WO2005065074A2

WO2005065074A2 - Protection of tissues and cells from cytotoxic effects of ionizing radiation by abl inhibitors

Info

Publication number: WO2005065074A2
Application number: PCT/US2004/028654
Authority: WO
Inventors: E Premkumar Reddy; M. V. Ramana Reddy; Stephen C. Cosenza; Kiranmai Gumireddy
Original assignee: Temple Univ School of Medicine
Current assignee: Temple Univ School of Medicine
Priority date: 2003-09-09
Filing date: 2004-09-02
Publication date: 2005-07-21
Anticipated expiration: 2006-03-09
Also published as: WO2005065074A3

Abstract

Pre-treatment with one or more compounds of formula (I), as described herein, protects normal cells from the toxic side effects of ionizing radiation. Administration of one or more radioprotective compounds of formula I to a patient prior to anticancer radiotherapy reduces the cytotoxic side effects of the radiation on normal cells. The radioprotective effect of one or more compounds of formula I allows for the safe increase the dosage of anticancer radiation. Amelioration of toxicity following inadvertent radiation exposure may also be mitigated with administration of one or more compounds of formula (I).

Description

Protection of Tissues and Cells from Cytotoxic Effects of Ionizing Radiation by ABL Inhibitors Cross-Reference to Related Application This application claims the benefit of copending U.S. Provisional Application Serial No. 60/501,783, filed September 9, 2003, the entire disclosure of which is incorporated herein by reference. Field ofthe Invention The invention relates to the field of protecting normal cells and tissues from anticipated, planned or inadvertent exposure to ionizing radiation. In particular, the invention relates to radioprotective agents administered to an individual prior to or after exposure to ionizing radiation, such as occurs during anticancer radiotherapy.

Background ofthe Invention Ionizing radiation has an adverse effect on cells and tissues, primarily through cytotoxic effects. In humans, exposure to ionizing radiation occurs primarily through therapeutic techniques (such as anticancer radiotherapy) or through occupational and environmental exposure.

Sources and Effects of Ionizing Radiation A major source of exposure to ionizing radiation is the administration of therapeutic radiation in the treatment of cancer or other proliferative disorders. Individuals exposed to therapeutic doses of ionizing radiation typically receive between 0.1 and 2 Gy per treatment, and can receive as high as 5 Gy per treatment. Depending on the course of treatment prescribed by the treating physician, multiple doses may be received by an individual over the course of several weeks to several months. Therapeutic radiation is generally applied to a defined area of the individual's body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic ionizing radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment. There are also some treatments that require exposure ofthe individual's entire body to the radiation, in a procedure called "total body irradiation", or "TBI." The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors. Numerous methods have been designed to reduce normal tissue damage while still delivering effective therapeutic doses of ionizing radiation. These techniques include brachytherapy, fractionated and hyperfractionated dosing, complicated dose scheduling and delivery systems, and high voltage therapy with a linear accelerator. However, such techniques only attempt to strike a balance between the therapeutic and undesirable effects ofthe radiation, and full efficacy has not been achieved. For example, one treatment for individuals with metastatic tumors involves harvesting their hematopoietic stem cells and then treating the individual with high doses of ionizing radiation. This treatment is designed to destroy the individual's tumor cells, but has the side effect of also destroying their normal hematopoietic cells. Thus, a portion of the individual's bone marrow (containing the hematopoietic stem cells) is removed prior to radiation therapy. Once the individual has been treated, the autologous hematopoietic stem cells are returned to their body. However, if tumor cells have metastasized away from the tumor's primary site, there is a high probability that some tumor cells will contaminate the harvested hematopoietic cell population. The harvested hematopoietic cell population may also contain neoplastic cells if the individual suffers from cancers ofthe bone marrow such as the various French- American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia (ALL). Thus, the metastasized tumor cells or resident neoplastic cells must be removed or killed prior to reintroducing the stem cells to the individual. If any living tumorigenic or neoplastic cells are re-introduced into the individual, they can lead to a relapse. Prior art methods of removing tumorigenic or neoplastic cells from harvested bone marrow are based on a whole-population tumor cell separation or killing strategy, which typically does not kill or remove all of the contaminating malignant cells. Such methods include leukopheresis of mobilized peripheral blood cells, immunoaffinity-based selection or killing of tumor cells, or the use of cytotoxic or photosensitizing agents to selectively kill tumor cells. In the best case, the malignant cell burden may still be at 1 to 10 tumor cells for every 100,000 cells present in the initial harvest (Lazarus et al, J. Hematotherapy, 2(4):457-66, 1993). Thus, there is needed a purging method designed to selectively destroy the malignant cells present in the bone marrow, while preserving the normal hematopoietic stem cells needed for hematopoietic reconstitution in the transplantation subject. Exposure to ionizing radiation can also occur in the occupational setting. Occupational doses of ionizing radiation may be received by persons whose job involves exposure (or potential exposure) to radiation, for example in the nuclear power and nuclear weapons industries. There are currently 104 nuclear power plants licensed for commercial operation in the United States. Internationally, a total of 430 nuclear power plants are operating in 32 countries. All personnel employed in these nuclear power plants may be exposed to ionizing radiation in the course of their assigned duties. Incidents such as the March 28, 1979 accident at Three Mile Island nuclear power plant, which released radioactive material into the reactor containment building and surrounding environment, illustrate the potential for harmful exposure. Even in the absence of catastrophic events, workers in the nuclear power industry are subject to higher levels of radiation than the general public. Military personnel stationed on vessels powered by nuclear reactors, or soldiers required to operate in areas contaminated by radioactive fallout, risk similar exposure to ionizing radiation. Occupational exposure may also occur in rescue and emergency personnel called in to deal with catastrophic events involving a nuclear reactor or radioactive material. For example, the men who fought the April 26, 1986 reactor fire at the Chernobyl nuclear power plant suffered radiation exposure, and many died from the radiation effects. In August 2000, navy and civilian rescue personnel risked exposure to radiation when attempting to rescue the crew of the downed Russian nuclear-powered submarine Kursk. Salvage crews may still face radiation exposure if the submarine's reactor plant was damaged. Other sources of occupational exposure may be from machine parts, plastics, and solvents left over from the manufacture of radioactive medical products, smoke alarms, emergency signs, and other consumer goods. Occupational exposure may also occur in persons who serve on nuclear powered vessels, particularly those who tend the nuclear reactors, in military personnel operating in areas contaminated by nuclear weapons fallout, and in emergency personnel who deal with nuclear accidents. Humans and other animals (such as livestock) may also be exposed to ionizing radiation from the environment. The primary source of exposure to significant amounts of environmental radiation is from nuclear power plant accidents, such as those at Three Mile Island, Chernobyl and Tokaimura. A 1982 study by Sandia National Laboratories estimated that a "worst-case" nuclear accident could result in a death toll of more than 100,000 and long-term radioactive contamination of large areas of land. For example, the estimated number of deaths from the Chernobyl accident is from 8,000 to 300,000, and in the Ukraine alone, over 4.6 million hectares of land was contaminated with varying levels of radiation. Fallout was detected as far away as Ireland, northern Scandinavia, and coastal Alaska in the first weeks after the accident. 135,000 people were evacuated from a 30-mile radius "dead zone" around the Chernobyl plant, an area that is still not fit for human habitation. Approximately 1.2 million people continue to live in areas of low-level radiation outside the "dead-zone." Other nuclear power plant accidents have released significant amounts of radiation into the environment. The Three Mile Island accident was discussed above. In Japan, a cracked pipe leaked 51 tons of coolant water from the Tsuruga 2 nuclear plant in July of 1999. A more serious accident occurred on September 30, 1999 at a uranium reprocessing facility in Tokaimura, Japan, where 69 people received significant radiation exposure. The accident occurred when workers inadvertently started a self-sustaining nuclear chain reaction, causing a release of radiation into the atmosphere. A radiation count of 0.84 mSv/hour (4000 times the annual limit) was detected in the immediate area. Thirty-nine households (150 people) were evacuated and 200 meter radius around the site was declared off-limits. The roads within a 3 kilometer radius of the site were closed and residents within 10 kilometer radius of the site were advised to stay indoors. The Tokaimura "criticaliry event" is ranked as the third most serious accident - behind Three Mile Island and Chernobyl - in the history ofthe nuclear power industry. Environmental exposure to ionizing radiation may also result from nuclear weapons detonations (either experimental or during wartime), discharges of actinides from nuclear waste storage and processing and reprocessing of nuclear fuel, and from naturally occurring radioactive materials such as radon gas or uranium. There is also increasing concern that the use of ordnance containing depleted uranium results in low-level radioactive contamination of combat areas. Radiation exposure from any source can be classified as acute (a single large exposure) or chronic (a series of small low- level, or continuous low-level exposures spread over time). Radiation sickness generally results from an acute exposure of a sufficient dose, and presents with a characteristic set of symptoms that appear in an orderly fashion, including hair loss, weakness, vomiting, diarrhea, skin burns and bleeding from the gastrointestinal tract and mucous membranes. Genetic defects, sterility and cancers (particularly bone marrow cancer) often develop over time. Chronic exposure is usually associated with delayed medical problems such as cancer and premature aging. An acute total body exposure of 125,000 millirem may cause radiation sickness. Localized doses such as are used in radiotherapy may not cause radiation sickness, but may result in the damage or death of exposed normal cells. For example, an acute total body radiation dose of 100,000 - 125,000 millirem (equivalent to 1 Gy) received in less than one week would result in observable physiologic effects such as skin burns or rashes, mucosal and GI bleeding, nausea, diarrhea and/or excessive fatigue. Longer term cytotoxic and genetic effects such as hematopoietic and immunocompetent cell destruction, hair loss (alopecia), gastrointestinal, and oral mucosal sloughing, venoocclusive disease of the liver and chronic vascular hyperplasia of cerebral vessels, cataracts, pneumonites, skin changes, and an increased incidence of cancer may also manifest over time. Acute doses of less than 10,000 millirem (equivalent to 0.1 Gy) typically will not result in immediately observable biologic or physiologic effects, although long term cytotoxic or genetic effects may occur. A sufficiently large acute dose of ionizing radiation, for example

500,000 to over 1 million millirem (equivalent to 5 - 10 Gy) may kill an individual immediately. Doses in the hundreds of thousands of millirems may kill within 7 to 21 days from a condition called "acute radiation poisoning." Reportedly, some of the Chernobyl firefighters died of acute radiation poisoning, having received acute doses in the range of 200,000 - 600,000 millirem (equivalent to 2 - 6 Gy). Acute doses below approximately 200,000 millirem do not result in death, but the exposed individual will likely suffer long-term cytotoxic or genetic effects as discussed above. Acute occupational exposures usually occur in nuclear power plant workers exposed to accidental releases of radiation, or in fire and , rescue personnel who respond to catastrophic events involving nuclear reactors or other sources of radioactive material. Suggested limits for acute . occupational exposures in emergency operations were developed by the Brookhaven National Laboratories, and are given in Table 1. For radiation doses listed in column 1 of Table 1, 100,000 millirem equals one sievert (Sv). For penetrating radiation such as gamma radiation, one Sv equals approximately one Gray (Gy). Thus, the dosage in Gy can be estimated as 1 Gy for every 100,000 millirem.

Table 1:

A chronic dose is a low level (i.e., 100 - 5000 millirem) incremental or continuous radiation dose received over time. Examples of chronic doses include a whole body dose of approximately 5000 millirem per year, which is the dose typically received by an adult working at a nuclear power plant. By contrast, the Atomic Energy Commission recommends that members of the general public should not receive more than 100 millirem per year. Chronic doses may cause long-term cytotoxic and genetic effects, for example manifesting as an increased risk of a radiation-induced cancer developing later in life. Recommended limits for chronic exposure to ionizing radiation are given in Table 2.

Table 2:

By way of comparison, Table 3 sets forth the radiation doses from common sources.

Table 3:

Chronic doses of greater than 5000 millirem per year (0.05 Gy per year) may result in long-term cytotoxic or genetic effects similar to those described for persons receiving acute doses. Some adverse cytotoxic or genetic effects may also occur at chronic doses of significantly less than 5000 millirem per year. For radiation protection purposes, it is assumed that any dose above zero can increase the risk of radiation-induced cancer (i.e., that there is no threshold). Epidemiological studies have found that the estimated lifetime risk of dying from cancer is greater by about 0.04% per rem of radiation dose to the whole body. While anti-radiation suits or other personal protective equipment (PPE) may be effective at reducing radiation exposure, such specialized PPE is expensive, unwieldy, and generally not available to public. Moreover, radioprotective PPE will not protect normal tissue adjacent a tumor from stray radiation exposure during radiotherapy. What is needed, therefore, is a practical way to protect individuals who are scheduled to incur, or are at risk for incurring, exposure to ionizing radiation. In the context of therapeutic irradiation, it is desirable to enhance protection of normal cells while causing tumor cells to remain vulnerable to the detrimental effects of the radiation. Furthermore, it is desirable to provide systemic protection from anticipated or inadvertent total body irradiation, such as may occur with occupational or environmental exposures, or with certain therapeutic techniques. Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear. However, previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful. For example, cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al, Semin. Radial Oncol. 6:306-320, 1996), but do not confer systemic protection. Other chemical radioprotectors administered alone or in combination with biologic response modifiers have shown minor protective effects in mice, but application of these compounds to large mammals was less successful, and it was questioned whether chemical radioprotection was of any value (Maisin, J.R., Bacq and Alexander Award Lecture. "Chemical radioprotection: past, present, and future prospects," Int. J. Radiat. Biol. 73:443- 50, 1998). Pharmaceutical radiation sensitizers, which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for the general systemic protection of normal tissues from exposure to ionizing radiation.

ABL protein Kinase Protein kinases in general are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The phosphorylation serves as a basis for cellular signaling that regulates such fundamental cellular functions such as cellular growth, differentiation and proliferation. Accordingly, disorders associated with abnormal protein kinase activity have included many cancers and other proliferative disorders. Protein kinases are divided into tyrosine kinases and serine-threonine kinases. The protein tyrosine kinases are further classified as receptor tyrosine kinases and non-receptor tyrosine kinases, which are also called cellular tyrosine kinases (CTK's). Receptor tyrosine kinases include epithelial growth factor receptors (EGFR), insulin-like growth factor receptors (IGFR), platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR) and vascular endothelial growth factor receptors (VEGF). Non-receptor tyrosine kinases include Abelson (ABL) tyrosine kinase as well as ten other subfamilies of CTK's. ABL is a tyrosine kinase expressed by the c-abl proto-oncogene. Cloning ofthe c-abl gene has revealed that it spans at least 230kb, and contains at least 11 exons. Two alternative first exons exist, namely exon la and exon lb, which are spliced to the common splice acceptor site, exon 2. Exon la is 19 kb proximal to exon 2. Exon lb, which is somewhat smaller than exon la, is more than 200 kb proximal to exon 2. As a result of this configuration, at least two major c-abl messages are transcribed, differing in their 5' regions. See, Shtivelman et al, Cell 47, 277 (1986); Bernards et al, Mol. Cell. Biol. 7, 3231 (1987); and Fainstein et al, Oncogene 4, 1477-1481 (1989), the entire disclosures of which are incorporated herein by reference. If exon lb is used, the mRNA is 7.0 kb. If exon la is used, the mRNA is 6.0 kb. Each of exons la and lb are preceded by a transcriptional promotor. The 6-kb c-abl transcript consists of exons la through 11. The 7-kb transcript begins with exon lb, skips the 200 kb distance to exon 2, omits exon la, and joins to exons 2 through 11. Thus, both c-abl messages share a common set of 3' exons, starting from the c-abl exon 2. Consequently, the messages code for two proteins that share most of their amino acid sequence, except for the N- termini. Since the coding begins with the first exon, exonic selection will determine the protein product. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease caused by malignant transformation of stem cells as a result of fusion of the c-abl gene to the bcr gene. See, Calabretta et al, US patent 5,652,222, the entire disclosure of which is incorporated herein by reference. At the molecular level, the most notable feature of CML is the translocation ofthe proto-oncogene c-abl from the long arm of chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22, resulting in the formation of bcr-abl hybrid genes. The break occurs near the end of the long arm of chromosome 9 (band 9q34) and in the upper half of chromosome 22 (band 22ql 1). The 9;22 translocation in CML results in the abnormal juxtaposition of abl sequences adjacent to bcr sequences. The c-abl proto-oncogene is expressed in normal cells and plays a critical role in regulating normal hematopoiesis by encoding a protein with tyrosine kinase activity. This activity is augmented in cells carrying bcr-abl hybrid genes. The gene located at the breakpoint on chromosome 22 is called bcr because the break in chromosome 22 in CML occurs in a small 5.8-kilobase (kb) segment (breakpoint cluster region) ofthe gene on chromosome 22. The fusion of the BCR gene with c-abl leads to an 8.5 kb chimeric mRNA consisting of 5' BCR sequences and 3' abl sequences. The chimeric message is in turn translated into a larger chimeric abl protein (210 kDa) that has increased tyrosine kinase activity See, Konopka et al, Cell 37, 1035 (1984); Kloetzer et al, Virology 140, 230 (1985); Konopka et al, Proc. Natl. Acad. Sci. U.S.A. 82, 1810 (1985), the entire disclosures of which are incorporated herein by reference. The 210 kDa protein is considerably larger than the normal human protein of 145 kDa, and has a very high tyrosine kinase activity. Recently, the drig N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methylphenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide has been shown to selectively inhibit ABL activity and to be useful in the treatment of chronic myelogenous leukemia (CML). See Fabbro et al, Current Opinion in Drug Discovery & Development, 2002, Vol. 5, No. 5, page 701-712, the entire disclosure of which is incorporated herein by reference. Zimmerman et al. discloses a structure activity relationship (SAR) of a group of 2- anilinopyrimidine compounds (including N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylphenyl)-4-((4-methylpiperazin- l-yl)methyl)benzamide for ABL inhibition. See, Zimmerman; Bioorg. & Med. Chem. Lett., Vol. 7, Νo.2, pages 187-192, 1997, the entire disclosure of which is incorporated herein by reference. Several experimental compounds have also been shown to selectively inhibit ABL activity, e.g., Warmuth et al. Blood, Vol. 101, No. 2, January 15, 2003) (disclosing pyrrolopyrimidine compounds); Wisniewski et al, Cancer Research, Vol. 62, pages 4244-4255, August 1, 2002 (disclosing pyridopyrimidine compounds); Boschelli et al, US Patent 6,521,618 (disclosing 4-anilino-3-quinolinecarbonitriles); Gibson et al, WO 96/33980 (disclosing quinazoline compounds that demonstrate an SAR parallel to the 4-anilino-3- quinolinecarbonitriles against receptor tyrosine kinases); Kaur et al, Anticancer Drugs, 1994, Vol. 5, pages 213-222 (disclosing tyrphostin compounds); and Battastini et al, WO 97/46551 (disclosing indoline-2-ones). The entire disclosures ofthe above references are incorporated herein by reference. Antioxidant Compounds Oxidants are produced as part of the normal metabolism of all cells but also are an important component ofthe pathogenesis of many disease processes. Reactive oxygen species (ROS), for example, contribute to the pathogenesis of diseases of the lung, the central nervous system (CNS) and skeletal muscle. Oxygen free radicals also modulate the effects of nitric oxide, thereby contributing to the pathogenesis of vascular disorders, inflammatory diseases and the aging process. Free radicals are molecules with one or more unpaired electrons. Free radicals act as oxidants, rapidly reacting with other molecules, and starting oxidative chain reactions. Free radicals are a normal product of metabolism. However, ionizing radiation can significantly increase the number of free radicals in the body. Certain antioxidant compounds have been shown to have cytoprotective properties. Antioxidants are believed to act by scavenging free radicals. Normal cell and organ function is maintained via a balance of oxidant and antioxidant agents. Many antioxidant compounds, e.g., the enzyme superoxide dismutases (SODs) are produced physiologically and balance the naturally occurring free radicals. Several other important antioxidant enzymes are known to exist within cells, including catalase and glutathione peroxidase. While extracellular fluids and the extracellular matrix contain only small amounts of these enzymes, other extracellular antioxidants are also known to be present, including radical scavengers and inhibitors of lipid peroxidation, such as ascorbic acid, uric acid, and α-tocopherol.

Summary ofthe Invention We have now found that inhibitors of ABL, in particular small molecule inhibitors, provide significant and selective systemic protection of normal cells and normal tissues from radiation-induced damage in individuals exposed to ionizing radiation. It is an object of the invention to provide compositions and methods for protecting the normal cells and tissues from the cytotoxic and genetic effects of exposure to ionizing radiation, in individuals who have incurred or are at risk of incurring exposure to ionizing radiation. The exposure to ionizing radiation may occur in controlled doses during the treatment of cancer and other proliferative disorders, or may occur in uncontrolled doses beyond the norm accepted for the population at large during high risk activities or environmental exposures.

Radioprotection by Compounds of Formula I A method for protecting an individual from cytotoxic side effects of ionizing radiation is provided, comprising administering to said individual an effective amount of at least one compound of formula I:

wherein: L is selected from the group consisting of O, S, and N-R¹; R¹ is -H or -(Cι-C₇)hydrocarbyl, preferably -H or -(Cι-Ce)alkyl, more preferably -H or -(C]-C₃)alkyl, most preferably -H; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, preferably -(Cι-C6)alkyl and -(C₃-C₇)cycloalkyl; -CO₂H; -CO₂(Cι-C₁₂)hydrocarbyl, preferably -CO₂(C₃-Cι₂)cycloalkyl and -CO₂(Cι-C₆)alkyl; -CONH₂; -C(=O)NH(C₂-C₆)alkylene-NH₂, preferably -C(=O)NH(C₂-C₄)alkylene-NH₂; -O(Cι-C₇)hydrocarbyl, preferably -O(Cι-C₆)alkyl; -NH(C₁-C₇)hydrocarbyl, preferably -NH(C C₆)alkyl; -C(=O)(C₁-C₇)hydrocarbyl, preferably -C(=O)(C₁-C₆)alkyl and -C(=O)benzyl; -S(O)_d(C₁-C₇)hydrocarbyl, preferably -S(O)_d(C₁-C₆)alkyl and S(O)abenzyl; halogen, preferably chloro, fluoro and bromo; -(Cι-C₆)alkylene-OH, preferably -(Cι-C₄)alkylene-OH; substituted and unsubstituted aryl, preferably substituted and unsubstituted phenyl, more preferably substituted phenyl; substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; heterocyclyl(Cι-C₆)alkylene, preferably monocyclic heterocyclyl(Cι- Ce)alkylene; and heteroaryl(Cι-C₆)alkylene, preferably monocyclic heteroaryl(C ι -Cβ)alky lene; a and b are independently selected from the group consisting of 0, 1 and 2; preferably 0 and 1; d is 0, 1 or 2; preferably 0 or 2; each R³ is independently selected from the group consisting of -OH, -NH₂, -NO₂,

halogen, and a radical of formula (i)

wherein R is a divalent radical selected from the group consisting of formula (ii), (iii), (iv) and (v):

(ii) (iii) (iv) (V) wherein: h is 1 or 2; preferably 2; each R⁷ is independently selected from the group consisting of -H and (Cι-C6)alkyl, preferably -H and (C_!-C₃)alkyl, most preferably -H and methyl; R⁵ is O orN(R⁷); Y is (Cι-Cδ)alkylene; e and g are independently selected from the group consisting of 0 and 1; f is 0 or 1, provided that f is 0 when R³ is formula (ii) or (v); R⁶ is selected from the group consisting of -H;

-(C]-C )hydrocarbyl; substituted and unsubstituted aryl, preferably substituted and unsubstituted phenyl, more preferably substituted phenyl; and substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted heteroaryl; A is a radical selected from the group consisting of formula (vi),

(vii), (viii), and (ix):

wherein: R⁸ is selected from the group consisting of substituted or unsubstituted aryl, preferably substituted and unsubstituted phenyl, more preferably substituted phenyl; -(Cι-C6)alkylene-NH-(Cι-C6)alkyl, preferably -(C₂-C )alkylene-NH-(Cι-C₃)alkyl; (d-C₆)C(=O)NH(Cι- C₆)alkyl, preferably (Cι-C₆)C(=O)NH(C₂-C₄)alkyl; and substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted heteroaryl, more preferably substituted and unsubstituted pyridyl, pyrazinyl, pyrrolyl, indolyl, and imidazolyl; each R⁹ is independently selected from the group consisting of halogen, preferably chlorine, fluorine and bromine; and -(Cι-C₆)alkyl, preferably -(Cι-C₄)alkyl, most preferably methyl; i is 0, 1 or 2, preferably 0 or 1; U is selected from the group consisting of N(H), N(Cι-Cealkyl),

