WO2012058325A1

WO2012058325A1 - Compounds and methods useful for treatment of diseases mediated by hif-1

Info

Publication number: WO2012058325A1
Application number: PCT/US2011/057910
Authority: WO
Inventors: Scott Peterson; Linda Pestano; Kerry Fowler; Cong Hung Vo
Original assignee: Oncothyreon Inc.
Priority date: 2010-10-29
Filing date: 2011-10-26
Publication date: 2012-05-03

Abstract

Provided herein are compounds that are useful in treatment of diseases mediated by HIF-1.

Description

COMPOUNDS AND METHODS USEFUL FOR TREATMENT OF DISEASES

MEDIATED BY HIF-1

CROSS REFERENCE

[001] This application claims the benefit of U.S. Provisional Application No. 61/408,172 filed October 29, 2010, and U.S. Provisional Application No. 61/410,718 filed November 5, 2010, which are incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

[002] There is an ongoing need for new chemotherapeutics that treat cancer.

SUMMARY OF THE INVENTION

[003] Hypoxia inducible factor- 1 (HIF-1) plays a central role in multiple genetic pathways. It induces expression of proteins controlling glucose metabolism, cell proliferation, and/or vascularization. HIF-1 controls the expression of target genes whose protein products play crucial roles in allowing the survival of cells under adverse environmental conditions and/or in response to radiation or chemotherapy. These include the gene encoding VEGF, which is required for tumor angiogenesis, insulin-like growth factor 2 (IGF2), which promotes tumor cell survival, and glucose transporters 1 and 3, and glycolytic enzymes such as aldolase A and C, hexokinase 1 and 3, lactate dehydrogenase A and PGK. Provided herein are compounds and methods treatment of diseases mediated by HIF-1. Further provided herein are compounds and methods for treatment of cancers.

[004] Provided herein, in some embodiments, are methods for treatment of a disease mediated by Hypoxia Induced Factor - 1 (HIF-1) in an individual in need thereof comprising

administration of formulation comprising a compound of Formula I to an individual in need thereof:

Formula I;

wherein:

A is an aryl or heteroaryl ring;

ft¹ and Pv² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C₃-Cio cycloalkyl), -(L)_m-(C₂-Cio heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

or R¹ and R² taken together with the nitrogen atom to which they are attached form a C₂- Cio heterocycloalkyl ring wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m, NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a;

or R² is attached to an adjacent carbon atom on ring A to form a saturated, partially

saturated or unsaturated 5-6 member ring that is fused to ring A, and wherein the 5-6 membered ring that is fused to ring A is optionally substituted with 1-3 substituents selected from R⁵;

R³ and R⁴ are each independently, at each occurrence, H, -Ci-C₆ alkyl, halo, or -OH; each R⁵ is independently, at each occurrence, halo, -CN, -N0₂, -(L)_m-OR⁶, -(L)_m-SR⁷, - (L)_m-S(=0)R⁷, -(L)_m-S(=0)₂R⁷, -(L)_m-NHS(=0)₂R⁷, -(L)_m-C(=0)R⁷, -(L)_m- OC(=0)R⁷, -(L)_m-C0₂R⁶, -(L)_m-OC0₂R⁶, -(L)_m-CH(R⁶)₂, -(L)_m-N(R⁶)₂, -(L)_m- C(=0)N(R⁶)₂, -(L)_m-OC(=0)N(R⁶)₂, -(L)_m-NHC(=0)NH(R⁶), -(L)_m-NHC(=0)R⁷, - (L)_m-NHC(=0)OR⁷, -(L)_m-C(OH)(R⁶)₂, -(L)_m-C(NH₂)(R⁶)₂, -d-Cealkyl, -d- Cefluoroalkyl or -Ci-Ceheteroalkyl;

each R⁶ is independently, at each occurrence, H, a Ci-Cealkyl, a Ci-Cefiuoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or

two R⁶ groups attached to the same N atom are taken together with the N atom to which they are attached to form a C₂-Cioheterocycloalkyl wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m,

NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a;

each R⁷ is independently, at each occurrence, a Ci-Cealkyl, a Ci-Cefiuoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

each R⁸ is independently, at each occurrence, H, Ci-C₆ alkyl, Ci-C₆ heteroalkyl or -

alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- dalkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(d-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(d-C₃alkyl)₂, -(L)_m-C(=0)N(d-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefiuoroalkyl, or -Ci-Ceheteroalkyl;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl;

L is independently, at each occurrence, a bivalent radical selected from -(C₁-C₃

alkylene)_m-, -(C3-C7 cycloalkylene), -(C1-C3 alkylene)_m-0-(Ci-C₃ alkylene)_m-, and - (C1-C3 alkylene)_m-NH-(Ci-C₃ alkylene)_m-;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof;

provided that the formulation comprising a compound of Formula I does not comprise S-2- amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-

478).

[005] In some embodiments of the methods, the compound of Formula I has the structure of Formula IA:

Formula IA [006] In some embodiments of the methods, the compound of Formula I or Formula IA is a compound having the structure of Formula II:

Formula II;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[007] In some embodiments of the methods, the compound of Formula II has the structure of

Formula III:

Formula III;

wherein:

R⁹ is CN, halo, -C1-C3 alkyl, -0-Ci-C₃alkyl, -0-Ci-C₃ fiuoroalkyl or -Ci-C₃ fiuoroalkyl; and

k is 1, 2 or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[008] In some embodiments of the methods, the compound of Formula III has the structure of Formula III A, Formula IIIB or Formula IIIC:

Formula IIIA Formula IIIB

Formula IIIC;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[009] In some embodiments of the methods, the compound of Formula I or Formula IA has the structure of Formula IV:

Formula IV;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[010] In some embodiments of the methods, n is 1.

[011] In some embodiments of the methods, R³ and R⁴ are each, independently at each occurrence, H, -C₁-C3 alkyl, or halo.

[012] In some embodiments of the methods, p is 0.

[013] In some embodiments of the methods, the compound of Formula I or Formula IA is lected from

[014] In some embodiments of the methods, the compound of Formula I is a metabolite, derivative or analog of S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N- oxide dihydro chloride (PX-478). In some of such embodiments, a metabolite of PX-478 is

Compound 1. In some of the above embodiments, a compound suitable for treatment of a disease mediated by HIF-1 is Compound 1 or any salt or solvate thereof.

[015] In some embodiments of the methods, the disease mediated by HIF-1 is cancer, myocardial ischemia, cerebral ischemia, liver ischemia, kidney ischemia, pulmonary

hypertension, congenital heart disease, or chronic obstructive pulmonary disease.

[016] Accordingly, further provided herein are methods for treatment of cancer in an individual in need thereof comprising administration of a formulation comprising a compound of Formula I to an individual in need thereof:

Formula I;

wherein:

A is an aryl or heteroaryl ring; ft¹ and Pv² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C3-Cio cycloalkyl), -(L)_m-(C₂-Cio heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

or Pv¹ and R² taken together with the nitrogen atom to which they are attached form a C₂- Cio heterocycloalkyl ring wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m, NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a;

R³ and R⁴ are each independently, at each occurrence, H, -Ci-C₆ alkyl, halo, or -OH; each R⁵ is independently, at each occurrence, halo, -CN, -NO₂, -(L)_m-OR⁶, -(L)_m-SR⁷, - (L)_m-S(=0)R⁷, -(L)_m-S(=0)₂R⁷, -(L)_m-NHS(=0)₂R⁷, -(L)_m-C(=0)R⁷, -(L)_m- OC(=0)R⁷, -(L)_m-C0₂R⁶, -(L)_m-OC0₂R⁶, -(L)_m-CH(R⁶)₂, -(L)_m-N(R⁶)₂, -(L)_m- C(=0)N(R⁶)₂, -(L)_m-OC(=0)N(R⁶)₂, -(L)_m-NHC(=0)NH(R⁶), -(L)_m-NHC(=0)R⁷, - (L)_m-NHC(=0)OR⁷, -(L)_m-C(OH)(R⁶)₂, -(L)_m-C(NH₂)(R⁶)₂, -d-dalkyl, -d- Cefluoroalkyl or -Ci-dheteroalkyl;

each R⁶ is independently, at each occurrence, H, a Ci-Cealkyl, a Ci-Cefluoroalkyl, a Ci- dhetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-dalkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or

each R⁷ is independently, at each occurrence, a Ci-Cealkyl, a Ci-Cefluoroalkyl, a Ci- dhetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-dalkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- C₃alkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- dalkyl),

-(L)_m-C(=0) -(Ci-C₃alkyl), -(L)_m-OC(=0) - (d-Csalkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(Ci-C₃alkyl)₂, -(L)_m-C(=0)N(C₁-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(C₁-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-Cealkyl, -Ci-C₆fluoroalkyl, or -Ci-dheteroalkyl;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl;

L is independently, at each occurrence, a bivalent radical selected from -(Ci-C₃

alkylene)_m-, -(C₃-C₇ cycloalkylene), -(Ci-C₃ alkylene)_m-0-(Ci-C₃ alkylene)_m-, and - (Ci-C₃ alkylene)_m-NH-(Ci-C₃ alkylene)_m-;

each m is independently, at each occurrence, 0, 1 or 2; n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof;

478).

[017] In some embodiments of the methods described above, the compound of Formula I has the structure of Formula I A:

Formula IA.

[018] In some embodiments of the methods, the compound of Formula I or Formula IA is a compound having the structure of Formula II:

Formula II;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof. [019] In some embodiments of the methods, the compound of Formula II has the structure of Formula III:

Formula III;

wherein:

R is CN, halo, -C₁-C3 alkyl, -0-Ci-C₃alkyl, -0-Ci-C₃ fiuoroalkyl or -Ci-C₃ fiuoroalkyl; and

k is 1, 2 or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[020] In some embodiments of the methods, the compound of Formula III has the structure of Formula III A, Formula IIIB or Formula IIIC:

Formula IIIA Formula IIIB

Formula IIIC;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[021] In some embodiments of the methods, the compound of Formula I or Formula IA has the structure of Formula IV:

Formula IV;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[022] In some embodiments of the methods, n is 1.

[023] In some embodiments of the methods, R³ and R⁴ are each, independently at each occurrence, H, -C₁-C3 alkyl, or halo.

[024] In some embodiments of the methods, p is 0.

[025] In some embodiments of the methods described above, the compound of Formula I or F rmula IA is selected from

[026] In some embodiments of the methods, the compound of Formula I suitable for treatment of cancer is a metabolite, analog or derivative of S-2-amino-3-[4'-N,N,-bis(2- chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478). In some of such embodiments, a metabolite of PX-478 is Compound 1. In some of the above embodiments, a compound suitable for treatment of cancer is Compound 1 or any salt or solvate thereof, or a bioisostere thereof.

[027] In some embodiments of the methods, the cancer is selected from prostate, breast, colon, renal, ovarian and pancreatic cancer. In some embodiments of the methods, the cancer is breast cancer. In some embodiments of the methods, the cancer is selected from a solid tumor, a hematological cancer (including lymphoma, leukemia, myeloma), a carcinoma (including adenocarcinoma), a sarcoma, melanoma and the like. In some embodiments of the methods, the cancer is selected from anaplastic thyroid tumor, sarcoma of the skin, melanoma, adenocystic tumor, hepatoid tumor, lung cancer, chondrosarcoma, pancreatic islet cell tumor, esophageal cancer, prostate cancer, ovarian cancer, oral cancer, head and neck cancer, colorectal carcinoma, glioblastoma, cervical carcinoma, uterine cancer, endometrial carcinoma, gastrointestinal stromal tumor, gastric carcinoma, breast carcinoma, renal cell carcinoma, leukemia, lymphoma and myeloma.

[028] In some embodiments of the methods, the cancer is selected from non-small cell lung cancer, squamous cell carcinoma of the head and neck, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, nodal marginal zone B cell lymphoma (NMZL), mantle cell lymphoma, diffuse large B cell lymphoma, primary CNS lymphoma, plasma cell neoplasms, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, T cell prolymphocytic leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma, follicular lymphoma, Burkitt's lymphoma, gastric lymphoma, cutaneous T Cell lymphoma, anaplastic large cell lymphoma, and MALT

lymphoma.

[029] In some embodiments of the methods, the cancer expresses Hypoxia inducible factor- 1 alpha (HIF- la). [030] In some embodiments of the methods, administration of a compound of Formula I or Formula IA radio sensitizes a tumor. In some embodiments of the methods, administration of a compound of Formula I enhances radiation therapy in an individual in need thereof.

[031] In some embodiments of any of the methods described above, any one of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula and Formula IV, is administered in combination with an additional anti-cancer agent (e.g., any anti-cancer described herein).

[032] In some embodiments of the methods, the compound of Formula I or Formula IA suitable for radiosensitization and/or enhancing radiation therapy is a metabolite, analog or derivative of S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478). In some of such embodiments, a metabolite of PX-478 is Compound 1. In some of the above embodiments, a compound suitable for radiosensitization of a tumor and/or enhancing radiation therapy is Compound 1 or any salt or solvate thereof.

