NZ715471B2 - 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

Info

Publication number
NZ715471B2
NZ715471B2 NZ715471A NZ71547112A NZ715471B2 NZ 715471 B2 NZ715471 B2 NZ 715471B2 NZ 715471 A NZ715471 A NZ 715471A NZ 71547112 A NZ71547112 A NZ 71547112A NZ 715471 B2 NZ715471 B2 NZ 715471B2
Authority
NZ
New Zealand
Prior art keywords
substituted
unsubstituted
nrarb
compound
mmol
Prior art date
Application number
NZ715471A
Other versions
NZ715471A (en
Inventor
Gayatri Swaroop Merikapudi
Dhanapalan Nagarathnam
Swaroop Kumar V S Vakkalanka
Srikant Viswanadha
Original Assignee
Rhizen Pharmaceuticals Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhizen Pharmaceuticals Sa filed Critical Rhizen Pharmaceuticals Sa
Publication of NZ715471A publication Critical patent/NZ715471A/en
Publication of NZ715471B2 publication Critical patent/NZ715471B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

Provided are compounds of the general formulae (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, HE/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 r 2011 and 61/543157 dated 4th October 2011, each of which is hereby incorporated by reference.
Field of the ion 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 throughout 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.
Metabolic disorders in general and in ular, obesity 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 1990's. Obesity is one of the most important risk factors for NIDDM sulin-dependent diabetes mellitus) which is the result of an nce between c intake and energy expenditure, and is highly correlated with insulin resistance and diabetes in experimental animals and humans. y is a medical ion in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health ms. 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): 09; World Health zation – y pg 6 & 9, 2000). Obesity increases the hood of various diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and rthritis. y is most commonly caused by a combination of excessive food energy intake, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to t the view that some obese people eat little yet gain weight due to a slow metabolism is limited; on average obese people have a greater energy expenditure than their thin counterparts due to the energy required 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, besity 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, leading to earlier satiation and reduced ability to absorb nts from food.
Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century (see Barness LA et.al., "Obesity: c, molecular, and environmental aspects". Am. J. Med. Genet. A 143A (24): 3016–34, 2007). Obesity is stigmatized in much of the modern world (particularly in the n 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 coronary diseases is doubled in ts 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 ing from the said disease. The reason being, lack of sufficient sis and treatment, being made available to the ts. 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 improving the living nment. Yet, without effective prevention and control programmes, the incidence of diabetes is likely to continue rising globally.
Currently it’s estimated that 285 million people, ponding 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 es, 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 se. 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 middle-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 e enough insulin, or when the body cannot effectively use the insulin it produces.
Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems. It ated in the development of kidney disease, eye diseases and nervous system problems. Diabetes causes about 5% of all deaths globally each year and is likely to increase by > 50% in the next 10 years. Thus the pharmaceutical industry has been on a quest to terize more promising lar targets to satisfy stringent new criteria for yperglycaemic agents.
Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic beta-cells, and requires regular administration of exogenous insulin. Type 1 diabetes usually starts in childhood or young adulthood 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 te blood-glucose levels. NIDDM may be terized by a defect in insulin secretion or by insulin resistance. NIDDM is a genetically heterogeneous disease caused by various reasons such as c susceptibility to other environmental factors contributing to NIDDM, such as obesity, sedentary lifestyle, smoking, and n drugs. NIDDM is a chronic disease resulting from defects in both insulin secretion and sensitivity. In NIDDM patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia and poor outcome. Strategies for ing normoglycemia have focused on ing glucose stimulated insulin secretion (GSIS) through the targeting of G proteincoupled receptors (GPCRs), such as the glucagon-like peptide1 ) receptor, which have been shown to mediate this effect. In clinical therapy for NIDDM, metformin, α-glucosidase tors, thiazolidines (TZDs), and sulfonylurea (SU) derivatives (SUs) are widely used as hypoglycaemic ; 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 an al Society 239th National Meeting (2010, San Francisco).
Further glucagon-like peptide 1 receptor agonists have shown promising therapeutic benefit over the existing therapy by way of body weight loss in type 2 diabetics, however these being injectables (Exenatide, marketed as Byetta) lack patient compliance there by limiting their usage. Other glucagon-like peptide 1 receptor agonists such as Liraglutide (Victoza), Albiglutide and Taspoglutide are also injectables.
GPR119 ts have potential to achieve blood glucose control er 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 agonist would prove to a preferred choice of drug therapy for diabetics.
GPR119, a class-A (rhodopsin-like) G n-coupled receptor, sed ily 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 n secretion and sed 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 simultaneous 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, potent, selective, synthetic GPR119 ts: i) lowers blood glucose t 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 receptor having no close primary sequence relative in the human . Independently, GPR119 has been studied and described in the ture under various synonyms including SNORF25 (see: Bonini et al., US 6,221,660, US 756), RUP3 (Jones et al., WO 2004/065380.), GPCR2 (Takeda 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 933) and e-dependent notropic receptor (Chu et al., Keystone ium. 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 lly occurring 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) . 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 solved.
The demonstration that GPR119 agonists stimulate the release 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 col. ;440:269–279, 2002; Zander et al., 2002; Lancet.; 359:824–830. 2002 and Nielsen LL Drug Discov Today. 10,703–710, 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 1:532-P, 2007; Overton et. al., Cell Metab. 3,167–175, 2006). The hypoph agic 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] /www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib20 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib37 [Link] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268073/#bib37 administered sub-chronically in rodent models of obesity (Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes ;56 Suppl 1:532-P, 2007; Overton et. al., Cell Metab. 3,167–175, 2006).The testing of potent, selective ts for food intake and body weight effects in GPR119-deficient mouse models has not been reported so far.
There are ting evidence about the ms 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.; 1–388 ,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 ycaemia; slowing of diabetes progression; and most improtantaly helping in ion of food intake and body weight.
More recently Unmesh shah et. al., in Chapter-16 Vitamins & Harmones, Volume 84., pg 415-448 (2010), and Chapter-7.Annual reports in Med Chem 44 pg 149-170 (2009) have provided additional insight about GRP119 Patent literature belonging to some of these applicants include the following patents and/or patent applications: 005929A1, WO2009126245A1, WO2008005576A1, WO2008005569A2, WO2007120702A2, WO2007120689A2, WO2007035355A2, 7595A1, WO06083491A2, 6455A2, 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, 081208A1, WO2008081207 A1, WO2008081206A1, 081205A1,WO2008081204A1, WO2007116230A1, WO2007116229A1, WO2007003964A1, WO2007003962A2, WO2007003961A2, WO2007 003960A1, WO05061489A1;WO2011061679A1, WO2011036576A1, WO2010 140092A1, WO2010128425A1, WO2010128414A1, WO2010106457A2; WO2011 062889A1, WO2011 062885A1, WO2011053688A1, WO2010114958A1, WO2010 114957A1, WO2010 075273A1, WO2010075271A1, WO2010075269A1, WO2010 009208A1, WO2010 009207A1, WO2010009195A1, 143049A1, WO2009 055331A2, WO2008 130615A1, WO2008130584A1, WO2008130581A1, WO2008033465A1, WO2008 033464A2, WO2008033460A2, WO2008033456A1, WO2008033431A1, WO2011030139A1, WO2011019538A1, WO2011014520A2, 008663A1, WO2011044001A1, WO2011055770A1, WO2011066137A1, WO2011078306A1, WO2011093501A1, WO2011127051A1, WO2011127106A1, WO2011128394A1, WO2011128395A1, WO2011138427A2, WO2011140160A1, WO2011140161A1, WO2011147951A1, 159657A1, WO2011146335A1, WO2011145718A1, WO2011148922A1, WO2012006955A1, WO2012011707A2, WO2012025811A1, WO2012037393A1, WO2012040279A1, WO2012046249A1, WO2012045363A1, WO2012066077A1, WO2012069948A1, WO2012069917A1.
Further review and literature disclosure on GPR119 molecules have been given by Sempl, G et al., (See; Bio org. Med. Chem. Lett. (2011), doi: 10.1016 / j. bmcl. 3.007), Szewczyk ,J. W. Et al., (See; Bio org. Med. Chem .Lett. (2011), doi:10.1016 / j.bmcl. 2010.12.086), Vincent Mascitti et al., (See; Bioorganic & Medicinal Chemistry Letters 21 (2011) 1306–1309), Shigeru Yoshida et al., (See; Biochemical and Biophysical Research Communications 400 (2010) 745–751), Yulin Wu , (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 Pharmacology (2008 )153, S76–S81), Carolyn Root et al., (See; Journal of Lipid Research, Volume 43, 2002, Pg 1320-1330). All of these patents and/or patent applications and literature disclosures are incorporated herein as reference in their ty for all purposes. [25a] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful ative.
Despite the advances made in the treatment of metabolic disorders and in ular in the treatment of diabetes and obesity, challenges remain in terms of the complexities of the diseases ed, and most importantly the safety concerns expected from any ent. 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 ed herein relate generally to these needs. [26a] Unless the context clearly es ise, 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 “including, but not limited to”. [26b] Although the invention will be described with reference to specific examples it will be iated 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-IA), (A-IIA), (B-IA), (B-IIA), (B-IIIA) or ): X1 X (R6)p N R5 X4 O (A-IA) (A-IIA) N R 5 X 1 X X 4 X Ar G X 3 Ar G X 4 O X 2 X 1 O (R 6) p (R 6) p (B-IA) A) R 5 R 5 N N X 1 O X 4 O Ar G Ar G X 3 X 2 X 4 X X 1 X (R 6) p (R 6) p (B-IIA) (B-IVA) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt or N- oxide thereof, wherein Ar is G is independently selected from wherein variable R on tuent G is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or tituted alkynyl and substituted or unsubstituted cycloalkyl.
