NZ617816B2 - Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of GPR-119 - Google Patents

Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of GPR-119 Download PDF

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NZ617816B2
NZ617816B2 NZ617816A NZ61781612A NZ617816B2 NZ 617816 B2 NZ617816 B2 NZ 617816B2 NZ 617816 A NZ617816 A NZ 617816A NZ 61781612 A NZ61781612 A NZ 61781612A NZ 617816 B2 NZ617816 B2 NZ 617816B2
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substituted
unsubstituted
benzo
phenyl
nrarb
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NZ617816A
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Gayatri Swaroop Merikapudi
Dhanapalan Nagarathnam
Swaroop Kumar V S Vakkalanka
Srikant Viswanadha
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Rhizen Pharmaceuticals Sa
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Priority claimed from PCT/US2012/041632 external-priority patent/WO2012170867A1/en
Publication of NZ617816A publication Critical patent/NZ617816A/en
Publication of NZ617816B2 publication Critical patent/NZ617816B2/en

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Abstract

Provided are compounds of the general formula (A-I), (A-II), (A-III), (A-IV), (B-I), (B-II), (B-III) and (B-IV), wherein, the variables are as described in the specification. Examples of the compounds include 2-[1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]limidazole and Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}piperidine-carboxylate. The compounds are modulators of GPR-119. The compounds may be useful in the treatment of diabetes and obesity. d]limidazole and Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}piperidine-carboxylate. The compounds are modulators of GPR-119. The compounds may be useful in the treatment of diabetes and obesity.

Description

NOVEL 2,5- OR 2,6-DISUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS MODULATORS OF GPR-119 Related Applications This application claims the benefit of Indian Provisional Patent Application Nos. 1958/CHE/2011 dated 9th June 2011, 2352/CHE/2011 dated 11th July 2011, 3462/CHE/2011 dated 7th October 2011, 3463/CHE/2011 dated 7th October 2011, 82/CHE/2012 dated 9th January 2012, and US Provisional Patent Application Nos. 61/543152 dated 4th October 2011 and 61/543157 dated 4th October 2011, each of which is hereby incorporated by reference.
Field of the Invention The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases or disorders with them. ound of the Invention [02a] Any discussion of the prior art hout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. lic disorders in general and in particular, y and diabetes are the most common human health problems in the developed world. Its estimated that in developed countries around a third of the population is at least 20% overweight. In the United States, the percentage of obese people has increased from 25% at the end of the 1970's, to 33% at the beginning the . Obesity is one of the most important risk factors for NIDDM (noninsulin-dependent diabetes mellitus) which is the result of an imbalance between caloric intake and energy expenditure, and is highly correlated with insulin resistance and es in mental animals and .
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on , leading to d life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as overweight (pre-obese) if their BMI is between 25 and kg/m2, and obese when it is r than 30 kg/m2. (see Haslam DW, James WP (2005), "Obesity", Lancet 366 (9492): 1197–209; World Health Organization – Obesity pg 6 & 9, 2000). Obesity ses the likelihood of various diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis.
Obesity is most commonly caused by a ation of ive food energy intake, lack of physical ty, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to support the view that some obese people eat little yet gain weight due to a slow metabolism is d; on e obese people have a greater energy expenditure than their thin counterparts due to the energy ed to maintain an increased body mass.(http://en.wikipedia.org/wiki/Obesity) Dieting and physical exercise are the mainstays of treatment for obesity.
Moreover, it is important to improve diet quality by reducing the consumption of energydense foods such as those high in fat and sugars, and by increasing the intake of dietary fiber.
To supplement this, or in case of failure, anti-obesity drugs may be taken to reduce appetite or inhibit fat absorption. In severe cases, surgery is performed or an intragastric balloon is placed to reduce stomach volume and/or bowel length, g to earlier satiation and reduced ability to absorb nutrients from food.
Obesity is a leading preventable cause of death worldwide, with sing prevalence in adults and children, and ities view it as one of the most serious public health problems of the 21st century (see Barness LA et.al., "Obesity: genetic, molecular, and nmental aspects". Am. J. Med. Genet. A 143A (24): 3016–34, 2007). Obesity is stigmatized in much of the modern world (particularly in the Western world), though it was widely perceived as a symbol of wealth and fertility at other times in history, the low- and middle income people suffer from obsesity.
Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by % and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of ry diseases is doubled in subjects less than 50 years of age who are 30% overweight.
Diabetes is one of the major causes of ure illness and death worldwide.
Developing countries are on the radar with huge population especially the low- and middle income people being suffering from the said disease. The reason being, lack of sufficient diagnosis and treatment, being made available to the patients. This is reflected from the number of deaths attributable to diabetes in 2010 which shows a 5.5% increase over the estimates for the year 2007. Although 80% of type 2 diabetes is preventable by changing diet, increasing physical activity and ing the living environment. Yet, without ive tion and control programmes, the incidence of es is likely to continue rising globally.
Currently it’s estimated that 285 n people, corresponding to 6.4% of the world's adult population, is living with diabetes. The number is expected to grow to 438 million by 2030, corresponding to 7.8% of the adult population. The largest age group currently affected by diabetes is between 40-59 years. By 2030 this “record” is expected to move to the 60-79 age groups with some 196 n cases. With an estimated 50.8 million people living with diabetes, India has the world's largest diabetes population, followed by China with 43.2 million. Unless addressed, the mortality and disease burden from diabetes and other NCDs will continue to increase. WHO projects that globally, deaths caused by these health problems will increase by 17% over the next decade, with the greatest increase in low- and -income countries, mainly in the African (27%) and Eastern Mediterranean (25%) regions.(see : IDF, Diabetes Atlas, 4th edition) Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces.
Hyperglycemia, or raised blood sugar, is a common effect of rolled diabetes and over time leads to serious damage to many of the body's systems. It implicated in the development of kidney disease, eye diseases and nervous system ms. Diabetes causes about 5% of all deaths globally each year and is likely to se by > 50% in the next 10 years. Thus the pharmaceutical industry has been on a quest to characterize more promising molecular targets to satisfy stringent new criteria for anti-hyperglycaemic agents.
Type 1 diabetes, also known as insulin-dependent diabetes mellitus , is caused by the autoimmune destruction of the insulin producing pancreatic beta-cells, and requires regular administration of ous insulin. Type 1 es usually starts in childhood or young ood manifesting sudden symptoms of high blood sugar (hyperglycemia).
Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. NIDDM may be characterized by a defect in insulin secretion or by insulin resistance. NIDDM is a cally heterogeneous disease caused by various reasons such as genetic susceptibility to other environmental factors contributing to NIDDM, such as obesity, sedentary lifestyle, smoking, and certain drugs. NIDDM is a chronic disease resulting from defects in both n secretion and sensitivity. In NIDDM patients, the gradual loss of pancreatic β-cell function is a characteristic e of disease ssion that is associated with sustained hyperglycemia and poor outcome. Strategies for promoting normoglycemia have focused on ing glucose stimulated insulin secretion (GSIS) through the targeting of G proteincoupled receptors (GPCRs), such as the glucagon-like peptide1 (GLP-1) receptor, which have been shown to mediate this effect. In clinical y for NIDDM, metformin, α-glucosidase inhibitors, thiazolidines (TZDs), and sulfonylurea (SU) derivatives (SUs) are widely used as hypoglycaemic agents; however, the side effects of these compounds include hypoglycaemic episodes, weight-gain, gastrointestianal problems, and loss of therapy responsiveness.
Along with GLP-1 receptor as a major targets for the treatment of diabetes , GPR119 agonists have also been recognised as a major targets for the treatment of diabetes was discussed recently at the American Chemical Society 239th National Meeting (2010, San Francisco).
Further glucagon-like e 1 receptor agonists have shown ing therapeutic benefit over the ng therapy by way of body weight loss in type 2 diabetics, however these being injectables (Exenatide, ed as ) lack t compliance there by ng their usage. Other glucagon-like e 1 receptor agonists such as Liraglutide (Victoza), Albiglutide and Taspoglutide are also injectables.
GPR119 agonists have potential to achieve blood e control together with body weight loss in type 2 diabetics, similar to that of glucagon-like peptide 1 receptor agonists by way of oral route. Accordingly, oral GPR119 t would prove to a preferred choice of drug therapy for diabetics.
GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a drug target for NIDDM. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretion hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). (Overton H A et al. Cell Metab, 2006, 3, 167- 175). In rodent models, orally available GPR119-specific agonists have been shown to [Link] http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shah%20U%22%5BAuthor%5D [Link] javascript:AL_get(this,%20'jour',%20'Curr%20Opin%20Drug%20Discov%20Devel.'); [Link] javascript:AL_get(this,%20'jour',%20'Curr%20Opin%20Drug%20Discov%20Devel.'); [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib19 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib20 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib37 attenuate blood glucose levels with a aneous body weight loss. (Shah U. see Curr Opin Drug Discov Devel. 2009 Jul;12(4):519-32.).
In various animal models of type 2 diabetes and obesity, orally available, , selective, synthetic GPR119 agonists: i) lowers blood glucose without hypoglycaemia; ii) slow diabetes progression; and iii) reduce food intake and body weight.
GPR119 was first described by Fredriksson et al. (see Fredriksson R, et.al.
FEBS Lett. 2003; 554:381–388) as a class 1 (rhodopsin -type) orphan G-protein-coupled or having no close primary ce relative in the human genome. ndently, GPR119 has been studied and described in the literature under s synonyms including SNORF25 (see: Bonini et al., US 6,221,660, US 6,468,756), RUP3 (Jones et al., WO 2004/065380.), GPCR2 a et al., FEBS Lett. 2002; 520:97–101 2002), 19AJ (see Davey et.al., Expert Opin Ther Targets. 2004;8:165–170.2004), OSGPR116 ( see. US 7,083,933) and glucose-dependent insulinotropic receptor (Chu et al., Keystone Symposium. Diabetes: Molecular Genetics, ling Pathways and Integrated Physiology, Keystone, Colorado, USA, 14–19 January 2007, abstract 117 and abstract 230).
Early signs of GPR119 as an attractive target were established by the teachings of Hilary Overton and colleagues from (OSI) Prosidion, who found that the naturally ing lipid-signalling agent oleoylethanolamide, was capable of reducing the food intake and weight gain in rats, and can exert its effects through the G protein-coupled receptor (GPCR) GPR119. Found predominantly in the pancreas and digestive tract in humans and mice, as well as in the rodent brain, the mysterious/unknown function of GPR119 was .
The demonstration that GPR119 agonists stimulate the e of GLP-1 lends further credence to these agents having an effect on body weight, since GLP-1 is known to cause gastric deceleration and increase satiety, phenomena that lead to reduced caloric intake and weight loss in both animal models and human subjects (Meier et al., Eur J Pharmacol. ;440:269–279, 2002; Zander et al., 2002; Lancet.; 359:824–830. 2002 and Nielsen LL Drug Discov Today. –710, 2005). Possibly as a result of their effects on GLP-1 secretion, selective small-molecule GPR119 agonists inhibit gastric emptying and suppress food intake upon acute dosing to rats, with no indication of drug-induced malaise or conditioned taste aversion (Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes ;56 Suppl P, 2007; Overton et. al., Cell Metab. 3,167–175, 2006). The hypophagic actions of GPR119 agonists lead to reduced weight gain, fat pad masses and plasma leptin/triglyceride levels when [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib19 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib19 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib20 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib37 [Link] /www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib37 administered sub-chronically in rodent models of y (Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes ;56 Suppl P, 2007; n et. al., Cell Metab. 3,167–175, 2006).The testing of potent, selective agonists for food intake and body weight effects in GPR119-deficient mouse models has not been reported so far.
There are suggesting evidence about the isoforms of GPR119 been identified in a number of mammalian species, including rats, mice, hamsters, chimpanzees, rhesus monkeys, cattle and dogs. For example see. Fredriksson et al. FEBS Lett.; 554:381–388 ,2003 ; US 6,221,660; US 6,468,756 and EP 1338651-A1.
GPR 119 is thus an attractive target from a clinical perspective mainly because of GPR119 agonists are capable of lowering blood glucose without hypoglycaemia; slowing of diabetes progression; and most improtantaly helping in reduction of food intake and body weight.
More recently Unmesh shah et. al., in r-16 Vitamins & Harmones, Volume 84., pg 8 (2010), and Chapter-7.Annual reports in Med Chem 44 pg 149-170 (2009) have ed additional insight about GRP119 Patent literature belonging to some of these applicants e the following patents and/or patent applications: WO2011005929A1, WO2009126245A1, WO2008005576A1, WO2008005569A2, WO2007120702A2, WO2007120689A2, WO2007035355A2, WO06127595A1, WO06083491A2, WO06076455A2, WO2006 076243A1, WO05121121A2, WO05007658A2, WO05007647A1, WO04076413A2, WO2004065380;WO2010009183A1, WO2009012277A1, WO2008137436A1, WO2008 137435A1;WO2011041154A1, WO2010008739A2, WO2009014910A2, WO2009 123992A1, WO2008083238A2; WO2010103335A1,WO2010103334A1, WO2010 103333A1, WO2010004348A1, WO2010004347A1, WO2010001166A1, WO2009 050523A1, WO2009050522A1, WO2009034388A1, WO2008081208A1, 081207 A1, WO2008081206A1, WO2008081205A1,WO2008081204A1, WO2007116230A1, WO2007116229A1, WO2007003964A1, WO2007003962A2, WO2007003961A2, WO2007 003960A1, WO05061489A1;WO2011061679A1, WO2011036576A1, WO2010 140092A1, WO2010128425A1, WO2010128414A1, WO2010106457A2; WO2011 062889A1, WO2011 062885A1, 053688A1, WO2010114958A1, WO2010 114957A1, WO2010 075273A1, WO2010075271A1, WO2010075269A1, WO2010 009208A1, WO2010 009207A1, 009195A1, WO2009143049A1, WO2009 055331A2, WO2008 130615A1, WO2008130584A1, WO2008130581A1, WO2008033465A1, WO2008 033464A2, WO2008033460A2, WO2008033456A1, WO2008033431A1, WO2011030139A1, WO2011019538A1, WO2011014520A2, WO2011008663A1, WO2011044001A1, WO2011055770A1, WO2011066137A1, WO2011078306A1, WO2011093501A1, WO2011127051A1, WO2011127106A1, WO2011128394A1, WO2011128395A1, WO2011138427A2, WO2011140160A1, WO2011140161A1, WO2011147951A1, WO2011159657A1, WO2011146335A1, WO2011145718A1, WO2011148922A1, WO2012006955A1, WO2012011707A2, WO2012025811A1, WO2012037393A1, WO2012040279A1, WO2012046249A1, WO2012045363A1, WO2012066077A1, WO2012069948A1, WO2012069917A1.
Further review and literature sure on GPR119 molecules have been given by Sempl, G et al., (See; Bio org. Med. Chem. Lett. (2011), doi: 10.1016 / j. bmcl. 2011.03.007), Szewczyk ,J. W. Et al., (See; Bio org. Med. Chem .Lett. (2011), doi:10.1016 / . 2010.12.086), Vincent Mascitti et al., (See; anic & Medicinal Chemistry s 21 (2011) 1306–1309), Shigeru Yoshida et al., (See; Biochemical and Biophysical Research Communications 400 (2010) 745–751), Yulin Wu et.al., (See; Bioorganic & Medicinal Chemistry Letters 20 (2010) 2577–2581), Chu et al., (See; Endocrinology 2008 149:2038-2047), Y Ning et al., (see; British Journal of Pharmacology (2008) 155, 1056– 1065), HA Overton et al., (See; British Journal of cology (2008 )153, S76–S81), Carolyn Root et al., (See; Journal of Lipid Research, Volume 43, 2002, Pg 330). All of these patents and/or patent applications and ture disclosures are incorporated herein as reference in their entirety for all purposes. [25a] It is an object of the present invention to overcome or rate at least one of the antages of the prior art, or to provide a useful alternative.
Despite the advances made in the ent of metabolic disorders and in particular in the treatment of diabetes and obesity, nges remain in terms of the complexities of the diseases involved, and most importantly the safety concerns expected from any treatment. Accordingly, there is a l need in the art for additional GPR 119 modulators that may have improved efficacy and safety profiles. The compounds, compositions, and pharmaceutical methods provided herein relate generally to these needs. [26a] Unless the t clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of ding, but not limited to”. [26b] gh the invention will be described with reference to specific examples it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.
Summary of the Invention [26c] According to a first aspect of the present invention there is provided a compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV): (A-I) (A-II) (B-I) (B-III) (B-II) (B-IV) or a tautomer, stereoisomer, enantiomer, diastereomer, ceutically acceptable salt, or e thereof, wherein Ar is selected from substituted aryl, substituted or unsubstituted heteroaryl or Cy1; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is N; Z is CO, O or S(O)q; Cy1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group; each occurrence of R2, and R3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, n, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 lkenyl, -ORa, -S(=O)q-Ra, -NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, -CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb- , -S(=O) aRb-, q-NR -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb-; each occurrence of R1 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, -NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, - Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb-, q-NRaRb-, -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 lkyl, tuted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 lkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino , or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may ally include one or more heteroatoms which may be same or ent and are selected from O, NRc or S; each ence of Rc is independently selected from hydrogen, nitro, y, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or tituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; each occurrence of Y is independently selected from O, S, and NRa; and each occurrence of q independently represents 0, 1 or 2; D and E are ndently selected from CH or N; R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), tuted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, - NRaRb, -NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, -NRaC(S)Rb –NRaC(S)NRaRb, -SONRaRb-, -ORa, -ORaC(O)NRaRb, - ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, C(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa, -SO2Rm and -ONO2, each occurrence of Rd is independently en, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or tituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or tituted heterocyclyl, tuted or unsubstituted heterocyclcyalkyl, tuted or tituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or tituted heteroarylalkyl, and -ONO2; each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl is independently ed from hydrogen, nitro, hydroxy, cyano, n, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, tuted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally e one or more heteroatoms which may be the same or different and are selected from O, NR’ (where R’ is H or alkyl) or S, or (ii) an oxo (=O), thio (=S) or imino (=NR’) (where R’ is H or alkyl); Rm is en, nitro, hydroxy, cyano, halogen, substituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; and each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ≠ 0; wherein the term substituted refers to a substitution ed from en, hydroxy, halogen, yl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or tituted alkenyl, tuted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR’, -C(O)R’, -C(S)R’, R’R”, -C(O)ONR’R”, -NR’R”, -NR’CONR’R”, -N(R’)SOR”, -N(R’)SO2R”, -(=N-N(R’)R”), -NR’C(O)OR”, -NR’C(O)R”-, -NR’C(S)R”, -NR’C(S)NR”R”’, - SONR’R”-, -SO 2NR’R”-, -OR’, -OR’C(O)NR”R”’, -OR’C(O)OR”-, -OC(O)R’, -OC(O)NR’R”,- R’NR”C(O)R”’, -R’OR”, -R’C(O)OR”, -R’C(O)NR”R’”, -R’C(O)R”, O)R”, -SR’, -SCR’, -SO2R’, and -ONO2; wherein R’, R” and R”’ in each of the above groups can ndently be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, tuted or unsubstituted cycloalkyl, substituted or tituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or tituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or any two of R’, R” and R”’ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRX (where Rx is H or substituted or unsubstituted alkyl) or S or form oxo (=O), thio (=S) or imino (=NR’ where R’ is defined above); wherein the tuents in the aforementioned substituted groups cannot be further substituted; and with the proviso that the nd of formula (A-I) or (A-II) is not -(1-methyl-1H-indolyl)(piperidinyl)benzo[d]oxazole; -(1-methyl-1H-indolyl)(4-methylpiperazinyl)benzo[d]oxazole; 2-(4,4-dimethylpiperidinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; ethoxypiperidinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; 2-(azepanyl)(1-methyl-1H-indolyl)benzo[d]oxazole; tidinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; -(1-methyl-1H-indolyl)(pyrrolidinyl)benzo[d]oxazole; 2-(4-isopropylpiperazinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; -(1-methyl-1H-indolyl)(piperazinyl)benzo[d]oxazole; -(1-Methyl-1H-indolyl)(4-trifluoromethyl-piperidinyl)-benzooxazole; 2-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro-isoquinoline; 2-(1,3-Dihydro-isoindolyl)(1-methyl-1H-indolyl)-benzooxazole; 2-(2,3-Dihydro-indol-1 -yl)(1-methyl-1H-indolyl)-benzooxazole; 2-Methyl[5-(1-methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydro-2H- pyrazolo[4,3- c]pyridine; 2-(Hexahydro-cyclopenta[c]pyrrolyl)(1-methyl-1H-indolyl)-benzooxazole; 2-(1,3-Dihydro-isoindolyl)imidazo[1,2-a]pyridinyl-benzooxazole; -(3,4-Dihydro-2H-benzo[b][1,4]dioxepinyl)(1,3-dihydro-isoindolyl)- benzooxazole; 2-(1,3 -Dihydro-isoindolyl)-5 -(1-methyl-1H-indazol-5 -yl)-benzooxazole; 2-(5,7-Dihydro-pyrrolo[3,4-b]pyridinyl)(1-methyl-1H-indolyl)- benzooxazole; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-imidazo[1,2- a]pyrazine; 2-(3 ,4-Dihydro-1H-pyrrolo[1,2-a]pyrazinyl)-5 -(1-methyl-1H-indol-5 -yl)- benzooxazole; 2-(1,3-Dihydro-isoindolyl)(4-methoxymethyl-phenyl)-benzooxazole; 2-(1,3-Dihydro-isoindolyl)(3-methoxy-phenyl)-benzooxazole; 2-(1 ,3-Dihydro-isoindolyl)(3-methoxymethoxymethyl-phenyl)- benzooxazole; -Dihydro-isoindolyl)(2-methoxy-pyridinyl)-benzooxazole; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-imidazo[1,5- a]pyrazine; 6-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidine; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro- [1,7]naphthyridine; 2-(Hexahydro-pyrrolo[1 ,2-a]pyrazinyl) c (1-methyl-1H-indolyl)-benzooxazol ; 2-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro- [2,7]naphthyridine; 2-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrolyl)(1-methyl-1H-indolyl)- benzooxazole; l-Methyl-1H-indolyl)-benzooxazol-yl]-4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridine; 2-Methyl[5-(1-methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydrooxazolo ]pyridine; -[2-(1,3-Dihydro-isoindolyl)-benzooxazolyl]hydroxy-benzonitrile; 6-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro- [1,6]naphthyridine; 1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1 ,5- a]pyrazine; 1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro- [2,6]naphthyridine; 2,2,2-Trifluoro{4-[5-(1-methyl-1H-indol-5 -yl)-benzooxazolyl] -piperazinyl }-ethanone; 2-(1,3-Dihydro-pyrrolo[3,4-c]pyridinyl)(l-methyl-1H-indolyl)-benzooxazole; 1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyrazine; -[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydro- [1,2,3]triazolo[1,5- a]pyrazine; 2-(1,3-Dihydro-isoindolyl)-5 -(1-oxetanyl-1H-indolyl)-benzooxazole; 2-(1,3-Dihydro-isoindolyl)(3-ethoxyethoxymethyl-phenyl)-benzooxazole; -(1-Methyl-1H-indolyl)(4-phenyl-piperazinyl)-benzooxazole; 1-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro-quinoline; 2-(8-Aza-spiro[4.5]decyl)(1-methyl-1H-indolyl)-benzooxazole; 2-{5-[2-(1,3-Dihydro-isoindolyl)-benzooxazolyl]-indolyl}-acetamide; 2-(2-Aza-spiro[4.4]nonyl)(1-methyl-1H-indolyl)-benzooxazole; -(1-Methyl-1H-indolyl)[4-(2,2,2-trifluoro-ethyl)-piperazinyl]-benzooxazole; 3-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]aza-spiro[5.5]undecane; 2-(2,3-Dihydro-pyrrolo[2,3-b]pyridinyl)(1-methyl-1H-indolyl)- benzooxazole; -[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydro-pyrazolo[1 ,5- a]pyrazine; [5-(1-Methyl-1H-indolyl)-benzooxazolyl]-thiophenyl-amine; -(1-Methyl-1H-indolyl)(8-oxaaza-bicyclo[3.2.1]octyl)-benzooxazole; 6-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]trifluoromethyl-6,7-dihydro-5H- pyrrolo[3,4- d]pyrimidine; 3-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-2,3,4,5-tetrahydro-1H- benzo[d]azepine; or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof. [26d] ing to a second aspect of the present invention there is provided a compound of the formula (A-III) and (A-IV): (A-III) (A-IV) or a tautomer, stereoisomer, enantiomer, reomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein Ar, X1, X2, X3, X4, X, Z, D, E, R5, Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl are as defined in the first aspect of the present invention; with the proviso a) that for compound of formula ) , wherein Z is O or S and X4 is N or CR4 then Ar cannot be W W W W W N N N N N N , , , , , H H H H H H H H W W H W H W , , or H H b) that for nd of formula (A-IV) wherein Z is O or S and X1 is N or CR1 then Ar cannot be W W W W W N N N N N N , , , , , H H H H H H H H W W H W H W , H , or wherein R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- S(=O)2-R1, halo, or a 4 to 10-membered ally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R1a, at each occurrence, is independently hydrogen or (C1-C8)alkyl; R1 is optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, optionally tuted (C1-C10)aryl, a 4 to 10-membered optionally tuted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S, wherein each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ≠ 0; wherein the term “substituted” is as defined according to the first aspect of the invention; and with the o that the compound of formula (A-III) or (A-IV) is not 2-(4-isopropylpiperazinyl)(5-methyl-[1,2,4]oxadiazolyl)benzothiazole; sopropylpiperazinyl)(5-phenyl-[1,2,4]oxadiazolyl)benzothiazole; 2-(4-isopropylpiperazin-1 -yl)(5-pyridinyl-[ 1,2,4]oxadiazolyl)benzothiazole; 2-(4-Cyclopropylpiperazinyl)(3,4-dimethoxyphenyl)benzothiazole; 2-(4-Cyclopropylpiperazin-1 -yl)(6-methoxypyridinyl)benzothiazole; N-{4-[2-(4-Cyclopropylpiperazinyl)benzothiazolyl]phenyl}-acetamide; yclopropylpiperazinyl)(1,1-dioxo-16 -isothiazolidinyl)benzothiazole; hloromethoxypyridiny1)(4cyclopropylpiperazinyl) benzothiazole, trifluoroacetate; or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or e thereof. [26e] According to a third aspect of the present invention nthere is provided a compound of the formula (A-IA), (A-IIA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA): X1 X (R6)p N R5 X4 O (A-IA) (A-IIA) N R5 X1 X X4 X Ar G X3 Ar G X4 O X2 X1 O (R6)p (R6)p (B-IA) (B-IIIA) R5 R5 N N X1 O X4 O Ar G Ar G X3 X2 X4 X X1 X (R6)p (R6)p ) (B-IVA) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein X, X1, X2, X3, X4 and R5 are as defined in claim 1; Ar is G is ndently selected from R is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted lkyl; R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, tuted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or tituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, tuted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, -NRaRb, - NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , -NRaC(O)Rb-, - NRaC(S)Rb –NRaC(S)NRaRb, -SONRaRb-, -SO2NRaRb-, -ORa, -ORaC(O)NRaRb, - ORaC(O)ORb-, -OC(O)Ra, NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa -SO2Ra, and -ONO2; and each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, tuted or tituted C2-6 alkenyl, tuted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRd or S; p is 0, 1, 2, 3 or 4. wherein the term “substituted” is as d according to the first aspect of the invention; and wherein each occurrence of Rd is independently hydrogen, y, n, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or tituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, tuted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or tituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, tuted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO2. [26f] According to a fourth aspect of the present invention there is provided a compound of the formula A) or (A-IVA) (A-IIIA) (A-IVA) wherein Ar, G, R5, X1-X4, X, R6 and p are the same as defined in claim of the appended claims; with the proviso a) that for compound of formula (A-IIIA) , n Z is O or S and X4 is N or CR4 then Ar-G cannot be W W W W W N N N N N N , , , , , H H H H H H H H W W H W H W , or H , H b) that for nd of formula (A-IVA) wherein Z is O or S and X1 is N or CR1 then Ar-G cannot be W W W W W N N N N N N , , , , , H H H H H H H H W W H W H W , H , or wherein R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- S(=O)2-R1, halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms ed from N, O, and S; R1a, at each occurrence, is independently hydrogen or (C1-C8)alkyl; R1 is optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, optionally substituted (C1-C10)aryl, a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered cyclyl, which contains 1-4 heteroatoms selected from N, O, and S. [26g] According to a fifth aspect of the t ion there is provided a compound of the formula (A-IB) and (A-IIB) (A-IB) (A-IIB) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein X, X1, X2, X3, X4 and R5 are as in the first aspect of the present invention; Z is O or S; Ar1-G is p is 0, 1-7 or 8; R6 is selected from en, y, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, tuted or tituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or tituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, -NRaRb, -NRaCONRaRb, - N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , -NRaC(O)Rb-, -NRaC(S)Rb – NRaC(S)NRaRb, Rb-, -SO2NRaRb-, -ORa, -ORaC(O)NRaRb, -ORaC(O)ORb-, - OC(O)Ra, NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, -RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa -SO2Ra, and -ONO2; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or tituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or tituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more atoms which may be same or different and are selected from O, NRc or S. [26h] ing to a sixth aspect of the present invention there is provided a compound of the formula (A-IIIB) and (A-IVB) (A-IIIB) (A-IVB) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein; Z is O or S Ar1-G is p is 0, 1-7 or 8 and X, X1, X2, X3, X4 R5 and R6 are as defined in the fourth aspect of the present invention; with the proviso that a) that for compound of formula (A-IIIB) , wherein Z is O or S and X4 is N or CR4 then Ar1-G cannot be b) that for compound of formula (A-IVB) wherein Z is O or S and X1 is N or CR1 then Ar1-G cannot be wherein R1 and R4 is as defined above for compound of formula (A) W is -R1, S(=O)2-NR1aR1, -C(=O)-R1, -O-R1, -C(=O)-NR1aR1, -NR1a- S(=O)2-R1, halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R1a, at each occurrence, is independently hydrogen or (C1-C8)alkyl; R1 is optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, ally substituted (C2-C6)-alkynyl, optionally substituted 2)-cycloalkyl, optionally substituted (C1-C10)aryl, a 4- to 10-membered ally substituted heteroaryl, which contains 1-4 heteroatoms ed from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S. [26i] According to a seventh aspect of the present invention there is provided a compound selected from 2-[1-(5-Ethylpyrimidinyl)piperidinyl][2-fluoro(methylsulfonyl)phenyl]- 1H-benzo[d]imidazole: utyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]-1H-benzo[d]imidazol yl}piperidinecarboxylate: 2-[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro (methylsulfonyl)phenyl]benzo[d] oxazole: Tert-butyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]methyl-1H-benzo[d]imidazol- 2-yl}piperidinecarboxylate: Tert-butyl 4-{6-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: pyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- oxylate: Tert-butyl 4-{7-fluoro[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl} piperidinecarboxylate: Tert-butyl 4-[5-(4-cyanophenyl)benzo[d]oxazolyl]piperidinecarboxylate: Tert-butyl 4-{5-[3-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[4-(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Tert-butyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[3-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: 2-[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro(1H-tetrazol yl)phenyl]benzo[d]oxazole: utyl 4-[5-(4-cyanofluorophenyl)benzo[d]oxazolyl]piperidine ylate: Isopropyl 4-{5-[3-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[3-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-[5-(4-carbamoylchlorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Tert-butyl 4-[5-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine ylate: Tert-butyl 4-[5-(3-fluoroisopropoxyphenyl)benzo[d]oxazolyl]piperidine carboxylate: Cyclobutyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Sec-butyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Pentanyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: -[2-fluoro(1H-tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole: Isopropyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-[5-(4-formylphenyl)benzo[d]oxazolyl]piperidinecarboxylate: Isopropyl 4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-[5-(4-carbamoylchlorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-carbamoylfluorohenyl)benzo[d]oxazolyl]piperidine carboxylate: 1-{4-[5-(2-fluoro(1H-tetrazolyl)phenyl)benzo[d]oxazolyl]piperidinyl} propanone: Isopropyl 4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: 6-{2-[1-(isopropoxycarbonyl)piperidinyl]benzo[d]oxazolyl}nicotinic acid: -[2-fluoro(1H-tetrazolyl)phenyl][1-(methylsulfonyl)piperidin yl]benzo[d]oxazole: Isopropyl 5-carbamoylpyridinyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-[5-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-[5-(4-carbamoylchlorophenyl)benzo[d]oxazolyl]piperidine carboxylate: 2-Fluoro{2-[1-(3-methylbutanoyl)piperidinyl]benzo[d]oxazolyl}benzamide: 1-{4-[5-(2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl]piperidinyl} methylbutanone: -[2-fluoro(1H-tetrazolyl)phenyl][1-(2-methoxyethyl)piperidin yl]benzo[d]oxazole: Isopropyl 4-{5-[3-fluoro(methylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: 2-Fluoro[2-(1-isobutyrylpiperidinyl)benzo[d]oxazolyl]benzamide: Isopropyl 4-[6-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-{5-[3-fluoro(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{5-[3-fluoro(isopropylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: pyl 4-{5-[6-(methylcarbamoyl)pyridinyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{5-[3-methyl(methylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{5-[4-(cyclopropylcarbamoyl)fluorophenyl]benzo[d]oxazol eridinecarboxylate: 2-Fluoro{2-[1-(5-fluoropyrimidinyl)piperidinyl]benzo[d]oxazol yl}benzamide: Tert-butyl 4-[5-(4-carbamoylfluorophenyl)benzofuranyl]-5,6-dihydropyridine- 1(2H)-carboxylate: 2-fluoro{2-[1-(propylsulfonyl)piperidinyl]benzo[d]oxazolyl}benzamide: utyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]-1H-benzo[d]imidazolyl}-5,6- dihydropyridine-1(2H)-carboxylate; Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]-1H-benzo[d]imidazolyl} piperidinecarboxylate; -[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro(methylsulfonyl)phenyl]- 1H-benzo[d]imidazole; Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}-5,6- dihydropyridine-1(2H)-carboxylate; Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate; 2-[2-fluoro(methylsulfonyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoro acetate; -[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro(methylsulfonyl)phenyl] benzo [d]oxazole. utyl 4-{7-fluoro[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}-5,6- dihydropyridine-1(2H)-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}-5,6- dihydropyridine-1(2H)-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}piperidine- 1-carboxylate: Ethyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Ethyl 2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Ethyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine ylate: Benzyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine ylate: Isobutyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}piperidine- 1-carboxylate: Isopropyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-(2-p-tolylbenzo[d]oxazolyl)piperidinecarboxylate: 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[d]oxazolyl]-5,6- dihydropyridin-1(2H)-ylsulfonyl}propanol: 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[d]oxazolyl]piperidin ylsulfonyl}propanol: 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[d]oxazolyl]piperidin ylsulfonyl}propanol: Tert-butyl 4-[2-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: 2-[2-fluoro(methylsulfonyl)phenyl][4-(3-isopropyl-1,2,4-oxadiazol yl)piperidinyl]benzo[d]oxazole: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate Isopropyl 2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperazine- 1-carboxylate: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridinyl}-5,6- dihydropyridine-1(2H)-carboxylate: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridinyl}piperidine carboxylate. [26j] According to an eighth aspect of the present invention there is provided a compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV): (A-I) (A-II) (B-I) (B-III) (B-II) (B-IV) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or e thereof, wherein Ar is selected from substituted aryl, substituted or unsubstituted aryl or Cy1; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is N; Z is CO, O or S(O)q; Cy1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group; each occurrence of R2, and R3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, tuted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 lkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, -NRaRb, -Ra, -CRaRb-C(=Y)-Ra, -CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb- , -S(=O) aRb-, q-NR -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb-; each ence of R1 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, tuted or unsubstituted C3-6 cycloalkenyl, -ORa, q-Ra, -NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, - CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb-, -S(=O)q-NRaRb-, -NRa-S(=O)q- , and -NRa-NRaRb; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally e one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of Rc is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, tuted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; each occurrence of Y is ndently selected from O, S, and NRa; and each occurrence of q independently represents 0, 1 or 2; D is CH; each occurrence of E is independently ed from CH or N; R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, tuted or tituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted kyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, NRaRb, - NRaRb, -NRaCONRaRb, SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, -NRaC(S)Rb S)NRaRb, -SONRaRb-, -ORa, -ORaC(O)NRaRb, - ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa, -SO2Rm and -ONO2, each occurrence of Rd is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, tuted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO2; each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl is independently selected from hydrogen, nitro, hydroxy, cyano, n, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or tituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or tituted C3-6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally e one or more heteroatoms which may be the same or different and are selected from O, NR’ (where R’ is H or alkyl) or S, or (ii) an oxo (=O), thio (=S) or imino (=NR’) (where R’ is H or alkyl); Rm is hydrogen, nitro, hydroxy, cyano, halogen, substituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; and each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ≠ 0; and wherein the term tuted refers to a substitution ed from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, tuted or unsubstituted arylalkyl, -COOR’, -C(O)R’, -C(S)R’, -C(O)NR’R”, -C(O)ONR’R”, -NR’R”, -NR’CONR’R”, -N(R’)SOR”, -N(R’)SO2R”, (R’)R”), -NR’C(O)OR”, -NR’C(O)R”-, -NR’C(S)R”, -NR’C(S)NR”R”’, - SONR’R”-, -SO 2NR’R”-, -OR’, -OR’C(O)NR”R”’, O)OR”-, -OC(O)R’, -OC(O)NR’R”,- (O)R”’, -R’OR”, -R’C(O)OR”, -R’C(O)NR”R’”, -R’C(O)R”, -R’OC(O)R”, -SR’, -SCR’, -SO2R’, and -ONO2; wherein R’, R” and R”’ in each of the above groups can independently be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, tuted or unsubstituted alkoxy, substituted or tituted alkenyl, tuted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, tuted or tituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, tuted or unsubstituted aryl, substituted or unsubstituted arylalkyl, tuted or tituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or any two of R’, R” and R”’ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRX (where Rx is H or substituted or unsubstituted alkyl) or S or form oxo (=O), thio (=S) or imino (=NR’ where R’ is defined above); wherein the substituents in the aforementioned substituted groups cannot be further substituted. [26k] According to a ninth aspect of the present invention there is provided a compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV): (A-I) (A-II) (B-I) (B-III) (B-II) (B-IV) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein Ar is selected from substituted aryl, substituted or unsubstituted heteroaryl or Cy1; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is N; Z is CO, O or S(O)q; Cy1 is selected from substituted or unsubstituted lkyl or substituted or unsubstituted heterocyclic group; each occurrence of R2, and R3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 lkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, -NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, -Y-CRaRb-, -NRaRb-, -NRa-C(=Y)-NRaRb- , -S(=O) aRb-, q-NR -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb-; each occurrence of R1 and R4 may be same or different and is ndently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 lkylalkyl, substituted or tituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, -NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, - CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb-, -S(=O)q-NRaRb-, -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, y, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, ted or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of Rc is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 lkenyl; each occurrence of Y is independently selected from O, S, and NRa; and each occurrence of q independently represents 0, 1 or 2; D and E are independently selected from CH or N, with the proviso that D is CH in compounds of formula (A-I) and (A-II); R5 is selected from hydrogen, hydroxy, halogen, yl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkenyl, tuted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, tuted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or tituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, - NRaRb, NRaRb, -N(Ra)SORb, SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, S)Rb –NRaC(S)NRaRb, -SONRaRb-, -ORa, -ORaC(O)NRaRb, - ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa, -SO2Rm and -ONO2, each occurrence of Rd is independently hydrogen, y, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or tituted heterocyclyl, tuted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO2; each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl is ndently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or tituted C3-6 cycloalkyl, substituted or tituted C3-6 lkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more atoms which may be the same or different and are selected from O, NR’ (where R’ is H or alkyl) or S, or (ii) an oxo (=O), thio (=S) or imino (=NR’) (where R’ is H or alkyl); Rm is hydrogen, nitro, hydroxy, cyano, halogen, substituted C1-6 alkyl, substituted or tituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; and each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ≠ 0; and wherein the term substituted refers to a substitution selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted l, substituted or unsubstituted alkynyl, substituted or unsubstituted lkyl, substituted or tituted lkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, tuted or unsubstituted heterocycyl, substituted or unsubstituted cyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR’, -C(O)R’, -C(S)R’, -C(O)NR’R”, -C(O)ONR’R”, -NR’R”, -NR’CONR’R”, -N(R’)SOR”, SO2R”, -(=N-N(R’)R”), -NR’C(O)OR”, -NR’C(O)R”-, -NR’C(S)R”, S)NR”R”’, - SONR’R”-, -SO 2NR’R”-, -OR’, -OR’C(O)NR”R”’, -OR’C(O)OR”-, -OC(O)R’, -OC(O)NR’R”,- R’NR”C(O)R”’, -R’OR”, -R’C(O)OR”, -R’C(O)NR”R’”, -R’C(O)R”, -R’OC(O)R”, -SR’, -SCR’, -SO2R’, and -ONO2; wherein R’, R” and R”’ in each of the above groups can independently be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted l, substituted or unsubstituted alkynyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, tuted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, tuted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or any two of R’, R” and R”’ may be joined to form a substituted or unsubstituted saturated or rated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRX (where Rx is H or substituted or unsubstituted alkyl) or S or form oxo (=O), thio (=S) or imino (=NR’ where R’ is defined above); wherein the substituents in the aforementioned substituted groups cannot be further substituted. [26l] According to a tenth aspect of the present invention there is ed a pharmaceutical composition, comprising a nd of the first to ninth s and a pharmaceutically acceptable carrier. [26m] According to an eleventh aspect of the present invention there is provided use of a compound of the first to ninth aspects, and optionally an additional therapeutic agent, in the manufacture of a medicament for ting the activity of the GPR119 receptor in a mammalian subject in need thereof. [26n] According to a twelfth aspect of the present ion there is provided use of a compound of the first to ninth aspects, and optionally an additional therapeutic agent, in the cture of a medicament for the treatment, prevention and/or ameloriation of diseases or disorders associated with the GPR119 receptor in a ian subject in need thereof, wherein: (a) the diseases or disorders associated with the GPR119 receptor are selected from the group consisting of diabetes mellitus, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, ension, pancreatic beta-cell insufficiency, enteroendocrine cell iciency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic ovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition d to diabetes us, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's e, Parkinson's disease, Huntington's disease, prionassociated disease, stroke, motor-neuron disease, traumatic brain , spinal cord injury, y, d wound healing, abnormal heart function, myocardial ia, low HDL, high LDL, rdiac ischemia, vascular restenosis, pancreatitis, egenerative disease, lipid disorders, cognitive ment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma; (b) the additional therapeutic agent is selected from the group consisting of antidiabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic , chemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, antihyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic , anti-pancreatic agents, lipid lowering agents, appetite suppressants, treatments for heart failure, and treatments for peripheral arterial disease and flammatory agents.