In some embodiments of the methods, the compound of Formula I is selected from

[034] Also provided herein pharmaceutical compositions comprising a compound a compound of Formula I:

Formula I;

wherein:

A is an aryl or heteroaryl ring;

R¹ and R² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C₃-Cio cycloalkyl), -(L)_m-(C₂-Cio heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

each R⁶ is independently, at each occurrence, H, a Ci-Cealkyl, a Ci-Cefiuoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or two R⁶ groups attached to the same N atom are taken together with the N atom to which they are attached to form a C₂-Cioheterocycloalkyl wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m,

C(=0)-Ci-C6 alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- dalkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(d-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(d-C₃alkyl)₂, -(L)_m-C(=0)N(d-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefluoroalkyl, or -Ci-Ceheteroalkyl;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof; and

)harmaceutically acceptable carrier; provided that the composition comprising a compound of Formula I does not comprise S-2- amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX- 478).

[035] In some embodiments, the compositions comprise compounds of Formula I having the structure of Formula IA:

Formula IA.

[036] In another aspect, provided herein are methods for treatment of a disease mediated by Hypoxia Induced Factor - 1 (HIF-1) in an individual in need thereof comprising administration of a formulation comprising a compound of Formula V to an individual in need thereof:

Formula V;

wherein:

A is an aryl or heteroaryl ring;

ft¹ and Pv² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C₃-C₁₀ cycloalkyl), -(L)_m-(C₂-C₁₀ heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

saturated or unsaturated 5-6 member ring that is fused to ring A, and wherein the 5-6 membered ring that is fused to ring A is optionally substituted with 1-3 substituents selected from R⁵; R³ and R⁴ are each independently, at each occurrence, H, -Ci-C₆ alkyl, halo, or -OH; each R⁵ is independently, at each occurrence, halo, -CN, -NO₂, -(L)_m-OR⁶, -(L)_m-SR⁷, - (L)_m-S(=0)R⁷, -(L)_m-S(=0)₂R⁷, -(L)_m-NHS(=0)₂R⁷, -(L)_m-C(=0)R⁷, -(L)_m- OC(=0)R⁷, -(L)_m-C0₂R⁶, -(L)_m-OC0₂R⁶, -(L)_m-CH(R⁶)₂, -(L)_m-N(R⁶)₂, -(L)_m- C(=0)N(R⁶)₂, -(L)_m-OC(=0)N(R⁶)₂, -(L)_m-NHC(=0)NH(R⁶), -(L)_m-NHC(=0)R⁷, - (L)_m-NHC(=0)OR⁷, -(L)_m-C(OH)(R⁶)₂, -(L)_m-C(NH₂)(R⁶)₂, -d-dalkyl, -d- Cefluoroalkyl or -Ci-Ceheteroalkyl;

each R⁷ is independently, at each occurrence, a Ci-Cealkyl, a Ci-Cefluoroalkyl, a Ci- dhetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C3-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-dalkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

-(L)_m-C(=0) -(Ci-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(Ci-C₃alkyl), -(L)_m-OC0₂-(Ci-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(Ci-C₃alkyl)₂,

-(L)_m-OC(=0)N(d- C₃alkyl)₂,

-(L)_m-NHC(=0) ) -(d-dalkyl), -(L)_m- NHC(=0)0-(C₁-C₃alkyl), -(L)_m-C(OH)(C₁-C₃alkyl)₂, -(L)_m-C(NH₂)( Ci-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefluoroalkyl, or -Ci-Ceheteroalkyl;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere; each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

alkylene)_m-, -(C₃-C₇ cycloalkylene), -(Ci-C₃ alkylene)_m-0-(Ci-C₃ alkylene)_m-, and - (Ci-C₃ alkylene)_m-NH-(Ci-C₃ alkylene)_m-; each m is independently, at each occurrence, 0, 1 or 2; n is 1 , 2 or 3; and p is 0, 1 , 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[037] In some embodiments of the methods, the compound of Formula V is a compound having the structure of Formula VI:

Formula VI;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[038] In some embodiments of the methods, the compound of Formula V has the structure of Formula VII:

Formula VII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[039] In some embodiments of the methods, the compound of Fomula V has the structure of Formula VIII:

Formula VIII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[040] In some embodiments of the methods, the compound of Formula V has the structure of Formula IX:

Formula IX;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[041] In some embodiments of the methods described above, n is 1.

[042] In some embodiments of the methods described above, R³ and R⁴ are each,

independently at each occurrence, H, -C₁-C3 alkyl, or halo.

[043] In some embodiments of the methods described above, p is 0.

[044] In some embodiments of the methods described above, the compound of Formula V is selected from

[045] In some embodiments of the methods described above, the disease mediated by HIF-1 is cancer, myocardial ischemia, cerebral ischemia, liver ischemia, kidney ischemia, pulmonary hypertension, congenital heart disease, or chronic obstructive pulmonary disease.

[046] In a further aspect, provided herein is a method for treatment of cancer in an individual in need thereof comprising administration of a formulation comprising a compound of Formula V to an individual in need thereof:

Formula V;

wherein:

A is an aryl or heteroaryl ring;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

aceutically acceptable salt, N-oxide, solvate, or prodrug thereof. [047] In some embodiments of the methods described above, the compound of Formula V is a compound having the structure of Formula VI:

Formula VI;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[048] In some embodiments of the methods described above, the compound of Formula V has the structure of Formula VII:

Formula VII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[049] In some embodiments of the methods described above, the compound of Fomula V has the structure of Formula VIII:

Formula VIII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[050] In some embodiments of the methods described above, the compound of Formula V has the structure of Formula IX:

Formula IX;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[051] In some embodiments of the methods described above, n is 1. [052] In some embodiments of the methods described above, R³ and R⁴ are each, independently at each occurrence, H, -C1 -C3 alkyl, or halo.

[053] In some embodiments of the methods described above, p is 0.

[054] In some embodiments of the methods described above, the compound of Formula V is selected from

[055] In some embodiments of the methods, the cancer is selected from prostate, breast, colon, renal, ovarian and pancreatic cancer. In some embodiments of the methods, the cancer is breast cancer. In some embodiments of the methods described above, the cancer is selected from anaplastic thyroid tumor, sacrcoma of the skin, melanoma, adenocystic tumor, hepatoid tumor, lung cancer, chondrosarcoma, pancreatic islet cell tumor, esophageal cancer, prostate cancer, ovarian cancer, oral cancer, head and neck cancer, colorectal carcinoma, glioblastoma, cervical carcinoma, uterine cancer, endometrial carcinoma, gastrointestinal stromal tumor, gastric carcinoma, breast carcinoma, renal cell carcinoma, myeloma, leukemia, and lymphoma.

[056] In some embodiments of the methods described above, the cancer is selected from non- small cell lung cancer, squamous cell carcinoma of the head and neck, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, nodal marginal zone B cell lymphoma (NMZL), mantle cell lymphoma, diffuse large B cell lymphoma, primary CNS lymphoma, plasma cell neoplasms, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell pro lymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, T cell prolymphocyte leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma, follicular lymphoma, Burkitt's lymphoma, gastric lymphoma, cutaneous T Cell lymphoma, anaplastic large cell lymphoma, and MALT lymphoma. [057] In some embodiments of the methods described above, the cancer expresses Hypoxia inducible factor- 1 alpha (HIF-la).

[058] In some embodiments of the methods described above, adminstration of a compound of Formula V radiosensitizes a tumor in an indiviual in need thereof.

[059] In some embodiments of the methods described above, administration of a compound of Formula V enhances radiation therapy in an individual in need thereof.

[060] In some embodiments of any of the methods described above, any one of a compound of Formula V, Formula VI, Formula VII, Formula VIII, and Formula IX, is administered in combination with an additional anti-cancer agent (e.g., any anti-cancer described herein).

[061] Also provided herein is a pharmaceutical composition comprising a compound of Formula V:

Formula V;

wherein:

A is an aryl or heteroaryl ring;

R¹ and R² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C3-Cio cycloalkyl), -(L)_m-(C₂-Cio heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

R³ and R⁴ are each independently, at each occurrence, H, -Ci-C₆ alkyl, halo, or -OH; each R⁵ is independently, at each occurrence, halo, -CN, -NO₂, -(L)_m-OR⁶, -(L)_m-SR⁷, - (L)_m-S(=0)R⁷, -(L)_m-S(=0)₂R⁷, -(L)_m-NHS(=0)₂R⁷, -(L)_m-C(=0)R⁷, -(L)_m- OC(=0)R⁷, -(L)_m-C0₂R⁶, -(L)_m-OC0₂R⁶, -(L)_m-CH(R⁶)₂, -(L)_m-N(R⁶)₂, -(L)_m- C(=0)N(R⁶)₂, -(L)_m-OC(=0)N(R⁶)₂, -(L)_m-NHC(=0)NH(R⁶), -(L)_m-NHC(=0)R⁷, - (L)_m-NHC(=0)OR⁷, -(L)_m-C(OH)(R⁶)₂, -(L)_m-C(NH₂)(R⁶)₂, -Ci-C₆alkyl, -Ci- Cefluoroalkyl or -Ci-Ceheteroalkyl;

each R⁶ is independently, at each occurrence, H, a Ci-C₆alkyl, a Ci-Cefluoroalkyl, a Ci- Ceheteroalkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or

each R⁷ is independently, at each occurrence, a Ci-Cealkyl, a Ci-Cefluoroalkyl, a Ci- Cehetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- C₃alkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(C₁-C₃ alkyl), -(L)_m-S(=0)₂-(Ci- C₃alkyl), -(L)_m-NHS(=0)₂-(Ci-C₃alkyl), -(L)_m-C(=0) -(Ci-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(Ci-C₃alkyl), -(L)_m-OC0₂-(Ci-C₃alkyl), -(L)_m-CH(Ci- C₃alkyl)₂, -(L)_m-N(Ci-C₃alkyl)₂, -(L)_m-C(=0)N(Ci-C₃alkyl)₂, -(L)_m-OC(=0)N(Ci- C₃alkyl)₂, -(L)_m-NHC(=0)NH(Ci-C₃alkyl), -(L)_m-NHC(=0) ) -(Ci-C₃alkyl), -(L)_m- NHC(=0)0-(C₁-C₃alkyl), -(L)_m-C(OH)(C₁-C₃alkyl)₂, -(L)_m-C(NH₂)( Ci-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefluoroalkyl, or -Ci-Ceheteroalkyl;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof; and

a pharmaceutically acceptable carrier.

INCORPORATION BY REFERENCE

[062] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[063] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[064] Figure 1 shows effect of PX-478 (square) and 2-amino-3-(4-(2- chloroethylamino)phenyl)propanoic acid (Compound 1) (triangle) on MCF7 cell proliferation and MCF7 HIF-1 alpha levels.

DETAILED DESCRIPTION OF THE INVENTION

[065] The cellular response to oxygen is a central process in animal cells. The HIF (Hypoxia- Inducible Factor) and its regulator, the pVHL (Von Hippel-Lindau tumor suppressor protein) play a role in regulation of cellular response to oxygen. HIF1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. It induces expression of proteins controlling glucose metabolism, cell proliferation, and vascularization. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include Epo (Erythropoietin), LDHA (Lactate

Dehydrogenase- A), ET1 (Endothelin-1), transferrin, transferrin receptor, VEGF (Vascular Endothelial Growth Factor), Flkl, FLT1 (Fms-Related Tyrosine Kinase-1), PDGF-beta

(Platelet-Derived Growth Factor-beta), bFGF (basic Fibroblast Growth Factor), and others genes affecting glycolysis.

[066] HIF1 consists of a heterodimer of two basic helix- loop-helix PAS (Per-ARNT-Sim) proteins, HIF1 -alpha, and HIFl-beta. HIF1 -alpha accumulates under hypoxic conditions whereas HIFl-beta is constitutive ly expressed. HIF1 -alpha is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for solid tumor expansion including the angiogenic factor VEGF. HIFl-beta is the ARNT (Aryl hydrocarbon Receptor Nuclear Translocatorand plays a role in the xenobiotic response including the induction of metabolizing enzymes such as, e.g., the cytochrome P450 family of enzymes.

[067] Under normoxic conditions, HIF is targeted for destruction by an E3 ubiquitin ligase containing the pVHL. The ubiquitinylation of HIFl-alpha targets HIFl-alpha for degradation. Under hypoxic conditions the HIFl-alpha subunits are not recognized by pVHL, and they consequently accumulate and dimerize with HIFl-beta and translocate to the nucleus, where they activate transcription of target genes.

[068] HIF 1 -alpha-activated genes include VEGF, which promotes angiogenesis; GLUT1 (Glucose Transporter- 1), which activates glucose transport; LDHA (Lactate Dehydrogenase), which is involved in the glycolytic pathway; and Epo, which induces erythropoiesis. HIFl-alpha also activates transcription of NOS (Nitric Oxide Synthase), which promotes angiogenesis and vasodilation. ARNT2 and MOP3 (Member of Pas superfamily-3) are other proteins that have been shown to hetero dimerize with HIFl-alpha. HIFl-alpha can also be regulated by ERK2, which phosphorylate HIFl-alpha. HIFl-alpha also associates with the molecular chaperone HSP90 (Heat Shock Protein-90). Recently, a factor inhibiting HIFl-alpha activation, FIH

(Factor Inhibiting HIFl-alpha), has been described.

