 mmol), EDC (161 1 mg, 8.40 mmol), HOBt hydrate (1287 mg, 8.40 mmol), and N.Ndiisopropylethylamine

(1 .468 ml, 8.40 mmol) in DMF (40 ml) was stirred at room temperature for 10 min then treated with ammonium carbonate (2.307 g, 24.01 mmol) and stirred at room temperature over the weekend. The reaction mixture was diluted with water (50 mL) and 1 M aqu. NaOH (5 mL) and extracted with EtOAc (50 mL). The EtOAc layer was dried, evaporated and the crude product purified by chromatography (silica gel, gradient 5-40% EtOAc in heptanes) to afford 3-allyl-5- nitrobenzamide (220 mg, 1 .067 mmol, 26.7 % yield). ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 3.58 (d, J=6.59 Hz, 2 H) 5.1 1 - 5.22 (m, 2 H) 6.02 (ddt, J=16.92, 10.08, 6.78, 6.78 Hz, 1 H) 7.71 (br. s., 1 H) 8.15 - 8.25 (m, 2 H) 8.34 (br. s., 1 H) 8.56 (t, J=1 .77 Hz, 1 H).

c) 3-allyl-5-aminobenzamide

A suspension of 3-allyl-5-nitrobenzamide (220 mg, 1 .067 mmol) and zinc (dust, <10 urn) (698 mg, 10.67 mmol) in DCM (10 mL) at 0 °C was treated with acetic acid (1 mL) and stirred at 0 °C for 20 min. The reaction was filtered, washed with DCM then treated with sat. aqueous NaHC0 ₃ (40 ml) and extracted with DCM (50 mL x 2). The DCM layer was dried and evaporated to afford 3-allyl-5-aminobenzamide (190 mg, quant.). ¹ H NMR (400 MHz, DMSO- cfe) δ ppm 3.24 (d, J=6.84 Hz, 2 H) 4.99 - 5.13 (m, 2 H) 5.16 (s, 2 H) 5.93 (ddt, J=16.95, 10.1 1 , 6.75, 6.75 Hz, 1 H) 6.51 (s, 1 H) 6.81 - 6.90 (m, 2 H) 7.10 (br. s., 1 H) 7.69 (br. s., 1 H). d) 5-(N-(3-allyl-5-carbamoylphenyl)sμLfamoyl)-4-fluoro-2-hydro xybenzamide

A solution of 5-carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (270 mg), 3-allyl-5- aminobenzamide (188 mg), and pyridine (0.258 mL) in DCM (6 mL) was stirred at room temperature for 18h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL). The solids that woμLd not dissolve into water or EtOAc was dissolved into methanol. The EtOAc layer was washed with 1 N HCI and water, dried over Na ₂ S0 ₄ and combined with methanol solution then evaporated. The crude product was purified by chromatography (silica gel, gradient 5-75% DCM(10%MeOH) in DCM) to afford 5-(N-(3-allyl- 5-carbamoylphenyl^Lfamoyl)-4-fluoro-2-hydroxybenzamide (250 mg). LCMS m/z 392.2 (M- H)-.

e) 5-(N-(3-allyl-5-carbamoylphenyl)sμLfamoyl)-4-((2-(but-3-en- 1 -yloxy)ethyl)amino)-2- hydroxybenzamide

A solution of 2-(but-3-en-1 -yloxy)ethan-1 -amine (1 10 mg), 5-(N-(3-allyl-5- carbamoylphenyl^Lfamoyl)-4-fluoro-2-hydroxybenzamide (250 mg), and DIEA (0.166 mL) in 1 -butanol (10 mL) was heated at 150 °C for 45 min. under microwave irradiation. After 45 min, the reaction mixture was evaporated. The reaction mixture was evaporated then treated with 1 N HCI (50 mL) and extracted with EtOAc (50 mL). The EtOAc layer was washed with 1 N HCI (50 mL). The EtOAc layer was dried over Na ₂ S0 ₄ , filtered, and evaporated to afford 5- (N-(3-allyl-5-carbamoylphenyl)sμLfamoyl)-4-((2-(but-3-en-1 -yloxy)ethyl)amino)-2- hydroxybenzamide (360 mg) as brown oil. LCMS m/z 489.1 (M+H) ⁺ .

