BIGUANIDINE DERIVATIVES OF THERAPEUTIC AGENTS AND METHODS OF PREPARATION AND USE THEREOF

FIELD OF THE INVENTION

The present invention relates to novel biguanidine derivatives of therapeutic agents, methods of preparation and methods of use using these compounds for treating and /or preventing a wide variety of conditions and disorders. The invention also includes pharmaceutical compositions, preparation of prodrugs and mutual prodrugs comprising the compounds of Formula IA, Formula IB, Formula IC ,and Formula ID.

BACKGROUND OF THE INVENTION

Many therapeutic agents and drug candidates have several undesirable qualities such as poor solubility, intestinal membrane permeability, and oral bioavailability, which prevent them from becoming successful drugs. These drugs often have an erratic absorption profile and highly variable bioavailability because their performance is dissolution rate limited, and is affected by the fed / fasted state of the patient(Siriporn Okonogi et al., "Enhanced Dissolution of Ursodeoxycholic Acid from the Solid Dispersion," Drug Development and Industrial Pharmacy 23, no. 1 1 (January 1 , 1997): 1 115-21 , doi: 10.3109/03639049709150502; V. B. Patravale, Abhijit A. Date, and R. M. Kulkarni, "Nanosuspensions: A Promising Drug Delivery Strategy," Journal of Pharmacy and Pharmacology 56, no. 7 (July 1 , 2004): 827-40, doi: 10.121 1/0022357023691). The solubility behavior of a drug is a key determinant of its oral bioavailability and it has presented a challenge to the development of a suitable formulation for oral administration. Several techniques have been considered to improve solubility. Some of these include: 1) Incorporation of a polar and ionizable functional group, 2) Varying pKa (acid dissociation constant at logarithmic scale) of the compound, 3) Modulation of logP (logarithm of the ratio of the concentrations of the un-ionized solute), 4) Prodrug formation, and 5) A variety of formulation including complexation, co-solvents, emulsions microemulsions, micelles, polymeric micelles, liposomes, pharmaceutical salts, particle size reduction, percolation, solid state alternation, soft gel technology, and solid dispersion development.

The most of the viable drug molecules are able to permeate intestinal membranes via paracellular and transcellular routes. However, the high selectivity of biological membranes prohibits a set of potential drug candidates that can be passively transported with certain physiological parameters (Marilyn N. Martinez and Gordon L. Amidon, "A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption: A Review of Fundamentals," Journal of Clinical Pharmacology 42, no. 6 (June 2002): 620-43). Many promising drugs candidates with high potency and selectivity in vitro for the desired target are poor substrates for these active transport processes. Because of these limitations, they have very limited or no cell membrane permeability and hence they have poor oral bioavailability to be active in vivo. The prodrug strategy has proven to be promising in improving the intestinal membrane permeability for many drugs (Peter Ettmayer et al., "Lessons Learned from Marketed and Investigational Prodrugs," Journal of Medicinal Chemistry 47, no. 10 (May 6, 2004): 2393-2404, doi:10.1021/jm0303812). These covalent prodrug strategies offer tremendous potential for improving drug bioavailability and selectivity. However, a prodrug is indeed a new molecular entity. Thus there is a need for incorporation of important parameters when applying this approach, e.g. synergetic and/or additive effects on efficacy, distribution, metabolism, excretion and toxicity. It requires fine-tuned aqueous solubility, pKa, hydrophilicity, lipophilicity, clogP and enzymatic or non-enzymatic cleavage rate.

Drug discovery is a complex process and the drug failure rate remains high despite a significant increase in research and development spending. One of the major issues is to achieve therapeutic activity and selectivity for the treatment of diseases without significant toxicity (Bethan Hughes, "2007 FDA Drug Approvals: A Year of Flux," Nature Reviews Drug Discovery 7, no. 2 (February 2008): 107-9, doi:10.1038/nrd2514). Treatment of some diseases such as canceras well as metabolic and inflammation disorders rely on targets that are in ubiquitously present in healthy and diseased tissues. This requires specific target modulation, which can be achieved by the compensatory and synergetic mechanisms in complex biological systems (J. L. Hartman, B. Garvik, and L. Hartwell, "Principles for the Buffering of Genetic Variation," Science (New York, N. Y.) 291 , no. 5506 (February 9, 2001): 1001-4; Jorg Stelling et al., "Robustness of Cellular Functions," Ce// 1 18, no. 6 (September 17, 2004): 675-85, doi: 10.1016/j.cell.2004.09.008; Hiroaki Kitano, "A Robustness-Based Approach to Systems-Oriented Drug Design," Nature Reviews. Drug Discovery 6, no. 3 (March 2007): 202-10, doi: 10.1038/nrd2195). To overcome this compensation, much higher drug doses are required to achieve adequate tissue concertation which can induce undesired effects in other tissues (There are several multidrug delivery systems that have been developed. For instance, micelles of stearate-grafted chitosan oligosaccharide (CSO-SA) were used for the codelivery of paclitaxel (PTX) and doxorubicin (Meng-Dan Zhao et al., "Coadministration of Glycolipid-like Micelles Loading Cytotoxic Drug with Different Action Site for Efficient Cancer Chemotherapy," Nanotechnology 20, no. 5 (February 4, 2009): 055102, doi: 10.1088/0957-4484/20/5/055102). Another study employed nanoparticles of poly(D,L-lactide- co-glycolide acid) (PLGA) for simultaneous delivery of vincristine (VCR) and verapamil (VRP) (Xiangrong Song et al., "PLGA Nanoparticles Simultaneously Loaded with Vincristine Sulfate and Verapamil Hydrochloride: Systematic Study of Particle Size and Drug Entrapment Efficiency," International Journal of Pharmaceutics 350, no. 1-2 (February 28, 2008): 320-29, doi: 10.1016/j.ijpharm.2007.08.034). A liposomal delivery formulation for quercetin and VCR was also developed (Man-Yi Wong and Gigi N. C. Chiu, "Simultaneous Liposomal Delivery of Quercetin and Vincristine for Enhanced Estrogen-Receptor-Negative Breast Cancer Treatment," Anti-Cancer Drugs 21 , no. 4 (April 2010): 401-10, doi: 10.1097/CAD.0b013e328336e940). Additionally, Kwon et al. reported that poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b- PLA) micelles can deliver multiple drugs including combinations of PTX/17-allylamino-17- demethoxygeldanamycin (17- AAG), etoposide (ETO)/17-AAG, docetaxel (DTX)/17-AAG and PTX/ETO/17-AAG (Ho-Chul Shin et al., "Multi-Drug Loaded Polymeric Micelles for Simultaneous Delivery of Poorly Soluble Anticancer Drugs," Journal of Controlled Release: Official Journal of the Controlled Release Society 140, no. 3 (December 16, 2009): 294-300, doi: 10.1016/j.jconrel.2009.04.024). There is need for developing a method for finding cooperative multi-target drug combinations by identifying drugs that have the most phenotypic synergy and linking them together so that physiological properties such as solubility, ratio lipophilicity, hydrophilicity, and intestinal membrane permeability are improved. For example, linking of a therapeutic agent with higher lipophilicity with another therapeutic agent with higher hydrophilicity would potentially make ideal combination for the treatment.

A combination of two or more drugs can be made by connecting them via a linker(s) to from a single chemical entity wherein each constituent drug contains an appropriate chemical functional group to enable it to be connected other constituent drugs through cleavable and biologically labile covalent bonds. It is also possible to control the release of each individual drug by designing appropriate connecting moieties. When the drugs are chemically combined, the resulting combination drug may have different physicochemical properties when compared to the individual consituent drugs, which may provide superior a pharmacokinetic profile upon administration when compared to that of a physical mixture of these drugs. In addition, several efficacious drugs cannot be delivered by either intravenous or subcutaneous routes due to poor solubility. Therefore there is a need for the development of a combination of drugs that has synergetic therapeutic effects, improved solubility and an enhanced pharmacokinetic profile. There is also a need for linking lipophilic and poorly soluble drug swith another hydrophilic drugs to improve the solubility and pharmacokinetic profile of one or both the drugs. There are several drugs belongs to the biguanidine chemical class such as metformin, buformin and phenformin. These drugs belong to BCS class III and they possess a strongly basic biguanidine functionality, which also contributes to high polarity and hence low lipophilicity of these drugs. These drugs are primarily known as hepatic gluconeogenesis inhibitors for the treatment of type 2 diabetes. One of these biguanidine drugs, metformin is currently the drug of choice for the treatment of type 2 diabetes and it is being prescribed to at least 120 million people worldwide. Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 diabetes patients without causing evident hypoglycaemia (Benoit Viollet et al., "Cellular and Molecular Mechanisms of Metformin: An Overview," Clinical Science (London, England : 1979) 122, no. 6 (March 2012): 253-70, doi:10.1042/CS20110386). Metformin is also frequently described as an insulin-sensitizer, leading to reduction in insulin resistance and a significant decrease in plasma fasting insulin levels. The improvement in insulin sensitivity by metformin could be attributed to its positive effects on insulin receptor expression and tyrosine kinase activity (Jenny E. Gunton et al., "Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2," The Journal of Clinical Endocrinology and Metabolism 88, no. 3 (March 2003): 1323-32, doi: 10.1210/jc.2002-021394). Metformin may also exert its beneficial metabolic actions in part through the modulation of multiple components of the incretin axis. Maida et al. have recently reported that metformin acutely increases plasma levels of GLP-1 (glucagon-like peptide- 1) and induces islet incretin receptor gene expression through a mechanism that is dependent on peroxisomeproliferator- activated receptor (PPAR)-a (A. Maida et al., "Metformin Regulates the Incretin Receptor Axis via a Pathway Dependent on Peroxisome Proliferator-Activated Receptor- A in Mice," Diabetologia 54, no. 2 (February 201 1): 339^19, doi: 10.1007/s00125-010-1937-z). However, there are significant evidence from clinical studies and animal models that suggest that the primary function of metformin is to decrease hepatic glucose production (K. Cusi, A. Consoli, and R. A. DeFronzo, "Metabolic Effects of Metformin on Glucose and Lactate Metabolism in Noninsulin-Dependent Diabetes Mellitus," The Journal of Clinical Endocrinology and Metabolism 81 , no. 1 1 (November 1996): 4059-67, doi: 10.1210/jcem.81.11.8923861), mainly by inhibiting gluconeogenesis (R. S. Hundal et al., "Mechanism by Which Metformin Reduces Glucose Production in Type 2 Diabetes," Diabetes 49, no. 12 (December 2000): 2063-69; A. Natali and E. Ferrannini, "Effects of Metformin and Thiazolidinediones on Suppression of Hepatic Glucose Production and Stimulation of Glucose Uptake in Type 2 Diabetes: A Systematic Review," Diabetologia 49, no. 3 (March 2006): 434^11 , doi: 10.1007/s00125-006-0141-7). A preclinical study suggests that metformin reduces cardiac ischaemia/reperfusion injury. Yin and his colleagues (Meimei Yin et al., "Metformin Improves Cardiac Function in a Nondiabetic Rat Model of Post-MI Heart Failure," American Journal of Physiology. Heart and Circulatory Physiology 301 , no. 2 (August 2011): H459-68, doi: 10.1 152/ajpheart.00054.2011) have shown that metformin treatment improves cardiac function and reduces the infarct size after a myocardial infarction in Sprague-Dawley rats. Metformin alone or in combination with a sulfonylurea reduced the mortality and morbidity of type 2 diabetes patients with heart failure in comparison with sulfonylurea monotherapy (Michael R. MacDonald et al., "Treatment of Type 2 Diabetes and Outcomes in Patients with Heart Failure: A Nested Case-Control Study from the U.K. General Practice Research Database," Diabetes Care 33, no. 6 (June 2010): 1213-18, doi: 10.2337/dc09- 2227; Dean T. Eurich et al., "Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure," Diabetes Care 28, no. 10 (October 2005): 2345-51 ; Dean T. Eurich and Finlay A. McAlister, "Wrongfully Accused: Metformin Use in Heart Failure," Expert Review of Cardiovascular Therapy 9, no. 2 (February 201 1): 147-50, doi: 10.1586/erc.10.186).