X1 is CR1 or N, wherein R1 is H or halogen; X2 is CH; X3 is CH; X4 is CR4 or N, wherein R4 is H or halogen; X is CR, wherein R is hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or tituted C2-6 l, 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-, or -NRaRb-NRaRb-; each occurrence of Y is independently selected from O, S, and NRa; each occurrence of q independently represents 0, 1 or 2; 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 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, tuted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or tituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or tituted heteroaryl, tuted or unsubstituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, NRaRb, - NRaRb, -NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, S)Rb –NRaC(S)NRaRb, Rb-, -SO2NRaRb-, -ORa, - ORaC(O)NRaRb, -ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, - ORb, -RaC(O)NRaRb, -RaC(O)Rb, O)Rb, -SRa, -SORa -SO2Ra, and -ONO2, or any two of Ra and Rb which are directly bound to a common atom may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) 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, NRd or S, wherein 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 l, substituted or unsubstituted cycloalkyl, substituted or tituted 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; and R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or tituted alkoxy, substituted or tituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, tuted or tituted 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, –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-, aRb-, -ORa, -ORaC(O)NRaRb, - )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, substituted or unsubstituted C1-6 alkyl, tuted 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 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 ally 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; and n term “substituted” unless otherwise specified, refers to substitution with any one or any combination of the following substituents and may be the same or different which one or more are selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or tituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or tituted alkynyl, substituted or unsubstituted lkyl, 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 unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, –COOR’, ’, -C(S)R’, - ’R’’, NR’R’’, -NR’R’’, -NR’CONR’R’’, -N(R’)SOR’’, -N(R’)SO2R’’, -(=NN (R’)R’’), - NR’C(O)OR’’, -NR’R’’, -NR’C(O)R’’-, -NR’C(S)R’’ –NR’C(S)NR’’R’’’, - SONR’R’’-, -SO2NR’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’, -SOR’, -SO2R’, -ONO2 wherein R’, R’’ and R’’’ in each of the above groups can independently be hydrogen, en, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or tituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, tuted or unsubstituted cycloalkylalkyl, tuted 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 tuted 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, NRd or S or form oxo (=O), thio (=S) or imino (=NR’, where R’ is defined above), and wherein the tuents in the aforementioned "substituted" groups cannot be further substituted. [26d] According to a second aspect of the present invention there is provided a nd of formula (A-IIIA) or (A-IVA) (A-IIIA) (A-IVA) wherein Ar, G, R5, X, X1-X4, R6, p and the term ‘substituted” are the same as defined in the first aspect of the invention; with the provisos a) that for compound of a (A-IIIA), wherein X4 is N or CR4 then Ar-G cannot be b) that for compound of formula (A-IVA) wherein X1 is N or CR1 then Ar-G cannot be wherein R1 and R4 is as defined above for compound of formula (A-IA) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- -R1, halo, or a 4 to 10-membered optionally tuted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R1a, at each occurrence, is independently en or (C1-C8)alkyl; R1 is ally 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 heteroatoms selected from N, O, and S. [26e] According to a third aspect of the t invention there is provided a compound of formula (A-IB) and (A-IIB) (A-IB) (A-IIB) or a er, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt or N-oxide thereof, Z is O or S; Ar1-G is wherein G is as defined according to the first aspect of the t invention; p is 0, 1-7 or 8; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is CR; each occurrence 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 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, , -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-; 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 alkenyl, substituted or tituted alkynyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkenyl, 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, -C(S)Ra, -C(O)NRaRb, NRaRb, - NRaRb, -NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , - NRaC(O)Rb-, S)Rb –NRaC(S)NRaRb, -SONRaRb-, -SO2NRaRb-, -ORa, - ORaC(O)NRaRb, -ORaC(O)ORb-, -OC(O)Ra, -OC(O)NRaRb, -RaNRbC(O)Ra, -RaORb, - RaC(O)ORb, -RaC(O)NRaRb, )Rb, -RaOC(O)Rb, -SRa, -SORa -SO2Ra, and -ONO2; R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted 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, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or tituted heteroarylalkyl, –COORa, -C(O)Ra, -C(S)Ra, -C(O)NRaRb, -C(O)ONRaRb, -NRaRb, - NRaCONRaRb, 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, -OC(O)NRaRb, C(O)Ra, -RaORb, -RaC(O)ORb, - RaC(O)NRaRb, -RaC(O)Rb, -RaOC(O)Rb, -SRa, -SORa -SO2Ra, and -ONO2; each occurrence of Y is independently selected from O, S, and NRa; and each ence of q independently represents 0, 1 or 2; 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 cycloalkyl, substituted or tituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl, or when two Ra and/or Rb substituents are ly 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 ed 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 tituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; each occurrence of Rd is ndently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), tuted 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or tituted aryl, substituted or unsubstituted heteroarylalkyl, and -ONO2; and and n term “substituted” unless otherwise specified, refers to substitution with any one or any combination of the following substituents and may be the same or different which one or more are selected from the groups such as 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, substituted or unsubstituted heteroarylalkyl, , -C(O)R’, -C(S)R’, -C(O)NR’R’’, -C(O)ONR’R’’, -NR’R’’, -NR’CONR’R’’, SOR’’, - N(R’)SO2R’’, (R’)R’’), - NR’C(O)OR’’, -NR’R’’, O)R’’-, -NR’C(S)R’’ – NR’C(S)NR’’R’’’, -SONR’R’’-, -SO2NR’R’’-, -OR’, -OR’C(O)NR’’R’’’, -OR’C(O)OR’’-, - OC(O)R’, -OC(O)NR’R’’,- R’NR’’C(O)R’’’, ’, -R’C(O)OR’’, -R’C(O)NR’’R’’’, - R’C(O)R’’, -R’OC(O)R’’, -SR’, -SOR’, -SO2R’, -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 , substituted or unsubstituted alkyl, substituted or unsubstituted , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or tituted 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 kyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl, 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 atoms which may be the same or different and are selected from O, NRd or S or form oxo (=O), thio (=S) or imino (=NR’, where R’ is defined , and wherein the substituents in the aforementioned "substituted" groups cannot be further substituted. [26f] According to a fourth aspect of the present invention there is provided a compound of 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 wherein G is as defined according to the first aspect of the present invention; p is 0, 1-7 or 8; R5, X1-X4, X, R6 and the term “substituted” are as defined in any one or more of the preceding aspects of the invention; with the proviso that a) that for compound of formula (A-IIIB), n 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 nd of a (A-IA) W is S(=O)2-R1, S(=O)2-NR1aR1, -C(=O)-R1, -C(=O)-O-R1, -C(=O)-NR1aR1, -NR1a- -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, optionally substituted (C2-C6)-alkynyl, optionally substituted (C3-C12)-cycloalkyl, optionally substituted 0)aryl, a 4- to 10-membered optionally substituted heteroaryl, which ns 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. [26g] According to a fifth aspect of the present invention there is provided a compound selected from Tert-butyl 4-carbamoylfluorophenyl)benzofuranyl]-5,6-dihydropyridine- 1(2H)-carboxylate: and pharmaceutically acceptable salts thereof. [26h] ing to a sixth aspect of the present invention there is provided a pharmaceutical composition, comprising a compound of any one of aspects one to five and a pharmaceutically acceptable r. [26i] According to a seventh aspect of the present invention there is provided use of a therapeutically effective amount of a compound of any one of aspects one to five of the present invention and optionally an additional therapeutic agent in the manufacture of a medicament for ting the activity of the GPR119 receptor in a ian subject. [26j] According to a ninth aspect of the present invention there is provided use of a therapeutically effective amount of at least one compound, of any one of s one to five of the present invention, and optionally an additional therapeutic agent in the cture of a ment for the treatment, prevention and/or ration of diseases or disorders associated with the GPR119 receptor in a mammalian subject n: (a) the es or disorders associated with the GPR119 receptor are selected from the group consisting of diabetes mellitus, type 1 diabetes, type 2 diabetes, inadequate glucose nce, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, 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 e, prionassociated disease, stroke, motor-neuron disease, traumatic brain injury, spinal cord , obesity, delayed wound healing, abnormal heart function, myocardial ischemia, low HDL, high LDL, non-cardiac ischemia, vascular osis, pancreatitis, neurodegenerative disease, lipid disorders, ive impairment and dementia, bone disease, HIV protease associated lipodystrophy and ma; (b) the additional therapeutic agent is selected from the group consisting of antidiabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic , anti-retinopathic agents, anti-neuropathic agents, ephropathic agents, anti-atherosclerotic agents, antiischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, antihyperlipidemic agents, anti-hypertriglyceridemic agents, ypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, treatments for heart failure, and ents for peripheral arterial disease and antiinflammatory agents.
The present ion s 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 aryl 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 substituted or unsubstituted heterocyclic group; Cy1 is selected from substituted or unsubstituted lkyl or substituted or unsubstituted heterocyclic group; each occurrence of R, R1, R2, R3 and R4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, tuted or unsubstituted Cm alky], substituted or unsubstituted CM alkenyl, substituted or unsubstituted C24, alkynyl, substituted or unsubstituted CM cycloalkyl, substituted or unsubstituted C36 cycloalkylalkyl, and substituted or tituted (33.6 cycloalkenyl, — , -012“, -S(=O)q-R“, -NR“R", —C(=Y)-R“, (sunbeam-Ra, -CR“Rb-Y—CR“Rb-, -C(=Y)-NR“R"-, —NR”Rb-C(=Y)-NR“Rb-, sec),- NRaRb—, -NR“Rb-S(=O)q~NR“Rb-, -NR“Rb-NR“Rb-; each occurrence of RL‘ and Rh may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, tuted or unsubstituted Cm alkyl, substituted or unsubstituted CM alkenyl, substituted or unsubstituted (32.5 alkynyl, substituted or tituted C3.5 cycloalkyl, substituted or unsubstituted CM cycloalkylalkyl, and substituted or unsubstituted C34, cycloalkenyl, or when two R" and/or Rb substituents are directly bound to a common atom, they may be joined to form (i) an oxo (=0), thio (=3) or imlno (=NRd), or (ii) a substituted or tituted, saturated or rated 3-10 member ring, which may ally include one or more heteroatoms which may be same or different and are selected from O, NRc or S; each occurrence of R6 is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted Cm alkyl, tuted or unsubstituted CM alkeny], substituted or unsubstituted C245 alkynyl, substituted or unsubstituted C36 cycloalkyl, tuted or unsubstituted C34; cycloalkylalkyl, and substituted or unsubstituted CM cycloalkenyl; each occurrence of Rd is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, 0x0 (=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 cycloalkyialky], tuted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, tuted or unsubstituted heterocyclcyalky], substituted or unsubstituted aryl, substituted or tituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalky], and -ONOZ; each occurrence of Y is independently selected from O, S, and NR“; and each occurrence of q independently ents 0, 1 or 2. r ment is a compound of the formula (A-I), (A-II), (A-III), (A- IV), (B-I), (B-II), (B-III) or (B-IV): R1 Rj RkRa A' x “\l/XR x\ | l r 's I Is ‘\ l / E——-—R5 D E—Rs I Z: D X3\ / x/ \X4 Z I 1“ X4 l 1 in R" R! Ru Rh R‘ R“ R“ (A-I) (A-III) R‘ R’ R“ R' R: R1 RkRu Ar X‘\ Z X M Ms 1 1% e—Rs TYX4\l / w X2\X1/ 2\ x 2 l xi t 1“ Wu Re R, R9 R“ Rf R9 R“ (A-II) (A-IV) (B—II) (B-IV) or a tautomer, stereoisomer, enantiomer, reomer, salt (e.g., pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxide thereof, wherein Z is NR, CO, 0 or S(O)q; wherein R and q is as defned above for compound of fonnula (A) or (B); D and E are independently selected from CH or N; R5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, 0x0 (=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 cycloalkenyi, substituted or unsubstituted cycloalkylalky], substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, tuted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, —COOR“.