The present invention relates generally to novel compounds useful as GPR-119 modulators and in particular GPR-119 agonists.
In one embodiment, the compound of the present invention has the formula (A) and (B) (A) (B) or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g., pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxide thereof, wherein Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or Cy1; L1 is absent or is selected from NRa, O, S(O)q or CRaRb; L2 is absent or is selected from NRa, O, S(O)q or CRaRb; X1 is CR1 or N; X2 is CR2 or N ; X3 is CR3 or N and X4 is CR4 or N; X is CR or N; Z is NR, CO, O or S(O)q; Cy is selected from substituted or unsubstituted cycloalkyl or tuted or unsubstituted heterocyclic group; Cy1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group; each ence of R, R1, R2, R3 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C26 alkenyl, substituted or unsubstituted C26 alkynyl, substituted or unsubstituted C3_6 cycloalkyl, substituted or unsubstituted C3_6 cycloalkylalkyl, and substituted or unsubstituted C3_6 cycloalkenyl, - , -ORa, -S(=O)q-Ra, -NRaRb, —C(=Y)-Ra, CRaRb-C(=Y)-Ra, -CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRaRb-C(=Y)-NRaRb-, -S(=O)q- NRaRb-, -NRaRb-S(=O)q-NRaRb-, -NRaRb-NRaRb-; each occurrence of Ra and Rb may be same or ent and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C26 l, substituted or unsubstituted C26 alkynyl, substituted or unsubstituted C3_6 cycloalkyl, substituted or unsubstituted C3_6 cycloalkylalkyl, and substituted or unsubstituted C3_6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=0), thio (:8) or imino (=NRd), or (ii) a substituted or unsubstituted, ted or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of RC is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C26 alkenyl, substituted or tituted C26 alkynyl, tuted or unsubstituted C3_6 cycloalkyl, substituted or unsubstituted C3_6 cycloalkylalkyl, and substituted or unsubstituted C3_6 cycloalkenyl; each occurrence of Rd1 is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, tuted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted lkylalkyl, substituted or tituted lkenylalkyl, tuted or unsubstituted heterocyclyl, substituted or unsubstituted cyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONOZ; each ence of Y is independently selected from O, S, and NRa; and each occurrence of q independently represents 0, l or 2.
Another embodiment is a compound of the formula (A-I), (A-II), (A-III), (A- IV), (B-I), (B-II), ) or (B-IV): R] Rk RI Ri Rj Rk RI RI Ar X Ar X1\ X I Z l r ls r ls 1\ l \ D E_R5 XI / D E—RS X3 / 3\ / X Re Rf R9 Rh Rf R9 R“ (A-I) (A-HI) RkR' R’ R. Rj Rle Ri Ar X4 AI' X4\ X I Z I r IS r '5 \ I \ D E—RS D E—R5 I X2 x/ / X2 / x 2 l ] X1 [ lu 1 t u Re Rf R9 Rh Rf R9 Rh (A-II) (A-IV) (B-I) (B-III) R' Rk .
RJRi R5\E Is X4 X X4 Z uJTI%~wWI%~D D \ \ \ RhRg z x Re x2\x1/ RhRg Rf Re X2\x1/ (B-II) (B-IV) or a tautomer, stereoisomer, omer, diastereomer, salt (e.g., pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxide f, wherein Z is NR, CO, 0 or S(O)q; wherein R and q is as defned above for compound of formula (A) or (B); D and E are independently selected from CH or N; R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, tuted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl, —COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, NRaRb, — NRaR", -NRaCONRaRb, -N(Ra)SORb, -N(Ra)SOsz, -(=N-N(Ra)Rb), -NRaC(O)OR", — NRaC(O)Rb-, -NRaC(S)Rb —NRaC(S)NRaRb, -SONRaRb-, aRb-, —0Ra, — )NRaR", -ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaR", -RaNRbC(O)Ra, , — RaC(O)ORb, -RaC(O)NRaR", -RaC(O)Rb, -RaOC(O)Rb, -SRa, —SORa —sozRa, and -ONOz, n Ra and Rb are as defined in a (A) or (B); each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and R1 is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C26 alkenyl, substituted or unsubstituted C26 alkynyl, tuted or unsubstituted C3_6 cycloalkyl, substituted or unsubstituted C3_6 cycloalkylalkyl, and substituted or unsubstituted C3_6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, R, R], Rk, Rl may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from 0, NR7 (where R’ is H or alkyl) or S, or (ii) an oxo (=0), thio (:8) or imino (=NR7) (where R’ is H or alkyl); each of r, s, t and u is 0, l or 2 with the proviso that r+s+t+u 75 0; and and all the other variables are the same as described above for the compound of formula (A) and (B), with the proviso 1. that for compound of formula (A-III), wherein Z is O or S and X4 is N or CR4 then Ar cannot be \ \ NJN “Nd H H H H HH HH w “J4 “dd ”PM H w H ENG W q H q H 2. that for compound of formula (A-IV) wherein Z is O or S and X1 is N or CR1 then Ar cannot be \ \ NJN Md H H H H HH HH w M“ HF” WM’ H Wig w ~ H ’H wherein R1 and R4 is as d above for compound of formula (A) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)'O-R1, -C(=O)-NR1aR1, 'NRla'S(=O)2' R1, halo, or a 4 to lO-membered ally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; Rla, at each occurrence, is independently hydrogen or (C1-C8)alkyl; and R1 is optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted 2)-cycloalkyl, optionally substituted (C6-C10)aryl, a 4 to lO-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to lO-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S. r preferred is a compound of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), ) or (B-IV)wherein Ar is selected from 2012/041632 /N§“ F” /"§” “5" N \ N \ N \ \ N \/N \/N \/ gm \/N "h ’1'“ “m1“ N/N§"\ N/§"\ \//° \//° \/N\<j14¢‘\\/N O m //S\©/CF3 o//S\©/“m \//s// F \S//0 \//o Cl \s//0 F o 0// “m 0/0 JO“m “w \s//0 0 N/ \s/0 \s// N | F // / o// / o// / \ 4% ° | | l “\ m \ “Ma \ “LL.
N F " NC NC N \ HZNOC H2NOC I I N§N N§N F N/ \ N/ \ F N N Further preferred is a compound of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Ar is Cyl.
Further red is a nd of formula(A), (A-I), (A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Cy1 is selected from 0/ \o Dix, o//\ F F F F ‘11,.A “m fiF "rm %F Further preferred is a compound of formula (A) or (B) n L1 is absent.
Further preferred is a compound of formula (A) or (B) wherein L2 is absent.
Further red is a compound of formula (A), (A-I), (A-II), ), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Z is NH or N-CH3. r preferred is a compound of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Z is O.
Further preferred is a compound of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Z is S.
Further preferred is a compound of formula (A), (A-I), , (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein X1 is CR1 or N R1 is H or , wherein Halogen.
Further preferred is a compound of formula (A), (A-II), (A-IV), (B), (B-II) 0r (B-IV) wherein X2 is CH. r preferred is a compound of formula (A), (A-II), (A-IV), (B), (B-II) 0r (B-IV) wherein X3 is CH.
Further preferred is a nd of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein X4 is CR4 or N R4 is H or , wherein Halogen.
Further preferred is a compound of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein X is CR or N, wherein R is H, en, cyano, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C3_6 cycloalkenyl, -ORa, -NRaRb or —C(=Y)-Ra and Ra, Rb, and Y are as d above for compound of formula (A) or (B); Further preferred is a nd of formula (A), (A-I), (A-II), (A-III), (A- IV), (B), (B-I), (B-II), (B-III) or (B-IV): wherein Cy is selected from UTO$“GA“Cu/E “Cow“GA“Ofi @fi:“wagrr 00000000000000000000000 WO 70867 V14" O\\(O\N<j\r%\MN ”by.“ MN \ O>N @WO>N Yet another ment is a compound of formula (A-IA), (A-IIA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA): (:GTO\(X1_ mG x4 x I \ _5 p xl3‘:4/j::>—<:> R5(Rs) N R 2‘x1/ 0 (AIA) (A-IIA) RN5 N 1‘ X X II a (Re)P (R6)p (B-IA) (B-IIIA) (B-IIA) (B-IVA) or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g., pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxide thereof, n Ar is (R6)p / (R6)p /\ (R6)p G (R6)p (R6) G (R6)p X \/ PX I I I XWG X I L I L I M’\ W\ M“\ G M\ N W\N W\N G (Rah) (R6 (R6) 8 (R6>p )p O p N 6 AG A \é /\/ 4 H, NNR) 16s \ ,6 I I {J Page \\J (Rigs \\’” 5R) 6 (6) G ma)" 6 S/lms)p 4m /N\\p(Re) L/‘JW O \(Re)p R5\N9\/\/\>(R )ps/ANP 0’\/\/\ / "WT/R3) N ‘/ “7““ fig“ 3L \N e \N/ EV G is ndently selected from 0 o o o \S// F R /N=N F WM \“ \N \ "% O HzN H I NVNW N» F>L11 o F R\S// H // ”"4 F/L‘m HH>L¢L R is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or tituted alkynyl or substituted or unsubstituted cycloalkyl.
R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or tituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkenyl, substituted or tituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, tuted or unsubstituted kyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, —COORa, -C(O)Ra, a, -C(O)NRaRb, -C(O)ONRaR", -NRaRb, -NRaCONRaRb, — N(Ra)SORb, -N(Ra)SOsz, -(=N-N(Ra)Rb), -NRaC(O)ORb, , -NRaC(O)Rb-, -NRaC(S)Rb — NRaC(S)NRaR", -SONRaRb-, -SOZNRaRb-, —0Ra, -ORaC(O)NRaRb, -ORaC(O)ORb-, — OC(O)Ra, -OC(O)NRaR", C(O)Ra, -RaORb, -RaC(O)ORb, )NRaRb, -RaC(O)Rb, O)Rb, -SRa, -SORa -SOzRa, and -ONOz; each occurrence of Ra and Rb may be same or different and are ndently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C26 alkenyl, substituted or unsubstituted C26 alkynyl, substituted or tituted C3_6 cycloalkyl, substituted or unsubstituted C3_6 cycloalkylalkyl, and substituted or unsubstituted C3_6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=0), thio (:8) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRd1 or S; each occurrence of Rd1 is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted kyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONOZ; p is 0, l, 2, 3 or4; and all the other variables (Xl-X4, X, and R5) are the same as described above for compound of formula (A), (B), (A-I) or (B-II).
, (B-I) ,(A-II) Yet another embodiment is a nd of formula (A-IIIA) and (A-IVA) (A-IIIA) (A-IVA) wherein the variables Ar, G, R6, and p are defined as above with respect to as (A-IIIA) or (A-IVA), and all the other les (Xl-X4, X, and R5) are the same as described above for compound of formula (A), (B), (A-I) , (B-I) , (A-II) or (B-II) with the proviso 1. that for compound of formula (A-IIIA) Z is O or S and X4 is N or CR4 , wherein then Ar—G cannot be \ \ NJN H H H H HH HH w NJ" HM“ WM“ Hflw\ W q H ’H 2. that for compound of formula (A-IVA) wherein Z is O or S and X1 is N or CR1 then Ar-G cannot be \ \ NJN H H H H HH H” w Jud“ HM WW Hy\ W’ H ’H wherein R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)'O-R1, -C(=O)-NR1aR1, 'NRla'S(=O)2' R1, halo, or a 4- to lO-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms ed from N, O, and S; Rla, at each ence, is independently hydrogen or (C1-C8)alkyl; R1 is optionally substituted )-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, ally substituted (C6-C10)aryl, a 4-lO-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to bered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA), (A- IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein Ar is selected from.
(R6>p\/l G (R6)p\VG W)P\\//Nj/G(R6 INJ\ ENE/N Further preferred is a compound of formula , (A-IIA), (A-IIIA), (A- IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein G is selected from.
“XX, :XX Further preferred is a compound of formula (A-IA), ), (A-IIIA), (A- IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X1 is CR1 or N, wherein R1 is H or Halogen.
Further preferred is a compound of formula (A-IIA) or , (A-IVA) , (B-IIA) (B-IVA) n X2 is CH.
Further preferred is a compound of formula (A-IA) or (B- , A) , (B-IA) IIIA) wherein X3 is CH.
Further preferred is a compound of formula (A-IA), ), (A-IIIA), (A- IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X4 is CR4 or N R1 is H or , wherein Halogen.
Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA), (A- IVA), , (B-IIA), (B-IIIA) or ) wherein X is CH or N.
Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA) or (A- IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R5 is selected from 16%» vii, pk? “if” $19szW fWM Further preferred is a compound of formula , (A-IIA), (A-IIIA), (A- IVA) or (B-IVA) wherein R5 is BOC ( -C(O)OC(CH3)3).
, (B-IA), (B-IIA), (B-IIIA) Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA), (A- IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R5 is CH(CH3)2.
Further preferred is a compound of formula (A-IIA) or (B-IIA) wherein X1 is CH or CF.
In one preferred embodiment, X is N.
In one preferred ment, X is CH.
In one red embodiment, Z is S In one preferred embodiment, Z is O.
Further preferred is a compound of formula (A-IA), (A-IIA), A) , (A- IVA) or (B-IVA) wherein p is 0 or 1.
, (B-IA), (B-IIA), (B-IIIA) Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA), (A- IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R6 is n, substituted or unsubstituted alkyl or -ORa; wherein Ra is substituted or tituted alkyl.
Further preferred is a compound of formula ((A-IA), (A-IIA), (A-IIIA) , (A- IVA) or ) wherein R6 is -F, -CH3, -CF3 or -OCH3.
, (B-IA), (B-IIA), (B-IIIA) Yet r embodiment is a compound of formula (A-IB) and (A-IIB): R5(R6)p//Arl X(A—IIB) or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e. g., pharmaceutically acceptable salt), prodrug (e. g., ester), or N-oxide thereof, wherein Z is O or S Arl-G is (R6)p G (R6)p (R6)p .U ,iUw \N/ /\ /RG(6)P:\N/G (R6)p\ a a 2012/041632 p is 0, 1-7 or 8 and all the variables (R6, Xl-X4, X, and R5) are the same as described above Yet another embodiment is a compound of formula (A-IIIB) and (A-IVB): R5(R6)p//Arl (A-IIIB) (A-IVB) or a tautomer, stereoisomer, omer, diastereomer, salt (e.g., pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxide thereof, wherein Z is O or S Arl-G is (R6)p (Re \/\N/G )p\/\N/G (R)P:/\N/GG(Re Re)p\ (R6)p\ p is 0, 1-7 or 8 and all the variables (R6, Xl-X4, X, and R5) are the same as described above. 1. that for compound of a (A-IIIB) Z is O or S and , wherein X4 is N or CR4 then Arl-G cannot be N/w N/W N/W W \ \ MIN 2. that for compound of formula (A-IVB) wherein Z is O or S and X1 is N or CR1 then Arl-G cannot be \ \ MIN 2012/041632 wherein R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)'O-R1, -C(=O)-NR1aR1, 'NRla'S(=O)2' R1, halo, or a 4 to lO-membered optionally substituted heteroaryl, which ns 1-4 heteroatoms selected from N, O, and S; Rla, at each occurrence, is independently hydrogen or (C1-C8)alkyl; and R1 is optionally substituted (C1-C6)-alkyl, optionally tuted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, optionally substituted (C6-C10)aryl, a 4 to lO-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to lO-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S.
Yet another embodiment is a compound of formula (A-V): |// N (R6),, 0\>—<:N—R5 or a ceutically acceptable salt f, wherein R1 is en or F; R5 is as defined above; G is selected from —SOzRa, -C(O)RaRb, C1-C4 alkyl substituted with one or more halogens, and a tetrazole of the formula / \ "\/ "W. each occurrence of R6 is independently halogen; each occurrence of Ra and Rb is ndently hydrogen or tituted or substituted C1-C6 alkyl; and pis0, 1,20r3.
In one preferred embodiment of the compound of formula (A-V), R5 is selected from —COO-Ra and —SOz-Ra (wherein Ra is an unusubstituted C1-C4 alkyl, C1-C4 alkyl with one or more halogens, or C3-C6 cycloalkyl).
In a preferred embodiment of the compound of formula (A-V), G is ed from —SOZRa (Where Ra is an unsubstituted C1-C4 alkyl), -C(O)RaRb (Where Ra and Rb are independently selected from en and a C1-C4 alkyl optionally substituted with one or more halogen), a C1-C2 alkyl substituted with oneor more halogens, and a tetrazole of the formula above.
Yet another embodiment is a compound of formula (B-V): or a ceutically acceptable salt thereof, wherein R5 is as defined above; G is selected from —SOzRa; each ence of R6 is independently halogen; each occurrence of Ra is independently hydrogen or unsubstituted or substituted C1-C6 alkyl; pis0, 1,20r3.
In one preferred embodiment of the compound of formula (B-V), R5 is —COO- Ra Where Ra is an tituted or substituted C1-C6 alkyl. More preferably, Ra is an unusubstituted C1-C6 alkyl, such as an unsubstituted C1-C4 alkyl.
In a preferred embodiment of the compound of formula (B-V), G is selected from —SOZRa Where Ra is an unsubstituted C1-C4 alkyl, such as .
In a preferred embodiment of the nd of formula (B-V), p is l and R6 is fluorine. More preferably, the fluorine is at a position ortho the benzo[d]oxazole group.
Representative compounds of the present invention include those specified below (including Table l and Table 2) and pharmaceutically acceptable salts thereof. The present ion should not be ued to be limited to them. 1. 2-[1-(5 -Ethylpyrimidinyl)piperidinyl] [2-fluoro(methylsulfonyl)phenyl] - lH-benzo[d]imidazole: 2. Tert-butyl 4-{ 5- [2-fluoro(methylsulfonyl)phenyl] - lH-benzo[d]imidazol yl } piperidine- l -carboxylate: 3. 2-[1-(5 -ethylpyrimidinyl)piperidinyl] [2-fluoro (methylsulfonyl)phenyl]benzo[cfloxazole: 4. Tett-butyl 4-{ 5-[2-flu0r0—4-(methy1sulfony1)pheny1]benz0[cfloxazol-Z-yl}piperidine- 0xy1ate: . Tert-butyl 4-{ 5- [2-fluoro(methy1sulf0ny1)phenyl] - 1-methy1— 1H-benz0 [d]imidaz01— 2-y1}piperidinecarb0xy1ate: 6. Tert-butyl 4- { 6- [2-fluoro(methylsulfony1)pheny1]benz0[cfloxazol-Z-yl }piperidine- 0xy1ate: 7. pyl 4-{ 5-[2-flu0r0—4-(methy1sulfony1)pheny1]benz0[cfloxazol-Z-yl}piperidine- 1-carb0xy1ate: 8. Tert-butyl 4- { 7-flu0r0—5- [2-flu0r0(methylsulfony1)pheny1]benz0[cfloxazol-Z- yl}piperidinecarb0xy1ate: 9. Tert-butyl 4-[5-(4-cyan0pheny1)benz0[d]0xaz01—2-y1]piperidinecarb0xy1ate: . Tert-butyl 4- { 5 0r0—4-(methy1sulfony1)pheny1]benz0[cfloxazol-Z-yl}piperidine- 1-carb0xy1ate: 1 1. utyl 4-(1H—tetraz01y1)pheny1]benz0[cfloxazol-Z-yl}piperidine carboxylate: 12. Tert-butyl 4-{5-[2-flu0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxazol-Z-yl}piperidine- 1-carb0xy1ate: 13. Tert-butyl 4- { 5- [4-(trifluoromethy1)phenyl]benzo [cfloxazol-Z-yl } piperidine carboxylate: 14. Isopropyl 4-{ 5 -[2-flu0r0—4-(1H—tetraz01y1)phenyl]benz0[cfloxazol-Z-yl }piperidine- 1-carb0xy1ate: . Tert-butyl 4-{5-[3-flu0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxazol-Z-yl}piperidine- 1-carb0xy1ate: 16. 2-[1-(5-ethy1pyrimidiny1)piperidinyl][2-flu0r0—4-(1H—tetrazol y1)phenyl]benz0[d]0xazole: 17. Tert-butyl 4- [5 -(4-cyan0—3-flu0r0pheny1)benz0[cfloxazol-Z-y1]piperidine carboxylate: 18. Isopropyl 4-{ 5 - [3 -flu0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxazol-Z-yl}piperidine- 1-carb0xy1ate: 19. Tert-butyl 4- { 5-[3-flu0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxazol-Z-yl }piperidine- 1-carb0xy1ate: . Tert-butyl 4-[5-(4-carbam0y1chlor0pheny1)benz0[d]oxazol-Z-y1]piperidine carboxylate: 21. Tert-butyl 4- [5 -(4-carbam0y1-3 -flu0r0pheny1)benz0[cfloxazol-Z-yl]piperidine carboxylate: 22. Tert-butyl 4-[5-(3-fluorois0pr0p0xypheny1)benz0[cfloxaz01yl]piperidine ylate: 23. Cyclobutyl 4- { 5 -[2-flu0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxaz01 yl}piperidinecarb0xy1ate: 24. Sec-butyl 4-{ 5 0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxazoly1}piperidine- 1-carboxy1ate: . Pentany1 4- { 5 -[2-flu0r0—4-(1H—tetraz01y1)pheny1]benz0[cfloxaz01 yl}piperidinecarb0xy1ate: 26. 5- [2-flu0r0—4-( 1H-tetraz01- 1-y1)phenyl] (piperidiny1)benz0 [d]0xazole: 27. pyl 4- { 5- [4-(trifluoromethy1)pheny1]benzo[cfloxaz01y1 }piperidine carboxylate: 28. Isopropyl 4-[5-(4-f0rmy1pheny1)benz0[cfloxazoly1]piperidine- 1-carboxy1ate: 29. Isopropyl 4-{ 5-[4-(difluoromethy1)pheny1]benzo[d]0xaz01y1}piperidine carboxylate: . Isopropyl 4-[5-(4-carbam0y1ch10r0pheny1)benz0[d]oxaz01y1]piperidine carboxylate: 31. pyl 4- [5-(4-carbam0y1-3 heny1)benz0[cfloxazoly1]piperidine carboxylate: 32. 1- {4-[5-(2-flu0r0—4-(1H-tetraz01- 1-y1)pheny1)benz0[d]oxaz01y1]piperidiny1} methylpropan- 1-0ne: 33. Isopropyl 4-{ 6-[4-(difluoromethy1)pheny1]benzo[d]0xaz01y1}piperidine carboxylate: 34. 6- {2-[1-(isopropoxycarbony1)piperidiny1]benz0[d]0xaz01y1}nic0tinic acid: . 5-[2-flu0r0—4-(1H—tetraz01y1)pheny1]—2-[1-(methylsulfony1)piperidin yl]benz0[cfl0xazole: 36. Isopropyl 4- [5-(5 -carbam0y1pyridiny1)benzo[cfloxaz01yl]piperidine carboxylate: 37. Isopropyl 4- [5 -(4-carbam0y1flu0r0pheny1)benz0[cfloxaz01yl]piperidine carboxylate: 38. Isopropyl 4-carbamoylch10r0pheny1)benz0[d]oxaz01y1]piperidine carboxylate: 39. 2-F1u0r0—4- {2-[1-(3-methylbutanoy1)piperidiny1]benz0[cfloxaz01-5 -y1}benzamide: 40. 1- {4-[5-(2-flu0r0—4-(1H—tetraz01- 1-y1)pheny1]benz0[d]0xaz01y1]piperidiny1} methylbutan- 1-0ne: 41. 5-[2-flu0r0—4-(1H—tetraz01y1)pheny1]—2-[1-(2-methoxyethy1)piperidin yl]benz0[cfl0xazole: 42. Isopropyl 4-{ 5- [3-flu0r0—4-(methylcarbam0y1)pheny1]benz0 [cfloxazol-Z- yl}piperidinecarb0xy1ate: 43. 2-F1u0r0—4-[2-(1-is0butyry1piperidiny1)benz0[d]0xaz01y1]benzamide: 44. Isopropyl 4-[6-(4-carbam0y1flu0r0pheny1)benz0[cfloxazol-Z-y1]piperidine carboxylate: 45. Isopropyl 4- { 5 - [3 -flu0r0—4-(2-hydr0xyethylcarbam0y1)pheny1]benz0 [cfloxazol-Z- eridinecarb0xy1ate: 46. pyl 4-{ 5 - [3 -flu0r0—4-(is0pr0pylcarbam0y1)pheny1]benz0 [cfloxazol-Z- yl}piperidinecarb0xy1ate: 47. Isopropyl 4-{ 5 - [4-(N—methylsulfam0y1)pheny1]benz0 [cfloxazol-Z-yl } piperidine- 1- carboxylate: 48. Isopropyl 4- { 5- [6-(methylcarbam0y1)pyridin-3 -y1]benz0[cfl0xazoly1}piperidine carboxylate: 49. Isopropyl 4- { 5- hy1(methy1carbam0y1)pheny1]benz0 [cfloxazol-Z- yl}piperidinecarb0xy1ate: 50. pyl 4- { 5- [4-(cyclopropylcarbam0y1)flu0r0pheny1]benz0 [cfloxazol-Z- yl}piperidinecarb0xy1ate: 51. 2-F1u0r0—4- (5-fluoropyrimidiny1)piperidiny1]benz0[cfloxaz01 zamide: 52. Tert-butyl 4-[5-(4-carbam0y1flu0r0pheny1)benzofurany1]-5 ,6-dihydr0pyridine- 1(2H)-carb0xy1ate: 53. 2-flu0r0—4-{ 2-[1-(propylsulfony1)piperidiny1]benz0[cfloxaz01-5 -y1}benzamide: 56. Tett-butyl 4-{2-[2-flu0r0—4-(methylsulfony1)pheny1]-1H-benz0[d]imidaz01y1}-5,6- dihydropyridine- 1(2H)-carb0xy1ate; 57. Tett-butyl 4-{ 2-[2-fluoro(methy1su1f0ny1)pheny1]-1H-benz0[d]imidazol-5 -y1} piperidinecarboxy1ate; 58. 5-[1-(5 -ethy1pyrimidiny1)piperidiny1] [2-flu0r0—4-(methylsulfony1)phenyl] - 1H-benz0[d]imidazole; 59. Tett-butyl 4- { 2- [2-flu0r0—4-(methy1sulfony1)pheny1]benz0 [d]0xaz01y1 } -5 ,6- dihydropyridine- 1(2H)-carb0xy1ate; 60. Tett-butyl 4- { 2- [2-flu0r0—4-(methy1sulfony1)pheny1]benz0[d]0xaz01-5 -y1}piperidine- 1-carboxy1ate; 61. 2- [2-flu0r0—4-(methylsulfonyl)phenyl](piperidinyl)benz0[d]0xazole 2,2,2- trifluoro acetate; 62. 5-[1-(5 -ethylpyrimidinyl)piperidinyl] [2-flu0r0—4-(methylsulfonyl)phenyl] benzo [d]0xazole. 63. utyl 4- { 7-flu0r0—2- [2-fluoro(methylsulfonyl)phenyl]benz0[cfloxazol-S - yl}piperidinecarb0xylate: 64. Isopropyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benz0[cfloxazol-S -yl }piperidine- oxylate: 65. Tert-butyl 4- { 2- [2-flu0r0(methylsulfonyl)phenyl]benzo [d]thiazolyl } -5 ,6- dihydropyridine- 1(2H)-carb0xylate: 66. Tert-butyl 4- { 2- [2-flu0r0(methylsulfonyl)phenyl]benzo [d]thiazolyl } -5 ,6- opyridine- 1(2H)-carb0xylate: 67. Tert-butyl 4- { 2- [2-fluoro(methylsulfonyl)phenyl]benz0[cfloxazolyl }piperidine- 1-carboxylate: 68. Tert-butyl 4- { 2- r0—4-(methylsulfonyl)phenyl]benzo [cflthiazol-S-yl }piperidine- 1-carboxylate: 69. Ethyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benz0[cfloxazol-S -yl}piperidine ylate: 70. Tert-butyl 4- { 2- [4-(trifluoromethyl)phenyl]benzo [cfloxazol-S-yl } piperidine carboxylate: 71. Isopropyl 4- { 2- [2-fluoro(methylsulfonyl)phenyl]benz0[cfloxazolyl }piperidine- 1-carboxylate: 72. Ethyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benz0[cfloxazolyl }piperidine- 1- carboxylate: 73. Ethyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benz0[cfloxazolyl }piperidine- 1- carboxylate: 74. Benzyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benz0[cfloxazol-S -yl}piperidine carboxylate: 75. Isobutyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benz0[cfloxazol-S -yl}piperidine carboxylate: 76. pyl 4- { 2- [2-flu0r0—4-(methylsulfonyl)phenyl]benzo [cflthiazolyl idine- 1-carboxylate: 77. Isopropyl 4- { 2- [4-(trifluoromethyl)phenyl]benzo [cfloxazol-S-yl } piperidine carboxylate: 78. Isopropyl 4-(2-p—tolylbenz0[d]oxazolyl)piperidinecarboxylate: 79. 3- { 4- [2-(2-flu0r0—4-(methylsulfony1)pheny1)benz0 [cfloxazol-S-yl] -5 ,6- dihydropyridin- 1(2H)-ylsulf0ny1}pr0pan- 1-01: 80. 3- { 4- [2-(2-flu0r0—4-(methylsulfony1)pheny1)benz0 [cfloxazol-S-yl]piperidin- 1- ylsulfony1}pr0pan- 1-01: 81. 3- { 4- flu0r0—4-(methylsulfony1)pheny1)benz0 zol-S-yl]piperidin- 1- ylsulfony1}pr0pan- 1-01: 82. Tert-butyl 4- [2-(4-carbam0y1-3 -flu0r0pheny1)benz0[cfloxazol-S-y1]piperidine carboxylate: 83. 2-[2-flu0r0—4-(methy1sulfony1)pheny1][4-(3-is0pr0py1-1,2,4-oxadiaz01 y1)piperidiny1]benz0[cfl0xazole: 84. Tert-butyl 4-{2-[4-(trifluoromethy1)pheny1]benzo[cfloxaz01y1}piperidine carboxylate 85. Isopropyl 4- { 2- [2-flu0r0(methy1sulf0ny1)pheny1]benz0[cfloxazol-S -y1}piperazine- 1-carboxy1ate: 86. Tert-butyl 4- { 2- [4-(trifluoromethyl)phenyl]oxazolo [5 ,4-b]pyridiny1 } -5,6- dihydropyridine- carb0xy1ate: 87. Tert-butyl 4-{ 2-[4-(triflu0r0methy1)pheny1]oxaz010[5,4-b]pyridiny1}piperidine- 1- carboxylate: TABLE-1 Example Structure Example structure 1 M6028 O“HayF 2 MeOZS OMEMO.F 3 MeOZS O F 4 MeOZS F MeOZS F g 6 MeOZS F <:/\N_B°C OO/>—<:>N-Boc \ N (tentative) 11 NN='3‘ 12 NIN=NN \\/N F Q‘sOWN-Bee 0 O:\ N_B°c 13 no“ 14 NINCN F OO\>—<:/\N—BOCN \./\.::\>_<:N_/<Ofi<O o N: F 16 NQN F :/\N—<\:i/>—\ 17 18 N:N F NC :‘EON>—CN—Boo NJ Example Structure Example structure N 26 N 27 F3CN>_<::N_/<o< 28 OHCO>_<:/\N40% O O 29 W@fiiflmfiu 30 ‘(ZwO-{K 31 H2NOC\‘\.: 32 Niki]V O RoycwyF D yC JV~N 0 N o 33 FZHC O“$0404 34 H000 0 O \ OWN—«ONN 0 NtNN 36 / F l” {‘sz \ $0404N O 37 /\.:: 38 H2NOC 0 CI M“(Z4 D :VQJH0 :NHZNOC\‘\.::0N>—<:/\NNM 40 NM Boc\ | F \ 802Me .CF3COOH Boc\ \ $02Me Boc\ I F / 302Me Boc\ / 802Me EtO N \ 802Me 0 N / SOgMe A io N \ $02Me 84 BOC\N 85 PrOiiN OK» F “”ngK»swe 86 Boc\N 87 Boc\N \ N \ N | \ CF I \ 3 CF3 / / N O N O Yet another embodiment of the present invention is a method for ng a GPR119 receptor related disorder by administering to a subject in need of such treatment an effective amount of at least one compound of the present invention, such as a compound of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), ), (A-IIIA), (A-IVA), (A-IB), ), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B- IB) (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above.