S, arylene and heteroarylene; V is (C₂-C₆)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted heterocyclyl(C₂-C₆)alkylene-NH-, -NH(C₂- C₆)alkylene-N(C₁-C₆alkyl)₂, -NH(C₂-C₆)alkylene-O(Cι-C₆alkyl) and -N(Cι-C₆alkyl)₂; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R^u is -(Cι-C₇)hydrocarbyl or -(C₂-Cι₂)heteroalkyl; R¹² is selected from the group consisting of unsubstituted and substituted aryl, preferably unsubstituted and substituted phenyl; and unsubstituted and substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -(Cι-C₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)_j(C₁-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided: when X is N, R¹⁰ is bonded to the 7-position of the quinazoline ring system and -U-V-W is bonded to the 6-position of the quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position ofthe quinoline ring system and -U-V-W is bonded to the 7-position of the quinoline ring system. Quinazoline and quinoline ring systems are numbered as follows: 5 4 5 _d

quinoline quinazoline According to the invention, substituents on substituted aryl, heterocyclyl or heteroaryl groups are preferably independently selected from the group consisting of -(Cι-C₆)alkyl, -(d-C₆)alkoxy, halogen, -C(=O)(Cι-C₆)alkyl, -NH₂, -NH(Cι-C₆)alkyl, -N(C₁-C₆)alkyl)₂, -NHC(=O)(C_rC₆)alkyl, -NO₂, -CN, (C,- C₆)haloalkyl, -(C,-C₆)alkylene-NH₂, -CO₂H, CONH₂, C(=N)NH₂, and heterocyclyl(Cι-Cδ)alkyl; wherein heterocyclyl rings comprising heterocyclyl(Cι-C6)alkyl are optionally substituted by -(Cι-C₆)alkyl or C(=O)(Cι-C₆)alkyl. Substituents on substituted aryl, heterocyclyl or heteroaryl groups are more preferably independently selected from the group consisting of -(Ci- C₃)alkyl, -(C C₃)alkoxy, chlorine, fluorine, acetyl, -NH₂, -NHCH₃, -N(CH₃)₂, -NHC(=O)CH₃, -NO₂, -CN, -CF₃, tetrafluoroethoxy, -(Cι-C₆)alkyleneNH₂, -CO₂H, CONH₂, C(=N)NH₂, piperazinyl(Cι-C₆)alkyl, piperidinyl(C₁-C₆)alkyl, pyrrolyl(C ₁ -C_δ)alkyl, homopiperidinyl(C C6)alkyl, homopiperazinyl(C ₁ - Cδ)alkyl, morpholinyl(Cι-C₆)alkyl, and thiomorpholinyl(Cι-C6)alkyl; wherein heterocyclyl alkyl groups are optionally substituted on the heterocyclic ring by -(d-C₆)alkyl or -C(=O)(C₁-C₆)alkyl. Substituents on substituted aryl, heterocyclyl or heteroaryl groups are most preferably independently selected from the group consisting of -(Cι-C₃)alkyl, methoxy, chlorine, fluorine, acetyl, -NH₂, -NHCH₃, -N(CH₃)₂, -NHC(=0)CH₃, -NO₂, -CN, -CF₃, tetrafluoroethoxy, -(C₁-C₆)alkyleneNH₂, -CO₂H, 4-methylpiperazin- 1 -yl(C ₁ -Cβ)alkyl, 4-methylpiperidin- 1 -yl(C ₁- C₆)alkyl, 3-methylpyrrol-l-yl(Cι-C6)alkyl, 4-methylhomopiperidin-l-yl(Cι- C_δ)alkyl, 4-methylhomopiperazin-l-yl(Cι-C₆)alkyl, morpholin-l-yl(Cι-C₆)alkyl, and thiomorpholin- 1 -yl(C 1 -C6)alkyl. According to a second embodiment of the invention, there is provided a method for protecting an individual from cytotoxic side effects of ionizing radiation, comprising administering to said individual an effective amount of a combination comprising at least one compound of formula I, as defined above, and at least one radioprotective α,β-unsaturated aryl or heteroaryl sulfone, sulfoxide, sulfonamide or carboxamide. According to a third embodiment of the invention, there is provided a method for protecting an individual from cytotoxic side effects of ionizing radiation, comprising administering to said individual an effective amount of a combination comprising at least one compound of formula I, as defined above, and at least one antioxidant compound. Preferred embodiments of radioprotective compounds of formula I are described as follows. First Embodiment of Formula I Compounds According to a First Embodiment of the radioprotective compounds of formula I: L isN-R^!; and each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, preferably -(Cι-Cβ)alkyl, more preferably, -(Ci- C )alkyl, most preferably -CH₃; and -(C₃-C₇)cycloalkyl. According to one preferred sub-embodiment the radioprotective compound comprises a compound of formula 1(a):

wherein: R² is -(Cι-C₇)hydrocarbyl, preferably -(d-C₆)alkyl, more • preferably, -(Cι-C₄)alkyl, most preferably -CH₃; or -(C₃-C₇)cycloalkyl; a is 0 or 1; b is l; R³ is a radical of formula (i):

wherein: R⁴ is a divalant radical of formula (iii):

e is l; R⁸ is selected from the group consisting of substituted and unsubstituted aryl, preferably substituted and unsubstituted phenyl, more preferably substituted phenyl; -(d-C₆)alkylene-NH-(Cι-C₆)alkyl, preferably -(C₂-C4)alkylene-NH-(Cι-C₃)alkyl; (Cι-C₆)(C=0)NH(Cι- C₆)alkyl, preferably (Cι-C₆)(C=O)NH(C₂-C₄)alkyl; and substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted heteroaryl, more preferably substituted and unsubstituted pyridyl, pyrazinyl, pyrrolyl, indolyl, and imidazolyl; each R⁹ is independently selected from the group consisting of halogen, preferably chlorine, fluorine and bromine; and -(Cι-C₆)alkyl, preferably -(C)-C )alkyl, most preferably methyl; i is 0, 1 or 2, preferably 0 or 1; and R⁵, R⁶, Y, f and g are as defined above for formula I.

Preferably in formula 1(a): f and g are 0; R⁶ is substituted aryl, preferably substituted phenyl; R⁷ is -H; R⁸ is substituted or unsubstituted heteroaryl, preferably substituted and unsubstituted pyridyl, pyrazinyl, pyrrolyl, indolyl, and imidazolyl, more preferably unsubstituted pyridyl, pyrazinyl, pyrrolyl, indolyl, and imidazolyl; most preferably unsubstituted pyridyl; and i is 0; or a pharmaceutically acceptable salt of such a compound.

The substituents on substituted aryl R⁶ are preferably independently selected from the group consisting of heterocyclyl(Ci-Ce)alkyl, optionally substituted on the heterocycle by -(d-C₆)alkyl or C(=O)(C₁-C₆)alkyl. Substituents on substituted aryl R⁶ are more preferably independently selected from the group consisting of piperazinyl(Cι-C₆)alkyl, piperidinyl(Cj- C_δ)alkyl, pyrrolyl(Cι-C6)alkyl, homopiperidinyl(Cι-C₆)alkyl, homopiperazinyl(Cι-C6)alkyl, morpholinyl(Cι-C₆)alkyl, and thiomorpholinyl(Cι-C6)alkyl, each optionally substituted on the heterocycle by -(Cι-C₆)alkyl or C(=O)(d-C₆)alkyl. Substituents on substituted aryl R⁶ are most preferably independently selected from the group consisting of 4-methylpiperazin-l-yl(C₁-C₆)alkyl,

4-methylpiperidin-l-yl(Cι-C₆)alkyl, 3-methylpyrrol-l-yl(d-C₆)alkyl,

4-methylhomopiperidin- 1 -yl(C ι -C6)alkyl, 4-methylhomopiperazin- 1 -yl(C i- C₆)alkyl, morpholin-l-yl(Cι-C6)alkyl, and thiomorpholin-l-yl(C₁-C₆)alkyl.

Preferred compounds of formula 1(a) include for example: N-(3-(4- (pyridin-3 -yl)pyrimidin-2-y lamino)-4-methylphenyl)-4-((4-methylpiperazin- 1 - yl)methyl)benzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4- ((4-methylpiperazin-l-yl)methyl)benzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)phenyl)nicotinamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methylphenyl)-4-methylbenzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)phenyl)hexanamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methylphenyl)-2-naphthamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)- phenyl)-4-fluorobenzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)- phenyl)thiophene-2-carboxamide; N-(4-( 1 , 1 ,2,2-tetrafluoroethoxy)phenyl)-4-( 1 - (3-aminopropyl)- 1 H-indol-4-yl)pyrimidin-2-amine; N-(4-( 1 , 1 ,2,2-tetrafluoro- ethoxy)phenyl)-4-(lH-indol-3-yl)pyrimidin-2-amine; N-(3-(4-(pyridin-3-yl)- pyrimidin-2-ylamino)phenyl)benzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylphenyl)benzamide; 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)- N-(3-aminopropyl)benzamide; Ν-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)- phenyl)cyclohexanecarboxamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)- phenyl)isonicotinamide; Nl-(4-(pyridin-4-yl)pyrimidin-2-yl)benzene-l,3- diamine; Nl-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-l,3-diamine; N-(3-(4- (pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-2-methoxybenzamide; N- (3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-chlorobenzamide; N-(3-(2-(lH-imidazol-l-yl)ethoxy)phenyl)-4-(pyridin-3-yl)pyrimidin-2-amine; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-methylbenzamide; N-(3- nitrophenyl)-4-(pyridin-2-yl)pyrimidin-2-amine; N-(3-(4-(pyridin-3-yl)- pyrimidin-2-ylamino)phenyl)-4-cyanobenzamide; Nl-(5-methyl-4-(pyridin-3- yl)pyrimidin-2-yl)benzene-l,3-diamine; N-(3-chlorophenyl)-4-(pyridin-3-yl)- pyrimidin-2-amine; N-phenyl-4-(pyridin-3-yl)ρyrimidin-2-amine; N-(3-(4- (pyridin-3 -yl)pyrimidin-2-ylamino)phenyl)-2-methoxybenzamide; 2-(3 -(4-

(pyridin-3 -yl)pyrimidin-2-ylamino)phenylcarbamoyl)benzoic acid; N-(3-( 1 H- imidazol- 1 -yl)phenyl)-4-(pyridin-3 -yl)pyrimidin-2-amine; N-(3 -(4-(pyridin-3 - yl)pyrimidin-2-ylamino)phenyl)picolinamide; methyl 3-(4-(pyridin-3-yl)- pyrimidin-2-ylamino)benzoate; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methylphenyl)proρionamide; and pharmaceutically acceptable salts thereof. More preferred compounds of formula 1(a) include for example N-(3-(4- (pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-l- yl)methyl)benzamido; and pharmaceutically acceptable salts thereof.

Second Embodiment of Formula I Compounds According to a Second Embodiment of the radioprotective compounds of formula I: L is ΝR¹; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, preferably -(d-C6)alkyl and -(C₃-C₇)cycloalkyl; -O(Cι-C₇)hydrocarbyl, preferably -O(C₁-Cδ)alkyl, more preferably -OCH₃ and -OC₂H₅; -S(O)_d(Cι-C₇)hydrocarbyl, preferably -S(O)_d(Cι- Cβ)alkyl, more preferably -S(O)_d(Cι-C )alkyl, most preferably -S(O)_dCH₃; halogen, preferably chloro, fluoro and bromo, more preferably chloro and fluoro, most preferably fluoro; -(Cι-Cβ)alkylene- OH, preferably -(Cι-C₄)alkylene-OH, more preferably -CH₂OH; and substituted and unsubstituted heterocyclyl, preferably monocyclic heterocyclyl, more preferably non-aromatic monocyclic heterocyclyl; d is 0, 1 or 2, preferably 0 or 2, most preferably 0; each R³ is independently selected from the group consisting of -OH, -ΝH₂, -NO₂, -(Cι-Cβ)haloalkoxy, and halogen; and A is a radical of formula (viii):

wherein: R¹¹ and R¹² are defined as above for formula I. According to one sub-embodiment, the radioprotective compound comprises a compound of formula 1(b):

wherein: a is 1 or 2; b is O or 1; R^u is -(Cι-C₇)hydrocarbyl, preferably -(d-C₆)alkyl, more preferably -(Cι-C )alkyl, most preferably -CH₃; and R¹² is selected from the group consisting of substituted or unsubstituted aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl, most preferably di-substituted phenyl; and substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted monocyclic heteroaryl. Substituents on R¹² are preferably independently selected from the group consisting of -(Ci-d alkyl, -(Cι-Ce)alkoxy, halogen, -C(=O)(Cι-C6)alkyl, -NH2, -NH(d-C₆)alkyl, -N(d-C₆)alkyl)₂, -NHC(=O)(d-C₆)alkyl, -NO₂, -CN, (Cι-C₆)haloalkyl, -(d-C₆)alkyleneNH₂, -CO₂H, -CONH₂, and -C(=NH)NH₂. Substituents on R¹² are more preferably independently selected from the group consisting of -(Cι-C )alkyl, -(Cι-C₃)alkoxy, bromine, chlorine, fluorine, acetyl, -NH₂₎ -NHCH₃, -N(CH₃)₂, -NHC(=O)CH₃, -NO₂, -CN, -CF₃, tetrafluoroethoxy, -(d-C₆)alkylene-NH₂, -CO₂H, -CONH₂, and -C(=NH)NH₂. Substituents on R¹² are most preferably independently selected from the group consisting of bromine, chlorine, and fluorine. Preferred compounds of formula 1(b) include for example: 6-(2,6- dichlorophenyl)-2-[(4-fluoro-3-methylphenyl)amino]-8-methyl-8-hydro- pyridino[2,3-d]pyrimidιn-7-one; 6-(2,6-dichlorophenyl)-8-methyl-2-[(3-methyl- thiophenyl)amino]-8-hydropyridino[2,3-d]pyrimidin-7-one; 6-(2,6-dichloro- phenyl)-2- { [3 -(hydroxymethyl)pheύyl] amino} -8-methyl-8-hydropyridino [2,3 - d]pyrimidin-7-one; 6-(2,6-dichlorophenyl)-2-[(4-ethoxyphenyl)amino]-8- methyl-8-hydropyridino-[2,3-d]pyrimidin-7-one; 6-(2,6-dichlorophenyl)-2-[(4- fluorophenyl)amino]-8-methyl-8-hydropyridinophenyl)-8-methyl-2-[(4- morpholin-4-ylphenyl)amino]-8-hydropyridino[2,3-d]-pyrimidin-7-one; and pharmaceutically acceptable salts thereof.

Third Embodiment of Formula I Compounds According to a Third Embodiment of radioprotective compounds of formula I: L is NR¹; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, preferably -(Ci-Q alkyl and -(C₃-C₇)cycloalkyl; -O(Cι-C₇)hydrocarbyl, preferably -O(d-C6)alkyl; halogen, preferably bromo, chloro and fluoro; substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; heterocyclyl(d-C6)alkylene, and heteroaryl(Cι-C6)alkylene; a is 0, 1 or 2; R³ is selected from the group consisting of -NH₂, -NO₂, -(Ci- Ce)haloalkoxy, and halogen; b is 0 or 1; A is a radical of formula (vii):

wherein: X is C-CN; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl, preferably -O(Cι-C₆)alkyl, more preferably -O(C₁-C₄)alkyl, most preferably -OCH₃; U is selected from the group consisting of N(H); N(Cι-C₆alkyl); O; S; arylene, preferably phenylene, more preferably 1,4-phenylene; and heteroarylene; V is (Cι-C₆)alkylene, preferably (C₂-C₄)alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl, more preferably substituted and unsubstituted monocyclic non-aromatic heterocyclyl, most preferably substituted monocyclic non-aromatic heterocyclyl; substituted and unsubstituted -NH(Cι-C₆)alkylenylheterocyclyl; and -NH(C₂-C₆)alkylene-N(d-C₆ alkyl)₂. According to one sub-embodiment, the radioprotective compound comprises a compound of formula 1(c):

wherein: U is selected from the group consisting of O; S; arylene, preferably phenylene, more preferably 1,4-phenylene; and heteroarylene; V is (Cι-C_δ)alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, preferably monocyclic heterocyclyl, more preferably non-aromatic monocyclic heterocyclyl; substituted and unsubstituted -NH(Cι-Cδ)alkylenylheterocyclyl; and -NH(C₂- C₆)alkylene-N(d-C₆ alkyl)2. Substituents on heterocyclyl W are preferably -(Ci- C₇)hydrocarbyl, more preferably -(Cι-Cδ)alkyl, most preferably -CH₃.

Preferably in formula 1(c): U is O; V is -CH₂CH₂CH₂-; and W is 4- methylpiperazin-1-yl.

According to a sub-embodiment of formula 1(c): each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, preferably -(Cι-Cδ)alkyl and -(C₃-C₇)cycloalkyl; -O(d-C₇)hydrocarbyl, preferably -O(Ci-Ce)alkyl; and halogen, preferably bromo, chloro and fluoro; a and b are independently selected from the group consisting of 1 and 2; and each R³ is independently selected from the group consisting of -NH₂, -NO₂, -(Cι-C₆)haloalkoxy, and halogen. A preferred compound of formula 1(c) is 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazinyl)- proρoxy]quinoline-3-carbonitrile; and pharmaceutically acceptable salts thereof.

Fourth Embodiment of Formula I Compounds According to a Fourth Embodiment of radioprotective compounds of Formula I: L is selected from the group consisting of O, S and N-R¹; R' is -H; each R² is independently selected from the group consisting of -(C₁-C₇)hydrocarbyl, preferably -(Cι-C_δ)alkyl and -(C₃-C₇)cycloalkyl; -CO₂H; -CO₂(Cι-Cι₂)hydrocarbyl, preferably -CO₂(C₃-C₁₂)cycloalkyl and -CO₂(d-C₆)alkyl; -CONH₂; -C(=O)NH(C₂-C₆)alkylene-NH₂, preferably -C(=O)NH(C₂-C₄)alkylene-NH₂; -C(=O)(Cι-C₇)hydrocarbyl, preferably -C(=O)(C₁-C₆)alkyl and -C(=O)benzyl; -S(O)_d(Cι- C₇)hydrocarbyl, preferably -S(O)_d(Cι-Cβ)alkyl and S(O)_dbenzyl; halogen, preferably chloro, fluoro and bromo; -(d-C_δ)alkylene-QH, preferably -(Cι-C₄)alkylene-OH; and substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; a is 1 or 2; A is a radical of formula (ix):

wherein: each R¹³ is independently selected from the group consisting of -OH, -(Cι-Cδ)alkyl, -O(d-C₆)alkyl, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)_j(d-C₆)alkyl; j is 0, 1 or 2; and k is 1, 2 or 3.

According to one sub-embodiment, the radioprotective compound comprises a compound of formula 1(d):

wherein: R² is selected from the group consisting of -CO₂H, -CONH₂, -CO₂(Cι-C₆)alkyl, -CO₂(C₃-Cι₂)cycloalkyl, and substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; a is 1; and b is O.

Preferred compounds according to formula 1(d) include: methyl 4- {[(2,5-dihydroxyphenyl)methyl]amino}benzoate; 3-{[(2,5-dihydroxyphenyl)- methyl]amino}benzoic acid; 2-[(2,5-dihydroxyphenyl)methylthio]benzoic acid; 2-{[(2,5-dihydroxyphenyl)methyl]amino}benzamide; 2-{[(2,5-dihydroxy- phenyl)methyl] amino} benzoic acid; 4-{[(2,5-dihydroxyphenyl)methyl]- amino}benzamide; methyl 2-{[(2,5-dihydroxyphenyl)methyl]amino}benzoate; and pharmaceutically acceptable salts thereof.

Fifth Embodiment of Formula I Compounds According to a Fifth Embodiment of radioprotective compounds of formula I: L is R¹; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, preferably -(Cι-C_δ)alkyl and -(C₃-C₇)cycloalkyl; -O(Ci-C₇)hydrocarbyl, preferably -O(Cι-C_δ)alkyl; halogen, preferably bromo, chloro and fluoro; substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; heterocyclyl(Cι-C_δ)alkylene, and heteroaryl(C]-C_δ)alkylene; a is 1 or 2; b is 0; A is a radical of formula (vii):

X is N; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl, preferably -O(d-C₆)alkyl, more preferably -O(Cι-C₄)alkyl, most preferably -OCH₃; U is selected from the group consisting of N(H); N -Cβalkyl), preferably N(CH₃); O; S; arylene, preferably phenylene, more preferably 1,4-phenylene;. and heteroarylene; V is (Cι-Cδ)alkylene, preferably (C₂-C₄)alkylene; W is substituted or unsubstituted heterocyclyl, preferably- substituted or unsubstituted monocyclic heterocyclyl, more preferably substituted or unsubstituted monocyclic non-aromatic heterocyclyl, most preferably substituted monocyclic non-aromatic heterocyclyl; substituted and unsubstituted -NH(Cι-Cδ)alkylenylheterocyclyl; and -NH(C₂- C₆)alkylene-N(Ci-C₆ alkyl),. According to a preferred sub-embodiment, the radioprotective compound comprises a compound of formula 1(e):

wherein: U is selected from the group consisting of O; S; arylene, preferably phenylene, more preferably 1,4-phenylene; and heteroarylene; V is (Cι-C_δ)alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted -NH(d- C₆)alkylenylheterocyclyl, and -NH(C₂-C6)alkylene-N(Ci-C6alkyl)₂. Substituents on heterocyclyl W are preferably -(Cι-C₇)hydrocarbyl, more preferably -(Cι-C_δ)alkyl, most preferably -CH₃. Preferred compounds according to formula 1(e) include (3-chloro-4- fluorophenyl)[7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amine; and pharmaceutically acceptable salts thereof. According to some embodiments of the invention, the radioprotective compound or combination of compounds is administered before exposure to the ionizing radiation. According to some embodiments of the invention, the radioprotective compound or combination of compounds is administered after exposure to ionizing radiation. According to one embodiment of the invention, a method for protecting an individual from cytotoxic side effects of ionizing radiation is provided comprising administering to the individual an effective amount of at least one compound of formula I, and an effective amount of at least one compound of formula II:

wherein: Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably substituted or unsubstituted phenyl; more preferably substituted phenyl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below:

(0 (ii)

(iii) (iv) wherein: n is one or zero, preferably one; and R^x is -H, -(Cι-C₈)hydrocarbyl or -C(=O)(d-C₈)hydrocarbyl; or a pharmaceutically acceptable salt thereof. According to some preferred embodiments of compounds according to formula II, Q¹ is phenyl. According to other preferred embodiments of compounds according to formula II, Q² is phenyl. Accordmg to still other preferred embodiments of compounds according to formula II, both Q¹ and Q² are phenyl. According to one sub-embodiment of the compounds according to formula II, X is selected from the group consisting of (i), (ii) and (iii). According to another sub-embodiment of the compounds according to formula II, X is selected from the group consisting of (i) and (ii). According to yet another sub-embodiment of the compounds according to formula II, X is (i). According to some embodiments of compounds according to formula II, the aryl and heteroaryl groups comprising Q¹ and Q² are mono-, di- or tri- substituted. According to other embodiments of compounds according to formula II, the aryl and heteroaryl groups comprising Q¹ and Q² are substituted at all substitutable positions. Substituents for substituted aryl and heteroaryl groups comprising Q¹ and Q² are preferably independently selected from the group consisting of halogen, -R^x -NR^X ₂, -NHC(=O)R^y, -NHSO₂R^y, -NH(d-C₄)alkylene-CO₂R^x, -CO₂R^x, -C(=O)NHR^x, -NO₂, -CN, -OR^x, phosphonato, dimethylamino(C₂-C₆ alkoxy), -NHC(=NH)NHR^X, -(d-C₆)haloalkyl, -(Cι-C₆)haloalkoxy, -(C=O)(d- C₄)alkylene-NR^X ₂ and -NH-CH(R^z)-CO₂R^x, -(C=O)CH(R^z)-NR^x ₂; wherein: R^y is selected from -H, -(Cι-C₈)hydrocarbyl, -O(Cι- C₈)hydrocarbyl, substituted phenyl, substituted heterocyclyl(Cι-C₃)alkyl, heteroaryl(Cι-C₃)alkyl, -(C₂-Cιo)heteroalkyl, -(Cι-C₆)haloalkyl, -NHC(R^Z)NHR^X, -NHR^X, -(d-C₃)alkyleneNH₂, -(C_r C₃)alkyleneN(CH₃)₂, -(Cι-C₃)perfluoroalkyleneN(CH₃)2, -(d- C₃)alkyleneN⁺(Cι-C₃)₃, -(Ci-C₃)alkylene-N⁺(CH₂CH₂OH)₃, -(d- C₃)alkylene-OR', -(Cι-C )alkylene-CO₂R¹, -(Cι-C₄)alkylene- C(=O)halogen, and -(Cι-C₄)perfluoroalkylene-Cθ2R¹; and Substituents on substituted phenyl R^y are preferably selected from the group consisting of -NH₂, -NO₂, N-methylpiperazinyl, and -OR^x. R^z is selected from the group consisting of -H, -(Cι-C_δ)alkyl,

