Inhaled hypoxia and small molecule forms of hypoxia as novel anticancer agents

Abstract

Provided herein are compositions and method to treat cancer comprising administering to subject in need thereof an agent, such as a small molecule to induce systemic hypoxia, having the subject breathe hypoxic air or a combination thereof.

Description

INHALED HYPOXIA AND SMALL MOLECULE FORMS OF HYPOXIA AS NOVEL ANTICANCER AGENTS PRIORITY This application claims the benefit of the filing date of U.S. provisional application No. 63 / 599,768, filed on November 16, 2023, the disclosures of which is incorporated by reference herein in its entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING A Sequence Listing is provided herewith as an xml file, “3730227WO1.xml” created on November 7, 2024, and having a size of 2,894 bytes. The content of the xml file is incorporated by reference herein in its entirety. BACKGROUND Otto Warburg first proposed the idea of “starving the tumor” of nutrients to treat cancer. This led to decades of work attempting to limit nutrients through interventions like calorie restriction, intermittent fasting and cold exposure. While these approaches have shown preclinical efficacy, they are completely impractical for patient compliance. SUMMARY Provided herein are methods in which inhaled hypoxia and small molecule forms of hypoxia (e.g., compounds that increase oxygen hemoglobin binding affinity) reduce tumor growth, including tumors of pancreatic cancer, breast cancer, and other types of cancers. Provide herein are methods to treat cancer comprising administering to subject in need thereof a small molecule to induce systemic hypoxia, hypoxic air / exposure to a hypoxic environment, gene therapy to promote expression of fetal hemoglobin (HbF) or a combination thereof. In some embodiments, the small molecule increases the binding affinity of hemoglobin (Hb) for oxygen. In some embodiments, the small molecule induces anemia. In some embodiments, the small molecule comprises an allosteric effector of Hb (AEH) that left shifts Hb. In some embodiments, the AEH is selected from the group consisting of hydroxyurea, GBT440, HypoxyPill, substituted benzaldehydes, Tucaresol, aliphatic isothiocyanates, aromatic aldehydes or combination thereof. In some embodiments, the small molecule is a molecule of Formula I, Ia-Ic, II, IIa-IIC, II’, III, IIIa-IIIb, IV, V, Va, VI, VIa-VIb, VII, VIIa- VIIc or a combination thereof. In some embodiments, the gene therapy comprises administration of autologous hematopoietic stem cells treated ex vivo to reduce expression of BCL11A. In some embodiments, the autologous hematopoietic stem cells are treated ex vivo    using a CRISPR RNA-guided nuclease or base editor or with an inhibitory nucleic acid that targets and reduces expression of BCL11A. In some embodiments, anemia inducement comprises bloodletting or administration of an inhibitor of hypoxia inducible factor (HIF), HIF- 2a and / or HIF-1a. In some embodiments, the small molecule is an inhibitor of hypoxia inducible factor (HIF), HIF1, HIF2, HIF-2a and / or HIF-1a. In some embodiments, the inhibitor of HIF-2a is one or more of PT2399, PT2977, PT2385, PT2567, 163, 226, or 231. In some embodiments, the small molecule is an inhibitor is a molecule of Formula VIII, VIII-A-VIII- K, IX or a combination thereof. In some embodiments, the inhibitor of HIF comprises one or more of adaptauin, TAT-cyclo-CLLFVY (SEQ ID NO: 1), Dimethyloxallyl Glycine (DMOG), Echniomycin, FM19G11, GN 44028, KC7F2, LW 6, PX12, TC-S 7009, VH 032 or VH 298. In some embodiments, the hypoxic environment comprises about 5% O2 to about 21% O2, about 10% O2 to about 15% O2, about 10% O2 to about 12% O2, including about 8% O2, about 11% O2or about 15% O2. In some embodiments, the inhaled oxygen tension is at least about 5%. In some embodiments, the inhaled oxygen tension is about 5 to about 21%. In some embodiments, the hypoxic air comprises carbon monoxide (CO). In some embodiments, the small molecule comprises a carbon monoxide-releasing molecule (CORM). In some embodiments,the small molecule is or a combination thereof. In some embodiments, the methods further comprise an additional anti-cancer treatment, such as chemotherapy, radiology or immunotherapy. In some embodiments, the cancer comprises lung cancer, adenocarcinoma, adenocarcinoma of the lung, squamous carcinoma, squamous carcinoma of the lung, malignant mixed mullerian tumor, bladder cancer, head and / or neck cancer, breast cancer, esophageal cancer, mouth cancer, tongue cancer, gum cancer, skin cancer (e.g., melanoma, basal cell carcinoma, Kaposi's sarcoma, etc.), muscle cancer, heart cancer, liver cancer, bronchial cancer, cartilage cancer, bone cancer, stomach cancer, prostate cancer, testicular cancer, ovarian cancer; cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, colon cancer, colorectal, gastric cancer, kidney cancer, bladder cancer, lymphoma cancer, spleen cancer, thymus cancer, thyroid cancer, brain cancer, neuronal cancer, mesothelioma, gall bladder cancer, ocular cancer (e.g., cancer of the cornea,    cancer of uvea, cancer of the choroids, cancer of the macula, vitreous humor cancer, etc.), joint cancer (such as synovium cancer), glioblastoma, neuroblastoma, white blood cell cancer (e.g., lymphoma, leukemia, etc.), hereditary non-polyposis cancer (HNPC), and / or colitis-associated cancer. In some embodiments, the growth / proliferation of the cancer is inhibited. In some embodiments, the volume of the cancer is reduced. In some embodiments, the spread of metastases is inhibited. DRAWINGS Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive. FIGS. 1A-1B. A) Provides an experimental design in which mice with a xenograft model for cancer, such as pancreatic cancer (PDAC), were placed in different oxygen environments and tumor growth was monitored. B) Systemic hypoxia decreases tumor growth (for example, pancreatic cancer is suppressed by systemic hypoxia exposure (red and blue)). FIG.2. Breast cancer is suppressed by systemic hypoxia exposure (red and blue). FIGS. 3 and 4A-4B. Provide an experimental design for simultaneously testing the effects of systemic hypoxia on many tumor types in one experiment; multiple cell lines were pooled to assess cell line specific effects. For example, FIG.4 provides pooling / mixed cell line assay (representing ~20 pooled human lines / tumor types in NSG mice) showing growth suppression by systemic hypoxia (blue). FIG.4 B provide a panel of cancer types tested. FIG.5. Plot of different tumor types and hypoxia response. Relative cell line fitness in 21% vs 8% oxygen. Tumor types to the left of the plot showed the most dramatic growth suppression in hypoxia. Renal cell carcinomas outcompeted other lines in hypoxia. FIG.6. Nucleotides are depleted in hypoxic tumors / tumor metabolomics. Untargeted metabolomics of tumors from mice housed in hypoxia and normoxia revealed a depletion of most nucleotides and nucleotide-related metabolites. This demonstrates that systemic hypoxia affects nucleotide metabolism to suppress tumor growth (diminishes tumor nucleotide levels). FIGS. 7A-7B. Drug-Induced Systemic Hypoxia Decreases Tumor Growth. An example of such a “hypoxia pill” and the ability to suppress tumor growth in a pancreatic cancer model (pink and blue). DESCRIPTION All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention    belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 3rded., Revised, J. Wiley & Sons (New York, NY 2006); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 7thed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 4thed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012), provide one skilled in the art with a general guide to many of the terms used in the present application. Definitions References in the specification to "one embodiment," "an embodiment," etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described. The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations. “Plurality” means at least two. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrase "one or more" is readily understood by one of skill in the art, particularly when read in context of its usage. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is di-substituted. As used herein, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating a listing of items, “and / or” or “or” shall be interpreted as being inclusive, e.g., the inclusion of at least one, but also including more than one of a number of items, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of    elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” As used herein, the terms “including,” “includes,” “having,” “has,” “with,” or variants thereof, are intended to be inclusive similar to the term “comprising.” As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are useful to an embodiment, yet open to the inclusion of unspecified elements, whether useful or not. It will be understood by those within the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.” The term "about" can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term "about" is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. The term about can also modify the endpoints of a recited range as discuss above in this paragraph. Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.” As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements.    As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to," "at least," "greater than," "less than," "more than," "or more," and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation. The terms “patient,” “individual,” or “subject” are used interchangeably herein, and refer to a mammal, particularly, a human. The patient may have mild, intermediate or severe disease. The patient may be an individual, at risk of developing a disease, in need of treatment or in need of diagnosis based on particular symptoms or family history. In some cases, the terms may refer to treatment in experimental animals, in veterinary application, and in the development of animal models for disease, including, but not limited to, rodents including mice, rats, and hamsters, and primates. Mammals include, but are not limited to, humans, farm animals, sport animals and pets (e.g., companion animals, such as dogs, cats, mini pigs, birds).    