Recent clinical trials suggest that metformin, in addition to its efficacy in treating type 2 diabetes, may also have therapeutic potential in other conditions, including diabetic nephropathy, cardiovascular diseases, polycystic ovary disease and the prevention or treatment of cancer. There are more than 1600 clinical trials have been for more than 500 therapeutic indications according to https://clinicaltrials.gov.

Metformin has been also studied clinically in combination with other drugs (non- covalently linked) and comprehensive list of more than 650 clinical studies is outlined on the National Institutes of Health website for clinical trial (https://clinicaltrials.gov.) Few examples of such combination are listed below:

1. Study of metformin with carboplatin/paclitaxel chemotherapy in patients with advanced ovarian cancer

2. Gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin hydrochloride, and a standardized dietary supplement in treating patients with metastatic pancreatic cancer

3. Metformin hydrochloride, carboplatin, and paclitaxel in treating patients with recurrent ovarian, fallopiantube, or primary peritoneal cancer

4. Metformin hydrochloride, carboplatin, and paclitaxel in treating patients with recurrent ovarian, fallopiantube, or primary peritoneal cancer A randomized phase II study of metformin plus paclitaxel/carboplatin/bevacizumabin patients with adenocarcinoma.

Study of paclitaxel, carboplatin and oral metformin in the treatment of advanced stage ovarian carcinoma

Gemcitabine+nab-paclitaxel and folfirinox and molecular profiling for patients with advanced pancreatic cancer

Efficacy of pioglitazone in patients with inadequately controlled type 2 diabetes mellitus treated with stable triple oral therapy

Special drug use surveillance of pioglitazone/metformin hydrochloride combination tablets survey on long-term use for type 2 diabetes mellitus

Gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin hydrochloride, and a standardized dietary supplement in treating patients with metastatic pancreatic cancer

Metformin combined with gemcitabine as adjuvant therapy for pancreatic cancer after curative resection

Pre-surgical trial of the combination of metformin and atorvastatin in newly diagnosed operable breast cancer

A comparison of atorvastatin and glimepiride fixed dose combination and atorvastatin and glimepiride loose combination in the treatment of patients with type 2 diabetes mellitus A comparison of atorvastatin and glimepiride fixed dose combination and atorvastatin and glimepiride loose combination in the treatment of patients with type 2 diabetes mellitus Open label safety & pharmacodynamic study 24wk w/dio-902 combo w/metformin &atorvastatin in t2dm patients

Vincristine, dexamethasone, doxorubicin, and peg-asparaginase (VPLD) and metformin for relapsed childhood acute lymphoblastic leukemia (all)

Metformin and simvastatin use in bladder cancer

Study of metformin with simvastatin for men with prostate carcinoma

Study of dapagliflozin in combination with metformin XR to initiate the treatment of type 2 diabetes

Dapagliflozin and metformin, alone and in combination, in overweight/obese prior GDM women SUMMARY OF THE INVENTION

The present invention relates to the biguanidine derivatives of of Formula IA or Formula IB or Formula IC or Formula ID including pharmaceutically acceptable, prodrugs, metabolites and isomers thereof

Formula IA Formula IB

Formula IC Formula ID

Wherein: dashed bond defined by = represents a single or double bond which can be in the cis or trans configuration; k=1-5;

Ri and R2 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl; or Ri and R2 together may form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heterocyclyl wherein the heteroatom is nitrogen, oxygen or sulfur;

R3, R ₄ and R5 are independently selected from group consisting of hydrogen, hydroxyl, sulfhydryl, substituted or unsubstituted alkyl, -CN, -OR7, -SR ₇ , -S(0)R ₇ , -S0 ₂ R ₇ , -C(0)OR ₇ , C(0)R ₇ and -C(0)NR ₇ Rs or or R ₇ and Rs, optionally form a 4, 5, 6 or 7 member ring which can be further substituted;

wherein R ₇ and Rs are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl;

X is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted aralkyi, -(CR ₉ Rio)m-, -NR ₉ -, -C(O)-, -C(0)0-, -0-, -P(0) ₃ , -S-, -S(O)-, or -S(0) ₂ - wherein Rg and Rio are independently hydrogen, or substituted or unsubstituted alkyl; and m=0-10;

L is a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent alkenylene, substituted or unsubstituted divalent alkynylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent aralkyi, substituted or unsubstituted divalent cycloalkylene, substituted or unsubstituted divalent heterocyclolalkylene, substituted or unsubstituted divalent heteroarylene, - (CRiiRi ₂ )n-, -(O- alkylene -0) _n -, -(0-alkylene-0) _n -(C-RiiRi ₂ ) ₀ -, -C(0)(CRnRi ₂ ) _n -C(0)-, - 0(CRnR ₁₂ )n-C(0)-, -C(0)(CRnR ₁₂ )n-C(0)0-, -0(CRnR ₁₂ ) _n -C(0)0-, -S-(CRnR ₁₂ ) _n -0-,

-C(0)(CRiiRi ₂ ) _n -OC(0)-, -0(CRiiRi ₂ ) _n -OC(0)-, -(CRnRi ₂ ) _n -NR ₁₃ -, -(CRnRi ₂ ) _n -S-, -C(0)0-, -C(0)NRn-, -P(0) ₃ , -OP(0)ORiiO-, -OP(0)ORnNR ₁₂ -, -0-, -S-, -S(O)-, -S(0) ₂ - or - -W-U- wherein and L ₂ are independently selected from the group consisting of a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent alkenylene, substituted or unsubstituted divalent alkynylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent cycloalkylene, substituted or unsubstituted divalent heterocyclylalkylene, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent heteroarylene, -(CRi ₄ Ris)p-, -(O- substituted or unsubstituted alkylene -0) _p - , -(O- substituted or unsubstituted alkylene-0) _P -(C-Ri ₄ Ri5) _q -, -C(0)(CRi ₄ Ri ₅ ) _P -C(0)-,

-0(CR ₁₄ R ₁₅ )p-C(0)-, -C(0)(CR ₁₄ R ₁₅ )p-C(0)0-, -0(CR ₁₄ R ₁₅ ) _P -C(0)0-, -S-(CR ₁₄ R ₁₅ ) _P -0-,

-C(0)(CR ₁₄ R ₁₅ )p-OC(0)-, -0(CR ₁₄ R ₁₅ )p-OC(0)-, -(CR ₁₄ R ₁₅ ) _P -NR ₁₆ -, -(CR ₁₄ R ₁₅ ) _P -S-, -C(0)0-, -C(0)NR ₁₄ -, -P(0) ₃ , -OP(0)ORi ₄ 0-, -OP(0)ORi ₄ NR ₁₅ -, -0-, -S-, -S(O)- and -S(0) ₂ -; W is selected from the group consisting of a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent alkenyl, substituted or unsubstituted divalent alkynyl, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent cycloalkyi, substituted or unsubstituted divalent heterocyclylalkyl, substituted or unsubstituted divalent heteroarylene, -(CRi7 is)r-, -(O- substituted or unsubstituted alkylene -0) _r , -(O- substituted or unsubstituted alkylene-0) _r -(C- Ri7Rie)s-, -N R17-, =N-, -C(O)-, -C(0)0-, -C(0) N R ₁₇ -, -OC(0)N R ₁₇ -, -P(0) ₃ ,

-OP(0)ORi ₇ 0-, -OP(0)ORi ₇ N R ₁₈ -, -0-, -S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N R ₁₇ -, -OS(0) ₂ N R ₁₇ -,

-N(Ri ₇ )C(0) N Ri8- and -N(Ri ₇ )S(0) ₂ N Ri ₈ , or Rn and Ri ₂ , R _{i 2} and R13, R11 and R13, Rn and Ri5, Ri5 and Ri e, Rn and Rie, R17 and R18 optionally form a 4, 5, 6 or 7 member ring which can be futher substituted;

wherein Rn , Ri ₂ R13, Rn, R15, Rie, Ri7 and R18 are independently hydrogen, and substituted or unsubstituted alkyl, n=0-10, o=0-10, p=0-10, q=0-10, r=0-10 and s=0-10;

Y is a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent alkenylene, substituted or unsubstituted divalent alkynylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent aralkyi, substituted or unsubstituted divalent cycloalkylene, substituted or unsubstituted divalent heterocyclolalkylene, substituted or unsubstituted divalent heteroarylene, -(O- substituted or unsubstituted alkylene -0)r, -(O- substituted or unsubstituted alkylene-0)t-(C- Ri ₉ R ₂ o)u-, -C(0)(CR ₁₉ R ₂ o)t-C(0)-, -0(CR ₁₉ R ₂ o)t-C(0)-, -C(O)(CR ₁₉ R ₂₀ )t-C(O)O-, -O(CR ₁₉ R ₂₀ )t- C(0)0-, -S-(CR ₁₉ R ₂₀ )t-O-, -C(O)(CR ₁₉ R ₂₀ )t-OC(O)-, -O(CR ₁₉ R ₂₀ )t-OC(O)-, -(CR ₁₉ R ₂₀ )t-N R ₂₁ -, - (CRi ₉ R ₂₀ )t-S-, -N R ₁₉ -, -C(O)-, -C(0)0-, -C(0)N R ₁₉ -, -CH ₂ OC(0)-, -P(0) ₃ , -OP(0)ORi ₉ 0-, - OP(O)ORi ₉ N R ₂₀ -, -0-, -S-, -S(O)-, or -S(0) ₂ - , =N- and =N-N Ri ₉ -, or Ri ₉ and R ₂₀ , R ₂₀ and R ₂ i , and Ri ₉ and R ₂ i optionally form a 4, 5, 6 or 7 member ring which can be futher substituted;

wherein Ri ₉ , R ₂₀ and R ₂ i are independently hydrogen, or substituted or unsubstituted alkyl, and t=0-10 and u=0-10;

R6 is vitamins and therapeutic agents (including their prodrugs) comprising one or more of the functional groups selected from the group consisting of -OH , -SH, -CO, -COOH ,

-COOR ₂₂ , -N R ₂₂ R ₂₃ , -N R ₂₂ -OH , -C(0)N R ₂₂ R ₂₃ , -OC(0) N R ₂₂ R ₂₃ , -S(0) ₂ N R ₂₂ R ₂₃ , - OS(0) ₂ N R ₂₂ R ₂₃ , -N(R ₂₂ )C(0)N R ₂₃ R ₂₄ , -N(R ₂₂ )C(0)OR ₂₃ , -OC(0)N R ₂₃ R ₂₄ , -N(R ₂₂ )S(0) ₂ N R ₂₃ R ₂₄ , - P(0) ₃ , -OP(0)OR ₂₂ OR ₂₃ , and -OP(0)OR ₂₂ OR ₂₃ and R ₆ is connected to Y via these functional group; wherein R22, R23 and R24 are independently from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaralkyl or R22 and R23, R23 and R24, and R22 and R24 optionally form a 4, 5, 6 or 7 member ring which can be futher substituted; R ₂₆ is -H or -OH.

According to one embodiment, the present invention a compounds for improving pharmacological response, pharmacokinetic profile, toxicity, physicochemical propertiy and ease of administration of the therapeutic agent.

According to one embodiment, the present invention includes a compound of the present invention for improving pharmacological response of the therapeutic agent.

According to one embodiment, the present invention includes a compound of the present invention for improving pharmacokinetic profile of the therapeutic agent.

According to one embodiment, the present invention includes a compound of the present invention for improving toxicity of the therapeutic agent.

According to one embodiment, the present invention includes a compound of the present invention for improving physicochemical property of the therapeutic agent.

According to one embodiment, the present invention includes a compound of the present invention for improving ease of administration of the therapeutic agent.

According to another embodiment, the present invention includes pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. The pharmaceutical compositions of the present invention can be used for treating or preventing a wide variety of disease conditions or disorders. According to another aspect, the present invention includes a process to produce a compound of the present invention, their pharmaceutically acceptable salt and prodrugs thereof.