-C(O)R“, -C(S)R“, -C(O)NR“Rb, -C(O)ONR“Rb, - NR3Rb, -NR“CONR“R", -N(R“)SOR", -N(R“)SO;R", -(=N—N(R“)R*’), —NR"C(O)OR", — )Rb-, -NR“C(S)R" —NR“C(S)NR“R", -SONR“Rb—, -SOgNR“Rb-, -0R“, — OR“C(O)NR“Rb, -OR"C(O)ORb-, -OC(O)R“, NR“Rb, -R“NRbC(O)R“, 48012”, ~ R“C(O)OR", ~R“C(O)NR“R", )Rb, ~R“OC(O)Rb, -SR“, sona sent“, and -ONOg, wherein R3 and Rh are as defined in formula (A) or (B); each occurrence of Re, Rf, R3, Rh, Ri, R}, Rk and RI is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted CM alkyl, substituted or unsubstituted CM alkenyl, substituted or unsubstituted CM alkynyl, substituted or unsubstituted C36 cycloalkyl, substituted or unsubstituted CM cycloalkylalkyl, and tuted or tituted C36 cycloalkenyl; or any two of R", Rf, R5, 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 0, NR, (where R’ is H or alkyl) or S, or (ii) an 0x0 (=0), thio (:8) or imino (=NR’) (where R’ is H or alkyl); each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u ¢ 0; and and all the other les are the same as described above for the compound of formula (A) and (B), with the proviso 1. that for compound of a (A-III), wherein Z is O or S and X4 is N or CR‘I then Ar cannot be \ \ PM" ”Nd H H H H HH H” w N“ HM w’JJJ Hmr’“\N@W w . H ~H 2. that for compound of formula (A-IV) wherein Z is O or S and X; is N or CR1 then Ar cannot be \ \ ’JJN ,J‘rN\/l H H H H HH :4" w 4w“ HM WW HFN\NG/w w‘ H ~H wherein R] and R4 is as defined above for compound of a (A) W is S(=O)2-R1. -NR1aR1, -C(=O)-R1, -C(=O)-O-R1, 'C(=O)‘NR:.1R1, “NRla'S(=O)2" R], halo, or a 4 to lO-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; Rm, at each occurrence, is independently hydrogen or (Cg-Cs)alkyl; and R1 is optionally substituted )-alkyl, Optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-a1kynyl, optionally substituted g)~cycloalkyl, optionally substituted (C6-C10)aryl, a 4 to lO-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.
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-lV)wherein Ar is selected from N\/:\v N\/ "\/ \/ \Qflw “my \Qm 4% c; Cl W? F3 /° \//° On OmN\/N \//s\©/CF’ 0 “'91,, 4"“ 7//0 0 O 0 F 7% w v! 3/ “W “m. m. m N/ \s/0 F\s//o/ \s//0 i w 0/ / O// o// / \ l | ~\ “\ m In.“ \ m {31] Futher 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) n Ar is Cy'. [32} Further preferred is a compound of formula(A), (A-I), (A-II), (A-III), (A-IV), (B), (B-I), , (B-III) or (B-IV) wherein Cyl is selected from 0/ \O o//S\° O// \0 F F "tanO F N\ / N\%F «O FXFN [SN O/fN 072%), Further preferred is a compound of a (A) or (B) wherein L] is absent.
Further red is a compound of formula (A) or (B) wherein Lg is .
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 NH or N—CH3. [36} 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 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-II), (A-III), (A- IV), (B), (B-I), (13-11), (13-111) or (B~IV) wherein X‘ is CR1 or N , wherein R1 is H or Halogen.
Further red is a compound of formula (A), (A-II), (A-lV), (B), (3-11) or (B-IV) wherein x2 is CH.
Further red is a compound of formula (A), (A-II), (A-IV), (B), (8-11) or (B-IV) wherein X3 is CH.
Further preferred is a compound of formula (A), (A-I), (A-II), (A—III), (A- IV), (B), (3.1), (3—11), (3.111) or (B~IV) wherein x4 is CR4 or N , wherein R4 is H or 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, hydrogen, cyano, halogen, substituted or unsubstituted CM alkyl, substituted or unsubstituted C36 cycloalkyl, and substituted or unsubstituted C3.6 cycloalkenyl, —OR“, -NR“Rb or —C(=Y)-Ra and R“, R", and Y are as defined above for nd of formula (A) or (B); Further preferred is a compound of formula (A), (A-I), , (A-III), (A- IV), (B), (B-I), , (B-III) or (B-IV): wherein Cy is ed from UTVA “01¢:Ufi “Grave “0%‘03 @QKfirkbfii Yet another embodiment is a compound of formuia (A-IA), (A-IIA), (B-IA), , (B-IIIA) or (B-IVA): ‘X4 X1 (A-IA) (AJIA) N HiN IX‘I \ 96 "° X G \ x3 I W 4/ o ,1 G (R's)P (BJA) A) mM5 3‘“5 X1\ 0 x4\ 1 l (36);) (Rah; (B-IIA) (B-IVA) or a tautomer, stereoisomer, omer, diastereomer, salt (e.g., pharmaceutically acceptable salt), prodrug (e.g., ester), or N—oxide thereof, wherein Aris (R6)p>\, (R5)P>\/ (Re)p\/ G (R6)p(\/\ir6 (R6)P)< G I J I ' J‘J‘I\ 44‘“\ N‘N\ G Mk/N WKN (£26,311JJJ“\N (R5) o N 51/7des $5)th (Rex, /%(R5)p p\(/ f / 0/7\ lms) S I 1 NJ \> \\___U ° A? “\G \\J—-I--£R6) :P’J \ G G ,N“\ 455 G HE G G \ a 6 (R5) ""9 N (Rh /\~ /§ 5 /§ (126)» Ram/>41 w 0%\ / A @fi eHway(R6)p R5» R°\N,\/~‘/\>G s’\ ~ §~ o’”\\ N /\- G is independently selected from \ffl‘" M)h\/M KTJ“ NCJXMNN :>L 7% A; :>L R is substituted or unsubstituted alkyl, substituted or tituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl.
R6 is selected from hydrogen, hydroxy, n, carboxyl, cyano, nitto, substituted or tituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkeny], substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, tuted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyciyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, tuted or unsubstituted arylalkyl, —COORa, -C(0)R“, —C(S)R“, —C(O)NR“R", -C(O)ONR“R", -NR“R", -NR“CONR“R”, — N(R“)SOR", -N(R“)SOgRb, (R“)Rb), -NR“C(O)ORb, , -NR“C(O)Rb-, —NR3C(S)R” — NR°C(S)NR“Rb, -SONR"‘Rb-, -SOgNR“Rb-, on“, -OR“C(O)NR“R", -OR“’C(O)ORb-, - OC(O)R“, NR“R", -R“NR"C(0)R“, -R“ORb, -R“C(O)OR", -R"’C(O)NR“Rb, -R“C(O)Rb, -R“OC(O)R", —SR“, son“ scan", and -ONO;;_; each occurrence of R“ and Rh may be same or different and are ndently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted (31-5 alkyl, substituted or unsubstituted CM alkenyl, substituted or unsubstituted C36 alkynyl, substituted or unsubstituted C3.5 cycloalkyi, substituted or unsubstituted CM 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 fonn (i) an oxo (=0), thio (:3) or iiuino , 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 ed from O, NR“l or S; each ence of Rd is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=8), substituted or unsubstituted alkyl, substituted or tituted alkoxy, substituted or unsubstituted alkeny], substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, tuted 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 -ON02; p is 0,1, 2, 3 or4; and all the other variables (XI—X4, X, and R5) are the same as described above for compound of fonnula (A), (B), (A-I) , (B-I) ,(A-II) or (B-II).
Yet another embodiment is a nd of formula (A-IIIA) and (A-IVA) (AJIIA) (A-IVA) wherein the les Ar, G, R6, and p are defined as above with respect to as (A-IIIA) or (A-IVA), and all the other variables (X1-X4, X, and R5) are the same as dcscn‘bed above for compound of formula (A), (B), (A-I) , (B-I) , (A-II) or (3-11) with the proviso 1. that for compound of formula (A-IIIA) , wherein Z is G or S and X4 is N or CR4 then Ar—G cannot be \ \ NJN ,J’Nd H H H H HH HH w M“ ”a“ WM“ Hw‘\"Cr“, w or ‘ 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 \ \ ,r’N NJN\) H H H H HH H“ w 14"“ “M“ WM“ Hfiw\NGr“, W ‘ H ~H wherein R1 and R4 is as defined above for compound of formula (A) W is S(=O)2-R1, S(=0)2-NR:aRh -C(=O)-R1, -C(=0)-O-R1, -C(=O)-NRhR1, S(=O)2' R1, halo, or a 4— to lO-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; R”, at each occurrence, is independently hydrogen or (C1—C3)alkyl; R1 is optionally substituted (CI-C6)—alkyl, optionally substituted (C2-C6)~alkenyl, Optionally substituted (C2-Cg)-alkynyl, optionally substituted (C3-C12)-cycloalky1, ally substituted (Cg—Clo)aryl, a 4—10-membered optionally substituted heteroaryl, which contains 1—4 atoms ed from N, O, and S; or a 4- to lO-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; Further red is a compound of formula (A-IA), (A-IIA), (A~IIIA), (A- IVA), (B-IA), (B-IIA), (B—IIIA) or (B-IVA) wherein AI is selected from. (125),. / G (R6)p\/ G (Rah/V G ,r"\ fly\ N Jy‘\ Further preferred is a compound of a (A-IA), (A-IIA), (A-IIIA), (A- IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein G is ed from. 744% Mimi "sh Z>le FA Further preferred is a compound of formula (A-IA), (AleA), (A-IIIA), (A- IVA), (B-IA), (B—IIA), (B-IIIA) or (B-IVA) wherein x' is CRI or N, wherein R1 is H or Halogen.
Further prefeired is a compound of formula (A-IIA) , ) , (B—IIA) or (B-IVA) n x2 is CH.
Further red is a compound of formula (A-IA) , (A-IIIA) , (B-IA) or (B- 111A) wherein x3 is CH.
Further preferred is a nd of formula (AwIA), (A-IIA), A), (A- IVA), (B-IA), (B—IIA), (B-IIIA) or (B-IVA) wherein x4 is CR4 or N , wherein R1 is H or Halogen. {52] Further preferred is a compound of a (A-IA), (A-IIA), (A-IIIA), (A- IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X is CH or N. r 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%» 315. “wok? “16*? .“WWTi,“15%“?ka Further preferred is a compound of fonnula (A-IA), (A-IIA), (A—IIIA), (A- IVA) , (B-IA), (B-IIA), (B-IIIA) or (B—IVA) wherein R5 is BOC ( —C(O)OC(CI-13)3).
Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA), (A- IVA) (B-IA), (B-IIA), A) 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 embodiment, X is CH.
In one preferred embodiment, Z is S In one preferred embodiment, Z is O.
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 p is 0 or 1.