Yet another embodiment of the present invention is a method for treating a GPR119 receptor related er by administering to a subject in need of such treatment an effective amount of at least one compound of the present invention, such as a compound of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), A), (A-IVA), (A-IB), (A- IIB), (A-IIIB), ), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), , (B-IIA), (B- IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above, in combination (simultaneously or sequentially) with at least one other therapeutic agent. In a preferred embodiment, the GPR119 receptor related disorder is a metabolic disorder and in particular the metabolic disorder is diabetes and/or y.
More particularly, the compounds of a (A), (A-I), (A-II), (A-III), (A- IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B- IIIB), (B-IVB), and (B-V) as defined above can be administered for the treatment, prevention and/or amelioration of GPR119 receptor associated diseases or disorders including, but not d to, diabetes and other metabolic disorders or es.
Yet another ment of the present invention pertains to the use of a nd of the present ion, such as a compound of formula (A), (A-I), (A-II), (A- III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), , (A-IIB), B), (A-IVB), (A- V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), ), or (B-V) as defined above, or a composition thereof in the manufacture of a medicament for modulating the activity of a GPR 119 receptor.
More particularly, the present invention pertains to the use of a compound of the present invention, such as a compound of formula (A), (A-I), (A-II), (A-III), (A-IV), (A- IA), (A-IIA), (A-IIIA), (A-IVA), , (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B- 11), ), (B-IV), (B-IA), (B-IIA), A), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B- IVB), or (B-V) as defined above, or a composition thereof in the manufacture of a medicament for agonizing a GPR H9 receptor The compounds of the present invention, such as the compounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB) (A-IIB), (A- IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (BIVA ), (B-IB), (B-IIB), (B-IIIB). (B-IVB), and (B-V) as defined above are useful in the treatment of a variety of lic disorders including, but not limited to, diabetes mellitus, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, n resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, , me X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell iciency, glucosuria, metabolic acidosis, cataracts, ic nephropathy, diabetic neuropathy, eral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral ar disease, diabetic retinopathy, metabolic syndrome, a condition d to diabetes mellitus, myocardial tion, learning impairment, memory impairment, a neurodegenerative disorder, a condition rated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-neuron disease, traumatic brain injury, spinal cord injury, obesity, d wound g, abnormal heart function, myocardial ischemia, low HDL, high LDL, non- c ischemia, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma.
More particularly, the compounds of the present invention, such as the compounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (AIVA ), (A-IB), (A-IIB), B), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), ), (B-IIIA), (B-IVA), (B-IB) (B-IIB), (B-IIIB), (B-IVB), and (B-V) as defined above can be administered for the ent of metabolic-related disorder selected from the group ting of type 2 diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, type 1 diabetes, idiopathic type 1 diabetes (type Ib), latent autoimmune es in adults (LADA), early-onset type 2 diabetes (EOD), youth- onset al diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, vascular restenosis, restenosis, restenosis after angioplasty, peripheral vascular disease, claudication, intermittent claudication, cell death associated with myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), impaired glucose metabolism, conditions of impaired glucose metabolism, conditions of impaired fasting plasma glucose, metabolic acidosis, s, arthritis, obesity, orosis, ension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, ic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transient ischemic attacks, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, endothelial dysfunction, and impaired ar compliance.
More ularly, the compounds of the present invention, such as the compounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), ), (A-IIIA), (A- IVA), (A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B-IVB), and (B-V) as defined above can be administered for the treatment of type 2 diabetes, hyperglycemia, ipidemia,hypertriglyceridemia, type 1 diabetes, dyslipidemia, and syndrome X.
The invention further provides a ceutical composition sing one or more nds of the t invention together with a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anti-cancer agents. In one embodiment, the pharmaceutical composition includes a therapeutically effective amount of one or more compounds of the present invention, such as at least one compound of formula (A), (A-I), (A- 11), (A-III), , (A-IA), (A-IIA), (A-IIIA), ), (A-IB) (A-IIB), (A-IIIB), (A- IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above.
Yet another embodiment is a method of treating metabolic disorder in a subject in need thereof by administering a eutically effective amount of a compound of the present invention. For example, the compounds of the present invention are effective for treating diabetes (e.g., type II diabetes) and/or obesity.
BRIEF DESCRIPTION OF THE FIGURES Figure l is a graph of blood glucose over time in C57BI/6J mice according to the oral glucose tolerance test (Biological Assay Procedure E) before and after oral administration of vehicle (control), compound A (Example 64 @ 30 mg/kg), or sitagliptin (10 mg/kg @ 10 mg/kg).
Figure 2 is a graph of blood glucose over time in C57BI/6J mice according to the oral e tolerance test (Biological Assay Procedure E) before and after oral stration of vehicle (control), compound A (Example 42 @ 10 mg/kg), or iptin (10 mg/kg @ 10 mg/kg).
DETAILED DESCRIPTION It is appreciated that n features of the invention, which are, for clarity, described in the t of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the ion, which are, for brevity, described in the context of a single embodiment, may also be ed separately or in any le subcombination. Accordingly, all combinations of uses and l indications described herein specifically embraced by the t invention just as if each and every subcombination of uses and medical indications was individually and explicitly recited herein.
As used herein the following definition shall apply unless otherwise indicated.
Further many of the groups defined herein can be optionally substituted. The listing of tuents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the specification.
The term ‘alkyl’ refers to a straight or branched arbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having, unless otherwise indicated, from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, l-methylethyl (isopropyl), n-butyl, n-pentyl, and l,l-dimethylethyl (t-butyl).
The term substituted or unsubstituted (C1_4)alkyl refers to an alkyl group as defined above having up to 4 carbon atoms, and the term substituted or unsubstituted (C1- 6)alkyl refers to an alkyl group as d above having up to 6 carbon atoms.
The term “alkenyl “ refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having, unless otherwise indicated, 2 to about 10 carbon atoms, e. g., ethenyl, l-propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, l-butenyl, and 2-butenyl.
The term substituted or unsubstituted (C26) alkenyl refers to an l group as defined above having up to 6 carbon atoms.
The term “alkynyl” refers to a straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having, unless otherwise indicated, in the range of 2 up to 12 carbon atoms (with ls having in the range of about 2 up to 10 carbon atoms tly being preferred) e. g., ethynyl, propynyl, and butnyl.
The term substituted or unsubstituted (C26) alkynyl refers to an alkynyl group as defined above having up to 6 carbon atoms.
The term “alkoxy” s an alkyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of these groups are — OCH3 and -OC2H5.. The term “substituted alkoxy” refers to an alkoxy group where the alkyl tuent is substituted (i.e., -O-(substituted alkyl) wherein the term ituted alkyl” is the same as defined above for “alkyl”. For example “alkoxy” refers to the group -O-alkyl, ing, unless otherwise indicated, from 1 to 8 carbon atoms of a straight, branched, cyclic uration and combinations thereof attached to the parent structure through oxygen.
WO 70867 Examples e methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.
The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of, unless otherwise indicated, 3 to about 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of yclic cycloalkyl groups include perhydronapththyl, tyl and norbomyl groups, bridged cyclic groups, and sprirobicyclic groups, e. g., sprio (4,4) nonyl.
The term “C3_g cycloalkyl” refers to a cycloalkyl group as defined above having up to 8 atoms.
The term “cycloalkylalkyl” refers to a cyclic ring-containing radical containing, unless otherwise indicated, in the range of 3 up to about 8 carbon atoms directly attached to an alkyl group which are then attached to the main ure at any carbon from alkyl group that results in the creation of a stable structure such as cyclopropylmethyl, cyclobuyylethyl, and cyclopentylethyl.
The term “C3_6 lkylalkyl” refers to a cycloalkylalkyl group as defined above having up to 6 atoms.
The term “cycloalkenyl” refers to cyclic ring-containing radicals containing, unless otherwise indicated, in the range of 3 up to about 8 carbon atoms with at least one carbon- carbon double bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloalkenyl group directly attached to an alkyl group which are then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure The term “C3_6 cycloalkenyl” refers to a cycloalkenyl group as defined above having up to 6 atoms.
The term “aryl” refers to aromatic radicals having, unless otherwise indicated, in the range of 6 up to 20 carbon atoms such as phenyl, yl, tetrahydronapthyl, indanyl, and biphenyl.
The term “arylalkyl” refers to an aryl group as defined above ly bonded to an alkyl group as defined above. e. g., -CH2C6H5 and -C2H5C6H5.
The term “heterocyclic ring” refers to a non-aromatic 3 to 15 member ring radical which, consists of carbon atoms and at least one atom ed from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the en, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to s oxidation states. In addition, the nitrogen atom may be optionally quaternized. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term “heterocyclyl” refers to a heterocylic ring l as defined above.
The heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term “heterocyclylalkyl” refers to a heterocylic ring radical as d above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure. es of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- donyl, pyrrolidinyl, lidinyl, lidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.
The term “heteroaryl” refers to an optionally substituted 5 to 14 member aromatic ring having one or more heteroatoms ed from N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such “heterocyclic ring” or “heteroaryl” radicals include, but are not d to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl , isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, zinyl, 2-oxopiperazinyl, iperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4- piperidonyl, pyrrolidinyl, pyridazinyl, inyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, yranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl.
The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term “substituted heteroaryl” also es ring systems substituted with one or more oxide () substituents, such as nyl N-oxides.
The term “heteroarylalkyl” refers to heteroaryl ring radical as defined above directly bonded to an alkyl group. The heteroarylalkyl l may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
The term “heterocyclylalkyl” refers to a heterocylic ring radical as defined above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
The term “cyclic ring” refers to a cyclic ring containing, unless ise indicated, 3 to 10 carbon atoms.
The term “substituted” unless otherwise specified, refers to substitution with any one or any combination of the following tuents and may be the same or different which one or more are selected from the groups such as hydrogen, y, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted l, substituted or unsubstituted alkynyl, tuted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or tituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl, —COOR7, -C(O)R7, - C(S)R7, -C(O)NR’R”, —C(0)0NR’R”, —NR’R”, —NR’CONR’R”, —N(R’)SOR”, sozR”, — (=N—N(R’)R”), — )0R”, —NR’R”, -NR7C(O)R”-, —NR’C(S)R” —NR’C(S)NR”R’”, — W0 2012/170867 SONR’R”—, —sozNR’R”—, —0R’, —0R’C(0)NR”R”’, -OR7C(O)OR”-, -OC(O)R7, — OC(O)NR7R”,- R’NR”C(O)R’”, —R’0R”, -R7C(O)OR”, —R’C(0)NR”R’”, -R7C(O)R”, — RSOC(O)R”, -SR7, -SOR7, , -ONOZ wherein R, R” and Rm in each of the above groups can independently be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or tituted heterocyclcyalkyl, substituted or tituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or any two of R, R” and Rm may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are ed from O, NRX or S or form oxo (=0), thio (=S) or imino (=NR’, where R’ is defined above). The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on ituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl". Substitution or the combinations of tuents envisioned by this ion are preferably those that result in the formation of a stable or chemically feasible compound. The term stable as used herein refers to the compounds or the structure that are not substantially altered when subjected to ions to allow for their ion, production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition.
The term "halo", "halide", or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms lkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For e, the terms alkyl" and "fluoroalkoxy" refer to haloalkyl and koxy groups, respectively, in which the halo is fluorine.
The term "protecting group" or "PG" refers to a substituent that is employed to block or t a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a tuent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a y group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the y functionality. Suitable carboxy-protecting groups include, but are not limited to, -CH2CH2SOzPh, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, - 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
The term "stereoisomer" refers to compounds, which have cal chemical composition, but differ with regard to arrangement of the atoms and the groups in space.
These include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational s.
All the stereoisomers of compounds described herein are within the scope of this ion. Racemic mixtures are also encompassed within the scope of this invention.
Therefore, single stereochemical isomers as well enantiomeric, diastereoisomeric and geometric (or mational) mixtures of the present compounds fall within the scope of the invention.
Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, reomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present al entities, pharmaceutical compositions and methods are meant to include all such le isomers, ing racemic mixtures, optically pure forms and intermediate mixtures. For the instance the non-limiting example of intermediate mixutures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the nds include both E and Z geometric isomers.
The term "tautomers" refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be d by this invention. "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of ization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an nt double bond. Where tautomerization is possible (e.g. in on), a chemical equilibrium of ers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of nol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypentenone tautomers. r example of erization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridinol and pyridin-4(1H)-one tautomers .
A "leaving group or atom" is any group or atom that will, under the reaction ions, cleave from the starting al, thus promoting reaction at a specified site.
Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
The term "prodrug" refers to a compound, which is an ve precursor of a compound, converted into its active form in the body by normal metabolic processes.
Prodrug design is discussed generally in , et al. , Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). To illustrate, prodrugs can be converted into a pharmacologically active form through hydrolysis of, for e, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product. The prodrugs can be ed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life. Alternatively, gs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent nd. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the ally administered compound.
The term "ester" refers to a compound, which is formed by reaction between an acid and an alcohol with elimination of water. An ester can be represented by the general formula .
These prodrugs and esters are intended to be covered within the scope of this invention.
Additionally the instant invention also includes the nds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon.
The compounds of the present ion may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the nds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
Pharmaceutically acceptable salts g part of this invention e salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl ol; salts of natural amino acids such as glycine, alanine, valine, e, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, e, hydroxy proline, histidine, omithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of invention with alkyl halides, alkyl sulphates such as Mel and (Me)ZSO4; non-natural amino acids such as D—isomers or substituted amino acids; guanidine; and substituted ine wherein the tuents are selected from nitro, amino, alkyl, alkenyl, l, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, WO 70867 phosphates, perchlorates, borates, alides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, esulphonates, tes, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range ed to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or ises" or "having" or "including") includes those ments, for e, an embodiment of any composition of matter, composition, method, or process, or the like, that "consist of” or st essentially of” the described features.
The term "agonist" generally refers to a moiety that interacts and activates a receptor, such as, the GPR119 or and initiates a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.
The term "contact or contacting" refers to bringing the ted moieties together, whether in an in vitro system or an in vivo system. Thus, "contacting" a GPR 119 receptor with a compound of the invention includes the administration of a compound of the present invention to an dual, preferably a human, having a GPR 119 receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified ation containing a GPR 119 or.
The term "hydrate" as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.
The terms "in need of treatment" and "in need thereof," when referring to treatment are used interchangeably to refer to a judgment made by a caregiver (e.g. physician, nurse, or nurse practitioner in the case of humans; veterinarian in the case of s, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, ion or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
The term "modulate or modulating" refers to an increase or decrease in the amount, quality, response or effect of a ular activity, function or molecule.
The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, including but not limited to, salts, es, and hydrates of compounds of the present inventionm whereby the composition is le to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired cious outcome based upon the needs of the n.
The term "solvate" as used herein means a compound of the invention or a salt, thereof, that r includes a stoichiometric or non- stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
Abbreviations, unless ise indicated, used herein have their conventional meaning within the chemical and biological arts.
The term ministration, administered in combination with," and their grammatical lents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in te compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
The term "effective amount" or "therapeutically effective amount" refers to that amount of a nd described herein that is sufficient to effect the ed application including, but not limited to, disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e. g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e. g. reduction of et adhesion and/or cell ion. The specific dose will vary ing on the particular compounds chosen, the dosing regimen to be ed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the al delivery system in which it is carried.
As used herein, "treatment," "treating," or "ameliorating" are used interchangeably. These terms refers to an approach for obtaining beneficial or desired results ing but not limited to eutic benefit and/or a lactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying er being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. For prophylactic t, the compositions may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
A "therapeutic effect," as that term is used herein, encompasses a eutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or ion, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
The term "subject" or "individual" or "subject" is intended to mean any , including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and most preferably humans. In another embodiment, the individual is a human and in certain embodiments, the human is an infant, child, adolescent or adult. In one ment, the individual is at risk for developing a GPRll9-related disorder. In one embodiment, the individual is at risk for developing a metabolic-related e or disorder. Individuals who are at risk include, but are not limited to, those with hereditary history of a metabolic-related disease or er, or those in a state of al health which puts them at risk for a metabolic-related disease or disorder. In another embodiment, the individual has been determined, by the care-giver or someone acting under the guidance of the iver, to have a metabolic-related disease or disorder, The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more le diluents, fillers, salts, egrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, rs, excipients, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any tional media or agent is incompatible with the active ingredient, its use in the therapeutic itions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
METHOD OF TREATMENT In addition to the foregoing beneficial uses for compounds of the present invention as disclosed herein, compounds of the invention are useful in the treatment of additional diseases. Without limitation, these include the ing.
The most significant ogies in type 2 diabetes are impaired insulin signaling at its target tissues (”insulin resistance") and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.
Current therapies to treat the latter include inhibitors of the B-cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these es accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e. potentiators of glucose signaling.
Physiological signaling s which function in this manner are well- characterized and include the gut peptides GLPl, GIP and PACAP. These es act via their cognate G-protein coupled or to stimulate the production of cAMP in atic B-cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or preprandial state. However, a series of biochemical targets of cAMP signaling, including the ATP-sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, B-cell GPCRs, including GPRl 19, would also stimulate the release of endogenous insulin and consequently promote normoglycemia in type 2 diabetes.
It is also established that increased cAMP, for example as a result of GLP- 1 stimulation, promotes B-cell proliferation, inhibits B-cell death and thus improves islet mass.
This positive effect on B-cell mass is expected to be beneficial in both type 2 diabetes, where insufficient insulin is produced, and type 1 diabetes, where B-cells are destroyed by an inappropriate autoimmune response.
Some B-cell GPCRs, including GPRl 19, are also present in the hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or sing weight and energy iture. Hence, given their function within the hypothalamic try, agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
It is also well-established that metabolic diseases exert a negative influence on other physiological systems. Thus, there is often the co-development of multiple disease states (e.g. type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, n ance, lycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in "syndrome X") or es which clearly occur secondary to diabetes mellitus (e. g. kidney disease, peripheral neuropathy). Thus, it is expected that effective treatment of the ic condition will in turn be of benefit to such onnected disease states.
In some embodiments of the t invention the metabolic-related disorder is selected from type 2 es, hyperglycemia, hyperinsulinemia, ipidemia, hypertriglyceridemia, insulin resistance, type 1 es, idiopathic type 1 diabetes (type Ib), latent mune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth- onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, cardiovascular disease, coronary heart disease, vascular restenosis, osis, osis after angioplasty, peripheral vascular disease, claudication, intermittent cation, cell death associated with myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, randial lipemia, conditions of impaired glucose tolerance (IGT), impaired glucose metabolism, conditions of impaired glucose metabolism, conditions of impaired fasting plasma e, metabolic acidosis, ketosis, arthritis, obesity, orosis, ension, congestive heart failure, left ventricular hypertrophy, peripheral al disease, ic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transient ischemic attacks, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, tive s, endothelial dysfunction, and impaired vascular compliance.
It will be appreciated that the treatment methods of the invention are useful in the fields of human medicine and veterinary medicine. Thus, the individual to be treated may be a mammal, preferably human, or other animals. For veterinary es, individuals include but are not d to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
The ion also relates to a method of ng diabetes in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention.
In addition, the compounds described herein may be used for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a general term describing any hardening of medium or large es. Atherosclerosis is a ing of an artery specifically due to an atheromatous plaque.
Further the compounds described herein may be used for the treatment of glomerulonephritis. ulonephritis is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli. It may be asymptomatic, or present with hematuria and/or proteinuria. There are many recognized types, divided in acute, te or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.
Additionally, the compounds described herein may be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune tis, coeliac disease, Crohn's e, diabetes mellitus (type 1), goodpasture's syndrome, graves' disease, guillain-barre syndrome (GBS), hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus me (OMS), optic neuritis, ord's thyroiditis, Ostheoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, reiter's syndrome, takayasu‘s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, chagas1 disease, c fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, dosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, icitis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, , pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, titis, pyelonephritis, is, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, s, vaginitis, vasculitis, or vulvitis.
The invention also relates to a method of treating a cardiovascular disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention. Examples of cardiovascular conditions include, but are not limited to, atherosclerosis, osis, ar occlusion and carotid obstructive disease.
The invention further provides methods of ting GPR119 activity by ting a GPR119 or with an amount of a compound of the invention sufficient to modulate the activity of the GPR119. Modulate can be inhibiting or activating GPR119 activity. In some embodiments, the invention provides methods of agonizing GPR119 activity by ting a GRP119 receptor with an amount of a compound of the ion sufficient to activate the activity of the GPR119 receptor. In some embodiments, the invention provides methods of agonising in a solution by contacting said solution with an amount of a compound of the invention sufficient to activate the activity of the GPR119 receptor in said solution. In some embodiments, the ion es methods of agonizing 2012/041632 GPR119 activity in a cell by contacting said cell with an amount of a compound of the invention sufficient to activate the activity of GPR119 receptor in said cell. In some ments, the invention provides methods of agonizing GPR119 activity in a tissue by contacting said tissue with an amount of a compound of the invention sufficient to activate the activity of GPR119 receptor in said tissue. In some embodiments, the invention provides methods of agonizing GPR119 activity in a organism by contacting said sm with an amount of a compound of the invention sufficient to activate the activity of GPR119 receptor in said organism. In some embodiments, the invention provides methods of agonizing GPR119 activity in a animal by contacting said animal with an amount of a compound of the ion ient to activate the activity of GPR119 receptor in said animal. In some embodiments, the invention es methods of ing GPR119 activity in a mammal by contacting said mammal with an amount of a compound of the invention sufficient to activate the activity of GPR119 receptor in said mammal. In some embodiments, the invention es methods of ing GPR119 activity in a human by contacting said human with an amount of a compound of the invention sufficient to te the ty of GPR119 receptor in said human.
COMBINATION TREATMENT The present invention also provides methods for combination therapies in which is an agent known to modulate other pathways, or other components of the same pathway, or even pping sets of target enzymes or receptors are used in combination with a compound of the present invention. In one aspect, such therapy es but is not limited to the combination of the subject compound with other agents such as known antidiabetic, anti-obesity agents or any other agents use for the treatment of metabolic disorders to provide a synergistic or additive eutic .
In the context of the present invention, a compound as described herein or a pharmaceutical composition thereof can be utilized for modulating the activity of GPR H9 receptor related diseases, conditions and/or disorders as described herein. Examples of modulating the activity of GPRl l9 receptor related diseases include the treatment of metabolic related disorders. lic related disorders include, but are not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes, and ions associated therewith, such as, but not limited to coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, claudication, intermittent claudication, cell death associated with myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma e, metabolic acidosis, s, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, strual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, dial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, n resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, elial dysfunction and impaired vascular compliance. In some embodiments, metabolic related disorders e type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and me X. Other examples of modulating the activity of GPRl l9 receptor related diseases include the treatment of obesity and/or overweight by decreasing food intake, inducing satiation (i.e., the feeling of fullness), controlling weight gain, sing body weight and/or affecting metabolism such that the recipient loses weight and/or maintains weight.
While a compound of the invention can be administered as the sole active pharmaceutical agent (i.e., herapy), the compound can also be used in combination with one or more ceutical agents (i.e., combination-therapy) either administered together or separately for the ent of the diseases / conditions / disorders described herein. Therefore, another aspect of the t invention includes methods of treatment of a lic related disorder, including a weight related disorder, such as obesity, comprising administering to an individual in need of prophylaxis and/or ent a therapeutically effective amount of a compound of the t invention in combination with one or more additional pharmaceutical agent as described .
Suitable pharmaceutical agents that can be used in ation with the compounds of the present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A) agonists, nin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic , B3 rgic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogues, cannabinoid 1 receptor antagonists [for example, SR141716: N-(piperidin-l-yi)(4- phenyl)-l-(2,4-dichlorophenyl)methyl-lH-pyrazolecarboxamide], melanin trating e antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e., Orlistat), tic agents (such as a bombesin t), eptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin or antagonists, urocortin binding protein nists, on- like peptide- 1 receptor agonists, ciliary neutrotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic agents (for example, phentermine, mazindol and the like) and appetite suppressants (for example, bupropion).
Other besity agents, including the agents set forth infra, are well known, or will be y apparent in light of the instant disclosure, to one of ordinary skill in the art.
It is understood that the scope of combination-therapy of the compounds of the present invention with other anti-obesity agents, anorectic agents, appetite suppressant and related agents is not limited to those listed above, but includes in principle any combination with any ceutical agent or pharmaceutical composition useful for the treatment of overweight and obese individuals.
It is understood that the scope of combination-therapy of the compounds of the present invention with other pharmaceutical agents is not limited to those listed herein, supra or infra, but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of es, conditions or disorders that are linked to metabolic related disorders.
Some ments of the present invention include methods of treatment of a disease, disorder, condition or cation thereof as described herein, comprising administering to an individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention in combination with at least one pharmaceutical agent selected from the group consisting of: ylureas (for example, glyburide, glipizide, glimepiride and other ylureas known in the art), inides (for e, repaglinide, nateglinide and other meglitinides known in the art), biguanides (for example, biguanides include phenformin, metformin, buformin, and biguanides known in the art), (x-glucosidase inhibitors [for example, se, -dihydroxypropyl)valiolamine ic name; voglibose), miglitol, and (x-glucosidase inhibitors known in the art], peroxisome proliferators- activated receptor-y (i.e.,PPAR-y) agonists (for example, rosiglitazone, pioglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501516 and PPAR-y agonists known in the art), insulin, insulin analogues, HMG-CoA reductase inhibitors (for example, rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, atin, cerivastatin, statin, pitavastatin, BMS‘s "superstatin", and HMG-CoA reductase inhibitors known in the art), cholesterol-lowering drugs (for example, fibrates that include: bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, and fibrates known in the art; bile acid sequestrants which include: cholestyramine, colestipol and the like; and niacin), antiplatelet agents (for example, aspirin and adenosine phate receptor antagonists that include: clopidogrel, ticlopidine and the like), angiotensin- ting enzyme tors (for example, captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, opril, opril, quinapril, spirapril, temocapril, trandolapril, and angiotensin converting enzyme inhibitors known in the art), angiotensin II receptor antagonists [for e, losartan (and the potassium salt , angiotensin II receptor antagonists known in the art, adiponectin, squalene synthesis inhibitors (for example, -[bis[2,2-dimethyl-l-oxopropoxy)methoxy] phosphinyl]phenoxybenzenebutanesulfonic acid, mono potassium salt (BMS- 188494) and squalene synthesis inhibitors known in the art), and the like. In some embodiments, compounds of the present invention and the pharmaceutical agents are administered separately. In further embodiments, compounds of the present ion and the pharmaceutical agents are administered together.
Suitable pharmaceutical agents that can be used in conjunction with nds of the present invention include, but not limited to, amylin agonists (for example, pramlintide), insulin secretagogues (for example, GLP-I agonists; exendin-4; insulinotropin (NN2211); acyl CoA cholesterol acetyltransferase inhibitors (for example, ezetimibe, eflucimibe, and like compounds), cholesterol absorption inhibitors (for example, ezetimibe, pamaqueside and like compounds), cholesterol ester transfer protein inhibitors (for e, CP-529414, JTT-705, CETi-I, and like compounds), microsomal triglyceride transfer protein inhibitors (for example, implitapide, and like nds), cholesterol modulators (for e, NO- 1886, and like compounds), bile acid modulators (for example, GT103-279 and like compounds), insulin signaling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructosephosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucosephosphatase (G6Pase), inhibitors of fructose- 1,6-bisphosphatase (F-l,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate ykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, tors of gastric ng, (x2- adrenergic antagonists, retinoid X receptor (PVXR) agonists, and dipeptidyl peptidase-4 (DPP-IV) inhibitors.
In accordance with the present invention, the combination can be used by mixing the respective active components, a nd of the present invention and pharmaceutical agent, either all together or independently with a physiologically acceptable carrier, excipient, binder, diluent, etc., as described herein above, and administering the e or es either orally or ally as a pharmaceutical ition. When a compound or a mixture of compounds of the present invention are administered as a combination y with r active compound the therapeutic agents can be formulated as separate pharmaceutical compositions given at the same time or at different times; or the compound or a mixture of compounds of the present invention and the therapeutic agent(s) can be formulated together as a single unit dosage.
Further eutic agents that can be combined with a subject compound may be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by n, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.
The compounds described herein can be used in ation with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the compounds of the invention will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein may be administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
That is, a compound described herein and any of the agents bed above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In r alternative, a nd of the present invention can be administered just followed by and any of the agents described above, or vice versa. In the separate administration protocol, a compound of the t ion and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart.
The methods in accordance with the invention may include administering a GPR 119 agonist with one or more other agents that either enhance the activity of the agonist or ment its activity or use in treatment. Such additional factors and/or agents may produce an augmented or even synergistic effect when administered with a GPR 119 agonist, or minimize side effects.
The following general ology described herein provides the manner and s of making and using the compound of the present invention and are illustrative rather than limiting. Further cation of provided ology and onally new methods may also be devised in order to achieve and serve the purpose of the invention. Accordingly, it should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the specification hereto.
Representative compounds of the present invention include those specified above in Table 1 and pharmaceutically acceptable salts thereof. The present invention also includes the ediate compounds discussed in the examples and elsewhere in the specification as well as their salts. The present invention should not be construed to be limited to them.
GENERAL METHOD OF PREPARATION OF COMPOUNDS OF THE INVENTION The compounds of the present invention may be prepared by the following processes. Unless otherwise ted, the variables (e.g. Z, X, X1, X2, X3, X4, Cy, L and Ar) when used in the below formulae are to be understood to present those groups described above in relation to a (A) and (B).
Scheme 1: This scheme provides a method for the preparation of a compound of formula (A) wherein L2 is absent, NH or O, X is N, Z is NR or O and other variables such as Cy, X1, X2, X3, X4, and are the same as bed above in relation to formula (A). L2 is shown as L in the scheme below.
Scheme 1 X1 O / 1 N Hal ii + H0 —> Cy X / o 3 3\ PPA,180 C Hal/)|(|"/ \X4 Z ZH Cy l 2 Base Pd(PPh3)4, K2003, 1 ,4-Dioxane, reflux Ar\L:—:: IX\>—Cy A ”2/X3\::E:\>—Cy A compound of formula (1) wherein Hal represent halogen and Z is NH or O can be coupled with a compound of formula (2) in the presence of a suitable poly phosphoric acid at a sufficiently high temperature to give a compound of (3). The compound of a (3) can then be coupled with a compound of formula Ar-B(OH)2 in the presence of a st, such as Palladium tetrakis triphenylphosphine, and a suitable base, such as potassium carbonate, to give the desired compounds of formula (A), i.e wherein L is absent X is N, Z is O or NR and other variables are the same as described above in relation to formula (A).