According to one embodiment, the present invention includes use of a compound of present invention for the preparation of a pharmaceutical composition useful in the treatment and/or prevention of acne, attention deficit hyperactivity disorder(ADHD), acquired immune deficiency syndrome (AIDS)/ human immunodeficiency virus(HIV), allergies, Alzheimer's, angina, anxiety, arthritis, asthma, bipolar disorder, bronchitis, cancer, cardiovascular, central nervous system disorders, cholesterol, colds & flu, constipation, congestion, chronic obstructive pulmonary disease (COPD), depression, diabetes (type 1), diabetes (type 2), diarrhea, eczema, erectile dysfunction, fibromyalgia, gastrointestinal disease, gastroesophageal reflux disease (GERD), gout, hair loss, hayfever, heart disease, hepatitis A, hepatitis B, herpes, hypertension, hypothyroidism, incontinence, infectious disease, inflammation, inflammatory bowel disease(IBD), insomnia, metabolic disease, menopause, mental health disorder, migraine, osteoarthritis, osteoporosis, pain, parkinsonism, parkinson's disease, psychosis, ulcers psoriasis, rheumatoid arthritis, schizophrenia, seizures, sexual health disorder, stroke, swine flu, urinary tract infection (UTI) and weight loss.

DETAILED DESCRIPTION OF THE INVENTION

The scope of the present invention includes all combinations of aspects and embodiments.

The following definitions are meant to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, terms are used within their accepted meanings.

The chemical names of the compounds used herein are common names, or generic names, or popular name, or tradename, or created in similar fashion as represented by Scifinder or generated using generated by using ChemBioOffice 2014 software.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CONH2- is equivalent to -NH2CO-.

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 ,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH ₂ -N(CH ₃ )-CH3, -CH ₂ - S-CH2-CH3, -CH2-CH2, -S(0)-CH ₃ , -CH2-CH ₂ -S(0)2-CH ₃ , -CH=CH-0-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ - CH=N-OCH ₃ , -CH=CH-N(CH ₃ )-CH ₃ , 0-CH ₃ , -0-CH ₂ -CH ₃ , and -CN. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH ₃ and -CH2-0-Si(CH ₃ ) ₃ . Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH- CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)2 '- represents both -C(0)2R'- and -R'C(0)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0)NR', -NR'R", -OR', -SR', and/or -S0 ₂ R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 4, 5-dimethyl-1 ,3-dioxol-2-one, 1-(1 , 2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and "heterocycloalkylene" refer to a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci- C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.

The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4- biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2- oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene" refers to a divalent radical derived from a aryl and heteroaryl, respectively.

For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyi) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyi" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy) propyl, and the like).

Heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. "3 to 7 membered"), the term "member" refers to a carbon or heteroatom.

The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =0, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(0)R', C(0)R', -CO2R', -CONR'R", -OC(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR"C(0) ₂ R', -NR- C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(0)R', -S(0) ₂ R', -S(0) ₂ NR'R", -NRSO2R', -CN and -N02 in a number ranging from zero to (2 m'+1), where m' is the total number of carbon atoms in such radical. R', R", R'" and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyi groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., - CF ₃ and -CH ₂ CF ₃ ) and acyl (e.g., -C(0)CH ₃ , -C(0)CF ₃ , -C(0)CH ₂ OCH ₃ , and the like).

Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: halogen, -OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(0)R', -C(0)R', -C0 ₂ R', -CONR'R", -OC(0)NR'R", -NR"C(0)R', -NR'- C(0)NR"R"', -NR"C(0) ₂ R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(0)R', -S(0) ₂ R', S(0) ₂ NR'R", -NRS0 ₂ R', -CN and -N0 ₂ , -R', -N ₃ , -CH(Ph) ₂ , fluoro(Ci-C ₄ )alkoxy, and fluoro(Ci- C ₄ )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'" and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') _q -U-, wherein T and U are independently -NR-, -0-, CRR'- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH ₂ ) _r B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, S(0) ₂ -, -S(0) ₂ NR'- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') _S -X'-(C"R"V, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0) ₂ -, or -S(0) ₂ NR'-. The substituents R, R', R" and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). A "substituent group," or "substitution" term as used herein, means a group selected from the following moieties:

(A) -H, -OH, -NH2, -SH, -CN, -CF ₃ , -NO2, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyi, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyi, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(i) oxo, -OH, -NH ₂ , -SH, -CN, -CF ₃ , -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyi, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyi, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(a) oxo, -H, -OH, -NH ₂ , -SH, -CN, -CF ₃ , -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyi, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyi, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from oxo, -H, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyi, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

A "size-limited substituent" or "size-limited substituent group," as used herein means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyi is a substituted or unsubstituted C ₄ - Cs cycloalkyi, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A "lower substituent" or "lower substituent group," as used herein means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyi is a substituted or unsubstituted C5-C7 cycloalkyi, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.

The compounds of the present invention may exist as salts. The present invention includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (eg (+) -tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ l) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. The term "relatively nontoxic" refers to a level of toxicity insufficient to militate against use by a health care practitioner (for example, medical or veterinary) in the treatment of a subject. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

Thus, the compounds of the present invention may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. Prodrugs described herein are compounds that readily undergo chemical changes under physiological conditions to provide drugs to a biological system from the drug moieties attached to the prodrug.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ l) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.

Description of compounds of the present invention is limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

The term therapeutic agent, as used herein, means biologically active molecules used to treat or prevent any disease or disorder of the body. It includes drugs, vitamins, and other molecules, agents or substances concerned with or contributing to the prevention, treatment and cure of disease(s) contributing to the general wellbeing of a mammal or human. Therapeutic agents can be known drugs, investigational drugs or drug candidates. They have been listed in drug databases, for example the Orange Book (http://www.accessdata.fda.gov/scripts/cder/ob/), the FDA drug database (the Drugs@FDA Database, http://www.fda.gov/Drugs/lnformationOnDrugs/ucm135821.htm), the Merck Index, the World Drug Index and Integrity databases by Thomson Reuters, the Pubchem database by NCBI/NIH and the like. The Orange Book is the list of approved drug products with therapeutic equivalence evaluations published and maintained by FDA. It identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. Drugs@FDA is a searchable catalog of FDA approved drug products both prescription and over the counter. The Merck Index is an encyclopedia of chemicals, drugs and biologicals with over 10,000 monographs on single substances or groups of related compounds. The World Drug Index is an authoritative index for marketed and development drugs, consisting of internationally-recognized drug names, synonyms, trade names, trivial names and trial preparation codes, compound structures and activity data (http://thomsonreuters.com/en/products-services/pharma-life- sciences/life-science- research/world-drug-index.html). The Integrity databases encompass over 330,000 compounds with demonstrated biological activity and over 145,000 patent families revealing new drugs, biologies, and targets (http://thomsonreuters.com/content/dam/openweb/documents/pdf /pharma- life-sciences/fact-sheet/integrity-for-medical-chemists-fact sheet.pdf). PubChem is a database of chemical molecules and their activities against biological assays (https://pubchem.ncbi.nlm.nih.gov/).

The term vitamin refers to an organic compound and a vital nutrient that an organism requires in limited amounts (e.g., Vitamin A, Vitamin B1-9, Vitamin B12, Vitamin C, inositol, nicotinic acid, pyridoxal 5-phosphate, ergosterol, Vitamin D, Vitamin D, Vitamin D, Vitamin E, menadoxime, menadiol, and Vitamin K). The term "peptide" means any chain of amino acid monomers linked by amide bonds, including, but not limited to, large and small peptides, and targetable small peptides such as a dipeptide, tripeptide, etc.

The term "ligand" means a small or large molecule that binds to a macromolecule and modulates the activity of the macromolecule.

The terms "treating" or "treatment" refers to any signs of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, certain methods provided herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer.

According to one embodiment, the present invention relates to the biguanidine derivatives of of Formula IA or Formula IB or Formula IC or Formula ID including pharmaceutically acceptable, prodrugs, metabolites and isomers thereof

Formula IA Formula IB

Formula IC Formula ID Wherein: dashed bond defined by = represents a single or double bond which can be in the cis or trans configuration; k=1-5;

Ri and R2 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyi; or Ri and R2 together may form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heterocyclyl wherein the heteroatom is nitrogen, oxygen or sulfur;

R3, R ₄ and R5 are independently selected from group consisting of hydrogen, hydroxyl, sulfhydryl, substituted or unsubstituted alkyl, -CN, -OR7, -SR ₇ , -S(0)R ₇ , -S0 ₂ R ₇ , -C(0)OR ₇ , C(0)R ₇ and -C(0)NR ₇ Rs or or R ₇ and Rs, optionally form a 4, 5, 6 or 7 member ring which can be further substituted;

wherein R ₇ and Rs are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl;

X is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted aralkyi, -(CR ₉ Rio)m-, -IMR9-, -C(O)-, -C(0)0-, -0-, -P(0) ₃ , -S-, -S(O)-, or -S(0) ₂ - wherein Rg and R10 are independently hydrogen, or substituted or unsubstituted alkyl; and m=0-10;

L is a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent alkenylene, substituted or unsubstituted divalent alkynylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent aralkyi, substituted or unsubstituted divalent cycloalkylene, substituted or unsubstituted divalent heterocyclolalkylene, substituted or unsubstituted divalent heteroarylene, - (CRi i Ri ₂ )n-, -(O- alkylene -0) _n -, -(0-alkylene-0) _n -(C-Rn Ri ₂ ) ₀ -, -C(0)(CRn Ri ₂ )n-C(0)-, -

0(CRn Rl2)n-C(0)-, -C(0)(CRn Rl2)n-C(0)0-, -0(CRn Rl2)n-C(0)0-, -S-(CRn Rl2)n-0-,

-C(0)(CRi i Ri ₂ )n-OC(0)-, -0(CRi i Ri ₂ )n-OC(0)-, -(CRn Ri ₂ ) _n -NR ₁₃ -, -(CRn Ri ₂ ) _n -S-, -C(0)0-, -C(0)NRi i-, -P(0) ₃ , -OP(0)ORi iO-, -OP(0)ORn NR ₁₂ -, -0-, -S-, -S(O)-, -S(0) ₂ - or - -W-U- wherein and L ₂ are independently selected from the group consisting of a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent alkenylene, substituted or unsubstituted divalent alkynylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent cycloalkylene, substituted or unsubstituted divalent heterocyclylalkylene, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent heteroarylene, -(CRi ₄ Ris)p-, -(O- substituted or unsubstituted alkylene -0) _p - , -(O- substituted or unsubstituted alkylene-0) _P -(C-Ri ₄ Ri5) _q -, -C(0)(CRi ₄ Ri ₅ ) _P -C(0)-,

0(CR ₁₄ R ₁₅ )p-C(0)-, -C(0)(CR ₁₄ R ₁₅ )p-C(0)0-, -0(CR ₁₄ R ₁₅ ) _P -C(0)0-, -S-(CR ₁₄ R ₁₅ ) _P -0-,

C(0)(CR ₁₄ R ₁₅ )p-OC(0)-, -0(CR ₁₄ R ₁₅ )p-OC(0)-, -(CR ₁₄ R ₁₅ ) _P -NR ₁₆ -, -(CR ₁₄ R ₁₅ ) _P -S-, -C(0)0-, C(0)NR ₁₄ -, -P(0) ₃ , -OP(0)ORi ₄ 0-, -OP(0)ORi ₄ NR ₁₅ -, -0-, -S-, -S(O)- and -S(0) ₂ - ;