[069] Hypoxia also induces p53 protein accumulation. p53 directly interacts with HIFl-alpha and limits hypoxia- induced expression of HIFl-alpha by promoting ubiquitination and proteasomal degradation under hypoxic conditions. Hypoxia contributes to the pathophysiology of major categories of human disease, including myocardial, renal, hepatic and cerebral ischemia, cancer, pulmonary hypertension, congenital heart disease, chronic obstructive pulmonary diseases (COPD) and the like. Semenza G.L. et. al. Trends Mol Med 2001, 7:345-50. Accordingly, contemplated within the scope of diseases mediated by HIF-1 are cancers as described herein, ischemia (including myocardial, liver, renal or cerebral ischemia), pulmonary hypertension, congenital heart disease, and chronic obstructive pulmonary diseases (COPD). Compounds

[070] Accordingly provided herein are compounds that modulate the activity of HIF-1. In some embodiments, a modulator of HIF-1 described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) inhibits or reduces the activity of HIF-1 alpha. In some embodiments, a modulator of HIF-1 described herein (e.g., a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) inhibits or reduces the activity of HIF-1 beta. In some embodiments, a modulator of HIF-1 descrsibed herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) mediates the activity of HIF-1 under normoxia. In some embodiments, a modulator of HIF-1 described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) mediates the activity of HIF-1 under hypoxia.

[071] Further provided herein are compounds that are useful in the treatment of ischemia, including myocardial, renal, hepatic or cerebral ischemia in an individual in need thereof. In some other embodiments, provided herein are compounds that are useful in the treatment of pulmonary hypertension, congenital heart disease and/or chronic obstructive pulmonary disease in an individual in need thereof.

[072] Also provided herein are compounds that are useful in treatment of cancer. In some embodiments, the compounds described herein that are useful in treatment of cancer are alkylating agents. In some embodiments, the compounds provided herein that are useful in the treatment of cancer regulate the activity of cells, including cancer cells, under hypoxic conditions. In some embodiments, the compounds provided herein that are useful in the treatment of cancer regulate the activity of cells, including cancer cells, under normoxic conditions.

[073] In some of the embodiments described above, upon administration of compounds described herein to an individual in need thereof (e.g., an individual suffering from or suspected to be suffering from cancer), cellular protein levels of HSP-90 client proteins, cyclin Bl, mutant p53 and histone HI are not substantially affected by the administration the compounds. In some of the embodiments described above, upon administration of compounds described herein to an individual in need thereof (e.g., an individual suffering from or suspected to be suffering from cancer), cellular protein levels of HSP-90 client proteins, cyclin Bl, mutant p53 and histone HI are changed by the administration the compounds. In some of such embodiments, such changes are used as biomarkers to determine the therapeutic efficacy of the administered compounds.

[074] In some of the embodiments described above, a compound that is a modulator of HIF-1 alpha activity is a salt, analog, metabolite or derivative of S-2-amino-3-[4'-N,N,-bis(2- chloroethyl)amino]phenyl propionic acid N-oxide (PX-478). In some of the embodiments described above, a compound that is useful in the treatment of ischemia, or COPD, or pulmonary hypertension is a salt, analog, metabolite or derivative of S-2-amino-3-[4'-N,N,- bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478). Also included within the scope of embodiments presented above are any other pharmaceutically acceptable salts of S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N- oxide, or metabolite, analog or derivative thereof.

[075] In some of the embodiments described above, a compound that is useful in the treatment of cancer is a salt, analog, metabolite or derivative of S-2-amino-3-[4'-N,N,-bis(2- chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478).

[076] In any of the above embodiments, the analog or metabolite or derivative of S-2-amino-3-

[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478) is 2- amino-3-(4-(2-chloroethylamino)phenyl)propanoic acid or a salt thereof.

[077] Provided herein, in some embodiments, are compounds of Formula I:

Formula I;

wherein:

A is an aryl or heteroaryl ring;

ft¹ and Pv² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C₃-Cio cycloalkyl), -(L)_m-(C₂-Cio heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵; or R¹ and R² taken together with the nitrogen atom to which they are attached form a C₂- Cio heterocycloalkyl ring wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m, NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a;

each R⁷ is independently, at each occurrence, a Ci-Cealkyl, a Ci-Cefiuoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; each R is independently, at each occurrence, H, Ci-C₆ alkyl, Ci-C₆ heteroalkyl or -

alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- dalkyl), -(L)_m-S-(d-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(d-C₃alkyl), -(L)_m-OC(=0) - (d-C₃alkyl), -(L)_m-C0₂-(d-C₃alkyl), -(L)_m-OC0₂-(d-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(d-C₃alkyl)₂, -(L)_m-C(=0)N(d-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-Cealkyl, -Ci-dfiuoroalkyl, or -Ci-dheteroalkyl;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof;

provided that the compound of Formula I is not S-2-amino-3-[4'-N,N,-bis(2- chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478).

[078] In some embodiments, compounds of Formula I have the structure of Formula IA:

Formula IA.

[079] In some embodiments, a compound of Formula I or Formula IA is a compound having the structure of Formula II:

Formula II;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[080] In some embodiments, a compound of Formula II has the structure of Formula III:

Formula III;

wherein:

R⁹ is CN, halo, -C1 -C3 alkyl, -0-Ci-C₃alkyl, -0-Ci-C₃ fluoroalkyl or -Ci-C₃ fluoroalkyl; and

k is 1, 2 or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[081] In some embodiments, the compound of Formula III has the structure of Formula IIIA, Formula IIIB or Formula IIIC:

Formula IIIA Formula IIIB

Formula IIIC;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof. [082] In some embodiments, the compound of Fomula I or Formula IA has the structure of Formula IV:

Formula IV;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[083] In some embodiments, for any compound described above, n is 1. In some embodiments, for any compound described above, n is 2.

[084] In some embodiments, for any compound described above, R³ and R⁴ are each, independently at each occurrence, H, -C₁-C₃ alkyl, or halo. In some embodiments, for any compound described above, R³ and R⁴ are H.

[085] In some embodiments, for any compound described above, p is 0. In some embodiments, for any compound described above, p is 1. In some embodiments, for any compound described above, R⁵ is selected from -OH, CN, halo, -C₁-C₃ alkyl, -O-C₁-C₃ alkyl, and -O-C₁-C3 fluoroalkyl.

[086] In some embodiments, a compound of Formula I or Formula IA is selected from compounds in Table 1. In some embodiments, a compound of Formula I or Formula IA is a metabolite of compounds in Table 1.

Table 1

[087] Provided herein are compounds of Formula V

Formula V;

wherein:

A is an aryl or heteroaryl ring;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[088] In some embodiments, the compound of Formula V is a compound having the structure of Formula VI:

Formula VI;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[089] In some embodiments, the compound of Formula V has the structure of Formula VII:

Formula VII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[090] In some embodiments, the compound of Fomula V has the structure of Formula VIII:

Formula VIII; or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[091] In some embodiments, the com ound of Formula V has the structure of Formula IX:

Formula IX;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

[092] In some embodiments, for the compounds described above, n is 1. In some embodiments, for the compounds described above, R³ and R⁴ are each, independently at each occurrence, H, - C₁-C3 alkyl, or halo. In some embodiments, for the compounds described above, p is 0.

[093] In some embodiments, for the compounds described above, the compound of Formula V is selected from

[094] In some embodiments, any compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is a metabolite, derivative or analog of S-2-amino-3-[4'-N,N,- bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478). In some embodiments, a compound suitable for any of the methods described herein is a metabolite of PX-478 and has the following structure:

[095] In certain embodiments, compounds described herein have one or more chiral centers. As such, all stereoisomers are envisioned herein. In various embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieve in any suitable manner, including by way of non-limiting example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In some embodiments, mixtures of one or more isomer is utilized as the therapeutic compound described herein. In certain embodiments, compounds described herein contains one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and/or separation of a mixture of

enantiomers and/or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.

[096] In various embodiments, pharmaceutically acceptable salts described herein include, by way of non-limiting example, a nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-tolunenesulfonate, mesylate and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium- dependent or potassium), ammonium salts and the like.

[097] Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited t .o 2 Hr ,, 3x H_j, l l Ci, 13^ C, 14 C, 36 CI, 18_c 123_T 125_{T 1 3}-v _T l₅-v _T l₅ > 18^ 32_D 35 _c „ , ι ι ·. τ

t , 1, 1, , , O, O, O, P, S or the like. In some embodiments, isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies. In some embodiments, substitution with heavier isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In some embodiments, ubstitution with positron emitting isotopes, such as 1 1 C, 18 F, 15 O and 13 N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[098] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANIC CHEMISTRY 4^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^rd Ed., (Wiley 1999) (all of which are

incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. As a guide the following synthetic methods are utilized.

[099] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

Formation of Covalent Linkages by Reaction of an Electrophile with a Nucleophile

[0100] The compounds described herein are modified using various electrophiles and/or nucleophiles to form new functional groups or substituents. Table A entitled "Examples of Covalent Linkages and Precursors Thereof lists selected non-limiting examples of covalent linkages and precursor functional groups which yield the covalent linkages. Table A is used as guidance toward the variety of electrophiles and nucleophiles combinations available that provide covalent linakges. Precursor functional groups are shown as electrophilic groups and nucleophilic groups.

Table A: Examples of Covalent Linkages and Precursors Thereof

Sulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

[0101] In the reactions described, it is necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In some embodiments it is

contemplated that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0102] In some embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydro lytically removable. [0103] In some embodiments carboxylic acid and hydroxy reactive moieties are blocked with hydro lytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.

[0104] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

[0105] Typically blocking/protecting groups are selected from:

allyl Bn Cbz alloc M e

Et t-butyl TBDMS Teoc _Q

(CHaJsC-

Boc PMB trityl acetyl Fmoc

[0106] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and

Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Certain Terminology

[0107] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In this application, the use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0108] An "alkyl" refers to an aliphatic hydrocarbon. The alkyl may be saturated or unsaturated. The alkyl, whether saturated or unsaturated, is a branched alkyl or straight chain alkyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, and the like.

[0109] The term "alkylene" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In one aspect, an alkylene is a Ci-Cealkylene. In another aspect, an alkylene is a Ci- C₄alkylene. Typical alkylene groups include, but are not limited to, straight chain alkylenes, e.g., methylene, ethylene, propylene and butylene. Typical alkylene groups include branched chain alkylenes including, but not limited to, -CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH₂CH₂-, - CH₂CH(CH₃)-, -CH₂C(CH₃)₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, and the like.

[0001] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0110] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo or iodo. [0111] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.

[0112] The term "heteroalkyl" refers to optionally substituted alkyl, alkenyl and alkynyl radicals which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. NH or Nalkyl), sulfur, phosphorus, silicon, or combinations thereof. In some embodiments, one aspect, heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is oxygen. In some embodiments, heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is NH or Nalkyl. In some embodiments, in another aspect, a heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is O or S. Exemplary heteroalkyls include, but are not limited to, -(CH₂)_nO-CH₃, - (CH₂)_nOCH(CH₃)₂, -CH(CH₃)0-(CH₂)_n-CH₃, -C(CH₃)₂0-CH₃, -(CH₂)_nS-CH₃, - (CH₂)_nSCH(CH₃)₂, -CH(CH₃)S-(CH₂)_n-CH₃, -CH(CH₃)S0₂-(CH₂)_n-CH₃, -C(CH₃)₂S0₂-CH₃, - CH₂NH-(Ci-C₆alkyl), -C(CH₃)₂NH-(Ci-C₆alkyl), -CH(CH₃)NH-(Ci-C₆alkyl)₂, In certain embodiments, the heteroatom(s) is placed at any interior position of the heteroalkyl group.

Examples include, but are not limited to, -CH₂-0-CH₃, -CH₂-CH₂-0-CH₃, -CH₂-NH-CH₃, -CH₂- CH₂-NH-CH₃, -CH₂-N(CH₃)-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -0-CH₂-CH₂- N(CH₃)-CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂,-S(0)-CH₃, -CH₂-CH₂-S(0)₂-CH₃, -0-CH₂-CH₂- S(0)₂-CH₃,-CH=CH-0-CH₃, -Si(CH₃)₃, -CH₂-CH=N-OCH₃, and -CH=CH-N(CH₃)-CH₃. In some embodiments, up to two heteroatoms are consecutive, such as, by way of example, -CH₂- NH-OCH₃ and -CH₂-0-Si(CH₃)₃.

[0113] The term "optionally substituted" or "substituted" means that the referenced group may be unsubstituted, or may be substituted with one or more additional group(s) individually and independently selected from R^a as described herein. In some embodiments, an optional substituent is selected from oxo, halogen, -CN, -NH₂, -OH, -NH(CH₃), -N(CH₃)₂, alkyl

(including straight chain, branched and/or unsaturated alkyl), cycloalkyl, heterocycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, -S-alkyl,-S(=0)₂alkyl, -C(=0)NH(alkyl or phenyl), -C(=0)N(alkyl)₂, -OC(=0)N(alkyl)₂, -NHC(=0)NH(alkyl or phenyl), -NHC(=0)alkyl, -N(alkyl)C(=0)alkyl, -NHC(=0)0(alkyl), -C(OH)(alkyl)₂, and -C(NH₂)(alkyl)₂. In some embodiments, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, - CN, -NH₂, -OH, -NH(CH₃), -N(CH₃)₂, -CH₃, -CH₂CH₃, -CH(CH₃)₂, -CF₃, -CH₂CF₃, -OCH₃, - OCH₂CH₃, -OCH(CH₃)_2, -OCF₃, - OCH₂CF₃, -S(=0)₂-CH₃, -C(=0)NH₂, -C(=0)-NHCH₃, - NHC(=0)NHCH₃, -C(=0)CH₃, -C(=0)OH. In some embodiments, substituted groups are substituted with one, two or three of the preceding groups. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups.

[0114] As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings described herein include rings having five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl.