f) Mixture of (E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-15,45-dicarboxamide 3,3-dioxide and (Z)-44- hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1 -ene- 15,45-dicarboxamide 3,3-dioxide

A mixture of 5-(N-(3-allyl-5-carbamoylphenyl)sμLfamoyl)-4-((2-(but-3-en- 1 -yloxy)ethyl)amino)- 2-hydroxybenzamide (360 mg) in DCM (60 mL) was degassed with argon for 2 min. then treated with [1 ,3-bis(2,6-di-i-propylphenyl)imidazolidin-2-ylidene]{2-[[1 -

(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy] benzylidene}ruthenium(ll) dichloride (28.9 mg) and stirred at room temperature for 18h. 2-Methyltetrahydrofuran (20 mL) was then added, the mixture stirred for 3 h, then evaporated. The crude product was purified by chromatography [C-18 silica, gradient 3-28% acetonitrile in H ₂ 0 (0.1 % NH ₄ OH)] to afford a mixture of (E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphan-1 1 - ene-15,45-dicarboxamide 3,3-dioxide and (Z)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-15,45-dicarboxamide 3,3-dioxide (82 mg) as colorless solid. LCMS m/z 459.2 (M-H)-.

g) 44-hvdroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)-dibenzenacvclotridecaphane-15,45- dicarboxamide 3,3-dioxide

A solution of a mixture of (E)-44-hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)- dibenzenacyclotridecaphan-1 1 -ene-15,45-dicarboxamide 3,3-dioxide with (Z)-44-hydroxy-8- oxa-3-thia-2,5-diaza-1 (1 ,3),4(1 ,2)-dibenzenacyclotridecaphan-1 1 -ene-15,45-dicarboxamide 3,3-dioxide (60 mg) in methanol (20 mL) hydrogenated over 5%Pd/C (6.93 mg) at room temperature and 1 atmosphere of hydrogen gas for 3d. The mixture was filtered through celite, evaporated then treated with EtOAc and hexanes (1 :1 , 10 mL) and filtered to afford 44- hydroxy-8-oxa-3-thia-2,5-diaza-1 (1 ,3), 4(1 ,2)-dibenzenacyclotridecaphane-15,45- dicarboxamide 3,3-dioxide (12 mg) as colorless solid. LCMS m/z 463.3 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-deJ δ ppm 13.52 (br. s., 1 H), 9.96 (br. s., 1 H), 8.26 (s, 1 H), 8.20 (br s, 1 H), 7.85 (br. s., 1 H), 7.65 (br s, 1 H), 7.40 (d, J=9.12 Hz, 2 H), 7.31 (s, 1 H), 7.10 (s, 1 H), 6.38 (br. s., 1 H), 6.08 (s, 1 H), 3.37 - 3.47 (m, 2 H), 3.23 (d, J=4.31 Hz, 2 H), 2.59 - 2.66 (m, 2 H), 2.46 (br. s.,2 H), 1 .60 (br. s., 2 H), 1 .36 - 1 .53 (m, 2 H), 1 .06 - 1 .31 (m, 2 H).