W is selected from the group consisting of a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent alkenyl, substituted or unsubstituted divalent alkynyl, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent cycloalkyi, substituted or unsubstituted divalent heterocyclylalkyl, substituted or unsubstituted divalent heteroarylene, (CRi ₇ Ri8)r, -(O- substituted or unsubstituted alkylene -0) _r , -(O- substituted or unsubstituted alkylene-0)r(C-Ri ₇ Ri ₈ )s-, -NR ₁₇ -, =N-, =N-NR ₁₇ -, -C(O)-, -C(0)0-, -C(0)NR ₁₇ -, -OC(0)NR ₁₇ -, - P(0) ₃ , -OP(0)OR ₁₇ 0-, -OP(0)OR ₁₇ NR ₁₈ -, -0-, -S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ NR ₁₇ -, -OS(0) ₂ NR ₁₇ -, - N(Ri ₇ )C(0)NRi8- and -N(Ri ₇ )S(0) ₂ NRi8, or Rn and Ri ₂ , Ri ₂ and Ri ₃ , Rn and Ri ₃ , R _M and Ri ₅ , Ri5 and Ri6, Ri ₄ and Ri6, Ri ₇ and Ris optionally form a 4, 5, 6 or 7 member ring which can be futher substituted;

wherein Rn , Ri ₂ Ri ₃ , Ri ₄ , R15, R16, Ri ₇ and Ris are independently hydrogen, and substituted or unsubstituted alkyl, n=0-10, o=0-10, p=0-10, q=0-10, r=0-10 and s=0-10;

Y is a bond, substituted or unsubstituted divalent alkylene, substituted or unsubstituted divalent alkenylene, substituted or unsubstituted divalent alkynylene, substituted or unsubstituted divalent heteroalkylene, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent aralkyl, substituted or unsubstituted divalent cycloalkylene, substituted or unsubstituted divalent heterocyclolalkylene, substituted or unsubstituted divalent heteroarylene, -(O- substituted or unsubstituted alkylene -0)r, -(O- substituted or unsubstituted alkylene-0) _t -(C-R ₁₉ R2o)u-, -C(0)(CR ₁₉ R2o)t-C(0)-, -0(CR ₁₉ R2o)t-C(0)-, -C(0)(CR ₁₉ R2o)t-C(0)0-, - O(CR ₁₉ R ₂₀ )t-C(O)O-, -S-(CR ₁₉ R ₂₀ )t-O-, -C(O)(CR ₁₉ R ₂₀ )t-OC(O)-, -O(CR ₁₉ R ₂₀ )t-OC(O)-,

(CR ₁₉ R ₂ o)t-NR ₂₁ -, -(CR ₁₉ R ₂₀ )t-S-, -NR ₁₉ -, -C(O)-, -C(0)0-, -C(0)NR ₁₉ -, -CH ₂ OC(0)-, -P(0) ₃ , OP(0)ORi ₉ 0-, -OP(O)ORi ₉ NR ₂₀ -, -0-, -S-, -S(O)-, or -S(0) ₂ - , =N- and or Ri ₉ and R ₂₀ , R20 and R21 , and Ri ₉ and R21 optionally form a 4, 5, 6 or 7 member ring which can be futher substituted;

wherein Ri ₉ , R20 and R21 are independently hydrogen, or substituted or unsubstituted alkyl, and t=0-10 and u=0-10;

R6 is vitamins and therapeutic agents (including their prodrugs) comprising one or more of the functional groups selected from the group consisting of -OH, -SH, -CO, -COOH,

COOR22, -NR22R23, -NR22-OH, -C(0)NR ₂₂ R23, -OC(0)NR ₂₂ R23, -S(0) ₂ NR ₂₂ R23, -OS(0) ₂ NR ₂₂ R23, - N(R ₂₂ )C(0)NR ₂ 3R24, -N(R ₂₂ )C(0)OR ₂ 3, -OC(0)NR ₂₃ R24, -N(R22)S(0) ₂ NR ₂ 3R24, -P(0) ₃ ,

OP(0)OR220R23, and -OP(0)OR220R23 and R6 is connected to Y via these functional group;

wherein R22, R23 and R24 are independently from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaralkyl or R22 and R23, R23 and R24, and R22 and R24 optionally form a 4, 5, 6 or 7 member ring which can be futher substituted; R ₂₆ is -H or -OH.

According to one embodiment, Ri and R2 are independently selected from hydrogen, C1- C4 alkyl or (CH ₂ ) _v Ph wherein v=1-3.

According to one embodiment, Ri and R2 are independently selected from hydrogen, methyl, ethyl, propyl, butyl or phenethyl.

According to another embodiment, R3, R4 and R5 are independently selected from hydrogen, C1-4 alkyl and -CN. According to another embodiment, X is selected from a bond, -CH2-, -C(O)-, -C(0)0-, -P(0) ₃ , or -S-.

According to another embodiment, L is selected from -(CRn Ri2)n-, substituted or unsubstituted divalent arylene, substituted or unsubstituted divalent substituted or unsubstituted cycloalkylene, substituted or unsubstituted divalent heterocyclylalkylene, -(O- substituted or unsubstituted alkylene-0) _n -, -(O- substituted or unsubstituted alkylene-0) _n -(C-Rn Ri2)o-, or wherein and L2 are independently selected from a bond, -(CRi4Ris)p-, substituted or unsubstituted divalent cycloalkylene, -(O- substituted or unsubstituted alkylene-0) _p - , -(O- substituted or unsubstituted alkylene-0) _p -(C-Ri4Ri5) _q -;

W is selected from a bond, -(CRi ₇ Ri8)r, -(O- substituted or unsubstituted alkylene-0) _r , -(O-substituted or unsubstituted alkylene-0) _r (C-Ri ₇ Ri ₈ )s-, -NRi ₇ -, -C(O)-, -C(0)0-, -C(0)NRi ₇ -, -OC(0)NR ₁₇ -, -OP(0)ORi ₇ 0-, -NP(0)ORi ₇ 0-, -O- and -S-,

wherein Rn , R12, R14 R15, R17 and R18 are independently selected from hydrogen and alkyl; n=1-10, o=1-10, p=1-10, q =1-10, r =1-10 and s=1-10.

According to another embodiment, Y is selected from a -(C-RigR2o)r, -NR19-, -C(O)-, -C(0)0-, -C(0)NRi9-, -OP(0)ORi ₉ 0-, -NP(0)ORi ₉ 0-, -0-, -S-, -S(O)-, or -S(0) ₂ - wherein R ₁₉ and R20 are independently selected from hydrogen and a substituted or unsubstituted alkyl; and t=1- 10.

According to another embodiment, R6 is selected from therapeutic agents (including their prodrugs) form the group consisting of: sedatives, hypnotics, antidepressants, antipsychotics, antimanics, analgesics, antipyretics, antimigraine agents, anticonvulsants, drugs used in parkinsonism and movement disorders, drugs for dementia, antiemetics, drugs for vertigo, CNS stimulants activators, anti- infective eye preparations, anti-inflammatory agent, antiallergic preparations, antiglucoma drugs, preparations to cure eye diseases, aural preparations, nasal preparations, oropharyngeal preparations, antiarrhythemic drugs, antihypertensives, alpha/beta- blockers, ACE inhibitors, angiotensin II receptor antagonists, diuretics, antianginals, nitrates, calcium channel blockers, drugs for cardiac failure and shock, vasodilators, coagulants, anticoagulants, thrombolytics antiplatelet drugs, respiratory stimulants, antitussives, expectorants, mucolytics, decongestants, antihistamine agents, antiasthmatics; antiulcer agents, antisecretory drugs, H2 receptor antagonists, proton pump inhibitors, prostaglandin analogues, antacids, antispasmodics, drugs modifying intestinal motility, antidiarrhoeals, antimotility drugs, antimicrobial drugs, drugs acting on gall bladder, urinary antiinfectives, urinary analgesics, antispasmodics, anti-infective drugs acting on urethra and vagina, drugs acting on uterus, drugs for pro static hypertrophy, antiandrogens, drugs for erectile dysfunction, spermicidals, nonhormonal contraceptives, emollients, keratolytics, topical anti infectives, topical antifungals, topical parasiticidals, topical steroids, topical drugs for acne vulgaris, drugs for psoriasis, pigmentation disorders, and antiseborrhoeics, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, antiarthritic agents, immunosuppressants, topical analgesics, muscle relaxants, neuromuscular drugs, antianaerobics, antitubercular drugs, antileprosy drugs, antifongals, antiprotozoals, anthelminthics, antiinfestive drugs, antimalarials, antivirals, anabolics, androgenic steroids, corticosteroids, oestrogens, progestogens and hormonal contraceptives, fertility agents, tropic hormones and related drugs, thyroid and antithyroid drugs, antidiabetics and hyperglycaemics, vitamins, amino acids, anti-obesity drugs, hypolipidaemic drugs, fibric acid derivatives, HMG CoA reductase inhibitors, nicotinic acid group, drugs used for gout, drugs affecting bone metabolism, kinase inhibitors, bisphosphonates, anticancer drugs, cytotoxic antibiotics, antimetabolites, topoisomerase 1 inhibitors, cytotoxic immunosuppressants, imnmnostimulants, cytoprotectives, hormone antagonists, antineoplastic drugs, histamine receptor blockers, local anesthetics, intravenous anesthetics, inhalation anesthetics, and muscle relaxants.

According to another embodiment, R6 (including their prodrugs) is selected from therapeutic agents form the group consisting of: analgesics, antipyretics, antimigraine agents, CNS stimulants activators, anti-inflammatory agent, antiallergic preparations, antiglucoma drugs, antiarrhythemic drugs, antihypertensives, alpha/beta-blockers, ACE inhibitors, angiotensin II receptor antagonists, diuretics, calcium channel blockers, drugs for cardiac failure and shock, vasodilators, antiasthmatics; antiulcer agents, antimicrobial drugs, drugs acting on gall bladder, drugs acting on uterus, drugs for erectile dysfunction, spermicidals, topical steroids, drugs for psoriasis, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, antiarthritic agents, immunosuppressants, neuromuscular drugs, antitubercular drugs antiinfective drugs, antimalarials, antivirals, thyroid and antithyroid drugs, antidiabetics and hyperglycaemics, vitamins, amino acids, anti-obesity drugs, hypolipidaemic drugs, HMG CoA reductase inhibitors, drugs affecting bone metabolism, kinase inhibitors, anticancer drugs, cytotoxic antibiotics, antimetabolites, topoisomerase 1 inhibitors, sodium-glucose transport proteins (SGLT2) inhibitors, cytotoxic immunosuppressants, imnmnostmulants, cytoprotectives, hormone antagonists, antineoplastic drugs, histamine receptor blockers, intravenous anaesthetics.

According to another embodiment, Re (including their prodrugs) is selected from belonging to following therapeutic categories: analgesics, anesthetics, antibacterials, anticonvulsants, antidementia agents, antidepressants, antiemetics, antifungals, antigout agents, antiinflammatory agents, antimigraine agents, antimyasthenic agents, antimycobacterials, antineoplastics, antiparasitics, antiparkinson agents, antipsychotics, antispasticity agents, antivirals, anxiolytics, bipolar agents, blood glucose regulators, cardiovascular agents, central nervous system agents, dental and oral agents, dermatological agents, enzyme replacements/modifiers, gastrointestinal agents, genitourinary agents, hormonal agents, hormonal agents, inflammatory bowel disease agents, metabolic disease agents, ophthalmic agents, optic agents, respiratory tract agents, sedatives/hypnotics, skeletal muscle relaxants, therapeutic nutrients and minerals.

According to another embodiment, R6 (including their prodrugs) is selected from therapeutic agents belonging to following therapeutic categories: Analgesics, anti-inflammatory agents, antimigraine agents, antineoplastics, antiparasitics, antiparkinson agents, blood glucose regulators, cardiovascular agents, central nervous system agents, gastrointestinal agents, hormonal agents, inflammatory bowel disease agents, metabolic disease agents, respiratory tract agents, sedatives/hypnotics and skeletal muscle relaxants.