[0115] The terms "heteroaryl" or, alternatively, "hetero aromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N- containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. In certain embodiments, heteroaryl groups are monocyclic or polycyclic. Illustrative examples of heteroaryl groups include the followin moieties:

and the like.

[0116] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In various embodiments, cycloalkyls are saturated, or partially unsaturated. In some embodiments, cycloalkyls are fused with an aromatic ring. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

OO CO CO and the like. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicylclic cycloalkyls include, but are not limited to tetrahydronaphthyl, indanyl, tetrahydropentalene or the like. Polycyclic cycloalkyls include admantane, norbornane or the like. The term cycloalkyl includes "unsaturated nonaromatic carbocyclyl" or "nonaromatic unsaturated carbocyclyl" groups both of which refer to a nonaromatic carbocycle, as defined herein, that contains at least one carbon carbon double bond or one carbon carbon triple bond.

[0117] The term "heterocycloalkyl" refers to heteroalicyclic groups containing one to four ring heteroatoms each selected from O, S and N. In certain instances, each heterocycloalkyl group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. In some embodiments, heterocycloalkyls are fused with an aromatic ring. An example of a 3-membered heterocycloalkyl group is aziridine. Examples of 4-membered heterocycloalkyl groups include azetidine, a beta lactam and the like. Examples of 5-membered heterocycloalkyl groups include pyrrolidine, oxazolidine, thiazolidinedione and the like. Examples of 6-membered heterocycloalkyl groups include and are not limited to piperidine morpholine, piperazine and the like. Other examples of heterocycloalkyl groups are

and the like.

[0118] The terms "treat," "treated," or "treating" as used herein, in some embodiments, refers to therapeutic treatment. In other embodiments, the terms "treat," "treated," or "treating" as used herein refer to prophylactic and/or preventative measures. In some embodiments, "treating" slows down (lessen) an undesired physiological condition, disorder or disease (e.g., by delaying metastasis), to obtain beneficial or desired clinical results. In some embodiments, "treating" allows for beneficial or desired clinical results including, but not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In certain embodiments, treatment is prophylactic treatment that prevents a disease or condition.

Combination therapy

[0119] In some embodiments, any compound (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) and/or composition thereof described herein is administered to an individual in need thereof (e.g., an individual suffering from cancer) in combination with one or more therapeutic agents. In some embodiments, the one or more therapeutic agents is an anti-cancer agent, or a chemotherapeutic agent (e.g., an alkylating agent, an antimetabolite, a cytotoxic agent, an apoptotic agent, and the like). In some embodiments, the one or more therapeutic agents is an antibody. In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) is administered in combination with radiation therapy (e.g., involved-field radiation therapy, extended field radiation therapy, radiotherapy and the like). In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) is administered in combination with stem cell therapy. In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) is

administered in combination with an antisense therapeutic agent. In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) is administered in combination with radiation and a chemotherapeutic agent or a chemotherapy regimen described herein. [0120] In some embodiments, a compound described herein is administered in combination with a currently used chemotherapy regimen. Examples of currently used chemotherapy regimens include a CHOP regimen (cyclophosphamide (also called Cytoxan/Neosar), Doxorubicin (or Adriamycin), Vincristine (Oncovin) and Prednisolone), a R-CHOP regimen (Rituxan-CHOP), a ABVD regimen (Adriamycin (doxorubicin), Blenoxane (bleomycin), Velban (vinblastine), DTIC (dacarbazine)), a BEACOPP regimen (Cytoxan/Neosar (Cyclophosphamide),

Adriamycin/Rubex (Doxorubicin), VePesid (Etoposide), Matulane (Procarbazine), Prednisone, Blenoxane (Bleomycin), Oncovin (Vincristine)), a Stanford V regimen (Adriamycin/Rubex (Doxorubicin), Velban (Vinblastine), Mustargen (Mechloroethamine/ Nitrogen Mustard), VePesid (Etoposide), Blenoxane (Bleomycin), Oncovin (Vincristine), Prednisone, and radiation), and the like. By way of example, in some embodiments, a compound described herein is used in combination with any one of the aforementioned regimens for treatment of individuals suffering from hematological cancers (e.g., lymphoma, leukemia, myeloma and the like).

[0121] Examples of antibodies suitable for use in combination with a compound described herein include and are not limited to Rituxan, Zevalin (Ibritumomab Tiuxetan), Bexxar

(Tositumomab), Gemtuzumab (Mylotarg), alemtuzumab, trastuzumab, bortezomib (velcade), nimotuzumab, cetuximab, bevacizumab, and the like. In some embodiments, antibodies are specific to epitopes on cancer cells. In some embodiments, antibodies are tagged with radioactive isotopes and deliver radiation at the targeted site.

[0122] Examples of additional anti-cancer and/or chemotherapeutic agents suitable for use in combination with any compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) include and are not limited to methotrexate (RHEUMATREX®, Amethopterin) cyclophosphamide (CYTOXAN®), thalidomide (THALIDOMID®), acridine carboxamide, actimid®, actinomycin, 17-N- allylamino-17-demethoxygeldanamycin, aminopterin, amsacrine, anthracycline, antineoplastic, antineoplaston, 5-azacytidine, azathioprine, BL22, bendamustine, biricodar, bleomycin, bortezomib, bryostatin, busulfan, calyculin, camptothecin, capecitabine, carboplatin,

chlorambucil, cisplatin, cladribine, clofarabine, cytarabine, dacarbazine, dasatinib, daunorubicin, decitabine, dichloro acetic acid, discodermolide, docetaxel, doxorubicin, epirubicin, epothilone, eribulin, estramustine, etoposide, exatecan, exisulind, ferruginol, floxuridine, fludarabine, fluorouracil, fosfestrol, fotemustine, ganciclovir, gemcitabine, hydroxyurea, IT-101, idarubicin, ifosfamide, imiquimod, irinotecan, irofulven, ixabepilone, laniquidar, lapatinib, lenalidomide, lomustine, lurtotecan, mafosfamide, masoprocol, mechlorethamine, melphalan, mercaptopurine, mitomycin, mitotane, mitoxantrone, nelarabine, nilotinib, oblimersen, oxalip latin, PAC-1, paclitaxel, pemetrexed, pentostatin, pipobroman, pixantrone, plicamycin, procarbazine, proteasome inhibitors (e.g., bortezomib), raltitrexed, rebeccamycin, revlimid®, rubitecan, SN- 38, salinosporamide A, satraplatin, streptozotocin, swainsonine, tariquidar, taxane, tegafur- uracil, temozolomide, testolactone, thioTEPA, tioguanine, topotecan, trabectedin, tretinoin, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zosuquidar, or the like.

[0123] Examples of antisense therapeutic agents include and are not limited to OGX-427 (ISIS), ISIS-EIF4E_Rx, LY2181308 (Lilly), OGX-01 l/TV-1011 (ISIS), and the like.

Radiation therapy enhancement

[0124] The presence of oxygen during irradiation allows for generation of free oxygen radicals that cause DNA damage with subsequent tumor killing. Tumor hypoxia is often associated with tumor radio -resistance. HIF-1 is often upregulated in hypoxic conditions and/or in irradiated tumors. In some instances, such activation of HIF-1 promotes cell healing (e.g., healing of tumor cells) following radiation-induced damage. In such cases, inhibition or partial inhibition of HIF-1 (downregulation of HIF-1) reduces the ability of tumor cells to heal after a patient has been administered radiation therapy, thereby enhancing the patient's response to radiation therapy. Accordingly, in some embodiments, administration of a compound described herein (e.g., a compound of Formula I, Formula I A, Formula II, Formula III, Formula III A, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX), or a pharmaceutical composition thereof, to an individual in need thereof (e.g., an individual undergoing radiation therapy for treatment of cancer) reduces or prevents tumor growth or regrowth, and/or increases tumor cell killing. In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula

IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX), or a pharmaceutical composition thereof, is a radio-sensitizer. In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX), or a pharmaceutical composition thereof, is a radiation treatment enhancer. In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula

IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX), or a pharmaceutical composition thereof, in combination with a second therapeutic agent (e.g., a chemotherapeutic agent, or radiation therapy) improves therapeutic outcome for a patient compared to administration of either agent alone.

[0125] The amount of radiation used in radiation therapy is measured in gray (Gy), and varies depending on the type and stage of cancer being treated. For example, a typical dose for a solid tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy. Preventative and/or adjuvant doses are typically around 45 - 60 Gy in 1.8 - 2 Gy fractions. Many other factors are considered by radiation oncologists when selecting a dose, including whether the patient is receiving chemotherapy, patient comorbidities, whether radiation therapy is being administered before or after surgery, and the like. The total dose is fractionated (spread out over time). In North America, Australia, and Europe, a typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week.

[0126] Radiation therapy includes and is not limited to external beam radiotherapy,

brachytherapy, and systemic radioisotope therapy. Brachytherapy uses sealed radioactive sources placed precisely in the area under treatment. Systemic radioisotopes are given by infusion or oral ingestion. Examples of isotopes used for irradiation include and are not limited to lutetium-177, yttrium-90, strontium-89, samarium- 153 Sm, iodine-131, Cobalt-60, and the like. Radiation is optionally administered in conjunction with imaging techniques including and not limited to magnetic resonance imaging (MRI), or positron emission tomography (PET) allowing for intensity-modulated radiation therapy (IMRT) and/or image-guided radiation therapy (IGRT).

[0127] In some embodiments, provided herein is a method for enhancing radiation therapy in an individual in need thereof comprising administration of radiation therapy in combination with a compound described herein (e.g., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX), to the individual in need thereof. In some embodiments, a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, is administered to the individual in need thereof before radiation therapy (e.g., for two days before start of radiation therapy) and provides

radio sensitization of tumor cells, thereby providing enhanced tumor cell killing. In some embodiments, a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, is administered to the individual in need thereof after irradiation (e.g., as an adjuvant on days 1 and 2 after radiation therapy) and reduces or inhibits tumor cell healing or regrowth, thereby enhancing therapeutic effect of irradiation. In some embodiments, a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, is administered to the individual in need thereof concurrently with irradiation (e.g., day before radiation and then on next day just prior to onset of irradiation).

[0128] In some embodiments, provided herein is a method for inducing radiosensitization in an individual in need thereof (e.g., an individual not responding to radiation therapy) comprising administration of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, to the individual in need thereof. In some of such embodiments, administration of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, to individuals in need thereof allows for radiation treatment of individuals who have acquired tumor radio -resistance from prior radiation therapy.

[0129] In some of the above embodiments, a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, is administered in combination with radiation and a further chemotherapeutic agent or regimen as described above. Accordingly, by way of example only, a combination therapy regimen for an individual suffering from cancer comprises administration of Compound 1, 1 or 2 Gy via ⁶⁰Co unit (1.8 Gy/min) radiation, and gemcitabine.

[0130] In some of the above embodiments, administration of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, to an individual in need thereof (e.g., an individual undergoing radiation therapy) provides HIF- 1 inhibition and/or enhancement of the effects of radiation and/or interrupts downstream tumor stromal adaptation thereby providing enhanced therapeutic benefit to the individual when compared to therapeutic benefit in the absence of administration of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof. [0131] In some of such embodiments, administration of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or pharmaceutical composition thereof, in combination with radiation causes radiation enhancement in a ratio of at least about 1.1 to about 1.2 under conditions of normoxia and of at least about 1.1 to about 1.4 under conditions of hypoxia. In any of the embodiments mentioned above, a a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX in an inhibitor or partial inhibitor of HIF-1 alpha. In any of the embodiments mentioned above, a a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX in an inhibitor or partial inhibitor of HIF-1 alpha under hypoxic conditions. In any of the embodiments mentioned above, a a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX in an inhibitor or partial inhibitor of HIF-1 alpha under normoxic conditions.

Examples of Pharmaceutical Compositions and Methods of Administration

[0132] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound described herein (e.g., a compound of any one of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX).

[0133] Pharmaceutical compositions are formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Ea hston, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0134] Provided herein are pharmaceutical compositions that include one or more compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). As used herein, compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX refers to one or more compounds of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC, and Formula IV. In addition, a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is optionally administered as pharmaceutical compositions in which it is mixed with other active ingredients, as in

combination therapy. In some embodiments, the pharmaceutical compositions includes other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In addition, the pharmaceutical compositions also contain other therapeutically valuable substances.

[0135] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX are administered in a pharmaceutical composition to a mammal having a condition, disease, or disorder to be treated. Preferably, the mammal is a human. A therapeutically effective amount varies depending on the severity and stage of the condition, the age and relative health of an individual, the potency of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX used and other factors. The compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is optionally used singly or in combination with one or more therapeutic agents as components of mixtures.

[0136] The pharmaceutical formulations described herein are optionally administered to an individual by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. By way of example only, Example 17a is describes a parenteral formulation, Example 17f describes a rectal formulation. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0137] The pharmaceutical compositions will include at least one compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX having the same type of activity. In some situations, compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Additionally, the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX exists in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX presented herein are also considered to be disclosed herein.