Example 45

(16E)-22-ethyl-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.23- triazatetracvcloM 7.6.1.0 ⁴ ' ⁹ .0 ²⁰ ' ²⁴ 1hexacosa-1 (26).4.6.8.16.19.21 ,24-octaene-6- carboxamide. trifluoroacetic acid salt and

(16Z)-22-ethyl-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.23- triazatetracyclon 7.6.1.0 ⁴ ' ⁹ .0 ²⁰ ' ²⁴ 1hexacosa-1 (26).4.6.8.16.19.21 ,24-octaene-6-

a) 5-{[2-ethyl-4-(prop-2-en-1 -yl>1 H-indol^

A solution of 4-allyl-2-ethyl-1 H-indol-6-amine (1 13 mg, 0.564 mmol) and pyridine (0.053 mL, 0.651 mmol) in DCM (2 mL) at 0°C was treated dropwise with a sonicated suspension of 5- carbamoyl-2-fluoro-4-hydroxybenzenesμLfonyl chloride (127 mg, 0.501 mmol) in DCM (4 mL) and the mixture was stirred for 2 h at 0 °C. The reaction mixture was poured into EtOAc (15 mL) and water (5 mL with 3 drops of 1 M aq. HCI). The aqueous phase was extracted with EtOAc (10 mL), the combined organics were dried over Na ₂ S0 ₄ , filtered, and evaporated to afford the desired product (220 mg, quant.) as a brown foam. LCMS m/z 417.1 (M-H) ⁺ . ¹ H NMR (400MHz, DMSO-de) δ = 14.05 (br. s., 1 H), 10.83 (d, J=1 .5 Hz, 1 H), 9.98 (s, 1 H), 8.59 (br. s., 1 H), 8.30 (d, J=8.1 Hz, 1 H), 8.06 (br. s., 1 H), 6.90 (d, J=1 1 .2 Hz, 2H), 6.54 (d, J=1 .7 Hz, 1 H), 6.07 (d, J=1 .0 Hz, 1 H), 5.86 (tdd, J=6.6, 10.2, 16.9 Hz, 1 H), 5.02 - 4.92 (m, 2H), 2.66 (q, J=7.6 Hz, 2H), 1 .22 (t, J=7.6 Hz, 3H).

b) 4-{[2-(but-3-en-1 -yloxy)ethyllamino>-5-f[2-ethyl-4-(prop-2-en-1 -yl)-1 H-indol-6- yllsLiLfamoyl)-2-hvdroxybenzamide.

A solution of 5-{[2-ethyl-4-(prop-2-en-1 -yl)-1 H-indol-6-yl]sμLfamoyl}-4-fluoro-2- hydroxybenzamide (220 mg, 0.527 mmol) in 1 -butanol (4.0 mL) was treated with 2-(but-3-en-1 - yloxy)ethan-1 -amine (182 mg, 1 .581 mmol) and DIEA (0.276 mL, 1 .581 mmol) and the mixture was stirred at heated at 155 °C under microwave irradiation for 30 min.. The solution was cooled, evaporated and treated with EtOAc (15 mL) and water (5 mL with 3 drops of 1 M aq. HCI). The layers were separated, the organics were dried over Na ₂ S0 ₄ , filtered, evaporated and the residue triturated with DCM (10 mL) with sonication and filtered to afford the desired product (155 mg, 0.281 mmol, 53.4 % yield) as a tan solid. LCMS m/z 513.1 (M-H) ⁺ . Ή NMR (400MHz, DMSO-de) δ = 13.68 (br. s., 1 H), 10.80 (d, J=1 .5 Hz, 1 H), 9.57 (br. s., 1 H), 8.21 (br. s., 1 H), 8.09 (s, 1 H), 7.54 (br. s., 1 H), 6.82 (d, J=1 .0 Hz, 1 H), 6.49 (d, J=1 .7 Hz, 1 H), 6.28 (t, J=5.3 Hz, 1 H), 6.12 - 6.00 (m, 2H), 5.93 - 5.70 (m, 2H), 5.14 - 4.88 (m, 4H), 3.46 - 3.38 (m, 6H), 3.23 (q, J=5.4 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 2.29 - 2.20 (m, 2H), 1 .27 - 1 .17 (m, 3H).