As used herein, “health care provider” includes either an individual or an institution that provides preventive, curative, promotional or rehabilitative health care services to a subject, such as a patient. In one embodiment, the data is provided to a health care provider so that they may use it in their diagnosis / treatment of the patient. An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art, especially in light of the detailed disclosure provided herein. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect. The terms "treating," "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate. A “compound,” as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above. As used herein, the term “pharmaceutically-acceptable carrier” means a chemical composition with which an appropriate compound or derivative can be combined and which, following the combination, can be used to administer the appropriate compound to a subject. “Pharmaceutically acceptable” means physiologically tolerable, for either human or veterinary application. As used herein, “pharmaceutical compositions” include formulations for human and veterinary use.  The use of the word “detect” and its grammatical variants refers to measurement of thespecies w    grammatical variants are meant to refer to measurement of the species with quantification. The terms “detect” and “identify” are used interchangeably herein. Tumor hypoxia has been repeatedly linked to worse cancer outcomes, shaping the field’s simplified intuition that hypoxia is universally detrimental in this setting. However, this refers specifically to low oxygen within the tumor. Provided herein is a novel and counterintuitive paradigm – systemic, organismal hypoxia to treat solid tumors. It has been shown that systemic hypoxia (equivalent to 4500m altitude) results in a starvation-like metabolic state that is well-tolerated in mammals with no adverse effects (Midha et al. Cell Metab. 2023 Mar 7; 35(3);504-516). In this state, fuel sources (glucose, fatty acids, etc.) are consumed at greater rates to generate the same amount of ATP as in normoxic environments. It is hypothesized that systemic hypoxia results in a competition between the host and tumor for limited fuel sources, thereby resulting in impaired tumor growth. Data is provided in several preclinical cancer models (e.g., breast cancer, pancreatic cancer and several other cancer types) showing that inhaled hypoxia significantly reduces tumor growth. This concept has been tested across different cancer types and a range of hypoxia-centric therapeutic regimens. Further, a novel strategy to “bottle-up hypoxia” into a small molecule that decreases tissue oxygen delivery, enabling rapid translation to patients has been created (e.g., “HypoxyPill”). Cancer Provided herein are compositions and methods to treat cancer. Cancer can include, but is not limited to, sarcomas (such as osteosarcoma and Kaposi's sarcoma) and carcinomas. Cancer can include, but is not limited to, lung cancer, adenocarcinoma, adenocarcinoma of the lung, squamous carcinoma, squamous carcinoma of the lung, malignant mixed mullerian tumor, head and / or neck cancer, breast cancer, esophageal cancer, mouth cancer, tongue cancer, gum cancer, skin cancer (e.g., melanoma, basal cell carcinoma, Kaposi's sarcoma, etc.), muscle cancer, heart cancer, liver cancer, bronchial cancer, cartilage cancer, bone cancer, stomach cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, gastric cancer, kidney cancer, bladder cancer, spleen cancer, thymus cancer, thyroid cancer, brain cancer, neuronal cancer, mesothelioma, gall bladder cancer, ocular cancer (e.g., cancer of the cornea, cancer of uvea, cancer of the choroids, cancer of the macula, vitreous humor cancer, etc.), joint cancer (such as synovium cancer), glioblastoma, neuroblastoma, white blood cell cancer (e.g., lymphoma, leukemia, etc.), hereditary non-polyposis cancer (HNPC), and / or colitis-associated cancer.    Compounds / Screen The most practical form of “hypoxia therapy” is a small molecule, such as “HypoxyPill”. This includes small molecules that increase the binding affinity of hemoglobin for oxygen, such as left shifting molecules (molecules that increase hemoglobin affinity for oxygen and an increased reluctance to release oxygen). This decreases oxygen delivery to tissues, causing tissue hypoxia. An existing small molecule, further discussed below, was used and demonstrated to cause moderate tissue hypoxia without toxicity. The present methods include administering a treatment that will induce "left shifting" of hemoglobin. A "left shift" refers to a change in the hemoglobin-O2dissociation curve, and leftward movement of the curve is a sign of hemoglobin's increased affinity for oxygen, i.e., indicates that the hemoglobin has an increased affinity for oxygen so that hemoglobin binds oxygen more easily, and releases it more slowly. Inhaled carbon monoxide (CO), a classic hemoglobin left shifter, can be used in the present methods (see, e.g., Hess, Respiratory Care October 2017, 62 (10) 1333-1342; WO2008003953; US8389572; Romao et al., Chem Soc Rev. 2012;41(9):3571-8; Gullotta et al., IUBMB Life. 2012;64(5):378-86). In some embodiments, sufficient CO is delivered to provide an average carboxyhemoglobin level of at least 10%, 15%, 20%, 25%, 30%, or 35%, e.g., with a maximum average level of up to about 20%, 25%, 30%, 35%, or 40%, e.g., with a maximum instantaneous level (e.g., immediately or shortly after dosing) of about 20%, 25%, 30%, 35%, or 40%. In some embodiments, sufficient CO is delivered to provide an average carboxyhemoglobin level of 10-20% or 10-15%. In some embodiments, CO is delivered in discrete doses, e.g., as "puff therapy," rather than as a continuously administered dose. In mice, carboxyhemoglobin is rapidly cleared, so carbon monoxide must be given continuously. In humans, clearance of carboxyhemoglobin is slower, which allows for "puff therapy," e.g., wherein the subject receives a small dose multiple times per day, e.g., one, two, three, four or more times per day. In some embodiments the subject is given a puff in the morning and a puff in the evening. Such discrete doses can be used gently and durably (in humans) to left shift the hemoglobin. In some embodiments, vaping devices or modified vaping devices are used. Carbon monoxide-releasing molecules (CORMs) may also be used, e.g., organometallic carbonyl complexes such as CORM-I, CORM-2, CORM-3, CORM-401, ALF492, CORM-Al, Bl2-ReCORM-2, Re-CORM-I, CORMA-l-PLAandALF186 as well as nonmetallic compounds and enzyme-triggered CORMs (ET-CORMs) (see, e.g., Faizan et al., Materials (Basel). 2019 May; 12(10): 1643; Schatzschneider, Br J Pharmacol. 2015 Mar; 172(6): 1638-1650). Carbon monoxide-releasing molecules (CORMs) are chemical    compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols. As an example, the structure of CORM-l(gly)(CO)3. The structures of CORMs are publicly available. In some embodiments, small molecule allosteric effectors of Hb (AEHs) that left shift Hb can be used. Examples include hydroxyurea, VOXELOTOR (previously GBT440) which is being developed as an orally available left shifter for sickle cell anemia (Dufu and Oksenberg, Hematol Rep. 2018;10(2):7419. Published 2018 May 14), and other drugs that modify hemoglobin, e.g., by forming a Schiff base adduct with the globin N-termini and stabilizing hemoglobin in its oxy configuration (e.g., substituted benzaldehydes such as BW12C (Merrett et al., Biochem J. 1986;239(2):387-392; Beddell et al., Br J Pharmacol. 1984;82(2):397-407; Zaugg et al., J. Biol. Chem.1977;252:8542-8548); Tucaresol (Arya et al., Br J Haematol. 1996;93(4):817-821); aliphatic isothiocyanates (e.g., alkyl isothiocyanate and aryl isothiocyanate); and aromatic aldehydes such as vanillin, thiazo-vanillin, furfural, 5- Hydroxymethyl-2-furfural (5-HMF), and 5-ethyl-2-furfural (5-EF) (Abdulmalik et al., Brit J Haematol. 2005;128(4):552-561); and pyridyl derivatives of vanillin INN-312 and INN-298; see, e.g., Hebbel and Hedlund, Am J Hematol. 2018;93:321-325; Safo and Kato, Hematol Oncol Clin North Am. 2014 Apr; 28(2): 217-231. Alternatively, gene therapy can be used to promote expression of fetal hemoglobin (HbF), which is naturally left-shifted, e.g., targeting BCLIIA, a transcriptional repressor required to maintain silencing of fetal hemoglobin expression. For example, ex vivo editing of autologous stem cells using CRISPR RNA-guided genome editing, e.g., using a nuclease or base editor (e.g., as described in Antoniani et al., (Blood. 2018;13 l(l 7): 1960-1973) or RNA interference / small hairpin RNAs ( e.g., using a lentiviral vector expressing a short-hairpin RNA targeting BCLI IA (see, e.g., Guda et al., Mol Ther.2015 Sep;23(9): 1465-74; Brendel et al., J Clin Invest.2016;126(10):3868-3878; Wilber et al., Blood.2011 Mar 10; 117(10):2817-26) or siRNA (see, e.g., Taghavi et al., Indian J Hematol Blood Transfus. 2019 Oct;35(4):758-764) can be used; see, e.g., Hobanetal., Blood. 2016Feb 18; 127(7): 839-848. BCL11A is highly expressed in several hematopoietic lineages, and plays a role in the switch from γ- to β- globin expression during the fetal to adult erythropoiesis transition. The sequence of the human BCL11A gene is in GenBank at RefSeqGene ID. NG_0l 1968.1 (Range 4845-107979). Human    mRNA sequence can be found at accession numbers NM_018014, NM_022893, NM_138553, NM_138559 and / or NM_001363864, while human protein sequence can be found at NP_060484, NP_075044, NP_612569, NP_001350793, and / or NP_001352538. Alternatively, or in addition, the present methods can include administering a treatment that will induce anemia, e.g., sufficient to correspond to an FIO2 of 5-20%, 5-15%, e.g., 10- 12%, e.g., 11 %, or levels below 13.2 to 16.6 grams (g) of hemoglobin per deciliter (dL) of blood for men, 11.6 to 15. g / dL for women, or less than approximately 13.5 g / dL (135 g / L) in a child age 6 to 12 years. In some embodiments, such a treatment can include the use of bloodletting (phlebotomy). Alternatively, small molecule compounds that induce anemia, including hypoxia inducible factor (HIF)-2alpha (HIF-2a) inhibitors, can be used; such inhibitors cause anemia because HIF2 helps to make red blood cells. HIF2 inhibitors include PT2399, PT2977 andPT2385, and PT2567, the latter two of which are currently in clinical trials for cancer, that have an on-target effect of inducing anemia. Some of the structures are shown below; the molecules can be obtained from commercial sources including MedChemExpress or from Peloton Therapeutics, Inc. “Inhaled hypoxia” also includes breathing hypoxic gas or living in a hypoxic environment. Such a hypoxic environment includes, but is not limited to, about 5% O2 to about 20% O2, about 10% O2to about 15% O2, about 10% O2to about 12% O2, including about 8% O2, about 11% O2, about 15% O2or about 20% O2. The exposure of the subject to a hypoxic environment can be from about 30 minutes to 24 hours or greater. The subject can also be exposed to a hypoxic environment multiple times during treatment, for example, the subject can undergo continuous hypoxia treatment or 12h / day hypoxia (to mimic sleeping in hypoxia). A hypoxic environment can be created in an enclosed space, such as a tent or chamber or with a breathing apparatus (e.g., hypobaric chamber where the chamber has an atmospheric pressure equal to the atmospheric pressure at an elevation between 1,500 to 10,000 meters above sea level (e.g., an atmospheric pressure equal to the atmospheric pressure at an elevation between 1,500 to 8,000 meters or between 2,000 to 4,500 meters above sea level) (see, for example, US20210093660, which is incorporated herein by reference)). Other drugs known to cause hemolytic anemia include cephalosporins; dapsone; levodopa; levofloxacin; pmethyldopa; nitrofurantoin; nonsteroidal anti-inflammatory drugs (NSAIDs); penicillin and its derivatives; phenazopyridine (pyridium); alkylating agents; the plant alkaloids vinblastine and vincristine; antibiotics used in cancer chemotherapy; and quinidine. See also Girdwood, Drugs.1976;11(5):394-404.    