Further preferred is a compound of fonnula (A-IA), (A-IIA), A), (A- IVA) , (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R6 is halogen, substituted or unsubstituted alkyl or -OR“; wherein R“ is tuted or unsubstituted alkyl.
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 -F, -CI-13, -CF3 or -OCI-13.
Yet another embodiment is a nd of a (A-IB) and (A-IIB): Gar)“ N—Rs /Arl _. 5 (AXIB)Z x(A-118) or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g., pharmaceuticaily acceptable salt), prodrug (e. g., ester), or N—oxide thereof, wherein Z is O or S Ari—G is (RS)p .0 W:.LJL)/G(Ra)P GUZD(R8)p\ (R‘)p\\ p is 0, 1—7 or 8 and all the variables (R6, XI-X4, X, and R5) are the same as described above Yet another embodiment is a compound of formula (A-IIIB) and (A-IVB): l Z (A—IIIB) (A-IVB) or a tautomer, isomer, enantiomer, diastereomer, salt (e.g., phm‘maeeutically acceptable salt), g (e. g., ester), or N—oxide thereof, wherein Z is O or S AIl-G is (R5)? Qfiwe”MG(RR5) (Rs) (RR3) 025),, ” “’6 \ JZNQ 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 formula (A-IIIB) , wherein Z is O or S and X4 is N or CR4 then Arl-G cannot be \ \ pNM 2. that for compound of formula (A-IVB) wherein Z is O or S and X1 is N or CR1 then Ari-G cannot be wherein R1 and R"1 is as defined above for compound of formula (A) W is S(=O)2-Ri, S(=O)2‘NRlaRls -R1, —O-R:, -C(=O)~NRnRi, -NR1a-S(=O)2- R1, halo, or a 4 to 1bercd Optionally tuted heteroaiyl, which contains 1-4 atoms selected from N, O, and 8; RM, at each occurrence, is independently hydrogen or (CI-Cs)alkyl; and R] is Optionally substituted (C.«C(,)-alkyl, optionally substituted (C2-C6)—alkeny], optionally substituted (C2-C6)-a1kynyl, optionally substituted (C3-C12)'Cy01081ky1, Optionally substituted (C5-C10)aryl, a 4 to lO-membered optionally substituted heteroary], which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclo, which contains 1—4 heteroatoms selected from N, O, and S.
Yet another embodiment is a compound of a (A-V): / N or a phannaceutically acceptable salt thereof, wherein R3 is hydrogen or F; R5 is as defined above; G is selected from —SOZR", —C(O)R"Rb, C1-C4 alkyl tuted with one or more halogens, and a tetrazole of the fonnula "/\/"%;\ each occurrence of R6 is independently halogen; each occurrence of R“ and Rb is independently hydrogen or unsubstituted or substituted C1—C6 alkyl; and pisO,1,20r3.
In one preferred embodiment of the compound of formula (A-V), R5 is selected from ~~COO-R"l and —SOz-Ra in Ra is an unusubstituted C1—C4 alkyl, C1—C4 alkyl with one or more halogens, or C3-C5 Cycloalkyl). [68} In a preferred embodiment of the compound of formula (A-V), G is selected from ~SOZR“ (where Ra is an unsubstituted C1-C4 alkyl), -C(O)R"‘Rb (where R3 and Rb are ndently selected from hydrogen 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): N .— \ / G 0 /\(R6),, or a phannaceutically acceptable salt thereof, wherein R5 is as defined above; G is selected from ~SOzR“; each occurrence of R6 is independently halogen; each Occurrence of Ra is independently hydrogen or unsubstituted or substituted C1-C6 alkyl; pisO, 1, 20r3.
In one preferred embodiment of the compound of formula (B-V), R5 is —COO- R3 where R“ is an unsubstituted or substituted C1-C5 aikyl. More preferably, R“ is an unusubstituted C1-C5 alkyl, such as an unsubstituted C1-C4 alkyi.
In a preferred ment of the compound of formula (B-V), G is selected from —SOzRa where R.1 is an unsubstituted C1-C4 alkyl, such as .
In a preferred ment of the compound of formula (B-V), p is l and R6 is fluorine. More preferably, the fluorine is at a position ortho the benzo[d]oxazoie group.
Representative compounds of the t ion include those specified below (including Table 1 and Table 2) and pharmaceutically acceptable salts thereof. The present invention should not be construed to be limited to them. 1. 2-[1-(5—Ethylpyrimidin—Q—yl)pipei‘idin~4—yi]-5—[’2-fluoro(methylsulfonyl)phenyl3- zo[cl]imidazole: l0 utyl 4—{ 5-[2-fluoro—4~(methylsulfonyl)phenyl]— 1H-benzo[d}imidazol yl}piperidine—1-carboxylate: 3. 2-[1—(5—ethylpyrimidin~2-yl)piperidin—4-yl]—5—[2-fluoro (methylsulfonyl)phenyl]benzoId]oxazole: 4. Ten-buy] 4—{5-[2-fiuoro(methylsulfonyl)pheny1]benzo[d]oxazol-2~y1}piperidine- 1-carboxylate: . Tert-buLyI 4-{5-[2—Huoro—4-(memylsulfonyl)pheny1]-l-methyl—1H—benzo[d]imidazol~ 2-y1}piperidine—l-carboxylate: 6. Terr-buty] 4-{6-[2-fluoro(methylsulfonyl)pheny1]benzo[cfloxazol-Z—yl}piperidine- 1-cm‘boxylate: 7. yi 4-{ 5—[2—flu0r0(methylsulfonyl)phenyl]benzo[(l]0xazoly1}piperidine- l-carboxylate: 8. Tert-butyl 4- { o-5—[Cl-fluoro-4~(methyIsulfonyl)pheny1]benzo[d]oxazol-2— y1}piperidine—1-carboxylate: 9. Tert—butyl 4-[5-(4wcyan0pheny1)benzo{dloxazol-Z—yllpiperidine-l-carboxylate: . Tert—butyl 4-{ 5-[3-fluoro—4-(melhylsulfonyl)phenyl]benzo[(l]oxazol-2—yl }piperidine— 1-carboxy1ate: 11. Tert-butyl 4-{5-[4-( lH—tetmzolyl)phenyl]benzo[(l]oxazol—2-yl )piperidine- 1- ylate: 12. utyl 4—{ 5-[2~fluoro(1H—Letrazol-1~yl)phenyl]benzo[cl]0xazol~2~yl}piperidine- 1-carboxylatc: 13. Tert-butyl 4— { 5- [4-(irifluoromethyl)phenyl]benzo [dloxazol—Q-yl ] dine carboxylate: 14. Isopropyl 4- { 5-[2-fluoro(1H-tetraz01y1)phenyHbenzo[(onazol-Q-yl }piperidine- l-carboxylate: . Tert-butyl 4— { 5-[3-f1u01'o(lH-tetrazol—1-yl)phenyl]benzoitfloxazoI-Z-yl}piperidine- oxylate: 16. 2—[1—(5-ethylpyrimidiny1)piperidiny1]-3—[2-fluoro(1H-te11azol y])phenyl]benzo[(1]oxazolc: 17. Tert—butyl 4-[5—(4-cyano—3-fluoropheny1)benzo[d]oxazol-Z-y1]piperidine carboxy]ate: 18. ISOpropyl 4~{ 5—[3-fluoro(1H—tetrazol—1-y1)pheny1]benzo[d]oxazoI-2—y}}piperidine~ 1-carb0xy1ate: 19. Tert—butyl 4- { 5—[3-fluoro(1H~tetrazolyl)pheny1]benzo[djoxazol-Z-yl }piperidine- l—carboxylate: . Tert-buLyl 4-[5—(4—carbamoyIchlor0pheny1)benzo[(Z]0xazoly1]piperidine—1— carboxylate: 21. Ter't-butyl 4-{5-(4-ca1'bamoy]—3~flu0r0pheny1)benzo[d]oxazol—Q—yl]piperidine carboxylate: 22. Tert-butyl 4-{5—(3-fluoro—4—isopropoxyphenyl)benzoEd]oxazol—Q-y1]piperidine—1— carboxylate: 23. Cyclobutyl 4-{5-[2-fluoro-4~(lH-Letrazoly1)phenyl]benzoitfloxazol-Q- y] }piperidine-l-carboxylate: . Sec-butyl 4-{5~[2-flu0ro(1H—tetrazol-I-yl)phenyl]benzoiclloxazol—Z-yl}piperidine— l~carboxylatez Pentanyl 4-{5—[2—fluoro(lH—tetrazolyI)phenyl]benzo[(l]oxazol«2- y1}piperidine-l-carboxylate: . u0ro-4—(1H-tetrazolyl)phenyl]—2-(piperidin—4-yl)benzo[(l]0xazole: Isopropyl 4— { 5-[4—(trifluoromethyl)phenyl]benzo[d]oxazol—2—y1 ]piperidine-1» carboxylate: . pyl 4-[5-(4-fonnylpheny1)benzo[d]oxazol—Z-yllpiperidine-l-carboxylate: Isopropyl 4—{ 5- [Ll—(difluoromethyl)phenyl]benzo[d]oxazoly1 } pipeddine— 1 - carboxylate: Isopropyl 4—[5-(4-carbamoyl—3-chlor0phenyl)benzo[Illoxazol-Z-yl]piperidine- 1- carboxylate: . pyl 4-[5-(4-carbamoylfluoroheny1)benzo[d]0xazolyl]piperidine carboxylale: 1- { 4-[5-(2—t1u0ro(1I-I-tetrazolyl)pheny1)benzo{d]0xazol—2-yl]piperidin— l-yl } ~2- methylpropan—l—one: 33. Isopropyl 4-{ difluoromethyl)phenyl]benzo[d]oxazol—2-y1 }piperidine—1 ~ carboxylate: 34. 6— { 2—[1-(i30propoxycarbonyl)pipen'diny]]benzo[d]oxazolyl }nicotinic acid: 35A S-[Z—fluoro(lH-tetrazol- I-yl)pheny1]—?.-[ l-(mefllylsulfony1)pipefidin y1]benzo[d]oxazole: 36. Isopropy} 4-[5-(5-ca1‘bamoylpyridin~2~yDbenzo[d]oxazol-Z—yl]piperidine—1 - carboxylate: 37. ISOpIOpy} 4-[5-(4—carbamoyl~2—f1uorophenyl)benzo[d]oxazol—Z-pripericIine—1- carboxylate: 38. Isopropyl 4-[5—(4-carbamoyI-ZZ-chlorophenyl)benzo[(1]oxazoI-2—y1]piperidine—1- y]ate: 39. 2—FIuoro{2-[1-(3-methylbutanoyl)pipen'din-4—y1]benzo[(ljoxazo]y1}benzamide: 40. I— {4—[5-(2—fluoro(lH-tell'azolyl)phenyl]benzo[cljoxazoI—Z-priperidin- 1—y1} methylbutan- 1-one: 41. 5-[2—flu0ro-4—(1H—tetrazol—1-y1)phenyI][1-(2—methoxyethyl)piperidin»4- yl]benzo[d]oxazolez . Isopropyl 4-{ S—[3—fluor0(methylcarbamoyl)pheny1]benzo[d]oxazol—Q» yl } pipen‘dine— 1 -carb0xylate: 43. 2-F1uoro[2~(1—is0butyry1pipen‘din-4—y1)benzo[cljoxazoly1]benzamide: 44. ISOpIOpyI 4-[6-(4—carbamoyl-3~fluoropheny1)benzo[d}oxazol—2—y1]piperidine carboxylate: 45. [sopmpyi 4— { 5 ~[3-fluoro(Z-llydroxyethylcarbamoyl)phenyl]benzo [djoxazol-2— yl }pipen'dine~l—carboxylate: 46. pyl 4—{ 5-[3-fluoro-4—(isopropylcarbamoyl)pheny1]benzo[d]oxazol-Z- eridine-l-carboxylate: 47. ISOpIOpyl 4-(N-methylsulfamoyl)phenyl1benzo[d]oxazol—2—y1]pipen‘dine-l- carboxylate: 48. Isopropyl 4— { 5-[6-(methylcarbamopryridinyl]benzo[d]oxazoly1}piperidine— 1— carboxylate: 49. Isopropyl 4-{ 5-[3-melhyl-4—(1nelhylcarbamoy1)phenyl]benzo[(floxazol-Q- yl }pipen‘dine—l-carboxylate: 50. Isopropyl 4- { 5-[4-(cyclopropylcarbamoyDfluoropheny]]benzo{d]oxazol yl } ine—l-carboxylate: 51. r0{2-[1-(5-fluoropyrimidin—Q—y1)piperidinyI]benzo[d]oxazol yI }benza1nide: Tert—butyl 4—[5-(4-carbamoylfluoropheny1)benzofuranyl]-5,6-dihydropyridine— 1(2H)-carboxy1ate: 53. 