Similarly, the ponding compound of formula (3) can be coupled with a compound of the formula Ar—NH2 or Ar—OH in the presence of a suitable base, such as ium ate, to give the desired compounds of formula (A), wherein L is NH or O, X is N, Z is O or NR and other variables are the same as described above in relation to formula (A).
Illustration: 2012/041632 Br NH2 NH2 HO>—<:N—H—>PPA 180 OC IPA» DiPEA Boc—anhydride H3002$ A< Pd<PPhg)4, K2003, A( N O 1,4-Dioxane, reflux Br N O \ \ F 0 *CN4 Hscozs N N>—<:N_\< O O H B/OH H F OH Scheme 2: This scheme provides a method for the preparation of a compound of formula (A-I) wherein L1 and L2 are , X is N, Z is O, D is CH, E is N and other variables such as R“, X1, X3 and X4 are the same as bed above in relation to formula (A-I).
Scheme2 _ R] Rk RiRj RkR Hal X1 XH R' R' T o + N—H X3 / Hakij: PPA, 180 0 X4 OH HO C Rh X4 Re f 9R Rf Rg :R R 1a 2a R5-Lg IPA DiPEA _ R1 Rk Rj Rk R' R' Ri RI ArYX1\ X H Hal X1 X| 19—0 E—R5 \f j:\X N-R5 3x4 2 ReHRh Pd(PPh3)4,K2CO3, sz/ o Rh 4 Rr 14-Dioxane reflux Re R9 1 1 Rf Rg A-l 4 A compound of formula (la) wherein Hal represents halogen can be coupled with a nd of formula (23) in the presence of a suitable poly phosphoric acid at a sufficiently high temperature to give a compound of formula (33). The compound of formula (33) can then be d with a compound of formula RS-Lg (Where Lg represents a leaving group) in the presence of a suitable base such as diisoprpyl amine to give a compound of formula (4).
The compound of formula (4) can then be coupled with a compound of a Ar-B(OH)2 in the presence of a catalyst, such as Palladium tetrakis triphenylphosphine, and a suitable base, such as potassium carbonate, to give the desired compounds of formula (A-I), Where X is N Z is O, D is CH, E is N and other variables are the same as described above in relation to formula (A-I).
WO 70867 ration: Br NH2 OH HO PPA 180 °C CH‘NE? IPA, DiPEA chozs 0 Pd(PPh3)4, K2003, 1,4-Dioxane, reflux N N | ‘— O F 0 amO N gym N N . VI OH N Scheme 3: This scheme provides a method for the preparation of a compound of formula (A-II) wherein L1 and L2 are absent, X is N, Z is O, D is CH, E is N and other variables such as R“, X1, X2 and X4 are the same as described above in relation to formula (A-II) Scheme3 _ Rj Rk RiRj RkR Hal x4 XH R' R' T o + N—H X2. / 0X2HaIWXI x1 OH HO C Rh PPA 180 x: Re f QR Rf Rg R 1b 2b :R IPA, DiP:Aj:R5-I_g - RJ Rk Rj Rk R' R' - ArYX4‘ 71—? R' R| X Hal X4 x X| j: \>—D E—R5 \W I \ N—R5 2-X z eHRh Pd(PPh3)4,KZCO3, X2.X/ o 1 R 1 Re Rh Rf R9 14D'- onane, reflux , Rf R9 A-ll 4a A compound of formula (1b) wherein Hal represent halogen and Z is NH or O can be coupled with a nd of a (2b) in the presence of a suitable poly phosphoric acid at a sufficiently high temperature to give a compound of a (3b). The nd of formula (3b) can then be coupled with a compound of formula RS-Lg (Where Lg is a leaving group) in the presence of a suitable base such as diisoprpyl amine to give the compound of formula (43). The compound of formula (43) can then be coupled with a compound of formula Ar—B(OH)2 in the presence of a catalyst, such as Palladium tetrakis triphenylphosphine, and a suitable base, such as potassium carbonate, to give the desired compounds of formula (A-II), X is N Z is O, D is CH, E is N and other variables are the same as bed above in relation to a (A-II).
Scheme 3A: This scheme provides a method for the preparation of a compound of formula (A-II) n L1 and L2 are absent, X is CH, Z is O, D is CH, E is N and other variables such as R“, X1, X2 and X4 are the same as described above in relation to formula (A-II).
Scheme 3A trisopropyl borate Ar Base n-BuLi 0 ! -o 5% IRj Rk Ar x4 X RHR Ar \xfi J:\>—D E—R5<— \ / N—Boc 2‘X1 Z 0 Re Rh Rf R9 A compound of formula (1d) can be coupled with a compound of formula (2c) in the presence of catalyst, such as Palladium tetrakis triphenylphosphine, and a suitable base, such as potassium carbonate, to give a compound of (3c). The compound of formula (3c) can then be lithiated followed by ent with triisopropyl borate to give the compound of formula (4b). The compound of formula (4b) can then be coupled with a compound of formula (4c) to give a compound of formula (53) which can then be reduced using suitable reducing agent to give the desired compounds of formula (A-II) wherein X is C, Z is O, D is CH, E is N and all the other variables are the same as described above in relation to formula (A-II).
Illustration: F O H2NOC I Br Pd catal st 0 Base 0 \ O O trisopropylborate n-BuLi F +0 16h, RT H2NOC N / Q‘s—OF0. F FXF H2NOC \ / N—Boc <— O O \ B(OH)2 Scheme 4: This scheme provides a method for the preparation of compound of a (B) wherein L1 is absent, NH or O, X is N, Z is NR or 0, L2 is absent and other les such as Ar, Cy, X1, X2, X3 and X4 are the same as described above in relation to formula (B).
Scheme4 Step-1 x/Xx ° X1 x; \ Hal in? j: + HQ —> Hal—T/ “\> Ar X3\X/ PPA,180°C ZH Ar 3\X4 2 1 5 6 Step-2 X X / 1 N C / 1 X 2‘2 \ \ CyLH y\ >l<g \ \ / Hal-T Ar _> L1 .. L2 3‘X4/ Base 2 X3\X4/ 2 X1 X/ 0\ \ X2/ \ X\H Cv—If ,BT c-_. / \>—L2 z x, 0 X3\ / 2 X4 Pd(PPh3)4, K2003, 1 ,4-Dioxane, reflux A compound of formula (1) wherein Hal represent halogen and Z is NH or O can be coupled with a compound of formula (5) in the presence of poly phosphoric acid at a sufficiently high temperature to give a compound of formula (6). The compound of formula (6) can then be d with a compound of formula Cy-NHZ or Cy-OH in the presence of a suitable base, such as potassium carbonate, to give the desired compounds of formula (B) wherein L1 is NH or O, X is N, Z is O or NR and other variables are the same as described above in relation to formula (B). ately, the compound of formula (6) can be converted to compound of formula (63) using 4,4,4‘,4‘,5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) under Suzuki ng conditions. The compound of a (63) can then be coupled with a compound of formula Cy-Lg (wherein Lg is an leaving group) in the presence of a catalyst, such as Palladium is triphenylphosphine, and a suitable base, such as potassium carbonate, to give the desired compounds of formula (B), i.e wherein L1 is absent, X is N, Z is O or NR and other variables are the same as described above in relation to formula (B).
Illustration: 802:} H???50ch3 B\©:NN>—©78020H3fa 8020H 3 PPA, 180 0C ;@ 0 N\jLOTf Pd(PPh3)4, K2003, ii 14-Dioxane reflux N >Lo N\ 02W F 30ch3 I N \ Hydrogenation SOZCHg Scheme 5: This scheme provides a method for the preparation of a compound of formula (B-I) wherein L1 and L2 are absent, X is N, D is CH, E is N, Z is O and other variables such as R“, X1, X3 and X4 are the same as described above in on to formula (B-I).
Scheme 5 WO 70867 Hal X1 XH Hal XL X r / + fl XI 1H 3'X4 OH 0°C 3'X4 0 1b 5 6 Suzuki coupling R Rl k .
RJRi 3)4, K2003, Pg\N ‘ 1,4-Dioxane, reflux (a H \H/ 13[5 X1 X Ar 0/ T L -RJ' Rk Rhgfex./o X\>_A r R R R R' R' 3 x/ X 3. 4 o ,1 X4 8 LgO ’ N-Pg Rh 6c Rf R9 R' Rk ,- .
RS‘E r P9\N i. Deprotection WD X1 X HDYXK X\ \||/ J: \>—Ar I 0) Ar ii. Coupling HRng Re Xa~ / Z A compound of formula (1b) wherein Hal represents halogen can be coupled with a compound of formula (5) in the ce of poly phosphoric acid at a sufficiently high temperature to give a compound of formula (6b). The compound of formula (6b) can then be converted to a compound of formula (6c) using Suzuki coupling. The compound of formula (6c) can then be coupled with a compound of formula (7) (wherein Pg is a protecting group) using palladium tetrakis triphenylphosphine and a suitable base, such as potassium carbonate, to provide a compound of a (8). The compound of formula (8) can then be subjected to hydrogenation to give the compound of formula (9). The compound of formula (9) can then be de-protected followed by coupling with a nd of formula Rs-Lg wherein Lg is a leaving group to give the desired compounds of formula (B-I).
Illustration: WO 70867 Br N Br NH2 0 \ so CH 50ch3 2 3 + o OH HO PPA, 180 0c: Pd(PPh3)4 K2003 3249 F 14—Dioxane reflux O’B N socha U; ow SOzCHs ‘HydrogenationlDeprotection HOUZF>3 IPA DIPEA/T\91%: 30ch3 / CHg Scheme 6: This scheme provides a method for the preparation of a compound of formula (B-II) wherein L1 and L2 are absent, X is N, D is CH, E is N, Z is O and other variables such as R“, X1, X2 and X4 are the same as described above in relation to formula (B-II).
Scheme6 Hal XH Hal X4~ X \r X4\XI + Ar-COOH —> / XI j: >_Ar 2’X1 0 OH PPA,18000 2‘X1 1c 5 6 Suzukl coupllng R R| k .
RJRI Pd(PPh3)4, K2003, P9\N ‘ \ X X 1,4-Dioxane, reflux (I) . O/BYX4 \>—A X2 I: P9\Hwy/A —>"i. Derotection Mr 1%X r "”'COUplmg' H R Rg f Re X / 2, Z RhRQRfRe X2~X/ O X1 Illustration: 2012/041632 N OH HO F \ N\ OHO I Br + F —> I / / 5h,—>reflux Br NH2 0 F Br H |:>oc:|3 Pd cat. 105°C,15h (3333' BOogfi % Pd/C stirr under H2 re Boc\ A compound of a (1c) wherein Hal represents halogen can be coupled with a compound of formula (5) in the presence of a suitable poly phosphoric acid at sufficiently high temperature to give a nd of formula (6d). The nd of formula (6d) can then be converted to compound of formula (6e) using Suzuki coupling. The compound of formula (6e) can then be coupled with a compound of formula (7) using palladium tetrakis triphenylphosphine and a suitable base, such as ium carbonate, to provide a compound of formula (83). The compound of formula (83) can then be ted to hydrogenation to give the compound of formula (93). The compound of formula (93) can then be de-protected followed by coupling with a nd of formula RS-Lg wherein Lg is a leaving group to give the desired compounds of formula (B-II).
Similar methodologies with certain modifications as known to those skilled in the art can be used to synthesize compounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), A), (B-IVA), (B-IB) (B-IIB), (B-IIIB), (B- IVB), and (B-V) wherein all the variables are to be understood to present those groups described above in relation to formula (A) 01' (B) using suitable intermediates and reagents.
EXPERIMENTAL Unless otherwise ned, work-up refers to distribution of a reaction mixture between the aqueous and organic phases indicated within parenthesis, separation and drying over NaZSO4 of the organic layer and evaporating the t to give a residue. Unless WO 70867 ise stated, purification refers to column chromatography using silica gel as the stationary phase and a mixture of petroleum ether (boiling at 60-80°C) and ethyl acetate or dichloromethane and methanol of suitable polarity as the mobile phases. RT lly refers to ambient temperature (25-28°C).
Intermediates Br N Br N Br _ F N U\>—<:/\N-BocNN H H o’ $02Me H Intermediate 2 Intermediate 4 Intermediate 1 ediate 3 8(2wa Br N _ Br N Intermediate 6 flu:m Intermediates Intermediate 7 Intermediate 8 Br(wow0 Br\CE />—<::N—BocN0 Br N Br N\>—<:N-Boc N O O Intermediate 9 F Intermediate 12 Intermediate 10 Intermediate 11 Br(lawN 0 BrUEHN0 o 0 OiPr .249,B o O OiPr Intermediate 13 N/>—<3N OiPr Intermediate 15 Intermediate 16 Br—< E>—<\ HZNOC N’N l F O0 Intermediate 17 Intermediate 20 HZNOC O H2NOC ] BFUOHO o awn0N O \ 0 Intermediate 24 Intermediate 21 Intermediate 22 F F Br Br U\N UN\ 802Me $02Me H Intermediate 28 Intermediate 25 Intermediate 26 Intermediate 27 F 7%: F Q P Br N F o o’E N \ SOzMe N 802Me \ $02Me o’ 0 o \ NH 802Me Intermediate 29 o F Intermediate 32 Intermediate 30 Intermediate 31 F F F s Br S F SO2Me U/ 802Me f: o’ s Br NH N , $02Me N Br>‘:\<BNH $02Me ediate 33 Intermediate 34 rO Intermediate 35 Intermediate 36 F F Br N NH 802Me 802Me 802Me U\ S 7%fiewe BrU/0 N Br S F Intermediate 38 Intermediate 40 ediate 39 Intermediate 37 7*mew BrUK»0N 724B0O, N Intermediate 41 Intermediate 43 0 Intermediate 44 ediate 42 Br 7240éo’ B00 UKM0 \ N 0 , CHF2 N Intermediate 46 N Intermediate 48 CHF; Intermediate 47 Intermediate 45 Boc~N Boc\N B0C \ Boc \ N N O I I C N\>_NH2 N N \>—NH2 N\>_Br Intermediate 49 0 0 0 Intermediate 50 Intermediate 51 Intermediate 52 BrUOHNH BrUKM0 / NJKQ N Br GAO H Intermediate 54 CF3 CF3 Intermediate 55 Intermediate 56 Intermediate 53 BrU \ N / \>—©7CF3 N 0 Intermediate 57 VXEU:K» Intermediate 58 Intermediate 1: 5-Br0m0(piperidinyl)-1H-benz0[d]imidazole: 4- bromobenzene-1,2-diamine (1.43 g, 7.64 mmol) and piperidinecarboxy1ic acid (0.99 g, 7.64 mmol) were dissolved in polyphosphoric acid (20 g). This e was heated at 190 0C for three and half hours. on mixture cooled to It and diluted with water (100 ml).
Aqueous layer basified with sodium hydroxide pellets to pH 14. Solid was filtered, washed with ol and dried to obtain the title compound (1 g) as a dark brown solid. ediate 2: 5-Br0m0(1-(5-ethylpyrimidinyl)piperidinyl)-1H- benz0[d]imidazole: Intermediate 1 (500 mg, 1.69 mmol) and 2-chloroethylpyrimidine (264 mg, 1.86 mmol) were dissolved in propanol (25 ml). To this mixture N,N— Diisopropylethyl amine (1.8 ml, 10.1 mmol) added and stirred at 90 0C for 12 h. After completion of the on, propanol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOET and Petether (40:60) as eluent to afford the titled compound (0.2 g) as a pale-yellow solid.
Intermediate 3: 2-[2-Flu0r0(methylsulfonyl)phenyl]-4,4,5,5- tetramethyl-1,3,2-di0xab0rolane:1-bromofluoro(methylsulfonyl)benzene (900 mg, 3.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.15 g, 4.5 mmol) and potassium acetate (1.13 g, 11.48 mmol) were dissolved in e (30 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (85 mg, 0.1 mmol). This mixture stirred at 105 0C for 12 h. on mixture diluted with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (20:80) to afford the titled compound (900 mg) as a white solid. 1H-NMR (8 ppm, CDC13, 400 MHz): .92 (m, 1H), 7.70 (dd, J 1.4, 7.7, 1H), 7.60 (dd, J 1.2, 8.1, 1H), 3.05 (s, 3H), 1.37 (s, 12H).
Intermediate 4: Tert-butyl romo-1H-benzo[d]imidazol yl)piperidinecarb0xylate: Intermediate 1 (200 mg, 0.68 mmol) was dissolved in DCM (40 ml) and added TEA (0.2 ml, 0.68 mmol). Reaction mixture cooled to 0 0C and added di- tert-butyl dicarbonate (0.2 ml, 0.68 mmol). Reaction mixture stirred at 0 0C for 2 h. After completion of the reaction, reaction mixture washed with water, DCM layer dried over NaZSO4 and removal of DCM afforded the crude. Crude was purified by combiflash using AcOEt and er (35: 65) as eluent to afford the titled compound (60 mg) as a brown solid.
Intermediate 5: 5-Bromo(piperidinyl)benz0[d]0xazole: 2-amino bromophenol (1.2 g, 5.8 mmol) and piperidinecarboxylic acid (0.74 g, 5.8 mmol) were dissolved in polyphosphoric acid (30 g). This e was heated at 190 0C for three and half hours. Reaction mixture cooled to rt and diluted with water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (AcOEt/H20) followed removal of AcOEt afforded the titled compound (0.8 g) as a pale-yellow gummy solid.
Intermediate 6: S-Bromo-Z-[1-(S-ethylpyrimidin-Z-yl)piperidin yl]benz0[d]0xazole: Intermediate 5 (800 mg, 2.85 mmol) and 2-chloroethylpyrimidine (447 mg, 3.14 mmol) were ved in propanol (25 ml). To this mixture N,N— Diisopropylethyl amine (3.1 ml, 17.12 mmol) added and stirred at 90 0C for 12 h. After completion of the reaction, propanol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (80 mg) as a pale-yellow solid. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72 (d, J 13.6, 2H), 3.27-3.11 (m, 3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J 2.6, 13.1, 2H), 2.02-1.90 (m, 2H), 1.19 (t, J 7.6, 3H).
Intermediate 7: Tert-butyl 4-(5-bromobenzo[d]0xazolyl) piperidine-l- carboxylate: Intermediate 5 (500 mg, 1.78 mmol) was dissolved in DCM (30 ml) and added TEA (180 mg, 1.78 mmol). Reaction mixture cooled to 0 0C and added di-tert—butyl dicarbonate (388 mg, 1.78 mmol). Reaction mixture stirred at 0 0C for 1 h. After completion of the reaction, on mixture washed with water, DCM layer dried over NaZSO4 and removal of DCM afforded the crude. Crude was purified by combiflash using AcOEt and Petether (8: 92) as eluent to afford the titled compound (150 mg) as an ite solid.
Intermediate 8: tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)benz0[d] yl)piperidinecarb0xylate: Intermediate 7 (1.8 g, 6.6 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.2 g, 8.6 mmol) and potassium acetate (2.1 g, 21.8 mmol) were dissolved in dioxane (20 ml) under N2 atmosphere. This mixture was ed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (210 mg, 0.26 mmol). on e was stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up /H20) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (10:90) as eluent to afford the titled compound (1.3 g) as a brown solid.
Intermediate 9: 6-br0mo(piperidinyl)benzo[d]oxazole: 2-amino henol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190 0C for 3 h. After 3 h, reaction mixture cooled to It and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H20) followed by l of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification.
Intermediate 10: tert-butyl 4-(6-br0m0benzo[d]oxazolyl)piperidine carboxylate: Intermediate 9 (500 mg, 1.77 mmol) was dissolved in DCM (20 mol), cooled to 0 0C and added TEA (0.25 ml, 1.77 mmol). To this mixture (Boc)zO (0.4 ml, 1.77 mmol) was added and stirred at rt for 3 h. At this stage, reaction mixture diluted with water and extracted with DCM. DCM removed on pour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (7.5%) as eluent to obtain the title compound (500 mg). 1H-NMR (8 ppm, CDC13, 400 MHz): 7.65 (d, J 1.6, 1H), 7.53 (d, J 8.4, 1H), 7.43 (dd, J 1.7, 8.4, 1H), 4.13 (d, J 9.9, 2H), 3.17-3.05 (m, 1H), 2.97 (t, J 12.6, 2H), 2.20-2.08 (m, 2H), 1.96- 1.82 (m, 2H), 1.47 (s, 9H).
Intermediate 11: 5-br0m0flu0r0(piperidinyl)benz0[d]0xazole: 2- aminobromofluorophenol (1.7 g, 8.24 mmol) and isonipecotic acid (1.06 g, 8.24 mmol) were dissolved in polyphosphoric acid (28 g). This mixture was heated to 195 0C for 3 h.
After 3 h, reaction mixture cooled to It and basified with aqueous NaOH solution to pH 14.
Solid that obtained was ed and dried to obtain the title compound (1.3 g) as a brown solid.
Intermediate 12: Tert-butyl 4-(5-br0mofluorobenzo[d]oxazolyl) piperidinecarb0xylate: Intermediate 11 (1.3 g, 4.36 mmol) was dissolved in DCM (40 mol), cooled to 0 0C and added TEA (1.2 ml, 8.72 mmol). To this mixture (Boc)zO (950 mg, 4.36 mmol) was added and stirred at rt for 3 h. At this stage reaction mixture diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by ash using EtOAc and Petether (10:90) as eluent to obtain the title compound (200 mg) as a brick brown solid.
Intermediate 13: Isopropyl 4-(5-bromobenzo[d]oxazolyl)piperidine carboxylate: ediate 5 (980 mg, 3.31 mmol) was dissolved in DCM (50 mol) and added TEA (0.45 ml, 3.31 mmol). Reaction mixture cooled to 0 0C, isopropylchloro formate (2.7 ml, 6.62 mmol) was added and d the reaction e for 3 h at It. Work up (DCM/H20) followed by column purification on 60-120 mesh silica gel using EtOAc and Petether (15: 85) as eluent afforded the titled nd (500 mg) as a pale-red solid.
Intermediate 14: Isopropyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan- 2-yl)benz0[d]0xaz01yl)piperidinecarb0xylate: Intermediate 7 (0.35 g, 0.95 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (0.31 g, 1.23 mmol) and potassium acetate (0.3 g, 3.14 mmol) were dissolved in e (20 ml) under N2 here. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (31 mg, 0.04 mmol). Reaction mixture was stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up /H20) afforded the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and Petether (20:80) as eluent to afford the titled compound (03 g) as a pale-red solid.
Intermediate 15: Isopropyl 4-(6-bromobenzo[d]oxazolyl)piperidine carboxylate: Intermediate 9 (1.3 g, 4.4 mmol) was ved in DCM (50 mol) and added TEA (1.22 ml, 8.8 mmol). Reaction mixture cooled to 0 0C, isopropylchloro forrnate (2.6 ml, 6.6 mmol) was added and stirred the reaction mixture for 3 h at rt. Work up (DCM/H20) followed by purification on combiflash using gradient e of EtOAc and Petether (15: 85) as eluent afforded the titled compound (510 mg) as a brown s liquid. ediate 16: Isopropyl 4-(6-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan- 2-yl)benz0[d]0xaz01yl)piperidinecarb0xylate: Intermediate 15 (0.51 g, 1.4 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (0.45 g, 1.8 mmol) and potassium acetate (0.4 g, 4.2 mmol) were ved in dioxane (20 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (45 mg, 0.05 mmol). Reaction mixture was stirred at 105 0C for 12 h. Reaction mixture d with water and work up (AcOEt/H20) afforded the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and Petether (15:85) as eluent to afford the titled compound (0.36 g) as a brown viscous liquid.
Intermediate 17: 5-(4-br0m0flu0r0phenyl)-1H-tetrazole: 2-Fluoro bromobenzonitrile (300 mg, 1.5 mmol) dissolved in EtOH, added sodium azide (320 mg, 4.9 mmol), Zinc de (240 mg, 1.8 mmol). This mixture was stirred refluxed for 38 h. Work up (EtOAc/H20) afforded the crude. Crude was washed with petether to obtain the titled compound (120 mg) as a white solid. 1H-NMR (8 ppm, DMSO-dg, 400 MHz): 7.89-7.79 (m, 1H), 7.59 (dd, J 1.6, 10.04, 1H), 7.45 (dd, J 1.8, 8.3, 1H).
Intermediate 18: 5-Br0mo[1-(5-flu0r0pyrimidinyl)piperidin yl]benzo[d]0xazole: Intermediate 5 (1 g, 3.4 mmol) and 2-Chlorofluoropyrimidine was dissolved in panol (20 ml) and added N,N—diisopropylethyl amine (2.4 ml). This e was stirred at 900C for 90 mins. Isopropanol was d on rotavapour to obtain a residue. Work up (EtOAc/H20) followed by purification on combiflash using a nt mixture of EtOAc and er (7:93) as eluent afforded the titled compound as a pink solid.
Intermediate 19: 2-[1-(5-Flu0r0pyrimidinyl)piperidinyl](4,4,5,5- tetramethyl-1,3,2-di0xab0rolanyl)benzo[d]oxazole: Intermediate 18 (0.28 g, 1.74 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (0.24 g, 1.0 mmol) and potassium acetate (0.22 g, 2.2 mmol) were dissolved in dioxane (20 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (24 mg, 0.03 mmol). Reaction mixture was stirred at 105 0C for 12 h.
Reaction mixture diluted with water and work up (AcOEt/H20) afforded the crude. Crude was purified by column chromatography on 60-120 mesh silica gel using a gradient mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (0.15 g) as a pink solid.
Intermediate 20: 4-(Benzofuran-S-yl)flu0r0benzamide: Following the general procedure-1 the titled nd (200 mg) was obtained from 5-Bromobenzofuran (200 mg, 1 mmol) and 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (320 mg, 1.2 mmol) as a brown solid. 1HNMR (8 ppm, DMSO-dg, 400 MHz): 8.05 (d, J 2.2, 2H), 8.02 (bs, 1H), 7.76-7.72 (m, 1H), 7.70-7.65 (m, 3H), 7.64-7.58 (m, 3H), 7.01 (d, J 1.9, 1H).
Intermediate 21: 5-(4-carbamoylflu0rophenyl)benzofuran-Z-ylboronic acid: Intermediate 20 (100 mg. 0.4 mmol) was dissolved in THF (10 ml) and this mixture was cooled to -780C under N2 atmosphere. n-BuLi (0.5 ml, 1.3 mmol) was added to the above mixture and d at same temperature for 20 mins. Reaction mixture warmed to 00C and stirred for 2 hrs. After that trisopropyl borate (88 mg, 0.47 mmol) was added and stirred the reaction for 16 h at rt. on mass quenched with 2N HCl worked it up (EtOAC/HZO) to afford the titled compound (110 mg) as a crude. It was used in the next step without further purification.
Intermediate 22: 1-Benzyl-N-(5-br0m0hydr0xyphenyl)piperidine carboxamide: 1-Benzylpiperidinecarboxylic acid (29 g, 0.13 mol) dissolved in DCM (300 ml), cooled to 0 0C and added oxalyl chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to this mixture and strirred at It for 2 h. After 2 h, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtainl-benzylpiperidinecarbonyl chloride quantitatively. 2-Aminobromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 1-benzylpiperidinecarbonyl chloride (29 g, 0.12 mol) in DCM (100 ml).
After continuing stirring at rt for 2 h, DCM was removed on the rotavapour to obtain the titled compound (47.6 g), which was used in the next step without further purification.
Intermediate 23: 2-(1-Benzylpiperidinyl)br0m0benz0[d]0xazole: Intermediate 22 (47.6 g, 0.122 mol) was dissolved in xylene (500 ml) and added p- Toluenesulphonic acid (46 g, 0.24 mol). This mixture was refluxed for 20 h under a dean- stark ser. Xylene was removed and pH of the e was adjusted to 9 using aq NaHC03 solution. Work up (EtOAc/H20) afforded the crude. Crude was purified by column on 60-120 mesh silicagel using a gradient mixture of EtOAc and Petether (10:90) as eluent to afford the titled compound (11 g) as brown solid. ediate 24: 4-(2-(1-benzylpiperidinyl)benz0[d]0xazolyl) fluorobenzamide: Following the l procedure-3, the titled compound (4.8 g) was prepared from intermediate 23 (6g, 16.2 mmol) and 2-fluoro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)benzamide (4.7 g, 17.8 mmol) as a brown solid.
Intermediate 25: 2-Flu0r0(2-(piperidinyl)benz0[d]0xazol yl)benzamide: Intermediate 24 (100 mg, 0.23 mmol) dissolved in MeOH (10 ml) and added Pd/C (100 mg). This mixture was stirred under 60Psi hydrogen atmosphere in an autoclave for 16. After 16 h, reaction mass filtered through celite and celite was washed with MeOH.
MeOH was removed on rotavapour to obtain the titled compound (80 mg) as an off-white solid.
Intermediate 26: 5-Bromo[2-fluoro(methylsulfonyl)phenyl]-1H- benz0[d]Imidazole: obenzene-1,2-diamine (1.75 g, 9.39 mmol) and 2-fluoro lsulfonyl)benzoic acid (2 g, 9.39 mmol) were dissolved in osphoric acid (70 g).
This e was heated at 195 0C for three and half hours. Reaction mixture cooled to It and diluted with ice water (100 ml). Aqueous layer ed with sodium hydroxide pellets to pH 9. Work up (EtOAc/H20) ed by l of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (1.5 g) as an off-white solid.
Intermediate 27: 2-[2-Flu0r0(methylsulfonyl)phenyl](4,4,5,5- tetramethyl-1,3,2-di0xab0rolanyl)-1H-benz0[d]imidazole: Intermediate 26 (1.5 g, 4.1 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.34 g, 5.3 mmol) and potassium acetate (1.32 g, 13.5 mmol) were dissolved in dioxane (60 ml) under N2 here. This e was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (133 mg, 0.16 mmol). This mixture stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (33:67) to afford the titled compound (880 mg) as an off-white solid.
Intermediate 28: 5-Bromo[2-fluoro (methylsulfonyl)phenyl]benz0[d]0xazole: 2-Aminobromophenol (1.77 g, 9.4 mmol) and 2-fluoro(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were dissolved in polyposphoric acid (60 g). This mixture was heated at 195 0C for three and half hours. Reaction mixture cooled to It and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H20) followed by evaporation of EtOAc ed the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (2.8 g) as an off-white solid.
Intermediate 29: 2-[2-Flu0r0(methylsulfonyl)phenyl](4,4,5,5- ethyl-1,3,2-di0xab0rolanyl)benzo[d]oxazole: ediate 28 (2.8 g, 7.6 mmol) 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.5 g, 9.9 mmol) and potassium acetate (2.46 g, 25.08 mmol) were dissolved in dioxane (150 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (248 mg, 0.3 mmol). This mixture stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up /H20) afforded the crude. Crude was purified by combiflash using a nt mixture of AcOEt and Petether (33:67) to afford the titled compound (1 g) as an off-white solid.
Intermediate 30: 5-Br0m0flu0r0[2-flu0r0 (methylsulfonyl)phenyl]benz0[d]0xazole: 2-Aminobromofluorophenol (2.6 g, 9.7 mmol) and 2-fluoro(methylsulfonyl)benzoic acid (2.1 g, 9.7 mmol) were dissolved in polyposphoric acid (63.5 g). This mixture was heated at 195 0C for three and half hours.
Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H20) followed by evaporation of EtOAc afforded the crude. Crude (3.1 g) was used in the next step without further purification. ediate 31: 7-Flu0r0[2-flu0r0(methylsulfonyl)phenyl] (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)benz0[d]0xazole: Intermediate 30 (1.5 g, 3.87 mmol) 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (1.28 g, 5 mmol) and potassium acetate (1.25 g, 12.8 mmol) were dissolved in dioxane (20 ml) under N2 atmosphere. This mixture was ed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (126 mg, 0.15 mmol). This mixture stirred at 105 0C for 12 h. Reaction mixture d with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and Petether (18:82) as eluent to afford the titled compound (620 mg) as an off-white solid.
Intermediate 32: N-(4-Br0moflu0r0phenyl)flu0r0 (methylsulfonyl)benzamide: 2-Fluoro(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM (10 ml), cooled to 0 0C and added oxalyl chloride (1.2 ml, 13.8 mmol).
Catalytic amount of DMF was added to this mixture and strirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro(methylsulfonyl)benzoyl chloride quantitatively. ofluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogen here. This mixture stirred at It for 30 mins and added 2-fluoro lsulfonyl)benzoyl de (2.08 g, 8.84 mmol). After continuing stirring at It for 15 mins, reaction e diluted with water and extracted with DCM. DCM layer washed with aq. NaHC03 and DCM removed on pour to obtain the solil. Solid was triturated with EtzO and Petether mixture (4: 1) to obtain the titled compound (1 g) as a brown solid.
Intermediate 33: N-(4-Bromofluorophenyl)fluoro (methylsulfonyl)benzothioamide: Intermediate 32 (1 g, 2.56 mmol) dissolved in toluene (10 ml) and added P285 (0.57 g, 2.56 mmol). This e was refluxed for 18 h. Toluene WO 70867 removed on rotavapour to obtain the crude. Crude was purified by column chromatography on 60-120 mesh silicagel using EtOAc and Petether (20:80) as eluent to afford the title compound (500 mg) as a yellow solid. 1H-NMR (5 ppm, DMSO-dg, 400 MHz): 11.02 (s, 1H), 7.92-7.85 (m, 2H), 7.69 (dd, J 1.6, 8.1, 1H), 7.63 (dd, J 1.6, 9, 1H), 7.33-7.27 (m, 2H), 3.02 (s, 3H). ediate 34: 6-Bromo[2-fluoro (methylsulfonyl)phenyl]benz0[d]thiazole: Intermediate 33 (600 mg, 1.47 mmol) dissolved in DMF (7 ml) and added N32CO3 (156 mg, 1.47 mmol). This mixture stirred at 110 0C for 17 h. Work up (EtOAc/HZO) afforded the crude. Crude was triturated with Petether and dried to obtain the titled compound (360 mg) as a white solid. 1H-NMR (5 ppm, CDC13, 400 MHz): 8.71-8.65 (m, 1H), 8.13 (d, J 1.9, 1H), 8.01 (d, J 8.7, 1H), 7.91-7.83 (m, 2H), 7.66 (dd, J 1.9, 8.7, 1H), 3.12 (s, 3H). eidate 35: 2-[2-Flu0r0(methylsulfonyl)phenyl](4,4,5,5- tetramethyl-1,3,2-di0xab0rolanyl)benzo[d]thiazole: Intermediate 34 (360 mg, 0.94 mmol) 4,4,4‘,4‘,5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane) (300 mg, 1.2 mmol) and potassium acetate (300 mg, 1.2 mmol) were ved in dioxane (10 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (30 mg, 0.04 mmol). This mixture stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (12:88) as eluent to afford the titled compound (300 mg) as an off-white solid. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.74-8.69 (m, 1H), 8.46 (s, 1H), 8.14 (d, J 8.2, 1H), 7.97 (dd, J 1, 8.2, 1H), 7.91-7.83 (m, 2H), 3.12 (s, 3H), 1.38 (s, 12H).