Hemoglobin modifier compounds (such as small molecule left shifters) for use in the methods provided herein also include the following: In embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I) wherein, R1is H or D; L1is X or -C(R7)(R8)-; X is -O-, -S-, -S(O)-, -S(O2)- or -NR4-; R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H or D; R3is H or D; ring A is a bicyclic heterocycle or a bicyclic carbocycle, provided that ring A is not indazolyl; ring C is a monocyclic heterocycle or a monocyclic carbocycle; ring D is a monocyclic heterocycle, bicyclic heterocycle, monocyclic carbocycle, or a bicyclic carbocycle; each RA, RCand RDare independently H, D, halogen, -CN, -OH, -OD, -OR5, -SR5, - S(=O)R6, -NO2, -N(R5)2, -S(=O)2R6, -NHS(=O)2R6, -S(=O)2N(R5)2, -C(=O)R6, -OC(=O)R6, - CO2R5, -OCO2R6-C(=O)N(R5)2 -OC(=O)N(R5)2 -NR5C(=O)N(R5)2 -NR5C(=O)R6- NR5C(=O C6alkeny    C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein a hydrogen atom on a substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl is optionally replaced with at least one D; each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein a hydrogen atom on a substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C2-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl is optionally replaced with at least one D; or two R5on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycloalkyl; each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. In embodiments, the compound of Formula (I) has the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:Formula (Ia). I pharmac   . Formula (Ib). In some embodiments, the compound of Formula (I) has a structure of Formula (Ic), or pharmaceutically acceptable salt or solvate thereof:Formula (Ic). In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II) wherein, R1is H or D; L X    R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1- C6deuteroalkyl; R3is D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; or R2and R3together with the carbon that they are attached to form a substituted or unsubstituted C2-C6cycloalkyl or a substituted or unsubstituted C2-C8heterocycloalkyl; or R2and R3are taken together with the carbons that they are attached to form a substituted or unsubstituted C2-C6cycloalkyl or a substituted or unsubstituted C2- C8heterocycloalkyl; or R3and RCare taken together with the carbons that they are attached to form a substituted or unsubstituted C3–C6cycloalkyl or a substituted or unsubstituted C2- C8heterocycloalkyl; or R3and RAare taken together with the carbons that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C2- C8heterocycloalkyl; ring A is a monocyclic carbocycle, monocyclic heterocycle, bicyclic carbocycle, or bicyclic heterocycle; ring C is a monocyclic heterocycle or a monocyclic carbocycle; ring D is a monocyclic heterocycle, bicyclic heterocycle, monocyclic carbocycle, or a bicyclic carbocycle; each RA, RC, and RDis independently H, D, halogen, -CN, -OH, -OR5, -SR5, -S(=O)R6, -NO2, - N(R5)2, -S(=O)2R6, -NHS(=O)2R6, -S(=O)2N(R5)2, -C(=O)R6, -OC(=O)R6, -CO2R5, - OCO2R6, -C(=O)N(R5)2, -OC(=O)N(R5)2, -NR5C(=O)N(R5)2, -NR5C(=O)R6, -NR5C(=O)OR6, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C2-C6alkenyl substituted or unsubstituted C2-C6alkynyl substitut substitut    each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R5on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycloalkyl; each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted CrC6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. In some embodiments, the compound of Formula (II) has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereofFormula (IIa) In some embodiments, the compound of Formula (II) has the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof   In some embodiments, the compound of Formula (II) has the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereofFormula (IIc) In embodiments, the compound is a compound of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof:Formula (II') wherein, R1is H or D; L1is X or -C(R7)(R8)-; X is -O-, -S-, -S(O)-, -S(O2)- or -NR4-; R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1- C6deuteroalkyl; R3is D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6het    or R2and R3together with the carbon that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C2-C8heterocycloalkyl; or R7and R3are taken together with the carbons that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C2- C8heterocycloalkyl; ring A is a monocyclic carbocycle, monocyclic heterocycle, bicyclic carbocycle, or bicyclic heterocycle; ring C is a monocyclic heterocycle or a monocyclic carbocycle; ring D is a monocyclic heterocycle, bicyclic heterocycle, monocyclic carbocycle, or a bicyclic carbocycle; each RA, RC, and RDis independently H, D, halogen, -CN, -OH, -OR5, -SR5, -S(=O)R6, -NO2, - N(R5)2, -S(=O)2R6, -NHS(=O)2R6, -S(=O)2N(R5)2, -C(=O)R6, -OC(=O)R6, -CO2R5, - OCO2R6, -C(=O)N(R5)2, -OC(=O)N(R5)2, -NR5C(=O)N(R5)2, -NR5C(=O)R6, -NR5C(=O)OR6, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R5on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycloalkyl; each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. I acceptab   Formula (III) R1is H or D; L1is X or -C(R7)(R8)-; X is -O-, -S-, -S(O)-, -S(O2)- or -NR4-; R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H, or D; R3is H, or D; ring A is phenyl or a monocyclic heterocycle;r bicyclic    each RA, RC, and RDis independently H, D, halogen, -CN, -OH, -OR5, -SR5, -S(=O)R6, -NO2, - N(R5)2, -S(=O)2R6, -NHS(=O)2R6, -S(=O)2N(R5)2, -C(=O)R6, -OC(=O)R6, -CO2R5, - OCO2R6, -C(=O)N(R5)2, -OC(=O)N(R5)2, -NR5C(=O)N(R5)2, -NR5C(=O)R6, -NR5C(=O)OR6, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R5on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycloalkyl; each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. In some embodiments, ring A is a bicyclic heterocycle that is a 8-, 9- or 10-membered bicyclic heterocycle. In some embodiments, ring A is a bicyclic heterocycle that has 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the bicyclic ring. In some embodiments, ring A is a bicyclic heterocycle that has 0-4 N atoms, 1 O atom or 1 S atom in the bicyclic ring. In some embodiments, the compound of Formula (III) has a structure of Formula (IIIa), or pharmaceutically acceptable salt or solvate thereof:F l (III )    In some embodiments, the compound of Formula (III) has a structure of Formula (IIIb), or pharmaceutically acceptable salt or solvate thereof:Formula (IIIb). In embodiments, the compound is a compound of Formula (IV):Formula (IV) wherein, R1is Hor D; R2is H orD; R3is H or D; RAis H, D, or F; RCis H, D, or F; and RDis H, D, C1-C6alkyl, or C1-C6deuteroalkyl; provided that when RDis H or C1-C6alkyl then at least one of R1, R2, R3, RAand RDis In embodiments, the compound is a compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof:   Formula (V) wherein: R1is H or D; L1is X or -C(R7)(R8)-; X is -O-, -S-, -S(O)-, -S(O2)- or -NR4-; R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1- C6deuteroalkyl; R3is H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; or R2and R3together with the carbon that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C2-C8heterocycloalkyl; ring A is a monocyclic carbocycle, monocyclic heterocycle, bicyclic carbocycle, or bicyclic heterocycle; ring C is a monocyclic heterocycle or a monocyclic carbocycle; each RA, RC, and RDis independently H, D, halogen, -CN, -OH, -OR5, -SR5, -S(=O)R6, -NO2, - N(R5)2, -S(=O)2R6, -NHS(=O)2R6, -S(=O)2N(R5)2, -C(=O)R6, -OC(=O)R6, -CO2R5, - OCO2R6, -C(=O)N(R5)2, -OC(=O)N(R5)2, -NR5C(=O)N(R5)2, -NR5C(=O)R6, -NR5C(=O)OR6, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substitut d b tit t d C C fl lk l b tit t d b tit t d C C h t lk l substitut    each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R5on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycloalkyl; each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. In some embodiments, the compound of Formula (V) has the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:Formula (Va) In embodiments, the compound is a compound of Formula (VI) or a pharmaceutically acceptable salt or solvate thereof:F l (VI) w    R1is H or D; L1is X or -C(R7)(R8)-; X is -O-, -S-, -S(O)-, -S(O2)- or -NR4-; R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H, or D; R3is H, D; ring A is phenyl or a monocyclic heterocycle;each RA, RC, and RDis independently H, D, halogen, -CN, -OH, -OR5, -SR5, -S(=O)R6, -NO2, -N(R5)2, -S(=O)2R6, -NHS(=O)2R6, -S(=O)2N(R5)2, -C(=O)R6, -OC(=O)R6, -CO2R5, - OCO2R6, -C(=O)N(R5)2, -OC(=O)N(R5)2, -NR5C(=O)N(R5)2, -NR5C(=O)R6, -NR5C(=O)OR6, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; o attached    each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. In some embodiments, the compound of Formula (VI) has a structure of Formula (VIa), or pharmaceutically acceptable salt or solvate