c) (16E)-22-ethyl-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.23- triazatetracvclo[17.6.1 .0 ^{4 9} .0 ^{20 24} lhexacosa-1 (26),4,6,8,16,19,21 ,24-octaene-6- carboxamide, trifluoroacetic acid salt and (16Z)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-

3A ⁶ -thia-2.10.23-triazatetracvclo[17.6.1 .0 ^{4 9} .0 ^{20 24} lhexacosa-1 (26V4.6.8.16.19.21 .24- octaene-6-carboxamide, trifluoroacetic acid salt

A suspension of 4-{[2-(but-3-en-1 -yloxy)ethyl]amino}-5-{[2-ethyl-4-(prop-2-en-1 -yl)-1 H-indol-6- yl^Lfamoyl}-2-hydroxybenzamide (145 mg, 0.283 mmol) in EtOAc (4 mL) and warmed to near boiling then treated with i-PrOH (3.0 mL) to produce a clear solution. [1 ,3-Bis(2,6-di-i- propylphenyl)imidazolidin-2-ylidene]{2-[[1 -(methoxy(methyl)amino)-1 -oxopropan-2- yl]oxy]benzylidene}ruthenium(ll) dichloride (9 mg, 0.01 1 mmol) was then added and the mixture was stirred and heated at 50°C for 5 h. The reaction mixture was evaporated and the residue purified by chromatography [C-18 silica, 5 micron, 30 x 50 mm, gradient elution 20-65% ACN in water (0.1 % TFA)] to afford the desired product (28 mg; 17%) as a colorless solid as a mixture of (16E)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,23- triazatetracyclo[17.6.1 .0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4,6,8,16,19,21 ,24-octaene-6-carboxamide, trifluoroacetic acid salt and (16E,Z)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2, 10,23- triazatetracyclo[17.6.1 .0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4,6,8,16,19,21 ,24-octaene-6-carboxamide, trifluoroacetic. LCMS m/z 485.2 (M-H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 13.40 (s, 1 H), 1 1 .08 - 10.58 (m, 1 H), 9.57 - 9.23 (m, 1 H), 8.34 - 7.78 (m, 2H), 7.55 (br. s., 1 H), 7.02 - 6.80 (m, 1 H), 6.77 - 6.52 (m, 1 H), 6.46 (t, J=5.4 Hz, 1 H), 6.12 (s, 1 H), 6.09 (d, J=1 .0 Hz, 1 H), 5.70 - 5.32 (m, 2H), 3.75 - 3.34 (m, 8H, partially obscured by water peak), 2.68 (q, J=7.6 Hz, 2H), 2.39 - 2.19 (m, 2H), 1 .24 (t, J=7.5 Hz, 3H). ¹ H NMR integration ~7 to 1 mixture of olefin isomers.

Example 46

22-ethyl-7-hvdroxy-3.3-dioxo-13-oxa-3A ⁶ -thia-2.10.23- triazatetracyclon 7.6.1.0 ⁴ , ⁹ .0 ² °, ²⁴ 1hexacosa-1 (26),4,6, 8,19,21 ,24-heptaene-6-carboxamide,

A solution of (16E,Z)-22-ethyl-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2, 10,23- triazatetracyclo[17.6.1.0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4,6,8,16,19,21 ,24-octaene-6-carboxamide, trifluoroacetic acid salt (16 mg, 0.027 mmol) in EtOAc-MeOH (1 :1) (2 mL) was hydrogenated over 10%P/C (Degussa Type) (3 mg) at room temperature and atmospheric pressure for 30 min. The mixture was filtered and evaporated to afford the desired product