[0138] "Carrier materials" include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. [0139] Moreover, the pharmaceutical compositions described herein, which include a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt

formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations. In some embodiments, a formulation comprising a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is a solid drug dispersion. A solid dispersion is a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (or fusion), solvent, or melting-solvent methods. (Chiou and Riegelman, Journal of Pharmaceutical Sciences, 60, 1281 (1971)). The dispersion of one or more active agents in a solid diluent is achieved without mechanical mixing. Solid dispersions are also called solid-state dispersions. In some embodiments, any compound described herein (e.g., a compound of any one of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) is formulated as a spray dried dispersion (SDD). An SDD is a single phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution prepared by dissolving the drug and a polymer in a solvent (e.g., acetone, methanol or the like) and spray drying the solultion. The solvent rapidly evaporates from droplets which rapidly solidifies the polymer and drug mixture trapping the drug in amorphous form as an amorphous molecular dispersion. In some embodiments, such amorphous dispersions are filled in capsules and/or constituted into oral powders for reconstitution. Solubility of an SDD comprising a drug is higher than the solubility of a crystalline form of a drug or a non-SDD amorphous form of a drug. In some embodiments of the methods described herein, compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX are administered as SDDs constituted into appropriate dosage forms described herein.

[0140] Pharmaceutical preparations for oral use are optionally obtained by mixing one or more solid excipient with a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, micro crystalline cellulose,

hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as:

polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0141] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions are generally used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments are optionally added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0142] In some embodiments, the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. By way of example, Example 17b describes a solid dosage formulation that is a capsule. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations of a compound of Formula I, Formula I A, Formula II, Formula III, Formula III A, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX are optionally administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.

[0143] In another aspect, dosage forms include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0144] Exemplary microencapsulation materials useful for delaying the release of the formulations including a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol®, carboxymethylcelluloses and salts of

carboxymethylcelluloses (CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D

Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[0145] The pharmaceutical solid oral dosage forms including formulations described herein, which include a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, are optionally further formulated to provide a controlled release of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX . Controlled release refers to the release of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to an individual over an extended period of time according to a predetermined profile. Such release rates provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

[0146] In other embodiments, the formulations described herein, which include a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. Pulsatile dosage forms including the formulations described herein, which include a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, are optionally administered using a variety of pulsatile formulations that include, but are not limited to, those described in U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329. Other pulsatile release dosage forms suitable for use with the present formulations include, but are not limited to, for example, U.S. Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284.

[0147] Liquid formulation dosage forms for oral administration are optionally aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al, Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to the compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, the liquid dosage forms optionally include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions further includes a crystal- forming inhibitor.

[0148] In some embodiments, the pharmaceutical formulations described herein are self- emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase is optionally added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS provides

improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms include, but are not limited to, for example, U.S. Pat. Nos.

5,858,401, 6,667,048, and 6,960,563.

[0149] Suitable intranasal formulations include those described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents are optionally present.

[0150] For administration by inhalation, the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is optionally in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX and a suitable powder base such as lactose or starch. By way of example, Example 17e describes an inhalation formulation.

[0151] Buccal formulations that include a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX include, but are not limited to, U.S. Pat. Nos.

4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein optionally further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, is provided essentially throughout. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. The bioerodible

(hydrolysable) polymeric carrier generally comprises hydrophilic (water-soluble and water- swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers" (Carbopol®, which may be obtained from B.F. Goodrich, is one such polymer). Other components also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions optionally take the form of tablets, lozenges, or gels formulated in a conventional manner. By way of example, Example 17c and Example 17d describe sublingual formulations.

[0152] Transdermal formulations of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX are administered for example by those described in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201, 211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144. By way of example, Example 17g describes a topical formulation.

[0153] The transdermal formulations described herein include at least three components: (1) a formulation of a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX ; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations include components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulation further includes a woven or non- woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In other embodiments, the transdermal

formulations described herein maintain a saturated or supersaturated state to promote diffusion into the skin.

[0154] In some embodiments, formulations suitable for transdermal administration of a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX employ transdermal delivery devices and transdermal delivery patches and are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches are optionally constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is optionally accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches provide controlled delivery of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX . The rate of absorption is optionally slowed by using rate-controlling membranes or by trapping the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX within a polymer matrix or gel. Conversely, absorption enhancers are used to increase absorption. An absorption enhancer or carrier includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX optionally with carriers, optionally a rate controlling barrier to deliver the compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0155] Formulations that include a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene- glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection also contain optional additives such as preserving, wetting, emulsifying, and dispensing agents.

[0156] For intravenous injections, a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.

[0157] Parenteral injections optionally involve bolus injection or continuous infusion.

Formulations for injection are optionally presented in unit dosage form, e.g., in ampoules or in multi dose containers, with an added preservative. In some embodiments, the pharmaceutical composition described herein are in a form suitable for parenteral injection as sterile

suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX in water soluble form. Additionally, suspensions of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX are optionally prepared as appropriate oily injection suspensions.

[0158] In some embodiments, the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is administered topically and formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0159] The compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is also optionally formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

Examples of Methods of Dosing and Treatment Regimens

[0160] A compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is optionally used in the preparation of medicaments for the prophylactic and/or therapeutic treatment of diseases mediated by HIF-1. In addition, a method for treating any of the diseases or conditions described herein in an individual in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.

[0161] In the case wherein the patient's condition does not improve, upon the doctor's discretion the administration of the a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula

VII, Formula VIII, or Formula IX is optionally administered chronically and/or at a higher dose, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the disease progression.

[0162] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula

VIII, or Formula IX is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0163] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of improvement in a patient, to a level at which the improved disease is retained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or condition.

[0164] In some embodiments, the pharmaceutical compositions described herein are in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX . In some embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or in multi dose containers, with an added preservative.

[0165] The daily dosages appropriate for the a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX are from about 0.01 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. Suitable unit dosage forms for oral administration include from about 1 to 500 mg active ingredient, from about 1 to 250 mg of active ingredient, or from about 1 to about 100 mg active ingredient. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages are optionally altered depending on a number of variables, not limited to the activity of the compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX used, the condition being treated, the mode of administration, the requirements of an individual, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0166] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. Compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is optionally used in formulating a range of dosage for use in human. The dosage of such a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

Screening assays

[0167] The compounds described herein (e.g., compounds of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX) are screened for activity using suitable cancer cell lines. Typically, the screening assays involve incubation of cells in the presence of test compounds in a suitable culture medium under normoxic (-21 % oxygen) or hypoxic (~ 1.5% oxygen) conditions. The anticancer activity of test compounds is determined by

(1) measuring cell viability in a MTT assay;

(2) measuring expression of HIF-Ι and HIF-2a by Western blotting and/or flow cytometry;

(3) measuring apoptosis by annexin V/PI staining followed by flow cytometry; or any combination thereof.

[0168] Suitable cancer cell lines include and are not limited to the NCI60 human tumor cell line panel (See, Nature Reviews Cancer 2006, 6, 813-823) that includes leukemia, non-small cell lung cancer, colon, CNS, Melanoma, ovarian, renal, prostate and breast cancer cell lines.

Examples of cell lines in the NCI60 human tumor cell line include and are not limited to A549, K-562, HT29, SF-268, M14, IGROV1, TK-10, PC-3, MCF7 and the like. EXAMPLES

Example 1 - Synthesis of 4-[(2'-chloroethyl)amino]-L-phenylalanine (6):

Scheme-1

(5) <«>

4-Nitro-N-boc-L-phenylalanine methyl ester (2):

[0169] Triethylamine (8 ml) was added to a suspension of 4-nitro-L-phenylalanine methyl ester hydrochloric acid salt (1) (7.0 g, 26.82 mmol) in dichloromethane (50 ml) followed by boc anhydride (6.2 g, 28.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml), and the organic layer was separated. The aqueous layer was extracted with dichloromethane (50 ml). The combined organic extract was washed with water (50 ml) and dried over MgS04. The extract was concentrated under reduced pressure and the residue was purified over a silica gel column chromatography eluting with 35% ethyl acetate/hexane to yield the desired product as a white solid, 7.8 g, 95%> yield.

4-Amino-N-boc-L-phenylalanine methyl ester acetic acid salt (3):

[0170] To a solution of 4-nitro-N-boc-L-phenylalanine methyl ester (2) (7.6 g, 23.4 mmol) in methanol/ethyl acetate (1 : 1, 40 ml) was added acetic acid (1.5 ml) followed by 10%> Pd/C (50%> weight, 0.9 g). This mixture was subjected to hydrogenation at 60 PSI for 4 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield the desired product as yellow syrup, 7.7 g. This product was used for the next reaction without further purification. 4-[(2'-Chloroethyl)amino]-N-boc-L-phenylalanine methyl ester (4):

[0171] A solution of sodium cyanoborohydride (2.86g, 45.4 mmol) in ethanol (15 ml) and acetic acid (1 ml) was added slowly to a solution of 4-amino-N-boc-L-phenylalanine methyl ester acetic acid salt (3) (7.7 g, 21.7 mmol) in dimethy formamide (15 ml). The resulting mixture was stirred at room temperature for 15 minutes. Then a solution of a-chloroacetaldehyde (45% in water, 4.2 ml, 23.8 mmol) was added drop wise. After 2 hr, solvents were removed under reduced pressure. The residue was diluted with water (50 ml) and extracted with

dichloromethane (2x40 ml). The combined extract was washed with water (50 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure. The residue was purified over a silica gel column eluting with 3%

methanol/dichloromethane to yield the desired product as a yellow syrup, 5.0 g, 65%> yield. 4-[(2'-Chloroethyl)amino]-N-boc-L-phenylalanine (5):

[0172] 4-[(2'-Chloroethyl)amino]-N-boc-L-phenylalanine methyl ester (4) (5.0 g, 14.7 mmol) was subjected to base hydrolysis with IN LiOH (1.5 eq) in 1 : 1 methanol/water (40 ml) at 0 °C overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 ml) and acidified to pH 4.0 with cold IN hydrochloric acid. This was extracted with 2% methanol in dichloromethane (2x40 ml). The combined extract was washed with water (50 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure to yield the free acid, 4.5 g. This was used for the next reaction without further purification.

4- [(2 '-Chloroethyl)amino] -L-phenylalanine (6) :

[0173] The concentrated hydrochloric acid (4.2 ml, 3 eq) was added to a solution of 4-[(2'- chloro ethyl) amino ]-N-boc-L-phenylalanine (5) (4.5 g, 13.8 mmol) in tetrahydrofuran (25 ml) stirred at room temperature overnight. THF was removed under reduced pressure and the residue was diluted with water (25 ml) and washed with ethyl acetate (25 ml). The aqueous layer was neutralized with 0.5 N sodium hydroxide to pH 7. This was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography eluting with 20-30%) methanol/dichloromethane. The desired product was isolated as off white solid, 2.3 g, 69% yield. Example 2 - Synthesis of 4-[(2'-chloroethyl)amino]-D-phenylalanine (9):

Scheme-2

(9)

4-[(2'-Chloroethyl)amino]-N-boc-D-phenylalanine (8):

[0174] A solution of sodium cyanoborohydride (315 mg, 5.0 mmol) in ethanol (1 ml) and acetic acid (0.15 ml) was added slowly to a solution of 4-amino-N-boc-D-phenylalanine (7) (0.7 g, 2.5 mmol) in dimethy formamide (2 ml). The resulting mixture was stirred at room temperature for 15 minutes. Then a solution of a-chloroacetaldehyde (45% in water, 0.47 ml, 2.7 mmol) was added drop wise. After 2 hr, solvents were removed under reduced pressure. The residue was diluted with water (20 ml) and extracted with dichloromethane (2x20 ml). The combined extract was washed with water (20 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure, and the residue was purified over a silica gel column eluting with 3% methanol/ dichloromethane to yield the desired product as a yellow syrup, 600 mg, 74% yield.

4- [(2 '-Chloroethyl)amino] -D-phenylalanine (9) :

[0175] The concentrated hydrochloric acid (0.6 ml, 3 eq) was added to a solution of 4-[(2'- chloroethyl)amino]-N-boc-D-phenylalanine (8) (0.6 g, 1.84 mmol) in tetrahydrofuran (2 ml) and stirred at room temperature overnight. THF was removed under reduced pressure and the residue was diluted with water (5 ml) and washed with ethyl acetate (5 ml). The aqueous layer was neutralized with 0.5 N sodium hydroxide to pH 7. This was concentrated udder reduced pressure and the residue was purified over a silica gel column chromatography eluting with 20- 30%) methanol/dichloromethane. The desired product was isolated as off white solid, 210 mg, 47% yield. Example 3 - Synthesis of 4-[(2'-chloroethyl)-N-methylamino]-L-phenylalanine (12):

Scheme-3

(4) (1 0)

4-[(2'-Chloroethyl)-N-methyl amino] -N-boc-L-phenylalanine methyl ester (10):

[0176] A solution of sodium cyanoborohydride (252 mg, 4.0 mmol) in ethanol (1 ml) and acetic acid (0.1 ml) was added slowly to a solution of 4-[(2'-chloroethyl)amino]-N-boc-L- phenylalanine methyl ester (4) (0.68 g, 2.0 mmol) in dimethy formamide (2 ml). The resulting mixture was stirred at room temperature for 15 minutes. Then a solution of formaldehyde (37%, 173 μΐ) was added drop wise. After 2 hr, solvents were removed under reduced pressure. The residue was diluted with water (5ml) and extracted with dichloromethane (2x20 ml). The combined extract was washed with water (30 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure, and the residue was purified over a silica gel column eluting with 30% ethyl acetate/hexane to yield the desired product as a yellow syrup, 590 mg, 83% yield.