-(CH₂)₃-ΝH-C(ΝH₂)(=ΝH), -CH₂C(=O)NH₂, -CH₂COOH, -CH₂SH,

-(CH₂)₂C(=O)-NH₂, -<CH₂)2COOH, -CH₂-(2-imidazolyl), -(CH₂)₄-NH₂, -(CH₂)₂-S-CH₃, phenyl, substituted phenyl, -CH₂-ρhenyl, -CH₂-OH, -CH(OH)-

CH₃, -CH₂-(3-indolyl), and -CH₂-(4-hydroxyphenyl). Substituted phenyl R^z is preferably mono- di- or tri-substituted, more preferably mono or di substituted, most preferably mono-substituted by substituents independently selected from the group consisting of -R^x, -NR^x ₂, -NO₂, -OR^x, -CN, -CO₂R^x, halogen, -SR^X and SO₂R^x. Substituents on substituted phenyl R^z are more preferably independently selected from the group consisting of -(Cι-Cδ)alkyl, -NH₂, NH(d-Cδ)alkyl, -NO₂, -O(d-C₆)alkyl, -OH, -CN, -CO₂(Cι-C₆)alkyl, CO₂H, , halogen, -S(d- C₆)alkyl, -SH, and SO₂(C₁-C₆)alkyl. Substituents on substituted phenyl R^z are most preferably independently selected from the group consisting of methyl, ethyl, -NH₂, NHCH₃, -NO₂, -OCH₃, -OH, -CN, -CO₂CH3, CO2Et, CO₂H, , halogen, -SCH₃, -SH, and SO₂CH₃. Substituents on substituted heterocyclyl(d-C_δ)alkyl R^y are preferably selected from -(Cι-C₇)hyrocarbyl, preferably -(Ci-C₆)alkyl; -C(=O)d-C₆)alkyl, preferably -C(=O)Cι-C₃)alkyl, most preferably acetyl; and -(d- C_δ)perfluoroalkyl, preferably -(Cι-C₃)perfluoroalkyl, most preferably -CF₃. Substituents for substituted aryl and heteroaryl groups comprising Q¹ and Q² are more preferably independently selected from the group consisting of halogen, -R^x -NR^X ₂, -NHC(=0)R^y, -NHSO₂R^y, -NH(C,-C₄)alkylene-CO₂R^x, -CO₂R^x, -C(=O)NHR^x, -NO₂, -CN, -OR^x, phosphonato, dimethylamino(C₂-C₆ alkoxy), -NHC(=NH)NHR^X, -(Cι-C₆)haloalkyl and -(d-C₆)haloalkoxy. Substituents for substituted aryl and heteroaryl groups comprising Q¹ and Q² are most preferably independently selected from the group consisting of halogen, -NR^X ₂, -NHC(=0)R^y, -NHSO₂R^y, -NH(d-C₄)alkylene-CO₂R^x,

-CO₂(Cι-C₈)hydrocarbyl, -C(=O)NHR^x, -NO₂, -CN, -OH, -OCH₃ and phosphonato. R^x is preferably selected from the group consisting of-H, -(Cι-C_δ)alkyl, benzyl, -C(=O)(Cι-C₆)alkyl and-C(=O)benzyl. R^x is more preferably selected from the group consisting of -H, -(Ci- C₆)alkyl, and-C(=O)(Cι-C₆)alkyl. R^x is most preferably -H or -(Cι-C₆)alkyl. R^y is preferably selected from -H, -(d-C^hydrocarbyl, -O(Cι- C₈)hydrocarbyl, substituted phenyl, -NHR^X, -(d-C₆)haloalkyl, -(Ci- C₃)alkyleneNH₂, -(Cι-C₃)alkyleneN(CH₃)₂, -(Cι-C₃)alkylene-OR¹, -(Ci- C₄)alkylene-CO₂R¹, and -(Ci-C^perfluoroalkylene-CO∑R¹. R^y is more preferably selected from -H, -(Cι-C₈)hydrocarbyl, -O(Cι-

C₈)hydrocarbyl, substituted phenyl, -(Cι-Cδ)perfluoroalkyl, -NHR , -(Ci- C₃)alkyleneNH₂, -(d-C₃)alkyleneN(CH₃)₂, -(Cι-C₃)alkylene-O(C,-

C₈)hydrocarbyl, -(Ci-C₄)alkylene-CO2(Ci-Cs)hydrocarbyl and -(Ci-

C₄)perfluoroalkylene-CO₂(C ₁ -C8)hydrocarbyl. R^z is' preferably selected from the group consisting of-H, -(Cι-C₆)alkyl, and phenyl. Preferred compounds according to formula II include, for example: 4-

((l£)-2-{[(4-fluorophenyl)methyl]sulfonyl}vinyl)benzoic acid; 4-((l£)-2-{[(4- iodophenyl)methyl] sulfonyl} vinyl)benzoic acid; 4-(( lE)-2- { [(4-chlorophenyl)- methyl]sulfonyl} vinyl)benzoic acid; l-[5-((\E)-2-{ [(4-chlorophenyl)methyl]- sulfonyl}vinyl)-2-fluorophenyl]-2-(dimethylamino)ethan-l-one; (\E)-2-(2,4- difluoropheny 1)- 1 - { [(4-bromophenyl)methyl] sulfonyl} ethene; ( 1 E)-2-(3 -amino- 4-fluorophenyl)-l-{[(4-chlorophenyl)methyl]sulfonyl}ethene; 2-(5-(((E)-2,4,6- trimethoxystyrylsulfonyl)methyl)-2-methoxyρhenylamino)-acetic acid; (R)-2-(5- (((R)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)- propanoic acid; (S)-2-(5-(((£ -2,4,6-trimethoxystyrylsulfonyl)methyl)-2- methoxyphenylamino)-propanoic acid; racemic-2-(5-(((JS)-2,4,6-trimethoxy- styrylsulfonyl)methyl)-2-methoxyphenyl-amino)propanoic acid; (R)-2-(5-(((E)- 2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)-2-phenylacetic acid; (S)-2-(5-(((i5)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl- amino)-2-phenylacetic acid; racemic-2-(5-((( )-2,4,6-trimethoxystyryl- sulfonyl)methy l)-2-methoxyphenyl-amino)-2-pheny lacetic acid; N-(3 -(((£)- 2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl)-4-(4-methyl- piperazin- 1 -yl)benzamide; 2-((-5)-2-(4-methoxybenzylsulfonyl)vinyl)- 1,3,5- trimethoxybenzene; l-(((£)-4-chlorostyrylsulfonyl)methyl)-2-chloro-4- fluorobenzene; 4-((-5)-2-(4-chlorobenzylsulfonyl)vinyl)- l-fluoro-2-nitro- benzene; 4-((£)-2-(3-amino-4-methoxybenzylsulfonyl)vinyl)benzoic acid; 5 - (((-5)-2,4-difluorostyrylsulfonyl)methyl)-2-methoxybenzenamine; l-bromo-4- (((j5)-perfluorostyrylsulfonyl)methyl)benzene; l-(((£)-2,^,5,6-tetrafluorostyryl- sulfonyl)methyl)-4-bromobenzene; l-(((ii)-2,4,5-frifluorostyrylsulfonyl)- methyl)-4-bromobenzene; 1 -(((^)-2,4,6-trifluorostyrylsulfonyl)methyl)-4- bromobenzene; l-(((£)-2,3,6-trifluorostyrylsulfonyl)methyl)-4-bromobenzene; 5-(((-5)-2,4-difluorostyrylsulfonyl)methyl)-2-bromobenzenamine; 4-(((E)-2,4- difluorostyrylsulfonyl)methyl)benzoic acid; 5-(((j5)-2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-bromobenzenamine; 4-((-5)-2-(4-bromobenzylsulfonyl)- vinyl)- 1 -fluoro-2-nitrobenzene; 4-((E)-2-(4-chloro-2-nitrobenzylsulfonyl)vinyl)- l-fluoro-2-nitrobenzene; 5-((-5)-2-(4-bromobenzylsulfonyl)vinyl)-2-fluoro- benzenamine; 5-((R)-2-(4-iodobenzylsulfonyl)vinyl)-2-fluorobenzenamine; 5- (((-5)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzonitrile; 4-(((E)- 2,4,6-trimethoxystyrylsulfonyl)methyl)benzoic acid; 3-((E)-2-(4-bromobenzyl- sulfonyl)vinyl)-2,6-difluorophenol; and salts thereof. More preferred compounds according to formula II include, for example: 4-((lR)-2-{[(4-fluorophenyl)methyl]sulfonyl}vinyl)benzoic acid; 4-((lE)-2- { [(4-iodoρhenyl)methyl]sulfonyl} vinyl)benzoic acid; 4-((lE)-2- { [(4-chloro- phenyl)-methyl]sulfonyl}vinyl)benzoic acid; l-[5-((lR)-2-{[(4-chlorophenyl)- methy 1] -sulfonyl } vinyl)-2-fluorophenyl] -2-(dimethylamino)ethan- 1 -one; (IE)- 2-(2,4-difluorophenyl)- 1 - { [(4-bromophenyl)methyl] sulfonyl} ethene; ( lu 2-(3 - amino-4-fluorophenyl)- 1 - { [(4-chlorophenyl)methyl]sulfonyl} ethene; 1 -(((£)-4- chlorostyrylsulfonyl)methyl)-2-chloro-4-fluorobenzene;l-(((-5)-2,4,5-trifluoro- styrylsulfonyl)-methyr 4-bromobenzene; N-(3-(((£)-2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-methoxyphenyl)-4-(4-methyl-piperazin- 1 -yl)benzamide; 4- ((£T)-2-(3-amino-4-methoxybenzylsulfonyl)vinyl)benzoic acid; 5-(((E)-2,4- difluorostyrylsulfonyl)methyl)-2-methoxybenzenamine; l-(((E)-2,4,6-trifluoro- styry lsulfonyl)methy l)-4-bromobenzene; 1 -(((E)-2,3 ,6-trifluorostyry lsulfony 1)- methyl)-4-bromobenzene; 5-(((£)-2,4,6-trimethoxystyryl-sulfonyl)methyl)-2- bromobenzenamine; 5-((£)-2-(4-iodobenzylsulfonyl)vinyl)-2-fluoro- benzenamine; 5-(((-5)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxy- benzonitrile; 4-(((-5)-2,4,6-trimethoxystyrylsuhOnyl)methyl)benzoic acid; 3- ((£)-2-(4-bromobenzyl-sulfonyl)vinyl)-2,6-difluorophenol; (R)-2-(5-(((E)-2,4,6- trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)-propanoic acid; (S)- 2-(5-(((j^-2,4,6-ttimethoxystyιylsulfonyl)methyl)-2-methoxyphenylamino)- propanoic acid; racemic-2-(5-(((J_ -2,4,6-trimethoxy-styrylsulfonyl)methyl)-2- methoxyphenyl-amino)propanoic acid; (R)-2-(5-(((£)-2,4,6-trimethoxy- styrylsulfonyl)methyl)-2-methoxyphenylamino)-2-phenylacetic acid; (S)-2-(5- (((jB)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl-amino)-2- phenylacetic acid; racemic-2-(5-(((j5)-2,4,6-trimethoxystyryl-sulfonyl)methyl)- 2-methoxyphenyl-amino)-2-phenylacetic acid; 5-((2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-methoxy-N-methylbenzenamine and pharmaceutically acceptable salts thereo 1 According to another embodiment of the invention, a method for protecting an individual from cytotoxic side effects of ionizing radiation is provided comprising administering to the individual an effective amount of at least one compound of formula I, and an effective amount of at least one antioxidant compound. According to another embodiment of the invention, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable carrier, at least one compound according to formula I as defined above, and at least one compound according to formula II as defined above. According to another embodiment of the invention, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable carrier, at least one compound according to formula I as defined above, and at least one antioxidant compound. According to another embodiment of the invention, a method of treating an individual with a proliferative disorder is provided, comprising: (a) administering to the individual an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound; and (b) administering an effective amount of therapeutic ionizing radiation. According to one sub-embodiment of the method of the invention for treating a proliferative disorder, the proliferative disorder is cancer. According to another embodiment of the invention, a method of safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders is provided, comprising administering to the individual an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound. According to one sub-embodiment of the above method of safely increasing dosages of therapeutic ionizing radiation, the radioprotective compound or combination of compounds is administered prior to administration ofthe therapeutic ionizing radiation. According to a further sub-embodiment of the above method of safely increasing dosages of therapeutic ionizing radiation, the radioprotective compound or combination of compounds induces a temporary radioresistant phenotype in the normal tissue ofthe individual. According to another embodiment ofthe invention, a method is provided for treating an individual who has incurred, or is at risk for incurring, remediable radiation damage from exposure to ionizing radiation, comprising administering to the individual an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound The compound or compounds may be administered before or after incurring remediable radiation damage from exposure to ionizing radiation. According to another embodiment ofthe invention, a method is provided of reducing the number of malignant cells in bone marrow of an individual, comprising: (1) removing a portion ofthe individual's bone marrow; (2) administering to the removed bone marrow an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound; and (3) irradiating the bone marrow with an effective amount of ionizing radiation. The bone marrow is reimplanted into the individual. According to another sub-embodiment of the bone marrow treatment method, the individual receives therapeutic ionizing radiation prior to reimplantation ofthe bone marrow. According to another sub-embodiment ofthe bone marrow treatment, the individual receives therapeutic ionizing radiation prior to reimplantation of the bone marrow, and is administered a radioprotective compound or combination of compounds as defined above prior to receiving the therapeutic ionizing radiation. According to another embodiment of the invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, is used in the manufacture of a medicament for protecting an individual from cytotoxic side effects of ionizing radiation. According to another aspect of the invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound of formula II, are used in the manufacture of a medicament for protecting an individual from cytotoxic side effects of ionizing radiation. According to another aspect of the invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, and an antioxidant compound are used in the manufacture of a medicament for protecting an individual from cytotoxic side effects of ionizing radiation. According to one embodiment, the compounds are for administration before exposure to ionizing radiation. According to another embodiment, the compounds are for administration after exposure to ionizing radiation. According to another embodiment, the formula I compounds are for administration before or after administration of therapeutic ionizing radiation, for treatment of a proliferative disorder. According to yet another embodiment of the invention, the compounds, are for treating an individual who has incurred or is at risk of incurring remediable radiation damage from exposure to ionizing radiation. According to another embodiment of the invention, the compounds are used for the preparation of a medicament for treating bone marrow prior to irradiating the bone marrow with an effective amount of ionizing radiation. According to another embodiment of the invention, the compounds are used for the preparation of a medicament for safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders. Definitions The term "individual" includes human beings and non-human animals and, as used herein, refers to an organism which is scheduled to incur, is at risk of incurring, or has incurred, exposure to ionizing radiation. As used herein, "ionizing radiation" is radiation of sufficient energy that, when absorbed by cells and tissues, induces formation of reactive oxygen species and DNA damage. This type of radiation includes X-Rays, gamma rays, and particle bombardment (e.g., neutron beam, electron beam, protons, mesons and others), and is used for medical testing and treatment, scientific purposes, industrial testing, manufacturing and sterilization, weapons and weapons development, and many other uses. Radiation is typically measured in units of absorbed dose, such as the rad or gray (Gy), wherein 1 rad = 0.01 Gy, or in units of dose equivalence, such as the rem or sievert (Sv), wherein 1 rem = 0.01 Sv. The Sv is the Gy dosage multiplied by a factor that includes tissue damage done. For example, penetrating ionizing radiation (e.g., gamma and beta radiation) have a factor of about 1, so 1 Sv = ~1 Gy. Alpha rays have a factor of 20, so 1 Gy of alpha radiation = 20 Sv. By "effective amount of ionizing radiation" is meant an amount of ionizing radiation effective in killing, or in reducing the proliferation, of abnormally proliferating cells in an individual. As used with respect to bone marrow purging, "effective amount of ionizing radiation" means an amount of ionizing radiation effective in killing, or in reducing the proliferation, of malignant cells in a bone marrow sample removed from an individual. By "acute exposure to ionizing radiation" or "acute dose of ionizing radiation" is meant a dose of ionizing radiation absorbed by an individual in less than 24 hours. The acute dose may be localized, as in radiotherapy techniques, or may be absorbed by the individual's entire body. Acute doses are typically above 10,000 millirem (0.1 Gy), but may be lower. By "chronic exposure to ionizing radiation" or "chronic dose of ionizing radiation" is meant a dose of ionizing radiation absorbed by an individual over a period greater than 24 hours. The dose may be intermittent or continuous, and may be localized or absorbed by the individual's entire body. Chronic doses are typically less than 10,000 millirem (0.1 Gy), but may be higher. By "at risk of incurring exposure to ionizing radiation" is meant that an individual may intentionally, e.g., by scheduled radiotherapy sessions, or inadvertently be exposed to ionizing radiation in the future. Inadvertent exposure includes accidental or unplanned environmental or occupational exposure. By "small molecule" in meant a monomeric organic compound having a molecular weight of less than about 1000. By a "radioprotective α,β-unsaturated (aryl or heteroaryl) sulfone, sulfonamide or carboxamide" is meant a compound ofthe formula II:

Q¹ X — CH=CH— Q² II wherein, Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably substituted or unsubstituted phenyl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below:

(i) (ϋ)

(iii) (iv) wherein n is one or zero; and R^X is -H, -(Cι-C₈)hydrocarbyl or -C(=O)(Cι-C₈)hydrocarbyl; or a pharmaceutically acceptable salt thereof. By the term "antioxidant" is meant a pharmaceutically acceptable chemical compound that prevents or slows the breakdown of another substance by oxygen. Preferably, antioxidants useful in the methods of the present invention are small molecule organic compounds. By the expression "effective amount" in the context of an amount of radioprotective compound is meant an amount, alone, or in combination with either another radioprotective compound or an antioxidant compound, which is effective to reduce or eliminate the toxicity associated with radiation in normal cells ofthe individual. As used with respect to bone marrow purging, "effective amount" of a radioprotective compound means an amount of the compound effective to reduce or eliminate the toxicity associated with radiation in bone marrow removed from an individual. The term "alkyl", by itself or as part of another substituent means, unless otherwise stated, a straight, branched or cyclic chain saturated hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated in an expression such as (C_x-C_y)alkyl. The expression (C_x-C_y)alkyl wherein x < y, represents an alkyl chain containing a minimum of x carbon atoms and a maximum of y carbon atoms. Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclohexyl and cyclopropylmethyl. Preferred is (d-C₃)alkyl, particularly ethyl, methyl and isopropyl. The term "cycloalkyl" refers to alkyl groups that contain at least one cyclic structure. Examples include cyclohexyl, cyclopentyl, norbornyl, adamantyl and cyclopropylmethyl. Preferred is (C₃-Cι₂)cycloalkyl, particularly cyclopentyl, norbornyl, and adamantyl. The term "alkylene" refers to a divalent alkyl radical having the number of carbon atoms designated (i.e. (d-Cβ) means -CH₂-; -CH₂CH₂-; -CH2CH2CH2-; -CH₂CH₂CH₂CH₂-; -CH₂CH₂CH2CH₂CH2-; and -CH2CH2CH2CH2CH2CH2-, and also includes branched divalent structures such as, for example, -CH₂CH(CH₃)CH₂CH₂- and -CH(CH₃)CH(CH₃)-, and divalant cyclic structures such as, for example 1,3-cyclopentyl. The term "arylene", by itself or as part of another substituent means, unless otherwise stated, a divalent aryl radical. Preferred are divalent phenyl radicals, or "phenylene" groups, particularly 1 ,4-divalent phenyl radicals. The term "heteroarylene", by itself or as part of another substituent means, unless otherwise stated, a divalent heteroaryl radical. Preferred are five- or six-membered monocyclic heteroarylene. More preferred are heteroarylene moieties comprising divalent heteroaryl rings selected from the group consisting of pyridine, piperazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, thiazole, imidazole and oxazole, such as, for example 2,5-divalent pyrrole, thiophene, furan, thiazole, oxazole, and imidazole. The term "alkoxy" employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred are (Ci- C₆)alkoxy, particularly ethoxy and methoxy. The carbon chains in the alkyl and alkoxy groups which may occur in the compounds of the invention may be cyclic, straight or branched, with straight chain being preferred. The expression "(Cι-C_δ)alkyl" thus extends to alkyl groups containing one, two, three, four, five or six carbons. The expression "(C]-C_δ)alkoxy" thus extends to alkoxy groups containing one, two, three, four, five or six carbons. The term "hydrocarbyl" refers to any moiety comprising only hydrogen and carbon atoms. The term includes, for example, alkyl, alkenyi, alkynyl, aryl and benzyl groups. Preferred are (Cι-C₇)hydrocarbyl. More preferred are (Ci- Cβ)alkyl and (C₃-Ci2)cycloalkyl. The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH₂-CH₂-CH₃, -CH₂- CH₂CH₂-OH, -CH₂-CH₂-NH-CH₃, -CH₂-S-CH₂-CH₃, and -CH₂CH₂-S(=O)-CH₃. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH- OCH₃, or-CH₂-CH₂-S-S-CH₃. The terms "halo" or "halogen" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (4n + 2) delocalized π (pi) electrons). The term "aromatic" is intended to include not only ring systems containing only carbon ring atoms but also systems containing one or more non- carbon atoms as ring atoms. Systems containing one or more non-carbon atoms may be known as "heteroaryl" or "heteroaromatic" systems. The term "aromatic" thus is deemed to include "aryl" and "heteroaryl" ring systems. The term "aryl" employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl; anthracyl; and naphthyl which may be substituted or unsubstituted. The aforementioned listing of aryl moieties is intended to be representative, not limiting. The term "heterocycle" or "heterocyclyl" or "heterocyclic" by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, monocyclic or polycyclic heterocyclic ring system which consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a stable structure. Heterocyclyl groups are inclusive of monocyclic and polycyclic heteroaryl groups and monocyclic and polycyclic groups that are not aromatic, such as saturated and partially saturated and monocyclic and polycyclic partially saturated monocyclic and polycyclic groups. The term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character, and includes both monocyclic heteroaryl groups and polycyclic heteroaryl groups. A polycyclic heteroaryl group may include one or more rings which are partially saturated. Examples of monocyclic heteroaryl groups include: Pyridyl; pyrazinyl; pyrimidinyl, particularly 2- and 5-pyrimidyl; pyridazinyl; thienyl; furyl; pyrrolyl, particularly 2-pyrrolyl and l-alkyl-2-pyrrolyl; imidazolyl, particularly 2-imidazolyl; thiazolyl, particularly 2-thiazolyl; oxazolyl, particularly 2- oxazolyl; pyrazolyl, particularly 3- and 5-pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl; and 1,3,4-oxadiazolyl. Examples of monocyclic heterocycles that are not aromatic include saturated monocyclic groups such as: Aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, 1,4-dioxane, 1,3-dioxane, sulfolane, tetrahydrofuran, thiophane, piperazine, morpholine, thiomorpholine, tetrahydropyran, homopiperazine, homopiperidine, 1,3-dioxepane, hexamethyleneoxide and piperidine; and partially saturated monocyclic groups such as: 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, 2,3-dihydrofuran, 2,5-dihydrofuran , 2,3-dihydropyran, 1,2-dihydrothiazole, 1,2- dihydrooxazole, 1,2-dihydroimidazole and 4,7-dihydro-l,3-dioxepin. Examples of polycyclic heteroaryl groups include: Indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl, quinolyl, isoquinolyl, particularly 1- and 5- isoquinolyl, cinnolinyl, quinoxalinyl, particularly 2- and 5-quinoxalinyl, quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, benzofuryl, particularly 3-, 4-, 1,5-naphthyridinyl, 5-, 6- and 7-benzofuryl, 1,2- benzisoxazolyl, benzothienyl, particularly 3-, 4-, 5-, 6-, and 7-benzothienyl, benzoxazolyl, benzthiazolyl, particularly 2-benzothiazolyl and 5-benzothiazolyl, purinyl, benzimidazolyl, particularly 2-benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, tetrahydroquinolyl; 1,2,3,4-tetrahydroisoquinolyl; dihydrocoumarinyl; 2,3- dihydrobenzofuryl; 2,3-dihydrobenzothienyl, N-methyl-2-indolinyl; and indolinyl. Examples of non-aromatic polycyclic heterocycles include: pyrrolizidinyl and quinolizidinyl. The aforementioned listing of non-aromatic heterocyclic moieties and heteroaryl moieties is intended to be representative, not limiting. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; pyrazinyl; 2- and 5- pyrimidinyl; 3-pyridazinyl; 2- and 3-thienyl; 2- and 3-furyl; pyrrolyl; particularly N-methylpyrrol-2-yl; 2-imidazolyl; 2-thiazolyl; 2-oxazolyl; pyrazolyl; particularly 3- and 5-pyrazolyl; isothiazolyl; 1,2,3-triazolyl; 1,2,4- triazolyl; 1,3,4-triazolyl; tetrazolyl, 1,2,3-thiadiazolyl; 1,2,3-oxadiazolyl; 1,3,4- thiadiazolyl and 1,3,4-oxadiazolyl; indolyl, particularly 2-, 3-, 4-, 5-, 6- and 7- indolyl; cinnolinyl; quinoxalinyl, particularly 2- and 5-quinoxalinyl; quinazolinyl, particularly 2-, 5-, 6-, 7- and 8-quinazolinyl; phthalazinyl; 1,8- naphthyridinyl; 1,5-naphthyridinyl, particularly l,5-naphthyridin-3-yl and 1,5- naphthyridin-4-yl; 1,4-benzodioxanyl; coumarinyl; benzofuryl, particularly 2-, 3- 5-, 6- and 7-benzofuryl; 1,2-benzisoxazolyl; benzothienyl, particularly 2-, 3-, 4-, 5-, 6-, and 7-benzothienyl; benzoxazolyl; benzthiazolyl, particularly 2- benzothiazolyl and 5-benzothiazolyl; purinyl; benzimidazolyl, particularly 2- benzimidazolyl; benztriazolyl; thioxanthinyl; carbazolyl; carbolinyl; and acridinyl, particularly 6-acridinyl. More preferred heteroaryl groups are 2, 3- and 4-pyridyl; 2- and 3- thienyl; 2- and 3 -furyl; 2-pyrrolyl; 2-imidazolyl; 2-thiazolyl; 2-oxazolyl; 2- and 3-indolyl; 2-, and 3-benzofuryl; 3-(l,2-benzisoxazolyl); 2-, and 3-benzothienyl; 2-benzoxazolyl; 1- and 2-benzimidazolyl, 2-, 3- and 4-quinolyl; and 2- and 5- benzthiazolyl. Most preferred heteroaryl groups are 2- and 3-indolyl; 2- and 3- pyrrolyl, 2-, and 3-benzofuryl; and 2-, and 3-benzothienyl. The term "substituted" means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. For aryl and heteroaryl groups, the term "substituted" refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. The expression "substituted and unsubstituted -NH(Cι- C_δ)alkylenylheterocyclyl" refers to a monovalent substituent that is a substituted or unsubstituted heterocyclyl ring bonded to an alkylene group, which alkylene group is bonded through a divalent nitrogen to the molecule on which it is a substituent. Examples include sub-structures such as those shown below:

Some ofthe radioprotective small molecule inhibitors of ABL kinase and all of the α,β-unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides are characterized by isomerism resulting from the presence of a double bond. This isomerism is commonly referred to as cis-trans isomerism, but the more comprehensive naming convention employs E and Z designations. The compounds are named according to the Cahn-Ingold-Prelog system, the IUPAC 1974 Recommendations, Section E: Stereochemistry, in Nomenclature of Organic Chemistry, John Wiley & Sons, Inc., New York, NY, 4^th ed., 1992, p. 127-138. Using this system of nomenclature, the four groups about a double bond are prioritized according to a series of rules. Then, that isomer with the two higher ranking groups on the same side of the double bond is designated Z (for the German word "zusammen", meaning together). The other isomer, in which the two higher-ranking groups are on opposite sides of the double bond, is designated E (for the German word "entgegen", which means "opposite"). Thus if the four groups on a carbon-carbon double bond are ranked with A being the lowest rank and D being highest, A > B > C > D, the isomers would be named as in Scheme 1.