(16 mg; quant.). LCMS m/z 487.1 (M-H) ⁺ . Ή NMR (400MHz, DMSO-d ₆ ) δ = 13.31 - 13.24 (m, 1 H), 13.27 (s, 1 H), 10.85 - 10.77 (m, 1 H), 10.81 (s, 1 H), 9.40 - 9.32 (m, 1 H), 9.36 (s, 1 H), 8.34 - 8.28 (m, 1 H), 8.30 (s, 1 H), 7.93 (br. s., 1 H), 7.69 (br. s., 1 H), 6.78 (s, 1 H), 6.68 (d, J=1.5 Hz, 1 H), 6.51 (t, J=4.8 Hz, 1 H), 6.07 (s, 1 H), 5.99 (s, 1 H), 3.37 (td, J=5.0, 10.5 Hz, 4H), 3.11 (d, J=4.2 Hz, 2H), 2.80 - 2.72 (m, 2H), 2.66 (q, J=7.4 Hz, 2H), 1 .62 (br. s., 2H), 1.42 (br. s., 2H), 1.26 - 1 .20 (m, 5H).

Example 47

7-hydroxy-3,3-dioxo-13,16-dioxa-3A ⁶ -thia-2,10-diazatricycloH 7.3.1.0 ⁴ , ⁹ 1tricosa-

1 (23), 4( xamide

a) 2-(2-bromoethoxy)ethanol

A solution of 2,2'-oxydiethanol (25 g, 236 mmol) in DCM (250 mL) was treated with triphenylphosphine (30.9 g, 1 18 mmol) and the solution was stirred at room temperature for 30 min. Carbon tetrabromide (39.1 g, 1 18 mmol) was added to the solution dropwise over 60 min. then mixture was stirred at 20 °C overnight. The mixture was evaporated and purified by chromatography (silica gel, 0.2-0.33% EtOAc in pet. ether) to afford the desired product (5.0 g; 12%) as a colorless oil. LCMS m/z 192.9 and 190.8 (M+Na) ⁺ , 170.9 and 168.8 (M+H) ⁺

b) 2-(2-(2-hvdroxyethoxy)ethyl)isoindoline-1 ,3-dione

A solution of 2-(2-bromoethoxy)ethanol (5 g, 29.6 mmol) in DMF (50 mL) was treated with potassium 1 ,3-dioxoisoindolin-2-ide (4.93 g, 26.6 mmol) an the reaction mixture was heated to 100 °C and stirred for 16 h. The mixture was evaporated to afford the desired product (9.0 g; 91 %) as a yellow semi-solid. LCMS m/z 235.9 (M+H) ⁺ .

c) 2-(2-(2-bromoethoxy)ethyl)isoindoline-1 ,3-dione

A solution of 2-(2-(2-hydroxyethoxy)ethyl)isoindoline-1 ,3-dione (9 g, 38.3 mmol) in DCM (100 mL) was treated with triphenylphosphine (14 g, 53.4 mmol) and the solution was stirred for 30 min at room temperature. Carbon tetrabromide (14 g, 42.2 mmol) was added portionwise to the solution over 2 h then the mixture was stirred at 25 °C for 16 h. The mixture was evaporated and purified by chromatography (silica gel, 0-50% EtOAc in pet.ether) to afford the desired product (5.0 g; 42%) as a colorless oil. LCMS m/z 321 .8 and 319.7 (M+Na) ⁺ .

d) 2-(3-nitrophenyl)ethanol

A solution of borane (3 g, 217 mmol) THF (80 mL) was treated with 2-(3-nitrophenyl)acetic acid (10 g, 55.2 mmol) and the mixture was stirred in sealed vessel at 60 °C for 6 hr. The mixture was cooled to room temperature then treated with 10% aq. NaOH (10 mL) and evaporated. The residue was washed with DCM (100 mL) and the solids purified by chromatography (silica gel, 0-40% EtOAc in pet.ether) to afford the desired product (5.0 g; 49%) as a colorless solid. LCMS m/z 130.1 (M-HN0 ₂ ) ⁺ .