4-[(2'-Chloroethyl)-N-methyl amino] -N-boc-L-phenylalanine (11):

[0177] 4-[(2'-Chloroethyl)-N-methylamino]-N-boc-L-phenylalanine methyl ester (10) (590 mg, 1.7 mmol) was subjected to base hydrolysis with IN LiOH (1.5 eq) in 1 : 1 methanol/water (5 ml) at 0 °C overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (20 ml) and acidified to pH 4.0 with cold IN hydrochloric acid. This was extracted with 2% methanol in dichloromethane (2x30 ml). The combined extract was washed with water (50 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure to yield the free acid, 0.5 g. This was used for the next reaction without further purification. 4-[(2'-Chloroethyl)-N-methylamino]-L-phenylalanine (12):

[0178] The concentrated hydrochloric acid (3 eq) was added to a solution of 4-[(2'-chloroethyl)- N-methylamino]-N-boc-L-phenylalanine (11) (0.5 g, 1.48 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature overnight. THF was removed under reduced pressure and the residue was diluted with water (5 ml) and washed with ethyl acetate (5 ml). The aqueous layer was neutralized with 0.5 N sodium hydroxide to pH 7. This was concentrated udder reduced pressure and the residue was purified over a silica gel column chromatography eluting with 20-30% methanol/ dichloromethane. The desired product was isolated as off white solid, 230 mg, 61% yield.

Example 4 -Synthesis of 4-[(2'-Chloroethyl)hydroxy]-L-phenylalanine (16):

Scheme-4

(15) (16)

4-[(2'-Chloroethyl)hydroxy]-N-boc-L-phenylalanine methyl ester (14):

[0179] Potassium carbonate (0.95 g, 7.0 mmol) and l-chloro-2-bromoethane (0.73 g, 5.1 mmol) were added to a solution of N-Boc-tyrosine methyl ester (13) (1.0 g, 3.4 mmol) in acetone (10 ml). The resulting mixture was refluxed under argon atmosphere for 3 days. The solid was filtered and the filtrate was concentrated under reduced pressure. The residue was purified over a silica gel column chromatography eluting with 35% ethyl acetate/hexane. The desired product was isolated as a white solid, 380 mg, 32%> yield.

4-[(2'-Chloroethyl)hydroxy]-N-boc-L-phenylalanine (15):

[0180] 4-[(2'-Chloroethyl) hydroxy]-N-boc-L-phenylalanine methyl ester (14) (380 mg, 1.06 mmol) was subjected to base hydrolysis with IN LiOH (1.5 eq) in 1 : 1 methanol/water (5 ml) at 0 C overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 ml) and acidified to pH 4.0 with cold IN hydrochloric acid. This was extracted with 2% methanol in dichloromethane (2x30 ml). The combined extract was washed with water (30 ml), and brine (30 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure to yield the free acid, 325 mg. This was used for the next reaction without further purification.

4-[(2'-Chloroethyl)-hydroxy]-L-phenylalanine (16):

[0181] The concentrated hydrochloric acid (3 eq) was added to a solution of 4-[(2'- chloroethyl)hydroxy]-N-boc-L-phenylalanine (14)(325 mg, 0.91 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature overnight. THF was removed under reduced pressure and the residue was diluted with water (5 ml) and washed with ethyl acetate (5 ml). The aqueous layer was neutralized with 0.5 N sodium hydroxide to pH 7. This was concentrated udder reduced pressure and the residue was purified over a silica gel column chromatography eluting with 20-30% methanol/dichloromethane. The desired product was isolated as off white solid, 150 mg, 68% yield.

Example 5 - Synthesis of 4-[(2'-Chloroethyl)amino]-phenethylamine (21):

Scheme-5

4-Nitro-N-boc-phenethylamine (18):

[0182] Following the procedure for the synthesis of compound (2), 4-nitro-phenethylamine hydrochloric acid salt (17)(2.0 g, 9.87 mmol ) was converted to 4-nitro-N-boc-phenethylamine (18), 2.4 g, 93% yield. 4-Amino-N-boc-phenethylamine acetic acid salt (19):

[0183] Following the procedure for the synthesis of compound (3), 4-nitro-N-boc- phenethylamine (18)(2.4 g, 9.0 mmol ) was converted to 4-amino-N-boc-phenethylamine acetic acid salt (19), 2.5 g. This product was used for the next reaction without further purification. 4-[(2'-Chloroethyl)amino]-N-boc-phenethylamine (20):

[0184] Following the procedure for the synthesis of compound (4), 4-amino-N-boc- phenethylamine acetic acid salt (19)(1.0 g, 3.3 mmol ) was converted to 4-[(2'- chloro ethyl) amino ]-N-boc-phenethylamine (20), 660 mg, 62% yield.

4-[(2'-Chloroethyl)amino]-phenethylamine (21):

[0185] Following the procedure for the synthesis of compound (6), 4-[(2'-chloroethyl)amino]- N-boc-phenethylamine (20) (0.6 g, 2.0 mmol ) was converted to 4-[(2'-chloroethyl)amino]- phenethylamine (21), light brown syrup, 155 mg, 40% yield.

Example 6 - Synthesis of 4-[(2'-Chloroethyl)amino]-phenylbutyric acid (23):

Scheme-6

(22) (23)

[0186] Following the procedure for the synthesis of compound (4), 4-amino-phenylbutyric acid (22)(0.5 g, 2.78 mmol ) was converted to 4-[(2'-chloroethyl)amino]-phenyl butyric acid(23), pale yellow solid, 492 mg, 72% yield.

Example 7 - Synthesis of 4-[(2'-Chloroethyl)amino]-phenylpropionic acid (25):

Scheme-7

(24) (25) [0187] Following the procedure for the synthesis of compound (4), 4-amino-phenylpropionic acid (24)(0.5 g, 3.0 mmol ) was converted to 4-[(2'-chloroethyl)amino]-phenyl propionic acid(25), white solid, 544 mg, 79% yield.

Example 8 - Synthesis of 3-[(2'-Chloroethyl)amino]-L-phenylalanine (31):

Scheme-8

3-Nitro-N-boc-L-phenylalanine methyl ester (27):

[0188] To a solution of 3-nitro-N-boc-L-phenylalanine (26) (1.0 g, 3.22 mmol) in acetone (25 ml) was added anhydrous K2C03 (0.67 g, 4.83 mmlo) and stirred for 15 minutes. To this mixture was added methyl iodide (0.59 g, 4.2 mmol), and refiuxed for 4 hr. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to yield the desired methyl ester, 1.0 g, 97% yield.

3-Amino-N-boc-L-phenylalanine methyl ester acetic acid salt (28):

[0189] Following the procedure for the synthesis of compound (3), 3-nitro-N-boc-L- phenylalanine methyl ester (27) (1.0 g, 4.46 mmol) was converted to 3-amino-N-boc-L- phenylalanine methyl ester acetic acid salt (28), 1.1 g. This product was used for the next reaction without further purification.

3-[(2'-Chloroethyl)amino]-N-boc-L-phenylalanine methyl ester (29):

[0190] Following the procedure for the synthesis of compound (4), 3-amino-N-boc-L- phenylalanine methyl ester acetic acid salt (28)(1.1 g, 3.3 mmol) was converted to 3-[(2'- chloro ethyl) amino ]-N-boc-L-phenylalanine methyl ester (29), 796 mg, 72% yield.

3-[(2'-Chloroethyl)amino]-N-boc-L-phenylalanine (30):

[0191] Following the procedure for the synthesis of compound (5), 3-[(2'-chloroethyl)amino]-

N-boc-L-phenylalanine methyl ester (29) (0.79 g, 2.33 mmol) was converted to 3-[(2'- chloro ethyl) amino ]-N-boc-L-phenylalanine (30), 0.74 g, 98% yield. Used for the next reaction without further purification.

3- [(2 '-Chloroethyl)amino] -L-phenylalanine (31):

[0192] Following the procedure for the synthesis of compound (6), 3-[(2'-chloroethyl)amino]- N-boc-L-phenylalanine (30)(0.74 g, 2.2 mmol ) was converted to 3-[(2'-chloroethyl)amino]-L- phenylalanine (31), 420 mg, 76% yield.

Example 9 - Synthesis of 4- [(2'-Chloroethyl)amino] -L-phenylalanine tetrazole (38):

Scheme-9

Trifluoroacetic anhydride

DMF Pyridine

(32)

(33)

4-Nitro-alfa-N-ethoxycarbamate-L-phenylalanine amide (33):

[0193] To a solution of 4-nitro-N-ethoxycarbamate-L-phenylalanine (32) (1.9 g, 6.7 mmol) in

DMF (10 ml) and pyridine (266 mg, 3.3 mmol) was added BOC-anhydride (1.9 g, 8.7 mmol) and stirred for 15 minutes. Then added ammonium bicarbonate (0.69 g, 8.7 mmol) and stirred overnight. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2x40 ml) and dried over MgS04. The extract was concentrated to yield the desired product, 1.7 g, 1.72 g, 92% yield.

4-Nitro-alfa-N-ethoxycarbamate-L-phenylacetonitrile (34) :

[0194] To a solution of 4-nitro-N-ethoxycarbamate-L-phenylalanine amide (33) (1.7 g, 6.0

mmol) in anhydrous 1,4-dioxane (25 ml) was added pyridine (0.95 g, 12.0 mmol). The reaction was cooled in ice bath and added drop wise trifluoro acetic ahdydride (1.38 g, 6.6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 4 hr. The reaction mixture was diluted with ice cold water (75 ml) and extracted with dichloromethane (2x50 ml). The combined extract was washed with water (70 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure. The residue was purified over a silica gel column eluting with 30% ethyl acetate/hexane to yield the desired product, 1.45 g, 91% yield.

4-Nitro - alfa-N-ethoxycarbamate-L-phenylalanine tetrazole (35):

[0195] To a solution of 4-nitro-alfa-N-ethoxycarbamate-L-phenylacetonitrile (34) (1.45 g, 5.5 mmol) in 2-propanol/water (1 :2, 45 ml were added sodium azide (715 mg, 11.0 mmol) and zinc bromide. The resulting mixture was refluxed for 16 hr. The reaction mixture was cooled and added 3N hydrochloric acid (20 ml) and ethyl acetate (50 ml). The organic layer was separated and aqueous later was re-extracted with ethyl acetate (50 ml). The combined extract was washed with water (70 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure. The residue was purified over a silica gel column eluting with 40%> ethyl acetate/hexane to yield the desired product, 1.24 g, 73%> yield.

4- Amino - alfa-N-ethoxycarbamate L-phenylalanine tetrazole acetic acid salt (36):

[0196] Following the procedure for the synthesis of compound (3), 4-nitro -L-phenylalanine tetrazole (35) (1.24 g, 4.06 mmol) was converted to 4-Amino -L-phenylalanine tetrazole acetic acid salt (36) 1.3 g. Used for the next reaction without further purification.

4-[(2'-Chloroethyl)amino]- alfa-N-ethoxycarbamate -L-phenylalanine tetrazole (37):

[0197] Following the procedure for the synthesis of compound (4), 4-Amino -L-phenylalanine tetrazole acetic acid salt (36) (1.3 g, 3.8 mmol) was converted to 4-[(2'-chloroethyl)amino]-L- phenylalanine tetrazole (37), 945 mg, 67%> yield.

4-[(2'-Chloroethyl)amino] -L-phenylalanine tetrazole (38):

[0198] 4-[(2'-Chloroethyl)amino]- alfa-N-ethoxycarbamate -L-phenylalanine tetrazole (37) (339 mg, 1.0 mmol) was dissolved and refluxed with 48%> aqueous HBr (2 ml) for 3 hr. The reaction mixture was cooled to room temperature and diluted with water (20 ml). Then mixture was basified with saturated sodium bicarbonate, and extracted with 2% methanol in dichloromethane (2x30 ml). The combined extract was washed with water (30 ml), and brine (30 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure. The residue was purified over a silica gel column chromatography eluting with 5-15%

methanol/dichloromethane. The desired product was isolated as off white solid, 150 mg, 56%> yield. HPLC showed purity around 70%. The following reaction was carried out to improve the purity.

4-[(2'-Chloroethyl)amino] -L-phenylalanine tetrazole (38):

[0199] 4-[(2'-Chloroethyl)amino]- alfa-N-ethoxycarbamate -L-phenylalanine tetrazole (37) (339 mg, 1.0 mmol) was dissolved in HBr in acetic acid (2 ml) and stirred at 45 0°C for 6 fir. The reaction was cooled to room temperature and diluted with water (20 ml). The mixture was basified with saturated sodium bicarbonate. This was extracted with 2% methanol in

dichloromethane (2x30 ml). The combined extract was washed with water (30 ml), and brine (30 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure. The residue was purified ove a silica gel column chromatography eluting with 5-15% methanol/dichloromethane. The desired product was isolated as off white solid, 175 mg, 66% yield. This sample was impure and HPLC showed purity around 75%.

[0200] The previous product was dissolved in ethyl acetate (5 ml). To this was added drop wise HC1 in ethyl acetate (1 ml) and stirred for 1 fir. The solid separated was filtered and washed with ethyl acetate (10 ml) and dried. The solid was suspended in 2% methanol/dichloromethane (10 ml) and basified with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was re-extracted with 2% methanol/dichloromethane (10 ml). The combined extract was passed through a short bed silica gel and eluted with 2% methanol/ dichloromethane. The desired product was isolated as off white solid, 100 mg.