Intermediate 36: N-(2,5-Dibromophenyl)fluoro (methylsulfonyl)benzamide: 2-Fluoro(methylsulfonyl)benzoic acid (1 g, 4.6 mmol) dissolved in DCM (15 ml), cooled to 0 0C and added oxalyl chloride (0.6 ml, 6.9 mmol). tic amount of DMF was added to this mixture and strirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and tilled the residue two times with DCM to obtain 2-fluoro(methylsulfonyl)benzoyl chloride quantitatively. 2,5-Dibromoaniline (0.9 g, 3.59 mmol) dissolved in DCM (10 ml) and added Pyridine (0.34 g, 4.30 mmol) under nitrogen atmosphere. This mixture d at rt for 30 mins and added o (methylsulfonyl)benzoyl chloride (1.01 g, 3.59 mmol). After continuing stirring at It for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq.
NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with EtzO and Petether mixture (4:1) to obtain the titled compound (1.6 g) as a brown solid. 1H-NMR (5 ppm, DMSO-dg, 400 MHz): 10.34 (s, 1H), 8.34-7.99 (m, 1H), 7.98-7.93 (m, 2H), 7.92-7.89 (m, 1H), 7.68 (d, J 8.6, 1H), 7.43 (dd, J 2.4, 8.6, 1H), 3.33 (s, 3H).
Intermediate 37: N-(2,5-Dibromophenyl)fluoro (methylsulfonyl)benzothioamide: Intermediate 36 (1.5 g, 3.34 mmol) dissolved in toluene (20 ml) and added P285 (0.74 g, 3.34 mmol). This mixture was refluxed for 18 h. Toluene removed on pour to obtain the crude. Crude was ed by column chromatography on 60-120 mesh gel using EtOAc and Petether (20:80) as eluent to afford the title compound (480 mg) as a yellow solid. 1H-NMR (5 ppm, DMSO-dg, 400 MHz): 12.26 (s, 1H), 7.94-7.83 (m, 3H), 7.78-7.72 (m, 2H), 7.55 (dd, J 2.3, 8.6, 1H), 3.32 (s, 3H).
Intermediate 38: 5-Bromo[2-fluoro (methylsulfonyl)phenyl]benz0[d]thiazole: Intermediate 37 (0.48 g, 1.03 mmol) dissolved in ylpyrrolidinone (0.97 ml) and added NaH (52 mg, 2.2 mmol). This mixture was stirred at 140 0C for 3 h. on mixture cooled to It and diluted with water to obtain the solid. Solid was filtered and dried to obtain the crude. Crude was purified on column chromatography using 60-120 mesh silicagel and DCM as eluent to afford the titled compound (260 mg) as a white solid. 1H-NMR (5 ppm, CDC13, 400 MHz): 8.71-8.66 (m, 1H), 8.32 (d, J 1.7, 1H), 7.92-7.83 (m, 3H), 7.59 (dd, J 1.8, 8.6, 1H), 3.13 (s, 3H).
Intermediate 39: 2-[2-Flu0r0(methylsulfonyl)phenyl](4,4,5,5- tetramethyl-1,3,2-di0xab0rolanyl)benzo[d]thiazole: ediate 38 (360 mg, 0.94 mmol) 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane) (220 mg, 0.88 mmol) and potassium acetate (220 mg, 2.2 mmol) were dissolved in dioxane (10 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (22 mg, 0.03 mmol). This mixture stirred at 105 0C for 12 h. on mixture diluted with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and er (12:88) as eluent to afford the titled compound (230 mg) as a yellow solid. 1H-NMR (5 ppm, CDC13, 400 MHz):8.73-8.67 (m, 1H), 8.62 (s, 1H), 7.98 (d, J 8, 1H), 7.90-7.81 (m, 3H), 3.12 (s, 3H), 1.39 (s, 12 H).
Intermediate 40: 0[2-flu0r0 (methylsulfonyl)phenyl]benz0[d]0xazole: 2-aminobromophenol (1.72 g, 9.2 mmol) and 2-fluoro(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) were dissolved in sphoric acid (30 g). This mixture was heated at 195 0C for three and half hours. Reaction mixture cooled to It and d with ice water (100 ml). Aqueous layer basified with sodium ide pellets to pH 9. Solid that formed was filtered and dried to obtain the crude. Crude was purified by combiflash using a gradient mixture of EtOAc and Petether (1:3) as eluent to afford the titled compound (450 mg) as a dark brown solid.
Intermediate 41: 2-[2-fluoro(methylsulf0nyl)phenyl](4,4,5,5- tetramethyl-1,3,2-di0xab0rolanyl)benzo[d]oxazole: Intermediate 40 (1.5 g, 4.1 mmol) 4,4,4‘,4‘,5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (1.35 g, 5.29 mmol) and potassium acetate (1.32 g, 13.45 mmol) were dissolved in dioxane (10 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (133 mg, 0.16 mmol). This mixture stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (AcOEt/H20) afforded the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and Petether (1:3) as eluent to afford the titled compound (500 mg) as a pink solid. ediate 42: N-(5-Br0m0hydr0xyphenyl) (trifluor0methyl)benzamide: 4-(Trifluoromethyl)benzoic acid (1 g, 5.3 mmol) dissolved in DCM (10 ml), cooled to 0 0C and added oxalyl chloride (0.7 ml, 7.9 mmol). Catalytic amount of DMF was added to this mixture and strirred at It for 30 mins. After 30 mins, DCM d on rotavapour and co-distilled the residue two times with DCM to obtain 4- (trifluoromethyl)benzoyl chloride quantitatively. 2-Aminobromophenol (0.8 g, 4.25 mmol) dissolved in DCM (20 ml) and added Pyridine (0.4 ml, 5.1 mmol) under nitrogen atmosphere.
This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (1.06 g, .1 mmol). After continuing stirring at rt for 15 mins, reaction mass d with water and extracted with DCM. DCM layer washed with aq. NaHC03 and DCM removed on rotavapour to obtain the solid. Solid was triturated with EtzO and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid. 1H-NMR (8 ppm, , g, 400 MHz): .15 (bs, 1H), 9.75 (s, 1H), 8.13 (d, J 8.1, 2H), 7.92-7.87 (m, 3H), 7.20 (dd, J 2.5, 8.6, 1H), 6.88 (d, J 8.6, 1H).
Intermediate 43: o[4-(trifluoromethyl)phenyl]benzo[d]0xazole: Intermediate 42 (1 g, 2.77 mmol) was dissolved in 1,4-Dioxane and added Phosphorus oride (0.76 ml, 8.3 mmol). This mixture was d for 2 h. 1,4-Dioxane d on pour to obtain the e. Residue was washed with water to obtain solid. Solid was filtered and dried to obtain the titled compound (630 mg) as an off-white solid. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.35 (d, J 8.2, 2H), 7.93 (d, J 1.5, 1H), 7.79 (d, J 8.3, 2H), 7.52- 7.49 (m, 2H).
Intermediate 44: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)(4- (trifluor0methyl)phenyl)benz0[d]0xazole: Intermediate 43 (630 mg, 1.84 mmol), 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (600 mg, 2.4 mmol) and potassium acetate (590 mg, 6.1 mmol) were dissolved in 1,4-dioxane (10 ml) under N2 here. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (60 mg, 0.08 mmol). This mixture stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (AcOEt/H20) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (400 mg) as a yellow solid. 1H-NMR (8 ppm, CDCl3, 400 MHz): 8.38 (d, J 8.1, 2H), 8.25 (s, 1H), 7.86 (dd, J 1, 7.9, 1H), 7.78 (d, J 8.3, 2H), 7.59 (d, J 8.6, 1H), 1.38 (s, 12H).
Intermediate 45: N-(4-Br0m0hydr0xyphenyl) (difluoromethyl)benzamide: 4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0 0C and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and strirred at It for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4- (difluoromethyl)benzoyl chloride quantitatively. 2-Aminobromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at It for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHC03 and DCM removed on rotavapour to obtain the solid. Solid was triturated with EtzO and er mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (8 ppm, DMSO-dg, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).
Intermediate 46: 6-Br0m0[4-(diflu0r0methyl)phenyl]benzo[d]0xazole: N-(4-Bromohydroxyphenyl)(difluoromethyl)benzamide (0.5 g, 1.5 mmol) was dissolved in 1,4-Dioxane (10 ml) and added Phosphorus oxychloride (0.4 ml, 4.4 mmol). This mixture was refluxed for 2 h. 1,4-Dioxane removed on rotavapour to obtain the residue.
Residue was washed with water to obtain solid. Solid was purified by column on 60-120 mesh silica gel using DCM as eluent to obtain the titled compound (130 mg) as an ite solid. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.28 (d, J 8.4, 2H), 7.74 (d, J 1.7, 1H), 7.65-7.58 (m, 3H), 7.46 (dd, J 1.8, 8.4, 1H), 6.68 (t, J 56.2, 1H).
Intermediate 47: Difluoromethyl)phenyl](4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-Z-yl)benz0[d]0xazole: Intermediate 46 (130 mg, 0.4 mmol) 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2-dioxaborolane) (130 mg, 0.52 mmol) and potassium acetate (110 mg, 1.2 mmol) were dissolved in 1,4-dioxane (15 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (13 mg, 0.02 mmol). This mixture stirred at 105 0C for 4 h. Reaction mixture diluted with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled nd (100 mg) as a yellow solid.
Intermediate 48: Tert-butyl 4-{2-[4- oromethyl)phenyl]benzo[d]oxazolyl}-5,6-dihydr0pyridine-1(2H)-carb0xylate: Following the general procedure-2, the titled compound was prepared from ediate 47 (0.1 g, 0.27 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)- carboxylate (89 mg, 0.27 mmol) as an off-white solid. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.34 (d, J 8.4, 2H), 7.72 (d, J 8.4, 1H), 7.67 (d, J 8.2, 2H), 7.58 (d, J 1.4, 1H), 7.43 (dd, J 1.6, 8.4, 1H), 6.72 (t, J 56.2, 1H), 6.12 (bs, 1H), 4.12 (d, J 2.7, 2H), 3.68 (t, J 5.6, 2H), 2.60 (bs, 2H), 1.50 (s, 9H).
Intermediate 49: tert-butyl 4-(2-p—tolylbenzo[d]oxazolyl)piperidine carboxylate: Intermediate 48 (45 mg, 0.14 mmol) dissolved in MeOH (10 ml) and added Pd/C (5%) (100 mg). This mixture was d under 60Psi en pressure for 15 h in an autoclave. After completion of the reaction, reaction mixture filtered through a bed of celite and celite was washed with MeOH. Combined MeOH layers were removed on rotavapour to obtain the residue. Residue was ated with petether to obtain the titled compound (40 mg) as an off-white solid. MS (m/z): 393.2 [M+H]+, Intermediate 50: Tert-butyl 4-(2-aminobenzo[d]oxazolyl)—5,6- dihydropyridine-1(2H)-carb0xylate: 5-Bromobenzo[djoxazolamine (824 mg, 3.9 mmol) and utyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.8 g, .8 mmol), Potassium fluoride (674 mg, 11.61 mmol) were dissolved in DMF under N2 atmosphere. This mixture was purged with N2 for 30 mins. Pd(dppf)2Cl2.CH2Cl2 (252 mg, 0.3 mmol) was added to the above mixture and again purged with N2 for 30 mins. The reaction mixture was stirred at 900C for 12 h. Work up (EtOAc/H20) followed by column purification on combiflash using a gradient mixture of EtOAc and er (1:1) as eluent ed the titled compound (550 mg) as an off-white solid. 1H-NMR (8 ppm, DMSO-dg, 400 MHz): 7.38-7.36 (m, 2H), 7.26-7.22 (m, 2H), 7.02 (d, J 7.9, 1H), 6.05 (s, 1H), 4.01-3.90 (m, 2H), 3.49-3.55 (m, 2H), .40 (m, 2H), 1.50 (s, 9H).
Intermediate 51: utyl 4-(2-aminobenzo[d]oxazolyl)piperidine carboxylate: Intermediate 50 (550 mg, 0.14 mmol) dissolved in MeOH (25 ml) and added Pd/C (5%) (700 mg). This mixture was stirred under 80Psi en pressure for 12 h in an autoclave. After completion of the reaction, reaction mixture filtered through a bed of celite and celite was washed with MeOH. MeOH was removed on rotavapour to obtain the residue. e was triturated with petether to obtain the titled compound (400 mg) as an off-white solid. ediate 52: Tert-butyl 4-(2-br0m0benz0[d]oxazolyl)piperidine carboxylate: Intermediate 51 (400 mg, 1.3 mmol) was dissolved in acetonitrile (50 ml) and added CuBr2 (563 mg, 2.5 mmol). This mixture stirred at rt for 15 mins. utyl nitrite (259 mg, 2.5 mmol) was added to the above mixture for 5 mins and stirred at 450C for 2 h.
Work up (DCM/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (1:3) as eluent afforded the titled compound (130 mg) as an off-white solid. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.28 (bs, 1H), 7.41 (s, 1H), 6.91 (s, 1H), 4.35- 4.19 (m, 2H), 3.21-3.10 (m, 1H), 2.85 (t, J 11.3, 2H), 1.90-1.80 (m, 2H), 1.60-1.40 (m, 11H).
Intermediate 53: N-(4-bromohydroxyphenyl) (trifluor0methyl)benzamide: 4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20 ml), cooled to 0 0C and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and strirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4- (trifluoromethyl)benzoyl de quantitatively. 2-Aminobromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added ne (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added fluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stirring at It for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHC03 and DCM removed on rotavapour to obtain the solid. Solid was triturated with EtzO and er mixture (4: 1) to obtain the titled compound (0.6 g) as a yellow solid.
Intermediate 54: 6-br0mo(4-(trifluoromethyl)phenyl)benzo[d]0xazole: Intermediate 53 (940 mg, 2.6 mmol) was dissolved in xylene (25 ml) and added p- esulphonic acid (991 mg, 5.22 mmol). This mixture was refluxed to 1600C for 12 h under a dean-stork condenser. Xylene removed from the reaction mixture and basified the residue with aq. NaHC03 (30 ml). Work up (EtOAc/H20) followed by purification with combiflash using a gradient mixture of EtOAc and er (5:95) as eluent to afford the titled compound (650 mg) as an Off-White solid.
Intermediate 55: 6-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)[4- (trifluoromethyl)phenyl]benz0[d]0xazole: Intermediate 54 (630 mg, 1.84 mmol) 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane) (600 mg, 2.4 mmol) and potassium acetate (590 mg, 3.3 mmol) were ved in 1,4-dioxane (30 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CHzClz (60 mg, 0.074 mmol). This mixture stirred at 105 0C for 17 h. Reaction mixture diluted with water and work up (AcOEt/H20) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (20:80) as eluent to afford the titled compound (420 mg) as an off-white solid. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.39 (d, J 8.1, 2H), 8.05 (s, 1H), 7.84 (dd, J 0.8, 8, 1H), 7.82-7.76 (m, 3H), 1.38 (s, 12 H). ediate 56: N-(5-bromo-Z-hydroxypyridinyl) (trifluor0methyl)benzamide: 4-(Trifluoromethyl)benzoic acid (2.45 g, 12.9 mmol) dissolved in DCM (30 ml), cooled to 0 0C and added oxalyl chloride (3.4 ml, 38.6 mmol).
Catalytic amount of DMF was added to this mixture and strirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Hydroxyamino bromopyridine (2.4 g, 11.1 mmol) dissolved in DCM (15 ml) and added Pyridine (1.74 g, 22 mmol) under nitrogen atmosphere. This mixture stirred at It for 30 mins and added 4- oromethyl)benzoyl de (2.4 g, 13.3 mmol). After continuing stirring at rt for 30 mins, reaction mass diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified on column using 60-120 mesh silica gel and a gradient mixture of MeOH and DCM (2:98) as eluent to afford the titled compound (2.1 g) as a brown solid. 1H-NMR (8 ppm, DMSO-dg, 400 MHz): 12.43 (bs, 1H), 9.58 (s, 1H), 8.37 (d, J 2.6, 1H), 8.09 (d, J 8.2, 2H), 7.91 (d, J 8.2, 2H), 7.48 (d, J 2.6, 1H).
Intermediate 57: 6-bromo(4-(trifluoromethyl)phenyl)oxazolo[5,4- b]pyridine : Intermediate 56 (2.1 g, 5.4 mmol) was dissolved in Dioxane (30 ml) and added POC13 (1.5 ml). This e was refluxed for 5 h. After 5 h, dioxane was removed on rotavapour to obtain the residue. Work up (EtOAc/HZO) of the residue afforded the crude.
Crude was purified by column on 60-120 mesh silica gel using DCM as eluent to afford the titled compound (1.2 g). 1H-NMR (8 ppm, CDC13, 400 MHz): 8.46 (d, J 2.1, 1H), 8.41 (d, J 8.2, 2H), 8.24 (d, J 2.1, 1H), 7.83 (d, J 8.2, 2H).
Intermediate 58: 6-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)[4- (trifluoromethyl)phenyl]0xazolo[5,4-b]pyridine: ediate 57 (1.2 g, 3.5 mmol) 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (973 mg, 3.8 mmol) and potassium acetate (1.03 g, 10.5 mmol) were dissolved in 1,4-dioxane (40 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (113 mg, 0.14 mmol). This mixture stirred at 105 0C for 15 h. Reaction mixture diluted with water and work up /HZO) afforded the crude. Crude was purified by combiflash using a nt mixture of AcOEt and Petether (5:95) as eluent to afford the titled compound (1.2 g) as an off-white solid. 1H-NMR (5 ppm, CDC13, 400 MHz): 8.77 (d, J 1.5, 1H), 8.46 (d, J 1.5, 1H), 8.41 (d, J 8.1, 2H), 7.80 (d, J 8.1, 2H), 1.38 (s, 12 H).
General Procedure-1 for Suzuki coupling: Aryl bromide (1 eq.) was dissolved in Dioxane and water (5:1) and added arylboronic acid (1.3 eq), Pd(PPh3)4 (0.08 eq) and N32CO3 (3.3 eq). Reaction mixture degassed with N2 for 30 mins and refluxed until both the ng materials disappeared.
Work-up (HzO/AcOEt) and purification gave the desired product. l ure-2 for Suzuki coupling: Aryl e (1 eq), arylboronic acid (1 eq.), Sodium carbonate (3 eq) dissolved in DMF and water (4:1) and degassed with N2 for 15 mins. To this mixture Pd(dppi)2Clz.CH2Clz (0.08 eq) was added and degassed again with N2 for 15 mins. This mixture was irradiated in micro wave for 105 mins, at 80 0C. Work-up cOEt) and purification gave the desired product.
General Procedure-3 for Suzuki coupling: Same as General Procedure-2 except that KF was used instead of , General Procedure-4 for Suzuki coupling: Same as General Procedure-2 except that Dioxane was used instead of DMF.
Example 1 2-[1-(5-Ethylpyrimidinyl) piperidinyl][2-flu0r0(methylsulfonyl)phenyl]-1H- benzo[d]imidazole Following the General Procedure-1, the titled compound (25 mg) was prepared from ediate 2 (80 mg, 0.199 mmol) and Intermediate 3 (79 mg, 0.26 mmol) as a yellow solid. M.P.: 186.5-190 0C. 1H-NMR (5 ppm, DMSO-dg, 400 MHz): 12.41 (d, J 4, 1H), 8.26 (s, 2H), 7.90-7.80 (m, 3H), 7.79-7.50 (m, 2H), 7.40-7.32 (m, 1H), 4.66 (d, J 13.1, 2H), 3.29 (s, 3H), 3.21 (t, J 8.3, 1H), 3.09 (t, J 11.7, 2H), 2.43 (q, J 7.73, 2H), 2.06 (d, J 12.5, 2H), 1.82-1.71 (m, 2H), 1.13 (t, J 7.5, 3H).
Example 2 Tert-butyl 4-{5-[2-flu0r0(methylsulfonyl) phenyl]-1H-benz0[d]imidazol eridinecarb0xylate Following the General Procedure-1, the titled compound (40 mg) was ed from Intermediate 4 (100 mg, 0.25 mmol) and Intermediate 3 (98 mg, 0.33 mmol) as a yellow solid. M.P.: 88-92 0C. 1H-NMR(8 ppm, DMSO-dg, 400 MHz): 12.39 (s, 1H), 7.89-7.81 (m, 3H), 7.69-7.58 (m, 2H), 7.40-7.32 (m, 1H), 4.01 (d, J 12.5, 2H), 3.30 (s, 3H), 3.12-3.05 (m, 1H), 3.00-2.88 (m, 2H), 2.00 (d, J 11.8, 2H), 1.76-1.55 (m, 2H), 1.41 (s, 9H).
Example 3 2-[1-(5-ethylpyrimidinyl) piperidinyl][2-flu0r0(methylsulfonyl)phenyl] benzo[d]0xazole Following the General Procedure-1, the titled compound (30 mg) was prepared from Intermediate 6 (80 mg, 0.21 mmol) and Intermediate 3 (80 mg, 0.27 mmol) as an ite solid. M.P.: 0 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.20 (s, 2H), 7.86 (s, 1H), 7.80 (m, 1H), 7.79-7.74 (m, 1H), 7.66 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.75 (d, J 13.4, 2H), 3.35-3.15 (m, 3H), 3.11 (s, 3H), 2.47 (q, J 7.6, 2H), 2.31-2.22 (m, 2H), 2.09-1.94 (m, 2H), 1.20 (t, J 7.6, 3H).
Example 4 tert-butyl 4-{5-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate Following the General ure-1, the titled compound (40 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and Intermediate 3 (154 mg, 0.51 mmol) as an off-white solid. M.P.: 144—147 0C. lH-NMR (5 ppm, CDClg, 400 MHz): 7.87 (s, 1H), 7.82 (d, J 8, 1H), 7.77 (dd, J 1.4, 9.4, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.15 (d, J 7.7, 2H), 3.22-3.10 (m, 4H), 3.00 (t, J 11.3, 2H), 2.21-2.12 (m, 2H), 2.00- 1.88 (m, 2H), 1.48 (s, 9H).
Example 5 Tert-butyl 4-{5-[2-flu0r0(methylsulf0nyl)phenyl]methyl-1H-benz0[d]imidazol yl}piperidinecarb0xylate: Tert-butyl 4-{ 5- [2-fluoro(methylsulfonyl)phenyl] - 1H-benzo [d]imidazol yl}piperidinecarboxylate (85 mg, 0.17 mmol) dissolved in THF (15 ml) and cooled to 0 0C.
Sodium hydride (9 mg, 0.342 mmol) added to the above mixture and stirred at the same temperature for 30 mins. To this e methyl iodide (48 mg, 0.342 mmol) added at same temperature and stirred the reaction mixture at It for 3 h. Reaction mixture d with ice and worked up (EtOAc/HZO). Crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc: Petether (3:1) as eluent to afford the title compound (50 mg) as an orange solid. M.P.: 85-88 0C. 1H-NMR(8 ppm, CDClg, 400 MHz): 7.85-7.75 (m, 2H), 7.73— 7.64 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.45 (m, 1H), .21 (m, 2H), 3.82 (s, 3H), 3.11 (s, 3H), 3.10-3.00 (m, 2H), 3.00-2.88 (m, 2H), 2.05-1.93 (m, 3H), 1.48 (s, 9H).
Example 6 utyl 4-{6-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-1, the titled compound (21 mg) was prepared from Intermediate 10 (100 mg, 0.26mmol) and ediate 3 (102 mg, 0.34 mmol) as an off-white solid. M.P.: 174-1783 0C. 1H-NMR(8 ppm, CDClg, 400 MHz): .75 (m, 3H), 7.73-7.64 (m, 2H), 7.50 (d, J 8.2, 1H), 4.15 (d, J 12.4, 2H), 3.20-3.10 (m, 4H), 3.0 (t, J 12.5, 2H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Example 7 Isopropyl 4-{5-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: [25 1] Tert-butyl 4-{ 5- [2-fluoro(methylsulfonyl)phenyl]benzo[cfloxazol yl}piperidinecarboxylate (200 mg, 0.42 mmol) dissolved in DCM and added Trifluoroacetic acid (0.75 ml). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain 5-(2-fluoro(methylsulfonyl)phenyl)(piperidin yl)benzo[d]oxazole 2,2,2-trifluoroacetate (190 mg). 5-(2-fluoro(methylsulfonyl)phenyl) (piperidinyl)benzo[d]oxazole 2,2,2-trifluoroacetate (190 mg, 0.39 mmol) was dissolved in DCM (20 ml) and added TEA (0.43 ml, 3.12 mmol). This mixture stirred at It for 30 mins and added isopropyl chloroformate in toluene (0.095 g, 0.78 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether ) as eluent to afford the titled compound (120 mg) as a pale-yellow solid. M.P.: 965-1012 0C. lH-NMR (5 ppm, CDC13, 400 MHz): 7.87 (s, 1H), 7.81 (dd, J 1.7, 8, 1H), 7.80-7.75 (m, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.94 (septet, J 6.2, 1H), 4.19 (d, J 10.9, 2H), 3.22-3.13 (m, 1H), 3.12 (s, 3H), 3.04 (t, J 10.9, 2H), 2.22-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 8 Tert-butyl 4-{7-flu0r0[2-flu0r0(methylsulf0nyl)phenyl]benzo[d]0xazol yl}piperidinecarb0xylate: Following the General ure-1, the titled compound (50 mg) was prepared from Intermediate 12 (200 mg, 0.50mmol) and Intermediate 3 (151 mg, 0.50 mmol) as an off-white solid. M.P.: 584 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 7.82 (dd, J 1.8, 8.1, 1H), 7.78 (dd, J 1.7, 9.4, 1H), 7.69-7.63 (m, 2H), 7.29 (td, 1.3, 10.6, 1H), 4.16 (d, J 11.2, 2 H), 3.22- 3.16 (m, 1H), 3.11 (s, 3H), 3.00 (t, J 13.3, 2H), 2.21-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Example 9 Tert-butyl 4-[5-(4-cyanophenyl)benzo[d]oxazolyl]piperidine-l-carboxylate: Following the General Procedure-1, the titled compound (45 mg) was prepared from Intermediate 7 (140 mg, 0.37 mmol) and 4-Cyanophenylboronic acid (53 mg, 0.37 mmol) as an off-white solid. M.P.: 1373-1412 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 7.88 (d, 1.4, 1H), 7.74 (dd, J 1.8, 8.5, 2H), 7.69 (dd, J 1.8, 8.5, 2H), 7.58 (d, J 8.5, 1H), 7.53 (dd, J 1.8, 8.5, 2H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.2, 2H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H). e 10 Tert-butyl 3-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the l Procedure-1, the titled compound (30 mg) was prepared from ediate 8 (100 mg, 0.23 mmol) and 4-bromofluoro(methylsulfonyl)benzene (70 mg, 2012/041632 0.37 mmol) as an off-white solid. M.P.: 1743—1775 0C. 1H-NMR(8 ppm, CDC13, 400 MHz): 8.03 (t, J 7.9, 1H), 7.88 (d, J 1.6, 1H), 7.61-7.51 (m, 3H), 7.46 (dd, J 1.6, 11.1, 1H), 4.15 (d, J 11.2, 2H), 3.26 (s, 3H), 3.20—3.11 (m, 1H), 3.00 (t, J 12.2, 2H), 2.20—2.12 (m, 2H), 1.98-1.84 (m, 2H), 1.48 (s, 9H).
Example 11 Tert-butyl 4-{5-[4-(1H-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-1, the titled compound (80 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromophenyl)-1H-tetrazole (100 mg, 0.44 mmol) as a brown solid. M.P.: 207-211 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.02 (s, 1H), 7.91 (d, J 1.2, 1H), 7.82-7.79 (m, 4H), 7.62-7.55 (m, 2H), 4.16 (d, J 10.6, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.3, 2H), 2.20-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Example 12 Tert-butyl 4-{5-[2-flu0r0(1H-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-1, the titled nd (10 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromofluorophenyl)-1H-tetrazole (110 mg, 0.45 mmol) as a brown solid. M.P.: 7 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.71-7.58 (m, 4H), 7.52 (td, 1.6, 8.4, 1H), 4.16 (d, J 10.8, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.2, 2H), 2.21-2.13 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Example 13 Tert-butyl 4-{5-[4-(trifluoromethyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General ure-1, the titled compound (40 mg) was ed from Intermediate 7 (150 mg, 0.4 mmol) and 4-(trifluoromethyl)phenylboronic acid (74 mg, 0.39 mmol) as an off-white solid. M.P.: 9 0C. 1H-NMR (8 ppm, CDC13, 400 MHZ): 7.88 (d, J 1.2, 1H), .67 (m, 4H), 7.59-7.52 (m, 2H), 4.15 (d, J 10, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.6, 2H), 2.21-2.12 (m, 2H), 1.99-1.86 (m, 2H), 1.48 (s, 9H).
Example 14 Isopropyl 4-{5-[2-flu0r0(1H-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Tert—butyl 4- { 5-[2-fluoro(1H—tetrazolyl)phenyl]benzo[cfloxazolyl }piperidine- 1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM and added Trifluoroacetic acid (0.5 ml).
This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain 5-(2- fluoro(1H-tetrazolyl)phenyl)(piperidinyl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg). 5-(2-fluoro(1H-tetrazolyl)phenyl)(piperidinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (70 mg, 0.17 mmol) was dissolved in DCM (15 ml) and added TEA (0.2 ml, 1.4 mmol). This mixture stirred at It for 30 mins and added isopropyl chloroformate in toluene (42 mg, 0.34 mmol). After 1 h, reaction mass d with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled nd (30 mg) as an off-white solid. M.P.: 168-171 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), .58 (m, 3H), 7.54-7.50 (m, 1H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.2, 2H), 2.22-2.15 (m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 15 Tert-butyl 4-{5-[3-flu0r0(lH-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-3, the titled compound (22 mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and 1-(4-bromofluorophenyl)-1H—tetrazole (56 mg, 0.23 mmol) as a ellow solid. M.P.: 154-159 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.14 (d, J 2.5, 1H), 8.04 (t, J 7.8, 1H), 7.91 (d, J 3.9, 1H), 7.64-7.54 (m, 4H), 4.16 (d, J 10, 2H), 3.21- 3.13 (m, 1H), 3.01 (t, J 11.9, 2H), 2.21-2.12 (m, 2H), 2.00-1.87 (m, 2H), 1.48 (s, 9H).
Example 16 2-[1-(5-ethylpyrimidinyl)piperidinyl][2-flu0r0(1H-tetrazol yl)phenyl]benzo[d]0xazole: Tert—butyl 4- { 5-[2-fluoro(1H—tetrazolyl)phenyl]benzo[cfloxazolyl }piperidine- oxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (0.5 ml). This mixture was stirred at It for 2 h. DCM removed from the on mixture to obtain 5-[2-fluoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[cfloxazole 2,2,2- trifluoroacetate (150 mg). 5-[2-fluoro(1H—tetrazolyl)phenyl](piperidin yl)benzo[d]oxazole 2,2,2-trifluoroacetate (70 mg, 0.15 mmol) was dissolved in IPA (10 ml), added DiPEA (0.25 ml, 1.2 mmol) and stirred at rt for 30 mins. 2-Chloroethyl dine was added to the above reaction mixture and heated the reaction mixture to 90 0C for overnight.
After completion of the reaction, work-up (EtOAc/HZO) followed by purification on combiflash using the gradient mixture of ethyl acetate and er (1:1) as eluent afforded the titled nd (20 mg) as an off-white solid. M.P.: 188-192 0C. lH-NMR (5 ppm, CDC13, 400 MHz): 9.03 (s, 1H), 8.20 (s, 2H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), 7.65-7.58 (m, 3H), 7.54-7.49 ((m, 1H), 4.80-4.70 (m, 2H), 3.33-3.23 (m, 1H), 3.22 (t, J 14, 2H), 2.48 (q, J 7.6, 2H), .22 (m, 2H), 2.07-1.95 (m, 2H), 1.20 (t, J 7.6, 3H). e 17 Tert-butyl 4-[5-(4-cyanofluorophenyl)benzo[d]0xazolyl]piperidinecarb0xylate: Following the General Procedure-2, the titled nd (70 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromofluorobenzonitri1e (70 mg, 0.35 mmol) as a white solid. M.P.: 138-142 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 7.87 (d, J 1.6, 1H), 7.72- 7.68 (m, 1H), 7.59 (d, J 8.5, 1H), 7.53-7.42 (m, 3H), 4.15 (d, J 10.6, 2H), 3.20-3.11 (m, 1H), 3.00 (t, J 11.8, 2H), 22-212 (m, 2H), .86 (m, 2H), 1.56 (S, 9H).
Example 18 Isopropyl 4-{5-[3-flu0r0(1H-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Tert—butyl 4- { 5-[3-fluoro(1H—tetrazoly1)pheny1]benzo[cfloxazolyl }piperidine- 1-carboxy1ate (120 mg, 0.26 mmol) dissolved in DCM (15 m1) and added Trifluoroacetic acid (0.5 m1). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain 5-[3-fluoro(1H—tetrazoly1)phenyl](piperidinyl)benzo[cfloxazole 2,2,2- trifluoroacetate (120 mg). 5-[3-fluoro(1H—tetrazoly1)pheny1](piperidin yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg, 0.25 mmol) was ved in DCM (15 m1) and added TEA (0.27 ml, 2 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroforrnate in toluene (61 mg, 0.34 mmol). After 1 h, reaction mass diluted with water and ted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (20 mg) as an off-white solid. M.P.: 187-191 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.14 (d, J 2.6, 1H), 8.02 (t, J 8.2, 1H), 7.90 (d, J 1.4, 1H), 7.63-7.55 (m, 4H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.4, 2H), 2.18 (d, J 10.8, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 19 Tert-butyl 4-{5-[3-flu0r0(1H-tetrazol-S-yl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-2, the titled compound (6 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and intermediate 17 (85 mg, 0.35 mmol) as a brown solid.
M.P.: 163-167 0C. 1H-NMR (5 ppm, CDC13, 400 MHz): 8.15 (s, 1H), 8.11 (t, J 8, 1H), 7.86 (d, J 12.2, 1H), 7.82-7.77 (m, 3H), 3.95 (d, J 13.4, 2H), 3.42-3.35 (m, 1H), 3.05-2.92 (m, 2H), 2.14-2.06 (m, 2H), .64 (m, 2H), 1.41 (s, 9H).
Example 20 Tert-butyl 4-[5-(4-carbamoylchlorophenyl)benz0[d]0xazolyl]piperidine carboxylate: Following the General Procedure-2, the titled compound (25 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and 2-chloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)benzamide (110 mg, 0.4 mmol) as a brown solid. M.P.: 169-171 0C. lH-NMR (5 ppm, DMSO-d6, 400 MHz): 8.03 (s, 1H), 7.87 (bs, 1H), 7.82-7.75 (m, 2H), .66 (m, 2H), 7.59 (bs, 1H), 7.52 (d, J 7.9, 1H), 3.94 (d, J 12.9, 2H), .22 (m, 1H), 3.08-2.92 (m, 2H), 2.09 (d, J 10.6, 2H), 1.75-1.63 (m, 2H), 1.40 (s, 9H).