e) 2-(2-(2-(3-nitrophenethoxy)ethoxy)ethyl)isoindoline-1 ,3-dione

A solution of 2-(3-nitrophenyl)ethanol (3.2 g, 19.14 mmol) in DMF (5 mL) was cooled in an ice-water bath then treated portionwise with sodium hydride (1 .531 g, 38.3 mmol). The solution was

stirred for 50 min. then treated portionwise with 2-(2-(2-bromoethoxy)ethyl)isoindoline-1 ,3- dione (5.71 g, 19.14 mmol) over 20 min. The mixture was stirred at room temperature overnight. The mixture was treated with water (50 mL) then extracted with EtOAc (3 x 50 mL) then the organic layers dried and evaporated and the residue purified by chromatography (silica gel, 0-5% MeOH in DCM) to afford the desired product (1 .2 g) as a colorless solid. LCMS m/z 406.9 (M+Na) ⁺ , 385.0 (M+H) ⁺ .

f) 2-(2-(2-(3-aminophenethoxy)ethoxy)ethyl)isoindoline-1 ,3-dione

A solution of 2-(2-(2-(3-nitrophenethoxy)ethoxy)ethyl)isoindoline-1 ,3-dione (1 .2 g, 3.12 mmol) in EtOAc (30 ml_) was hydrogenated over Pd/C (500 mg) at room temperature and atmospheric pressure overnight. The mixture was filtered and evaporated and the residue purified by chromatography (silica gel, 0-10% MeOH in DCM) to afford the desired product (1 .8 g; 58%) as a colorless solid. LCMS m/z 376.8 (M+Na) ⁺ , 354.9 (M+H) ⁺ .

g) 2-(2-(2-(3-aminophenethoxy)ethoxy)ethyl)isoindoline-1 ,3-dione

A solution of 2-(2-(2-(3-aminophenethoxy)ethoxy)ethyl)isoindoline-1 ,3-dione (800 mg, 2.257 mmol) in THF (20 ml_) was treated with N,N-dimethylpyridin-4-amine (138 mg, 1 .129 mmol) and 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 ^Lfonyl chloride (573 mg, 2.257 mmol) and the reaction mixture was stirred at 50 °C overnight. The mixture was evaporated and purified by chromatography (silica gel, 0-20% MeOH in DCM) to afford the desired product (300 mg; 19%) as a yellow solid. LCMS m/z 593.7 (M+Na) ⁺ , 571 .7 (M+H) ⁺ .

h) 5-(N-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)phenyl)s Lfamoyl)-4-fluoro-2- hydroxybenzamide

A solution 5-(N-(3-(2-(2-(2-(1 ,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)phenyl^Lfamoyl)- 4- fluoro-2-hydroxybenzamide (300 mg, 0.525 mmol) in ethanol (10 mL) was treated with hydrazine hydrate (28.9 mg, 0.577 mmol) and the reaction mixture was stirred at 60 °C for 24 h. The mixture was evaporated and purified by chromatography (silica gel, 0-10% MeOH in DCM) to afford the desired product (100 mg; 41 %) as a colorless solid. LCMS m/z 441 .8 (M+H) ⁺ . i) 7-hvdroxy-3,3-dioxo-13,16-dioxa-3A ⁶ -thia-2,10-diazatricvclo[17.3.1 .0 ⁴ , ⁹ ltricosa- 1 (23),4(9),5,7,19,21 -hexaene-6-carboxamide

A solution of 5-(N-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)phenyl)sμLfamoyl) -4-fluoro-2- hydroxybenzamide (100 mg, 0.227 mmol) in 1 -butanol (5 mL) was treated with DIEA (0.040 mL, 0.227 mmol) and the reaction mixture was stirred and heated at 140 °C under microwave irradiation for 1 h. The mixture was cooled and evaporated and the residue purifed by chromatography (silica gel, prep-TLC, 5% MeOH in DCM) then further purified by chromatography (C-18 silica, gradient elution 30-40% ACN in water (0.1 % formic acid)) to afford the desired product (10 mg; 10%) as a colorless solid. LCMS m/z 443.8 (M+Na) ⁺ , 421 .8 (M+H) ⁺ . Ή NMR (400 MHz, DMSO-d6) δ ppm 13.69 (s, 1 H), 9.93 (s, 1 H), 8.25 (m, 2H), 7.63 (s, 1 H), 7.09 (m, 2H), 6.99 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 7.2 Hz, 1 H), 6.17 (s, 1 H),

6.07 (s, 1 H), 3.61 (m, 2H), 3.56 - 3.43 (m, 6H), 3.26 (m, 2H), 2.74 (m, 2H). The following compounds were prepared generally according to the above procedures and are included in the compounds of the invention as Examples 48 to 61 .