According to another embodiment, Re (including their prodrugs) is selected from therapeutic agents belonging to following therapeutic categories: antineoplastics, cardiovascular agents and metabolic disease agents.

a I I

Formula II

According to one embodiment , a compound of Formula I I I

Formula III

Formula IV

Accord

Formula V According to one embodiment , a compound of formula VI

Formula VI

Accordin to one embodiment , a compound of formula VII

Formula VII

Accordin to one embodiment , a compound of formula VIII

Formula VIII

According to one embodiment , a compound of Formula IX Formula IX

According to one embodiment , a compound of Formula X

Formula X

According to one embodiment , a compound of Formula XI

Formula XI

According to one embodiment , a compound of Formula XII

Formula XII

According to one embodiment , a compound of formula XIII Formula XIII

According to one embodiment , a compound of Formula XIV

Formula XIV

According to one embodiment , a compound of Formula XV

Formula XV

According to one embodiment , a compound of Formula XVI

Formula XVI

According to one embodiment , a compound of Formula XVII

^R 3\ / ^R 4

HNf Formula XVII

Accord

Formula XVIII

Accord

Formula XIX

Acco

Formula XX

Formula XXI Accord

Formula XXII

According to one embodiment, present invention includes compounds provided in Tables A1-A7, B1-3, C1-3, D1-3, E1-3, F1-3, G1-3, H1-3, 11-3, J1-3, K1-3, L1-3, M1-3, N1-3, 01-3, P1- 3, Q1-3, S1-3, T1-3 and U1-3.

According to one embodiment, a compound of the present invention for improving pharmacological response, pharmacokinetic profile, toxicity, physicochemical propertiy and ease of administration of the therapeutic agent.

According to one embodiment, a compound of the present invention for improving pharmacological response of the therapeutic agent.

According to one embodiment, a compound of the present invention for improving pharmacokinetic profile of the therapeutic agent.

According to one embodiment, a compound of the present invention for improving toxicity of the therapeutic agent.

According to one embodiment, a compound of the present invention for improving physicochemical property of the therapeutic agent.

According to one embodiment, a compound of the present invention for improving ease of administration of the therapeutic agent.

According to another embodiment, the present invention includes pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. The pharmaceutical compositions of the present invention can be used for treating or preventing a wide variety of disease conditions or disorders. According to another aspect, the present invention includes process to produce a compound of present invention, their pharmaceutically acceptable salt and prodrugs thereof.

According to one embodiment, the present invention includes use of a compound of present invention for the preparation of a pharmaceutical composition useful in the treatment and/or prevention of acne, attention deficit hyperactivity disorder(ADHD), acquired immune deficiency syndrome (AIDS)/ human immunodeficiency virus(HIV), allergies, Alzheimer's, angina, anxiety, arthritis, asthma, bipolar disorder, bronchitis, cancer, cardiovascular, central nervous system disorders, cholesterol, colds & flu, constipation, congestion, chronic obstructive pulmonary disease (COPD), depression, diabetes (type 1), diabetes (type 2), diarrhea, eczema, erectile dysfunction, fibromyalgia, gastrointestinal disease, gastroesophageal reflux disease (GERD), gout, hair loss, hayfever, heart disease, hepatitis A, hepatitis B, herpes, hypertension, hypothyroidism, incontinence, infectious disease, inflammation, inflammatory bowel disease(IBD), insomnia, metabolic disease, menopause, mental health disorder, migraine, osteoarthritis, osteoporosis, pain, parkinsonism, parkinson's disease, psychosis, ulcers psoriasis, rheumatoid arthritis, schizophrenia, seizures, sexual health disorder, stroke, swine flu, urinary tract infection (UTI) and weight loss.

The compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as XRPD patterns (diffractograms), solubility in various solvents, and melting point.

Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by the formulae of the present invention, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

The present invention includes a salt or solvate of the compounds herein described, including combinations thereof such as a solvate of a salt. The compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such forms. The salts of the present invention can be pharmaceutically acceptable salts which include non-toxic salts of the compounds set forth herein.

Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and Ν,Ν'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt. The salts may be in some cases hydrates or ethanol solvates.

Although it is possible to administer the compound of the present invention in the form of a bulk active chemical, it is preferred to administer the compound in the form of a pharmaceutical composition or formulation. Thus, pharmaceutical compositions are provided that include one or more compounds of Formula IA and Formula IB, and/or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients. Another aspect of the invention provides a process for the preparation of a pharmaceutical composition including admixing one or more compounds of Formula IA and Formula IB, and/or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

The manner in which the compounds set forth herein may be administered can vary. According to one embodiment, the compounds can be administered orally. Preferred pharmaceutical compositions may be formulated for oral administration in the form of tablets, capsules, caplets, syrups, solutions, and suspensions. Such oral formulations can be provided in modified release dosage forms such as time-release tablet and capsule formulations. Pharmaceutical compositions can also be administered via injection, namely, intravenously, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally, and intracerebroventricularly. Intravenous administration is a preferred method of injection. Suitable carriers for injection are well known to those of skill in the art and include 5% dextrose solutions, saline, and phosphate buffered saline. Pharmaceutical compositions may also be administered using other means, for example, rectal administration. Formulations useful for rectal administration, such as suppositories, are well known to those of skill in the art. The compounds can also be administered by inhalation, for example, in the form of an aerosol; topically, such as, in lotion form; transdermal^, such as, using a transdermal patch (for example, by using technology that is commercially available from Novartis and Alza Corporation); by powder injection; or by buccal, sublingual, or intranasal absorption. Pharmaceutical compositions may be formulated in unit dose form, or in multiple or subunit doses.

The administration of the pharmaceutical compositions described herein can be intermittent, or at a gradual, continuous, constant or controlled rate. The pharmaceutical compositions may be administered to a warm-blooded animal, for example, a mammal such as a human being. In addition, the time of day and the number of times per day that the pharmaceutical composition is administered can vary.

The compounds as provided herein may also be used for the preparation of a medicament for the treating or preventing or delaying the onset of, or slowing the progression of disorders of a disease or condition.

According to one embodiment, the methods for treating, preventing, delaying the onset of, or slowing the progression of disorders mediated by proteins involved in the regulation of gene expression, in mammals in need of such treatment are also provided. The methods involve administering to a subject a therapeutically effective amount of a compound of present invention as provided herein, including a salt thereof, or a pharmaceutical composition that includes such compounds.

According to one embodiment, the methods include the administration of compounds provided in Tables A1-A7, B1-3, C1-3, D1-3, E1-3, F1-3, G1-3, H1-3, 11-3, J1-3, K1-3, L1-3, M1- 3, N1-3, 01-3, P1-3, Q1-3, S1-3, T1-3 and U1-3.

The compounds as provided herein may be used in the treatment of a variety of disorders and conditions and, as such, may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions. Thus, one embodiment of the present invention includes the administration of the compound of the present invention in combination with other therapeutic compounds. Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect. The administration in combination of a compound of the present invention with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including either compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second. Such sequential administration may be close in time or remote in time.

Another aspect of the present invention includes combination therapy comprising administering to the subject a therapeutically or prophylactically effective amount of the compound of the present invention and one or more other therapy including chemotherapy, radiation therapy, gene therapy, or immunotherapy.

The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the present invention along with methods for their preparation. The compounds can be prepared according to the methods described below using readily available starting materials and reagents. In these reactions, variants may be employed which are themselves known to those of ordinary skill in this art but are not described in detail here. Those skilled in the art of organic synthesis will appreciate that there exist multiple means of producing compounds of the present invention. Illustrative synthetic methods, including those directed to specific, selected compounds noted in Tables A1-A7, B1-3, C1-3, D1-3, E1-3, F1-3, G1-3, H1-3, 11-3, J1-3, K1-3, L1-3, M1-3, N1-3, 01-3, P1-3, Q1-3, S1-3, T1-3 and U1-3 are set forth herein.

Examples Synthetic Methods

The compounds of this invention described herein can be prepared by any number of methods known/obvious to those skilled in the art. As a matter of illustration, any of the approaches shown in the following schemes can be used to make such compounds of the formula (I) described herein. Compounds of this invention can be prepared in accordance with one or more of the Schemes discussed below. These procedures of each reaction will be understandable to and can be carried out by someone of ordinary skill in organic chemistry. Starting materials may be prepared according to procedures provided in references below, or can be prepared by procedures reported in literature or are commercially available. Unless otherwise defined below, variables used in the Schemes are as defined in the specification or in the claims. PG is a suitable protecting groups (PGs) include, but not limited to, acetyl, Boc, Fmoc, benzoyl, pivaloyl, trityl, tetrahydropyranyl (THP), alkyl ester and silyl (TBDMS, TMS, etc.). More information about the selection of protecting groups is described in the book "Greene's Protective Groups in Organic Synthesis" 5th Edition, by Peter G. M. Wuts, Publisher: John Wiley & Sons. LG is suitable leaving group such as a halide, imidazole, O-succinimide, 4-nitrophenoxide, ester and the like, which can be reacted with nucleophilic group of the linker in the absence or presence of a suitable base and solvent. More examples and preparation are described in the book Organic Chemistry (8th Edition) by L. G. Wade Jr, Publisher: Pearson.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high- performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

The reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

The therapeutic agent (Re) may have more than one functional group, in those cases, the other functional group(s) may be protected by appropriate protecting group(s) and the they can be deprotected to obtain the desired compound. Scheme 1

5

A sulfide derivative 1 can be treated with sulfuryl chloride in an organic solvent to get corresponding sulfenyl chloride 3 (Chiara Falciani et al., "Design and in Vitro Evaluation of Branched Peptide Conjugates: Turning Nonspecific Cytotoxic Drugs into Tumor-Selective Agents," ChemMedChem 5, no. 4 (April 6, 2010): 567-74, doi: 10.1002/cmdc.200900527). Alternately compound 3 also can be obtained by treating a disulfide derivative 2 with sulfuryl chloride in an organic solvent (Victor R. Guarino, Veranja Karunaratne, and Valentino J. Stella, "Sulfenamides as Prodrugs of NH-Acidic Compounds: A New Prodrug Option for the Amide Bond," Bioorganic & Medicinal Chemistry Letters 17, no. 17 (September 1 , 2007): 4910-13, doi: 10.1016/j.bmcl.2007.06.037). The sulfuryl chloride 3 can be reacted with a biguanidine derivative 4 in presence of an inorganic or organic base in an appropriate solvent to get the final compound 5 of the Claim 1. Scheme 2

A phthalimido derivative 7 can be prepared by reacting a thiol derivative 1 with N- bromophthalimide 6 using organic or aqueous solvent (Tunde-Zita lllyes, Tamas Szabo, and Laszlo Szilagyi, "Glycosylation via Mixed Disulfide Formation Using Glycosylthio-Phthalimides and -Succinimides as Glycosylsulfenyl-Transfer Reagents," Carbohydrate Research 346, no. 12 (September 6, 2011): 1622-27, doi: 10.1016/j.carres.201 1.04.020; Kai Kang, Chunfa Xu, and Qilong Shen, "Copper-Catalyzed Trifluoromethylthiolation of Aryl and Vinyl Boronic Acids with a Shelf-Stable Electrophilic Trifluoromethylthiolating Reagent," ORGANIC CHEMISTRY ^ , no. 3 (March 25, 2014): 294-97, doi: 10.1039/C3QO00068K; Elise Sarrazin et al., "Elucidation of the 1 ,3-Sulfanylalcohol Oxidation Mechanism: An Unusual Identification of the Disulfide of 3-Sulfanylhexanol in Sauternes Botrytized Wines," Journal of Agricultural and Food Chemistry 58, no. 19 (October 13, 2010): 10606-13, doi: 10.1021/jf 102022s; Michiel de Greef, "Novel applications of xanthates radical chemistry (masked radical formylation, synthesis of structurally divers spiroketals and synthesis of phosphorus-containing compounds)," 2006; Marcello Allegretti and Aramini, Andrea, Sulfonic acids, their derivatives and pharmaceutical compositions containing them, EP1457485 A1 , n.d).

Alternatively compound 7 can be made by reacting a disulfide derivative with N- bromophthalimide 6 in an organic solvent at room temperature; or with conventional heating or microwave conditions (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1 , n.d).