thereof:Formula (VIa). In some embodiments, the compound of Formula (VI) has a structure of Formula (VIb), or pharmaceutically acceptable salt or solvate thereof:Formula (VIb). In embodiments, the compound is a compound of Formula (VII) or a pharmaceutically acceptable salt or solvate thereof:   Formula (VII) wherein: R1is H or D; L1is X ; X is -O-, -S-, -S(O)-, or -S(O2)-; R7and R8are each independently H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6deuteroalkyl; R4is hydrogen, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; R2is H, D, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1- C6deuteroalkyl; R3is H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; or R2and R3together with the carbon that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C2-C8heterocycloalkyl; or R7and R3are taken together with the carbons that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C2- C8heterocycloalkyl; ring A is a monocyclic carbocycle, monocyclic heterocycle, bicyclic carbocycle, or bicyclic heterocycle; ring C is a monocyclic heterocycle or a monocyclic carbocycle; ring D is a monocyclic heterocycle, bicyclic heterocycle, monocyclic carbocycle, or a bicyclic carbocycle; e -NO2, -N    OCO2R6, -C(=O)N(R5)2, -OC(=O)N(R5)2, -NR5C(=O)N(R5)2, -NR5C(=O)R6, -NR5C(=O)OR6, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R5is independently H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R5on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycloalkyl; each R6is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and n is 0, l, 2 or 3. In some embodiments, the compound of Formula (VII) has a structure of Formula (VIIa), or pharmaceutically acceptable salt or solvate thereof:Formula (VIIa). In some embodiments, the compound of Formula (VII) has a structure of Formula (VIIb), or pharmaceutically acceptable salt or solvate thereof:   Formula (VIIb). In some embodiments, the compound of Formula (VII) has a structure of Formula (VIIc), or pharmaceutically acceptable salt or solvate thereof:Formula (VIIc). In some embodiments, ring A is a bicyclic heterocycle that is a 8-, 9- or 10-membered bicyclic heterocycle. In some embodiments, ring A is a bicyclic heterocycle that has 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the bicyclic ring. In some embodiments, ring A is a bicyclic heterocycle that has 0-4 N atoms, 1 O atom, or 1 S atom in the bicyclic ring. In some embodiments, ring A is a bicyclic heterocycle that is quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, azaindazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, azabenzotriazolyl, benzoxazolyl, azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, azabenzothiazolyl, or purinyl. In some embodiments, ring A is a bicyclic heterocycle that is indolinyl, isoindolinyl, indolinonyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 3, 4-dihydro- 2(lH)-quinolinonyl, dihydrobenzofuranyl, dihydroisobenzofuran, dihydrobenzo[b]thiophenyl, or dihydrobenzo[c]thiophenyl.    In some embodiments, ring A is a bicyclic heterocycle that is quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, indolizinyl, indolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, or purinyl. In some embodiments,  In some embodiments, ring A is a bicyclic carbocycle that is naphthyl, indanyl, or indenyl. In some embodiments, the groupsadjacent atoms of ring A. In some embodiments, ring A is phenyl.   In some embodiments, L1is X; and X is O or S. In some embodiments, X is O.In embodiments, the groupsare on adjacent atoms of ring C. In some embodiments, ring C is a monocyclic heterocycle. In some embodiments, ring C is a monocyclic heterocycle with 1-3 N atoms in the ring. In some embodiments, ring C is a monocyclic 6-membered heterocycle with 1-3 N atoms in the ring. In some embodiments, ring C is a monocyclic 6-membered heterocycle that is pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl.In some embodiments, . In some embodiments, ring C is a monocyclic heterocycle. In some embodiments, ring C is a monocyclic heterocycle with 1-3 N atoms in the ring. In some embodiments, ring C is a monocyclic 6-membered heterocycle with 1-3 N atoms in the ring.    In some embodiments, ring C is a monocyclic 6-membered heterocycle that is pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some embodiments, ring C is a monocyclic 6-membered heterocycle that isIn some embodiments, In some embodiments, ring D is a monocyclic heterocycle. In some embodiments, ring D is a monocyclic N-containing heterocycle. In some embodiments, ring D is a monocyclic 5- membered N containing heterocycle or a monocyclic 6-membered N-containing heterocycle. In some embodiments, ring D is a monocyclic N-containing heterocycle that is pyrrolyl,    oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some embodiments, ring D is a 5-membered monocyclic N-containing heterocycle. In some embodiments, ring D is a 5-membered monocyclic N-containing heterocycle that is pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, or thiadiazolyl.In some embodiments, ring D is a monocyclic heterocycle that is a b -lactam, g -lactam, d-lactam, or e-lactam.In some embodiments, In some embodiments, ring D is a bicyclic heterocycle. In some embodiments, ring D is a bicyclic heterocycle that is a fused bicyclic heterocycle, bridged bicyclic heterocycle, or spiro bicyclic heterocycle.    In some embodiments,In some embodiments, RDis H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl. In some embodiments, RDis C1-C6deuteroalkyl. In some embodiments, RD is - CH(CD3)2. In some embodiments, RDis H, D, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl. In some embodiments, R1is D. In some embodiments, R2is H or D; and R3is substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C1-C3fluoroalkyl, or substituted or unsubstituted C1-C3heteroalkyl. In some embodiments, R2is H; and R3is substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C1-C3fluoroalkyl, or substituted or unsubstituted C1-C3heteroalkyl. In some embodiments, R2and R3are each substituted or unsubstituted C1-C3alkyl. In some embodiments, R2and R3together with the carbon that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C3-C8heterocycloalkyl. In some embodiments, R2is D; and R3is D. In some embodiments, R2is H; and R3is H. In some embodiments, R2is D; and R3is D. In some embodiments, R2is H; and R3is substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C1-C3fluoroalkyl, or substituted or unsubstituted C1-C3heteroalkyl. In some embodiments, R2and R3are each substituted or unsubstituted C1-C3alkyl. In some embodiments, R2and R3together with the carbon that they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or a substituted or unsubstituted C3- C8hetero I    In some embodiments, RCis H or F. In some embodiments, RCis F. In some embodimentsIn some embodiments, are on adjacent atoms of ring C.In some embodiments, are on adjacent atoms of ring C. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is selected from:                       In some embodiments, the compound of the present disclosure, or the pharmaceutically from:    . Inhibitors of HIF proteins (Hypoxia-Inducible Factor (HIF)-1 and / or Hypoxia- Inducible Factor (HIF)-2) can also be used in the methods provide herein (decrease hematocrit and therefore oxygen delivery). HIF inhibitors include, TAT-cyclo-CLLFVY (SEQ ID NO: 1; a selective HIF-1 dimerization inhibitor; CLLFVY CGRKKRRQRRRPPQ (SEQ ID NO: 2; modifications: lactam bridge: Cys-1 to Tyr-6), disulfide bridge: 1-1*)), DMOG    (Dimethyloxallyl Glycine), Echniomycin, FM19G11     indirect HIF-1 inhibition have made it to clinical trials and a few have been US FDA-approved for cancer treatment, such as: camptothecins: camptothecin, topotecan, irinotecan; bortezomib, romidepsin, temsirolimus, perifosine, 2-Methoxyestradiol, echinomycin; ansamycins: Geldanamycin, 17-AAG, and / or 17-DMAG. The methods can also include use of inhibitors disclosed in Wehn et al., J. Med. Chem. 2018, 61, 21, 9691-9721; Wehn et al., Journal of Medicinal Chemistry 2019, 62, 15, 6876-6893 (PT2977); US10155726; US20160368893; US9796697; or US20190015377 (e.g., compounds 163, 226, or 231 disclosed therein, as shown below).  Other HIF-2a inhibitors can also be used, e.g., as described in WO2018160772, e.g., cardiac glycoside, such as digoxin, ouabain, proscillaridinA, digitoxin, acetydigitoxin, convallatoxin, peruvoside, strophanthin K, nerifolin, cymarin, or periplocymarin (see e.g., Zhang et al., Proc. Natl. Acad. Sci. USA 105: 19579-19586, 2008), rapamycin or an analog thereof (such as rapamycin, everolimus, temsirolimus, or tacrolimus), an anthracycline or analog thereof (such as doxorubicin or daunorubicin), a proteasome inhibitor (such as bortezomib (PS-341)), or camptothecin or an analog thereof (such as CRLX-101, SN-38, EZN- 2208, irinotecan, or topotecan). In additional examples, a HIF-2a small molecule inhibitor includes echinomycin (see, e.g., Kong et al., Cancer Res.65:9047-9055, 2005), 17-allylamino- 17-demethoxygeldanamycin (see, e.g., Liu et al., Mol. Cell 25:207-217, 2007), 17- dimethylaminoethylamino-17-demethoxygeldanamycin (e.g., WO 02 / 079167), NSC 644221 (see, e.g., Creighton Gutteridge et al., Clin. Cancer Res.13: 1010-1018, 2007), YC-1 (e.g., Yeo et al., J. Natl. Cancer Inst. 95:498-499, 2003), PX-478 (see, e.g., U.S. Pat. 7,399,785), 2- methoxyestradiol or derivatives thereof (e.g., ENMD-1198 or ENMD-2076), wondonin (e.g., Jun et al., FEBS Lett. 581:4977-4982, 2007), Palomid-529 (Paloma Pharmaceuticals), CLT- 003 (Charlesson), cyclopentabenzofuranes (e.g., IMD-026260; WO 2010 / 063471), furoquinoline- based molecules (e.g., Lohar et al., Bioorg. Med. Chem. Lett. 18:3603-3606, 2008), BAY 87- 2243, BTG-6228 (BTG), or KC7F2 (e.g., Naria et al., Clin. Cancer Res. 15:6128-6136, 2009); alpha-ketoglutarates (e.g., WO 06 / 01614 2010); E    385, 2011); CX-4715 or CX-3800 series compounds (Cylene Pharmaceuticals), or N-(3- Chloro-5-fluorophenyl)-4-nitrobenzo[ c] [ l ,2,5]oxadiazol-5-amine (HIF-2 antagonist 2). See also Li et al., Journal of Medicinal Chemistry 2019, 62,12, 5725-5749. HIF-2α inhibitors for use in the methods provided herein also include the following: In embodiments, the compound is a HIF-2a inhibitor. In embodiments, the HIF-2a inhibitor is a compound of formula (VIII):Formula (VIII) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR5or N; Y is CR6or N; Z is O, S, CHR7, NR8or