8-chloro-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,23-

59 triazatetracyclo[17.6.1 .0 ⁴ , ⁹ .0 ²⁰ , ²⁴ ]hexacosa-1 (26),4,6,8,19,21 ,24- j heptaene-6-carboxamide

8-chloro-7-hydroxy-3,3-dioxo-13,21 -dioxa-3A ⁶ -thia-2,10,18-

60 triazatetracyclo[16.6.2.0 ⁴ , ⁹ .0 ²² , ²⁶ ]hexacosa-1 (24),4,6, 8,22,25- hexaene-6-carboxamide

8-chloro-7-hydroxy-3,3-dioxo-13-oxa-3A ⁶ -thia-2,10,19-

61 triazatetracyclo[17.5.2.0 ⁴ , ⁹ .0 ²² , ²⁶ ]hexacosa-1 (24) ,4,6,8,22,25- hexaene-6-carboxamide

The following compound is prepared generally according to the above procedures.

Example 63: 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 15μΙ_ 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 15μΙ_ 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 20μΙ_ of 0.1 % TFA and 6.25 μΜ C13-adenosine internal standard in water. 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 no compound (DMSO) assay controls and a four parameter curve fit is applied in Activity Base XE to determine the potency of the test compound. Example 64 - CapsuLe Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin οβρεμίβ with the ingredients in the proportions shown in Table 2, below.

Table 2

INGREDIENTS AMOUNTS

(18E)-7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10- 7 mg

diazatetracyclo[19.3.1 .1 ¹² , ¹⁶ .0 ⁴ , ⁹ ]hexacosa-

1 (25),4(9),5,7,12,14,16(26), 18,21 ,23-decaene-6- carboxamide (Compound of Example 1)

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg

Example 65 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1 .7% by weight of 7-hydroxy-3,3-dioxo-3A ⁶ -thia-2,10-diazatetracyclo[19.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]hexacosa- 1 (25),4(9),5,7,12,14,16(26),21 ,23-nonaene-6-carboxamide (Compound of Example 2) in 10% by volume propylene glycol in water.

Example 66 Tablet Composition

The sucrose, calcium εμίίβίβ dihydrate and a CD73 inhibitor as shown in Table 3 below, are mixed and granμLated in the proportions shown with a 10% gelatin solution. The wet granμLes are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.

Table 3

INGREDIENTS AMOUNTS

7-hydroxy-3,3-dioxo-18-oxa-3A ⁶ -thia-2,10- 12 mg

diazatetracyclo[18.3.1 .1 ¹² , ^l6 .0 ⁴ , ⁹ ]pentacosa- 1 (24),4(9),5,7,12,14,16(25),20,22-nonaene-6- carboxamide (Compound of Example 3)

calcium εμίίβίβ 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 to the above assay. The compounds of Examples 1 to 61 were found to be active CD73 inhibitors when tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited a plC50 value from 5.2 to 8.6 against CD73.

The compounds of Examples 1 , 6, 10, 14, 17, 23, 29, 37, 44, 46, 49, and 56, 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 19 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 5.7 against CD73.

The compound of Example 33 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 45 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 8.2 against CD73. The compound of Example 51 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 6.8 against CD73. The compound of Example 57 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 8.0 against CD73. The compound of Example 59 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 8.4 against CD73.

The compound of Example 61 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 7.9 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.