The compound 7 can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 5 of the claim 1 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1 , n.d). N Lr/ R, ₆

LG= Leaving group

A biguanidine derivative 8 with a linker having a nucleophilic group can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 8 can be reacted with compound 9 having a leaving group (LG) using appropriate reaction condition reported in the literature to get the corresponding final compound 10.

Scheme 4

A biguanidine derivative 11 with a linker having an electrophilic group can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7. Compound 11 can be reacted with compound 12 having a nucleophilic group using appropriate reaction condition reported in the literature to get the corresponding final compound 13.

Scheme 5

R = H or any substituent

A biguanidine derivative 14 with a linker having a carboxylic acid group can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 14 can be reacted with compound 15 with reactive group functionality (for example: NHR, OH, SH or COOH functionality wherein R is a substitution) to using appropriate reaction condition reported in the literature to get the corresponding final compound 16.

Scheme 6

'6

YH = NHR, OH, SH or COOH

R = H or any substituent

A biguanidine derivative 17 with a linker having a reactive group YH (NHR, OH, SH or COOH functionality wherein R is a substitution) can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 17 can be reacted with compound 18 having a carboxylic acid functional group using appropriate reaction condition reported in the literature get the corresponding final compound 19.

Scheme 7

ZH = NHR, OH, SH or COOH

R = H or any substituent

A biguanidine derivative 20 with a linker having a carboxylic acid can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 20 can be reacted with compound 21 with linker having a reactive group ZH (NHR, OH, SH or COOH functionality wherein R is a substitution) using appropriate reaction condition reported in the literature get the corresponding final compound 22.

Scheme 8

² 23 ⁵ conditions ² ₂₅ ^R s

WH = NHR, OH, SH or COOH

R = H or any substituent

LG= Leaving group

A biguanidine derivative 23 with a linker having a reactive group WH (NHR, OH, SH or COOH functionality wherein R is a substitution) can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 23 can be reacted with compound 24 with linker having a leaving group (LG) using appropriate reaction condition reported in the literature get the corresponding final compound 25. Scheme 9

conditions RW _{2 2G}

ZH = NHR, OH, SH or COOH

R = H or any substituent

LG= Leaving group

A biguanidine derivative 26 with a linker having a leaving group (LG) can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 26 can be reacted with compound 27 with linker having a reactive group ZH (NHR, OH, SH or COOH functionality wherein R is a substitution) using appropriate reaction condition reported in the literature get the corresponding final compound 28.

Scheme 10

ZH = NHR, OH, SH or COOH

R = H or any substituent

A biguanidine derivative 29 with a linker having a reactive group ZH (NHR, OH, SH or COOH) functionality wherein R is a substitution) can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 29 can be reacted with compound 30 with linker having a carboxylic acid group using appropriate reaction condition reported in the literature get the corresponding final compound 31. Scheme 11

L1 Y ¾ I O

Z., H = NHR, OH, SH or COOH

Z ₂ H = NHR, OH, SH or COOH

R = H or any substituent

A biguanidine derivative 32 with a linker having a reactive group Zi H (NHR, OH, SH or COOH functionality wherein R is a substitution) can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 32 can be reacted with compound 33 with linker having a reactive group Z2H (NHR, OH, SH or COOH) using appropriate one step or two step reaction conditions reported in the literature get the corresponding final compound 34.

Scheme 12 n

ZH = NHR, OH, SH or COOH

R = H or any substituent

P

A phthalimido derivative 37 with a linker having a carboxylic acid group can be prepared by reacting a thiol derivative 35 with N-bromophthalimide 6 using organic or aqueous solvent, followed by deprotection of a protecting group (Wyes, Szabo, and Szilagyi, "Glycosylation via Mixed Disulfide Formation Using Glycosylthio-Phthalimides and -Succinimides as Glycosylsulfenyl-Transfer Reagents"; Kang, Xu, and Shen, "Copper-Catalyzed Trifluoromethylthiolation of Aryl and Vinyl Boronic Acids with a Shelf-Stable Electrophilic Trifluoromethylthiolating Reagent"; Sarrazin et al., "Elucidation of the 1 ,3-Sulfanylalcohol Oxidation Mechanism"; Greef, "Novel applications of xanthates radical chemistry (masked radical formylation, synthesis of structurally divers spiroketals and synthesis of phosphorus-containing compounds)"; Allegretti and Aramini, Andrea, Sulfonic acids, their derivatives and pharmaceutical compositions containing them).

Alternatively compound 37 can be made by reacting a disulfide derivative 36 with N- bromophthalimide 6 an organic solvent at room temperature; or with conventional heating or microwave conditions ((Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1 , n.d).), followed by deprotection of a protecting group.

The carboxylic acid derivative 37 can reacted with compound 38 with functionality Zi H (NHR, OH, SH or COOH functionality wherein R is a substitution) using appropriate coupling conditions to obtain compound 39.

The compound 39 can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 40 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1).

Scheme 13

1.N-bromophthalimide 6

PG

ZH

R = H or any substituent

PG=

LG=

A phthalimido derivative 43 a linker having a reacting group (WH) can be prepared by reacting thiol derivative 41 with N-bromophthalimide 6 using conditions using organic or aqueous solvent, followed by deprotection of a protecting group (Wyes, Szabo, and Szilagyi, "Glycosylation via Mixed Disulfide Formation Using Glycosylthio-Phthalimides and -Succinimides as Glycosylsulfenyl-Transfer Reagents"; Kang, Xu, and Shen, "Copper-Catalyzed Trifluoromethylthiolation of Aryl and Vinyl Boronic Acids with a Shelf-Stable Electrophilic Trifluoromethylthiolating Reagent"; Sarrazin et al., "Elucidation of the 1 ,3-Sulfanylalcohol Oxidation Mechanism"; Greef, "Novel applications of xanthates radical chemistry (masked radical formylation, synthesis of structurally divers spiroketals and synthesis of phosphorus-containing compounds)"; Allegretti and Aramini, Andrea, Sulfonic acids, their derivatives and pharmaceutical compositions containing them).

Alternatively compound 43 can be made by reacting a disulfide derivative 45 with N- bromophthalimide 6 an organic solvent at room temperature; or with conventional heating or microwave conditions conditions conditions (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1), followed by deprotection. The compound 43 can be reacted with a compound 44 with linker having a leaving group (LG) to afford compound 45. The compound 45 then can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 46 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1).

Scheme 14

1.N-bromophthalimide 6

2. Deprotection

48

ZH = NHR, OH, SH or COOH

R = H or any substituent

A phthalimido derivative 49 a linker having a leaving group (LG) can be prepared by reacting thiol derivative 47 with N-bromophthalimide 6 using conditions using organic or aqueous solvent, followed by deprotection of a protecting group (lllyes, Szabo, and Szilagyi, "Glycosylation via Mixed Disulfide Formation Using Glycosylthio-Phthalimides and -Succinimides as Glycosylsulfenyl-Transfer Reagents"; Kang, Xu, and Shen, "Copper-Catalyzed Trifluoromethylthiolation of Aryl and Vinyl Boronic Acids with a Shelf-Stable Electrophilic Trifluoromethylthiolating Reagent"; Sarrazin et al., "Elucidation of the 1 ,3-Sulfanylalcohol Oxidation Mechanism"; Greef, "Novel applications of xanthates radical chemistry (masked radical formylation, synthesis of structurally divers spiroketals and synthesis of phosphorus-containing compounds)"; Allegretti and Aramini, Andrea, Sulfonic acids, their derivatives and pharmaceutical compositions containing them).

Alternatively compound 49 can be made by reacting a disulfide derivative 48 with N- bromophthalimide 6 an organic solvent at room temperature; or with conventional heating or microwave conditions (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1).

The compound 49 can reacted with compound 50 with functionality ZH (NHR, OH, SH or COOH functionality wherein R is a substitution) using appropriate reaction conditions to obtain compound 51. The compound 51 hen can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 52 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1).

Scheme 15

54 2. Deprotection

Z = NR, O, S or COO

R = H or any substituent

PG= Protecting group

LG= Leaving group

A phthalimido derivative 55 a linker having a reactive group ZH (NHR, OH, SH or COOH functionality wherein R is a substitution) can be prepared by reacting silver salt of a thiol derivative 53 with N-bromophthalimide 6 using conditions using organic or aqueous solvent, followed by deprotection of a protecting group (Wyes, Szabo, and Szilagyi, "Glycosylation via Mixed Disulfide Formation Using Glycosylthio-Phthalimides and -Succinimides as Glycosylsulfenyl-Transfer Reagents"; Kang, Xu, and Shen, "Copper-Catalyzed Trifluoromethylthiolation of Aryl and Vinyl Boronic Acids with a Shelf-Stable Electrophilic Trifluoromethylthiolating Reagent"; Sarrazin et al., "Elucidation of the 1 ,3-Sulfanylalcohol Oxidation Mechanism"; Greef, "Novel applications of xanthates radical chemistry (masked radical formylation, synthesis of structurally divers spiroketals and synthesis of phosphorus-containing compounds)"; Allegretti and Aramini, Andrea, Sulfonic acids, their derivatives and pharmaceutical compositions containing them).

Alternatively compound 55 can be made by reacting a disulfide derivative 54 with N- bromophthalimide 6 an organic solvent at room temperature; or with conventional heating or microwave conditions (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1), followed by deprotection.

The compound 55 obtained by using any of the above reaction condition can be reacted with a compound 56 with linker having a carboxy group using a coupling agent to afford compound 57. The compound 57 hen can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 58 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337

A1).

Scheme 16

A biguanidine derivative 59 with a linker having an amino group can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection (if necessary). Compound 59 can be reacted with compound 60 having a cabonyl functional group using appropriate reaction condition reported in the literature get the corresponding final compound 61.

Scheme 17

R= H or substitution

A biguanidine derivative 62 with a linker having an carbolyl group can be prepared by using procedure similar to the procedure described to prepare compounds 3 and 7 and subsequent deprotection if needed. Compound 62 can be reacted with compound 63 having an amino functional group using appropriate reaction condition reported in the literature get the corresponding final compound 64.

Scheme 18

A therapeutic agent (Re) 65 with a linker having an phthalimido group can be prepared by using procedure similar to any of the procedures described to prepare compounds 7, 37, 43, 49, or 55. The compound 65 hen can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 66 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1).

Scheme 19

A therapeutic agent (Re) 67 with a linker having an phthalimido group can be prepared by using procedure similar to any of the procedures described to prepare compounds 39, 45, 51, 57, or 65. The compound 67 hen can be reacted with a biguanidine derivative 4 using appropriate reaction conditions to get the final compound 68 (Kristiina M. Huttunen et al., "The First Bioreversible Prodrug of Metformin with Improved Lipophilicity and Enhanced Intestinal Absorption," Journal of Medicinal Chemistry 52, no. 14 (July 23, 2009): 4142-48, doi: 10.1021/jm900274q; Kristiina Huttunen et al., Novel prodrugs of metformin, WO2010100337 A1).

The compounds of Tables A1-A7, B1-3, C1-3, D1-3, E1-3, F1-3, G1-3, H1-3, 11-3, J1-3, K1-3, L1-3, M1-3, N1-3, 01-3, P1-3, Q1-3, S1-3, T1-3 and U1-3 can be prepared by following the any of the reaction shemes mentioned above

Table A3

72

Table Bl

O °

B31 1460.83

B32 1467.86

0

Table B2

Table B3

Mol.

No. Lx

Weight

B65 1434.83

0 0

o

B66 1509.93

B67 1268.65

— ' 0

Table CI

Mol.

No. Lx

Weight

CI 879.06

0 0

o

C2 954.16

Table C2

Table C3

Table El

Table E3

F21 1117.24

F22 1073.19

^Η 0

F23 1017.12

Η Ο

F24 869.95

F25 1191.32 ο _Η 0

F26 1147.26

F27 1103.21

F28 1059.16

F29 1192.30

0 0

F30 1148.25 ο °

F31 1104.20

F32 1111.23

0

Table F3

0 °

F95 1132.25

F96 1139.28

0

Table Gl

0 0

G30 1009.27 o °

G31 965.22

G32 972.25

0

Table G2

Table G3

Table HI

Table H2

Mol.