Example 10 - Synthesis of 4- [(2'-Chloroethyl)hydroxy] -L-phenylalanine (42):

Scheme-10

4-[(2'-Chloroethyl)tert-butyldimethylsilyloxy]-N-boc-L-phenylalanine methyl ester (39):

[0201] Following the procedure for the synthesis of compound (4), 4-amino-N-boc- phenylalanine acetic acid salt (3)(1.50 g, 4.4 mmol ) was reacted with (tert- butyldimethy[silyloxy)acetaldehyde (0.77 g, 4.4 mmo!) to yield 4-[(2'-chloroethyl)tert- butyldimethylsilyloxy]-N-boc-L-phenylalanine methyl ester (39), 1.24 g, 62% yield.

4-[(2'-Chloroethyl)hydroxy]-N-boc-L-phenylalanine methyl ester (40):

[0202] To a THF (15 ml) solution of 4-[(2'-chloroethyl)tert-butyldimethylsilyloxy]-N-boc-L- phenylalanine methyl ester (39) (1.24 g, 2.74 mmol) was added 1M THF solution of tetrabutyl ammonium fluoride (0.788 g, 3.0 mmol) drop wise at 0°C. After 4 hr, the reaction mixture was diluted with water (25 ml) and THF was removed by concentrating at reduced pressure. This mixture was extracted with dichloro methane (2x50 ml). The combined extract was washed with water (50 ml), and brine (50 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure, and the residue was purified over a silica gel column with eluting with 50%> ethyl acetate/hexane. The desired product was isolated as colorless oil, 0.79 g, 86% yield.

4- [(2 '-Chloroethyl) hydroxy] -N-boc-L-phenylalanine (41): [0203] Following the procedure for the synthesis of compound (5), 4-[(2'-chloroethyl)hydroxy]- N-boc-L-phenylalanine methyl ester (40) (0.79 g, 2.33 mmol) was converted to 4-[(2'- chloroethyl)hydroxy]-N-boc-L-phenylalanine (41), 0.70 g, 96% yield. This product was used for the next reaction without further purification.

4- [(2 '-Chloroethyl) hydroxy] -L-phenylalanine (42) :

[0204] Following the procedure for the synthesis of compound (6), 4-[(2'-chloroethyl)hydroxy]- N-boc-L-phenylalanine (41) (0.70 g, 2.16 mmol ) was converted to 4-[(2'- chloroethyl)hydroxy]-L-phenylalanine (42), white solid, 360 mg, 76% yield.

Example 11 - Large scale Synthesis of 4-[(2'-Chloroethyl)amino]-L-phenylalanine (6):

Scheme-11

(5) (6)

4-Amino-N-boc-L-phenylalanine acetic acid salt (44):

[0205] To a solution of 4-nitro-N-boc-L-phenylalanine(43)(25.0 g, 80.5 mmol) in

methanol/ethyl acetate (1 : 1, 120 ml) was added acetic acid (15 ml) followed by 10%> Pd/C (50%> weight, 5.0 g). This mixture was subjected to hydrogenation at 60 PSI for 4 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield the desired product as yellow syrup, 26.0 g. This product was used for the next reaction without further purification.

4-[(2'-Chloroethyl)amino]-N-boc-L-phenylalanine (5):

[0206] A solution of sodium cyanoborohydride (9.63 g, 152.8 mmol) in ethanol (40ml) and acetic acid (4.0 ml) was add drop wise to a solution 4-amino-N-boc-L-phenylalanine acetic acid salt (44) (26.0 g, 76.4 mmol) in methanol (120 ml). The resulting mixture was stirred at room temperature for 15 minutes. Then added drop wise a-chloroacetaldehyde solution (45% in water, 13.7 ml, 78.0 mmol). After 2 hr, solvents were removed under reduced pressure. The residue was diluted with water (200 ml) and extracted with dichloromethane (2x150 ml). The combined extract was washed with water (150 ml), and brine (150 ml), and dried over anhydrous MgS04. The extract was concentrated under reduced pressure. The residue was purified over a silica gel column eluting with 3% methanol/ dichloromethane. The desired product was isolated as a yellow syrup, 20.4 g, 78% yield.

4- [(2 '-Chloroethyl)amino] -L-phenylalanine (6) :

[0207] A solution of hydrochloric acid in ethyl acetate (3 eq) was added to a solution of 4-[(2'- chloro ethyl) amino ]-N-boc-L-phenylalanine (5) (20.4 g, 59.5 mmol) in ethyl acetate (120 ) with vigorous stirring. After 3 hr, the solid separated was filtered and washed with ethyl acetate (2x50 ml). The solid was dried and dissolved in 2-propanol (75 ml) and cooled in ice bath. To this was added solid potassium carbonate (18.0 g, 130 mmol) and stirred for 3 hr. Then the mixture was filtered and washed with methanol (75 ml). The combined filtrate was concentrated under reduced pressure. The residue was purified over a silica gel column chromatography eluting with 20-30% methanol/dichloromethane. The desired product was isolated as off white solid, 10.28 g, 71% yield.

Example 12 - Synthesis of 4- [(2'-Bromoethyl)amino] -L-phenylalanine (45):

Scheme-12

(46)

4- [(2 '-bromoethyl)amino] -N-boc-phenylamine (45) : [0208] Following the procedure for the synthesis of compound (7), 4-amino-N-boc-L- phenethylamine acetic acid salt (44)(0.6 g, 2.0 mmol ) was reacted with alfa- bromoacetaldehyde (2.0 m mol) to yield 4-[(2'-bromoethyl)amino]-N-boc-phenylalanine (44), 538 mg, 68% yield. 4- [(2 '-bromoethyl)amino] -L-phenylamine (46) :

[0209] A solution of hydrochloric acid in ethyl acetate (3 eq) was added to a solution of 4-[(2'- bromoethyl)amino]-N-boc-phenylalanine (45) (0.53 g, 1.39 mmol) in ethyl acetate (15 ml) with vigorous stirring. After 3 hr the solid separated was filtered and washed with ethyl acetate (10 ml) to yield 4-[(2'-bromoethyl)amino]-L-phenylalanine hydrochloric acid salt (45) as light yellow solid, 105 mg, 40% yield.

Example 13 - Assays

[0210] HIFlalpha levels were measured by ELISA using whole cell extracts from MCF7 cells. Cell proliferation assays were performed by ATP quantification (CellTiter-Glo® Luminescent Cell Viability Assay, Promega) using MCF7 cells.

[0211] Table 2 below shows data for certain compounds described herein.

Table 2

Example 14 - Animal study - lung cancer

[0212] Cells from two human lung adenocarcinoma cell models (PC14-PE6 and NCI-H441) or two human small cell lung cancer (SCLC) models (NCI-H187 and NCI-N417) are injected into the left lungs of nude mice and are randomized 16 to 18 days after injection. Mice are subjected to daily oral treatment with Compound 1 or vehicle for 5 days.

[0213] The median primary lung tumor volume, mediastinal metastasis and prolonged survival in the Compound 1 - treated groups is compared versus the vehicle treatment group to determine therapeutic efficacy of Compound 1.

Example 15 - Animal study - lymphoma

[0214] This study is adapted from an animal model reported by Bittner, C. et al, Lab Invest 2000, 80: 1523-1531. A murine anaplastic lymphoid cell line TS1G6 (about 10⁴ cells) is injected into nude or immunocompetent C57B1/6 mice. Mice develop tumors within 4-8 weeks. Mice are subjected to daily oral treatment with Compound 1 or vehicle for 5 days.

[0215] Tumor weight, tumor size and the ratio of total tumor to total body weight is determined in the treatment group and control group to determine therapeutic efficacy of Compound 1. Example 16 - Animal study - radiation treatment

[0216] The protocol described in Schwartz et al, Mol. Cancer Ther., 2010, 9, 2057 is used with some modification. The effect of Compound 1 in combination with radiation or as a combination with radiation and gemcitabine is examined in this study.

[0217] About 10⁷ CF-PAC-1 pancreatic cancer cells are injected subcutaneously into the flanks of SCID mice. When tumors reach volumes between 150-400 mm³, Compound 1 is

administered the day before commencement of radiation and on the day of radiation. Radiation, or (gemcitabine and radiation) are then commenced. Control animals receive vehicle alone. Tumor volume and Logio cell kill is calculated as described in Schwartz et al, Mol. Cancer Ther., 2010, 9, 2057.

Example 17 - Pharmaceutical Compositions

Example 17a: Parenteral Composition

[0218] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for

administration by injection.

Example 17b: Oral Composition

[0219] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, e.g., a hard gelatin capsule, which is suitable for oral administration.

Example 17c: Sublingual (Hard Lozenge) Composition

[0220] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.

Example 17d: Fast-Disintegrating Sublingual Tablet

[0221] A fast-disintegrating sublingual tablet is prepared by mixing 48.5% by weigh of a compound of Formula I, Formula I A, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, 44.5%) by weight of micro crystalline cellulose (KG-802), 5%> by weight of low-substituted hydroxypropyl cellulose (50 μιη), and 2%> by weight of magnesium stearate. Tablets are prepared by direct compression (AAPS PharmSciTech. 2006;7(2):E41). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the amount of compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX with the total quantity of micro crystalline cellulose (MCC) and two-thirds of the quantity of low-substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer (lnversina ®, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing.

Example 17e: Inhalation Composition

[0222] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Example 17f: Rectal Gel Composition

[0223] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration.

Example 17g: Topical Gel Composition

[0224] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Example 17h: Ophthalmic Solution Composition

[0225] To prepare a pharmaceutical opthalmic solution composition, 100 mg of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is mixed with 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. Example 17i: Nasal spray solution

[0226] To prepare a pharmaceutical nasal spray solution, 10 g of a compound of Formula I, Formula IA, Formula II, Formula III, Formula IIIA, Formula IIIB, Formula IIIC Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 μΐ of spray for each application.

Example 18 - Clinical trial - breast cancer

[0227] The purpose of this research study is to determine if a HIF-1 alpha inhitor, Compound 1, is safe and effective in treating patients with breast cancer. Patients with histologically or cytologically confirmed breast cancer, or locally advanced recurrent breast cancer that is unresectable and for which standard curative or palliative measures do not exist or are no longer effective, will be enrolled in the study. Patients must have had at least 1 prior chemotherapy regimen, with no limit on total number of prior therapies.

[0228] Patients will be administered Compound 1 orally or intravenously. Primary outcome is to determine safety and tolerability of Compound 1 in patients with breast cancer. Progression free survival will be evaluated over 5 years.

[0229] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treatment of a disease mediated by Hypoxia Induced Factor - 1 (HIF-1) in an individual in need thereof comprising administration of a formulation comprising a compound of Formula I to an individual in need thereof:

Formula I;

wherein:

A is an aryl or heteroaryl ring;

R³ and R⁴ are each independently, at each occurrence, H, -Ci-C₆ alkyl, halo, or -OH; each R⁵ is independently, at each occurrence, halo, -CN, -N0₂, -(L)_m-OR⁶, -(L)_m-SR⁷, -

(L)_m-S(=0)R⁷, -(L)_m-S(=0)₂R⁷, -(L)_m-NHS(=0)₂R⁷, -(L)_m-C(=0)R⁷, -(L)_m- OC(=0)R⁷, -(L)_m-C0₂R⁶, -(L)_m-OC0₂R⁶, -(L)_m-CH(R⁶)₂, -(L)_m-N(R⁶)₂, -(L)_m- C(=0)N(R⁶)₂, -(L)_m-OC(=0)N(R⁶)₂, -(L)_m-NHC(=0)NH(R⁶), -(L)_m-NHC(=0)R⁷, - (L)_m-NHC(=0)OR⁷, -(L)_m-C(OH)(R⁶)₂, -(L)_m-C(NH₂)(R⁶)₂, -d-Cealkyl, -d-

Cefluoroalkyl or -Ci-Ceheteroalkyl; each R⁶ is independently, at each occurrence, H, a Ci-C₆alkyl, a Ci-Cefluoroalkyl, a Ci- dhetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-dalkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or

C(=0)-Ci-C₆ alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- C₃alkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(C₁-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(C₁-C₃alkyl)₂, -(L)_m-C(=0)N(C₁-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-dalkyl), -(L)_m- NHC(=0)0-(d-C3alkyl), -(L)_m-C(OH)(Ci-C₃alkyl)₂, -(L)_m-C(NH₂)( Ci-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefluoroalkyl, or -Ci-Ceheteroalkyl;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl; L is independently, at each occurrence, a bivalent radical selected from -(C₁-C₃ alkylene)_m-, -(C3-C7 cycloalkylene), -(C1-C3 alkylene)_m-0-(Ci-C3 alkylene)_m-, and - (C1-C3 alkylene)_m-NH-(Ci-C₃ alkylene)_m-;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof;

478).

2. The method of claim 1, wherein the compound of Formula I is a compound having the structure of Formula II:

Formula II;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

3. The method of claim 2, wherein the compound of Formula II has the structure of Formula III:

Formula III;

wherein:

Pv⁹ is CN, halo, -C₁-C₃ alkyl, -0-Ci-C₃alkyl, -O-C₁-C₃ fiuoroalkyl or -C₁-C₃ fiuoroalkyl; and

k is 1, 2 or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

4. The method of claim 3, wherein the compound of Formula III has the structure of Formula III A, Formula IIIB or Formula IIIC:

Formula IIIA Formula IIIB

Formula IIIC;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

5. The method of claim 1, wherein the compound of Fomula I has the structure of Formula

IV:

Formula IV;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

6. The method of any one of claims 1-5, wherein n is 1.

7. The method of any one of claims 1-5, wherein R³ and R⁴ are each, independently at each occurrence, H, -C₁-C3 alkyl, or halo.