Z configuration E configuration Scheme 1 Unless otherwise indicated, both configurations and mixtures thereof are included in the scope of "radioprotective ABL inhibitor" and in the scope of

"α,β-unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides." Some ofthe radioprotective small molecule inhibitors of ABL kinase and some of the α,β-unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides may be characterized by isomerism resulting from the presence of a chiral center. The isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable isomers that are called "enantiomers."

Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system. See March, Advanced Organic Chemistry, 4^th Ed., (1992), p. 109. Once the priority ranking ofthe four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order ofthe other groups proceeds clockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated (S). In the example below, the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.

(R) configuration (S) configuration Scheme 2 Unless otherwise indicated, both absolute configurations and mixtures thereof are included in the scope of "radioprotective ABL inhibitor" and in the scope of "α,β-unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides." Nomenclature employed herein for providing systematic names for compounds useful in the claimed method may be derived using the Nomenclator^® facility within the computer program package, ChemDraw^®. When compounds of the invention characterized by E-/Z- isomerism or by isomerism resulting from the presence of a chiral center, are named herein, the absence ofE- or Z-, or R- or S- designation in the name is intended to mean that the named compound includes all possible isomeric forms and all mixtures thereof.

Brief Description of the Figures FIG. 1 shows a fixed polyacrylamide gel showing qualitatively the inhibition of ABL kinase activity by N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylphenyl)-4-((4-methylpiperazin- 1 -yι)methyl)benzamide (a compound of formula I), by 4-((lE)-2-{[(4-chlorophenyl)- methyl]sulfonyl}vinyl)benzoic acid (a compound of formula II) and by a combination ofthe two compounds, all as a function of dose. FIG. 2 shows quantitatively the inhibition of ABL kinase activity by N- (3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methyl- piperazin-l-yl)methyl)benzamide plotted as percent of solvent treated control. FIG. 3 shows the radioprotective effect of N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-l-yl)methyl)- benzamide (Compound of Formula I) on human fibroblasts HFL-1 exposed to 10 Gy of ionizing radiation. FIG. 4 shows the inhibition of cbll growth of K562 cells by a treatment with a combination of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methylphenyl)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide (Compound of

Formula I) and (lE)-2-(2,4-difluorophenyl)-l-{[(4-bromoρhenyl)methyl]- sulfonyl} ethene (Compound of Formula II) FIG. 5 shows quantitatively the inhibition of ABL kinase activity by compounds 1 (■), 2 (Δ), 3 (V), 4 (0), 5 (•) and 6 (o) plotted as percent of solvent treated control. FIG. 6 shows quantitatively the inhibition of ABL kinase activity by compounds 7 (■), 8 (Δ), 9 (V), 10 (0), 11 (•) and 12 (a), plotted as percent of solvent treated control. FIG. 7 shows quantitatively the inhibition of ABL kinase activity by compounds 13 (■), 14 (Δ), 15 (repeated three times as V, •, and G), and 16 (0), plotted as percent of solvent treated control. FIG. 8 shows quantitatively the inhibition of ABL kinase activity by compounds 17 (■), 18 (Δ), and 19 (V) plotted as percent of solvent treated control. FIG. 9 shows quantitatively the inhibition of ABL kinase activity by compounds 20 (■), 21 (Δ), and 22 (V) plotted as percent of solvent treated control.

Detailed Description o the Invention It has now been found that small molecule inhibitors of ABL activity are also capable of protecting cells, tissues and individuals from the cytotoxic effects of ionizing radiation. The radioprotective compounds protect normal cells and tissues from the effects of acute and chronic exposure to ionizing radiation. Further, compositions comprising a small molecule inhibitor of ABL activity, in combination with either an antioxidant compound or an α,β- unsaturated (aryl or heteroaryl) sulfone, sulfonamide or carboxamide, are capable of protecting cells, tissues and individuals from the cytotoxic effects of ionizing radiation. Preferred antioxidant compounds useful in combination small molecule inhibitors of ABL activity include, for example, carotenoids, catechins, isoflavones, flavanones, flavanols, flavanoid chalcones, vitamin E compounds, (3-aminopropyl)[2-(phosphonothio)ethyl]amine, ascorbic acid, cysteine, glutathione, probucol, β-mercaptoethanol dithiothreitol, pyrrolidine dithiocarbamate, N-acetyl-L-cysteine, ubiquinone, and porphyrin compounds such as those disclosed in EP 1,045,851, the entire contents of which is incorporated herein by reference. Preferred carotenoids include β-carotene, α- carotene, lutein. lycopene. Preferred catechins include gallic acid, propyl gallate, (+)-catechin, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)- epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), (-)-catechin gallate (CG), and (-)-gallocatechin gallate. Preferred isoflavones include genistein and daidzein. Preferred flavanols include hesperitin, hesperidin, and quercetin, kaempferol, myricetin. Preferred flavanoid chalcones include xanthohumol and isoxanthohumol. Preferred vitamin E compounds include tocopherols and tocotrienols. Antioxidant compounds more preferably include, for example, β- carotene, α-carotene, lutein, lycopene, gallic acid, propyl gallate, (+)-catechin, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), (-)-catechin gallate (CG), (-)-gallocatechin gallate, genistein, hesperitin, hesperidin, quercetin, kaempferol, myricetin, xanthohumol, isoxanthohumol, tocopherols, tocotrienol, (3-aminopropyl)[2- (phosphonothio)ethyl]amine, ascorbic acid, cysteine, glutathione, probucol, β- mercaptoethanol dithiothreitol, pyrrolidine dithiocarbamate, N-acetyl-L- cysteine, ubiquinone, meso-tetrakis-(N-alkylpyridinium-2-yl)porphyrins, meso- tetrakis-(N-alkylpyridinium-3-yl)porphyrins, and salts of such compounds. The meso-tetrakis-(N-alkylpyridinium-2-yl)porphyrins, meso-tetrakis- (N-alkylpyridintum-3-yl)porphyrins are disclosed in EP 1,045,851 as having the formulae VI and VII:

wherein Alkyl is preferably (d-C₈) alkyl, more preferably (Cι-C₄)alkyl; and each M is independently selected from the group consisting of -H, -ΝO₂, -CN, -CH=CH2 and -CHO; and the compound is complexed with a metal selected from the group consisting of iron, copper, cobalt, nickel and zinc. The precise mechanism of action of the radioprotective compounds disclosed herein is unknown. However, based on experimental models, and without wishing to be bound by any theory, the compounds are believed to inhibit the tyrosine kinase activity ofthe ABL protein. Individuals may be exposed to ionizing radiation when undergoing therapeutic irradiation for the treatment of proliferative disorders. Such disorders include cancerous and non-cancer proliferative disorders. For example, the present compounds and pharmaceutical compositions are believed effective in protecting normal cells during therapeutic irradiation of a broad range of tumor types, including but not limited to the following: breast- prostate, ovarian, lung, colorectal, brain (i.e., glioma) and renal. The compounds and compositions are also effective in protecting normal cells during therapeutic irradiation of leukemic cells. The compounds are also believed useful in protecting normal cells during therapeutic irradiation of abnormal tissues in non-cancer proliferative disorders, including but not limited to the following: hemangiomatosis in newborn, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget's Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis. The radioprotective ABL inhibitors of formula I useful in the method of the invention may be prepared by organic synthesis using techniques that are known in the art or readily adapted from techniques known in the art. The following general synthesis methods are representative of methods whereby the compounds useful in the claimed method may be prepared.

Synthesis of Formula 1(a) Compounds The compounds of formula 1(a) comprise anilinopyrimidines which may be prepared according to the method of Zimmermann et al, Bioorg. & Med. Chem. Lett., Vol. 7, No. 2, pp. 187-192 and Zimmermann et al, US Patent

5,521,184, the entire disclosures of which are incorporated herein by reference.

The method is described in Scheme 3:

A. According to Scheme 3, ketone 1 is reacted with dimethylacetamide dimethylacetal to form the enamine 2 by heating the reagents together in a suitable inert solvent. Suitable inert solvents include, for example, alkyl alcohols, such as methanol, ethanol, and isopropanol; esters such as methyl acetate or ethyl acetate; halogenated solvents, such as methylene chloride, chloroform or carbon tetrachloride; ethers such as tetrahydrofuran, 1,4-dioxane or tert-butylethylether; and aromatic solvents such as toluene. The reaction may be conveniently carried out at a temperature in the range, for example, from about 25°C to about 150°C, preferably in the range from about 25°C to about 80° C, most preferably at the reflux temperature ofthe reaction mixture. The desired enamine intermediate 2 may be isolated from the reaction mixture by, for example, removing the volatile components of the reaction mixture under vacuum and purifying the residue by chromatographic separation. B. The enamine 2 is reacted with a suitably substituted phenyl guanidine 3 in a suitable solvent as defined above, preferably a polar solvent, to generate the anilinopyrimidine 4. The polar solvent may comprise an alkyl alcohol such as, for example, isopropanol. The reaction of 2 with 3 may be carried out at an elevated temperature of from about 30°C to about 150°C, conveniently at the boiling point ofthe solvent in which the reaction is performed. Synthesis of Formula Kb) Compounds The compounds of formula 1(b) comprise pyridopyrimidines which may be prepared according to the method of Boschelli etal, J. Med. Chem. 1998, 41, pp. 4865-4377, the entire disclosure of which is incorporated herein by reference. The method is described in Scheme 4:

A. According to Scheme 4, starting material 5 is reacted with an aryl or heteroaryl acetonitrile in a suitable inert solvent in the presence of a suitable base under basic conditions to effect annulation of the pyridine ring to yield an intermediate 6-aryl and heteroaryl pyridopyrimidine-2-thiomethyl-5-imino derivative, 6. Suitable inert solvents include, for example alkyl alcohols, such as methanol, ethanol, isopropanol; esters such as methyl acetate or ethyl acetate; halogenated solvents, such as methylene chloride, chloroform or Carbon tetrachloride; ethers such as tetrahydrofuran, 1,4-dioxane or tert-butylethylether; aromatic solvents such as toluene; and polar aprotic solvents such as, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or N- methylpyrrolidinone (NMP). Suitable bases include, for example, organic amine bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or l,8-diazabicyclo[5.4.0]undecane; and alkali or alkaline earth metal carbonates or hydroxides, for example, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide; alkali metals or alkaline earth metal amides, for example sodium amide or sodium bis(trimethylsilyl)amide. Suitable bases may also include a reagent that is immobilized on a solid phase support. Examples of solid phase amine bases include diisopropylethylamine bound to polystyrene. The reaction may be conveniently carried out at a temperature in the _λ range, for example, from about 25° C. to about 150° C, preferably in the range from about 25° C to about 100° C. B. The amidino group of 6 is then converted from the amidine to the corresponding lactam by first acylating the imino nitrogen of 6 with a suitable acylating agent such as, for example, acetic anhydride. The acylated amidine is then subjected to hydrolytic conditions such as, for example, concentrated aqueous HCl to form lactam intermediate 7. C. The thioether group of intermediate 7 is then oxidized to the sulfone to provide a leaving group at the 2-position. The oxidation may be done in a suitable inert solvent by reaction with any suitable oxidizing agent to form the corresponding 2-methylsulfonyl-6-aryl intermediate 8. Suitable oxidizing agents are those capable of selectively oxidizing a sulfide to a sulfone, for example meta-chloroperoxybenzoic acid (mCPBA). A suitable inert solvent for the oxidation reaction is a solvent that is not oxidized under the reaction conditions. Preferred solvents include halogenated solvents such as, for example, chloroform, methylene chloride and carbon tetrachloride; and aromatic solvents such as toluene. D. Reaction of the 2-methylsulfonyl-6-aryl intermediate 8 with a suitably substituted aniline, with or without an additional solvent at an elevated temperature, for example, from about 100° C to about 200° C, yields the pyridopyrimidines of Formula 1(b). Additional solvents suitable for the reaction of intermediate 8 with a substituted aniline include, for example, aromatic solvents such as xylene or mesitylene. Synthesis of Formula Kc) Compounds The compounds of formula 1(c) comprise anilino-3- quinolinecarbonitriles which may be prepared according to the method of Boschelli et al, J. Med. Chem., 44, pp. 3965-3977, and US Patent 6,521,618, the entire disclosures of which are incorporated herein by reference. The method is described in Scheme 5, wherein WVU* represents the substitution at the 7-position of the quinoline-3-nitriles as described herein and synthetic precursors to the quinoline-3-nitriles.

Scheme 5 The 3-cyanoquinoline intermediate 10 comprises a leaving group at the 4-position. The leaving group may be a halogen, or a sulfonate group such as a triflate, mesylate, nosylate or tosylate. Intermediate 10 is reacted with a suitably substituted aniline with or without an additional solvent to yield the 4-anilino-3- quinolinecarbonitriles of formula 1(c). Additional solvents suitable for the reaction of intermediate 10 with a substituted aniline include, for example, aromatic solvents such as xylene or mesitylene. The reaction is preferably performed at a temperature of from about 100°C to about 200°C, preferably about 150°C.

Synthesis of Formula Kd) Compounds Compounds of formula 1(d) comprise tyrphostins which may be prepared via S_N2 reaction between a benzyl halide or similar electrophile and an aniline, phenol or thiophenol nucleophile. The method is described in Scheme 6:

Scheme 6

Compounds of formula 1(d) are prepared from an intermediate 11 which comprises a nucleophilic group L*. Group L* corresponds to the divalent group L in formula 1(d). The group L* may thus represent -OH, -SH or a primary or secondary amino group. Intermediate 12 comprises a suitable leaving group such as, for example, a halogen or a sulfonate such as a tosylate, nosylate, mesylate or triflate group. Intermediates 11 and 12 are reacted together under suitable conditions such that the nucleophilic group L* on intermediate 11, effects an SN2 displacement of the leaving group of intermediate 12, thereby generating a compound of formula 1(d) as defined herein. Suitable conditions for the reaction of intermediates 11 and 12 include reaction in a suitable solvent, preferably in the presence of an acid scavenging reagent. Suitable solvents include, for example halogenated solvents, such as methylene chloride, chloroform or carbon tetrachloride; alkyl nitriles such as acetonitrile; ethers such as tetrahydrofuran, 1,4-dioxane or tert-butylethylether; aromatic solvents such as toluene; and polar aprotic solvents such as, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or N- methylpyrrolidinone (NMP). The acid scavenger may be a soluble base that is otherwise unreactive under the reaction conditions, such as, for example a tertiary amine such as triethylamine, 2,6-lutidine or l,8-diazabicyclo[5.4.0]undecane. Alternatively, the acid scavenger may be an inorganic base that is insoluble or has limited solubility in the organic solvent, such as potassium carbonate. The acid scavenger may also be a reagent that is immobilized on a solid phase support. Examples of solid phase acid scavengers include diisopropylethylamine bound to polystyrene. The product of formula 1(d) may be isolated from the reaction mixture, for example by concentrating the reaction mixture under vacuum and subjecting the residue to chromatographic separation.

Synthesis of Formula 1(e) Compounds The compounds of formula 1(e) comprise quinazolines which may be prepared according to the method of Gibson et al See Gibson et al, US patents 5,770,599 and 5,770,603 the entire disclosures of which are incorporated herein by reference. The method is described in Scheme 7 and Scheme 8:

Scheme 7 According to Scheme 7, quinazoline 13, comprising a suitable leaving group at the 4-position, is reacted with aniline intermediate 14, preferably in the presence of a suitable base, to yield a compound of formula 1(e). Suitable leaving groups on quinazoline 14 include, for example, halogen, such as chloro, bromo and iodo; alkoxy, such as methoxy or ethoxy; aryloxy, such as phenoxy; and sulphonyloxy groups, such as methanesulphonyloxy

(mesylate), toluene-4-sulphonyloxy (tosylate) and trifluoromethanesulfonyloxy group (triflate). Suitable bases for the reaction include, for example, amine bases such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine and 1,8- diazabicyclo[5.4.0]undecane; alkali or alkaline earth metal carbonates or hydroxides, for example sodium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide; alkali metal or alkaline earth metal amides, for example sodium amide or sodium bis(trimethylsilyl)amide; and reagents that are immobilized on a solid phase support, such as solid phase amine bases, e.g., diisopropylethylamine bound to polystyrene. The reaction may be preferably carried out in the presence of a suitable inert solvent or diluent, for example an alkyl alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate; a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride; an ether such as tetrahydrofuran or 1,4-dioxane; an aromatic solvent such as toluene; or a polar aprotic solvent such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N- methylpyrrolidin-2-one (ΝMP) or dimethylsulphoxide (DMSO). The reaction may be conveniently carried out at a temperature in the range of from about 10° C. to about 150° C, preferably in the range from about 20° C to about 80° C. For the production of those compounds of formula 1(e) wherein -U-V-W is an amino-substituted alkoxy group, the intermediate quinazoline 13 may be prepared according to Scheme 8 from a corresponding quinazoline 13a that is substituted at the 6-position with a hydroxyl group .

Scheme 8 The 6-hydroxyl group of quinazoline intermediate 13a may be conveniently alkylated in the presence of a suitable base. Suitable alkylating agents include any agent known in the art for the alkylation of a hydroxy group to produce an amino-substituted alkoxy group. Examples of such alkylating agents include amino-substituted alkyl halides, such as amino-substituted alkyl chlorides, bromides or iodides. Alternatively the alkyl halide may be substituted with a functional group that is a precursor to an amine. Examples of such precursors include nitro groups; aldehydes, ketones and ketals; and amines protected by protecting groups such as, for example, tert-butoxycarbonyl (t- BOC) and carbobenzyloxy (CBZ). The alkylation reaction shown in Scheme 8 is preferably performed in the presence of a suitable base, and in a suitable inert solvent as defined above in the synthesis of formula 1(e) compounds. The alkylation reaction is preferably performed at a temperature in the range of from about 10° C to about 140° C, conveniently at or near about 80° C. Alternatively, for the production of those compounds of formula 1(e) wherein -U-V-W is an amino-substituted alkoxy group, the intermediate quinazoline 13 may be prepared according to Scheme 8 from a corresponding quinazoline 13b that is substituted at the 6-position with a hydroxyalkyl group, or a reactive derivative thereof, which group may be conveniently aminated with an appropriate amine in the presence of a suitable base as defined above in the synthesis of formula 1(e) compounds. A suitable reactive derivative of a hydroxy(C₁-Cδ)alkoxy group is, for example, a derivative comprising a leaving group as described above in the quinazoline synthesis method. The amination reaction of Scheme 8 is preferably carried out in the presence of a suitable inert solvent as defined hereinbefore in the quinazoline synthesis method, and at a temperature in the range of from about 10° C to about 150° C, conveniently at or near about 50° C.

Synthesis of ocβ-Unsaturated (Aryl or Heteroaryl) Sulfones and Sulfoxides of Formula II A. Synthesis of α,β-unsaturated (aryl or heteroaryl) sulfones and sulfoxides of formula II containing an (Z?)-double bond, may be accomplished according to the method of Reddy et al, US Patent 6,359,013, the entire disclosure of which is incorporated herein by reference. The method is described in Scheme 9:

According to Scheme 9, a mercaptan 15 is slowly added to a solution of sodium hydroxide (8 g, 0.2 mol) in methanol (200 mL). Then, chloroacetic acid

(0.1 mol) is added portionwise and the reaction mixture may be reftuxed for 2-3 hours, then cooled to ambient temperature. The cooled reaction mixture is poured onto crushed ice and neutralized with dilute hydrochloric acid (200 mL). The resulting thioacetic acid 16 (0.1 mol) may be oxidized to the corresponding sulfonyl acetic acid 17b by use of any reagent capable of oxidizing a sulfide to a sulfone. The thioacetic acid 16 may alternately be oxidized to the sulfinyl acetic acid 17a by treatment with any reagent capable of selectively oxidizing a sulfide to a sulfoxide. Suitable oxidizing reagents for both oxidation reactions include peroxides such as hydrogen peroxide, peracids such as meta-chloroperoxybenzoic acid (MCPBA) or persulfates such as OXONE® (potassium peroxymonosulfate). The reaction is preferably carried out in the presence of a suitable solvent. Suitable solvents include, for example, water, acetic acid or non-polar solvents such as dichloromethane (DCM). Reaction to selectively form the sulfinyl acetic acid 17a is preferably performed at low temperature, more preferably from about -10 to about 20°C. A reaction to form the sulfinyl acetic acid 17a is preferably monitored so as to terminate the reaction prior to appreciable oxidation to the sulfonyl acetic acid 17b. When the reaction is complete, the reaction mixture may be poured onto crushed ice. A solid precipitate may be collected by filtration and recrystallized from hot water to yield the purified sulfinyl acetic acid 17a. Reaction to form the sulfonyl acetic acid 17 b may be performed at higher temperature, for example, from about 30 to about 100°C with 30% hydrogen peroxide (0.12 mol) in glacial acetic acid (25 mL) by refluxing for 1-2 hours. When the reaction is complete, the reaction mixture may be cooled to ambient temperature and poured onto crushed ice. A solid precipitate may be collected by filtration and recrystallized from hot water to yield the purified sulfonyl acetic acid 17b. The ,β-unsaturated sulfone 19b may be prepared by mixing the sulfonyl acetic acid 17b (0.001 mol), an aromatic aldehyde 18 (0.001 mol) and benzylamine (1 mL) in glacial acetic acid (15 mL) and heating the mixture at reflux temperature for 2-3 hours. Similarly, the ,β-unsaturated sulfoxide 19a may be prepared by mixing the sulfinyl acetic acid 17a (0.001 mol), an aromatic aldehyde 18 (0.001 mol) and benzylamine (1 mL) in glacial acetic acid (15 mL) and heating the mixture at reflux temperature for 2-3 hours. When the reaction is complete, (the reaction forming sulfone 19b or (the reaction forming sulfoxide 19a) the reaction mixture may be cooled to ambient temperature and treated with dry ether (50 mL). Any precipitated product may be collected by filtration. The filtrate may be diluted with more ether and washed successively with a saturated solution of sodium bicarbonate (20 mL), sodium bisulfite (20 mL), dilute hydrochloric acid (20 mL) and finally with water (35 mL). Evaporation of the dried ether layer yields a solid compound of formula II in many cases. However, in some cases a syrupy material separates and may be solidified on treatment with 2-propanol. The purity of the product may be checked by TLC (silica gel, hexane/ethyl acetate 3:1). B. Synthesis of α,β-unsaturated (aryl or heteroaryl) sulfones and sulfoxides of formula II containing a (Z)-double bond, may be accomplished according to the method of Reddy et al, US Patent 6,359,013, the entire disclosure of which is incorporated herein by reference. The method is described in Scheme 10:

( )-SuIfone Compound of formula II (2T)-Sulfoxide Compound of formula II Scheme 10

A. According to Scheme 10, an aromatic mercaptan may be converted to the corresponding sodium thiolate 21. To the thiolate, in an alkyl alcohol is added an aryl acetylene 20. The reaction is preferably performed at elevated temperature, more preferably at the reflux temperature of the reaction mixture. When the reaction is complete, the reaction mixture may be poured onto water ice. The crude product may be collected by filtration and purified, preferably by recrystallization from a suitable solvent, to yield a pure (Z)-α,β-unsaturated (aryl or heteroaryl)sulfide 22. Preferable recrystallization solvents include water miscible alcohols and aqueous mixtures of water-miscible alcohols.