No. Lx

Weight

H

H33 973.24

0 0

o

H34 1048.34

H35 807.06

0

Table H3

0 _| _ _| 0

H90 1022.30

0 °

H91 978.25

H92 934.20

H93 1067.34 o o

H94 1023.29 o ⁰

H95 979.24

H96 986.27

O

Table 11

Mol.

No. Lx

Weight

11 837.09

O 0

o

12 912.19

13 670.91

— ' 0

O °

127 890.15

128 846.10

129 979.24

O 0

130 935.19 o ⁰

131 891.14

132 898.17

0

0 0

L94 1095.68 o °

L95 1051.63

L96 1058.66

0

Table Ml

Table N2

Table PI

Table P3

Table Ql

Table Q3

Table S2

Table S3

Table T2

Experimental procedures

Example-1 (Scheme 19):

4-(((1 S,2R)-1-benzamido-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6 ,12b-diacetoxy-12- (benzoyloxy)-4,11 -dihvdroxy-4a,8,13,13-tetramethyl-5-oxo-

2a,3A4a,5,6,9,10,11 ,12,12a,12b-dodecahvdro-1 H-7,11 -methanocyclodecar3,41benzori ,2- b1oxet-9-yl)oxy)-3-oxo-1 -phenylpropan-2-yl)oxy)-4-oxobutanoic acid (INT-1 ): To a stirred solution compound paclitaxel (2.0 g, 2.3 mmol) in pyridine (20 ml_) and dry DICLOROMETHANE (18 ml_) was added succinic anhydride (0.281 g, 2.8 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hour. The reaction mixture was evaporated under reduced pressure. The crude product was purified by Prep-HPLC to produce 1.5 gm (68%) of the 4-(((1S,2R)-1-benzamido-3-(((2aR,4S,4aS,6R,9S, 1 1S,12S, 12aR, 12bS)- 6, 12b-diacetoxy-12-(benzoyloxy)-4, 1 1 -dihydroxy-4a,8, 13, 13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9, 10, 11 , 12,12a, 12b-dodecahydro-1 H-7, 1 1-methanocyclodeca[3,4]benzo[1 ,2- b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)-4-oxobutanoi c acid (INT-1) as a white solid. The product was analysed by NMR and LCMS.

4- ((tert-Butoxycarbonyl)amino)cvclohexyl methanesulfonate (INT-2) : To a stirred solution of tert-butyl (4-hydroxycyclohexyl)carbamate (25.0 g, 116.1 mmol, 1eq) in dry dicloromethane (250 ml_) was added triethylamine (32.2 ml_, 232.3 mmol) at 0 °C under N2 atmosphere at room temperature. Mesyl chloride (10 ml_, 127.7 mmol) was added drop wise to the above reaction mixture after 15 min. Then reaction mixture was stirred at room temperature for 16 hour. The reaction mixture was quenched with aq. sodium bicarbonate, extracted with dichloromethane. The combined extracts were washed with water, brine and dried over anhydrous sodium sulphate, filtered and solvents evaporated from the filtrate under reduced pressure to obtain crude product which was purified by column chromatography to yield 25.0 g (73.5 %) of 4-((tert- butoxycarbonyl)amino)cyclohexyl methanesulfonate (INT-2). The final product was characterized by NMR.

5- (4-((tert-Butoxycarbonyl)amino)cvclohexyl) ethanethioate (INT-3): To a stirred solution of 4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate(INT-2) (15.0 g, 51.17 mmol) in dry dimethylformamide (150 ml_) was added potassium thioacetate (58.4 g, 511.7 mmol) at room temperature and the reaction mixture was stirred at 80-90 °C for 3 hour. The reaction mixture was diluted with ethyl acetate, added cool water, extracted organic layer twice. The combined extracts were washed with water, brine, dried over anhydrous sodium sulphate, filtered and solvents evaporated from the filtrate under reduced pressure to obtain crude product which was purified by column chromatography to obtain 8.0 g (57.2 %) of the S-(4-((tert- butoxycarbonyl)amino)cyclohexyl) ethanethioate (INT-3) as a brown solid. The final product was characterized by NMR. tert-Butyl (4-mercaptocyclohexyl)carbamate (INT-4): To a stirred solution S-(4-((tert- butoxycarbonyl)amino)cyclohexyl) ethanethioate (8.0 g, 29.2 mmol) in methanol (80 ml_) was added 30% NaOMe in methanol (24 ml_, 1 17.1 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with acidic resin, then filtered through celite pad wash with ethyl acetate twice and evaporated under reduced pressure to get 6.6 g (99 %) of tert-butyl (4-mercaptocyclohexyl)carbamate (INT-4) as white solid. The crude product was subjected to next reaction without any further purification. The final product was characterized by NMR.

Di-tert-butyl (disulfanediylbis(cvclohexane-4,1-diyl))dicarbamate (INT-5): To a solution of tert-butyl (4-mercaptocyclohexyl)carbamate (INT-4) (6.6 g, 28.5 mmol) in ethyl acetate (97 ml_) were added Nal (0.042 g, 0.28 mmol) and 30% H2O2 (2.6 ml_, 28.5 mmol) at 0 °C under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aq. sodium thiosulphate and extracted organic layer. The combined extracts were washed with water, brine and dried over anhydrous sodium sulfate, filtered and solvents evaporated from the filtrate under reduced pressure to obtain crude product which was purified by column chromatography to yield 5.6 g (42.6%) of di-tert-butyl (disulfanediylbis(cyclohexane-4, 1-diyl))dicarbamate (INT-5)as a white solid. The final product was characterized by NMR. tert-Butyl (4-((1 ,3-dioxoisoindolin-2-yl)thio)cvclohexyl)carbamate (INT-6): To a stirred solution of 2-bromoisoindoline-1 ,3-dione (1.0 g, 9.77 mmol) in benzene (45 ml_) was added di- tert-butyl (disulfanediylbis(cyclohexane-4, 1-diyl))dicarbamate (INT-5) (4.5 g, 9.77 mmol) under N ₂ atmosphere at room temperature. Then reaction mixture was stirred for 3 hours at 50 °C The reaction mixture was evaporated under reduced pressure to obtain crude product which was purified by column chromatography to yield 1.5 g (20 %) of tert-butyl (4-((1 ,3-dioxoisoindolin-2- yl)thio)cyclohexyl)carbamate (INT-6) as a white solid. The product was analysed by NMR.

2-((4-aminocvclohexyl)thio)isoindoline-1 ,3-dione (INT-7): To a stirred solution of tert-butyl (4- ((1 ,3-dioxoisoindolin-2-yl)thio)cyclohexyl)carbamate (1.4 g, 3.71 mmol) in Dry dicloromethane (15 ml_) was added TFA (0.5 ml_, 7.43 mmol) at 0 °C. Then reaction mixture was stirred at room temperature for 16 hour. The reaction mixture was evaporated under reduced pressure and washed with diethyl ether to obtain 1.0 g(98 %) crude product 2-((4- aminocyclohexyl)thio)isoindoline-1 ,3-dione (INT- 7) as a white solid which was subjected to next reaction without any purification. The product was analysed by NMR.

(2aR,4S,4aS,6R,9S, 11 S, 12S, 12aR, 12bS)-9-(((2R,3S)-3-benzamido-2-((4-((4-((1 ,3- dioxoisoindolin-2-yl)thio)cvclohexyl)amino)-4-oxobutanoyl)ox y)-3-phenylpropanoyl)oxy)- 12-(benzoyloxy)-4,11-dihvdroxy-4a,8,13,13-tetramethyl-5-oxo- 3,4,4a,5,6,9,10,11 ,12,12a- decahvdro-1 H-7,11 -methanocvclodecar3,41benzori ,2-b1oxete-6,12b(2aH)-diyl diacetate (INT-8): To a solution of 4-(((1S,2R)-1-benzamido-3-(((2aR,4S,4aS,6R,9S, 1 1S,12S, 12aR, 12bS)- 6, 12b-diacetoxy-12-(benzoyloxy)-4, 1 1 -dihydroxy-4a,8, 13, 13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9, 10, 11 , 12, 12a, 12b-dodecahydro-1 H-7, 1 1 -methanocyclodeca[3,4]benzo[1 ,2- b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)-4-oxobutanoi c acid (INT-1) (1.9 g, 1.99 mmol) in dry dicloromethane (20.0 ml_) was DIPEA (0.7 Ml, 3.98 mmol) and HBTU (1.13 g, 2.98 mmol) at 0 °C under N2 atmosphere. After 15 min 2-((4-aminocyclohexyl)thio)isoindoline-1 ,3-dione (INT- 7) was added and mixture was stirred at room temperature for 6 hour. The reaction mixture was evaporated under reduced pressure and poured onto ice followed by extraction with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and solvents evaporated from the filtrate under reduced pressure to obtain crude product which was purified by using grace column chromatography using a solvent gradient of 10% MeOH in dicloromethane as eluent to obtain 1.5 g (62.5%) of (2aR,4S,4aS,6R,9S, 1 1S, 12S, 12aR, 12bS)- 9-(((2R,3S)-3-benzamido-2-((4-((4-((1 ,3-dioxoisoindolin-2-yl)thio)cyclohexyl)amino)-4- oxobutanoyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4, 11-dihydroxy-4a,8, 13, 13- tetramethyl-5-oxo-3,4,4a,5,6,9, 10, 11 , 12, 12a-decahydro-1 H-7, 11 - methanocyclodeca[3,4]benzo[1 ,2-b]oxete-6, 12b(2aH)-diyl diacetate (INT-8) as a white solid. The product was analysed bu LCMS and NMR.

(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzam ido-2-((4-((4-(((E)-2-(N,N- dimethylcarbamimidoyl)guanidino)thio)cyclohexyl)amino)-4-oxo butanoyl)oxy)-3- phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13, 13-tetramethyl-5-oxo- 3,4,4a,5,6,9,10,11,12,12a-decahydro-1 H-7,11-methanocyclodeca[3,4]benzo[1 ,2-b]oxete- 6,12b(2aH)-diyl diacetate (Target compound): To a solution of

(2aR,4S,4aS,6R,9S, 11 S,12S, 12aR, 12bS)-9-(((2R,3S)-3-benzamido-2-((4-((4-((1 ,3- dioxoisoindolin-2-yl)thio)cyclohexyl)amino)-4-oxobutanoyl)ox y)-3-phenylpropanoyl)oxy)-12- (benzoyloxy)-4, 1 1 -dihydroxy-4a,8, 13, 13-tetramethyl-5-oxo-3,4, 4a, 5,6,9, 10, 11 , 12, 12a- decahydro-1 H-7, 1 1-methanocyclodeca[3,4]benzo[1 ,2-b]oxete-6, 12b(2aH)-diyl diacetate (INT-8) (1.3 g, 1.07 mmol, 1 eq) in acetonitrile (15.0 ml_), DI PEA (1.0 ml) was added 3- (diaminomethylene)-1 ,1-dimethylguanidine, at room temperature (0.138 g, 1.07 mmol, 1 eq) and the reaction mixture was stirred for 3h.at room temperature and monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced to obtain crude product. The crude compound was purified by using prep HPLC to obtain 0.13 g (10.1 %) of the target compound (2aR,4S,4aS,6R,9S, 1 1S, 12S, 12aR, 12bS)-9-(((2R,3S)-3-benzamido-2-((4-((4-(((E)-2- (N,N-dimethylcarbamimidoyl)guanidino)thio)cyclohexyl)amino)- 4-oxobutanoyl)oxy)-3- phenylpropanoyl)oxy)-12-(benzoyloxy)-4, 11 -dihydroxy-4a,8, 13, 13-tetramethyl-5-oxo- 3,4,4a,5,6,9, 10, 1 1 , 12, 12a-decahydro- 1 H-7, 11 -methanocyclodeca[3,4]benzo[1 ,2-b]oxete- 6,12b(2aH)-diyl diacetate as acetic acid salt. The final product (Example-1) was analysed by LCMS and NMR.