Example 21 Tert-butyl 4-[5-(4-carbam0ylflu0r0phenyl)benz0[d]0xazolyl]piperidine ylate: Following the General Procedure-3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromofluorobenzamide (77 mg, 0.35 mmol) as a white solid. M.P.: 202-206 0C. 1H-NMR (5 ppm, DMSO-dé, 400 MHz): 8.22 (t, J 8.3, 1H), 7.89 (s, 1H), 7.59-7.49 (m, 3H), 7.37 (dd, J 1.6, 13.24, 1H), 6.71 (d, J 9.5, 1H), 5.85 (s, 1H), 4.15 (d, J 10.7, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.8, 2H), 2.20-2.12 (m, 2H), 1.99-1.85 (m, 2H), 1.48 (s, 9H).
Example 22 Tert-butyl 4-[5-(3-flu0r0isopropoxyphenyl)benzo[d]0xazolyl]piperidine carboxylate: ing the General Procedure-3, the titled compound (25 mg) was ed from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromofluoroisopropoxybenzene (81 mg, 0.35 mmol) as a white solid. M.P.: 124-128 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 7.81 (d, J 1.4, 1H), 7.53-7.45 (m, 2H), 7.35-7.27 (m, 2H), 7.05 (t, J 8.6, 1H), 4.58 (septet, J 6.1, 1H), 4.15 (d, J .4, 2H), 3.20-3.10 (m, 1H), 2.99 (t, J 11.7, 2H), 2.15 (dd, J 2.8, 13.4, 2H), 1.97-1.86 (m, 2H), 1.56 (s, 9H), 1.39 (d, J 6.1, 6H).
Example 23 utyl 4-{5-[2-flu0r0(lH-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Tert-butyl 4- { uoro(1H—tetrazolyl)phenyl]benzo[cfloxazolyl }piperidine- 1-carboxylate (300 mg, 0.65 mmol) dissolved in DCM (15 ml) and added roacetic acid (1.5 ml). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain 5-[2-f1uoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (300 mg). 5-[2-fluoro(1H—tetrazolyl)phenyl](piperidin yl)benzo[cfloxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at It for 1 h. To this mixture added cyclobutanol (0.05 ml, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60 0C for overnight. Work up (EtOAc/HZO) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (25 mg) as an off-white solid. M.P.: 165-169 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), .50 (m, 1H), 4.96 (septet, J 7.8, 1H), 4.20 (d, J 12.4, 2H), 3.22-3.13 (m, 1H), 3.06 (t, J 9.8, 2H), 2.40-2.30 (m, 2H), .15 (m, 2H), .02 (m, 2H), 2.00-1.90 (m, 2H), 1.78 (q, J 10, 2H).
Example 24 Sec-butyl 4-{5-[2-flu0r0(lH-tetrazolyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Tert-butyl 4- { 5-[2-fluoro(1H—tetrazolyl)phenyl]benzo[cfloxazolyl }piperidine- 1-carboxylate (250 mg, 0.54 mmol) ved in DCM (15 ml) and added Trifluoroacetic acid (1 ml). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain -[2-f1uoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[cfloxazole 2,2,2-trifluoro acetate (260 mg). 5-[2-f1uoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2-trif1uoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N- Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added 2- butanol (46 mg, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60 0C for overnight.
Work up (EtOAc/HZO) and purification of the crude by combiflash with gradient mixture of ethyl acetate and er (1:1) as eluent afforded the titled compound (30 mg) as an off-white solid. M.P.: 118-122 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72- 7.58 (m, 4H), 7.55-7.50 (m, 1H), 4.82-4.73 (m, 1H), 4.21 (d, J 12.7, 2H), 3.24-3.13 (m, 1H), 3.06 (t, J 11.6, 2H), 2.19 (d, J 10.9, 2H), 2.00-1.88 (m, 2H), 1.69-1.50 (m, 2H), 1.24 (d, J 6.2, 3H), 0.92 (t, J 7.4, 3H). e 25 Pentanyl 2-flu0r0(lH-tetrazolyl)phenyl]benz0[d]oxazolyl}piperidine carboxylate: Tert-butyl 4- { 5-[2-fluoro(1H—tetrazolyl)phenyl]benzo[cfloxazolyl }piperidine- 1-carboxylate (250 mg, 0.54 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (1 ml). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain -[2-f1uoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[cfloxazole 2,2,2- trifluoroacetate (260 mg). 5-[2-fluoro(1H—tetrazolyl)phenyl](piperidin yl)benzo[cfloxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at It for 1 h. To this mixture added 3-pentanol (46 mg, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60 0C for overnight. Work up (EtOAc/HZO) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent ed the titled compound (20 mg) as an off-white solid. M.P.: 114-117 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.54-7.50 (m, 1H), 4.69 et, J 6, 1H), 4.23 (d, J 13.5, 2H), 3.25-3.15 (m, 1H), 3.07 (t, J 11.9, 2H), 2.21-2.17 (m, 2H), 2.02-1.88 (m, 2H), .50 (m, 4H), 0.91 (t, J 7.4, 6H).
Example 26 -[2-flu0r0(1H-tetrazolyl)phenyl](piperidinyl)benz0[d]0xazole: 5-[2-f1uoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (50 mg) was dissolved in DCM (15 ml) and added TEA (0.3 ml). This e stirred for 3 h at It. Work up (DCM/H20) followed by purification of the crude by ative TLC using MeOH and DCM (1:5) as eluent afforded the titled compound (15 mg) as an off- white solid. M.P.: 148-151 0C. 1H-NMR (8 ppm, DMSO-dg, 400 MHz): 10.17 (s, 1H), 8.03 (d, J 9.6, 1H), 7.95-7.79 (m, 4H), 7.58 (d, J 8.5, 1H), 3.22-3.13 (m, 1H), 3.07 (d, J 12.4, 2H), 2.70 (t, J 11.2, 2H), 2.06 (d, J 11.1, 2H), 1.82-1.70 (m, 2H).
Example 27 Isopropyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]0xazolyl}piperidine carboxylate: Following the General Procedure-1, the titled compound (100 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(trifluoromethyl)phenylboronic acid (124 mg, 0.65 mmol) as an off-white solid. M.P.: 6 0C. 1H-NMR(8 ppm, CDC13, 400 MHz): 7.88 (d, J 1, 1H), 7.72-7.68 (m, 4H), 7.60-7.53 (m, 2H), 4.95 (septet, J 6.3, 1H), 4.20 (d, J 13.3, 2H), .12 (m, 1H), 3.04 (t, J 11.3, 2H), 2.17 (dd, J 2.6, 13.2, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 28 Isopropyl 4-[5-(4-formylphenyl)benzo[d]oxazolyl]piperidinecarb0xylate: Following the General Procedure-1, the titled compound (100 mg) was prepared from Intermediate 13 (270 mg, 0.73 mmol) and nylphenylboronic acid (132 mg, 0.88 mmol) as an off-white solid. M.P.: 167-170 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 10.07 (S, 1H), 7.96 (dd, J 1.7, 6.6, 2H), 7.93 (s, 1H), 7.76 (d, J 8.2, 2H), 7.58 (s, 2H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.1, 2H), .13(m, 1H), 3.04 (t, J 11.3, 2H), 2.18 (dd, J 2.8, 13.3, 2H).
Example 29 pyl 4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidinecarb0xylate: Isopropyl 4-[5-(4-forrnylphenyl)benzo[cfloxazolyl]piperidinecarboxylate (100 mg, 0.25 mmol) dissolved in DCM and added DAST (123 mg, 0.76 mmol) and stirred the reaction mixture at 55 0C. Work up (DCM/H20) followed by purification on combiflash with a gradient mixture of EtOAc and Petether (1 :4) as eluent afforded the titled compound (35 mg) as an off-white solid. M. P.: 151-154 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 7.88 (s, 1H), 7.68 (d, J 8.2, 2H), 7.60 (d, J 8.2, 2H), 7.58-7.52 (m, 2H), 6.70 (t, J 56.5, 1H), 4.95 (septet, J 6.2, 1H), 4.19 (d, J 11.1, 2H), 3.21-3.13 (m, 1H), 3.04 (t, J 11.4, 2H), 2.17 (d, J 10.4, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 30 Isopropyl 4-[5-(4-carbamoylchlor0phenyl)benz0[d]0xazolyl]piperidine carboxylate: Following the l ure-2, the titled compound (30 mg) was prepared from Intermediate 13 (150 mg, 0.41 mmol) and 2-chloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamide (110 mg, 0.41 mmol) as a pale-yellow solid. M.P.: 178-181 0C. 1H-NMR (5 ppm, DMSO-d6, 400 MHz): 8.04 (d, J 1.7, 1H), 7.88 (bs, 1H), 7.80 (d, J 1.7, 1H), 7.77 (d, J 8.5, 1H), 7.73-7.68 (m, 2H), 7.62-7.58 (m, 1H), 7.52 (d, J 8, 1H), 4.78 (septet, J 6.2, 1H), 3.97 (d, J 13.2, 2H), 3.34-3.24 (m, 1H), 3.10-3.00 (m, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H), 1.19 (d, J 6.2, 6H).
Example 31 Isopropyl 4-[5-(4-carbamoylfluorohenyl)benzo[d]oxazolyl]piperidine carboxylate: Following the General Procedure-2, the titled compound (30 mg) was prepared from Intermediate 14 (300 mg, 0.72 mmol) and 4-bromofluorobenzamide (157 mg, 0.72 mmol) as an ite solid. M.P.: 7 0C. lH-NMR (5 ppm, DMSO-dg, 400 MHz): 8.08 (d, J 1.4, 1H), 7.80-7.72 (m, 3H), 7.70-7.62 (m, 4H), 4.78 (septet, 6.2, 1H), 3.97 (d, J 13.4, 2H), 3.33- 3.25 (m, 1H), 3.10-2.98 (m, 2H), 2.15-2.07 (m, 2H), 1.76-1.64 (m, 2H), 1.19 (d, J 6.2, 6H).
Example 32 1-{4-[5-(2-flu0r0(1H-tetrazolyl)phenyl)benzo[d]0xazolyl]piperidinyl} methylpropan-l-one: Tert-butyl 4- { 5-[2-fluoro(1H—tetrazolyl)phenyl]benzo[cfloxazolyl }piperidine- 1-carboxylate (100 mg, 0.22 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (0.4 ml). This mixture stirred at It for 3 h. After completion of the reaction, DCM removed on pour and e was co-distilled with ether to obtain 5-[2-fluoro(1H—tetrazol yl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2-trifluoroacetate (100 mg). 5-[2-fluoro (1H—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2-trifluoroacetate (100 mg, 0.21 mmol) was dissolved in DMF (3 ml) and added isobutyric acid (202 mg, 0.23 mmol), EDC.HCl (99 mg, 0.52 mmol), HOBt (33 mg, 0.25 mmol) and TEA (0.23 ml, 1.7 mmol). After tion of the reaction, work up (EtOAc/H20) followed by purification on ash using the gradient mixture of EtOAc and Petether (65:35) as eluent afforded the titled compound (20 mg) as a brown solid. M.P.: 190-194 0C. 1H-NMR (8 ppm, CDCl3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), .59 (m, 2H), 7.52 (td, J 1.6, 8.4, 1H), 4.58 (d, J 12.1, 1H), 4.04 (d, J 13.2, 1H), 3.35-3.22 (m, 2H), 2.96 (t, J 12, 1H), 2.85 (septet, J 6.8, 1H), 2.30-2.18 (m, 2H), 2.05-1.72 (m, 2H), 1.16 (d, J 6.8, 6H)..
Example 33 Isopropyl 4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidinecarb0xylate: Following the General Procedure-1, Isopropyl 4-[6-(4-formylphenyl)benzo[d]oxazol- 2-yl]piperidinecarboxylate (140 mg) was prepared from Intermediate 15 (300 mg, 0.82 mmol) and 4-formylphenylboronic acid (146 mg, 0.98 mmol) as an off-white solid. Isopropyl 4- [6-(4-formylphenyl)benzo[cfloxazolyl]piperidinecarboxylate (100 mg, 0.25 mmol) was dissolved in DCM (5 ml) and added DAST (0.1 ml, 0.76 mmol). This mixture stirred at reflux for 2 h. Work up (DCM/H20) followed by the purification of the crude on combiflash using gradient e of EtOAc and Petether (1 :4) as eluent afforded the titled compound (35 mg) as an off-white solid. M. P.: 149-153 0C. MS (m/z): 415.1 [M+H]+.
Example 34 6-{2-[1-(isopropoxycarbonyl)piperidinyl]benz0[d]0xazolyl}nic0tinic acid: Following the General Procedure-2, Methyl 1-(isopropoxycarbonyl)piperidin yl)benzo[d]oxazolyl]nicotinate (50 mg) was prepared from Intermediate 14 (400 mg, 0.97 mmol) and methyl 6-chloronicotinate (166 mg, 0.97 mmol) as a brown solid. Methyl 1- (isopropoxycarbonyl)piperidinyl)benzo[d]oxazolyl]nicotinate (35 mg, 0.08 mmol) was dissolved in MeOH (5 ml) and added K2CO3 (22 mg, 0.17 mmol). This mixture was stirred at reflux for overnight. MeOH removed on rotavapour and pH ed to 6 using acetic acid to obtain a solid. Solid was ed and dried to obtain the titled compound (20 mg) as a grey solid. M. P.: 239-242 0C. MS (m/z): 410.4 [M+H]+, Example 35 -[2-flu0r0(1H-tetrazolyl)phenyl][1-(methylsulfonyl)piperidin yl]benzo[d]0xazole: 5-[2-fluoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[cfloxazole 2,2,2- trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DCM (5 ml) and added TEA (60mg, 0.6 mmol) and stirred the mixture at rt for 30 mins. To this mixture added methanesulphonyl chloride (14 mg, 0.12 mmol) and d at It for 2 h. Work up (DCM/H20) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (7:3) as eluent afforded the titled nd (17 mg) as a brown solid. M. P.: 209-212 0C. MS (m/z): 443.2 [M+Hl+.
Example 36 Isopropyl 4-[5-(5-carbamoylpyridinyl)benzo[d]oxazolyl]piperidinecarb0xylate: Following the General Procedure-3, the titled compound (40 mg) was prepared from Intermediate 14 (250 mg, 0.6 mmol) and 6-chloronicotinamide (94 mg, 0.6 mmol) as an off- white solid. M.P.: 227-230 0C. MS (m/z): 409.1 [M+H]+, Example 37 Isopropyl 4-[5-(4-carbam0ylflu0r0phenyl)benz0[d]oxazolyl]piperidine carboxylate: Following the General ure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromofluorobenzamide (105 mg, 0.48 mmol) as an off-white solid. M.P.: 194-197 0C. MS (m/z): 426.0 [M+H]+, Example 38 Isopropyl 4-[5-(4-carbamoylchlor0phenyl)benz0[d]0xazolyl]piperidine carboxylate: Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromochlorobenzamide (105 mg, 0.48 mmol) as a brown solid. M.P.: 178-182 0C. MS (m/z): 442.0 , Example 39 2-Flu0r0{2-[1-(3-methylbutanoyl)piperidinyl]benzo[d]0xazolyl}benzamide: Tert-butyl 4- [5 -(4-carbamoyl-3 -fluorophenyl)benzo[cfloxazolyl]piperidine carboxylate (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (1 ml). This e d at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and e was co-distilled with ether to obtain 2-fluoro(2-(piperidin yl)benzo[d]oxazolyl)benzamide 2,2,2-trifluoroacetate (140 mg). ro(2-(piperidin yl)benzo[d]oxazolyl)benzamide 2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5 ml) and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147 mg, 0.77 mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (20 mg) as a brown solid. M.P.: 186-190 0C. MS (m/z): 424.1 [M+H]+.
Example 40 1-{4-[5-(2-flu0r0(1H-tetrazolyl)phenyl]benz0[d]0xazolyl]piperidinyl} methylbutan-l-one: 5-[2-fluoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (140 mg, 0.29 mmol) was dissolved in DMF (4 ml) and added isovaleric acid (38 mg, 0.37 mmol), EDC.HCl (147 mg, 0.73 mmol), HOBt (47 mg, 0.35 mmol) and TEA (88 mg, 0.88 mmol). After completion of the reaction, work up (EtOAc/HZO) followed by purification of crude on combiflash using a nt mixture of EtOAc and Petether (7:3) as eluent ed the titled compound (100 mg) as a pale-yellow solid. M.P.: 168-172 0C. MS (m/z): 449.1 [M+H]+, Example 41 -[2-flu0r0(1H-tetrazolyl)phenyl][1-(2-methoxyethyl)piperidin yl]benzo[d]0xazole: WO 70867 luoro(1H—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (30 mg, 0.06 mmol) was ved in DMF (2 ml) and added K2CO3 (40 mg, 0.29 mmol) and stirred the mixture at rt for 15 mins. To this mixture added oxyethyl methanesulfonate (45 mg, 0.29 mmol) and stirred at It for 17 h. Work up (EtOAc/HZO) followed by purification by column chromatography on 60-120 mesh silicagel using a gradient mixture of DCM and MeOH (98:2) as eluent afforded the titled compound (90 mg) as a brown solid (15 mg). M.P.: 148-152 0C. MS (m/z): 423.3 [M+H]+, Example 42 pyl 4-{5-[3-flu0r0(methylcarbamoyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromofluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown solid. M.P.: 116-120 0C. MS (m/z): 440.3 [M+H]+ Example 43 2-Flu0r0[2-(1-isobutyrylpiperidinyl)benz0[d]0xazolyl]benzamide: Tert-butyl 4- [5-(4-carbamoyl-3 -flurophenyl)benzo[cfloxazolyl]piperidine carboxylate (190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added roacetic acid (1.5 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro(2-(piperidin zo[d]oxazolyl)benzamide 2,2,2-trifluoroacetate (190 mg). 2-Fluoro(2-(piperidin yl)benzo[d]oxazolyl)benzamide 2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was ved in DMF (7 ml) and added isobutyric acid (47 mg, 0.46 mmol), EDC.HCl (200 mg, 1.04 mmol), HOBt (70 mg, 0.5 mmol) and TEA (0.7 ml, 3.3 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (120 mg) as a brown solid. M.P.: 193-196 0C. MS (m/z): 410.2 [M+H]+ Example 44 Isopropyl 4-[6-(4-carbam0ylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: ollowing the General Procedure-3, the titled compound (55 mg) was prepared from Intermediate 16 (360 mg, 0.87 mmol) and 4-bromofluorobenzamide (190 mg, 0.87 mmol) as an off-white solid. M.P.: 178-181 0C. MS (m/z): 425.45 [M+H]+, Example 45 Isopropyl 4-{5-[3-flu0r0(2-hydroxyethylcarbamoyl)phenyl]benz0[d]0xazol yl}piperidinecarb0xylate: Following the General Procedure-3, the titled compound (65 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and ofluoro-N-(2-hydroxyethyl)benzamide (110 mg, 0.43 mmol) as a brown solid. M.P.: 145-147 0C. MS (m/z): 470.4 [M+H]+ Example 46 Isopropyl 3-flu0r0(is0pr0pylcarbamoyl)phenyl]benzo[d]0xazolyl}piperidine- 1-carb0xylate: Following the General Procedure-3, the titled compound (45 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 3-fluoro(isopropylcarbamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a grey solid. M.P.: 147-150 0C. MS (m/z): 468.4 [M+H]+, Example 47 Isopropyl 4-{5-[4-(N-methylsulfamoyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: ollowing the General Procedure-3, the titled nd (35 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(N-methylsulfamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a white solid. M.P.: 179-181 0C. MS (m/z): 458.3 [M+H]+, Example 48 Isopropyl 4-{5-[6-(methylcarbamoyl)pyridinyl]benz0[d]0xazolyl}piperidine carboxylate: Following the General Procedure-l, the titled compound (20 mg) was ed from Intermediate 13 (300 mg, 0.82 mmol) and N-methyl(4,4,5,5-tetramethyl-l,3,2- dioxaborolanyl)picolinamide (256 mg, 0.98 mmol) as a brown solid. M.P.: 158-161 0C.
MS (m/z): 423.5 [M+H]+, Example 49 pyl 4-{5-[3-methyl(methylcarbamoyl)phenyl]benzo[d]0xazolyl}piperidine- 1-carb0xylate: Following the General Procedure-3, the titled compound (30 mg) was prepared from Intermediate 13 (250 mg, 0.68 mmol) and N,2-dimethyl(4,4,5,5-tetramethyl-l,3,2- dioxaborolanyl)benzamide (187 mg, 0.68 mmol) as an off-white solid. M.P.: 151-154 0C.
MS (m/z): 436.5 [M+H]+.
Example 50 Isopropyl 4-(cyclopropylcarbamoyl)flu0r0phenyl]benz0[d]0xazol yl}piperidinecarb0xylate: Following the General Procedure-3, the titled compound (20 mg) was prepared from Intermediate 14 (250 mg, 0.61 mmol) and 4-bromo-N—cyclopropylfluorobenzamide (156 mg, 0.61 mmol) as an off-white solid. M.P.: 5 0C. MS (m/z): 466.3 [M+H]+, Example 51 2-Flu0r0{2-[1-(5-flu0r0pyrimidinyl)piperidinyl]benz0[d]0xazol yl}benzamide: Following general procedure-3 and using DMF as solvent titled compound (40 mg) was obtained from intermediate 19 (150 mg, 0.35 mmol) and ofluorobenzamide (77 mg, 0.35 mmol) as a brown solid. M.P.: 226-229 0C. MS (m/z): 436.5 , Example 52 Tert-butyl 4-[5-(4-carbamoylflu0r0phenyl)benzofuranyl]-5,6-dihydr0pyridine- 1(2H)-carb0xylate: Following the general procedure-4, the titled nd (370 mg) was obtained from ediate 21 (1.5 g, 5.02 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6- dihydropyridine-1(2H)-carboxylate (1.99 g, 6 mmol) as a white solid. M.P.: 189-1910C. 1H- NMR (8 ppm, DMSO-dg, 400 MHz): 7.95 (s, 1H), 7.77-7.71 (m, 1H), 7.69-7.58 (m, 6H), 6.91 (s, 1H), 6.50 (s, 1H), 4.10-4.05 (m, 2H), 3.56 (t, J 5.5, 2H), 3.30-3.20 (m, 2H), 1.42 (s, 9H).
Example 53 2-flu0r0{2-[1-(propylsulfonyl)piperidinyl]benz0[d]0xazolyl}benzamide: Intermediate 25 (80 mg, 0.24 mmol) was dissolved in DCM (10 ml) and added TEA (35 mg, 0.35 mmol). This mixture was stirred at rt for 15 mins. Reaction mixture cooled to 00C and added propanesulphonylchloride (33 mg, 0.23 mmol). Reaction mixture stirred at It for 2 h. Work up (DCM/HZO) ed the crude product. Crude was purified by column chromatography on 60-120 mesh silica gel using a nt mixture of EtOAC and Petether (70:30) as eluent to afford the titled compound (8 mg) as a white solid. M.P.: 222-2250C. 1H- NMR (5 ppm, DMSO-dg, 400 MHz): 8.09 (d, J 1.3, 1H), 7.82-7.72 (m, 3H), 7.71-7.61 (m, 4H), 3.67-3.58 (m, 2H), .22 (m, 2H), 3.09-2.99 (m, 2H), .16 (m, 2H), 1.92-1.79 (m, 2H), 1.69 (hextet, J 7.6, 2H), 0.98 (t, J 7.4, 3H).
Example 56 Tert-butyl 4-{2-[2-flu0r0(methylsulf0nyl)phenyl]-lH-benzo[d]imidazolyl}-5,6- dihydropyridine-1(2H)-carb0xylate: 2-[2-fluoro(methylsulfonyl)phenyl](4,4,5,5-tetramethyl-1,3,2-dioxa n -benzo[d]imidazole (880 mg, 2.12 mmol), utyl 4-(trifluoromethylsulfonyloxy)-5,6- dihydropyridine-1(2H)-carboxylate (700 mg, 2.12 mmol) and sodium carbonate (1.13 g, 11.48 mmol) were dissolved in DMF (20 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (138 mg, 0.17 mmol). This mixture stirred at 80 0C for 90 mins in microwave. Reaction mixture diluted with water and work up (AcOEt/H20) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (35:65) to afford the titled compound (240 mg) as an off-white solid. 1H-NMR (8 ppm, DMSO-dg, 400 MHz): 12.80 (s, 1H), 8.49 (t, J 7.5, 1H), 8.02 (d, J 10.4, 1H), 7.92 (d, J 8.2, 1H), 7.88-7.67 (m, 1H), 7.66-7.54 (m,1H), .39 (m, 1H), 6.18 (bs, 1H), 4.02 (bs, 2H), 3.57 (bs, 2H), 3.34 (s, 3H), 2.60-2.55 (m, 2H), 1.43 (s, 9H).
Example 57 Tert-butyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]-1H-benz0[d]imidazol yl}piperidinecarb0xylate: Example 56 (240 mg, 0.51 mmol) was dissolved in MeOH (25 ml) and added % Pd/C (100 mg). This mixture was stirred in an auto clave under hydrogen atmosphere at 55 psi for 14 h. After 14 h, reaction mass filtered through a pad of celite and celite washed thoroughly with methanol. Methanol removed on rotavapour to obtain the titled compound (200 mg) as an off-white solid. M.P.: 208-2115 0C. lH-NMR (5 ppm, DMSO-dg, 400 MHz): 12.71 (s, 1H), 8.47 (t, J 7.7, 1H), 8.01 (d, J 10.4, 1H), 7.91 (dd, J 1.4, 8.2, 1H), 7.65- 7.40 (m, 2H), 7.30-7.24 (m, 1H), 4.08 (d, J 11.1, 2H), 3.33 (s, 3H), 2.92-2.74 (m, 3H), 1.81 (d, J 12.2, 2H), 1.54 (d, J 10.4, 2H), 1.42 (s, 9H).
Example 58 -[1-(5-ethylpyrimidinyl)piperidinyl][2-flu0r0(methylsulfonyl)phenyl]-1H- d]imidazole: e 57 (150 mg, 0.3 mmol) ved in DCM (12 ml) and added TFA (0.45 ml). This mixture stirred at rt for 3 h. After 3 h, DCM d on rotavapour and co- distilled with DCM to obtain 2-[2-fluoro(methylsulfonyl)phenyl](piperidinyl)-1H- benzo[cflimidazole 2,2,2-trifluoroacetate (150 mg). 2-[2-fluoro(methylsulfonyl)phenyl] (piperidinyl)-1H—benzo[cflimidazole 2,2,2-trifluoroacetate (150 mg, 0.4 mmol) and 2- chloroethylpyrimidine (60 mg, 0.4 mmol) were dissolved in propanol (10 ml) and added DiPEA (0.6 ml, 3.2 mmol). This mixture was refluxed at 90 0C for 12 h. After 12 h, propanol removed on rotavapor to obtain the residue. Residue was purified on combiflash using Ethyl acetate and Petether (1:1) as eluent to afford the titled nd (50 mg) as a white solid. M.P.: 220-223.5 0C. 1H-NMR (8 ppm, , DMSO-dg, 400 MHz): 12.69 (d, J 12.8, 1H), 8.49-8.45 (m, 1H), 8.24 (s, 2H), 8.00 (dd, J 1.5, 10.4, 1H), 7.91 (d, J 8.3, 1H), 7.67-7.56 (m, 1H), 7.55-7.40 (m, 1H), 7.22-7.12 (m, 1H), 4.80 (d, J 12.6, 2H), 3.33 (s, 3H), 2.97-2.91 (m, 3H), 2.43 (q, J 7.5, 2H), 1.89 (d, J 12.4, 2H), 1.69-1.54 (m, 2H), 1.13 (t, J 7.6, 3H).
Example 59 Tert-butyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}-5,6- dihydropyridine-1(2H)-carb0xylate: 2-[2-fluoro(methylsulfonyl)phenyl](4,4,5,5-tetramethyl-1,3,2-dioxa borolanyl)benzo[cfloxazole (50 mg, 0.12 mmol), tert-butyl 4-(trifluoromethylsulfonyloxy)- ,6-dihydropyridine-1(2H)-carboxylate (39 mg, 0.12 mmol) and sodium carbonate (38 mg, 0.36 mmol) were dissolved in DMF (2 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CH2Clz (10 mg, 0.009 mmol). This mixture stirred at 80 0C for 90 mins in microwave. Reaction e diluted with water and work up (AcOEt/H20) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (27:73) to afford the titled compound (25 mg) as an ite solid.
M.P.: 149-151 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.47 (t, J 7.4, 1H), 7.93-7.80 (m, 3H), 7.65-7.57 (m, 1H), 7.53-7.45 (m, 1H), 6.20-6.02 (m, 1H), 4.12 (bs, 2H), 3.68 (t, J 5.3, 2H), 3.13 (s, 3H), 2.65-2.55 (m, 2H), 1.50 (s, 9H).
Example 60 Tert-butyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Example 59 (300 mg, 0.64 mmol) was dissolved in MeOH (25 ml) and added % Pd/C (100 mg). This mixture was d in an auto clave under hydrogen atmosphere at 55 psi for 14 h. After 14 h, reaction mass filtered through a pad of celite and celite washed ghly with methanol. Methanol removed on rotavapour to obtain the titled compound (200 mg) as an off-white solid. M.P.: 168-171 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.46 (t, J 7.1, 1H), 7.87 (t, J 7.6, 2H), 7.69 (s, 1H), 7.57 (d, J 8.4, 1H), 7.30 (d, J 7.7, 1H), 4.35- 4.20 (m, 2H), 3.13 (s, 3H), 2.90-2.75 (m, 3H), 1.90 (d, J 12.6, 2H), 1.63-1.74 (m, 2H), 1.49 (s, 9H).
Example 61 2-[2-flu0r0(methylsulfonyl)phenyl](piperidinyl)benz0[d]0xazole 2,2,2- trifluoroacetate: Example 60 (170 mg, 0.36 mmol) dissolved in DCM (15 ml) and added TFA (0.6 ml). This mixture stirred at rt for 3 h. After 3 h, DCM removed on rotavapour and co- distilled with DCM to obtain 2-[2-fluoro(methylsulfonyl)phenyl](piperidin yl)benzo[d]oxazole 2,2,2-trifluoroacetate (180 mg). M.P.: 223—227 0C. lH-NMR (5 ppm, DMSO-d6, 400 MHz): 8.61 (bs, 1H), 8.47 (t, J 7.6, 1H), 8.39 (bs, 1H), 8.07 (d, J 10, 1H), 7.98 (d, J 8.1, 1H), 7.83 (d, J 8.4, 1H), 7.74 (s, 1H), 7.39 (d, J 8.3, 1H), 3.45-3.33 (m, 5H), 3.10-2.98 (m, 3H), 2.02 (d, J 12.9, 2H), 1.93-1.80 (m, 2H). e 62 -[1-(5-ethylpyrimidinyl)piperidinyl][2-flu0r0 (methylsulfonyl)phenyl]benzo[d]0xazole: e 61 (150 mg, 0.31 mmol) and 2-chloroethylpyrimidine (48 mg, 0.34 mmol) were dissolved in propanol (20 ml) and added DiPEA (0.4 ml, 2.45 mmol).
This mixture was refluxed at 90 0C for 12 h. After 12 h, propanol removed on rotavapor to obtain the residue. Residue was purified on combiflash using Ethyl acetate and er (35:65) as eluent to afford the titled compound (30 mg) as a white solid. M.P.: 190-194 0C. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.49-8.43 (m, 1H), 8.20 (s, 2H), 7.90-7.84 (m, 2H), 7.71 (s, 1H), 7.57 (d, J 8.4, 1H), 7.33 (d, J 7.6, 1H), 4.91 (d, J 13.3, 2H), 3.13 (s, 3H), 3.05- 2.90 (m, 3H), 2.48 (q, J 7.5, 2H), 2.00 (d, J 13, 2H), 1.83-1.70 (m, 2H), 1.20 (t, J 7.6, 3H).
WO 70867 Example 63 utyl 4-{7-flu0r0[2-flu0r0(methylsulf0nyl)phenyl]benzo[d]0xazol yl}piperidinecarb0xylate: ing the general procedure-1 Tert-butyl 4-{7-fluoro[2-fluoro (methylsulfony1)pheny1]benzo[cfloxazoly1}-5,6-dihydropyridine-1(2H)-carboxy1ate (180 mg) obtained from intermediate 31 (600 mg, 1.38 mmol) and tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxy1ate (456 mg, 1.38 mmol).
Tert—butyl 4- { o [2-fluoro(methylsulfony1)pheny1]benzo[cfloxazol-5 ,6- dihydropyridine-1(2H)-carboxy1ate (150 mg, 0.30 mmol) dissolved in MeOH and added Pd/C (71 mg). This mixture was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 h.
Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the titled compound (100 mg) as a brown solid. M.P.: 188- 192.4 0C. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.47 (t, J 7.12, 1H), 7.89 (t, J 7.6, 2H), 7.49 (s, 1H), 7.07 (d, J 11.2, 1H), 4.28 (bs, 2H), 3.13 (s, 3H), 2.90-2.72 (m, 3H), 1.95-1.85 (m, 2H), 1.72-1.56 (m, 2H). 1.49 (s, 9H).
Example 64 Isopropyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Example 61 (100 mg, 0.20 mmol) was dissolved in DCM (10 m1) and added TEA (1.4 m1). This mixture was stirred at It for 30 mins. Isopropyl chloroforrnate in toluene (50 mg, 0.41 mmol) added to the above mixture and stirred at It for 1 h. Reaction mixture diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by ash with EA and Petehter (35:65) as eluent to afford the title compound (50 mg) as an off-white solid. M.P.: 151.4-1565 0C. lH-NMR (5 ppm, , DMSO-dg, 400 MHz): 8.47 (t, J 7.8, 1H), 8.05 (d, J 10.3, 1H), 7.97 (dd, J 1.5, 8.2, 1H), 7.78- 7.74 (m, 2H), 7.42 (d, J 8.6, 1H), 4.79 (heptet, J 6.2, 1H), 4.12 (d, J 11.6, 2H), 3.29 (s, 3H), 2.95-2.80 (m, 3H), 1.86-1.77 (m, 2H), 1.65-1.55 (m, 2H), 1.20 (d, J 6.2, 6H).
Example 65 Tert-butyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benzo[d]thiazolyl}-5,6- dihydropyridine-1(2H)-carb0xylate: Following the l procedure-1, the titled compound (140 mg) was obtained from intermediate 35 (300 mg, 0.69 mmol) and tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (230 mg, 0.69 mmol) as a brown solid. M.P.: 1599-1635 0C. (8 ppm, , CDC13, 400 MHz): 8.68 (t, J 6.9, 1H), 8.09 (d, J 8.6, 1H), 7.94 (d, J 1.3, 1H), .82 (m, 2H), 7.88 (d, J 1.7, 8.2, 1H), 6.18 (s, 1H), 4.13 (d, J 2.3, 2H), 3.69 (t, J 5.6, 2H), 3.12 (s, 3H), 2.62 (bs, 2H), 1.50 (s, 9H).