absent; R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R2is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo, sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl; R3is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; or R2and R3taken together form a cyclic moiety; R4is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5, R6, R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. In embodiments, the compound is a compound of Formula (VIII-A):Formula (VIII-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR5or N;    Y is CR6or N; Z is O, S, CHR7, NR8or absent; R2is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; R3is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R2and R3taken together form a cyclic moiety; R4is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R5, R6, R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; W1is Nor CR10; R9is cyano, halo, alkyl or alkoxy; and R10is hydrogen, cyano, halo, alkyl or alkoxy. In embodiments, the compound is a compound of Formula (VIII-B):Formula (VIII-B) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR5or N; Y is CR6or N; Z is O, S, CHR7, NR8or absent; R2is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; R3is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R2and R3taken together form a cyclic moiety; R4is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R5, R6, R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; Rcis hydrogen, cyano, halo, alkyl or alkoxy; and n' is 0, 1, 2, 3 or 4. In embodiments, the compound is a compound of Formula (VIII-C):   Formula (VIII-C) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR5or N; Y is CR6or N; Z is O, S, CHR7, NR8or absent; R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R5, R6, R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; R11is hydrogen, hydroxy, alkoxy or amino; R12is hydrogen, alkyl, alkenyl or alkynyl; or R11band R12in combination form oxo or oxime; each of R13is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl, with the proviso that when R13is hydroxy, n is 1 or 2; or two R13s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and n is 0, 1, 2, 3 or 4. In embodiments, the compound is a compound of Formula (VIII-D), (VIII-E), (VIII- F), or (VIII-G):  Formula (VIII-G) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR5or N; Y is CR6or N; Z is O, S, CHR7, NR8or absent; R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R4is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R5, R6, R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and R11is hydrogen, hydroxy, alkoxy or amino. In embodiments, the compound is a compound of Formula (VIII-H), (VIII-I), (VIII-J), or (VIII-K):Formula (VIII-K) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR5or N; Y i CR6N Z    R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R4is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R5, R6, R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and R11is hydroxy or amino. In embodiments, the compound is a compound of Formula (IX):Formula (IX) or a pharmaceutically acceptable salt or prodrug thereof, wherein:(VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (VIII-I), (VIII-J), (VIII-K):and (IX) In some embodiments, R1is phenyl or monocyclic heteroaryl. In some further embodiments, R1is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In some embodiments, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In some embodiments, R1is bicyclic heteroaryl. In some embodiments, the bicyclic heteroaryl is substituted with one or more substituents selected from the group consisting of halo, C1-C4alkyl, C1-C4alkoxy and cyano. In some embodiments, R1is pyridyl N-oxide. In some embodiments, the pyridyl N- oxide is substituted with one or more substituents selected from the group consisting of halo, C1-C4alkyl, C1-C4alkoxy and cyano. In some embodiments, R1 iswherein the aryl ring may optionally besubstituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In some embodiments, the substituent(s) is selected from the group consisting of halo, C1-C4alkyl, C1-C4alkoxy and cyano.    In some embodiments,wherein W1 is N or CR10, R9 is cyano,halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy. In some embodiments, R9is cyano, halo, C1-C4 alkyl or C1-C4 alkoxy, and R10is hydrogen, cyano, halo, C1-C4 alkyl or C1-C4 alkoxy. In some embodiments, R1is selected from the group consisting of:   and the rings specified for R1may optionally be substituted with one or more substituents described for aryl and heteroaryl. In some embodiments, the substituent(s) is selected from the group consisting of halo, C1-C4alkyl, C1-C4alkoxy and cyano. In some embodiments, R1is selected from the group consisting of:and the rings specified for R1may optionally be substituted with one or more substituents described for cycloalkyl. In some embodiments, the substituent(s) is selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, cyano and oxo. In some embodiments, R1is cycloalkyl. In other embodiments, R1is heterocycloalkyl. In some embodiments, R1is C3-C6cycloalkyl or C3-C6heterocycloalkyl. In yet a further embodiment, R1is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In some embodiments, the substituent(s) is selected from the group consisting of halo, C1-C4alkyl, C1-C4alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. In some embodiments, R1is acyl or cyano. In some embodiments, R1is acetyl. In some embodiments, R1is alkyl. In some embodiments, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1is heteroalkyl. In some embodiments, R1is selected from the group consisting of:   wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In some embodiments, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4alkoxy and cyano. In some embodiments, R2is cyano, halo or alkyl. In some embodiments, R2is halo or alkyl. In some embodiments, R2is fluoro, chloro, bromo or iodo. In some embodiments, R2is fluoroalkyl. In some further embodiments, R2is -CH2F, -CHF2 or -CF3. In another embodiment, R2is hydrogen. In some other embodiments, R2is heteroalkyl, alkenyl or alkynyl. In some embodiments, R3is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R2and R3taken together form a cyclic moiety. In some embodiments, R3is halo, cyano or alkyl. In yet a further embodiment, R3is -(CH2)n-OH, wherein n is 1, 2 or 3. In still a further embodiment, R3is -CH2OH. In some embodiments, R2and R3taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spahybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following:   other representative compounds include, but are not limited to  other representative compounds include, but are not limited to  wherein the carbocycle formed by linking R2and R3may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In some embodiments, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R2and R3. In some embodiments, the substituent(s) is C3-C5 cycloalkyl or C3-C5 heterocycloalkyl. In other embodiments, the substituent is oxo. In some embodiments, R2and R3taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In some embodiments, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In some embodiments, R4is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R4is fluoroalkyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R4is fluoroalkyl. In yet another embodiment, R4is sulfonyl. In still another embodiment, R4is fluoroalkylsulfonyl. In some embodiments, R4is -S(=O)2Ra, wherein Rais alkyl or cycloalkyl. In some embodiments, Rais C1-C4alkyl, optionally substituted with one or more fluorines. Suitable    examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, -CH2F, -CHF2, - CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3 and -CF2CH3. In some embodiments, Rais methyl, optionally substituted with one or more fluorines. In some embodiments, R4is -S(=O)( NRb) Ra, wherein Rais alkyl or cycloalkyl and Rbis hydrogen, cyano or alkyl. In some embodiments, Rais C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4alkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3and - CF2CH3. In some embodiments, R4is -S(=O)2N(Ra)2, wherein each Rais independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Rais hydrogen. In some embodiments, both Ras are hydrogen. In another further embodiment, one Rais hydrogen, and the other Rais C1-C4 alkyl. In some embodiments, R4is selected from the group consisting of -CN, -CF3, - S(=O)CH3 , -S(=O)2CH3, -S(=O)2CH2F, -S(=O)2CHF2, -S(=O)2CF3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)(=NH)CH3, -S(=O)(NH)CH2F, -S(=O)(NH)CHF2, -S(=O)(=NH)CF3, - S(=O)( N-CN)CH3, -S(=O)(=NCN)CH2F, -S(=O)( N-CN)CHF2and -S(=O)(=N-CN)CF3. In some embodiments, R5is hydrogen. In some other embodiments, R5is C1-C4alkyl or C1-C4 alkoxy. In some embodiments, R5is methyl. In some embodiments, R6is hydrogen. In some other embodiments, R6is C1-C4alkyl or C1-C4alkoxy. In some embodiments, R6is methyl. In some embodiments, R7is hydrogen. In some other embodiments, R7is C1-C4 alkyl or C1-C4alkoxy. In some embodiments, R7is methyl. In some embodiments, R8is hydrogen. In some other embodiments, R8is C1-C4alkyl or C1-C4 alkoxy. In some embodiments, R8is methyl. In some embodiments, R9is cyano, halo, C1-C4 alkyl or C1-C4 alkoxy. In some embodiments, R10is hydrogen. In some embodiments, R11is hydroxy or amino. In some embodiments, R11is hydroxy. In some embodiments, R11is amino. In some embodiments, R12is hydrogen. In some embodiments, R12is alkyl or alkenyl. In some embodiments, R13is fluoro. In some embodiments, n is 1, 2 or 3. In some embodiments, two R13s in combination form oxo, oxime or methylene. In some embodiments, two R13s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or hetero    In some embodiments, R1is monocyclic aryl or monocyclic heteroaryl and is hydroxy or amino. In some embodiments, R13is fluoro. In some embodiments, n is 1, 2 or 3. In some embodiments, R1is phenyl or monocyclic heteroaryl, R11is hydroxy or amino, R13is fluoro, n is 1, 2 or 3, and R5is hydrogen. In some embodiments, R1is bi cyclic heteroaryl and R11is hydroxy or amino. In some embodiments, R13is fluoro. In some embodiments, n is 1, 2 or 3. In some embodiments, R1is bicyclic heteroaryl, R11is hydroxy or amino, R13is fluoro, n is 1, 2 or 3, and R5is hydrogen. In some embodiments, R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl, and is hydroxy or amino. In some embodiments, R12is hydrogen. In another further embodiment, R13is fluoro. In some embodiments, n is 1, 2 or 3.