B. The (Z)-α,β-unsaturated (aryl or heteroaryl)sulfide 22 may be oxidized to the corresponding sulfone by use of any reagent capable of oxidizing a sulfide to a sulfone. Likewise, the (Z)-α,β-unsaturated (aryl or heteroaryl)sulfide 22 may be oxidized to the corresponding sulfoxide by use of any reagent capable of oxidizing a sulfide to a sulfoxide. Suitable reagents and conditions for oxidation to a sulfone or sulfoxide are the same as the conditions for preparation of sulfonyl acetic acid 17b and sulfinyl acetic acid 17a. The purity ofthe (Z)-α,β- unsaturated (aryl or heteroaryl)sulfone or sulfoxide may be ascertained by thin layer chromatography and geometrical configuration may be assigned by analysis of infrared and nuclear magnetic resonance spectral data.

Synthesis of ocβ-Unsaturated (Aryl or Heteroaryl) Sulfonamides of Formula II A. Sulfonamides of formula II containing an (£)-double bond, may be prepared according to the method of Reddy et al, WO 02/067865, the entire disclosure of which is incorporated herein by reference. The method is described in Scheme 11. 1. Na₂S0₃ Cl- Br' "COOR^* 2. PC1₅ SO2 "COOR' + Q NH 23 24 25

Scheme 11 According to Scheme 11, a methyl (or ethyl) β-chlorosulfonylacetate intermediate 24 is prepared from methyl (or ethyl) bromoacetate (R' = methyl or ethyl). To do this, methyl (or ethyl) bromoacetate is reacted with sodium sulfate to form the sodium sulfoacetate intermediate a₂OSθ2CH₂Cθ2R'. Potassium ; sulfate may be used as a substitute for sodium sulfate. The sodium sulfoacetate intermediate is then reacted with a chlorinating agent, preferably PC1₅, to form the methyl (or ethyl) β-chlorosulfonylacetate intermediate 24. Reaction of intermediate 24 with the aromatic amine 25 yields the arylaminosulfonylacetate intermediate 26. The latter reaction may be conducted in a nonprotic solvent in the presence of a base. The same compound may serve as both the nonprotic solvent and the base. Such dual-function solvents include, for example, pyridine, substituted pyridines, trimethylamine and triethylamine. The arylaminosulfonylacetate 26 is then converted to the corresponding arylaminosulfonylacetic acid compound 27 by any base capable of hydrolyzing the ester function of 26 to an acid. Such bases include, for example, KOH and NaOH. In the final step, the arylaminosulfonylacetic acid compound is condensed with arylaldehyde 18 in the presence of a basic catalyst via a Rnoevenagel reaction and decarboxylation of an intermediate. Basic catalysts include, for example, pyridine and benzylamine. The reaction yields the desired N-(aryl)-2-arylethenesulfonamide of formula II.

Synthesis of (iD-α^β-Unsaturated Carboxamides of Formula II (E)-α,β-unsaturated (aryl or heteroaryl) carboxamides of formula II may be prepared according to the method of Reddy et al, US provisional patent application 60/406,766, filed August 29, 2002, and PCT Patent Application WO 04037751, filed August 28, 2003 and published May 6, 2004, the entire disclosures of which are incorporated herein by reference. The method is described in Scheme 12.

Formula II Scheme 12

A: Synthesis of an Alkyl -2(N-(aryl or heteroarvDaminocarbonvDacetate 26: According to Scheme 12, to a solution of an aromatic amine 30 (10 mmol) and TEA (10 mmol) in dichloromethane (DCM) (50 mL) at room temperature is slowly added a solution of an alkyl malonyl chloride (10 mmol) in DCM. The resulting mixture is stirred at room temperature. When the reaction is complete, the reaction mixture may be filtered and solvent removed under reduced pressure to yield a crude product. The crude product may be purified by column chromatography to yield an alkyl-2-(N-(aryl or heteroaryl)aminocarbonyl)-acetate 31

B : Synthesis of 3-(Aryl or heteroaryl)amino-3-oxopropanoic acid 32: The alkyl-2-(N-(aryl or heteroaryl)aminocarbonyl)-acetate 31 is heated at reflux temperature in a solution of sodium hydroxide (9.0 g) in water (90 mL) and ethanol (90 mL) and monitored, preferably by TLC or HPLC, for disappearance of 31. The reaction mixture is subsequently cooled and acidified with HCl to precipitate the crude product acid 32. The crude 3 -(aryl or heteroaryl)amino-3-oxopropanoic acid 32 may be removed by filtration and recrystallized from hot water. C: Condensation of a 3-(aryl or heteroaryl)amino-3-oxopropanoic acid 32 with an aromatic aldehyde 18: A solution of the (aryl or heteroaryl)amino-3-oxopropanoic acid 32 (10 mmol), an aromatic aldehyde 18 (10 mmol) and benzylamine (0.4 mL) is refluxed for 3 hours in glacial acetic acid (10 mL). The solution is then cooled. Cold ether (50 mL) is added. The organic layer is separated and washed with a saturated solution of sodium bicarbonate (30 mL), sodium bisulfite (30 mL) and dilute hydrochloric acid (30 mL). The ether solution may be then dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the corresponding N-(aryl or heteroaryl)-3-(aryl or heteroaryl)-2-propenamide of formula II (E-isomer). Synthesis of (E) or (Z)-α,β-Unsaturated (Aryl or Heteroaryl) Carboxamides of Formula II (E)- or (Z)-α,β-unsaturated (aryl or heteroaryl) carboxamides of formula II may be prepared according to the method of Reddy et al, US provisional patent application 60/406,766 and PCT Patent Application WO 04037751. The method is described in Scheme 13.

Condensation of (E) or (Z)- Aromatic acryloyl chlorides with aromatic amines: According to Scheme 13, an intermediate (E)- or (Zj-aromatic acryloylhalide 34 are prepared from the corresponding aromatic acrylic acid 33. To do this, the aromatic acrylic acid is reacted with a halogenating agent such as for example, thionyl chloride or phosphorous pentachloride to form the intermediate carboxylic acid halide 34. A solution of an aromatic amine 35 (10 mmol) in pyridine (75 mL) is reacted with the (E) or (Z)-aromatic acryloyl halide 34 (10 mmol) for 4 to 6 hours at 80° C. When the reaction is complete, the reaction mixture is cooled and poured into ice water (IL) and concentrated hydrochloric acid (100 mL) is added. The precipitated product may be separated by filtration and crystallized to yield a pure E- or Z-N-(aryl or heteroaryl)-3-(aryl or heteroaryl)-2- propenamide of formula II.

Administration of ABL inhibitors

Administration in Association With Therapeutic Ionizing Radiation According to the present invention, therapeutic ionizing radiation may be administered to an individual on any schedule and in any dose consistent with the prescribed course of treatment. The radioprotective compound is administered prior to the therapeutic ionizing radiation. The course of treatment differs from individual to individual, and those of ordinary skill in the art can readily determine the appropriate dose and schedule of therapeutic radiation in a given clinical situation. Hereinafter, reference to administration of radioprotective compound shall mean administration of a radioprotective compound according to formula I alone, or in combination with either a radioprotective compound of formula II, or an antioxidant compound. The formula II compound or antioxidant compound may be administered simultaneously with the formula I compound, or may be administered separately. The compounds may be administered by the same or by different routes. Where the formula I compound and (i) the formula II compound or (ii) the antioxidant compound are administered at different times, the administration times are preferably optimized to obtain the radioprotective benefit of the combination based on the pharmacokinetic profiles of the compounds administered. Where the formula I compound and (i) the formula II compound or (ii) the antioxidant compound are administered simultaneously, the administration may be by the same or by different routes. Preferably, simultaneous administration is done by administering the compounds as part of the same pharmaceutical composition. The radioprotective compound should be administered far enough in advance ofthe therapeutic radiation such that the compound is able to reach the normal cells of the individual in sufficient concentration to exert a radioprotective effect on the normal cells. The radioprotective compound may be administered as much as about 24 hours, preferably no more than about 18 hours, prior to administration of the radiation. In one embodiment, the radioprotective compound is administered at least about 6-12 hours before administration ofthe therapeutic radiation. Most preferably, the radioprotective compound is administered once at about 18 hours and again at about 6 hours before the radiation exposure. One or more radioprotective compounds may be administered simultaneously, or different radioprotective compounds may be administered at different times during the treatment. Where the therapeutic radiation is administered in serial fashion, it is preferable to intercalate administration of one or more radioprotective compounds within the schedule of radiation treatments. As above, different radioprotective compounds may be administered either simultaneously or at different times during the treatment. Preferably, an about 24 hour period separates administration of a radioprotective compound and the therapeutic radiation. More preferably, the administration of a radioprotective compound and the therapeutic radiation is separated by about 6 to 18 hours. This strategy will yield significant reduction in radiation-induced side effects without affecting the anticancer activity ofthe therapeutic radiation. For example, therapeutic radiation at a dose of 0.1 Gy may be given daily for five consecutive days, with a two-day rest, for a total period of 6-8 weeks. One or more compounds according to the invention may be administered to the individual 18 hours previous to each round of radiation. It should be pointed out, however, that more aggressive treatment schedules, i.e., delivery of a higher dosage, is contemplated according to the present invention due to the protection of the normal cells afforded by the radioprotective compounds. Thus, the radioprotective effect of the radioprotective compound increases the therapeutic index of the therapeutic radiation, and may permit the physician to safely increase the dosage of therapeutic radiation above presently recommended levels without risking increased damage to the surrounding normal cells and tissues.

Administration in Treatment of Bone Marrow The radioprotective compounds of the invention are further useful in protecting normal bone marrow cells from radiological treatments designed to destroy hematological neoplastic cells or tumor cells which have metastasized into the bone marrow. Such cells include, for example, myeloid leukemia cells. The appearance of these cells in the bone marrow and elsewhere in the body is associated with various disease conditions, such as the French-American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), and acute lymphocytic leukemia (ALL). CML, in particular, is characterized by abnormal proliferation of immature granulocytes (e.g., neutrophils, eosinophils, and basophils) in the blood, bone marrow, spleen, liver, and other tissues and accumulation of granulocytic precursors in these tissues. The individual who presents with such symptoms will typically have more than 20,000 white blood cells per microliter of blood, and the count may exceed 400,000. Virtually all CML patients will develop "blast crisis", the terminal stage of the disease during which immature blast cells rapidly proliferate, leading to death. Other individuals suffer from metastatic tumors, and require treatment with total body irradiation (TBI). Because TBI will also kill the individual's hematopoietic cells, a portion ofthe individual's bone marrow is removed prior to irradiation for subsequent reimplantation. However, metastatic tumor cells are likely present in the bone marrow, and reimplantation often results in a relapse of the cancer within a short time. Individuals presenting with neoplastic diseases of the bone marrow or metastatic tumors may be treated by removing a portion of the bone marrow (also called "harvesting"), purging the harvested bone marrow of malignant stem cells, and reimplanting the purged bone marrow. Preferably, the individual is simultaneously treated with radiation or some other anti-cancer therapy. Thus, the invention provides a method of reducing the number of malignant cells in bone marrow, comprising the steps of removing a portion of the individual's bone marrow, administering an effective amount of at least one radioprotective compound of formula I and irradiating the treated bone marrow with a sufficient dose of ionizing radiation such that neoplastic or tumor cells in the bone marrow are killed. As used herein, "malignant cell" means any uncontrollably proliferating cell, such a tumor cell or neoplastic cell. The radioprotective compound protects the normal hematopoietic cells present in the bone marrow from the deleterious effects ofthe ionizing radiation. The number of malignant cells in the bone marrow is significantly reduced prior to reimplantation, thus minimizing the occurrence of a relapse. Preferably, each radioprotective compound is administered in a concentration from about 0.25 to about 100 micromolar; more preferably, from about 1.0 to about 50 micromolar; in particular from about 2.0 to about 25 micromolar. Particularly preferred concentrations are 0.5, 1.0 and 2.5 micromolar and 5, 10 and 20 micromolar. Higher or lower concentrations may also be used. The radioprotective compound may be added directly to the harvested bone marrow, but are preferably dissolved in an organic solvent such as dimethylsulfoxide (DMSO). Pharmaceutical formulations of radioprotective compounds such as are described in more detail below may also be used. Preferably, the radioprotective compound is added to the harvested bone marrow about 20 hours prior to radiation exposure, preferably no more than about 24 hours prior to radiation exposure. In one embodiment, the radioprotective compound is administered to the harvested bone marrow at least about 6 hours before radiation exposure. One or more radioprotective compounds of formula I may be administered simultaneously, or different radioprotective compounds may be administered at different times. Other dosage regimens may also be used. If the individual is to be treated with ionizing radiation prior to reimplantation of the purged bone marrow, the individual may be treated with one or more radioprotective compounds of formula I prior to receiving the ionizing radiation dose, as described above.

Administration in Treatments Related to Non-therapeutic Exposure to Ionizing Radiation An individual may also be exposed to ionizing radiation from occupational or environmental sources, as discussed in the background section. For purposes of the invention, the source of the radiation is not as important as the type (i.e., acute or chronic) and dose level absorbed by the individual. It is understood that the following discussion encompasses ionizing radiation exposures from both occupational and environmental sources. Individuals suffering from effects of acute or chronic exposure to ionizing radiation that are not immediately fatal are said to have remediable radiation damage. Such remediable radiation damage can be reduced or eliminated by the compounds and methods ofthe present invention. An acute dose of ionizing radiation which may cause remediable radiation damage includes a localized or whole body dose, for example, between about 10,000 millirem (0.1 Gy) and about 1,000,000 millirem (10 Gy) in 24 hours or less, preferably between about 25,000 millirem (0.25 Gy) and about 200,000 (2 Gy) in 24 hours or less, arid more preferably between about 100,000 millirem (1 Gy) and about 150,000 millirem (1.5 Gy) in 24 hours or less. A chronic dose of ionizing radiation which may cause remediable radiation damage includes a whole body dose of about 100 millirem (.001 Gy) to about 10,000 millirem (0.1 Gy), preferably a dose between about 1000 millirem (.01 Gy) and about 5000 millirem (.05 Gy) over a period greater than 24 hours, or a localized dose of 15,000 millirem (0.15 Gy) to 50,000 millirem (0.5 Gy) over a period greater than 24 hours. The invention therefore provides a method for treating individuals who have incurred remediable radiation damage from acute or chronic exposure to ionizing radiation, comprising reducing or eliminating the cytotoxic effects of radiation exposure on normal cells and tissues by administering an effective amount of at least one radioprotective compound of formula I. The compound is preferably administered in as short a time as possible following radiation exposure, for example between 0 - 6 hours following exposure. Remediable radiation damage may take the form of cytotoxic and genotoxic (i.e., adverse genetic) effects in the individual. In another embodiment, there is therefore provided a method of reducing or eliminating the cytotoxic and genotoxic effects of radiation exposure on normal cells and tissues, comprising administering an effective amount of at least one radioprotective compound prior to acute or chronic radiation exposure. The compound may be administered, for example about 24 hours prior to radiation exposure, preferably no more than about 18 hours prior to radiation exposure. In one embodiment, the compound is administered at least about 6 hours before radiation exposure. Most preferably, the compound is administered at about 18 and again at about 6 hours before the radiation exposure. One or more radioprotective compounds of formula I may be administered simultaneously, or different compounds may be administered at different times. For administration of more than one radioprotective compound of formula I at different times, the administration times are preferably optimized to obtain the radioprotective benefit of the combination based on the pharmacokinetics ofthe compounds administered. For administration of more than one radioprotective compound of formula I simultaneously, the administration may be by the same or by different routes. Preferably, simultaneous administration of more than one compound of formula I is done by administering the compounds as part of the same pharmaceutical composition. When multiple acute exposures are anticipated, the radioprotective compound may be administered multiple times. For example, if fire or rescue personnel must enter contaminated areas multiple times, the radioprotective compound may be administered prior to each exposure. Preferably, an about 24-hour period separates administration of radioprotective compound and the radiation exposure. More preferably, the administration of a radioprotective compound and the radiation exposure is separated by about 6 to 18 hours. It is also contemplated that a worker in a nuclear power plant may be administered an effective amount of radioprotective compound prior to beginning each shift, to reduce or eliminate the effects of exposure to ionizing radiation. If an individual anticipates chronic exposure to ionizing radiation, the radioprotective compound may be administered periodically throughout the duration of anticipated exposure. For example, a nuclear power plant worker or a soldier operating in a forward area contaminated with radioactive fallout may be given a radioprotective compound of formula I every 24 hours, preferably every 6-18 hours, in order to mitigate the effects of radiation damage. Likewise, the radioprotective compound may be periodically administered to civilians living in areas contaminated by radioactive fallout until the area is decontaminated or the civilians are removed to a safer environment.

Routes of Administration As used herein, "administered" means the act of making the radioprotective compounds of formula I (alone, or in combination with a compound of formula II or an antioxidant) available to the individual such that a pharmacological effect of radioprotection is realized. This pharmacological effect may manifest as the absence of expected physiologic or clinical symptoms at a certain level of radiation exposure. One skilled in the art may readily determine the presence or absence of radiation-induced effects, by well- known laboratory and clinical methods. The radioprotective compound may thus be administered by any route which is sufficient to bring about the desired radioprotective effect in the patient. Routes of administration include, for example enteral (e.g., oral, rectal, intranasal, etc.) and parenteral administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intravaginal, intravesical (e.g., into the bladder), intradermal, topical or subcutaneous administration. Also contemplated within the scope of the invention is the instillation of drug in the body of the patient in a controlled formulation, with systemic or local release ofthe drug to occur at a later time. For example, a depot of a radioprotective compounds of formula I may be administered to the patient more than 24 hours before the administration of radiation. Preferably, at least a portion of the compound is retained in the depot and not released until an about 6-18 hour window prior to the radiation exposure.

Compositions for Administration The radioprotective compound may be administered in the form of a pharmaceutical composition comprising one or more compounds of formula I in combination with a pharmaceutically acceptable carrier. The active compound in such formulations may comprise from 0.1 to 99.99 weight percent. By "pharmaceutically acceptable carrier" is meant any carrier, diluent or excipient, which is compatible with the other ingredients of the formulation and is not deleterious to the individual. It is within the skill in the art to formulate appropriate pharmaceutical compositions with radioprotective compounds. For example, the radioprotective compound may be formulated into pharmaceutical compositions according to standard practices in the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, PA. Suitable pharmaceutical compositions include, for example, tablets, capsules, solutions (especially parenteral solutions), troches, suppositories, or suspensions. For parenteral administration, the radioprotective compound may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, cyclodextrans or a glycol such as propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain a pharmaceutically acceptable, water-soluble salt of the radioprotective compound. Stabilizing agents, antioxidizing agents and preservatives may also be added. Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol. For oral administration, the radioprotective compound may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, or other suitable oral dosage forms. For example, the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods. The specific dose and schedule of radioprotective compound to obtain the radioprotective benefit will, of course, be determined by the particular circumstances of the individual patient including, the size, weight, age and sex of the patient, the nature and stage of the disease being treated, the aggressiveness of the disease, and the route of administration, and the specific toxicity of the radiation. For example, a daily dosage of from about 0.01 to about 150 mg/kg/day may be utilized, more preferably from about 0.05 to about 50 mg/kg/day. Particularly preferred are doses from about 1.0 to about 10.0 mg/kg/day, for example, a dose of about 7.0 mg/kg/day. The dose may be given over multiple administrations, for example, two administrations of 3.5 mg/kg. Higher or lower doses are also contemplated. The radioprotective compounds may take the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metallic salts made from calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N.N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding radioprotective compound by reacting, for example, the appropriate acid or base with the free acid or free base ofthe compound. The compositions useful in the method ofthe present invention may also be formulated so as to provide slow or controlled-release ofthe active ingredient therein. In general, a controlled-release preparation is a composition capable of releasing the active ingredient at the required rate to maintain constant pharmacological activity for a desirable period of time. Such dosage forms may provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than other non-controlled formulations. For example, U.S. Patent No. 5,674,533 discloses controlled-release compositions in liquid dosage forms for the administration of moguisteine, a potent peripheral antitussive. U.S. Patent No. 5,059,595 describes the controlled-release of active agents by the use of a gastro-resistant tablet for the therapy of organic mental disturbances. U.S. Patent No. 5, 591,767 discloses a liquid reservoir transdermal patch for the controlled administration of ketorolac, a non-steroidal anti-inflammatory agent with potent analgesic properties. U.S. Patent No. 5,120,548 discloses a controlled-release drug delivery device comprised of swellable polymers. U.S. Patent No. 5,073,543 discloses controlled-release formulations containing a trophic factor entrapped by a ganglioside-liposome vehicle. U.S. Patent No. 5,639,476 discloses a stable solid controlled-release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer. The patents cited above are incorporated herein by reference. Biodegradable microparticles may be used in controlled-release formulations useful in the method of this invention. For example, U.S. Patent No. 5,354,566 discloses a controlled-release powder that contains the active ingredient. U.S. Patent No. 5,733,566 describes the use of polymeric microparticles that release antiparasitic compositions. These patents are incorporated herein by reference. The controlled-release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. Various mechanisms of drug release exist. For example, in one embodiment, the controlled-release component can swell and form porous openings large enough to release the active ingredient after administration to a patient. The term "controlled-release component" in the context of the present invention is defined herein as a compound or compounds, such as polymers, polymer matrices, gels, permeable membranes, liposomes and/or microspheres, that facilitate the controlled-release of the radioprotective compound of formula I in a pharmaceutical composition. In another embodiment, the controlled-release component may be biodegradable, induced by exposure to the aqueous environment, pH, temperature, or enzymes in the body. In another embodiment, sol-gels may be used, wherein the active ingredient is incorporated into a sol-gel matrix that is a solid at room temperature. This^* matrix is implanted into a patient, preferably a mammal, having a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing the active ingredient into the patient. The practice ofthe invention is illustrated by the following non-limiting examples. Examples

Example 1: Synthesis of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methyl-phenyl)-4-((4-methylpiperazin-l-yI)methyl)benzamide. The compound of Example 1, an anilinopyrimidine of formula 1(a), is synthesized according to Scheme 14.

A. (2E)-3 -(Dimethylamino)- 1 -(3 -pyridyl)prop-2-en- 1 -one 3-Acetyl pyridine [350-03-8] (Sigma Aldrich A2,120-7) (10 mmol, 1.21 g) is dissolved in tetrahydrofuran (THF). N,N-dimethylacetamide dimethyl acetal (Sigma Aldrich 26,148-3) (50 mmol, 6.7 g) is added, and the resulting mixture is heated to reflux and monitored by HPLC for disappearance of the starting 3-acetylpyridine. When the reaction is complete, the product 1(a), (2E)- 3-(dimethylamino)-l-(3-pyridyl)prop-2-en-l-one, is isolated by removing the volatiles under vacuum and purifying the residue by high throughput preparative HPLC.

B. (2-Methyl-5-nitrophenyl)(4-(3-pyridyl)pyrimidin-2-yl)amine. Intermediate 1(a) (9 mmol, 1.6 g) is dissolved in isopropanol. 2- Guanidino-4-nitrotoluene (9 mmol, 1.75g) is added and the resulting mixture is warmed to reflux under argon and monitored by HPLC. When the reaction is complete, the product 1(b), (2-methyl-5-nitrophenyl)(4-(3-pyridyl)pyrimidin-2- yl)amine, is isolated by removing the volatiles under vacuum and purifying the residue by high throughput preparative HPLC. C. (3-Amino-6-methylphenyl)(4-(3-pyridyl)pyrimidin-2-yl)amine. Intermediate 1(b) (8 mmol, 2.5 g) is dissolved in ethanol (50 mL) in a Parr hydrogenation bottle. Palladium on carbon (10%, 200mg) is added in an ethanol slurry. The mixture is hydrogenated at 50 psi (3 atm) until the theoretical amount of hydrogen is consumed. When the reaction is complete, the reaction is filtered through diatomaceous earth and concentrated under vacuum. The residue is then purified by preparative HPLC to yield intermediate 1(c), (3-amino-6-methylphenyl)(4-(3-pyridyl)pyrimidin-2-yl)amine.