2-fluoro { 2—[1-(propy]su]fonyl)piperidiny11benzo[cfloxazol-S -y] }benzamide: 56. Tert-butyl 4—{2—[2-fluoro(methylsulfonyl)phenyl]—1H—benzo[d]imidazol-S-yl}-5,6- dihydropyridine-1(2H)-carboxylate; 57. Ten-butyl 4- { 2—[2-fluoro-4—(methylsulfonyl)phenyl]-1H—benzoLd]imidazol-S-yl} piperidinecarboxy1ate; 58. 5-[1-(5—ethylpyrimidinyl)piperidiny1]—2-[2-fluoro-4—(methylsulfonprhenyl]— 1H-benzo[d]imidazole; 59. Text-butyl 4- { 2- [2-fluoro-4—(methylsulfonyl)pheny1]benzo [d}oxazoly1 } «5,6- dihydropyridine-l (2H)—carboxylate; 60. Tert—buty] 4-{ 2—[2-fluoro—4—(melhylsulfonyl)phenyl]benzo[d]oxazol-5—y1}piperidine- l-carboxy1ate; 61 . 2-[2-fluoro(Illemylsulfonylmhenyfl(piperidin—4-y1)benzo[d]oxazole 2,2,2 trifluoro acetate; 62. 5-[l—(5-eLhy1pyrimidinyi)piperidin—4-yl]-2—[2—fluoro-4—(n1ethylsulfony1)phenyl] benzo [d]oxazole. 63. Tert-butyl uoro[2-fluoro(methylsu1fony1)phenyl}benzo{d]oxazol-S- yl }pipen‘dinecarboxylate: 64. IsopIOpyl 4-{2-[2-fluoro-4—(111ethylsu1fonyl)phenyl]benzo[d]0xazo]y1}piperidine~ 1—carboxy1ate: 65. Tert-butyl 4-{ 2-[2-fluoro-4—(methylsulfonyl)phenyl]benzo[(11thiazoly} } -5,6- dihydropyridine- 1(2H)-carboxy1ate: 66. Tert-butyl 4- { 2- [2—fluor0(methylsulfonyl)phenyl]benzoidjthiazol-S—yl }~5,6~ dihydropyridine- I(2H)-carboxylate: 67. Tert-butyl 4- {2-[2-f1uoro(methylsulfonyl)phenyl]benzo[(l}oxazol-6—y]}piperidine— l-carboxylate: 68. Tert-butyl 4- [ 2-[2-11uoro(methylsulfonyl)pheny1]benzo[(1] thiazol—5~yl }piperidine- l-carboxylatc: 69. Ethyl 4- {2-[2—fluoro(methylsulfonyl)phenyl lbenzoklloxazol-S-yl }piperidine- 1- carboxylate: 7O. Tert—butyl 4-{2-[4-(trifluoromethyl)pheny1]benzo[(floxazol-S-yl }piperidine~1- carboxylate: 71 . Isopropyl 4- { 2-[2-fluoro(methylsulfony1)pheny1]benzo[d]oxazoly1 idine- l-carboxylate: . Ethyl 4- { 2—[2—fiuor0(methylsulfonyl)pheny1]benzo[(l]oxazol—6-y1 }piperidine carboxylate: 73. Ethyl 4- {2-[2-fluoro-4—(methylsulfonyl)phenyl]benzo[d]oxazoly1 }piperidine—1- carboxylate: 74. Benzy} 4- {2-[2-flu01'o(methylsulfonyl)pheny1]benzo[d]oxazol~5«yl }piperi(1ine-1— carboxylate: 75. yl 4- {2-[2—f1uoro(methylsulfonyl)phenyl1benzo[d]oxazol-5~y1 } dine carboxylate: 76. pyl 2-fluoro-4—(methylsulfonyl)phenyl]benzo[(IJthia201yl}piperidine— l-caxboxylate: 77. {SOpIOpyl 4- { 2—[4-(trifluoromethyl)phenyl]benzo{(HoxazoI-S-yl } piperidine» 1 - carboxy]ate: 78. Isopropyl 4-(2—p-toly1benzo[d]oxazol»6-y1)piperidine—1-carboxylate: 79. 3-{4-[2—(2—fluoro-4—(melhylsulfonyl)phenyl)benzo[d]oxazol—S-y1]-5,6- opyridin—l(2H)—ylsu1fony1}pr0pan—1-olz 80. 3-{4-[2-(2-fluor0(methylsulfonyl)pheny1)benzo[(floxazol-5~yl]piperidin ylsulfony1}propan-1~ol: 81. 3-{4-[2-(2-fluoro(methylsulfonyl)phenyl)benzo[(floxazol—5-y1]piperidin— 1- ylsulfony1}pr0pan-1—olz 82.1‘ez‘t-buty1 4-{2-(4-carbamoylfluorophenyl)benzo[(Ijoxazol—S—yl]piperidine carboxylate: 83. 2—[2—Huor0(methylsulfony1)phcny]]—5—{4-(3-isopropy]-1,2,4-oxadiazol-5— y1)pipen‘diny1]benzo[d]oxazole: 84. Tert-butyl 4- {2-[4-(trifluoromethyl)phenyl]benzo[(l]oxazolyl } piperidine— 1— carboxylate 85. Isopropyl 4-{ 2-[2-fluor0—4-(methylsulfony])pheny1]benzo[d]oxazol-S—y} }piperazine— l-carboxylate: 86. Tert-butyl 4- {2-[4-(trifluoromethyl)phenylloxazolo{5,4-12]pyridiny1 }-5,6- dihydropyridine-1(2H)-carboxylate: 87. Tert-butyl 4-{ 2-{4-(tn‘fluoromethyl)phenyl]oxazolo{5,4-b]pyridin—6-yl}piperidine-I- ylate: TABLE-1 NN MeHN0C N {74] Yet another embodiment of the present invention is a method for treating 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 nd of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), , ), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), , (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 d disorder by administering to a subject in need of such treatment an effective amount of at least one nd of the present invention, such as a nd of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A- 113), (A-IIIB), (A-IVB), (A-V), (B), (8-1), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B- IIIA), (B-IVA), (B-IB), (B~IIB), B), (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 lic er is diabetes and/or obesity.
More particularly, the compounds of a (A), (A-I), , (A-III), (A- IV), , (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (AN), (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 stered for the treatment, prevention and/or amelioration of GPR119 receptor associated diseases or disorders including, but not limited to, diabetes and other metabolic disorders or diseases. [77} Yet another embodiment of the t 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-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), (13-1113), (B—IIIB), (B-IVB), or (B-V) as defined above, or a composition thereof in the manufacture of a medicament for modulating the activity of a GPR H9 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-IV), (A- IA), ), (A-IIIA), (A-IVA), (A—IB), (A-IIB), B), (A-IVB), (A-V), (B), (B-I), (B- 11), (B-III), (B-IV), (B-IA), ), (B-IIIA), (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 119 or The compounds of the present invention, such as the nds 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), (AuV), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (BIVA ), (B—IB), ), B). ), and (B-V) as defined above are useful in the treatment of a variety of metabolic disorders including, but not limited to, diabetes mellitus, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, iglyceiidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic ccrcbrovascular disease, ic peripheral vascular disease, diabetic retinopathy, metabolic me, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition rated by increasing a blood GLP— 1 level in an individual with a neurodcgenerative disorder, excitotoxic brain damage caused by severe tic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion—associated disease, stroke, motornneuron diseasc, traumatic brain injury, spinal cord injury, obesity, delayed wound healing, abnormal heart function, myocardial isehemia, low I-IDL, high LDL, non— c ischemia, vascular osis, panereatitis, neurodegenerative e, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma.
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-IIA), (A-IIIA), (A- IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (8-1), (8-11), (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 metabolic—related disorder selected from the group consisting of type 2 diabetes, lycemia, hyperinsulinemia, hyperlipidemia, riglyceridemia, insulin resistance, type 1 diabetes, idi0pathic type 1 es (type lb), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth- onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related es, gestational diabetes, coronary heart disease, vascular restenosis, restenosis, restenosis after angioplasty, peripheral vascular disease, Claudication, ittent claudication, cell death associated with myocardial infarction (eg. necrosis and apoptosis), dyslipidemia, postprandial lipemia, conditions of impaired glucose tolerance (IGT), impaired glucose metabolism, conditions of impaired glucose metabolism, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, y, orosis, hypertension, tive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, ic neuropathy, metabolic syndrome, me X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transient ischemic attacks, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, elial dysfunction, and impaired vascular ance.
More particularly, the compounds of the present invention, such as the compounds of formula (A), (A-I), (A-II), (A-III), (A»IV), , (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-IIIA), (B-IVA), , (B-IIB), (B-IIIB), (B-IVB), and (B-V) as defined above can be administered for the treatment of type 2 es, hyperglycemia, hyperlipidemia,hypertriglyceridemia, type 1 diabetes, dyslipidemia, and syndrome X.
The invention further provides a pharmaceutical composition comprising one or more compounds of the present invention together with a ceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other ancer 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 nd of formula (A), (A—I), (A- ll), (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-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V) as d above.