Example-2 (Scheme 20)

(Z)-2-tert-butoxy-2-oxoethyl 2-(5-fluoro-2-methyl-1-(4- (methylsulfinyl)benzylidene)-1 H- inden-3-yl)acetate (INT-1 )

To a stirred solution of (Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1 H-inden-3- yl)acetic acid (6 g, 16.85mmol) in dicloromethane (60 ml_) were added TEA (3.4 ml, 33.71 mmol) followed by tert-butyl 2-bromoacetate (3.93 g, 20.22 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography on silica (eluting 0-20% ethyl acetate in pet-ether) to get 6 g, (75%) of (Z)-2-tert- butoxy-2-oxoethyl-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl) benzylidene)-1 H-inden-3-yl)acetate (INT-1) as a yellow solid. The final product was characterized by LCMS and NMR.

(Z)-2-(2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylid ene)-1 H-inden-3-yl)acetoxy acetic acid (INT-2)

To a stirred solution of (Z)-2-tert-butoxy-2-oxoethyl 2-(5-fluoro-2-methyl-1-(4- (methylsulfinyl)benzylidene)-1 H-inden-3-yl)acetate (INT-1) (6 g, 12.76 mmol) in dichloromethane (60 ml_) was added TFA (6 ml_) at 0 °C. The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure and the crude was triturated with diethyl ether to get 5 g (94%) (Z)-2-(2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene )- 1 H-inden-3-yl)acetoxy acetic acid (INT-2) TFA salt as a yellow solid. The final product was characterized by LCMS.

(Z)-2-(4-(1 ,3-dioxoisoindolin-2-ylthio)cyclohexylamino)-2-oxoethyl 2-(5-fluoro-2-methyl-1 - (4-(methylsulfinyl)benzylidene)-1 H-inden-3-yl)acetate (INT-3)

To a stirred solution of (Z)-2-(2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene )-1 H-inden-3- yl)acetoxy acetic acid (INT-2) (5 g, 12.01 mmol), 2-(4-aminocycloexylthio)isoindoline-1 ,3-dione (INT-7, Scheme 19) (3.33 g, 12.08 mmol) in DCM (50 ml_) were added DIPEA (3.4 ml, 33.70 mmol) followed HBTU (6.87 g, 18.12 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 ml_) and washed with water, brine; dried over Na2S0 ₄ and concentrated under reduced pressure the crude compound was obtained. The crude compound was purified by silica gel column chromatography, eluting with 0-80% ethyl acetate in pet ether to afford 4 g (49%) of (Z)-2-(4-(1 ,3-dioxoisoindolin-2-ylthio)cyclohexylamino)-2-oxoethyl 2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1 H-inden-3-yl)acetate (INT-3) as a yellow solid. The final product was characterized by LCMS.

2-(4-((£)-2-(N,N-dimethylcarbamimidoyl)guanidinothio)cyc lohexylamino)-2-oxoethyl 2- ((Z)-5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1 H-inden-3-yl)

To a stirred solution of (Z)-2-(4-(1 ,3-dioxoisoindolin-2-ylthio)cyclohexylamino)-2-oxoethyl 2-(5- fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1 H-inden-3-yl)acetate (INT-3) (2 g, 2.98mmol) in DMSO (20 ml_) was added DIPEA (3.85 ml, 29.761 mmol) followed by Metformin. HCI (0.768 g, 5.9522 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was triturated with diethyl ether to furnish the crude compound. The crude compound was purified by prep HPLC (mobile phase ACN, 0.1 % aqueous HCOOH) followed by lyophilization to afford 105 mg (5%) to give the target compound as a yellow solid. The final product (Example-2) was characterized by LCMS and NMR.

Example-3: Solubility tests aqueous buffer solutions:

The solubility of compound Example-1 was determined in Fasted State Simulated Intestinal Fluid (FaSSIF), Fed State Simulated Intestinal Fluid (FeSSIF), Fasted-State Simulated Gastric Fluid (FaSSGF) and Fed-State Simulated Gastric Fluid (FeSSGF) at 25 °C. 4 μΙ_ of 50 mM DMSO stock solution was added to 396 μΙ_ of simulated fluids and incubated for 4 h at room temperature with constant mixing at 1200 rpm. After incubation, the tubes were centrifuged for 10 min at 10,000 rpm. Later 200 of sample was taken and filtered. The filtrate was analyzed by HPLC- UV. The results are describe in Table 1.

Table 1.

FaSSIF Medium FeSSIF Medium FaSSGF Medium FeSSGF Medium

Compound Ave rage Ave rage Ave rage Ave rage

solubility (μΜ) SD solubility (μΜ) SD solubility (μΜ) SD solubility (μΜ) SD

Nimesulide 41 .18 1 .50 65.89 1.21 10.90 0.15 259.12 0.15

Warfarin 494.24 5.96 452.42 46.59 297.76 2.17 484.03 2.59

Example-1 0.50 0.00 171 .99 2.02 40.56 3.64 424.80 34.01 Example-4: Biological data- Cell Growth Inhibition

The human tumor cell lines of the cancer screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. For a typical screening experiment, cells are inoculated into 96 well microtiter plates in 100 μΙ_ at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates are incubated at 37° C, 5 % C02, 95 % air and 100 % relative humidity for 24 h prior to addition of experimental drugs.

After 24 h, two plates of each cell line are fixed in situ with TCA, to represent a measurement of the cell population for each cell line at the time of drug addition (Tz). Experimental drugs are solubilized in dimethyl sulfoxide at 400-fold the desired final maximum test concentration and stored frozen prior to use. At the time of drug addition, an aliquot of frozen concentrate is thawed and diluted to twice the desired final maximum test concentration with complete medium containing 50 μg/ml gentamicin. Additional four, 10-fold or ½ log serial dilutions are made to provide a total of five drug concentrations plus control. Aliquots of 100 μΙ of these different drug dilutions are added to the appropriate microtiter wells already containing 100 μΙ of medium, resulting in the required final drug concentrations.

Following drug addition, the plates are incubated for an additional 48 h at 37°C, 5 % C02, 95 % air, and 100 % relative humidity. For adherent cells, the assay is terminated by the addition of cold TCA. Cells are fixed in situ by the gentle addition of 50 μΙ of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 μΙ) at 0.4 % (w/v) in 1 % acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature. After staining, unbound dye is removed by washing five times with 1 % acetic acid and the plates are air dried. Bound stain is subsequently solubilized with 10 mM trizma base, and the absorbance is read on an automated plate reader at a wavelength of 515 nm. For suspension cells, the methodology is the same except that the assay is terminated by fixing settled cells at the bottom of the wells by gently adding 50 μΙ of 80 % TCA (final concentration, 16 % TCA). Using the seven absorbance measurements [time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)], the percentage growth is calculated at each of the drug concentrations levels. Percentage growth inhibition is calculated as:

[(Ti-Tz)/(C-Tz)] x 100 for concentrations for which Ti>/=Tz

[(Ti-Tz)/Tz] x 100 for concentrations for which Ti<Tz.

Three dose response parameters are calculated for each experimental agent. Growth inhibition of 50 % (GI50) is calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which is the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. The drug concentration resulting in total growth inhibition (TGI) is calculated from Ti = Tz. The LC50 (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment is calculated from [(Ti-Tz)/Tz] x 100 = -50. Values are calculated for each of these three parameters if the level of activity is reached; however, if the effect is not reached or is exceeded, the value for that parameter is expressed as greater or less than the maximum or minimum concentration tested. The results of compound of example 1 is hown below:

CeSi fine 6!50 TG! LD50 CeSS Sins Si5C TSf LD50

IGROVl I.98E-07 5.O0E-O5 5.00E-05 HCT-iS 3.-8E-07 > 5.O0E-O5 > 5.O0E-O5

OVCAR-3 1.43E-0S 5.O0E-O5 5.QOE-05 HT29 5.0QE-09 5.00E-05

OVCAR-4 4.70E-08 > S.OOE-OS S.OOE-OS M12 NT NT

OVCAR-5 2.17E-OS 5.O0E-O5 5.O0E-05 SW-62C 1.52E-OS 5.O0E-O5 5.00E-05

GV AR-8 2.2 IE-OS S.OOE-OS 5.00E-0S SF-2S8 2.44E-08 S.OOE-OS S.OOE-OS

«α/AOR-SES 1.64E-06 1.19E-Q5 > 5.00E-G5 SF-29S 3.34E-G9 3.7ΪΕ-03 > S.OOE-05

5S-OV-3 1.16E-0S S.OOE-OS S.OOE-OS SF-S33 7.67E-09 2.47E-OS > S.OOE-OS

¾?CF7 < S.OOE-OS S.OOE-OS S OC1E-OS S S-19 1.S8E-08 S.OOE-OS 5,O0E-O5 GA-M8-231/ATCC 1.89E-0S > 5. ODE -OS > S.OOE-OS Sfi6-75 < S.OOE-05 1.79E-08 S.OOE-OS

HS 57 ST 1.72E-C8 S.OOE-OS S OC1E-OS U251 i.iSE-08 S.OOE-OS 5,O0E-O5

BT-549 2.19E-OS > S.OOE-OS S.OOE-OS LOX fMVf 1.12E-OS S.OOE-OS > S.OOE-OS

MBA-MB- 68 1.07E-OS 4.23E-OS S.OOE-OS MAIME-3M > S.OOE-OS > S.OOE-OS

CCRF-CEM 1.53E-OS 5.O0E-O5 5.00E-05 Ml 4 i.OSE-08 5.00E-05

Hl-«¾TB) 1.04E-08 - S.OOE-OS !¾DA-!¾13-43S S.OOE-09 - 5.O0E-OS

K-5&2 8.0SE-G9 > 5.0GE-G5 > 5.00E-G5 S - EL-2 1.52 £-08 > S.OOE-05

MOLT- 4 1.35E-08 S.OOE-OS 5.00E-0S SC-MEL-28 S.OOE-OS S.OOE-OS

RPMS-S226 < 5. 0E-G9 3.78E-G5 5.00E-G5 SK-MEL-S 1 ^■ ■ 5! i"tl 8.08E-G5 > S.OOE-05

SS 7.9SE-Q9 S.OOE-OS > 5.00E-0S UAfX-257 8.4SE-QS S.OOE-Os S.OOE-05

A549/ATCC 1.21E-C8 S.OOE-OS S OC1E-OS UACC-82 2.37E-08 S.OOE-OS 5.O0E-O5

EKVJC 2.20E-OS > S.OOE-OS > S.OOE-OS 738-0 3.20E-07 > S.OOE-OS S.OOE-05

HOP-62 1.33E-OS S.OOE-OS S.OOE-OS A4S8 1.4SE-OS > S.OOE-OS > S.OOE-OS

HOP-92 > 5.O0E-O5 S.OOE-OS ACHN 7.92E-OS 5.O0E-G5 S.OOE-05

NCS-H22S 3.48E-0S S.OOE-OS S.OOE-OS CAtC!-i 1.79E-0& > S.OOE-OS > S.OOE-OS

Ua-H2i ^~ 1.41E-08 > 5.0GE-G5 > 5.00E-G5 RXF 393 1.3 E-08 > 5.0GE-G5 > S.OOE-05

HCS-H322M 2.45E-08 S.OOE-OS S.OOE-OS 3.43E-08 S.OOE-OS S.OOE-OS flCS-BiSO 3.52E-G9 > 5.0GE-G5 > 5.00E-G5 TK-10 2.0SE-08 i.6SE-05 > S.OOE-05

NC(-HS22 1.2SE-OS S.OOE-OS UG-31 1.20E-06 5.O0E-O5 5.00E-05

COLO 20S 3.98E-09 3.10E-GS S.OOE-OS PC-3 1.79E-OS > S.OOE-OS > 5.O0E-OS

HCC-2998 1.CSE-0S 3.79E-08 > 5.O0E-05 DU-145 1.3SE-0S S.OOE-OS s.ooE-as

HCT-I1S < 5.O0E-QS S.OOE-OS S OC1E-OS