8. The method of any one of claims 1-7, wherein p is 0.

9. The method of claim 1, wherein the compound of Formula I is selected from

10. The method of any one of claims 1-9, wherein the compound of Formula I is a metabolite, derivative or analog of S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478).

11. The method of any one of claims 1-10, wherein the disease mediated by HIF-1 is cancer, myocardial ischemia, cerebral ischemia, liver ischemia, kidney ischemia, pulmonary

12. A method for treatment of cancer in an individual in need thereof comprising

administration of a formulation comprising a compound of Formula I to an individual in need thereof:

Formula I;

wherein:

A is an aryl or heteroaryl ring; R¹ and R² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C₃-Cio cycloalkyl), -(L)_m-(C₂-Cio heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

each R⁷ is independently, at each occurrence, a Ci-Cealkyl, a Ci-Cefiuoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C3-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-dalkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- dalkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(d-C₃alkyl), -(L)_m-OC(=0) - (d-dalkyl), -(L)_m-C0₂-(d-C₃alkyl), -(L)_m-OC0₂-(d-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(d-C₃alkyl)₂, -(L)_m-C(=0)N(d-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefluoroalkyl, or -Ci-Ceheteroalkyl;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, bioisostere, or prodrug thereof;

provided that the formulation comprising a compound of Formula I does not comprise S-2- amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX- 478).

13. The method of claim 12, wherein the compound of Formula I is a compound having the structure of Formula II:

Formula II;

or pharmaceutically acceptable salt, N-oxide, solvate, bioisostere, or prodrug thereof.

14. The method of claim 13, wherein the compound of Formula II has the structure of Formula III:

Formula III;

wherein:

k is 1, 2 or 3;

15. The method of claim 14, wherein the compound of Formula III has the structure of Formula III A, Formula IIIB or Formula IIIC:

Formula IIIA Formula IIIB

Formula IIIC; or pharmaceutically acceptable salt, N-oxide, solvate, bioisostere, or prodrug thereof

16. The method of claim 12, wherein the compound of Fomula I has the structure of Formula

IV:

Formula IV;

17. The method of any one of claims 12-16, wherein n is 1.

18. The method of any one of claims 12-16, wherein R³ and R⁴ are each, independently at each occurrence, H, -C₁-C3 alkyl, or halo.

19. The method of any one of claims 12-18, wherein p is 0.

20. The method of claim 12, wherein the compound of Formula I is selected from

21. The method of any one of claims 12-20, wherein the compound of Formula I is a metabolite, analog or derivative of S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX-478).

22. The method of claim 12, wherein the cancer is selected from prostate, breast, colon, renal, ovarian and pancreatic cancer.

23. The method of claim 12, wherein the cancer is breast cancer.

24. The method of claim 12, wherein the cancer is selected from anaplastic thyroid tumor, sacrcoma of the skin, melanoma, adenocystic tumor, hepatoid tumor, lung cancer,

chondrosarcoma, pancreatic islet cell tumor, esophageal cancer, prostate cancer, ovarian cancer, oral cancer, head and neck cancer, colorectal carcinoma, glioblastoma, cervical carcinoma, uterine cancer, endometrial carcinoma, gastrointestinal stromal tumor, gastric carcinoma, breast carcinoma, renal cell carcinoma, myeloma, leukemia, and lymphoma.

25. The method of claim 12, wherein the cancer is selected from non- small cell lung cancer, squamous cell carcinoma of the head and neck, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, nodal marginal zone B cell lymphoma (NMZL), mantle cell lymphoma, diffuse large B cell lymphoma, primary CNS lymphoma, plasma cell neoplasms, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, T cell prolymphocytic leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma, follicular lymphoma, Burkitt's lymphoma, gastric lymphoma, cutaneous T Cell lymphoma, anaplastic large cell lymphoma, and MALT

lymphoma.

26. The method of claim 12, wherein the cancer expresses Hypoxia inducible factor-1 alpha (HIF-la).

27. The method of any one of claims 12-26, wherein adminstration of a compound of Formula I radio sensitizes a tumor in an indiviual in need thereof.

28. The method of any one of claims 12-26, wherein administration of a compound of Formula I enhances radiation therapy in an individual in need thereof.

29. The method of any one of claims 12-26, wherein the compound of Formula I is selected fr m

30. The method of any one of claims 12-26, further comprising administration of an additional anti-cancer agent.

31. A pharmaceutical composition comprising a compound of Formula I:

Formula I;

wherein:

A is an aryl or heteroaryl ring;

R^b is COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

R¹⁰ is H, or Ci-Cg alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof; and

a pharmaceutically acceptable carrier;

provided that the composition comprising a compound of Formula I does not comprise S-2- amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydro chloride (PX- 478).

32. A method for treatment of a disease mediated by Hypoxia Induced Factor - 1 (HIF-1) in an individual in need thereof comprising administration of a formulation comprising a compound of Formula V to an individual in need thereof:

Formula V;

wherein:

A is an aryl or heteroaryl ring;

each R⁶ is independently, at each occurrence, H, a Ci-Cealkyl, a Ci-Cefiuoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or two R⁶ groups attached to the same N atom are taken together with the N atom to which they are attached to form a C₂-Cioheterocycloalkyl wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m, NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a;

C(=0)-Ci-C6 alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- dalkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(d-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(d-C₃alkyl)₂, -(L)_m-C(=0)N(d-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-Cealkyl, -Ci-Cefluoroalkyl, or -Ci-Ceheteroalkyl;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

33. The method of claim 32, wherein the compound of Formula V is a compound having structure of Formula VI:

Formula VI;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

34. The method of claim 32, wherein the compound of Formula V has the structure of Formula VII:

Formula VII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

35. The method of claim 32, wherein the compound of Fomula V has the structure of Formula VIII:

Formula VIII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

36. The method of claim 32, wherein the compound of Formula V has the structure of Formula IX:

Formula IX;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

37. The method of any one of claims 32-36, wherein n is 1.

38. The method of any one of claims 32-37, wherein R³ and R⁴ are each, independently at each occurrence, H, -C₁-C3 alkyl, or halo.

39. The method of any one of claims 32-38, wherein p is 0.

40. The method of claim 32 wherein the compound of Formula V is selected from

41. The method of any one of claims 32-40, wherein the disease mediated by HIF-1 is cancer, myocardial ischemia, cerebral ischemia, liver ischemia, kidney ischemia, pulmonary hypertension, congenital heart disease, or chronic obstructive pulmonary disease.

42. A method for treatment of cancer in an individual in need thereof comprising

administration of a formulation comprising a compound of Formula V to an individual in need thereof:

Formula V;

wherein:

A is an aryl or heteroaryl ring;

R¹ and R² are each, independently H, -Ci-C₆ alkyl, -Ci-C₆ heteroalkyl, -(L)_m-(C₃-C₁₀ cycloalkyl), -(L)_m-(C₂-C₁₀ heterocycloalkyl); and wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R⁵;

or R¹ and R² taken together with the nitrogen atom to which they are attached form a C₂- C₁₀ heterocycloalkyl ring wherein the ring optionally comprises one or more moieties selected from O, C=0, S(0)_m, NR⁸S(0)_m, NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a; or R² is attached to an adjacent carbon atom on ring A to form a saturated, partially saturated or unsaturated 5-6 member ring that is fused to ring A, and wherein the 5-6 membered ring that is fused to ring A is optionally substituted with 1-3 substituents selected from R⁵;

each R⁶ is independently, at each occurrence, H, a Ci-Cealkyl, a Ci-Cefluoroalkyl, a Ci- C₆hetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-C₄alkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; or

- I l l - each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- dalkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(Ci-C₃alkyl), -(L)_m-S(=0)₂-(d- dalkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(d-C₃alkyl), -(L)_m-OC(=0) - (d-C₃alkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(d-C₃alkyl)₂, -(L)_m-C(=0)N(d-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-C₃alkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(d-C₃alkyl)₂, -(L)_m-C(NH₂)( d-C₃alkyl)₂, - Ci-dalkyl, -Ci-C₆fluoroalkyl, or -Ci-dheteroalkyl;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

each m is independently, at each occurrence, 0, 1 or 2;

n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

43. The method of claim 42, wherein the compound of Formula V is a compound having the structure of Formula VI:

Formula VI;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

44. The method of claim 42, wherein the compound of Formula V has the structure of

Formula VII:

Formula VII; or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

45. The method of claim 42, wherein the compound of Fomula V has the structure of Formula VIII:

Formula VIII;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

46. The method of claim 42, wherein the compound of Formula V has the structure of Formula IX:

Formula IX;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof.

47. The method of any one of claims 42-46, wherein n is 1.

48. The method of any one of claims 42-47, wherein R³ and R⁴ are each, independently at each occurrence, H, -C1 -C3 alkyl, or halo.

49. The method of any one of claims 42-48, wherein p is 0.

50. The method of claim 49 wherein the compound of Formula V is selected from

51. The method of claim 42, wherein the cancer is selected from prostate, breast, colon, renal, ovarian and pancreatic cancer.

52. The method of claim 42, wherein the cancer is breast cancer.

53. The method of claim 42, wherein the cancer is selected from anaplastic thyroid tumor, sacrcoma of the skin, melanoma, adenocystic tumor, hepatoid tumor, lung cancer, chondrosarcoma, pancreatic islet cell tumor, esophageal cancer, prostate cancer, ovarian cancer, oral cancer, head and neck cancer, colorectal carcinoma, glioblastoma, cervical carcinoma, uterine cancer, endometrial carcinoma, gastrointestinal stromal tumor, gastric carcinoma, breast carcinoma, renal cell carcinoma, myeloma, leukemia, and lymphoma.

54. The method of claim 42, wherein the cancer is selected from non-small cell lung cancer, squamous cell carcinoma of the head and neck, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, nodal marginal zone B cell lymphoma (NMZL), mantle cell lymphoma, diffuse large B cell lymphoma, primary CNS lymphoma, plasma cell neoplasms, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, T cell prolymphocytic leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma, follicular lymphoma, Burkitt's lymphoma, gastric lymphoma, cutaneous T Cell lymphoma, anaplastic large cell lymphoma, and MALT

lymphoma.

55. The method of claim 42, wherein the cancer expresses Hypoxia inducible factor- 1 alpha (HIF-la).

56. The method of any one of claims 42-55, wherein adminstration of a compound of Formula I radio sensitizes a tumor in an indiviual in need thereof.

57. The method of any one of claims 42-55, wherein administration of a compound of Formula I enhances radiation therapy in an individual in need thereof.

58. The method of any one of claims 42-55, further comprising administration of an additional anti-cancer agent.

59. A pharmaceutical composition comprising a compound of Formula V:

wherein: A is an aryl or heteroaryl ring;

NR⁸(C=0) and N-R⁸, and wherein the ring is optionally substituted with 1-3 substituents selected from R^a; each R⁷ is independently, at each occurrence, a Ci-C₆alkyl, a Ci-Cefluoroalkyl, a Ci- dhetero alkyl, a C₃-Ciocycloalkyl, a C₂-Cioheterocycloalkyl, an aryl, a heteroaryl, - Ci-C₄alkyl-(C₃-Ciocycloalkyl), -Ci-C₄alkyl-(C₂-Cioheterocycloalkyl), -Ci-dalkyl- (aryl), or -Ci-C₄alkyl-(heteroaryl), and wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a;

alkyl, and wherein each alkyl, and heteroalkyl is independently, at each occurrence, optionally substituted with 1-3 substituents selected from R^a; each R^a is independently, at each occurrence, oxo, halo, -CN, -N0₂, -(L)_m-0-(Ci- C₃alkyl), -(L)_m-S-(Ci-C₃alkyl), -(L)_m-S(=0) -(d-C₃ alkyl), -(L)_m-S(=0)₂-(d- C₃alkyl), -(L)_m-NHS(=0)₂-(C₁-C₃alkyl), -(L)_m-C(=0) -(C₁-C₃alkyl), -(L)_m-OC(=0) - (Ci-C₃alkyl), -(L)_m-C0₂-(C₁-C₃alkyl), -(L)_m-OC0₂-(C₁-C₃alkyl), -(L)_m-CH(d- C₃alkyl)₂, -(L)_m-N(C₁-C₃alkyl)₂, -(L)_m-C(=0)N(C₁-C₃alkyl)₂, -(L)_m-OC(=0)N(d- C₃alkyl)₂, -(L)_m-NHC(=0)NH(d-C₃alkyl), -(L)_m-NHC(=0) ) -(d-dalkyl), -(L)_m- NHC(=0)0-(d-C₃alkyl), -(L)_m-C(OH)(Ci-C₃alkyl)₂, -(L)_m-C(NH₂)( Ci-C₃alkyl)₂, - Ci-Cealkyl, -Ci-dfiuoroalkyl, or -Ci-dheteroalkyl;

R⁹ is N(R¹⁰)₂, or COOR¹⁰, tetrazolyl, or carboxylic acid bioisostere;

each R¹⁰ is independently, at each occurrence, H, or Ci-C₆ alkyl;

alkylene)_m-, -(C3-C7 cycloalkylene), -(C1-C3 alkylene)_m-0-(Ci-C3 alkylene)_m-, and - (C1-C3 alkylene)_m-NH-(Ci-C₃ alkylene)_m-;

each m is independently, at each occurrence, 0, 1 or 2; n is 1, 2 or 3; and

p is 0, 1, 2, or 3;

or pharmaceutically acceptable salt, N-oxide, solvate, or prodrug thereof; and

a pharmaceutically acceptable carrier.