Yet another embodiment is a method of treating metabolic disorder in a t in need thereof by administering a therapeutically 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 C57Bl/6J mice according to the oral glucose tolerance test (Biological Assay ure 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 CS7BI/6J mice according to the oral glucose tolerance test gical Assay Procedure )3) before and after oral administration of vehicle ol), compound A (Example 42 @ 10 mg/kg), or sitagliptin (10 mg/kg @ 10 mg/kg).
DETAILED DESCRIPTION It is appreciated that n features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be ed separately or in any suitable subcombination. ingly, all combinations of uses and medical indications described herein specifically embraced by the present invention just as if each and every subcomblnation of uses and medical indications was individually and explicitly recited herein.
As used herein the following definition shall apply unless otherwise ted.
Further many of the groups defined herein can be optionally tuted. The listing of substituents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the cation.
The term ‘alkyl’ refers to a straight or branched hydrocarbon 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, 1-methylethyl (isopropyl), n—butyl, n-pentyl, and 1,1-dimethylethyl (t—butyl).
The term substituted or unsubstituted (C;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 defined above having up to 6 carbon atoms. {90] 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, ylpropenyl, l-butenyl, and 2—butenyl.
The term substituted or unsubstituted (CM) alkenyl refers to an alkenyl group as defined above having up to 6 carbon atoms. {92] The term “alkynyl” refers to a ht or branched chain hydrocarbyl ls 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 presently being preferred) e.g., ethynyl, propynyl, and butnyl.
The term substituted or unsubstituted ) alkynyl refers to an alkynyl group as defined above having up to 6 carbon atoms.
The term “alkoxy” denotes an alkyl group as defined above attached via an oxygen linkage to the rest of the le. Representative examples of these groups are — OCH; and -OC2H5.. The term “substituted alkoxy” refers to an alkoxy group where the alkyl constituent is substituted (i.e., bstituted alkyl) wherein the term ituted alkyl” is the same as defined above for “alkyl”. For example “alkoxy” refers to the group -O-a1kyl, including, unless otherwise indicated, from 1 to 8 carbon atoms of a ht, branched, cyclic configuration and combinations thereof attached to the parent structure h oxygen.
Examples include methoxy, ethoxy, propoxy, isopropoxy, cyc10pr0pyloxy, and cyciohexyloxy.
The term “cycioalkyl” denotes a non-aromatic mono or yclic ring system of, unless otherwise indicated, 3 to about 12 carbon atoms such as cyclopropyl, utyl, cyclopenty], and cyclohexyl. Examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and yl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) yi.
The term “C34; cycloalkyl” refers to a cycioalkyl group as d above having up to 8 atoms.
The term “cycloalkylaflcyl” refers to a cyclic ring-containing radical containing, unless otherwise indicated, in the range of 3 up to about 8 carbon atoms directly ed 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 such as cyclopropylmethyl, cyclobuyylethyl, and cyclopentylethyl. {98} The term “C3.6 cycloalkylalkyl” refers to a cycloalkylalkyl group as defined above having up to 6 atoms.
The term “cycloalkenyl” refers to cyclic fing~containing radicals ning, unless otherwise indicated, in the range of 3 up to about 8 carbon atoms with at least one carbon- carbon double bond such as cyclopropeny], cyclobutenyl, and cyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloallcenyl group directly attached to an alkyl group which are then attached to the main structure at any carbon from alkyl gIOup that results in the creation of a stable structure The term “C36 lkenyi” refers to a cycloalkenyl group as d 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, naphthyl, tetrahydronapthyl, indanyi, and biphenyl.
The term “arylaikyl” refers to an aryl group as defined above directly bonded to an alkyl group as defined above. e.g., ~CI-12C6t15 and ~C2H5C6H5.
The term “heterocyclic ring” refers to a non-aromatic 3 to 15 member ring radical which, ts of carbon atoms and at least one heteroatom selected from the group ting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a mono-, bii, tri- or tetracyclic ring system, which may include fused, bridged or Spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be Optionally oxidized to various 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 cylic ring radical 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 defined above ly bonded to an alkyl group. The heterocyclylalkyl radical may be ed to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure. Examples of such heterocycloalkyl ls include, but are not limited to, dioxolanyl, l[1,3]dithiany], decahydroisoquinolyl, imidazoliny], imidazolidinyl, isothiazolidiny], isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidiny], 2-oxopyrrolidiny1, oxazolidinyl, piperidinyl, pipcrazinyl, 4- pipericlonyl, pyrrolidinyl, pyrazolidinyl, lidiny], thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, rpholinyl, thiamorpholinyl, l~ox0-thiomorpholinyl, and 1,1-dioxo-thiomorpholiny1.
The term “heteroaryl” refers to an optionally substituted 5 to 14 member aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms. The heteroaryl may be a mono—, bi- or tricyclic ring system. es of such “heterocyclic ring” or “heteroaryl” radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, l, nyl, pyrimidinyl, pyraziny], benzofuranyl, indoly], benzothiazolyl, benzoxazolyl, car-bazolyl, quinolyl , nolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxany], benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenaziny], phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, ydroisoquinolyl, dinyl, piperazinyl, 2-ox0piperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, Z—oxoazepinyl, azepiny], 4— piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, idinyl, m’azolyl, indanyl, isoxazolyl, olidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidiny], isothiazolidinyl, isoindoiyl, indolinyi, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzoPyranyl, tetrahydrofuryi, tetrahydropyranyl, thienyl, benzothieny], thiamorphoiinyl, thiamorpholinyl sulfoxide, rpholinyl sulfone, dioxaphospholauyl, oxadiazolyl, chromanyl, and omanyl.
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 pyridinyl N—oxides.
The term “heteroarylalkyl” refers to aryl 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 “heterocyclylaikyl” refers to a heterocylic ring l 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 s in the creation of a stable structure. {109] The term “cyclic ring” refers to a cyclic ring containing, unless otherwise ted, 3 to 10 carbon atoms.
The term “substituted” unless otherwise ied, refers to substitution with any one or any combination of the following substituents and may be the same or different which one or more are ed from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=8), 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, tuted 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(0)0NR’R", —NR’R”, -NR'CONR’R", —N(R')SOR", —N(R’)sozn", ~ =N-N(R')R"), - NR'C(0)0R”, NR‘R”, —NR'C(0)R”—, —NR’C(S)R" —NR‘C(S)NR"R”’, - SONR'R"—, soZNR‘R'l, -on’, -0R'C(0)NR”R"’, -OR'C(O)OR”-, -OC(O)R', - 0C(0)NR'R",- R'NR"C(0)R"', -R'0R", —R‘C(0)0R", -R‘C(0)NR"R"’, -R'C(O)R”, — R’OC(O)R", —SR', -SOR’, -SOzR,, —ON02 wherein R’, R" and R" in each of the above groups can independently be en, hydrogen, y, n, y], cyano, nitro, oxo (=0), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted , substituted or unsubstituted alkeny], substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylaikyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryialkyl, 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 selected from O, NRX or S or form 0x0 (=0), thio (28) or imino (=NR’, where R’ is defined above). The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the tuent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl". Substitution or the combinations of substituents envisioned by this invention are preferably those that result in the ion of a stable or chemically le compound. The term stable as used herein refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their isolation, production, detection and preferably their recovery, purification and incorporation into a pharmaceutical ition.
The term "halo", "halide“, or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms lkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, l and alkoxy structures that are substituted with one or more halo groups or with ations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" refer to haloalkyl and haloalkoxy groups, tively, in which the halo is e.
The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent 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, acety], roacetyl, text—butoxycarbonyl (BOC), benzyloxycarbonyl (C82) and 9-fluorenylmethylenoxycarbonyl (Fmoc). rly, a "hydroxy-protecting group" refers to a substituent of a hydroxy 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 carboxy functionality. Suitable carboxy-protecting groups include, but are not d to, -CH2CI-12S02Ph, thyl, ethylsilyl)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 identical 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 isomers.
All the stereoisomers of compounds described herein are within the scope of this invention. Racemic mixtures are also encompassed within the scope of this invention.
Therefore, single stereochemical isomers as well enantiomeric, diastereoisomeric and geometric (or conformational) mixtures of the present compounds fall within the scope of the invention.
Certain of the nds described herein contain one or more asymmetric centers and can thus give rise to omers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic es, lly 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 ts, or resolved using conventional techniques. When the nds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless ied otherwise, it is intended that the compounds include both E and Z ric isomers.
The term mers" refers to compounds, which are characterized by vely easy interconversion of isomeric forms in equilibrium. These s are intended to be covered by this ion. ”Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or n-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of erization is keto—enol tautomerization. A specific e of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent—3-en—2-one tautomers.
Another example of tautomerizatlon is phenol-keto tautomen‘zation. 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 conditions, cleave from the starting material, thus promoting reaction at a specified site.
Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, p-nitrohenzensulphonyloxy and tosyloxy groups.
The term "pi'odiug" refers to a compound, which is an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes.
Prodrug design is discussed lly in , et al. (Eds), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodiugs 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 phannacologically active form through hydrolysis of, for example, an ester or amide e, thereby introducing or exposing a functional group on the resultant product. The prodrugs can be designed to react with an endogenous compound to form a water—soluble conjugate that further es 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, e, glutathione, amino acids, or acetate. The resulting conjugate can be vated and excreted in the urine, or rendered more potent than the parent compound. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic ge, and released back into the ation, thereby effectively increasing the biological half-life of the originally administered compound.
The term "ester" refeis 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 RCOOR'.
These prodrugs and esters are intended to be covered within the scope of this invention.
Additionally the instant ion also includes the compounds which differ only in the presence of one or more isotopically ed atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by ”C- or MCenriched carbon.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine—125 ('25I) or carbon-l4 (”C). All ic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present ion.
Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as iacetylethylenediamine, glucamine, tn‘elhylamine, choline, hydroxide, ohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as henylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, 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 tuted amino acids; guanidine; and substituted ine wherein the substituents are ed from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted um salts and aluminum salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosPhates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, es, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ates, glycerophosphates, and ketoglutarates.
When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical ae, all combinations and binations 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 referred 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 "comprises" or "having" or "including") includes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that "consist 01” or "consist essentially of” the bed es.
The term st" generally refers to a moiety that interacts and activates a receptor, such as, the GPR119 receptor 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 indicated moieties er, whether in an in vitro system or an in vivo . Thus, ”contacting" a GPR 119 receptor with a compound of the invention includes the administration of a compound of the present ion to an individual, 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 preparation containing a GPR 119 receptor.