D . N-(3 -(4-(pyridin-3 -yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4- methylpiperazin- 1 -vDmethyDbenzamide. Intermediate 1(c) is converted to a benzamide under standard Schotten-

Baumann conditions as follows. Intermediate 1(c) (7 mmol, 1.98 g) is dissolved in THF (50 mL). A 20% (wt./V) solution of potassium carbonate (100 mL) is added. Acid chloride intermediate 1(d) (14 mmol, 3.5 g) is dissolved in THF (50 mL) and added dropwise over approximately one hour. The resulting mixture is stirred at ambient temperature and monitored by HPLC for disappearance of the starting aniline derivative 1(c). When the reaction is complete, the product, N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl- phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide, is isolated by acid base extraction. The extract is dried and concentrated under vacuum, and the resulting residue is purified by high throughput preparative HPLC. Example 2: Synthesis of 6-(2,6-dichlorophenyl)-8-methyl-2~[(3-methyl- thio-phenyl)ammo]-8-hydropyridino[2,3-d]pyrimidin-7-one. The compound of Example 2, a pyridopyrimidine of formula 1(b), is synthesized according to Scheme 15.

A Ethyl-4-methylamino-2-methylthio-5-pyrimidinecarboxylate. Ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate [5909-24-0]

(Sigma Aldrich, 14,596-3)(10 mmol, 2.3. g) is warmed to reflux in methyl amine (40% aqueous, lOOmL). The reaction is monitored by HPLC for disappearance of the starting chloropyrimidine. When the reaction is complete, the product, ethyl-4-methylamino-2-methylthio-5-pyrimidinecarboxylate, is isolated by removing the volatiles under vacuum and purifying the residue by preparative HPLC.

B . [4-(Methylamino)-2-methylthiopyrimidin-5-yl]methan- 1 -ol Intermediate ethyl-4-methylamino-2-methylthio-5-pyrimidine- carboxylate (9 mmol, 2.1 g) is dissolved in dry THF and cooled to 0° C in an ice-water bath. Lithium aluminum hydride (anhydrous powder, 340 mg, 9 mmol) is added. The reaction is monitored by HPLC for disappearance of the starting carboxylic ester. When the reaction is complete, the reaction is quenched at 0°C by adding 10%) acetic acid dropwise. The mixture is then diluted with water and extracted with ethyl acetate. The organic extract is concentrated under vacuum and the product, [4-(methylamino)-2- methylthiopyrimidin-5-yl]methan-l-ol, is isolated by removing the volatiles under vacuum and purifying the residue by high throughput preparative HPLC.

C. 4-(Methylamino)-2-metl ylthiopyrimidine-5-carbaldehyde Intermediate [4-(methylamino)-2-methylthiopyrimidin-5-yl]methan- l-ol

(7 mmol, 1.3 g) is dissolved in chloroform. Manganese (TV) oxide (10 mmol, 0.87 g) is added, and the mixture is stirred at ambient temperature and monitored by HPLC for disappearance ofthe starting benzyl alcohol. When the reaction is complete, the mixture is then diluted with water and extracted with ethyl acetate. The organic extract is concentrated under vacuum and the product 2(b), [4-(methylamino)-2-methylthiopyrimidine-5-carbaldehyde, is isolated by removing the volatiles under vacuum and purifying the residue by high throughput preparative HPLC.

D. 6-(2,6-dichlorophenyl)-8-methyl-2-methylthio-8-hydropyridino[^'2.3- dlpyrimidin-7-imine, 2(c) Intermediate 2(b), 4-(methylamino)-2-methylthiopyrimidine-5- carbaldehyde (6 mmol, 1.12 g) is dissolved in anhydrous DMF and added dropwise under argon to a stirred mixture of potassium carbonate (60 mmol, 8.3g) and 2,6-dichlorophenylacetonitrile [1194-65-6] (Sigma-Aldrich, 12,601- 2)(12 mmol, 2.25 g) stirred at 50° C. The reaction is monitored by HPLC for disappearance of the starting pyrimidine aldehyde 2(b). When the reaction is complete, the mixture is cooled to ambient temperature, diluted with water and extracted with ether. The ether extract is concentrated and the residue is purified the residue by preparative HPLC to yield the product 2(c), 6-(2,6- dichlorophenyl)-8-methyl-2-methylthio-8-hydropyridino[2,3-d]pyrimidin-7- imine. E. 6-(2,6-dichlorophenyl)-8-methyl-2-methylthio-8-hvdropyridinor2 - d]pyrimidin-7-one.2(d) A mixture of 2(c) (6 mmol, 2.1 g) and acetic anhydride (16 mL) is heated to reflux for 30 minutes. The reaction mixture is then cooled to ambient temperature, diluted with ether and concentrated under vacuum. The resulting residue is triturated in ether to yield 2(d), 6-(2,6-dichlorophenyl)-8-methyl-2- methylthio-8-hydropyridino[2,3-d]pyrimidin-7-one.

F. 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8-hvdropyridino[2.3- dlpyrimidin-7-one, 2(e) Intermediate 2(d) (5 mmol, 2.1g) is taken up in chloroform (100 mL).

To this is added m-CPBA (77% max, 15 mmol max). The reaction mixture is stirred at ambient temperature for two hours. The reaction mixture is then washed with saturated aqueous sodium bicarbonate and dried (MgSO₄) and concentrated under vacuum. The resulting residue is triturated in ethyl acetate/hexane to yield 2(e).

G. 6-(2,6-dichlorophenyl)-8-methyl-2-r(3-methylthio-phenyl)amino]-8- hydropyridinor2.3-d1pyrimidin-7-one. Intermediate 2(e), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8- hydropyridinoi2,3-d]pyrimidin-7-one (5 mmol, 1.91 g) is added to 3- aminothioanisole (15 mmol, 2.1 g). The mixture is warmed to 150 °C. The reaction is monitored by HPLC for disappearance ofthe starting 2(e). When the reaction is complete, the mixture is purified by preparative HPLC to yield the Example 2 compound, 6-(2,6-dichlorophenyl)-8-methyl-2-[(3-methylthio- phenyl)amino]-8-hydro-pyridino-[2,3-d]pyrimidin-7-one.

Example 3. Synthesis of 4-[(2,4-dichIoro-5-methoxyphenyI)amino]-6- methoxy-7-[3-(4-methyIpiperazinyl)-propoxy]quinoIine-3-carbonitrile The title compound of Example 3, an anilino-3^quinolinecarbonitriles of formula 1(c) is synthesized according to Scheme 16.

A. Methyl 4-(3-chloropropoxy)-3-methoxybenzoate, 3(b). A mixture of 3(a) methyl vanillate ([3943-74-6], Acros Chemicals, AC16030)(10 mmol, 1.82 g), potassium carbonate (13 mmol, 1.8 g), 3- chloropropyltoluene sulfonate (ACX No. XI 153955-0) (15 mmol, 3.75 g) and tricaprylmethylammonium chloride (Sigma Aldrich, 20,561-3)(0.1 mmol, 40 mg) is dissolved in dry acetone (30mL) and stirred at reflux overnight. When the reaction is complete the reaction mixture is cooled to ambient temperature filtered to remove the solid precipitate. The supernatant is concentrated and the residue redissolved in methylene chloride. The methylene chloride solution is washed with IN NaOH, 10% aqueous KOH, aqueous sodium bicarbonate and brine, then dried (MgSO₄) and concentrated to yield the product 3(b), methyl 4- (3-chloropropoxy)-3-methoxybenzoate. B. Methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate. 3(c) To a solution of 3(b) (2.6 g, 10 mmol) glacial acetic acid (10 mL), is added 70% nitric acid (3 mL) dropwise over 20 minutes. The reaction mixture is heated to reflux for two hours, then poured into ice-water, and extracted with methylene chloride. The organic layer is washed with water and 0.5N NaOH, and then dried (MgSO₄), and concentrated to yield the 2-nitro derivative. The nitro intermediate is reduced by heating at reflux in a solution of ammonium chloride (1.7 g, 32 mmol) and iron dust (1.16 g, 20 mmol) in water methanol (10 mL/25 mL). When the reaction is complete, the reaction mixture is cooled to ambient temperature and filtered and extracted with methylene chloride. The methylene chloride extract is dried and concentrated. The resulting residue is purified by trituration with ether hexane (1:10) to yield intermediate 3(c), methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate.

C. 7-(3-Chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile.3(d). A mixture of intermediate 3(c) (2,0 g, 7.2 mmol) and DMF dimethylacetal (1.3 g, 11 mmol) is heated to reflux for about 8 hours. When the reaction is complete the reaction mixture is concentrated under vacuum to provide crude intermediate quinoline ester, 5-(3-chloropropoxy)-2- {[(dimethylamino)methylene] amino }-4-methoxybenzoate that is used without additional purification in the next step. n-Butyl lithium (20 mmol of 1.6M in hexane) is dissolved in dry THF (25 mL) at -78° C. Dry acetonitrile (15 mmol, 0.62 mL) dissolved in THF (25 mL) is added dropwise. The resulting mixture is stirred for fifteen minutes. A solution df 5-(3-chloropropoxy)-2- { [(dimethylamino)methylene]amino} -4- methoxybenzoate, in THF (20 mL) is added dropwise over about thirty minutes. The reaction mixture is stirred for about 30 minutes at -78° C. Acetic acid (21 mmol, 1.3 g) is added and the mixture is allowed to warm to ambient temperature and stir overnight. The mixture is then diluted with water (80 mL) and stirred rapidly for about twenty minutes. The solid precipitate is separated by filtration, washed with ether and dried to yield the intermediate 3(d). D. 4-Chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile, 3(e). A mixture of intermediate 3(d) (1 g, 3.4 mmol) and phosphorous oxy chloride (4.7 g, 30 mmol) is heated to reflux for one hour. The mixture is then concentrated. Aqueous sodium bicarbonate is added to the residue. The resulting precipitate is removed by filtration and dried to yield the intermediate 3(e), 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile.

E. 4-[(2.4-dichloro-5-methoxyphenyl)amino1-6-methoxy-7-[3-(4-methyl- piperazinyl)-propoxy1quinoline-3-carbonitrile. Intermediate 3(e) (1 mmol, 310 mg) in a mixture of pyridine hydrochloride ((130 mg, 1.1 mmol) and 2-ethoxyethanol (20 mL) is reacted with 2,4-dichloro-5-methoxy aniline (1.1 mmol) by heating to reflux for about six hours. When the reaction is complete, the mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated under vacuum to yield the 4-anilinoquinoline. This intermediate is used without further purification in the next step. The intermediate, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(3- chloropropoxy)-6-methoxyquinoline-3-carbonitrile is added to N- methylpiperazine (2 mL) along with a catalytic amount of sodium iodide. The mixture is heated to 90° C for 17 hours. When the reaction is complete, the reaction mixture is partitioned between brine (10 mL) and ethyl acetate (20 mL). The organic layer is dried (sodium sulfate) and concentrated. The resulting residue is purified by preparative HPLC to yield Example 3, 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazinyl)- propoxy]quinoline-3-carbonitrile.

Example 4. Synthesis of 2-{f(2,5-dihvdroxyphenyl)methyllamino}- benzamide The title compound of Example 4, a tyrphostin of formula 1(d). is synthesized according to Scheme 17.

Scheme 17

A. (2,5-Dimethoxyphenyl)methyl methylsulfonate. 2,5-Dimethoxybenzyl alcohol 4(a) [33524-31-1] (Aldrich, 18,787-9) (10 mmol, 1.7 g) is dissolved in methylene chloride (25 mL). N,N-(Diisopropyl)- aminomethylpolystyrene (Argonaut, #80279)(10 equivalents) is added. Methanesulfonyl chloride (Aldrich, 47,125-9) (10 mmol, 1.15 g) is added dropwise. The resulting suspension is stirred 12 hours at ambient temperature. The mixture is filtered and concentrated and the residue is used for the following step without further purification

B. 2-{[(2,5-Dimethoxyphenyl)methyl]aminolbenzamide, 4(d). (2,5-Dimethoxyphenyl)methyl methylsulfonate 4(b), anthranilamide 4(c) [88- 68-6] (Acros, AC0490) (10 mmol) and potassium carbonate (50 mmol) are stirred together in acetonitrile at 50° C for 12 hours. When the reaction is complete, the reaction mixture is filtered, concentrated and purified by preparative HPLC to yield the intermediate 4(d).

C. 2-([(2,5-Dihydroxyphenyl)methyl]amino}benzamide. 2-{[(2,5-Dimethoxyphenyl)methyl]amino}benzamide 4(d), is dissolved in methylene chloride and cooled to 0° C in an ice-water bath. Boron tribromide (2 equivalents) is added dropwise and the reaction mixture is stirred and allowed to come to ambient temperature over 12 hours. The reaction mixture is concentrated under vacuum and the residue is purified by preparative HPLC to yield the tyrphostin Example 4 compound.

Example 5. Synthesis of (3-chloro-4-fluorophenyl)[7-methoxy-6-(3- morpholin-4-ylpropoxy)quinazolin-4-yl]amine The title compound of Example 5, a quinazoline of formula 1(e). is synthesized according to Scheme 18.

A. 6-Hydroxy-7-methoxy-3,4-dihvdroquinazolin-4-one. 5(b). 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one 5(a) (European Patent Application No. 0 566 226, Example 1 thereof; (26.5 g) is added portionwise to stirred methanesulphonic acid (175 mL). L-Methionine (22 g) is added and the reaction mixture is heated to reflux for 5 hours. The mixture is cooled to ambient temperature and poured into ice-water (750 mL). The mixture is neutralized by the addition of a concentrated (40%) aqueous sodium hydroxide solution. The precipitate is collected by filtration, washed with water and dried to yield 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one., 5(b)

B. 6-Acetoxy-7-methoxy-3.4-dihvdroquinazolin-4-one. 5(c). A mixture of 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one 5(b) (14.18 g), acetic anhydride (110 mL) and pyridine (14 mL) is stirred and heated to 100° C for 2 hours. The mixture is cooled to ambient temperature and poured into ice-water (200 mL). The resulting precipitate is collected by filtration, washed with water and dried to yield 5(c) 6-acetoxy-7-methoxy-3,4- dihydroquinazolin-4-one. C. 6-Acetoxy-4-chloro-7-methoxyquinazoline, 5(d). A mixture of 5(c) 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (15 g), thionyl chloride (215 mL) and DMF (4.3 mL) is stirred and heated to 90° C for 4 hours. The mixture is cooled to ambient temperature and concentrated under vacuum to yield 5(d), 6-acetoxy-4-chloro-7-methoxyquinazoline, hydrochloride salt, which intermediate is used without further purification.

P. 6-Acetoxy-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline. 5(e) A mixture of 5d, 3-chloro-4-fluoroaniline [367-21-5] (9.33 g) and isopropanol (420 mL) is heated to 90° C for ,5 hours, then cooled to ambient temperature. The precipitate formed is collected by filtration, washed in turn with isopropanol and methanol, and then dried to yield the HCl salt of 5(e), 6- acetoxy-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline.

E. 4-(3'-Chloro-4'-fluoroanilino)-6-hvdroxy-7-methoxyquinazoline, 5(f). A concentrated aqueous ammonium hydroxide solution (28% weight/volume, 7.25 mL) is added to a stirred mixture of 5e in methanol (520 mL). The resulting mixture is stirred at ambient temperature for 17 hours and then heated to 100° C for 1.5 hours. The mixture is then cooled and the precipitate collected by filtration and dried to yield 5(f), 4-(3'-chloro-4'- fluoroanilino)-6-hydroxy-7-methoxyquinazoline.

F. 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)- quinazoline, 5(g). A mixture of 5(f), 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7- methoxyquinazoline (1 g), 3-morpholinopropyl chloride (J. Amer. Chem. Soc, 1945, 67, 736; 0.62 g), potassium carbonate (2.5 g) and DMF (50 mL) is heated to 80° C for 2 hours. A second portion (0.1 g) of 3-morpholinopropyl chloride is added and the mixture is heated to 80° C for an additional 1 hour. The mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography (25%) methanol in ethyl acetate) to yield the Example 5 compound, 4-(3 '-chloro-4'-fluoroanilino)-7-methoxy-6-(3 -morpholinopropoxy)- quinazoline.

Example 6: Inhibition of ABL Tyrosine Kinase by N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)- methyl)benzamide: Method A The inhibition of ABL activity by compounds of formula I was demonstrated as follows. Purified (5-10 ng) recombinant human c-abl (Abll, Histidine tagged, Panvera, CA) was incubated with various concentrations of N- (3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methyl- piperazin-l-yl)methyl)benzamide (Abl inhibitor) for 30 minutes in kinase buffer (50 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), 0.1% ΝP-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl₂, pH 7.5) at room temperature in a total volume of 15 μl. Following the incubation period, kinase reactions were performed by adding cold ATP and γ-32P-ATP in the presence of 6 μg of ABL kinase substrate (recombinant murine Crk) for 20 minutes at 30°C. The reactions were stopped by the addition of 20 μl of 2x SDS sample buffer. The samples were boiled and resolved on a 10 % SDS-polyacrylamide gel. The gel was fixed, and exposed to X-ray film. The exposed gel is reproduced in Figure 1, wherein the darker spots on the film indicate less enzyme inhibition. Quantitation of Crk phosphorylation may also be determined using a phosphoimager system (Fuji).

Example 7: Inhibition of ABL Tyrosine Kinase by N-(3-(4-(pyridin-3- yI)pyrimidin-2-ylamino)-4-methyl-phenyI)-4-((4-methyIpiperazin-l- yl)methyl)benzamide: Method B - Quantitation using filter assay. Purified (5-10 ng) recombinant human c-abl (Abll, Histidine tagged, Panvera, CA) was incubated with various concentrations of N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)- benzamide for 30 minutes in kinase buffer (50 mM HEPES, 0.1% ΝP-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl₂, pH 7.5) at room temperature in a total volume of 15 μl. Following the incubation period, kinase reactions were perfonned by adding cold ATP and γ-32P-ATP in the presence of Crk (6 μg) for 20 minutes at 30° C. After incubation, 10 μl aliquots were spotted onto 2 cm x 2 cm P81 phosphocellulose paper. The paper was air dried and then washed 3x with 0.75% phosphoric acid, and fixed with acetone for 5 minutes. The wet filters were then placed into scintillation vials containing scintillation fluid (Ecolume) and counted for 32P using a scintillation counter. The counts per minute (CPM) of each treated sample were compared to the amount of radioactivity resulting from control reactions in the presence of DMSO. The reactions were performed in triplicates, and the average CPM +/- SD for each were plotted as percent of solvent treated control. The dose response data are listed in Table 4 and plotted in Figure 2. Table 4:

Example 8: Inhibition of ABL Tyrosine Kinase by Compounds according to Formula II: Method B - Quantitation using filter assay. Purified (5-10 ng) recombinant human c-abl (Abll, Histidine tagged, Panvera, CA) was incubated with various concentrations of each compound of Formula II listed in Table 5 for 30 minutes in kinase buffer (50 mM HEPES, 0.1% NP-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl₂, pH 7.5) at room temperature in a total volume of 15 μl. Following the incubation period, kinase reactions were performed by adding cold ATP and γ-32P-ATP in the presence of Crk (6 μg) for 20 minutes at 30° C. After incubation, 10 μl aliquots were spotted onto 2 cm x 2 cm P81 phosphocellulose paper. The paper was air dried and then washed 3x with 0.75% phosphoric acid, and fixed with acetone for 5 minutes. The wet filters were then placed into scintillation vials containing scintillation fluid (Ecolume) and counted for 32P using a scintillation counter. The counts per minute (CPM) of each treated sample were compared to the amount of radioactivity resulting from control reactions in the presence of DMSO. The reactions were performed in triplicates, and the average CPM +/- SD for each were plotted as percent of solvent treated control. The ICso's of compounds 1-24 are listed in Table 5. The dose response curves for compounds 1-5, 6-10, 11-15, 16-20, and 21-24 are provided in Figures 5, 6, 7, 8 and 9, respectively. Table 5

-

* indicates IC₅₀ > 10μM; ** indicates lμM > IC₅₀ > 10μM; *** indicates IC₅₀ < lμM

Example 9: Inhibition of ABL Tyrosine Kinase by a Composition Comprising N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)- 4-((4-methylpiperazin-l-yl)methyl)benzamide and 4-((lE)-2-{[(4- chIorophenyl)methyl]sulfonyl}vinyl)benzoic acid: Method A Ten ng of recombinant c-Abl-1 protein (Panvera) was incubated with different concentrations of a mixture of N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide and 4-((lE)-2-{[(4-chlorophenyl)methyl]-sulfonyl}vinyl)benzoic acid (Compound 23 in Table 5) in a 15 μl reaction mixture (50 mM HEPES, 10 mM MgC12, 1 mM EDTA, 2 mM DTT and 0.01% NP-40, pH 7.5) for 30 min at room temperature. Kinase reactions were initiated by the addition of 2 μl of 1 mM ATP (lOOμM concentration), 2 μl of γ32pATP (40 μci final concentration) and 6 μg of recombinant GST-Crk (Upstate). Reactions were performed for 20 min at 30°C and were stopped by the addition of 20 μl of 2XSDS-PAGE buffer, boiled and subjected to SDS-PAGE using a 12% polyacrylamide gel. Following electrophoresis, the gel was dried and exposed to X-ray film for 3-10 min. The exposed gel is reproduced in Figure 1, wherein the darker spots on the film indicate less enzyme inhibition. The data show that, for a composition containing 10 nM N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl- phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide and 1 nM of 4-((lE)-2- {[(4-chlorophenyl)methyl]sulfonyl}vinyl)benzoic acid, the kinase activity of C- abl was completely blocked. The concentration of either agent individually required to completely block c-abl kinase activity was 1 μM.

Example 10: Radioprotective Effect of N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide on Cultured Normal Cells: The radioprotective effect of N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide on cultured normal cells was evaluated as follows. HFL-1 cells, which are normal diploid lung fibroblasts, were plated into 24 well dishes at a cell density of 3000 cells per 10 mm² in DMEM completed with 10% fetal bovine serum and antibiotics. N-(3-(4-(pyridin-3-yl)pyrimidin- 2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide was added to the cells 24 hours later at concentrations 0.25, 0.5, 1.0 and 2.0 micromolar, using DMSO as a solvent. Control cells were treated with DMSO alone. The cells were exposed to the test compound or DMSO for 24 hrs. The cells were then irradiated with either 10 Gy or 15 Gy of ionizing radiation (IR) using a J.L. Shepherd Mark I, Model 30-1 Irradiator equipped with ¹³⁷cesium as a source. After irradiation, the medium on the test and control cells was removed and replaced with fresh growth medium without the test compounds or DMSO. The irradiated cells were incubated for 96 hours and duplicate wells were trypsinized and replated onto 100 mm² tissue culture dishes. The replated cells were grown under normal conditions with one change of fresh medium for 3 weeks. The number of colonies from each 100 mm² culture dish, which represents the number of surviving cells, was determined by staining the dishes as described below. To visualize and count the colonies derived from the clonal outgrowth of individual radioprotected cells, the medium was removed and the plates were washed one time with ambient temperature phosphate buffered saline. The cells were stained with a 1:10 diluted Modified Giemsa staining solution (Sigma) for 20 minutes. The stain was removed, and the plates were washed with tap water. The plates were air-dried, the number of colonies from each plate was counted and the average from duplicate plates was determined. The results are shown in Figure 3. The radioprotective activity of N-(3- (4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin- l-yl)methyl)benzamide is substantial, demonstrating a greater than 90% increase in the number of cells surviving irradiation when treated at 1.0 micromolar concentration.