[0406] In some embodiments, R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R11is hydroxy or amino; R13is fluoro; n is 1, 2 or 3; and R5is hydrogen. In some embodiments, R12is hydrogen. In some embodiments R11is hydroxy or amino and R12is hydrogen. In some embodiments, R13is fluoro. In still a further embodiment, n is 1, 2 or 3. In some embodiments R11is hydroxy or amino, R12is hydrogen, R13is fluoro, n is 1, 2 or 3, and R5is hydrogen. In some embodiments, R4is selected from the group consisting of -CN, -CF3, - S(=O)CH3, -S(=O)2CH3, -S(=O)2CH2F, -S(=O)2CHF2, -S(=O)2CF3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)(=NH)CH3, -S(=O)(NH)CH2F, -S(=O)( NH)CHF2, -S(=O)(=NH)CF3, -S(=O)(N-CN)CH3, -S(=O)(=NCN)CH2F, -S(=O)(N-CN)CHF2and -S(=O)(=N-CN)CF3. In some embodiments, R4is fluoroalkyl; n is 0, 1,2 or 3; Z is O; R11is hydroxy; and R12is hydrogen. In some embodiments, R4is sulfonyl or fluoroalkylsulfonyl; n is 0, 1, 2 or 3; Z is O; R11is hydroxy; and R12is hydrogen. In some embodiments, R3is hydrogen, R4is -S(=O)2 Raor -S(=O)(=NR6)Rc, wherein Rais fluoroalkyl, R6is hydrogen, cyano or alkyl and Rcis alkyl. In some embodiments, R1is selected from the group consisting of   wherein W1is N or CR10, R9is cyano,halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy; and mayoptionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In some embodiments, the alkyl is C1-C4 alkyl. In another further embodiment, the alkoxy is C1-C4alkoxy. In some embodiments, each of R2and R3is independently alkyl and R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R3is -CH2OH. In some embodiments, R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl and R5is hydrogen. In some embodiments, R2is cyano, halo or alkyl. In some embodiments, R1is phenyl or monocyclic heteroaryl; R2is nitro, halo, cyano or alkyl; R3is halo, cyano or alkyl; R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R4is selected from the group consisting of -CN, -CF3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2CH2F, -S(=O)2CHF2, -S(=O)2CF3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)(NH)CH3, -S(=O)(NH)CH2F, -S(=O)(NH)CHF2, - S(=O)(=NH)CF3, -S(=O)(N-CN)CH3, -S(=O)(N-CN)CH2F, -S(=O)(N-CN)CHF2 and - S(=O)(=NCN)CF3 In some embodiments, R5is hydrogen. In some embodiments, R1is bicyclic heteroaryl; R2is nitro, halo, cyano or alkyl; R3is halo, cyano or alkyl; R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5is hydrogen. In some embodiments, R1is phenyl, monocyclic heteroaryl or bicyclic heteroaryl; R2is halo, cyano or alkyl; R3is halo, cyano or alkyl; R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5is hydrogen. In some embodiments, R2and R3together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon; R4is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5is hydrogen embodim    In some embodiments, R3is -CH2OH and R4is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, Rs is hydrogen. In still a further embodiment, R2is cyano, halo or alkyl. In some embodiments, R2is halo, cyano or alkyl; R3is CH2OH; R4is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R4is selected from the group consisting of -CN, -CF3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2CH2F, -S(=O)2CHF2, - S(=O)2CF3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)(NH)CH3, -S(=O)(=NH)CH2F, - S(=O)(=NH)CHF2 , -S(=O)(NH)CF3, -S(=O)(N-CN)CH3, -S(=O)( N-CN)CH2F, -S(=O)( N- CN)CHF2and -S(=O)(=N-CN)CF3. In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5and Y is CR6. In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR7. In yet other embodiments, Z is NR8. In some embodiments, Z is absent. In embodiments, the compound is a compound of Formula (X):Formula (X) or a pharmaceutically acceptable salt or prodrug thereof, wherein: Z is O, S, CHR7, NR8or absent; R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R2is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; R14is hydrogen, deuterium or alkyl; R15is hydrogen, hydroxy or amino; or R14and R15in combination form oxo or methylene; R16and R17are independently selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl and cycloalkyl; or R16and R17and the carbon to which they are attached form C3-C8cycloalkyl or C5-C8heterocycloalkyl; R and cyan    n" is 1 or 2; and R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. In embodiments, the compound is a compound of Formula (X-A):Formula (X-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: Z is O, S, CHR7, NR8or absent; R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R2is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; R14is hydrogen, deuterium or alkyl; R15is hydrogen, hydroxy or amino; or R14and R15in combination form oxo or methylene; R18is O or NR19, wherein R19is selected from the group consisting of hydrogen, alkyl and cyano; and R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. In embodiments, the compound is a compound of Formula (X-B):Formula (X-B) or a pharmaceutically acceptable salt or prodrug thereof, wherein: Z is O, S, CHR7, NR8or absent; R1is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R2is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; R15is hydroxy or amino;    R18is O or NR19, wherein R19is selected from the group consisting of hydrogen, alkyl and cyano; and R7and R8are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. As it applies to the compounds of formulas (X), (X-A), and (X-B) In some embodiments, R1is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1is cycloalkyl, aryl or heteroaryl. In some embodiments, R1is aryl or heteroaryl. In a further embodiment, R1is phenyl. In another further embodiment, R1is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl. In some embodiments, R1is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl In some embodiments,wherein each of Reis independently hydrogen or alkyl, or two Res and the carbon atom to which they are attached form a 4- to 8- membered cyclic moiety; each of Rfis independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n" is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.    In some embodiments, R1is selected from the group consisting of:and the rings specified for R1may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In some embodiments, R1is cycloalkyl. In other embodiments, R1is heterocycloalkyl. In a further embodiment, R1is C3-C6cycloalkyl or C3-C6heterocycloalkyl. In yet a further embodiment, R1is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4alkyl, C1-C4alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. In some embodiments, R1is acyl or cyano. In a further embodiment, R1is acetyl. In some embodiments, R1is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1 -C4 alkyl, C1 -C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1is heteroalkyl.    In some embodiments, R1is selected from the group consisting of:wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1- C4 alkoxy and cyano. In some embodiments, R2is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R2is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R2is cyano, halo or alkyl. In some embodiments, R2is halo or alkyl. In a further embodiment, R2is fluoroalkyl. In a still further embodiment, R2is C1-C4fluoroalkyl. Exemplary C1-C4fluoroalkyl includes, but is not limited to, -CH2F, -CHF2, -CF2CH3 and the like. In some embodiments, R11is hydrogen or deuterium. In some embodiments, R11is alkyl. In a further embodiment, R11is C1-C4alkyl. In some embodiments, R14is hydrogen or deuterium. In some embodiments, R14is alkyl. In a further embodiment, R14is C1-C4 alkyl. In some embodiments, R15is hydroxy or amino. In some embodiments, R15is hydroxy. In some embodiments, R15is amino. In a further embodiment, R15is NH2. In some embodiments, each of R16and R17is independently hydrogen or fluoro. In some embodiments, each of R16and R17is hydrogen. In some embodiments, each of R16and R17is fluoro. In some embodiments, at least one of R16and R17is fluoro. In some embodiments, R18is O, N-CN, or NH. In some embodiments, R18is O. In some embodiments, R18is NH. In some embodiments, R18is N-CN.    In some embodiments, R11is hydrogen and R15is hydroxy or amino. In some further embodiments, R1is aryl or heteroaryl. In a further embodiment, R2is cyano, halo or alkyl. In a still further embodiment, R16and R17are fluoro. In some embodiments, R15is hydroxy or amino and R2is cyano, halo or alkyl. In a further embodiment, R2is fluoroalkyl. In a still further embodiment, at least one R16and R17is fluoro. In a yet still further embodiment, n" is 1. In some embodiments, R18is O or NH and R14is hydrogen. In some further embodiments, R1is aryl or heteroaryl. In a further embodiment, R2is cyano, halo or alky I. In a still further embodiment, at least one of R16and R17is fluoro. In some embodiments, n" is 1. In some further embodiments, R15 is hydroxy or amino and R16and R17are fluoro. In a further embodiment, R1is aryl or heteroaryl. In a still further embodiment, R1is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkoxy, cyano and alkyl. In some embodiments, a compound of Formula (X-B) may have an enantiomeric excess of at least about 70%, at least about 71 %, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81 %, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99%. In a further embodiment, the compound has an enantiomeric excess of at least about 90%. In another aspect, the present disclosure provides a compound or pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the compounds in Table 1 below.   37            5 47            5 57            5 67            5 77            5 87            5 97            5 08            5 18            5 28            5 38            5 48            5 58            5 68            5 78            5 88            5 98            5 09            5 19            5 29            5 39            5 49            5 59            5 69            5 79            5 89            5 99            5 001            5 101            5 201            5 301            5 401            501            5 601            5 701            5 801            5 901            5 011            5 111            5 211            5 311            5 411            5 511            5 611            5 711            5 811            5 911           5  In one aspect, compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In some embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the "prodrug") but then is metabolically hydrolyzed to provide the active entity. In some embodiments, the active    entity is a phenolic compound as described herein. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), (II), (II'), (III), (IV), (V), (VI), or (VII), as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound. In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. "Pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not    abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound described herein with a base to form a salt. Compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid to form a salt such as, for example, a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, a phosphoric acid salt, a metaphosphoric acid salt, and the like; or with an organic acid to form a salt such as, for example, an acetic acid salt, a propionic acid salt, a hexanoic acid salt, a cyclopentanepropionic acid salt, a glycolic acid salt, a pyruvic acid salt, a lactic acid salt, a malonic acid salt, a succinic acid salt, a malic acid salt, a maleic acid salt, a fumaric acid salt, a trifluoroacetic acid salt, a tartaric acid salt, a citric acid salt, a benzoic acid salt, a 3-(4-hydroxybenzoyl)benzoic acid salt, a cinnamic acid salt, a mandelic acid salt, a methanesulfonic acid salt, an ethanesulfonic acid salt, a 1,2-ethanedisulfonic acid salt, a 2-hydroxyethanesulfonic acid salt, a benzenesulfonic acid salt, a toluenesulfonic acid salt, a 2- naphthalenesulfonic acid salt, a 4-methylbicyclo-[2.2.2]oct-2-ene-lcarboxylic acid salt, a glucoheptonic acid salt, a 4,4' -methylenebis-(3-hydroxy-2-ene-l-carboxylic acid) salt, a 3- phenylpropionic acid salt, a trimethylacetic acid salt, a tertiary butylacetic acid salt, a lauryl sulfuric acid salt, a gluconic acid salt, a glutamic acid salt, a hydroxynaphthoic acid salt, a salicylic acid salt, a stearic acid salt, a muconic acid salt, a butyric acid salt, a phenylacetic acid salt, a phenylbutyric acid salt, a valproic acid salt, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. a lithium salt, a sodium salt, or a potassium salt), an alkaline earth ion (e.g. a magnesium salt, or a calcium salt), or an aluminum ion (e.g. an aluminum salt). In some cases, compounds described herein may coordinate with an organic base to form a salt, such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a tromethamine salt, a N-methylglucamine salt, a dicyclohexylamine salt, or a tris(hydroxymethyl)methylamine salt. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, an arginine salt, a lysine salt, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.    It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary. Certain Terminology / Chemical Definitions 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. An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. The "alkyl" group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as "l to 6" refers to each integer in the given range; e.g., "l to 6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). In one aspect the alkyl is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, hexyl, and the like. In some embodiments, 1 or more hydrogen atoms of an alkyl are replaced with 1 or more deuterium atoms.    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. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)z-, - CH2CH2-, -CH2CH2CH2- and the like. The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is Hor an alkyl. Non-limiting examples of an alkenyl group include - CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. Non- limiting examples of an alkynyl group include -C=CH, -C=CCH3-C=CCH2CH3, -CH2C=CH. An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein. The term "alkylamine" refers to the -N(alkyl)xHy group, where x and y are selected from the group x= 1, y= 1 and x=2, y=0. The term "aromatic" refers to a planar ring having a delocalized n-electron system containing 4n+ 27t electrons, where n is an integer. Aromatics are optionally substituted. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused- ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term "carbocyclic" or "carbocycle" refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon. As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups are optionally substituted. In one aspect, an aryl is a phenyl or a naphthalenyl. In one aspect, an aryl is a phenyl. In one aspect, an aryl is a C6-C10aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). In some embodiments, 1 or more hydrogen atoms of an aryl are replaced with 1 or more deuterium atoms.    The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group, such as, but not limited to, cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentan-1,1-diyl, cyclohexan-1,1-diyl, cyclohexan-1,4-diyl, cycloheptan-1,1-diyl, and the like). In one aspect, a cycloalkyl is a CrC6cycloalkyl. The term "halo" or, alternatively, "halogen" or "halide" means fluoro (F), chloro (Cl), bromo (Br) or iodo (I). In some embodiments, halogen is For Cl. In some embodiments, halogen is F. The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is a C1-C6fluoroalkyl. In some embodiments, a fluoroalkyl is a monofluoroalkyl, wherein one hydrogen atom of the alkyl is replaced by a fluorine atom. In some embodiments, a fluoroalkyl is a difluoroalkyl, wherein two hydrogen atoms of the alkyl are replaced by a fluorine atom. In some embodiments, a fluoroalkyl is a trifluoroalkyl, wherein three hydrogen atom of the alkyl are replaced by a fluorine atom. In some embodiments, a fluoroalkyl is a monofluoroalkyl, difluoroalkyl, or trifluoroalkyl. In some embodiments, a monofluoroalkyl is -CH2F, -CHF2, -CF3, -CHFCH3, -CH2CH2F, -CH2CHF2, -CH2CF3, - CH2CH2CF3, -CH2CH2CH2CF3, -CHCH3CF3, -CH(CF3)2, or -CF(CH3)2. The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4heteroalkyl. In some embodiments, a heteroalkyl is an alkyl group in which one or more skeletal atoms of the alkyl is oxygen (e.g. a hydroxyalkyl or an alkoxyalkyl). The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to    four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from 0, Sand N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl. An example of a 4-membered heterocyclic group is azetidinyl. An example of a 5- membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non- aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3. l .0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3- yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles may her substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include the following moieties:    and thelike, Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazany. In some embodiments, a heteroaryl contains 0-3 N atoms in the ring. In some embodiments, a heteroaryl contains 1-3 N atoms in the ring, In some embodiments, a heteroaryl contains 0-3 N atoms, 0-10 atoms, and 0-1 S atoms in the ring, In some embodiments, a heteroaryl is a monocyclic or bicyclic heteroaryl. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group). A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group wherein at least one of the carbon atoms of the cycloalkyl is replaced with nitrogen (unsubstituted or substituted, e.g., -NH-, -NR23-), oxygen (-O-), or sulfur (e.g., -S-, -S(=O)- or -S(=O)2-). The radicals may be fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalky. In another aspect, a heterocycloalkyl is a C4- C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-20 atoms and 0-1 S atoms in the ring.    The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups. The term "moiety" refers to a specific segment or functional group of a molecule, Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), - N(CH3)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) includes oxo (=O). In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds, as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein    exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form. The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. Synthesis of Compounds The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Assays With the aid of the assays described herein a high-throughput assay to test compounds that increase hemoglobin-oxygen binding affinity is provided. Hemoglobin changes its spectral absorbance upon binding oxygen. This property will be used to develop a plate reader-based assay where human red blood cells are incubated with test compounds + / - an oxygen scavenger (e.g., sodium dithionite or equivalent). This will be followed by reading the absorbance across all visible wavelengths to measure oxygenated vs deoxygenated hemoglobin levels. The ratio of oxygenated to deoxygenated hemoglobin will change in the presence of compounds that change oxygen binding affinity. A compound library, such as the Diversity Core library (TargetMol), will allow for screening of thousands of compounds, such as initial screen of 100,000 compounds. They will be used to train a deep-learning model that performs in silico drug screening for ~10 million drug- like compounds for predicted efficacy, safety, bioavailability, and synthesizability. This will be followed by in silico and in vitro validation. Administration Recently, targeted therapies have become a viable strategy for specific cancers. However, resistant tumors rapidly emerge. In contrast, broad spectrum modalities (chemotherapies, radiation, immuno-oncology) are more generally effective and durable. It is believed that systemic hypoxia, which pits the body’s metabolism against that of the tumor, will similarly constitute a substantial leap forward in cancer treatment.    Centuries of work have focused on how low oxygen within a tumor leads to resistance against certain chemotherapies and radiation. What is proposed herein constitutes a paradigm shift. Otto Warburg first proposed the idea of “starving the tumor” of nutrients to treat cancer. This led to decades of work attempting to limit nutrients through interventions like calorie restriction, intermittent fasting and cold exposure. While these approaches have shown preclinical efficacy, they are completely impractical for patient compliance. In contrast, the strategy employed herein is a well-tolerated condition (equivalent to living at high altitude), coupled with a practical delivery (e.g., “HypoxyPill”). As civilizations have lived at high altitude for millennia, there is an abundance of safety and efficacy data, including: (i) tolerated hypoxia doses, (ii) the speed of “ascent to altitude” that facilitates organismal adaptation, (iii) the potential side effects and (iv) devices to measure target engagement (the pulse oximeter). Inhaled hypoxia can be administered through many different mechanisms, for example, there are devices to make any room hypoxic that are commercially available, people often use mobile gas tanks and nasal cannula for supplemental oxygen administration; this would be a similar set-up but using hypoxic gas mixtures instead of hyperoxic gas mixtures. Another form would be the use small-molecule left-shifters (e.g., HypoxyPill (an example of one), GBT-440).   Compounds can be developed that increase the binding affinity of hemoglobin for oxygen, thereby resulting in less oxygen offloading to tissues, resulting in organismal hypoxia. This is one of the first examples of converting a gas therapy to an oral drug. The methods described herein include the use of pharmaceutical compositions comprising an active ingredient described herein. Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of    microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.    For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Patent No. 6,468,798. Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. Therapeutic compounds that are or include nucleic acids can be administered by any method suitable for administration of nucleic acid agents, such as a DNA vaccine. These methods include gene guns, bio injectors, and skin patches as well as needle-free methods such as the micro- particle DNA vaccine technology disclosed in U.S. Patent No. 6,194,389, and the mammalian transdermal needle-free vaccination with powder-form vaccine as disclosed in U.S. Patent No. 6,168,587. Additionally, intranasal delivery is possible, as described in, inter alia, Hamajima et al, Clin. Immunol. Immunopathol., 88(2), 205-10 (1998). Liposomes (e.g., as described in U.S. Patent No.6,472,375) and microencapsulation can also be used. Biodegradable targetable microparticle delivery systems can also be used (e.g., as described in U.S. Patent No.6,471,996). In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No.4,522,811.    The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. Bibliography WO2020 / 0146758 US2019 / 0015377 WO 2017 / 218960 Each of the above three listed applications are herein incorporated by reference in their entirety, especially for the compounds and method of making the same as disclosed therein. Various embodiments of the invention are described above in the Detailed Description. While these descriptions directly describe the above embodiments, it is understood that those skilled in the art may conceive modifications and / or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall within the purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s). The foregoing description of various embodiments of the invention known to the applicant at this time of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limit the invention to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed for carrying out the invention. While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true scope of this invention. It will be understood by those within    the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