Example 66 Tert-butyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benzo[d]thiazolyl}-5,6- dihydropyridine-1(2H)-carb0xylate: Following the general procedure-1, the titled compound (120 mg) was obtained from intermediate 39 (230 mg, 0.53 mmol) and tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (175 mg, 0.53 mmol) as an yellow solid. M.P.: 170—1743 0C. 1H-NMR(8 ppm, , CDC13, 400 MHz): 8.71-8.67 (m, 1H), 8.13 (d, J 1.3, 1H), 7.95-7.82 (m, 3H), 7.55 (dd, J 1.7, 8.5, 1H), 6.19 (s, 1H), 4.14 (d, J 2.6, 2H), 3.70 (t, J 5.6, 2H), 3.12 (s, 3H), 2.70-2.60 (m, 2H), 1.51 (s, 9H).
Example 67 Tert-butyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: Following the general procedure-1 Tert-butyl 4-{2-[2-fluoro (methylsulfonyl)phenyl]benzo[cfloxazolyl} -5,6-dihydropyridine-1(2H)-carboxylate (35 mg) obtained from intermediate 41 (400 mg, 0.96 mmol) and tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (318 mg, 0.961 mmol).
Tert-butyl 4- { 2- [2-fluoro(methylsulfonyl)phenyl]benzo [cfloxazolyl } -5,6- dihydropyridine-1(2H)-carboxylate (50 mg, 0.11 mmol) dissolved in MeOH and added Pd/C (30 mg). This mixture was stirred in an auto clave under hydrogen atmosphere at 55 Psi for 12 h. on e filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the crude. Crude was ed by combiflash using EtOAc and Petether (38:62) as eluent to obtain titled compound (18 mg) as an off-white solid. M.P.: 1662-1693 0C. lH-NMR (5 ppm, , CDClg, 400 MHz): 8.48-8.46 (m, 1H), 7.91— 7.83 (m, 2H), 7.78 (d, J 8.3, 1H), 7.49 (s, 1H), 7.33—7.25 (m, 1H), 4.35—4.20 (m, 2H), 3.13 (s, 3H), 2.90—2.75 (m, 3H), 1.95-1.85 (m, 2H), 1.75-1.60 (m, 2H), 1.49 (s, 9H).
Example 68 {2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}piperidinecarb0xylate: [3 10] Tert—butyl 4- { 2- [2-f1uoro(methylsulfonyl)phenyl]benzo [cflthiazol-S- yl}piperidinecarboxylate (30 mg, 0.06 mmol) dissolved in MeOH and added Pd/C (30 mg). This mixture was stirred in an auto clave under hydrogen atmosphere at 55 Psi for 87 h.
Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on pour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (20:80) as eluent to obtain titled compound (12 mg) as a pale-yellow solid. M.P.: 781 0C. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.71-8.65 (m, 1H), 7.99 (s, 1H), 7.93- 7.82 (m, 3H), 7.35 (dd, J 1.5, 8.3, 1H), 4.35-4.20 (m, 2H), 3.12 (s, 3H), 2.91-2.79 (m, 3H), 1.96-1.88 (m, 2H), 1.80-1.68 (m, 2H), 1.50 (s, 9H).
Example 69 Ethyl 4-{2-[2-fluoro(methylsulf0nyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: [3 1 1] 2- [2-fluoro(methylsulfonyl)phenyl] (piperidinyl)benzo[d]oxazole 2,2,2-trif1uoroacetate (80 mg, 0.16 mmol) dissolved in DCM (10 ml) and added TEA (0.12 ml, 0.8 mmol). This e was stirred at It for 30 mins. Ethylchloro formate (35 mg, 0.33 mmol) was added to the above mixture and stirred at It for 30 mins. on mixture extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (38:62) as eluent to afford the titled compound (20 mg) as an off-white solid. M.P.: 8 0C. 1H-NMR(8 ppm, , CDClg, 400 MHz): 8.49- 8.44 (m, 1H), 7.90-7.84 (m, 2H), 7.69 (d, J 1.2, 1H), 7.58 (d, J 8.5, 1H), 7.30 (dd, J 1.6, 8.5, 1H), 4.40-4.28 (m, 2H), 4.17 (q, J 7.1, 2H), 3.13 (s, 3H), 2.95-2.79 (m, 3H), 1.96-1.88 (m, 2H), .65 (m, 2H), 1.29 (t, J 7.1, 3H).
Example 70 Tert-butyl 4-(trifluoromethyl)phenyl]benz0[d]0xazolyl}piperidine ylate: [3 12] Following the general ure- 1, Tert-butyl 4- { 2- [4- (trifluoromethyl)phenyl]benzo[cfloxazol-5 -yl}-5,6-dihydropyridine-1(2H)-carboxylate (90 mg) obtained from intermediate 44 (200 mg, 0.51 mmol) and Tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.511 mmol).
Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[cfloxazolyl}-5,6-dihydropyridine-1(2H)- ylate (90 mg, 0.2 mmol) dissolved in MeOH (30 ml) and added Pd/C (90 mg). This mixture was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered through celite and washed the cetile with MeOH. ol was removed on rotavapour to obtain the crude. Crude was triturated with Petether and EtOAc (1:1) to obtain the titled compound (50 mg) as an off-white solid. M.P.: 161-164 0C. lH-NMR (5 ppm, , CDCl3, 400 MHz): 8.36 (d, J 8.2, 2H), 7.78 (d, J 8.4, 2H), 7.63 (d, J 1.5, 1H), 7.53 (d, J 8.4, 1H), .20 (m, 1H), 4.34-4.20 (m, 2H), 2.90-2.75 (m, 3H), 1.93-1.84 (m, 2H), 1.74-1.62 (m, 2H), 1.49 (s, 9H).
Example 71 Isopropyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: [3 13] Tert-butyl 4- { 2- [2-fluoro(methylsulfonyl)phenyl]benzo[cfloxazol yl}piperidinecarboxylate (270 mg, 5.7 mmol) dissolved in THF (5 ml) and added EtzOHCl (10 ml). Reaction mixture stirred at It for 3 h. Ether removed on rotavapour to obtain crude. Crude was triturated with ether to obtain 2-[2-fluoro (methylsulfonyl)phenyl](piperidinyl)benzo[cfloxazole hydrochloride (225 mg). 2-[2- 4-(methylsulfonyl)phenyl](piperidinyl)benzo[cfloxazole hydrochloride (70 mg, 0.17 mmol) was dissolved in DCM (5 ml) and added TEA (0.11 ml, 0.85 mmol). This e stirred at It for 30 mins and added isopropylchloro formate in toluene (42 mg, 0.34 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAC and Petether (1:3) as eluent to afford the titled compound (30 mg) as a white solid. M.P.: 1703-1743 0C. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.47-8.44 (m, 1H), 7.90-7.83 (m, 2H), 7.78 (d, J 8.3, 1H), 7.49 (s, 1H), 7.28 (dd. J 1.5, 8.3, 1H), 4.96 (septet, J 6.2, 1H), 4.40- 4.28 (m, 2H), 3.13 (s, 3H), 2.92-2.80 (m, 3H), 1.96-1.88 (m, 2H), 1.75-1.62 (m, 2H), 1.28 (d, J 6.2, 6H).
Example 72 Ethyl 4-{2-[2-fluoro(methylsulf0nyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: [3 14] 2- [2-fluoro(methy1su1fony1)phenyl] (piperidiny1)benzo[d]oxazole hydrochloride (70 mg, 0.17 mmol) from Example 71 was dissolved in DCM (10 m1) and added TEA (0.12 ml, 0.83 mmol). This mixture stirred at It for 30 mins and added hloro formate (35 mg, 0.34 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on pour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (1:3) as eluent to afford the titled compound (30 mg) as a white solid. M.P.: 1535—1575 0C. 1H—NMR (5 ppm, , CDC13, 400 MHz): 8.49-8.43 (m, 1H), 7.90-7.82 (m, 2H), 7.78 (d, J 8.3, 1H), 7.49 (s, 1H), 7.28 (dd, J 1.4, 8.3, 1H), 4.42-4.28 (m, 2H), 4.17 (q, J 7.1, 2H), 3.13 (s, 3H), 2.95-2.80 (m, 3H), 1.96-1.88 (m, 2H), 1.75-1.65 (m, 2H), 1.29 (t, J 7.1, 3H).
Example 73 Ethyl 4-{2-[2-flu0r0(methylsulfonyhenyl]benzo[d]oxazolyl}piperidine carboxylate: [3 15] Tert—butyl 4- { 2- [2-f1uoro(methylsulfony1)pheny1]benzo azol-S- yl}piperidinecarboxylate (130 mg, 0.27 mmol) ved in DCM (5 m1) and added TFA (0.5 m1). Reaction mixture stirred at It for 3 h. DCM removed on rotavapour to obtain crude.
Crude was triturated with ether to obtain 2-[2-fluoro(methylsulfonyl)phenyl](piperidin- 4-y1)benzo[cflthiazole 2,2,2-trif1uoroacetate (150 mg). 2-[2-fluoro(methylsulfonyl) phenyl](piperidiny1)benzo[cflthiazole 2,2,2-trifluoroacetate (105 mg, 0.21 mmol) was dissolved in DCM (20 m1) and added TEA (0.23 ml, 1.66 mmol). This mixture stirred at rt for mins and added isopropylchloro formate in e (51 mg, 0.42 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and er (1:3) as eluent to afford the titled compound (60 mg) as a grey solid. M.P.: 174-177 0C. 1H- NMR (8 ppm, , CDC13, 400 MHz): 8.71-8.65 (m, 1H), 8.00 (d, J 1.2, 1H), 7.93-7.81 (m, 3H), 7.35 (dd, J 1.6, 8.4, 1H), 4.96 (septet, J 6.2, 1H), 4.40—4.22 (m, 2H), 3.12 (s, 3H), 2.95-2.82 (m, 3H), 20—190 (m, 2H), 1.80-1.64 (m, 2H), 1.28 (d, J 6.3, 6 H).
Example 74 Benzyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperidine carboxylate: [3 16] 2- [2-fluoro(methylsulfonyl)phenyl] (piperidinyl)benzo[d]oxazole 2,2,2-trif1uoroacetate (Example 61) (70 mg, 0.14 mmol) dissolved in DCM (10 ml) and added TEA (0.1 ml, 0.72 mmol). This e stirred at rt for 30 mins and added benzyl carbonochloridate in toluene (48 mg, 0.28 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (1:2) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 172—175 0C. 1H-NMR(8 ppm, , CDC13, 400 MHz): 8.49-8.43 (m, 1H), 7.90-7.84 (m, 2H), 7.68 (d, J 1.4, 1H), 7.57 (d, J 8.5, 1H), 7.42- 7.22 (m, 6H), 5.17 (s, 2H), 4.42-4.25 (bs, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), .88 (m, 2H), 1.80-1.65 (m, 2H).
Example 75 Isobutyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benzo[d]0xaz01yl}piperidine-l-carboxylate: [3 17] 2- [2-fluoro(methylsulfonyl)phenyl] (piperidinyl)benzo[cfloxazole 2,2,2-trif1uoroacetate (Example 61) (140 mg, 0.29 mmol), isobutanol (42 mg, 0.58 mmol), rbonyl diimidazole (82 mg, 0.50 mmol) and TEA (0.2 ml, 1.26 mmol) were ved in DMF (2.4 ml). Reaction mixture heated to 60 0C for 18 h. Work up /H20) followed by purification of the crude by column chromatography on 60-120 mesh silica gel using EtOAc and Petether as eluent to afford the titled compound as a white solid. M.P.: 169-173 0C. 1H-NMR (8 ppm, , CDC13, 400 MHz): .43 (m, 1H), 7.83-7.90 (m, 2H), 7.69 (d, J 1.4, 1H), 7.58 (d, J 8.5, 1H), 7.30 (dd, J 1.7, 8.5, 1H)4.42-4.26 (m, 2H), 3.90 (d, J 6.7, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m, 3H), 1.80-1.65 (m, 2 H), 0.96 (d, J 6.7, 6H).
Example 76 Isopropyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]thiazolyl}piperidine carboxylate: utyl 4- { 2- [2-fluoro(methylsulfonyl)phenyl]benzo azol yl}piperidinecarboxylate (190 mg, 0.38 mmol) dissolved in DCM, cooled to 0 0C, trifluoroacetic acid (0.8 ml) was added and stirred the on mixture at rt for 3 h. DCM and trifluoroacetic acid was removled on rotavapour to obtain the crude. Crude was washed with petether to obtain 2-[2-fluoro(methylsulfonyl)phenyl](piperidinyl)benzo[cflthiazole (190 mg) as an off-white solid. uoro(methylsulfonyl)phenyl](piperidin yl)benzo[d]thiazole (190 mg, 0.38 mmol) dissolved in DCM ( 20 ml). To this mixture added TEA (0.3 g, 3 mmol) and stirred the reaction mixture at It for 30 mins. on mixture cooled to 0 0C and added isopropylchloro formate (92 mg, 0.75 mmol). This mixture was stirred at It for 30 mins. Work up (DCM/H20) followed by evaporation of the DCM on rotavapour afforded crude. Crude was triturated with diethyl ether and dried on high vacuum to afford the titled compound (60 mg) as a white solid. M.P.: 163-166 0C. 1H—NMR (5 ppm, CDC13, 400 MHz): Example 77 Isopropyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]0xazolyl}piperidine carboxylate: Tert—butyl 4- { 2- [4-(trifluoromethyl)phenyl]benzo[cfloxazol-5 -yl } -5 ,6- dihydropyridine-1(2H)-carboxylate (80 mg, 0.17 mmol) dissolved in DCM (15 ml), cooled to 0 0C, trifluoroacetic acid (0.1 ml) was added and stirred the reaction e at rt for 3 h.
DCM and trifluoroacetic acid was removed on rotavapour to obtain the crude. Crude was washed with petether to obtain 5-(piperidinyl)(4- (trifluoromethyl)phenyl)benzo[d]oxazole 2,2,2-trifluoroacetate (90 mg) as an off-white solid. -(piperidinyl)(4-(trifluoromethyl)phenyl)benzo[d]oxazole trifluoroacetate (90 mg, 0.19 mmol) dissolved in DCM (15 ml). To this mixture added TEA (0.1 ml, 0.56 mmol) and stirred the reaction e at It for 30 mins. Reaction mixture cooled to 0 0C and added isopropylchloro formate (46 mg, 0.38 mmol). This mixture was stirred at It for 30 mins.
Work up (DCM/H20) followed by evaporation of the DCM on rotavapour afforded crude.
Crude was purified with combiflash using a gradient mixture of ethylacetate and petether ) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 145-148 0C. 1H-NMR (8 ppm, CDC13, 400 MHz): 8.36 (d, J 8.1, 2H), 7.78 (d, J 8.3, 2H), 7.62 (d, J 1.5, 1H), 7.54 (d, J 8.5, 1H), 7.29-7.21 (m, 1H), 4.96 (septet, 6.2, 1H), 4.31 (bs, 2H), 2.95- 2.76 (m, 3H), 1.90 (d, J 12.7, 2H), 1.75-1.63 (m, 2H), 1.27 (d, J 6.2, 6H).
WO 70867 2012/041632 Example 78 Isopropyl 4-(2-p-tolylbenzo[d]0xazolyl)piperidinecarb0xylate: Intermediate 49 (40 mg, 0.14 mmol) was dissolved in DCM (10 ml) and added trifluooroacetic acid (0.15 ml) at 00C. This mixture was stirred at It for 3 h. After 3 h DCM was removed on rotavapour and the residue that ed was washed with diethyl ether to obtain 6-(piperidinyl)p-tolylbenzo[d]oxazole 2,2,2-trifluoroacetate (40 mg). 6- (piperidinyl)p-tolylbenzo[d]oxazole 2,2,2-trif1uoroacetate (40 mg, 0.1 mmol) was dissolved in DCM (10 ml) and added TEA (0.1 ml, 0.79 mmol) at 00C. To the above mixture isopropylchloro e (24 mg, 0.2 mmol) was added and stirred at rt for 15 mins. Workup (DCM/H20) followed by column purification on 60-120 mesh silica gel using EtOAc and Petether (2:8) as eluent afforded the titled compound (12 mg) as an off-white solid. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.12 (d, J 8.2, 2H), 7.66 (d, J 8.2, 1H), 7.40 (d, J 1.2, 1H), 7.32 (d, J 8, 2H), 7.19 (dd, J 1.4, 8.2, 1H), 4.96 (septet, J 6.2, 1H), 4.32 (bs, 2H), 2.93-2.75 (m, 3H), 2.44 (s, 3H), 1.90 (d, J 13.4, 2H), 1.75-1.65 (m, 2H), 1.27 (d, J 6.2, 6H). e 79 3-{4-[2-(2-flu0r0(methylsulfonyl)phenyl)benz0[d]0xazolyl]-5,6-dihydr0pyridin- 1(2H)-ylsulf0nyl}pr0panol: Example 59 (200 mg, 0.42 mmol) was dissolved in DCM (30 ml) and added TFA (1.5 ml, 9.2 mmol). This mixture was d at It for 3 h and DCM was removed on rotavapour to obtain a residue. Residue was co-distilled with diethyl ether to obtain 2-(2- fluoro(methylsulfonyl)phenyl)(1,2,3,6-tetrahydropyridinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (210 mg). 2-(2-fluoro(methylsulfonyl)phenyl)(1,2,3,6- tetrahydropyridinyl)benzo[d]oxazole 2,2,2-trif1uoroacetate (200 mg, 0.4 mmol) was dissolved in DCM (10 ml) and added TEA (0.46 ml, 3.3 mmol). This mixture was stirred at rt for 30 mins. After 30 mins reaction mixture cooled to 00C and added ethyl 3- (chlorosulfonyl)propanoate (164 mg, 0.4 mmol). This reaction continued for 30 mins at rt.
Work up (HZO/DCM) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (45:55) as eluent afforded ethyl 2-{4-[2-(2-fluoro (methylsulfonyl)phenyl]benzo [cfloxazolyl } -5 ydropyridin- 1 (2H)-ylsulfonyl)acetate (120 mg). Ethyl 2-{4-[2-(2-fluoro(methylsulfonyl)phenyl]benzo[cfloxazolyl}-5,6- dihydropyridin-1(2H)-ylsulfonyl)acetate (100 mg, 0.19 mmol) was dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg, 0.38 mmol) at 00C. This mixture was stirred at same temperature for 90 mins. After completion of the reaction, reaction mass quenched with 1N HCl (7 ml). Work up 20) followed by purification on ash using a gradient mixture of EtOAc and Petether (80:20) as eluent ed the titled compound (40 mg) as a white solid. M.P.: 184-186 0C. 1H-NMR(8 ppm, , CDC13, 400 MHz): 8.48 (t, J 8.1, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 8.00-7.94 (m, 2H), 7.84 (d, J 8.6, 1H), 7.63 (dd, J 1.8, 8.5, 1H), 6.29 (s, 1H), 4.64 (t, J 5.3, 1H), 3.94 (d, J 2.9, 2H), 3.50-3.42 (m, 4H), 3.36 (s, 3H), 3.18-3.10 (m, 2H), 2.70-2.62 (m, 2H), 1.88-1.80 (m, 2H).
Example 80 3-{4-[2-(2-flu0r0(methylsulfonyl)phenyl)benzo[d]oxazol-S-yl]piperidin ylsulfonyl}pr0panol: e 61 (0.2 g, 0.41 mmol) was dissolved in DCM and and added TEA (0.33 g, 3.3 mmol). This mixture was stirred at It for 30 mins. After 30 mins reaction mixture cooled to 00C and added ethyl 3-(chlorosulfonyl)propanoate (245 mg, 1.2 mmol). This reaction continued for 30 mins at rt. Work up CM) followed by column cation on combiflash using a gradient mixture of EtOAc and Petether (65:35) as eluent afforded ethyl 2- { 4- [2-(2-fluoro(methylsulfonyl)phenyl)benzo [cfloxazol-S-yl]piperidin ylsulfonyl } acetate. Ethyl 2- { 4- [2-(2-fluoro(methylsulfonyl)phenyl)benzo [cfloxazol yl]piperidinylsulfonyl}acetate (100 mg, 0.19 mmol) was dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg, 0.37 mmol) at 00C. This mixture was stirred at same temperature for 90 mins. After completion of the reaction, reaction mass quenched with 1N HCl (7 ml). Work up (DCM/H20) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (65:35) as eluent afforded the titled compound (120 mg) as an off-white solid. M.P.: 6 0C 1H-NMR (5 ppm, , DMSO-dg, 400 MHz): 8.47 (t, J 8.03, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 7.97 (dd, J 1.6, 8.2, 1H), 7.82-7.75 (m, 2H), 7.43 (dd, J 1.5, 8.6, 1H), 4.66 (t, J 5.3, 1H), 3.74 (d, J 12.1, 2H), 3.50 (q, J 6.1, 2H), 3.38 (s, 3H), 3.12- 3.06 (m, 2H), 2.98-2.80 (m, 3H), 1.96-1.90 (m, 2H), 1.88-1.81 (m, 2H), 1.79-1.69 (m, 2H).
Example 81 2-(2-flu0r0(methylsulfonyl)phenyl)benzo[d]oxazol-S-yl]piperidin ylsulfonyl}pr0panol: 2012/041632 Example 61 (150 mg, and 0.31 mmol) and 2-Chlorofluoropyrimidine (44 mg, 0.34 mmol) were dissolved in panol (20 ml). To this mixture DiPEA (0.45 ml) was added and heated to 900C for 12 h. Isopropanol was d on rotavapour to obtain a residue. Residue was purified by combiflash using a gradient mixture of EtOAc and Petether (38:62) as eluent to afford the titled compound (30 mg) as an off-white solid. M. P.: 220- 22200 MS (m/z): 471.2 [M+H]+, Example 82 Tert-butyl 4-[2-(4-carbam0ylflu0r0phenyl)benz0[d]0xazolyl]piperidine carboxylate: Intermediate 52 (40 mg, 0.1 mmol), 2-fluoro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)benzamide (30 mg, 0.12 mmol) and KP (18 mg, 0.3 mmol) were dissolved in a mixture of DMF (1 ml) and and water (0.4 ml). This mixture was purged with N2 for 30 mins. Pd(dppf)Cl2.CH2Cl2 was added to the above mixture and again purged with N2 for 30 mins. This reaction mixture was heated to 900C for 12 h. Work up (EtOAc and H20) ed by purification on combiflash using a gradient mixture of EtOAc and Petether (55:45) as eluent afforded the titled nd (3 mg) as an Off-White solid. MS (m/z): 439.5 Example 83 2-[2-fluoro(methylsulf0nyl)phenyl][4-(3-is0pr0pyl-1,2,4-0xadiazolyl)piperidin- 1-yl]benz0[d]0xazole: Intermediate 28 (150 mg, 0.41 mmol), 3-isopropyl(piperidinyl)-1,2,4- oxadiazole hloride (96 mg, 0.5 mmol), K2C03 (59 mg, 0.43 mmol), CuCl (2 mg, 0.02 mmol), acetyl acetone (5 mg, 0.05 mmol) were dissolved in NMP (1 ml). This reaction mixture was stirred at 1300C for 16 h under N2 atmposphere. Work up (EtOAc/H20) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (30:70) as eluent afforded the titled compound (25 mg) as a pale-yellow solid. M. P.: 206- 2090C. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.26 (d, J 8.2, 1H), 7.97 (d, J 1.4, 1H), 7.69 (d, J 1.4, 1H), 7.63 (dd, J 1.5, 8.2, 1H), 7.56-7.48 (m, 2H), 3.49-3.39 (m, 2H), 3.15-3.04 (m, 5H), 3.03-2.93 (m, 2H), 2.25-2.16 (m, 4h), 1.36 (d, J 7, 6H).
Example 84 utyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidinecarb0xylate Following the general procedure, tert—butyl 4-[2-(4- (trifluoromethy1)pheny1]benzo[cfloxazoly1)-5,6-dihydropyridine- 1(2H)-carboxy1ate (260 mg) was prepared from intermediate 55 (420 mg, 1.08 mmol) and tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxy1ate (358 mg, 1.08 mmol). tert-butyl 4-[2-(4-(trifluoromethy1)pheny1]benzo[d]oxazoly1)-5,6-dihydropyridine-1(2H)- carboxylate (260 mg, 0.58 mmol) was dissolved in methanol (8 m1) and added Pd/C (5%) (520 mg). This mixture was stirred under H2 pressure (6.5 kg) for 12 h. Combined methanol fractions were evaporated on rotavapour to obtain the crude. Crude was purified on ash using a gradient mixture of EtOAc and Petether (1:9) as eluent to afford the titled compound (150 mg) as a white solid. M. P.: 174-1790C. MS : 446.46 [M+H]+, Example 85 Isopropyl 4-{2-[2-flu0r0(methylsulfonyl)phenyl]benz0[d]0xazolyl}piperazine carboxylate: Intermediate 28 (490 mg, 1.32 mmol), ylpiprazine (280 mg, 1.6 mmol), K2CO3 (190 mg, 1.4 mmol), CuCl (6.5 mg, 0.05 mmol), acetyl acetone (17 mg, 0.12 mmol) were ved in NMP (2 m1). This on mixture was stirred at 1300C for 15 h under N2 atmposphere. Work up (EtOAc/H20) followed by column purification on 60-120 mesh silica gel using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded 5-(4- benzylpiperaziny1)[2-f1uoro(methylsulfony1)pheny1]benzo[cfloxazole (250 mg) as a yellow solid. 5 -(4-Benzy1piperaziny1)[2-fluoro (methylsulfony1)pheny1]benzo[cfloxazole (130 mg, 0.28 mmol) dissolved in DCM (15 m1) and added pylchloro formate (102 mg, 0.84 mmol). This mixture was stirred at reflux for 18 h. Work up (DCM/H20) followed by purification of the crude by column tography on 230-400 mesh silica gel using a gradient mixture of EtOAc and Petether (30:70) as eluent afforded the titled compound (25 mg) as a pale-yellow solid. M.P.: 231- 2340C. 1H-NMR (8 ppm, , CDC13, 400 MHz): 8.28 (d, J 8.7, 1H), 7.96 (d, J 1.6, 1H), 7.68- 7.64 (m, 2H), 7.57-7.47 (m, 2H), 4.95 (septet, J 6.2, 1H), 3.71-3.63 (m, 4H), 3.12-3.06 (m, 4H), 1.26 (d, J 6.2, 6H).
Example 86 utyl 4-{2-[4-(trifluoromethyl)phenyl]0xazolo[5,4-b]pyridinyl}-5,6- dihydropyridine-1(2H)-carb0xylate: Following the general procedure-1, the titled compound (230 mg) was obtained from intermediate 58 (500 mg, 1.28 mmol) and tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (467 mg, 1.4 mmol) as an off-white solid. M.P.: 207—212 0C. lH-NMR (5 ppm, , CDC13, 400 MHz): 8.44-8.38 (m, 3H), 8.04 (d, J 2.2, 1H), 7.82 (d, J 8.3, 2H), 6.13 (bs, 1H), 4.14 (d, J 2.6, 2H), 3.70 (t, J 5.6, 2H), 2.59 (bs, 2H), 1.50 (s, 9H).
Example 87 Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridinyl}piperidine carboxylate: Tert-butyl 4- { 2- [4-(trif1uoromethyl)phenyl]oxazolo[5,4-b]pyridinyl } -5 ,6- dihydropyridine-1(2H)-carboxylate (170 mg, 0.38 mmol) was ved in methanol (10 ml) and added Pd/C (5%) (283 mg). This mixture was stirred under H2 pressure (6.5 kg) for 12 h.
Combined methanol fractions were evaporated on pour to obtain the crude. Crude was purified on combiflash using a gradient mixture of EtOAc and Petether (1:9) as eluent to afford the titled compound (35 mg) as a white solid. M. 13.; 184-18800 lH-NMR (5 ppm, CDC13, 400 MHz): 8.40 (d, J 8.1, 2H), 8.27 (d, J 2, 1H), 7.93 (d, J 2, 1H), 7.81 (d, J 8.3, 2H), 4.31 (d, J 13.5, 2H), 2.91-2.81 (m, 3H), 1.91 (d, J 12.9, 2H), 1.78-1.62 (m, 2H), 1.50 (s, 9H).
BIOLOGICAL ASSAY The ical properties of the compounds of this invention may be confirmed by a number of biological assays. The biological assays which can be been carried out with the compounds of the invention are exemplified below.
A. In Vitro cyclic AMP Assay: cAMP measurements were done using a Cisbio dynamic 2 HTRF kit o, Bedford, MA) according to the cturer’s protocol. Briefly, HEK293 cells (0.2 x 106/well) were plated in a 24 well plate and incubated overnight at 37°C. Cells were transfected with either empty vector DNA or human GPRl l9 expression plasmid DNA using Lipofectamine 2000 (Invitrogen). After 24 h, transfected cells were harvested, counted and plated at 1000 cells/5 ul in a black 384 welled small volume plate. Cells were treated with desired concentrations of compounds and incubated for 60 min at room temperature. Lysis buffer containing cAMP-d2 and cryptate conjugate were added and incubated for l h. HRTF ratio was measured on a microplate reader (BMG Labtech., Germany) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm with an integration time of 400 usec.Data were analyzed using Graphpad Prism (Graphpad software; San Diego CA) for EC50 determination.
Results: The results are as given in Table I as % Induction@ 10 uM Table II as % Induction@ 10 uM and EC 50 in nM B. In Vitro Mouse GPR 119 cyclic AMP Assay: cAMP measurements were done using a Cisbio c 2 HTRF kit (Cisbio, Bedford, MA) according to the manufacturer’s protocol. HEK293 Cells were stably transfected with Mouse GPRll9 sion plasmid DNA using Lipofectamine 2000 (Invitrogen) and ined in culture. Cells were harvested, counted and plated at 1000 cells/5 ul in a black 384 welled small volume plate. Cells were treated with desired concentrations of compounds and incubated for 60 min at room temperature. Lysis buffer containing cAMP-d2 and te conjugate were added and incubated for l h. HRTF ratio was measured on a microplate reader (BMG Labtech., Germany) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 615 nm with an ation time of 400 usec. Data were analyzed using Graphpad Prism (Graphpad re; San Diego CA) for EC50 determination.For example example 12 showed an EC 50 of < 25 nM C. In Vitro 5 cyclic AMP Assay: cAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio, d, MA) according to the manufacturer’s protocol. Briefly, HIT-T15 cells were harvested, counted and plated at 4000 cells/5 ul PBS-BSA solution in a black 384 welled small volume plate. Cells were treated with desired concentrations of compounds and ted for 60 min at room temperature. Lysis buffer containing cAMP-d2 and te conjugate were added and WO 70867 incubated for 1 h. HRTF ratio was measured on a microplate reader (BMG Labtech., Germany) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 615 nm with an integration time of 400 usec. Data were analyzed using Graphpad Prism (Graphpad software; San Diego CA) for EC50 ination. For instance example 12 showed an EC 50 of < 25 nM D. In Vitro HIT-T15 Insulin Assay: Insulin measurements were done using a Ultra Sensitive Insulin ELISA kit (Crystal Chem Inc, USA) according to the manufacturer’s protocol. Briefly, 2.5 x 105 HIT-15 cells/well were plated in 24 well plate and incubator for 24 hours. Next day, media was replaced with DMEM-3 mM Glucose with 10% Horse Serum, 2.5% PBS, 1% pen-strep and r incubated for 24 h. Cells were d with desired concentrations of compounds and incubated for 60 min at room temperature. Supernatant was collected, centrifuged and soup added to the pre-coated strips followed by ELISA. The absorbance was measured at 450 and 630 nM. Data were analyzed using Graphpad Prism (Graphpad software; San Diego CA) for EC50 determination.
Table I ND COMPOUND ion EC50* EXAMPLE—1 E—29 78.62 A+ EXAMPLE—2 EXAMPLE—30 62.20 C EXAMPLE—3 E—31 80.38 A++ EXAMPLE—4 EXAMPLE—32 63.93 EXAMPLE—5 EXAMPLE—33 10.61 EXAMPLE—6 E—34 — EXAMPLE—7 EXAMPLE—35 0.28 EXAMPLE—8 EXAMPLE—36 4.83 EXAMPLE—9 EXAMPLE—37 6.56 EXAMPLE—10 EXAMPLE—38 16.59 EXAMPLE—11 70.09 EXAMPLE—39 27.49 EXAMPLE—12 82.95 EXAMPLE—40 21.87 EXAMPLE—13_“ E—41 — ///////// EXAMPLE—14 EXAMPLE—42 78.40 EXAMPLE—15_“ EXAMPLE—43 48.77 /UWUUUUUUUEUEUUUUUUUUU> EXAMPLE—16 EXAMPLE—44 64.79 EXAMPLE—17 EXAMPLE—45 56.43 \ EXAMPLE—18 EXAMPLE—46 53.02 \ EXAMPLE—19 EXAMPLE—47 33.13 \ EXAMPLE—20 EXAMPLE—48 26.66 \ E—21 EXAMPLE—49 32.86 \ EXAMPLE—22 EXAMPLE—50 38.68 \ EXAMPLE—23 EXAMPLE—51 38.73 \ EXAMPLE—24 A++ EXAMPLE—52 68.36 EXAMPLE—25 EXAMPLE—53 39.87 / EXAMPLE—26 73.99 \D EXAMPLE—27 46.54 \D EXAMPLE—28 45.37 \D ND: Not done; A++ : 525 nM ; A+ : > 25 to 550 nM; A : > 50 to S 100 nM; B COMPOUND I Induction I EC50* COMPOUND ion EC50* : > 100 to S 500 nM; C : > 500 to S 1000 nM; *Emax varies between 65 to 80 Table II COMPOUND Induction EC50* COMPOUND Induction EC50* EXAVIPLE—56 38.53 - EXAVIPLE—72 81.57 A++ EXAVIPLE—57 47.05 EXAVIPLE—73 46.02 C AVIPLE—58 32.25 AVIPLE—74 14. 69 ND AVIPLE—59 63.76 EXAVIPLE—75 57.49 ND AVIPLE—60 72.78 AVIPLE—76 7490 A AVIPLE—61 29.77 AVIPLE—77 8037 A AVIPLE—62 59. 34 EXAVIPLE—78 59 36 \D LE—71 76.63 A++ LE—87 47.29 \D NDzVotdone;;A++:S25nM;A+:>25to§50nM;A:>50&<250nM;B:<500nM; C : > 500 to S 1000 nM; *Emax varies between 65 to 80 %.
E: Oral glucose tolerance test (OGTT) in C57Bl/6J mice: Results of the OGTT not only diagnose diabetes but can determine if a subject has impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Having either of these conditions indicates a significantly increased risk of developing diabetes in the future.
After the quarantine period, 6 hr fasted animals were ized and divided into various groups depending on their blood glucose levels. Test compounds or rd drug (sitagliptin) was prepared as a suspension in a vehicle ting of 0.5% methylcellulose and Tween 80 as a suspending agent. The standard drug, Compound A (example-64), nd B (example-42) or vehicle were administered by oral gavage in a volume of 10mL/kg. 1 h after the test compounds, standard drug and vehicle stration, blood was sampled from the tail vein of mice at time 0 min (baseline) and at 30, 60, 90 and 120 min after an oral glucose load of 2.0 g/kg of body weight. Food, but not water, was withheld from the cages during the course of experiment. The area under curve (AUC) of experimental animals was compared with that of vehicle-treated control group. The results are shown in s 1 and 2 and are discussed below.