The term te" as used herein means a compound of the invention or a salt f, that further includes a stoichiometric or non— stoichiometric amount of water bound by non-covalent olecular 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 (eg. physician, nurse, or nurse practitioner in the case of humans; veterinarian in the case of animals, 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, condition 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 ; 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 se or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
The term aceutical compositiOn" refers to a composition comprising at least one active ingredient, including but not limited to, salts, solvates, and hydrates of compounds of the present inventionm whereby the composition is amenable to investigation for a Specified, efficacious outcome in a mammal (for example, without limitation, a human).
Those of ordinary skill in the art will tand and appreciate the ques appropriate for detennining whether an active ingredient has a d efficacious outcome based upon the needs of the artisan.
The term "solvate" as used herein means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non- stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, xic, and/or acceptable for administration to humans in trace amounts.
Abbreviations, unless otherwise indicated, used herein have their conventional meaning within the chemical and biological arts.
The term ministration," "administered in combination with," and their grammatical equivalents, as used herein, asses stration 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 stration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
The term "effective amount" or peutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended ation 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 d, 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 ry skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular nds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical ry 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 including but not limited to therapeutic benefit and/or a prephylactic 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 ration of one or more of the physiological symptoms ated with the underlying er such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. For prophylactic , 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 e, even though a diagnosis of this disease may not have been made.
A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prepliylactic effect includes delaying or eliminating the appearance of a e or condition, delaying or eliminating the onset of symptoms of a disease or condition, 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 animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and most preferably humans. In another ment, the individual is a human and in n embodiments, the human is an infant, child, adolescent or adult. In one embodiment, the individual is at risk for developing a GPRll9—related disorder. In one embodiment, the dual is at risk for developing a metabolic-related disease or disorder. Individuals who are at risk include, but are not limited to, those with hereditary history of a metabolic-related diseasc or disorder, or those in a state of physical health which puts them at risk for a metabolicaelated disease or disorder In another embodiment, the individual has been determined, by the care-giver or someone acting under the guidance of the care-giver, to have a metabolic-related disease or disorder, The term "phannaceutically able r" 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 suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ient, its use in the therapeutic itions of the invention is contemplated. Supplementary active ients 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 following.
The most significant pathologies in type 2 diabetes are impaired insulin signaling at its target tissues ("insulin ance") and failure of the insulin-producing cells of the as to secrete an appropriate degree of n in response to a hyperglycemic signal.
Current therapies to treat the latter include inhibitors of the B-cell ATP-sensitive potassium channel to r the release of endogenous insulin stores, or administration of exogenous insulin. r of these achieves accurate normalization of blood glucose levels and both carry the risk of ng hypoglycemia. For these reasons, there has been e interest in the development of pharmaceuticals that function in a glucose«dependent , i.e. potentiators of glucose signaling.
Physiological signaling systems which function in this manner are well- characterized and include the gut peptides GLPl, GIP and PACAP. These hormones act via their e G~protein coupled or to stimulate the production of CAMP in pancreatic B-cells. The increased CAMP does not appear to result in stimulation of n 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 ls and the exocytotic machinery, are modified in such a way that the insulin ory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, B-cell GPCRs, including GPRI 19, would also stimulate the release of endogenous insulin and consequently promote nonnoglycemia in type 2 es.
It is also established that increased CAMP, for e as a result of GLP- l stimulation, promotes B-cell eration, 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 decreasing weight and energy expenditure. Hence, given their function within the hypothalamic circuitry, agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore te 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 le disease states (eg. type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, lycemia, hyperlipidemia, hypertriglyceridemia, holesterolemia, dyslipidemia, obesity or cardiovascular disease in "syndrome X“) or diseases which clearly occur secondary to diabetes mellitus (eg. kidney disease, peripheral neuropathy). Thus, it is expected that effective treatment of the diabetic condition will in turn be of benefit to such interconnected disease states.
In some embodiments of the present invention the metabolic-related disorder is selected from type 2 diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, type 1 diabetes, idiopathic type 1 diabetes (type 1b), latent autoimmune diabetes in adults (LADA), early-onset type 2 es (BOD), youth— onset atypical diabetes , maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational es, cardiovascular disease, coronary heart disease, vascular restenosis, restenosis, restenosis after angiOplasty, eral ar e, 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, tis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomeruloscierosis, chronic renal failure, ic neuropathy, metabolic syndrome, syndrome X, strual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, ent ischemic attacks, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, endothelial dysfunction, and impaired ar compliance.
It will be appreciated that the ent 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 purposes, individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; ion animals such as dogs and cats; exotic and/or 200 animals; laboratory animals including mice, rats, s, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
The invention also relates to a method of treating diabetes in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention.
In addition, the nds described herein may be used for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a general term describing any hardening of medium or large arteries. Atherosclerosis is a hardening of an artery specifically due to an atheromatous .
Further the compounds described herein may be used for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli. It may be asymptomatic, or t with hematuria and/0r proteinuria. There are many recognized types, divided in acute, te or chronic ulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), mune or paraneoplastic.
Additionally, the compounds described herein may be used for the treatment of bursitis, lupus, acute disseminated encephalomyeiitis (ADEM), addison‘s e, antiphOSpholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac e, Crohn‘s disease, diabetes mellitus (type 1), goodpasture’s syndrome, ' e, guillain—barre syndrome (GBS), hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic is, ord‘s thyroiditis, Ostheoarthritis, uveoretinitis, gus, polyarthiitis, primary y cirrhosis, reiter's syndrome, su's arteritis, al arteritis, warm autoimmune hemolytic anemia, Wegener‘s granulomatosis, alopecia universalis, chagasl e, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative s, vitiiigo, vulvodynia, appendicitis, intends, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, choiecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dennatomyositis, endocarditis, endometritis, enteritis, enterocolitis, dylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, gitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, 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 eutically effective amount of a compound of the present invention. Examples of vascular conditions include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and d obstructive disease.
The invention further provides s of modulating GPR119 activity by contacting a GPR119 receptor with an amount of a compound of the invention ient to modulate the activity of the GPR119. Modulate can be inhibiting or activating GPR119 activity. In some embodiments, the invention es methods of ing GPR119 activity by contacting a GRP119 receptor with an amount of a compound of the invention ent 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 invention provides methods of agonizing 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 or in said cell. In some embodiments, 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 organism with an amount of a compound of the invention sufficient to activate the ty 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 invention sufficient to te the activity of GPR119 receptor in said animai. In some embodiments, the invention provides methods of agonizing GPR119 activity in a mammal by ting 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 provides methods of agonizing GPR119 activity in a human by contacting said human with an amount of a compound of the invention sufficient to activate the activity 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 overlapping 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 nd 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 effect.
In the context of the present invention, a compound as described herein or a ceutical composition thereof can be utilized for modulating the activity of GPR 119 receptor related diseases, conditions and/or disorders as bed . es of modulating the activity of GPRI 19 receptor reiated diseases include the ent of lic related disorders. Metabolic related disorders include, but are not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes, and conditions ated therewith, such as, but not limited to coronary heart disease, ischemic , 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 glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, tive 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, premenstrual me, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, ent ischemic attacks, , vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired e nce, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, endothelial dysfunction and impaired vascular ance. In some embodiments, metabolic related disorders include type 1 diabetes, type 2 diabetes, inadequate glucose nce, insulin resistance, hyperglycemia, ipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X. Other examples of modulating the activity of GPRl l9 receptor related diseases e the treatment of obesity and/or overweight by decreasing food intake, inducing satiation (i.e., the feeling of fullness), controlling weight gain, decreasing body weight and/or affecting lism such that the recipient loses weight andfor maintains weight.
While a nd of the invention can be administered as the sole active ceutical agent (i.e,, herapy), the compound can also be used in ation with one or more pharmaceutical agents (i.e., combination~therapy) either administered together or separately for the ent of the diseases / conditions / disorders described . Therefore, another aspect of the present invention includes methods of treatment of a metabolic related disorder, including a weight related disorder, such as obesity, comprising administering to an individual in need of prophylaxis and/or treatment a eutically effective amount of a compound of the present invention in combination with one or more additional ceutical agent as described herein.
Suitable pharmaceutical agents that can be used in combination with the compounds of the t invention include anti—obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo—B/MTP) inhibitors, MGR-4 agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, amine), sympathomimetic agents, BB adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogues, cannabinoid 1 or antagonists [for example, SR14l7l6: N—(piperidin-l-yi)-5—(4— chlorophenyl)-l—(2,4—dichlorophenyl)-4—methyl-lH-pyrazole«3-carboxamide], melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase tors (such as tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin t), Neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin or antagonists, urocortin g protein antagonists, glucagon- like peptide- 1 receptor agonists, ciliary neutrotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc, Tarrytown, NY and Procter & Gamble y, Cincinnati, OH), human -relatcd proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic agents (for e, phentennine, mazindol and the like) and te suppressants (for example, bupropion).
Other anti-obesity agents, including the agents set forth infra, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
It is tood that the scope of combination-therapy of the nds of the present invention with other anti-obesity agents, anorcctic agents, appetite suppressant and d agents is not limited to those listed above, but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of overweight and obese individuals.
It is understood that the sc0pe 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 phannaceutical agent or phannaceutical ition useful for the treatment of diseases, conditions or disorders that are linked to metabolic related disorders.
Some embodiments of the present invention include methods of treatment of a disease, disorder, condition or complication 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 t invention in combination with at least one pharmaceutical agent selected from the group consisting of: sulfonylureas (for example, ide, glipizide, glimepiride and other sulfonylureas known in the art), meglitinides (for example, repaglinide, nateglinide and other meglitinides known in the art), ides (for example, biguanides include phenformin, metformin, buformin, and biguanides known in the an), a-glucosidase inhibitors [for example, acarbose, N-(l,3-dihydroxy-2~propyl)valiolamine (generic name; voglibose), miglitol, and d-glucosidase inhibitors known in the art], peroxisome proliferators- activated receptor-y (i.e.,PPAR-y) agonists (for example, rosiglitazone, pioglitazone, itazar, netoglitazone, GW-409544, GW—501516 and PPAR—y ts known in the art), insulin, n ues, I-IMG-CoA reductase inhibitors (for example, rosuvastatin, tatin and its sodium salt, simvastatin, lovastatin, statin, fluvastatin, cerivastatin, rosuvastatin, 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, ric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, rate, ronifibrate, simfibrate, theofibrate, and fibrates known in the art; bile acid sequestrants which e: cholestyramine, colestipol and the like; and niacin), antiplatelet agents (for example, aspirin and adenosine diphosphate receptor antagonists that include: ogrel, ticlopidine and the like), angiotensin- converting enzyme inhibitors (for example, captopril, enalapril, alacepn'l, il; ramipril, lisinopril, imidapn'l, benazepril, ceronapril, cilazapril, enalapn‘lat, fosin0pn'l, moveltopril, perindopri], quinapril, spirapril, temocapril, trandolapn'l, and angiotensin converting enzyme inhibitors known in the art), angiotensin II receptor antagonists [for example, losartan (and the potassium salt form)], ensin II receptor antagonists known in the art, adiponectin, squalene synthesis inhibitors (for example, (S)-o.-[bis[2,2-dimethyl~l—oxopropoxy)methoxy] phosphinyl]phcnoxybenzenebutanesulfonic acid, mono ium salt (BMS~ 188494) and squalene synthesis inhibitors known in the tut), and the like. In some embodiments, compounds of the present invention and the pharmaceutical agents are stered separately. In further embodiments, compounds of the t invention and the phannaceutical agents are administered together.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present invention e, but not limited to, amylin agonists (for example, pramlintide), insulin secretagogues (for example, GLP—I agonists; exendin-4; insulinotrOpin (NNZle); acyl CoA cholesterol acetyltransferase inhibitors (for example, ezetimibe, eflucimibe, and like compounds), cholesterol tion inhibitors (for example, ezetimibe, pamaqueside and like compounds), cholesterol ester transfer protein inhibitors (for example, CP-529414, JTT-705, CETi-I, and like compounds), microsomal triglyceride transfer protein inhibitors (for example, implitapide, and like compounds), cholesterol modulators (for example, NO— 1886, and like compounds), bile acid modulators (for example, GT103—279 and like compounds), insulin signaling pathway tors, like tors of protein tyrosine phOSphatases (PTPases), non-small molecule c nds and inhibitors of glutamine-fructose-6—phosphate antidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucosephosphatase (GéPase), inhibitors of fructose- 1,6-bisphosphatase (F—l,6—BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of oenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin ion enhancers, inhibitors of gastric emptying, a2— adrenergic nists, retinoid X receptor (PvXR) agonists, and dipeptidyl ase—4 (DPP—IV) inhibitors.