Claims

WHAT IS CLAIMED IS:

1. A method to treat cancer comprising administering to subject in need thereof a small molecule to induce systemic hypoxia, hypoxic air / exposure to a hypoxic environment, gene therapy to promote expression of fetal hemoglobin (HbF) or a combination thereof.

2. The method of claim 1, wherein the small molecule increases the binding affinity of hemoglobin (Hb) for oxygen.

3. The method of claim 1, wherein the small molecule induces anemia.

4. The method of claim 2, wherein the small molecule comprises an allosteric effector of Hb (AEH) that left shifts Hb.

5. The method of claim 4, wherein the AEH is selected from the group consisting of hydroxyurea, GBT440, HypoxyPill, substituted benzaldehydes, Tucaresol, aliphatic isothiocyanates, aromatic aldehydes or combination thereof.

6. The method of claim 1, wherein the small molecule is a compound of any one of Formula I, Ia-Ic, II, IIa-IIC, II’, III, IIIa-IIIb, IV, V, Va, VI, VIa-VIb, VII, VIIa-VIIc or a combination thereof.

7. The method of claim 1, wherein the gene therapy comprises administration of autologous hematopoietic stem cells treated ex vivo to reduce expression of BCL11A.

8. The method of claim 7, wherein the autologous hematopoietic stem cells are treated ex vivo using a CRISPR RNA-guided nuclease or base editor or with an inhibitory nucleic acid that targets and reduces expression of BCL11A.

9. The method of claim 3, where anemia inducement comprises bloodletting or administration of an inhibitor of hypoxia inducible factor (HIF), HIF-2a and / or HIF-1a.

10. The method of claim 1, wherein the small molecule is an inhibitor of hypoxia inducible factor (HIF), HIF1, HIF2, HIF-2a and / or HIF-1a.

11. The method of claim 9 or 10, wherein the inhibitor of HIF-2a is one or more of PT2399, PT2977, PT2385, PT2567, 163, 226, or 231.

12. The method of claim 9 or 10, wherein the inhibitor is a compound of any one of Formula VIII, VIII-A-VIII-K, IX or a combination thereof.

13. The method of claim 9 or 10, wherein the inhibitor of HIF comprises one or more of adaptauin, TAT-cyclo-CLLFVY (SEQ ID NO: 1), Dimethyloxallyl Glycine (DMOG), Echniomycin, FM19G11, GN 44028, KC7F2, LW 6, PX12, TC-S 7009, VH 032 or VH 298.

14. The method of claim 1, wherein the hypoxic environment comprises about 5% O2 to about 21% O2, about 10% O2to about 15% O2, about 10% O2to about 12% O2, including about 8% O2, about 11% O2or about 15% O2.

15. The method of claim 14, wherein the inhaled oxygen tension is at least about 5%.

16. The method of claim 14 or 15, wherein the inhaled oxygen tension is about 5 to about 21%.

17. The method of claim 1, wherein the hypoxic air comprises carbon monoxide (CO).

18. The method of claim 1, wherein the small molecule comprises a carbon monoxide- releasing molecule (CORM).

19. The method of claim 1, wherein the small molecule isor a combination thereof.

20. The method of any one of claims 1 to 19, further comprising an additional anti-cancer treatment, such as chemotherapy, radiology or immunotherapy.

21. The method of any one of claims 1 to 20, wherein the cancer comprises lung cancer, adenocarcinoma, adenocarcinoma of the lung, squamous carcinoma, squamous carcinoma of the lung, malignant mixed mullerian tumor, bladder cancer, head and / or neck cancer, breast cancer, esophageal cancer, mouth cancer, tongue cancer, gum cancer, skin cancer (e.g., melanoma, basal cell carcinoma, Kaposi's sarcoma, etc.), muscle cancer, heart cancer, liver cancer, bronchial cancer, cartilage cancer, bone cancer, stomach cancer, prostate cancer, testicular cancer, ovarian cancer; cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, colon cancer, colorectal, gastric cancer, kidney cancer, bladder cancer, lymphoma cancer, spleen cancer, thymus cancer, thyroid cancer, brain cancer, neuronal cancer, mesothelioma, gall bladder cancer, ocular cancer (e.g., cancer of the cornea, cancer of uvea, cancer of the choroids, cancer of the macula, vitreous humor cancer, etc.), joint cancer (such as synovium cancer), glioblastoma, neuroblastoma, white blood cell cancer (e.g., lymphoma, leukemia, etc.), hereditary non-polyposis cancer (HNPC), and / or colitis-associated cancer.

22. The method of any one of claims claim 1 to 21, wherein the growth / proliferation of the cancer is inhibited.

23. The method of any one of claims 1 to 22, wherein the volume of the cancer is reduced.

24. The method of any one of claims 1 to 23, wherein the spread of metastases is inhibited.

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