Example 11: Radioprotective Effect of a Composition Comprising a Mixture of iV-(3-(4-(pyridin-3-yl)pyrimidin-2-yIamino)-4-methyl-phenyl)-4- ((4-methyIpiperazin-l-yl)methyl)benzamide and a Compound of Formula II or an Antioxidant Compound on Cultured Normal Cells: The radioprotective effect of a composition comprising N-(3-(4-(pyridin- 3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l- yl)methyl)benzamide in combination with either a compound of formula II (e.g., 4-((lE)-2-{[(4-chlorophenyl)methyl]sulfonyl}vinyl)benzoic acid (compound 23 of Table 5)) or an antioxidant compound on cultured normal cells is evaluated as follows. HFL-1 cells, which are normal diploid lung fibroblasts, are plated into 24 well dishes at a cell density of 3000 cells per 10 mm² in DMEM completed with 10% fetal bovine serum and antibiotics. N-(3-(4-(pyridin-3-yl)pyrimidin- 2-y lamino)-4-methyl-phenyl)-4-((4-methy lpiperazin- 1 -yl)methy l)benzamide, is added to the cells 24 hours later at concentrations 0.25, 0.5, 1.0 and 2.0 micromolar, alone or in combination with either an antioxidant compound or a compound of formula II (e.g., compound 23) using DMSO as a solvent. Control cells are treated with DMSO alone. The cells are exposed to the test compound (or combination of compounds) or DMSO for 24 hrs. The cells are then irradiated with either 10 Gy or 15 Gy of ionizing radiation (IR) using a J.L. Shepherd Mark I, Model 30-1 Irradiator equipped with ¹³⁷cesium as a source. After irradiation, the medium on the test and control cells is removed and replaced with fresh growth medium without the test compounds or DMSO. The irradiated cells are incubated for 96 hours and duplicate wells are trypsinized and replated onto 100 mm² tissue culture dishes. The replated cells are grown under normal conditions with one change of fresh medium for 3 weeks. The number of colonies from each 100 mm² culture dish, which represents the number of surviving cells, is determined by staining the dishes as described below. To visualize and count the colonies derived from the clonal outgrowth of individual radioprotected cells, the medium is removed and the plates are washed one time with ambient temperature phosphate buffered saline. The cells are stained with a 1:10 diluted Modified Giemsa staining solution (Sigma) for 20 minutes. The stain is removed, and the plates are washed with tap water. The plates are air-dried, the number of colonies from each plate is counted and the average from duplicate plates is determined.

Example 12: Treatment of bcr-abl Transformed Leukemic Cells by a Composition Comprising N-(3-(4-(pyridin-3-yI)pyrimidin-2-ylamino)-4- methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide (A Compound of Formula T) and (lE)-2-(2,4-difluorophenyI)-l-{[(4- bromophenyl)methyl]sulfonyl}ethene (A Compound of Formula IT): K562 cells, a cell line isolated from a 35 year old patient with chronic myelogenous leukemia (CML), transformed due to the Philadelphia chromosome translocation resulting in the expression of bcr-abl kinase was used as the target cell line. K562 cells were plated at a cell density of 1.0 x 10⁵ cells/mL in 12 well dishes and treated with a constant concentration (0.2 μM) of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methyl- piperazin-l-yl)methyl)benzamide (a concentration that would reduce the growth of K562 cells by no more than 20% based upon previous dose response assays). The cells were further treated with a series of concentrations of the compound ( 1 E)-2-(2,4-difluorophenyl)- 1 - { [(4-bromophenyl)-methyl] sulfonyl} ethene. Following an incubation period of 96 hours at 37°C under 5% CO₂, the number of viable cells remaining in each well was determined by counting using a hemacytometer and trypan blue staining. The total number of viable cells remaining was calculated and plotted as the percent of vehicle treated control cells. The results are depicted in Figure 4. The data shows that a final concentration of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)- 4-((4-methylpiperazin-l-yl)methyl)benzamide at 0.2 μM resulted in only 20% inhibition of K562 cell growth. When these cells were treated in the presence of both N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4- methylpiperazin-l-yl)methyl)benzamide and the (lE)-2-(2,4-difluorophenyl)-l- {[(4-bromophenyl)methyl]sulfonyl}ethene, there was observed an additive effect on K562 cell growth.

Example 13: Effect of Exposure to Ionizing Radiation on Normal and Malignant Hematopoietic Progenitor Cell Growth After Pretreatment with N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4- methylpiperazin-l-yl)methyl)benzamide. The effect of ionizing radiation on normal and malignant hematopoietic progenitor cells which are pretreated with N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiρerazin- 1 -yl)methyl)benzamide is determined by assessing cloning efficiency and development of the pretreated cells after irradiation. To obtain hematopoietic progenitor cells, human bone marrow cells (BMC) or peripheral blood cells (PB) are obtained from normal healthy, or acute or chronic myelogenous leukemia (AML, CML), volunteers by Ficoll- Hypaque density gradient centrifugation, and are partially enriched for hematopoietic progenitor cells by positively selecting CD34⁺ cells with immunomagnetic beads (Dynal A.S., Oslo, Norway). The CD34⁺ cells are suspended in supplemented alpha medium and incubated with mouse anti- HPCA-I antibody in 1 :20 dilution, 45 minutes, at 4°C with gentle inverting of tubes. Cells are washed x 3 in supplemented alpha medium, and then incubated with beads coated with the Fc fragment of goat anti-mouse IgGi (75 μl of immunobeads/107 CD34⁺ cells). After 45 minutes of incubation (4°C), cells adherent to the beads are positively selected using a magnetic particle concentrator as directed by the manufacturer. ' 2 x 10⁴ CD34⁺ cells are incubated in 5 mL polypropylene tubes (Fisher Scientific, Pittsburgh, PA) in a total volume of 0.4 mL of Iscove's modified Dulbecco's medium (IMDM) containing 2% human AB serum and 10 mM Hepes buffer. N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4- ((4-methylpiperazin-l-yl)methyl)benzamide is added to the cells; in four different concentrations (0.25 μM, 0.5 μM, 1.0 μM and 2.0 μM) is added separately to the cells. Control cells receive DMSO alone. The cells are incubated for 20-24 hours and irradiated with 5 Gy or 10 Gy of ionizing radiation. Immediately after irradiation, the medium is removed and replaced with fresh medium without the test compound or DMSO. Twenty-four hours after irradiation, the treatment and control cells are prepared for plating in plasma clot or methylcellulose cultures. Cells (1 x 1Q⁴ CD34⁺ cells per dish) are not washed before plating. Assessment of the cloning efficiency and development of the treated hematopoietic progenitor cells are carried out essentially as reported in Gewirtz et al, Science 242, 1303-1306 (1988), the disclosure of which is incorporated herein by reference.

Example 14: Bone Marrow Purging with Ionizing Radiation After Pretreatment with N-(3-(4-(pyridin-3-yl)pyrimidin-2-yIamino)-4-methyI- phenyl)-4-((4-methylpiperazin-l-yl)methyI)benzamide. Bone marrow is harvested from the iliac bones of an individual under general anesthesia in an operating room using standard techniques. Multiple aspirations are taken into heparinized syringes. Sufficient marrow is wididrawn so that the individual will be able to receive about 4 x 10⁸ to about 8 x 10⁸ processed marrow cells per kg of body weight. Thus, about 750 to 1000 mL of marrow is withdrawn. The aspirated marrow is transferred immediately into a transport medium (TC-199, Gibco, Grand Island, New York) containing 10,000 units of preservative-free heparin per 100 mL of medium. The aspirated marrow is filtered through three progressively finer meshes to obtain a cell suspension devoid of cellular aggregates, debris and bone particles. The filtered marrow is then processed further into an automated cell separator (e.g., Cobe 2991 Cell Processor) which prepares a "buffy coat" product, (i.e., leukocytes devoid of red cells and platelets). The buffy coat preparation is then placed in a transfer pack for further processing and storage. It may be stored until purging in liquid nitrogen using standard procedures. Alternatively, purging can be carried out immediately, then the purged marrow may be stored frozen in liquid nitrogen until it is ready for transplantation. The purging procedure is carried out as follows. Cells in the buffy coat preparation are adjusted to a cell concentration of about 2 x 10⁷/mL in TC-199 containing about 20% autologous plasma. N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-pheny l)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide; for example, at a concentration of from 0.25 μM to 2.0 μM is added to the transfer packs containing the cell suspension and incubated in a 37°C waterbath for 20- 24 hours with gentle shaking. The transfer packs are then exposed to 5-10 Gy ionizing radiation. Recombinant human hematopoietic growth factors, e.g., rH IL-3 or rH GM-CSF, may be added to the suspension to stimulate growth of hematopoietic neoplasms and thereby increase their sensitivity to ionizing radiation. The cells may then either be frozen in liquid nitrogen or washed once at

4°C in TC-199 containing about 20% autologous plasma. Washed cells are then infused into the individual. Care must be taken to work under sterile conditions wherever possible and to maintain scrupulous aseptic techniques at all times. All references discussed herein are incorporated by reference. One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope ofthe invention.

Claims

CLAIMS What is claimed is:

1. A method for protecting an individual from cytotoxic side effects of ionizing radiation, comprising administering to said individual an effective amount of at least one compound of formula I:

wherein: L is selected from the group consisting of O, S, and N-R¹; R¹ is -H or -(C C₇)hydrocarbyl; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -CONH₂, -CO₂H, -CO₂(C_rC₁₂)hydrocarbyl, -C(=0)NH(C₂-C₆)alkylene-NH₂, -0(Ci-C₇)hydrocarbyl, -NH(Cι- C₇)hydrocarbyl, -C(=O)(Cι-C₇)hydrocarbyl, -S(O)_d(Cι-C₇)hydrocarbyl, halogen, -(Cι-C₆)alkylene-OH, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, heterocyclyl(Cι-C₆)alkylene, and heteroaryl(Cι-C₆)alkylene; a and b are independently selected from the group consisting of 0, 1 and 2; d is 0, 1 or 2; each R³ is independently selected from the group consisting of -OH, -NH₂, -NO₂, -(Cι-C₆)haloalkoxy, halogen, and a radical of formula (i)

R is a divalent radical selected from the group consisting of formula (ii), (iii), (iv) and (v): _S(0)h_ .

(«) (iϋ) (iv) (v)

wherein: h is 1 or 2; each R⁷ is independently selected from the group consisting of-H and (Cι-Ce)alkyl, R⁵ is O orN(R⁷); Y is (C_rC₆)alkylene e and g are independently selected from the group consisting of 0 and 1; f is 0 or 1, provided that f is 0 when R³ is a divalent radical of formula (ii) or (v); R⁶ is selected from the group consisting of -H, -(Cι-C₇)hydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A is a radical selected from the group consisting of formula (vi), (vii), (viii), and (ix):

(vi) (vϋ)

(viii) (ix) wherein: R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(Cι-C6)alkylene-NH-(Cι-C₆)alkyl, (C C6)acylamino(Cι-C6)alkyl, and substituted or unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(C]-C₆)alkyl; i is 0, 1 or 2; U is selected from the group consisting of N(H), N(Cι-C₆alkyl), N(C(=O)(Cι-C₆) alkyl), O, S, arylene and heteroarylene; V is (C₂-C₆)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted -NH(C₂-Cδ)alkylenylheterocyclyl, -NH(C₂- C₆)alkylene-N(Cι-C₆alkyl)₂ and -N(Cι-C₆alkyl)₂; R¹⁰ is -H or -0(C,-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R^u is -(Cι-C₇)hydrocarbyl or -(C₂-Cι₂)heteroalkyl; R¹² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -(Cι-C₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)_J(C₁-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided; when X is N, R¹⁰ is bonded to the 7-position and -U-V-W is bonded to the 6-position ofthe quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position and -U-V-W is bonded to the 7-position of the quinoline ring system; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein:

R² is -(Cι-C₇)hydrocarbyl.

3. The method of claim 2, wherein the administered compound comprises a compound of formula 1(a):

wherein: R² is -(Cι-C₇)hydrocarbyl; a is O or l; b is 1; R³ is a radical of formula (i):

wherein: R⁴ is a divalant radical of formula (iii):

(iii) e is 1; R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(Cι-C₆)alkylene-NH-(C₁-C₆)alkyl, (Q- C₆)(C=O)amino(Cι-C₆)alkyl, and substituted and unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(Cι-C₆)alkyl; i is 0, 1 or 2; or a pharmaceutically acceptable salt of such a compound.

4. The method of claim 3, wherein: f and g are 0; R⁶ is substituted aryl; R⁷ is -H; R⁸ is substituted or unsubstituted heteroaryl; and i is O.

5. The method of claim 4, wherein the compound is selected from the group consisting of: N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl- pheny l)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide; N-(3 -(4-(pyridin-3 - yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide; N-(3 -(4-(pyridin-3 -yl)pyrimidin-2-ylamino)phenyl)nicotinamide; N-(3 -(4-

(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-methylbenzamide; N-(3- (4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)hexanamide; N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methylphenyl)-2-naphthamide; N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-phenyl)-4-fluorobenzamide; N-(3 -(4-(pyridin-3 - yl)pyrimidin-2-ylamino)-phenyl)thiophene-2-carboxamide; N-(4-( 1 , 1 ,2,2- tetrafluoroethoxy)phenyl)-4-(l-(3-aminopropyl)-lH-indol-4-yl)pyrimidin-2- amine; N-(4-(l , 1 ,2,2-tetrafluoro-ethoxy)phenyl)-4-(l H-indol-3-yl)pyrimidin-2- amine; N-(3-(4-(pyridin-3-yl)-pyrimidin-2-ylamino)phenyl)benzamide; N-(3-(4- (pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)benzamide; 3-(4-(pyridin- 3 -yl)pyrimidin-2-ylamino)-N-(3 -aminopropyl)benzamide; Ν-(3 -(4-(pyridin-3 - yl)pyrimidin-2-ylamino)-phenyl)cyclohexanecarboxamide; N-(3 -(4-(pyridin-3 - yl)pyrimidin-2-ylamino)-phenyl)isonicotinamide; NI -(4-(pyridin-4- yl)pyrimidin-2-yl)benzene- 1 ,3 -diamine; NI -(4-(pyridin-3 -yl)pyrimidin-2- yl)benzene- 1 ,3 -diamine; N-(3 -(4-(pyridin-3 -y l)pyrimidin-2-ylamino)-4- methylphenyl)-2-methoxybenzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylphenyl)-4-chlorobenzamide; N-(3-(2-(lH-imidazol- 1 - yl)ethoxy)phenyl)-4-(pyridin-3-yl)pyrimidin-2-amine; N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)phenyl)-4-methylbenzamide; N-(3 -nitrophenyl)-4-

(pyridin-2-yl)pyrimidin-2-amine; N-(3-(4-(pyridin-3-yl)-pyrimidin-2- ylamino)phenyl)-4-cyanobenzamide; Nl-(5-methyl-4-(pyridin-3-yl)pyrimidin-2- yl)benzene- 1,3 -diamine; N-(3-chlorophenyl)-4-(pyridin-3-yl)-pyrimidin-2- amine; N-phenyl-4-(pyridin-3-yl)pyrimidin-2-amine; N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)phenyl)-2-methoxybenzamide; 2-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)phenylcarbamoyl)benzoic acid; N-(3-( 1 H-imidazol- 1 - yl)phenyl)-4-(pyridin-3 -y l)pyrimidin-2-amine; N-(3 -(4-(pyridin-3 -yl)pyrimidin- 2-y lamino)phenyl)picolinamide; methyl 3 -(4-(pyridin-3 -yl)-pyrimidin-2- y lamino)benzoate; N-(3 -(4-(pyridin-3 -yl)pyrimidin-2-ylamino)-4- methylphenyl)proρionamide; and pharmaceutically acceptable salts thereof.

6. The method of claim 5 wherein the administered compound is {4-[(4- methylpiperazinyl)methyl]phenyl}-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2- yl)amino]phenyl}carboxamide, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 wherein: L is ΝR¹; each R² is independently selected from the group consisting of -(C_rC₇)hydrocarbyl, -O(Cι-C₇)hydrocarbyl, -S(O)_d(C]-C₇)hydrocarbyl, halogen, -(Cι-C₆)alkylene-OH, and substituted and unsubstituted heterocyclyl; d is 0, 1 or 2; each R³ is selected from the group consisting of -OH, -ΝH₂, -NO₂, -(Cι-C₆)haloalkoxy, and halogen; and A is a radical of formula (viii):

(viii) wherein: R¹¹ is -(Cι-C₇)hydrocarbyl; and R¹² is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

8. The method of claim 7, wherein the administered compound comprises a compound of formula 1(b):

wherein: a is 1 or 2; b is 0 or 1; R¹¹ is -(Cι-C₇)hydrocarbyl; and R¹² is selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; or a pharmaceutically acceptable salt of such compound.

9. The method of claim 8, wherein the administered compound is selected from the group consisting of: 6-(2,6-dichlorophenyl)-2-[(4-fluoro-3- methylphenyl)amino]-8-methyl-8-hydropyridino[2,3-d]pyrimidin-7-one; 6-(2,6- dichlorophenyl)-8-methyl-2-[(3-methylthiophenyl)amino]-8-hydropyridino[2,3- d]pyrimidin-7-one; 6-(2,6-dichlorophenyl)-2- { [3-(hydroxymethyl)phenyl]- amino}-8-methyl-8-hydropyridino[2,3-d]pyrimidin-7-one; 6-(2,6-dichloro- phenyl)-2-[(4-ethoxyphenyl)amino]-8-methyl-8-hydropyridino-[2,3- d]pyrimidin-7-one; 6-(2,6-dichlorophenyl)-2-[(4-fluorophenyl)amino]-8-methyl- 8-hydropyridinophenyl)-8-methyl-2-[(4-morpholin-4-ylphenyl)amino]-8-hydro- pyridino[2,3-d]-pyrimidin-7-one; and pharmaceutically acceptable salts thereof.

10. The method of claim 1 , wherein: L is NR¹; each R² is independently selected from the group consisting of -(C]-C₇)hydrocarbyl, -O(Cι-C )hydrocarbyl, halogen, substituted and unsubstituted heterocyclyl, heterocyclyl(Cι-C₆)aϊkylene, and heteroaryl(C_!-C6)alkylene; a is 0, 1 or 2; R³ is selected from the group consisting of -NH₂, -NO₂, -(Cj- Ce)haloalkoxy, and halogen; b is 0 or 1; A is a radical of formula (vii):

(vii) wherein: X is C-CN; R¹⁰ is -H or -O(C_!-C₇)hydrocarbyl; U is selected from the group consisting of N(H), N(Cι-Cealkyl), O, S, arylene, and heteroarylene; V is (Cι-C₆)alkylene; and W is substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl(Cι-C₆)alkylenylamino, or -NH(C₂- C₆)alkylene-N(C₁-C₆ alkyl)₂.

11. The method of claim 10, wherein the administered compound comprises a compound of formula 1(c):

wherein: U is selected from the group consisting of O, S, arylene and heteroarylene; V is (Cι-C₆)alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclyl(Cι-C₆)alkylenylamino, and -NH(C₂-C_δ)alkylene-N(Cι-C₆ alkyl)₂; or a pharmaceutically acceptable salt of such a compound.

12. The method of claim 11, wherein: TJ is O; V is -CH₂CH₂CH₂-; and W is 4-methylpiperazin-l-yl.

13. The method of claim 12 wherein: each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -O(Cι-C₇)hydrocarbyl, and halogen; a and b are independently selected from 1 and 2; and each R³ is independently selected from the group consisting of -NH₂, -NO₂,

and halogen.

14. The method of claim 13 wherein the administered compound is 4-[(2,4- dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazinyl)- propoxy]-quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 wherein: L is selected from the group consisting of O, S and N-R¹; R' is -H; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocart>yl, -CO₂H, -CO₂(Cι-Cι₂)hydrocarbyl, -CONH₂, -C(=O)NH(C₂-C₆)alkylene-NH₂, -C(=O)(C₁-C₇)hydrocarbyl, -S(O)_d(Cι- C₇)hydrocarbyl, halogen, -(Cι-C6)alkylene-OH, and substituted and unsubstituted heterocyclyl; a is 1 or 2; A is a radical of formula (ix):

^(iχ) wherein: each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -O(d-C₆)alkyl, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)j(Cι-C₆)al yl; j is 0, 1 or 2; and k is 1, 2 or 3.

16. The method of claim 15 wherein the administered compound comprises a compound of formula 1(d):

wherein: R² is selected from the group consisting of -CO₂H, -CO₂(Cι- C₆)alkyl, -CO₂(C₃-Cι₂)cycloalkyl, and substituted and unsubstituted heterocyclyl; a is 1; and b is 0; or a pharmaceutically acceptable salt of such a compound.

17. The method of claim 16 wherein the administered compound is selected from the group consisting of: methyl 4-{[(2,5-dihydroxyphenyl)- methyl]amino}benzoate; 3-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid; 2-[(2,5-dihydroxyphenyl)methylthio]benzoic acid; 2-{[(2,5-dihydroxyphenyl methyl]amino}benzamide; 2-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid; 4-{[(2,5-dihydroxyphenyl)methyl]amino}benzamide; methyl 2-{[(2,5- dihydroxyphenyl)methyl]amino}benzoate;' and pharmaceutically acceptable salts thereof.

18. The method of claim 1 wherein: L is NR¹; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -O(C]-C₇)hydrocarbyl, halogen, substituted and unsubstituted heterocyclyl, heterocyclyl(Cι-C6)alkylene, and heteroaryl(C 1 -Ce)alkylene; a is 1 or 2; b is O; A is a radical of formula (vii):

(vii) wherein: X isN; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl; U is selected from the group consisting of N(H), N(Cι-C6alkyl), O, S, arylene and heteroarylene; V is (Cι-Ce)alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted -NH(Cr C₆)alkylenylheterocyclyl, and -NH(C2-C6)alkylene-N(C₁-C₆alkyl)₂.

19. The method of claim 18 wherein the administered compound comprises a compound of formula 1(e):

wherein: U is selected from the group consisting of O, S, arylene, and heteroarylene; V is (Cι-Ce)alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted -NH(Cι- C₆)alkylenylheterocyclyl, and -NH(C2-C6)alkylene-N(Cι-C6alkyl)₂; or a pharmaceutically acceptable salt of such a compound.

20. The method of claim 19 wherein the administered compound is (3- chloro-4-fluorophenyl)[7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4- yl]amine, or a pharmaceutically acceptable salt thereof.

21. The method of claim 1, wherein the radioprotective compound is administered before exposure to the ionizing radiation.

22. The method of claim 1, wherein the radioprotective compound is administered after exposure to ionizing radiation.

23. The method of claim 1, further comprising administering to said individual an effective amount of at least one compound of formula II:

Q 1. -x — CH=CH— cr wherein: Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below: O O - Ir(CH₂)_n-s II— §- -f — N — s n — %- O R^x O (i) (")

O O - § N— C II— i- - I|-(CH2)_n-S ii- i- R^x (iϋ) (iv) wherein, n is one or zero; and R^x is -H, -(Cι-C₈)hydrocarbyl or -C(=O)(C₁-C₈)hydrocarbyl; or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein X is selected from the group consisting of (i), (ii), and (iii) below:

25. The method of claim 24, wherein Q¹ is phenyl or substituted phenyl.

26. The method of claim 25, wherein Q² is phenyl or substituted phenyl.

27. The method of claim 26, wherein the compound of formula II is selected from the group consisting of: 4-((l£)-2-{[(4-fluorophenyl)- methyl] sulfonyl} vinyl)benzoic acid; 4-(( 1 E)-2- { [(4-iodophenyl)methyl]- sulfonyl}vinyl)benzoic acid; 4-((l-5)-2-{[(4-chlorophenyl)-methyl]- sulfonyl}vinyl)benzoic acid; l-[5-((li?)-2-{[(4-chlorophenyl)methyl]- sulfonyl } vinyl)-2-fluorophenyl]-2-(dimethy lamino)ethan- 1 -one; ( 1 E)-2-(2,4- difluorophenyl)-l-{[(4-bromophenyl)methyl]sulfonyl}ethene; (l£)-2-(3-amino- 4-fluorophenyl)- 1 - { [(4-chlorophenyl)methyl] sulfonyl} ethene; 2-(5-(((E)-2,4,6- trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)-acetic acid; (R)-2-(5- ((( )-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)- propanoic acid; (S)-2-(5-(((£)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2- methoxyphenylamino)-propanoic acid; racemic-2-(5-(((JS)-2,4,6-trimethoxy- styrylsulfonyl)methyl)-2-methoxyphenyl-amino)propanoic acid; (R)-2-(5-(((-5)- 2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)-2-phenylacetic acid; (S)-2-(5-(((E)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl- amino)-2-phenylacetic acid; racemic-2-(5-(((E)-2,4,6-trimethoxystyryl- sulfonyl)methy l)-2-methoxyphenyl-amino)-2-pheny lacetic acid; N-(3 -(((-5)- 2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl)-4-(4-methyl- piperazin-l-yl)benzamide; 2-((£)-2-(4-methoxybenzylsulfonyl)vinyl)- 1,3,5- trimethoxybenzene; l-(((£}-4-chlorostyrylsulfonyl)methyl)-2-chloro-4- fluorobenzene; 4-(( )-2-(4-chlorobenzylsulfonyl)vinyl)- 1 -fluoro-2-nitro- benzene; 4-((£)-2-(3-amino-4-methoxybenzylsulfonyl)vinyl)benzoic acid; 5- (((-5)-2,4-difluorostyrylsulfonyl)methyl)-2-methoxybenzenamine; l-bromo-4- (((£)-perfluorostyrylsulfonyl)methyl)benzene; l-(((_JE)-2,3,5,6-tetrafluorostyryl- sulfonyl)methyl)-4-bromobenzene; l-(((.5)-2,4,5-trifluorostyrylsulfonyl)- methyl)-4-bromobenzene; 1 -(((j5)-2,4,6-trifluorostyrylsulfonyl)methyl)-4- bromobenzene; 1 -(((E)-2,3 ,6-trifluorostyrylsulfonyl)methyl)-4-bromobenzene; 5-(((£)-2,4-difluorostyrylsulfonyl)methyl)-2-bromobenzenamine; 4-(((E)-2,4- difluorostyrylsulfonyl)methyl)benzoic acid; 5-(((E)-2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-bromobenzenamine; 4-((R)-2-(4-bromobenzylsulfonyl)- vinyl)- 1 -fluoro-2-nitrobenzene; 4-((-?)-2-(4-chloro-2-nitrobenzy lsulfonyl)vinyl)- l-fluoro-2-nitrobenzene; 5-((R)-2-(4-bromobenzylsulfonyl)vinyl)-2-fluoro- benzenamine; 5-((E)-2-(4-iodobenzylsulfonyl)vinyl)-2-fluorobenzenamine; 5- (((_JB)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzonitrile; 4-(((E)- 2,4,6-trimethoxystyrylsulfonyl)methyl)benzoic acid; 3-((E)-2-(4-bromobenzyl- sulfonyl)vinyl)-2,6-difluorophenol; 5-((2,4,6-trimethoxystyrylsulfonyl)methyl)- 2-methoxy-N-methylbenzenamine and pharmaceutically acceptable salts thereof.