Results: Compound A and Sitagliptin dosed as single agents lowered AUCglucose by 24% and 59%, respectively, and Compound B and sitagliptin dosed as single agents lowered AUCglucose by 22 and 50%, respectively.
F: Intraperitoneal glucose tolerance test (IPGTT) in C57Bl/6J mice: After the quarantine period, 6 hr fasted animals are to be randomized and divided into various groups depending on their blood glucose levels. Test compound or standard drug is to be prepared as a suspension in a vehicle consisting of 0.5% methylcellulose in which Tween 80 as a suspending agent. The compound or vehicle is to be administered by oral gavage in a volume of lOmL/kg. l h after drug or vehicle administration, blood is to be sampled from the tail vein of mice at time 0 min (baseline) and at 30, 60, 90 and 120 min after intraperitoneal administration of e solution of 2.0 g/kg of body . Food, but not water is to be withheld from the cages during the course of experiment. The area under curve (AUC) of mental animals will be ed with that of e-treated control group.
G: Oral glucose nce test (OGTT) in Streptozotocin & nicotinamide induced type 2 diabetes in CD-1 mice: After the tine period, animals are to be randomized and divided into various groups depending on their body weights and animals are to be administered with nicotinamide (100 mg/kg) and streptozotocin (150 mg/kg) by intraperitoneally to induce diabetes. Sham control mice are to be intraperitoneally administered with physiological saline. Two weeks later, the diabetic mice were grouped to provide similar mean non-fasting blood e levels in each group, 6 hr fasted animals are to be randomized and divided into various groups depending on their blood glucose levels. Test compound or rd drug is to be prepared as a suspension in a vehicle consisting of 0.5% methylcellulose in which Tween 80 as a suspending agent. The compound or vehicle is to be administered by oral gavage in a volume of lOmL/kg. l h after drug or vehicle administration, blood is to be d from the tail vein of mice at time 0 min (baseline) and at 30, 60, 90 and 120 min after an oral glucose load of 2.0 g/kg of body weight. Food, but not water is to be withheld from the cages during the course of ment. The area under curve (AUC) of mental animals will be compared with that of vehicle-treated control group.
H: Sub-acute treatment of test compound in Streptozotocin & nicotinamide induced type 2 diabetes in CD-1 mice: After the quarantine period, animals are to be randomized and divided into various groups depending on their body weights and animals are to be administered with nicotinamide (100 mg/kg) and streptozotocin (150 mg/kg) by intraperitoneally to induce diabetes. Sham control mice are to be intraperitoneally administered with physiological saline. Two weeks later, the diabetic mice are to be grouped to e similar mean non- fasting blood glucose levels in each group, on day 0, fasted animals are to be ized and divided into various groups depending on their blood glucose levels. Test compound or standard drug is to be prepared as a suspension in a vehicle consisting of 0.5% methylcellulose in which Tween 80 as a suspending agent. The compound or vehicle is to be administered by oral gavage in a volume of lOmL/kg. l h after drug or vehicle administration, blood is to be sampled from the tail vein of mice at time 0 min (baseline) and at 30, 60, 90 and 120 min after an oral glucose load of 2.0 g/kg of body . Food, but not water is to be withheld from the cages during the course of experiment. The area under curve (AUC) of experimental animals will be compared with that of vehicle- treated control group. After conducting the OGTT on day 0, the treatment will be continued for 14 days, on day 14, 6 hr fasted s will be used for the same OGTT procedure. After conducting the OGTT, blood samples will be collected from the animals and ed for the lipid profile, insulin, and GLP-1 levels.
Although the invention herein has been described with nce to particular embodiments, it is to be tood that these embodiments are merely illustrative of the principles and applications of the present invention. It is ore to be understood that numerous cations may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent and/or patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or WO 70867 patent application was specifically and individually indicated to be incorporated herein by reference.

Claims (33)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1.-
1. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV): (A-I) (A-II) (B-I) ) (B-II) (B-IV) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically able salt, or N-oxide thereof, wherein Ar is selected from substituted aryl, substituted or unsubstituted heteroaryl or Cy1; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is N; Z is CO, O or S(O)q; Cy1 is selected from substituted or unsubstituted lkyl or substituted or unsubstituted heterocyclic group; each occurrence of R2, and R3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, tuted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or tituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, , –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, -CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb- , -S(=O) aRb-, q-NR -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb-; each occurrence of R1 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, tuted or unsubstituted C3-6 cycloalkylalkyl, tuted or unsubstituted C3-6 lkenyl, -ORa, -S(=O)q-Ra, -NRaRb, –C(=Y)-Ra, -C(=Y)-Ra, - CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb-, -S(=O)q-NRaRb-, -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 l, tuted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of Rc is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 lkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; each occurrence of Y is independently selected from O, S, and NRa; and each occurrence of q independently represents 0, 1 or 2; D and E are independently selected from CH or N; R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), tuted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or tituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, tuted or unsubstituted heteroarylalkyl, , -C(O)Ra, -C(S)Ra, RaRb, -C(O)ONRaRb, - NRaRb, -NRaCONRaRb, -N(Ra)SORb, SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, -NRaC(S)Rb –NRaC(S)NRaRb, -SONRaRb-, -ORa, -ORaC(O)NRaRb, - ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa, -SO2Rm and -ONO2, each occurrence of Rd is independently en, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted l, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or tituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or tituted arylalkyl, tuted or unsubstituted heteroaryl, substituted or tituted heteroarylalkyl, and -ONO2; each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl may be joined to form (i) a substituted or unsubstituted, saturated or rated 3-14 membered ring, which may ally e one or more heteroatoms which may be the same or different and are selected from O, NR’ (where R’ is H or alkyl) or S, or (ii) an oxo (=O), thio (=S) or imino (=NR’) (where R’ is H or ; Rm is hydrogen, nitro, hydroxy, cyano, halogen, tuted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, tuted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; and each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ≠ 0; wherein the term substituted refers to a substitution selected from en, hydroxy, halogen, yl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, tuted or unsubstituted cycloalkenylalkyl, substituted or tituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or tituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR’, -C(O)R’, -C(S)R’, -C(O)NR’R”, -C(O)ONR’R”, -NR’R”, -NR’CONR’R”, -N(R’)SOR”, -N(R’)SO2R”, -(=N-N(R’)R”), -NR’C(O)OR”, O)R”-, S)R”, -NR’C(S)NR”R”’, - SONR’R”-, -SO 2NR’R”-, -OR’, -OR’C(O)NR”R”’, -OR’C(O)OR”-, R’, -OC(O)NR’R”,- R’NR”C(O)R”’, -R’OR”, -R’C(O)OR”, -R’C(O)NR”R’”, -R’C(O)R”, O)R”, -SR’, -SCR’, -SO2R’, and -ONO2; wherein R’, R” and R”’ in each of the above groups can independently be hydrogen, hydrogen, y, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or any two of R’, R” and R”’ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRX (where Rx is H or substituted or unsubstituted alkyl) or S or form oxo (=O), thio (=S) or imino (=NR’ where R’ is defined above); wherein the substituents in the entioned substituted groups cannot be further tuted; and with the proviso that the compound of formula (A-I) or (A-II) is not 5-(1-methyl-1H-indolyl)(piperidinyl)benzo[d]oxazole; 5-(1-methyl-1H-indolyl)(4-methylpiperazinyl)benzo[d]oxazole; 2-(4,4-dimethylpiperidinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; 2-(4-methoxypiperidinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; 2-(azepanyl)(1-methyl-1H-indolyl)benzo[d]oxazole; 2-(azetidinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; 5-(1-methyl-1H-indolyl)(pyrrolidinyl)benzo[d]oxazole; 2-(4-isopropylpiperazinyl)(1-methyl-1H-indolyl)benzo[d]oxazole; ethyl-1H-indolyl)(piperazinyl)benzo[d]oxazole; 5-(1-Methyl-1H-indolyl)(4-trifluoromethyl-piperidinyl)-benzooxazole; 2-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro-isoquinoline; 2-(1,3-Dihydro-isoindolyl)(1-methyl-1H-indolyl)-benzooxazole; 2-(2,3-Dihydro-indol-1 -yl)(1-methyl-1H-indolyl)-benzooxazole; 2-Methyl[5-(1-methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydro-2H- pyrazolo[4,3- c]pyridine; 2-(Hexahydro-cyclopenta[c]pyrrolyl)(1-methyl-1H-indolyl)-benzooxazole; 2-(1,3-Dihydro-isoindolyl)imidazo[1,2-a]pyridinyl-benzooxazole; 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepinyl)(1,3-dihydro-isoindolyl)- benzooxazole; 2-(1,3 -Dihydro-isoindolyl)-5 -(1-methyl-1H-indazol-5 -yl)-benzooxazole; 2-(5,7-Dihydro-pyrrolo[3,4-b]pyridinyl)(1-methyl-1H-indolyl)- benzooxazole; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-imidazo[1 ,2- zine; 2-(3 ydro-1H-pyrrolo[1,2-a]pyrazinyl)-5 -(1-methyl-1H-indol-5 -yl)- benzooxazole; 2-(1,3-Dihydro-isoindolyl)(4-methoxymethyl-phenyl)-benzooxazole; 2-(1,3-Dihydro-isoindolyl)(3-methoxy-phenyl)-benzooxazole; 2-(1 ,3-Dihydro-isoindolyl)(3-methoxymethoxymethyl-phenyl)- benzooxazole; 2-(1,3-Dihydro-isoindolyl)(2-methoxy-pyridinyl)-benzooxazole; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-imidazo[1,5- a]pyrazine; 6-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidine; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro- [1,7]naphthyridine; 2-(Hexahydro-pyrrolo[1 yrazinyl) c (1-methyl-1H-indolyl)-benzooxazol ; 2-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro- [2,7]naphthyridine; 2-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrolyl)(1-methyl-1H-indolyl)- benzooxazole; 5-[5-(l-Methyl-1H-indolyl)-benzooxazol-yl]-4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridine; 2-Methyl[5-(1-methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydrooxazolo [5,4-c]pyridine; 5-[2-(1,3-Dihydro-isoindolyl)-benzooxazolyl]hydroxy-benzonitrile; 6-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro- [1,6]naphthyridine; 7-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1 ,5- a]pyrazine; 2-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro- [2,6]naphthyridine; 2,2,2-Trifluoro{4-[5-(1-methyl-1H-indol-5 -yl)-benzooxazolyl] -piperazinyl }-ethanone; 2-(1,3-Dihydro-pyrrolo[3,4-c]pyridinyl)(l-methyl-1H-indolyl)-benzooxazole; 1-Methyl-1H-indolyl)-benzooxazolyl]-5,6,7,8-tetrahydro- ]triazolo[4,3- a]pyrazine; 5-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydro- [1,2,3]triazolo[1,5- a]pyrazine; 2-(1,3-Dihydro-isoindolyl)-5 etanyl-1H-indolyl)-benzooxazole; 2-(1,3-Dihydro-isoindolyl)(3-ethoxyethoxymethyl-phenyl)-benzooxazole; 5-(1-Methyl-1H-indolyl)(4-phenyl-piperazinyl)-benzooxazole; 1-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-1,2,3,4-tetrahydro-quinoline; 2-(8-Aza-spiro[4.5]decyl)(1-methyl-1H-indolyl)-benzooxazole; 2-{5-[2-(1,3-Dihydro-isoindolyl)-benzooxazolyl]-indolyl}-acetamide; 2-(2-Aza-spiro[4.4]nonyl)(1-methyl-1H-indolyl)-benzooxazole; 5-(1-Methyl-1H-indolyl)[4-(2,2,2-trifluoro-ethyl)-piperazinyl]-benzooxazole; 3-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]aza-spiro[5.5]undecane; 2-(2,3-Dihydro-pyrrolo[2,3-b]pyridinyl)(1-methyl-1H-indolyl)- benzooxazole; 5-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-4,5,6,7-tetrahydro-pyrazolo[1 ,5- a]pyrazine; [5-(1-Methyl-1H-indolyl)-benzooxazolyl]-thiophenyl-amine; 5-(1-Methyl-1H-indolyl)(8-oxaaza-bicyclo[3.2.1]octyl)-benzooxazole; 6-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]trifluoromethyl-6,7-dihydro-5H- pyrrolo[3,4- d]pyrimidine; 3-[5-(1-Methyl-1H-indolyl)-benzooxazolyl]-2,3,4,5-tetrahydro-1H- benzo[d]azepine; or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof.
2. A compound of the formula (A-III) and (A-IV): (A-III) (A-IV) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically able salt, or N-oxide thereof, wherein Ar, X1, X2, X3, X4, X, Z, D, E, R5, Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl are as d in claim 1; with the proviso a) that for compound of formula (A-III) , n Z is O or S and X4 is N or CR4 then Ar cannot be b) that for compound of formula (A-IV) wherein Z is O or S and X1 is N or CR1 then Ar cannot be wherein R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, S(=O)2-NR1aR1, -R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- S(=O)2-R1, halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R1a, at each ence, is independently hydrogen or (C1-C8)alkyl; R1 is optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, optionally substituted (C1-C10)aryl, a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 atoms selected from N, O, and S, wherein each of r, s, t and u is 0, 1 or 2 with the proviso that u ≠ 0; wherein the term “substituted” is as d according to claim 1; and with the proviso that the compound of formula (A-III) or (A-IV) is not 2-(4-isopropylpiperazinyl)(5-methyl-[1,2,4]oxadiazolyl)benzothiazole; 2-(4-isopropylpiperazinyl)(5-phenyl-[1,2,4]oxadiazolyl)benzothiazole; sopropylpiperazin-1 -yl)(5-pyridinyl-[ 1,2,4]oxadiazolyl)benzothiazole; 2-(4-Cyclopropylpiperazinyl)(3,4-dimethoxyphenyl)benzothiazole; 2-(4-Cyclopropylpiperazin-1 -yl)(6-methoxypyridinyl)benzothiazole; N-{4-[2-(4-Cyclopropylpiperazinyl)benzothiazolyl]phenyl}-acetamide; 2-(4-Cyclopropylpiperazinyl)(1,1-dioxo-16 -isothiazolidinyl)benzothiazole; 6-(5-Chloromethoxypyridiny1)(4cyclopropylpiperazinyl) benzothiazole, trifluoroacetate; or a tautomer, stereoisomer, enantiomer, diastereomer, ceutically acceptable salt, or N-oxide thereof.
3. A compound of claim 1 or claim 2, wherein Ar is selected from N N N N N N N N N N N N Cl Cl F N O N O N N S N N S CF3 O O O S F S Cl S F S O O O , , , , , , , , , , ,, , , , , , , , , , , N N S S O O O O ,
4. A compound of any one of the ing claims, wherein Z is O or S.
5. A compound of any one of the ing claims, wherein X1 is CR1 or N, and R1 is H or Halogen.
6. A compound of any one of the preceding claims, wherein X2 is CH.
7. A compound of any one of the preceding claims, wherein X3 is CH.
8. A compound of any one of the preceding , wherein X4 is CR4 or N, and R4 is H or Halogen.
9. A compound of any one of the preceding claims, wherein Cy1 is selected from N O N O N O F O O O F N O N O N O O O N O N O O , N O O NH N N O , O N N O O , O O N N O S S OH N S OH O , O , O , O N O N O N O F O O O F N O N O N O O O N N N N O N O N O F O O O F N N N O N O N O O O N N N O O O N N N N N N N N N N N N F N N N N N N N N N N N N O N O N O O O O N O N O O O O O F
10. A compound of the a (A-IA), (A-IIA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA): X1 X (R6)p N R5 X4 O (A-IA) (A-IIA) N R5 X1 X X4 X Ar G X3 Ar G X4 O X2 X1 O (R6)p (R6)p (B-IA) (B-IIIA) R5 R5 N N X1 O X4 O Ar G Ar G X3 X2 X4 X X1 X (R6)p (R6)p (B-IIA) (B-IVA) or a tautomer, stereoisomer, enantiomer, reomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein X, X1, X2, X3, X4 and R5 are as defined in claim 1; Ar is G is independently selected from R is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted lkyl; R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, tuted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted lkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or tituted arylalkyl, substituted or tituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, -NRaRb, - NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , -NRaC(O)Rb-, - NRaC(S)Rb –NRaC(S)NRaRb, -SONRaRb-, -SO2NRaRb-, -ORa, -ORaC(O)NRaRb, - )ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, O)Rb, -SRa, -SORa -SO2Ra, and -ONO2; and each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, n, substituted or unsubstituted C1-6 alkyl, substituted or tituted C2-6 alkenyl, tuted or tituted C2-6 alkynyl, tuted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRd or S; p is 0, 1, 2, 3 or 4; wherein the term “substituted” is as defined according to claim 1; and wherein each occurrence of Rd is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), tuted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, tuted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or tituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, tuted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, substituted or tituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO2.
11. A compound of the formula (A-IIIA) or (A-IVA) A) (A-IVA) wherein Ar, G, R5, X1-X4, X, R6 and p are the same as defined in claim 10; with the proviso a) that for compound of formula (A-IIIA) , wherein Z is O or S and X4 is N or CR4 then Ar-G cannot be b) that for compound of formula (A-IVA) wherein Z is O or S and X1 is N or CR1 then Ar-G cannot be R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, -NR1aR1, -C(=O)-R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- S(=O)2-R1, halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R1a, at each occurrence, is independently hydrogen or (C1-C8)alkyl; R1 is ally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted )-alkynyl, optionally substituted 2)-cycloalkyl, optionally substituted (C1-C10)aryl, a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S.
12. A compound of claim 10 or claim 11 wherein X1 is CR1 or N and R1 is H or Halogen.
13. A compound of any one of claims 10 to 12, wherein X2 is CH.
14. A compound of any one of claims 10 to 13, wherein X3 is CH.
15. A compound of any one of claims 10 to 14, wherein X4 is CR4 or N, and R4 is H or Halogen.
16. A compound of any one of claims 10 to 15, wherein R5 is ed from
17. A compound of claim 16, wherein R5 is -C(O)OC(CH3)3 or -C(O)OCH(CH3)2.
18. A compound of any one of claims 10 to 17, n p is 0 or 1.
19. A compound of any one of claims 10 to 18, wherein R6 is halogen, substituted or unsubstituted alkyl or -ORa; wherein Ra is substituted or unsubstituted alkyl.
20. A compound of claim 19, wherein R6 is -F, -CH3, -CF3 or -OCH3.
21. A compound of any one of claims 10 to 20, wherein Ar is selected from and wherein G is as d according to claim 10.
22. A compound of claim 21, wherein G is independently selected from
23. A compound of claim 21 or claim 22, wherein X1 is CH or CF; X is N and Z is S or O.
24. A compound of claim 23 wherein X1 is CH or CF; and Z is O.
25. A compound of the formula (A-IB) and (A-IIB) (A-IB) (A-IIB) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, wherein X, X1, X2, X3, X4 and R5 are as in claim 1; Z is O or S; Ar1-G is p is 0, 1-7 or 8; R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, tuted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, tuted or unsubstituted cyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, a, -C(O)NRaRb, -C(O)ONRaRb, -NRaRb, -NRaCONRaRb, - N(Ra)SORb, -N(Ra)SO2Rb, (Ra)Rb), -NRaC(O)ORb, , -NRaC(O)Rb-, -NRaC(S)Rb – NRaC(S)NRaRb, -SONRaRb-, aRb-, -ORa, -ORaC(O)NRaRb, -ORaC(O)ORb-, - OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, -RaC(O)ORb, -RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa -SO2Ra, and -ONO2; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, tuted or unsubstituted C1-6 alkyl, substituted or tituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or tituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally e one or more heteroatoms which may be same or different and are selected from O, NRc or S, wherein Rc, Rd and the definition of “substituted” are as defined according to claim 1.
26. A compound of the formula (A-IIIB) and (A-IVB) (A-IIIB) (A-IVB) or a tautomer, stereoisomer, enantiomer, diastereomer, ceutically acceptable salt, or N-oxide thereof, Z is O or S Ar1-G is p is 0, 1-7 or 8 and X, X1, X2, X3, X4 R5 and R6 are as defined in claim 25; with the proviso that a) that for compound of formula (A-IIIB) , wherein Z is O or S and X4 is N or CR4 then Ar1-G cannot be b) that for compound of formula (A-IVB) wherein Z is O or S and X1 is N or CR1 then Ar1-G cannot be R1 and R4 is as defined above for compound of formula (A) W is -R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- S(=O)2-R1, halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R1a, at each occurrence, is independently hydrogen or )alkyl; R1 is optionally substituted )-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, optionally substituted (C1-C10)aryl, a 4- to 10-membered ally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S.
27. A nd selected from 2-[1-(5-Ethylpyrimidinyl)piperidinyl][2-fluoro(methylsulfonyl)phenyl]- 1H-benzo[d]imidazole: Tert-butyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]-1H-benzo[d]imidazol yl}piperidinecarboxylate: 2-[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro (methylsulfonyl)phenyl]benzo[d] oxazole: Tert-butyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]methyl-1H-benzo[d]imidazol- 2-yl}piperidinecarboxylate: Tert-butyl 4-{6-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Isopropyl 4-{5-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{7-fluoro[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl} piperidinecarboxylate: Tert-butyl 4-[5-(4-cyanophenyl)benzo[d]oxazolyl]piperidinecarboxylate: utyl 4-{5-[3-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[4-(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine ylate: Tert-butyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[3-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: 2-[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro(1H-tetrazol yl)phenyl]benzo[d]oxazole: Tert-butyl 4-[5-(4-cyanofluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-{5-[3-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{5-[3-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-[5-(4-carbamoylchlorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Tert-butyl 4-[5-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Tert-butyl 4-[5-(3-fluoroisopropoxyphenyl)benzo[d]oxazolyl]piperidine carboxylate: Cyclobutyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazol eridinecarboxylate: Sec-butyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Pentanyl 4-{5-[2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: 5-[2-fluoro(1H-tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole: Isopropyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine ylate: Isopropyl 4-formylphenyl)benzo[d]oxazolyl]piperidinecarboxylate: Isopropyl 4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-carbamoylchlorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-[5-(4-carbamoylfluorohenyl)benzo[d]oxazolyl]piperidine carboxylate: 1-{4-[5-(2-fluoro(1H-tetrazolyl)phenyl)benzo[d]oxazolyl]piperidinyl} methylpropanone: pyl 4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: 6-{2-[1-(isopropoxycarbonyl)piperidinyl]benzo[d]oxazolyl}nicotinic acid: 5-[2-fluoro(1H-tetrazolyl)phenyl][1-(methylsulfonyl)piperidin yl]benzo[d]oxazole: Isopropyl 4-[5-(5-carbamoylpyridinyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-[5-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 4-[5-(4-carbamoylchlorophenyl)benzo[d]oxazolyl]piperidine carboxylate: 2-Fluoro{2-[1-(3-methylbutanoyl)piperidinyl]benzo[d]oxazolyl}benzamide: 1-{4-[5-(2-fluoro(1H-tetrazolyl)phenyl]benzo[d]oxazolyl]piperidinyl} methylbutanone: 5-[2-fluoro(1H-tetrazolyl)phenyl][1-(2-methoxyethyl)piperidin yl]benzo[d]oxazole: Isopropyl 4-{5-[3-fluoro(methylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: 2-Fluoro[2-(1-isobutyrylpiperidinyl)benzo[d]oxazolyl]benzamide: Isopropyl 4-[6-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: Isopropyl 3-fluoro(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{5-[3-fluoro(isopropylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{5-[6-(methylcarbamoyl)pyridinyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{5-[3-methyl(methylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: pyl 4-{5-[4-(cyclopropylcarbamoyl)fluorophenyl]benzo[d]oxazol yl}piperidinecarboxylate: 2-Fluoro{2-[1-(5-fluoropyrimidinyl)piperidinyl]benzo[d]oxazol yl}benzamide: utyl 4-[5-(4-carbamoylfluorophenyl)benzofuranyl]-5,6-dihydropyridine- 1(2H)-carboxylate: 2-fluoro{2-[1-(propylsulfonyl)piperidinyl]benzo[d]oxazolyl}benzamide: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]-1H-benzo[d]imidazolyl}-5,6- dihydropyridine-1(2H)-carboxylate; Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]-1H-benzo[d]imidazolyl} piperidinecarboxylate; 5-[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro(methylsulfonyl)phenyl]- 1H-benzo[d]imidazole; Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}-5,6- dihydropyridine-1(2H)-carboxylate; utyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate; 2-[2-fluoro(methylsulfonyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoro acetate; 5-[1-(5-ethylpyrimidinyl)piperidinyl][2-fluoro(methylsulfonyl)phenyl] benzo [d]oxazole. Tert-butyl 4-{7-fluoro[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazol yl}piperidinecarboxylate: Isopropyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}-5,6- dihydropyridine-1(2H)-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}-5,6- dihydropyridine-1(2H)-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}piperidine- 1-carboxylate: Ethyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine ylate: Tert-butyl 4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine- 1-carboxylate: Ethyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Ethyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Benzyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isobutyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Isopropyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}piperidine- oxylate: Isopropyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine ylate: Isopropyl 4-(2-p-tolylbenzo[d]oxazolyl)piperidinecarboxylate: 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[d]oxazolyl]-5,6- dihydropyridin-1(2H)-ylsulfonyl}propanol: 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[d]oxazolyl]piperidin onyl}propanol: 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[d]oxazolyl]piperidin ylsulfonyl}propanol: Tert-butyl 4-[2-(4-carbamoylfluorophenyl)benzo[d]oxazolyl]piperidine carboxylate: 2-[2-fluoro(methylsulfonyl)phenyl][4-(3-isopropyl-1,2,4-oxadiazol yl)piperidinyl]benzo[d]oxazole: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate Isopropyl 4-{2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperazine- oxylate: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridinyl}-5,6- dihydropyridine-1(2H)-carboxylate: Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridinyl}piperidine carboxylate.
28. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV): (A-I) (A-II) (B-I) (B-III) (B-II) (B-IV) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically able salt, or N-oxide thereof, wherein Ar is selected from substituted aryl, substituted or unsubstituted heteroaryl or Cy1; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is N; Z is CO, O or S(O)q; Cy1 is selected from substituted or unsubstituted cycloalkyl or substituted or tituted heterocyclic group; each occurrence of R2, and R3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, -NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, -Y-CRaRb-, -C(=Y)-NRaRb-, -NRa-C(=Y)-NRaRb- , -S(=O) aRb-, q-NR -NRa-S(=O)q- , and -NRa-NRaRb-; each occurrence of R1 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, , -Ra, -CRaRb-C(=Y)-Ra, - CRaRb-Y-CRaRb-, -NRaRb-, -NRa-C(=Y)-NRaRb-, -S(=O)q-NRaRb-, -NRa-S(=O)q- NRaRb-, and -NRa-NRaRb; each occurrence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C3-6 cycloalkyl, tuted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino , or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of Rc is ndently selected from hydrogen, nitro, y, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or tituted C3-6 cycloalkenyl; each occurrence of Y is independently selected from O, S, and NRa; and each occurrence of q independently represents 0, 1 or 2; D is CH; each occurrence of E is independently selected from CH or N; R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or tituted cycloalkylalkyl, substituted or tituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, tuted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, - NRaRb, -NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, -NRaC(S)Rb S)NRaRb, -SONRaRb-, -ORa, -ORaC(O)NRaRb, - ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, C(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa, -SO2Rm and -ONO2, each occurrence of Rd is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or tituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, tuted or unsubstituted cycloalkenyl, substituted or tituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO2; each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl may be joined to form (i) a substituted or unsubstituted, ted or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR’ (where R’ is H or alkyl) or S, or (ii) an oxo (=O), thio (=S) or imino (=NR’) (where R’ is H or alkyl); Rm is hydrogen, nitro, hydroxy, cyano, halogen, substituted C1-6 alkyl, tuted or tituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 lkenyl; and each of r, s, t and u is 0, 1 or 2 with the proviso that u ≠ 0; and wherein the term substituted refers to a substitution selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or tituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or tituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or tituted heteroarylalkyl, -COOR’, ’, -C(S)R’, -C(O)NR’R”, -C(O)ONR’R”, -NR’R”, -NR’CONR’R”, -N(R’)SOR”, -N(R’)SO2R”, -(=N-N(R’)R”), O)OR”, -NR’C(O)R”-, -NR’C(S)R”, -NR’C(S)NR”R”’, - SONR’R”-, -SO 2NR’R”-, -OR’, -OR’C(O)NR”R”’, O)OR”-, -OC(O)R’, -OC(O)NR’R”,- R’NR”C(O)R”’, -R’OR”, -R’C(O)OR”, -R’C(O)NR”R’”, -R’C(O)R”, O)R”, -SR’, -SCR’, -SO2R’, and -ONO2; n R’, R” and R”’ in each of the above groups can independently be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, tuted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or any two of R’, R” and R”’ may be joined to form a tuted or unsubstituted saturated or rated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRX (where Rx is H or substituted or unsubstituted alkyl) or S or form oxo (=O), thio (=S) or imino (=NR’ where R’ is defined above); wherein the tuents in the aforementioned substituted groups cannot be further substituted.
29. A compound of a (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV): (A-I) (A-II) (B-I) (B-III) (B-II) (B-IV) or a tautomer, stereoisomer, omer, diastereomer, pharmaceutically acceptable salt, or N-oxide f, wherein Ar is selected from substituted aryl, substituted or unsubstituted heteroaryl or Cy1; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is N; Z is CO, O or S(O)q; Cy1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group; each occurrence of R2, and R3 may be same or different and is independently selected from en, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1- 6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, - NRaRb, -Ra, -CRaRb-C(=Y)-Ra, -CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa- NRaRb- , -S(=O)q-NRaRb-, -NRa-S(=O)q-NRaRb-, and -NRa-NRaRb-; each occurrence of R1 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, tuted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, substituted or unsubstituted C3-6 cycloalkenyl, -ORa, -S(=O)q-Ra, - NRaRb, –C(=Y)-Ra, -C(=Y)-Ra, -CRaRb-Y-CRaRb-, -C(=Y)-NRaRb-, -NRa- C(=Y)-NRaRb-, -S(=O)q-NRaRb-, -NRa-S(=O)q-NRaRb-, and -NRa-NRaRb; each occurrence of Ra and Rb may be same or ent and are independently selected from en, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1- 6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb tuents are directly bound to a common atom, they may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of Rc is independently selected from hydrogen, nitro, y, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or tituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and tuted or unsubstituted C3-6 cycloalkenyl; each occurrence of Y is independently selected from O, S, and NRa; and each occurrence of q ndently ents 0, 1 or 2; D and E are independently selected from CH or N, with the proviso that D is CH in compounds of formula (A-I) and (A-II); R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, tuted or unsubstituted alkoxy, substituted or unsubstituted l, substituted or unsubstituted alkynyl, tuted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or tituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, - C(O)ONRaRb, -NRaRb, -NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), - NRaC(O)ORb, , -NRaC(O)Rb-, -NRaC(S)Rb –NRaC(S)NRaRb, -SONRaRb-, -ORa, - ORaC(O)NRaRb, -ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, , )ORb, -RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa, -SO2Rm and - ONO2, each ence of Rd is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or tituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, tuted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO2; each occurrence of Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, tuted or unsubstituted C3-6 lkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; or any two of Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR’ (where R’ is H or alkyl) or S, or (ii) an oxo (=O), thio (=S) or imino (=NR’) (where R’ is H or alkyl); Rm is en, nitro, hydroxy, cyano, halogen, tuted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, tuted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; and each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ≠ 0; and wherein the term substituted refers to a substitution selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or tituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted lkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR’, -C(O)R’, -C(S)R’, -C(O)NR’R”, -C(O)ONR’R”, -NR’R”, -NR’CONR’R”, -N(R’)SOR”, SO2R”, -(=N-N(R’)R”), O)OR”, -NR’C(O)R”-, -NR’C(S)R”, -NR’C(S)NR”R”’, - SONR’R”-, -SO 2NR’R”-, -OR’, -OR’C(O)NR”R”’, -OR’C(O)OR”-, -OC(O)R’, -OC(O)NR’R”,- R’NR”C(O)R”’, -R’OR”, -R’C(O)OR”, -R’C(O)NR”R’”, -R’C(O)R”, -R’OC(O)R”, -SR’, -SCR’, -SO2R’, and -ONO2; wherein R’, R” and R”’ in each of the above groups can ndently be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), tuted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or tituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, tuted or unsubstituted arylalkyl, tuted or unsubstituted heteroaryl, or tuted or unsubstituted heteroarylalkyl, or any two of R’, R” and R”’ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRX (where Rx is H or substituted or unsubstituted alkyl) or S or form oxo (=O), thio (=S) or imino (=NR’ where R’ is defined above); wherein the substituents in the aforementioned tuted groups cannot be further substituted.
30. A pharmaceutical composition, comprising a compound of any one of claims 1-29 and a pharmaceutically acceptable carrier.
31. The pharmaceutical composition of claim 30, further sing one or more additional therapeutic agents and mixtures thereof.
32. Use of a compound of any one of claims 1-29, and optionally an additional therapeutic agent, in the manufacture of a medicament for modulating the activity of the GPR119 receptor in a mammalian subject in need thereof.
33. Use of a compound of any one of claims 1-29, and optionally an additional therapeutic agent, in the manufacture of a medicament for the treatment, prevention and/or ameloriation of diseases or disorders associated with the GPR119 receptor in a mammalian subject in need f, wherein: (a) the diseases or disorders associated with the GPR119 receptor are ed from the group consisting of diabetes mellitus, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, lic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular e, diabetic peripheral ar disease, diabetic retinopathy, metabolic me, a ion related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a ion rated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, mer's disease, Parkinson's disease, Huntington's disease, prionassociated disease, stroke, motor-neuron disease, tic brain injury, spinal cord injury, obesity, delayed wound healing, abnormal heart function, myocardial ischemia, low HDL, high LDL, non-cardiac ischemia, vascular restenosis, pancreatitis, neurodegenerative disease, lipid ers, cognitive impairment and dementia, bone disease, HIV se associated lipodystrophy and glaucoma; (b) the additional therapeutic agent is ed from the group consisting of antidiabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, antiischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, perlipidemic , anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, treatments for heart failure, and treatments for peripheral arterial disease and antiinflammatory agents.
NZ617816A 2011-06-09 2012-06-08 Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of GPR-119 NZ617816B2 (en)

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Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
IN1958/CHE/2011 2011-06-09
IN1958CH2011 2011-06-09
IN2352/CHE/2011 2011-07-11
IN2352CH2011 2011-07-11
US201161543157P 2011-10-04 2011-10-04
US201161543152P 2011-10-04 2011-10-04
US61/543,152 2011-10-04
US61/543,157 2011-10-04
IN3463CH2011 2011-10-07
IN3462/CHE/2011 2011-10-07
IN3462CH2011 2011-10-07
IN3463/CHE/2011 2011-10-07
IN82/CHE/2012 2012-01-09
IN82CH2012 2012-01-09
PCT/US2012/041632 WO2012170867A1 (en) 2011-06-09 2012-06-08 Novel compounds as modulators of gpr-119

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NZ617816B2 true NZ617816B2 (en) 2017-07-04

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