[0001] The present application claims the benefit Indian Provisional Patent Application No. 201641022026 filed on 28-June-2016, Indian Provisional Patent Application No. 201641025259 filed on 22-July-2016 and Indian Provisional Patent Application No. 201741006185 filed on 21- February-2017 the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

[0002] This disclosure generally relates to compounds and compositions for the treatment of cancer. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

[0003] The 5-Fluorouracil (5-FU) is still a widely used anticancer drug. Since 1957, it has played an important role in the treatment of colon cancer and is used for patients with breast and other cancers, like those of the head and neck.

[0004] 5-FU is an effective chemotherapeutic drug developed as an inhibitor of TS, which leads to a thymine less cell death. And it is also a pyrimidine analogue misincorporated into RNA and DNA in place of uracil or thymine. However, its clinical application is greatly limited due to drug resistance, which could result from various causes, including alteration of drug influx and efflux, enhancement of drug inactivation and mutations of the drug target.

[0005] Unfortunately, in addition to its beneficial antitumor effects, 5-FU also possesses a number of important toxicities. Acute coronary syndrome (ACS) precipitated by the administration of 5-FU is a rare but well-established phenomenon and only one of several adverse cardiac effects related to this chemotherapeutic agent. Additional cardiotoxic effects include cardiomyopathy, vasospastic angina, coronary thrombosis and dissection, malignant arrhythmias, and sudden cardiac death.

SUMMARY OF THE INVENTION

[0006] The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as cancer.

[0007] The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable salts, carriers, vehicles or diluents. These com ositions may be used in the treatment of cancer and its associated complications.

[0008] In certain embodiments, the present invention relates to the compounds and compositions of formula I, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

or

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

[0009] The compositions are typically compounds of capecitabine in which the free hydroxyl groups of capecitabine are conjugated with one of the selected fatty acid compounds in an ester conjugate form. The invention also provides pharmaceutical compositions comprising compositions of formula I and pharmaceutically acceptable excipients.

[0010] In certain embodiments, the present invention relates to the compounds and compositions of formula II, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and

stereoisomers thereof;

Wherein,

R1, R3 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

[0011] In certain embodiments, the present invention relates to the compounds and compositions of formula III, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and

stereoisomers thereof;

Wherein,

R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

or

Within the proviso, Wherein n represents 0 to 12;

R6 independently represents NULL,

[0012] In certain embodiments, the present invention relates to the compounds and compositions of formula IV, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3, R5, R7 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4, R6, R8 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

[0013] In certain embodiments, the present invention relates to the compounds and compositions of formula V, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and

stereoisomers thereof;

Wherein,

R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4, R6 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

[0014] In certain embodiments, the present invention relates to the compounds and compositions of formula VI, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and

stereoisomers thereof;

Wherein,

R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R6 independently represents H, D, NULL,

or

Within the proviso,

Wherein

n represents 0 to 12;

R5 and R6 independently represents

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

Within the proviso,

Wherein

n represents 0 to 12;

R5 and R6 independently represents

or

[0016] In certain embodiments, the present invention relates to the compounds and compositions of formula VIII, or pharmaceutically acceptable salts thereof,

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and

stereoisomers thereof;

Wherein,

R1 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

Within the proviso,

Wherein

n represents 0 to 12;

R5 and R6 independently represents

[0017] The invention further provides methods for treating colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers and Bowen's disease and as eye drops for treatment of ocular surface squamous neoplasia, when administered to patients, preferably by oral, injection, rectal, aerosol, I.V, spray, solution, syrup, suppository, powder, i.v, solution, syrup, nanoparticle, sachet administration.

[0018] Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of cancer or its related complications.

[0019] The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.

[0020] Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of cancer or its related complications.

[0021] The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from cancer or its related complications manifested from metabolic or genetic conditions or disorders, metabolic diseases, chronic diseases or disorders; neurodegenerative disorders, metabolic condition, Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications.

[0022] In the illustrative embodiments, examples of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII and formula VIII are as set forth below:

DETAILED DESCRIPTION OF THE INVENTION

[0023] Definitions

[0024] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0025] The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII to be used as prodrugs). The compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII (hydration).

[0026] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or

more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

[0027] As used herein, the term "metabolic condition" refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. Metabolic or genetic disorders or condition associated diseases include: Hepatic, Neurologic, Psychiatric, Hematologic, Respiratory, Renal, Cardiovascular, Cancer, Musculoskeletal, Orthopedic and Gastrointestinal.

[0028] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0029] The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0030] A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

[0031] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0032] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0033] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0034] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0035] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0036] The term "predicting" as used herein refers to assessing the probability according to which a condition or disorder such as cancer or related diseases patient will suffer from abnormalities or complication and/or death (i.e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention. Preferably, however, the predictive window is an interval of one month, six months or one, two, three, four, five or ten years after appearance of the inflammatory complication (more preferably and precisely, after the sample to be analyzed by the method of the present invention has been obtained). As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for 100% of the subjects to be analyzed. The term, however, requires that the assessment will be valid for a statistically significant portion of the subjects to be analyzed. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test, etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983. Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %. The p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001. Preferably, the probability envisaged by the present invention allows that the prediction will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort.

[0037] The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the cancer or condition or disorders such as cancer condition of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.

[0038] The phrase "therapeutically effective amount" is an art -recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

[0039] In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

[0040] Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

CLAIMS

A compound of formula I:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

or

2. A compound of formula II:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

3. A compound of formula III:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

or

Within the proviso, Wherein n represents 0 to 12;

R6 independently represents NULL,

4. A compound of formula IV:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3, R5, R7 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4, R6, R8 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

or

5. A compound of formula V:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4, R6 independently represents

Within the proviso, Wherein n represents 0 to 12;

R5 and R6 independently represents

6. A compound of formula VI:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R6 independently represents H, D, NULL,

or

Within the proviso,

Wherein

n represents 0 to 12;

R5 and R6 independently represents

7. A compound of formula VII:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1, R3 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2, R4 independently represents

Within the proviso,

Wherein

n represents 0 to 12;

Rs and R6 independently represents

or

8. A compound of formula VIII:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein,

R1 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,

R2 independently represents

Within the proviso,

Wherein

n represents 0 to 12;

R5 and R6 independently represents

or

9. A Pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

10. A Pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

11. A Pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

12. A Pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.

13. A Pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

14. A Pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.

15. A Pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.

16. A Pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 9, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

18. The pharmaceutical composition of claim 10, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

19. The pharmaceutical composition of claim 11, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

20. The pharmaceutical composition of claim 12, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

21. The pharmaceutical composition of claim 13, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

22. The pharmaceutical composition of claim 14, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

23. The pharmaceutical composition of claim 15, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

24. The pharmaceutical composition of claim 16, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

25. Compounds and compositions of claim 17 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

26. Compounds and compositions of claim 18 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

27. Compounds and compositions of claim 19 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

28. Compounds and compositions of claim 20 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

29. Compounds and compositions of claim 21 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

30. Compounds and compositions of claim 22 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

31. Compounds and compositions of claim 23 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.

32. Compounds and compositions of claim 24 are formulated for the treatment of colorectal cancer, breast cancer (metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers), actinic keratoses, skin cancers, Bowen's disease, fungal infections, candidiasis and oral infectious diseases.