28. The method of claim 1, further comprising administering to said individual an effective amount of at least one antioxidant compound.

29. The method of claim 28 wherein the antioxidant compound is selected from the group consisting of carotenoids, catechins, isoflavones, flavanones, flavanols, flavanoid chalcones, vitamin E compounds, (3-aminopropyl)[2- (phosphonothio)ethyl] amine, ascorbic acid, cysteine, glutathione, probucol, β- mercaptoethanol dithiothreitol, pyrrolidine dithiocarbamate, N-acetyl-L- cysteine, ubiquinone, meso-tetrakis-(N-alkylpyridinium-2-yl)porphyrins, meso- tetrakis-(N-alkylpyridinium-3-yl)porphyrins, and salts thereof.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, (A) at least one compound according to formula I:

wherein: L is selected from the group consisting of O, S, and Ν-R¹; R¹ is -H or -(C₁-C₇)hydrocarbyl; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -COΝH₂, -CO₂H, -CO₂(C₁-Cι₂)hydrocarbyl, -C(=O)NH(C₂-C₆)alkylene-NH₂, -O(C_rC₇)hydrocarbyl, -NH(d- C₇)hydrocarbyl, -C(=O)(Cι-C₇)hydrocarbyl, -S(O)_d(C₁-C₇)hydrocarbyl, halogen, -(Cι-C6)alkylene-OH, substituted and unsubstituted aryl, substituted' and unsubstituted heterocyclyl, heterocyclyl(Cι-C6)alkylene, and heteroaryl(Cι-C6)alkylene; a and b are independently selected from the group consisting of

0, 1 and 2; d is 0, 1 or 2; each R³ is independently selected from the group consisting of -OH, -NH₂, -NO₂, -(Cι-C₆)haloalkoxy, halogen, and a radical of formula (i)

R⁴ is a divalent radical selected from the group consisting of formula (ii), (iii), (iv) and (v): S(0)_h-|-

(ii) (iii) (iv) (v) wherein: h is 1 or 2; each R⁷ is independently selected from the group consisting of-H and (Cι-Ce)alkyl, R⁵ is O orN(R⁷); Y is (Cι-C₆)alkylene e and g are independently selected from the group consisting of 0 and 1; f is 0 or 1, provided that f is 0 when R³ is a divalent radical of formula (ii) or (v); R⁶ is selected from the group consisting of -H,

-(Cι-C₇)hydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A is a radical selected from the group consisting of formula (vi), (vii), (viii), and (ix):

(vi) (vii)

(viii) (ix) wherein: R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(Ci-C₆)alkylene-NH-(C₁-C₆)alkyl, (Ci- C₆)acylamino(Cι-C₆)alkyl, and substituted or unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(Cι-C₆)alkyl; i is 0, 1 or 2; U is selected from the group consisting of N(H), N(Cι-Cβalkyl),

S,. arylene and heteroarylene; V is (C₂-Cβ)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted -NH(C₂-C6)alkylenylheterocyclyl, -NH(C₂- C₆)alkylene-N(Cι-C₆alkyl)2 and -N(Cι-C₆alkyl)₂; R¹⁰ is -H or -0(Cι-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R^u is -(Cι-C₇)hydrocarbyl or -(C₂-C₁₂)heteroalkyl; R¹² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -(CrC₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)_j(C₁-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided; when X is N, R¹⁰ is bonded to the 7-position and -U-V-W is bonded to the 6-position ofthe quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position and -U-V-W is bonded to the 7-position ofthe quinoline ring system; or a pharmaceutically acceptable salt thereof; and (B) either (1) , at least one compound according to formula II:

Q¹ X— CH=CH— Q² II wherein, Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below:

(i) (ϋ)

⁽"0 (^iv) wherein, n is one or zero; and R^x is -H, -(Cι-C₈)hydrocarbyl or-C(=O)(Cι-C₈)hydrocarbyl; or a pharmaceutically acceptable salt of such a compound; or (2) at least one antioxidant compound.

31. The pharmaceutical composition of claim 30, wherein X is selected from the group consisting of (i), (ii), and (iii) below:

32. The composition according to claim 31, wherein part B comprises a compound of formula II.

33. The composition of claim 32, wherein the compound of formula II is selected from the group consisting of: 4-((l£T)-2-{[(4-fluorophenyl)- methyl]sulfonyl}vinyl)benzoic acid; 4-((l-5)-2-{[(4-iodophenyl)methyl]- sulfonyl}vinyl)benzoic acid; 4-((lE)-2-{[(4-chlorophenyl)methyl]sulfonyl}- vinyl)benzoic acid; l-[5-((l-5)-2-{[(4-chlorophenyl)methyl]-sulfonyl}vinyl)-2- fluorophenyl]-2-(dimethylamino)ethan-l-one; (1.5)-2-(2,4-difluorophenyl)-l- {[(4-bromophenyl)methyl]sulfonyl}ethene; (l-S)-2-(3-amino-4-fluorophenyl)-l- {[(4-chlorophenyl)methyl] sulfonyl} ethene; 2-(5-(((£)-2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-methoxyphenylamino)acetic acid; (R)-2-(5-(((E)-2,4,6- trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoic acid; (S)- 2-(5-(((JS)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)- propanoic acid; racemic-2-(5-(((£)-2,4₅6-trimethoxy-styrylsulfonyl)methyl)-2- methoxyphenyl-amino)propanoic acid; (R)-2-(5-(((R)-2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-methoxyphenylamino)-2-phenylacetic acid; (S)-2-(5-(((-5)- 2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)-2-phenylacetic acid; racemic-2-(5-(((£)-2,4,6-trimethoxystyryl-sulfonyl)methyl)-2-methoxy- phenylamino)-2-phenylacetic acid; N-(3-(((£)-2,4,6-trimethoxystyryl- sulfonyl)methyl)-2-methoxyphenyl)-4-(4-methyl-piperazin- 1 -yl)benzamide; 2- ((E)-2-(4-methoxybenzylsulfonyl)vinyl)- 1 ,3,5-trimethoxybenzene; 1 -(((E)-4- chlorostyrylsulfonyl)methyl)-2-chloro-4-fluorobenzene; 4-((R)-2-(4-chloro- benzy lsulfonyl)vinyl)- 1 -fluoro-2-nitrobenzene; 4-((E)-2-(3 -amino-4-methoxy- benzylsulfonyl)vinyl)benzoic acid; 5-(((_JB)-2,4-difluorostyrylsulfonyl)methyl)-2- methoxybenzenamine; 1 -bromo-4-(((£T)-perfluorostyrylsulfony ^methyl- benzene; l-(((-5)-2,3,5,6-tetrafluorostyryl-sulfonyl)methyl)-4-bromobenzene; 1- (((-5T)-2,4,5-trifluorostyrylsulfonyl)-methyl)-4-bromobenzene; l-(((E)-2,4,6- trifluorostyrylsulfonyl)methyl)-4-bromobenzene; l-(((£T)-2,3,6-trifluorostyryl- sulfonyl)methyl)-4-bromobenzene; 5-(((£T)-2,4-difluorostyrylsulfonyl)methyl)- 2-bromobenzenamine; 4-(((£)-2,4-difluorostyrylsulfonyl)methyl)benzoic acid; 5-(((£')-2,4,6-trimethoxystyryl-sulfonyl)methyl)-2-bromobenzenamine; 4-((E)- 2-(4-bromobenzylsulfonyl)-vinyl)- 1 -fluoro-2-nitrobenzene; 4-((2s)-2-(4-chloro- 2-nitrobenzylsulfonyl)vinyl)- 1 -fluoro-2-nitrobenzene; 5-((E)-2-(4-bromobenzyl- sulfonyl)vinyl)-2-fluorobenzenamine; 5-((£)-2-(4-iodobenzylsulfonyl)vinyl)-2- fluorobenzenamine; 5-(((jE)-2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxy- benzonitrile; 4-(((£)-2,4,6-trimethoxystyrylsulfonyl)methyl)benzoic acid; 3- ((E)-2-(4-bromobenzylsulfonyl)vinyl)-2,6-difluorophenol; 5-((2,4,6-trimethoxy- styrylsulfonyl)methyl)-2-methoxy-N-methylbenzenamine and pharmaceutically acceptable salts thereof.

34. The composition according to claim 31, wherein part B comprises an antioxidant compound.

35. The composition of claim 34 wherein the antioxidant compound is selected from the group consisting of carotenoids, catechins, isoflavones, flavanones, flavanols, flavanoid chalcones, vitamin E compounds, (3- aminopropyl)[2-(phosphonothio)ethyl] amine, ascorbic acid, cysteine, glutathione, probucol, β-mercaptoethanol dithiothreitol, pyrrolidine dithiocarbamate, N-acetyl-L-cysteine, ubiquinone, meso-tetrakis-(N- alkylpyridinium-2-yl)porphyrins, meso-tetrakis-(N-alkylpyridinium-3-yl)- porphyrins, and salts thereof.

36. A method of treating an individual for a proliferative disorder, comprising: (a) administering to the individual an effective amount of at least one radioprotective compound of formula I:

wherein: L is selected from the group consisting of O, S, and N-R¹; R¹ is -H or -(Cι-C₇)hydrocarbyl; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -CONH₂, -CO₂H, -CO₂(C_rCi₂)hydrocarbyl, -C(=O)NH(C₂-C₆)alkylene-NH₂, -O(Cι-C₇)hydrocarbyl, -NH(d- C₇)hydrocarbyl, -C(=O)(Cι-C₇)hydrocarbyl, -S(O)_d(Cι-C₇)hydrocarbyl, halogen, -(Cι-C₆)alkylene-OH, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, heterocyclyl(C]-C6)alkylene, and heteroary 1(C i -Cβ)alkylene; a and b are independently selected from the group consisting of 0, 1 and 2; d is 0, 1 or 2; each R³ is independently selected from the group consisting of -OH, -NH₂, -NO₂, ~(Cι-C6)haloalkoxy, halogen, and a radical of formula (i)

(ϋ) (iii) (iv) (v) wherein: h is 1 or 2; each R⁷ is independently selected from the group consisting of-H and (Cι-Ce)alkyl, R⁵ is O orN(R⁷); Y is (Cι-C₆)alkylene e and g are independently selected from the group consisting of 0 and 1; f is 0 or 1, provided that f is 0 when R³ is a divalent radical of formula (ii) or (v); R⁶ is selected from the group consisting of -H, -(Cι-C₇)hydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A is a radical selected from the group consisting of formula (vi), (vii), (viii), and (ix):

(vi) (vii)

(viii) (ix) wherein: R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(C₁-C₆)alkylene-NH-(C₁-C₆)alkyl, (Ci- C₆)acylamino(Cι-C₆)alkyl, and substituted or unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(Cι-Ce)alkyl; i is 0, 1 or 2; U is selected from the group consisting of N(H), N(C]-C₆alkyl),

S, arylene and heteroarylene; V is (C₂-C₆)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted -NH(C₂-Cg)alkylenylheterocyclyl, -NH(C - C₆)alkylene-N(C₁-C₆alkyl)₂ and -N(Cι-C₆alkyl)₂; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R¹¹ is -(C C₇)hydrocarbyl or -(C₂-Cι₂)heteroalkyl; R¹² is unsubstituted or substituted aryl br unsubstituted or substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(C]-C₆)alkyl, -(d-C₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and

-S(O)_j(Cι-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided; when X is N, R¹⁰ is bonded to the 7-position and -U-V-W is bonded to the 6-position ofthe quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position and -U-V-W is bonded to the 7-position ofthe quinoline ring system; or a pharmaceutically acceptable salt thereof; and (b) administering an effective amount of therapeutic ionizing radiation.

37. The method of claim 36 wherein the proliferative disorder is cancer.

38. The method of claim 37, further comprising administering an effective amount of either: (A) at least one compound of formula II:

(0 (ϋ)

(iϋ) (iv) wherein: n is one or zero; and R^x is -H, -(Ci-Cs)hydrocarbyl or -C(=O)(C_rC₈)hydrocarbyl; or a pharmaceutically acceptable salt of such a compound; or (B) at least one antioxidant compound, prior to administering an effective amount of therapeutic ionizing radiation.

39. The method of claim 38, wherein X is selected from the group consisting of (i), (ii), and (iii) below!

40. A method of safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders, comprising administering to an individual an effective amount of at least one radioprotective compound according to formula I:

wherein: L is selected from the group consisting of O, S, and N-R ; R¹ is -H or -(Cι-C₇)hydrocarbyl; each R² is independently selected from the group consisting of -(C C₇)hydrocarbyl, -CONH₂, -CO₂H, -CO2(d-Ci₂)hydrocarbyl, -C(=O)NH(C₂-C₆)alkylene-NH₂, -O(d-C₇)hydrocarbyl, -NH(d- C₇)hydrocarbyl,

-S(O)_d(Cι-C₇)hydrocarbyl, halogen, -(Cι-C₆)alkylene-OH, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, heterocyclyl(Cι-C6)alkylene, and heteroaryl(Ci-Ce)alkylene; a and b are independently selected from the group consisting of 0, 1 and 2; d is 0, 1 or 2; each R³ is independently selected from the group consisting of -OH, -NH₂, -NO₂, -(Cι-Ce)haloalkoxy, halogen, and a radical of formula (i)

R⁴ is a divalent radical selected from the group consisting of formula (ii), (iii), (iv) and (v): S(0)_h-ϊ

(ii) (ϋi) (iv) (v) wherein: h is 1 or 2; each R⁷ is independently selected from the group consisting of-H and (Cι-C6)alkyl, R⁵ is O orN(R⁷); Y is (d-C₆)alkylene e and g are independently selected from the group consisting of 0 and 1: f is 0 or 1, provided that f is 0 when R is a divalent radical of formula (ii) or (v); R⁶ is selected from the group consisting of -H, -(d-C₇)hydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A is a radical selected from the group consisting of formula (vi), (vii), (viii), and (ix):

(vi) (vii)

(viii) (ix) wherein: R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(Cι-C₆)alkylene-NH-(d-C₆)alkyl, (C_r C₆)acylamino(Cι-C6)alkyl, and substituted or unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(Cι-Ce)alkyl; i is 0, 1 or 2; U is selected from the group consisting of N(H), N(Cι-Cealkyl), N(C(=O)(Cι-C6) alkyl), O, S, arylene and heteroarylene; V is (C₂-C₆)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted -NH(C₂-C6)alkylenylheterocyclyl, -NH(C₂- C₆)alkylene-N(C₁-C₆alkyl)₂ and -N(d-C6alkyl)₂; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R¹¹ is -(C C₇)hydrocarbyl or -(C₂-d₂)heteroalkyl; R¹² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -(d-C₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)_j(Cι-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided; when X is N, R¹⁰ is bonded to the 7-position and -U-V-W is bonded to the 6-position ofthe quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position and -U-V-W is bonded to the 7-position of the quinoline ring system; or a pharmaceutically acceptable salt thereof; prior to administration of the therapeutic ionizing radiation, which radioprotective compound induces a temporary radioresistant phenotype in the normal tissue ofthe individual.

41. The method of claim 40, further comprising administering an effective amount of either: (A) at least one compound of formula II:

Q ^■x— CH=CH— c wherein, Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below:

(0 (ϋ)

(iϋ) (iv) wherein: n is one or zero; and R^x is -H, -(Cι-C₈)hydrocarbyl or -C(=O)(Cι-C₈)hydrocarbyl; or a pharmaceutically acceptable salt of such a compound; or (B) at least one antioxidant compound, prior to administering an effective amount of therapeutic ionizing radiation.

42. The method of claim 41, wherein X is selected from the group consisting of (i), (ii), and (iii) below: 0 0 0 -HCH₂)n-S — I- " N— S— 5- -f N— C— |- 0 R O R^x 0) (ϋ) (iϋ)

43. A method for treating an individual who has incurred or is at risk for incurring remediable radiation damage from exposure to ionizing radiation, comprising administering an effective amount of at least one radioprotective compound according to formula I:

wherein: L is selected from the group consisting of O, S, and N-R¹; R¹ is -H or -(Cι-C₇)hydrocarbyl; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -CONH₂, -CO₂H, -CO₂(Cι-C,₂)hydrocarbyl, -C(=O)NH(C₂-C₆)alkylene-NH₂, -O(d-C₇)hydrocarbyl, -NH(Cι- C₇)hydrocarbyl, -C(=0)(C_rC₇)hydrocarbyl, -S(Q)_d(d-C₇)hydrocarbyl, halogen, -(Cι-C₆)alkylene-OH, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, heterocyclyl(Cι-C6)alkylene, and heteroaryl(d-C₆)alkylene; a and b are independently selected from the group consisting of 0, 1 and 2; d is 0, 1 or 2; each R³ is independently selected from the group consisting of -OH, -NH₂, -NO₂, -(Cι-C6)haloalkoxy, halogen, and a radical of formula (i)

(ϋ) (iii) (iv) (v) wherein: h is 1 or 2; each R⁷ is independently selected from the group consisting of-H and (C]-C6)alkyl, R⁵ is O or N(R⁷); Y is (Cι-C₆)alkylene e and g are independently selected from the group consisting of 0 and 1; f is 0 or 1, provided that f is 0 when R³ is a divalent radical of formula (ii) or (v); R⁶ is selected from die group consisting of -H, -(Cι-C₇)hydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A is a radical selected from the group consisting of formula (vi), (vii), (viii), and (ix):

(vi) (vϋ)

(viii) (ix) wherein: R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(C₁-C6)alkylene-NH-(d-C₆)alkyl, (Ci- C6)acylamino(Cι-C6)alkyl, and substituted or unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(Cι-C₆)alkyl; i is 0, 1 or 2; U is selected from the group consisting of N(H), N(d-C₆alkyl), N(C(=O)(Cι -Cβ) alkyl), O, S, arylene and heteroarylene; V is (C₂-C₆)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted -NH(C₂-C6)alkylenylheterocyclyl, -NH(C₂- C₆)alkylene-N(Cι-C₆alkyl)₂ and -N(Cι-C₆alkyl)₂; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R¹¹ is -(d-C₇)hydrocarbyl or -(C₂-Cι₂)heteroalkyl; R¹² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -(d-C₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)j(Cι-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided; when X is N, R¹⁰ is bonded to the 7-position and -U-V-W is bonded to the 6-position ofthe quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position and -U-V-W is bonded to the 7-position ofthe quinoline ring system; or a pharmaceutically acceptable salt thereof; prior to or after the individual incurs remediable radiation damage from exposure to ionizing radiation.

44. The method of claim 43, further comprising administering an effective amount of either: (A) a compound of formula II: _Q1 χ__CH=CH__Q2 I I wherein: Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below:

(0 (ϋ)

(iii) (iv) wherein: n is one or zero; and R^x is -H, -(Cι-Cs)hydrocarbyl or -C(=O)(Cι-C₈)hydrocarbyl; or a pharmaceutically acceptable salt of such a compound; or (B) at least one antioxidant compound, prior to or after the individual incurs remediable radiation damage from exposure to ionizing radiation.

45. The method of claim 44, wherein X is selected from the group consisting of (i), (ii), and (iii) below:

46. The method of claim 43 wherein the radioprotective compound is administered before incurring remediable radiation damage from exposure to ionizing radiation.

47. The method of claim 43, wherein the radioprotective compound is administered after incurring remediable radiation damage from exposure to ionizing radiation

48. A method of reducing the number of malignant cells in bone marrow of an individual, comprising: (1) removing a portion ofthe individual's bone marrow; (2) administering to the removed bone marrow an effective amount of at least one radioprotective compound according to formula I:

wherein: L is selected from the group consisting of O, S, and N-R¹; R¹ is -H or -(Cι-C₇)hydrocarbyl; each R² is independently selected from the group consisting of -(Cι-C₇)hydrocarbyl, -CONH₂, -CO₂H, -CO₂(Cι-Cι₂)hydrocarbyl, -C(=O)NH(C₂-C₆)alkylene-NH₂, -O(C C₇)hydrocarbyl, -NH(d- C₇)hydrocarbyl, -C(=0)(Ci-C₇)hydrocarbyl, -S(O)_d(Cι-C₇)hydrocarbyl, halogen, -(Cι-C6)alkylene-OH, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, heterocyclyl(Cι-C₆)alkylene, and heteroaryl(Cι-C₆)alkylene; a and b are independently selected from the group consisting of 0, 1 and 2; d is 0, 1 or 2; each R³ is independently selected from the group consisting of

-OH, -NH₂, -NO₂, -(Cι-C6)haloalkoxy, halogen, and a radical of formula (i)

R⁴ is a divalent radical selected from the group consisting of formula (ii), (iii), (iv) and (v): S(0)_h- i|-

(ii) (iii) (iv) (v) wherein: h is 1 or 2; each R⁷ is independently selected from the group consisting of -H and (C ₁ -Cό)alkyl, R⁵ is O orN(R⁷); Y is (d-C₆)alkylene e and g are independently selected from the group consisting of 0 and 1; f is 0 or 1, provided that f is 0 when R³ is a divalent radical of formula (ii) or (v); R⁶ is selected from the group consisting of -H, -(Cι-C₇)hydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A is a radical selected from the group consisting of formula (vi),

(vii), (viii), and (ix):

(viii) (ix) wherein: R⁸ is selected from the group consisting of substituted and unsubstituted aryl, -(Cι-C₆)alkylene-NH-(Cι-C₆)alkyl, (d- C6)acylamino(Cι-C₆)alkyl, and substituted or unsubstituted heterocyclyl; each R⁹ is independently selected from the group consisting of halogen, and -(Cι-C_δ)alkyl; i is 0, 1 or 2; U is selected from the group consisting of N(H), N(Cι-Cδalkyl), N(C(=O)(Cι-C6) alkyl), O, S, arylene and heteroarylene; V is (C₂-C₆)alkylene; W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted -NH(C2-C6)alkylenylheterocyclyl, -NH(C₂- C₆)alkylene-N(Cι-C₆alkyl)2 and -N(Cι-C₆alkyl)₂; R¹⁰ is -H or -O(Cι-C₇)hydrocarbyl; X is N, thereby forming a quinazoline ring, or C-CN, thereby forming a quinoline ring; R¹¹ is -(Cι-C₇)hydrocarbyl or -(C₂-C_]2)heteroalkyl; R¹² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; each R¹³ is independently selected from the group consisting of -OH, -(Cι-C₆)alkyl, -(d-C₆)alkoxy, halogen, -NH₂, -NO₂, -CN, -SH and -S(O)_j(C₁-C₆)alkoxy; j is 0, 1 or 2; and k is 1, 2 or 3; provided; when X is N, R¹⁰ is bonded to the 7-position and -U-V-W is bonded to the 6-position ofthe quinazoline ring system; and when X is C-CN, R¹⁰ is bonded to the 6-position and -U-V-W is bonded to the 7-position ofthe quinoline ring system; or a pharmaceutically acceptable salt thereof; to the bone marrow; and (3) irradiating the bone marrow with an effective amount of ionizing radiation.

49. The method of claim 48, further comprising administering to the removed bone marrow an effective amount of either: (A) at least one compound of formula II:

Q -X— CH=CH— Q wherein, Q¹ and Q² are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below: -(CH₂)_n

(i) (ϋ)

(iii) (iv) wherein: n is one or zero; and R^x is -H, -(Cι-C₈)hydrocarbyl or-C(=O)(Cι-C₈)hydrocarbyl; or a pharmaceutically acceptable salt of such a compound; or (B) at least one antioxidant compound, prior to irradiating the bone marrow with an effective amount of ionizing radiation.

50. The method of claim 49, wherein X is selected from the group consisting of (i), (ii), and (iii) below:

-f-(C

51. The method of claim 48, further comprising reimplanting the bone marrow into the individual.

52. The method of claim 51, wherein the individual receives therapeutic ionizing radiation prior to reimplantation ofthe bone marrow.