In accordance with the present invention, the combination can be used by mixing the respective active components, a compound of the present invention and phannaceutical agent, either all er or independently with a physiologically acceptable r, excipient, binder, diluent, etc., as described herein above, and administering the mixture or mixtures either orally or ally as a pharmaceutical ition. When a compound or a mixture of nds of the present invention are administered as a combination y with another active compound the therapeutic agents can be formulated as separate pharmaceutical compositions given at the same time or at ent 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 therapeutic 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 Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety. [164} The compounds described herein can be used in combination with the agents disclosed herein or other suitable , 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 ation can include simultaneous administration of the two agents in the same dosage form, simultaneous stration in separate dosage forms, and separate administration.
That is, a nd described herein and any of the agents described above can be formulated together in the same dosage form and stered simultaneously. Alternatively, a compound of the present invention and any of the agents bed above can be simultaneously administered, wherein both the agents are present in separate ations. In another alternative, a compound of the present invention can be administered just followed by and any of the agents described above, or vice versa. In the te stration protocol, a compound of the present invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart. [165} The methods in accordance with the ion may include administering a GPR 119 agonist with one or more other agents that either e the activity of the agonist or compliment its activity or use in treatment. Such additional factors and/0r agents may produce an augmented or even synergistic effect when administered with a GPR 119 agonist, or ze side ts.
The foilowing general methodology described herein provides the manner and process of making and using the compound of the present invention and are illustrative rather than limiting. Further modification of provided methodology and additionally 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. [167} Representative compounds of the present invention include those specified above in Table 1 and pharmaceutically acceptable salts thereof. The present invention also includes the intermediate 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 indicated, the variables (egg. 2, 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 formula (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 described above in relation to formula (A). L; is shown as L in the scheme below.
Scheme 1 xz/X1\ X1 NH2 0 X2/ \ .. N\ Hal—if + H0 —_..~._» HaIT/ CV X3\ / PPA,180 c0 3 2H Cy \X4 2 XB‘;//1,-4PdtPPh3).. -Dloxane, reflux A compound of formula (1) n 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 formula (3) can then be coupled with a compound of formula Ar—B(OI~I)2 in the presence of a catalyst, such as Palladium is ylphosphine, and a suitable base, such as potassium carbonate, to give the desired nds 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-NH; or Ar—OH in the presence of a suitable base, such as potassium carbonate, to give the desired compounds of formula (A), wherein L is NH or O, X is N, Z is O or NR and other les are the same as described above in relation to formula (A).
Illustration: BrUNH2 + r0— 8m:,2 NH2 HO PPA 180°C 12 IPA, DiPEAl Boc-anhydride H 0083 2 ONf‘CN-é Pd(PPh3)4. K2003, 1.4vDioxane, reflux BrUte—CN’KN O Hacozs I (pram H F 6H Scheme 2: This scheme provides a method for the preparation of a compound of formula (A-I) n L1 and L2 are absent, X is N, Z is O, D is CH, 13 is N and other variables such as R”, X1, X3 and X4 are the same as described above in on to formula (A-I).
Scheme 2 . k R] R ‘ R] Rk R' R‘ R‘ Rl Hat x1 XH Hal \ll/ x ‘ o x,‘ .3. —. Wl/ I \ _ N-H X3 / N H X3 / X4 OH HO R“ PPA. 180 C0 X, 0 Re R“ Rf R9 R' R9 1a 23 3 R5-Lg IPA. DiPEA - R] Rk l l . Rj Rk I ArYxR R' R x RHR Ha, x, x XI j: >_D E‘Rs \ N-R5 3 X Z ’ XI 4 ReA )4 Pd(PPh ) ,K CO h 34 2 3 3 j: R . X4 O R’ R9 1,4-Dioxane. reflux Re Rf R9 A-l 4 A compound of formula (la) wherein Hal represents n can be coupled with a compound of formula (23) in the presence of a suitable poly phOSphon‘c acid at a sufficiently high ature to give a compound of a (3a). The compound of formula (33) can then be coupled 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 formula Ar—B (OH)3 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 on to formula (A-I).
Illustration: Br NH2 0 OH HO PPA 180 °c CH‘NE? IPA. DiPEA chozs O Panama)M choa, 1,4-Dioxane, reflux N N“' F 0 H314?o N Q or *Ol N N e r \ F OH N / Scheme 3: This scheme provides a method for the ation of a compound of formula (A-II) wherein L1 and L2 are , X is N, Z is O, D is CH, E is N and other variables such as Ra", X1, X2 and X; are the same as described above in relation to formula (A-II) Scheme 3 RiRJ Rk R-R5 R Hale11$ R' RR —* Hai\rx' PPA, 180°C e Rh quI Rf R9 1b 2b Rebe RQR IPA, Dim;3R5-Lg . R1 Rk I R_RJ Rk Ar x4 R'j__kR | R' IIHEeX Ha'YI: Ne 2-x1 2 ReHRh Pd(PPh3)4, cho3. sz’ Rh Rf R9 1.4-Dioxane, reflux ReRf R9 A-ll 4‘3 A nd of formula (1b) wherein Hal represent halogen and Z is NH or O can be coupled with a compound of formula (2b) in the presence of a suitable poly phosphoric acid at a sufficiently high temperature to give a compound of formula (3b). The compound of formula (3b) can then be coupled with a compound of formula Rs-Lg (where Lg is a g 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 nd 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-II), X is N , Z is O, D is CH, E is N and other variables are the same as described above in relation to fomrula (A-II).
Scheme 3A: This scheme provides a method for the preparation of a compound of a (A-H) wherein 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 , 80%? Pd catal st ase n--BuLi +8,-8N3$§i Wl/ J:\>—DX4K X HE—R5-<——— \ / N-Boc z Hm o A compound of formula (Id) 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 ium ate, to give a compound of (3c). The compound of a (3c) can then be lithiated followed by treatment with triisopropyl borate to give the compound of a (4b). The compound of formula (4b) can then be coupled with a compound of formula (4c) to give a compound of formula (52) which can then be reduced using le 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 HZNOC I Br Pd catal st H2N on + m V, 0 Base O 0\ O trisopropylborate n—BuLi F O 16h,RT )"N / 0 o F Scheme 4: This scheme provides a method for the preparation of compound of formula (B) wherein L; is absent, NH or O, X is N, Z is NR or 0, L2 is absent and other variables such as Ar, Cy, X1, X2, X3 and X4 are the same as described above in relation to formula (B).
Scheme4 Slap-1 X /X1 x; K "“3 o N >52 \ Hal ,', + H0 —____.. HaIT/ Ar Xg\x‘/ PPA,180°C ZH Ar xx“ 2 1 5 6 Step-2 X Ar / N X / X X \ y .2 iii—bc -L-H \ x \ Hal-“'17"I \>—Ar L1_.).!(1E_. \>—~——L2/ 3‘X: 850 2 3‘X4/ 2 X / X o\ X/ 1\ X X2 \ .2 \ \ Cy n L2 ,3 l" A" WCY‘Lg xk / 2 \Ar 0 3\ / x4 Pd(PPh3)4, K2003, 1,4-Dioxane, reflux B A nd of formula (I) wherein I-Ial 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 nd of formula (6). The compound of formula (6) can then be coupled with a nd of formula Cy-NH; 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 variabies are the same as described above in relation to formula (B). Alternately, the compound of a (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 coupling conditions. The compound of formula (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 tetrakis lriphenylphosphine, and a suitable base, such as potassium carbonate, to give the desired compounds of a (B), i.e wherein L; is , X is N, Z is O or NR and other variables are the same as described above in relation to formula (B).
Illustration: BrUNH: 0 + SOZCH" *3 NH2 “0@SOZCH3 —’ 50 CH PPA 180°C 2 3 O NKJOTfH1.4-Dioxa4ne,Pd(pph3) K2C03, >L reflux AN >131 H Hydrogenation N‘ $020H3 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 bed above in on to formula (B-I).
Scheme 5 \xfi , ‘ + Ar-COOH -———-- xl ,j: ‘>—Ar 3‘x.1 OH PPA, 180°C 3x, 0 1b 5 6 Suzuki coupling R R1 k RjRi Pd(PPh3)4, K2003, Pg‘N ‘ \ 1,4-Dioxane, reflux 9 H0 I XIX‘HI' 0’BYX‘ . R] Rk R" RQRlRO A X3‘X¢/ 0 Fl’ Rt >_ r . X3X4/OI:\ 8 L90 ’I N-‘Pg Rh Sc 8' R9 R’ R" R RR P9\N>L</YR’R‘ at HR‘ = i. Deprolection D X1\ WMRQR‘R"‘1in W Ar ii. Coupling H«Jr91 o / R X Fl R 3 X4. 2 A nd of formula (lb) wherein Hal represents halogen can be coupled with a compound of fonnula (S) in the presence of poly phosphoric acid at a sufficiently high temperature to give a compound of formula (61)). 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 a (7) (wherein Pg is a protecting group) using palladium tetrakis triphenylphosphine and a suitable base, such as potassium carbonate, to provide a compound of formula (8). The compound of formula (8) can then be subjected to hydrogenation to give the nd of formula (9). The compound of formula (9) can then be tected followed by coupling with a compound of a Rs-Lg wherein Lg is 21 leaving group to give the desired compounds of a (B-I).
Illustration: BrUNH2 0 + SOQCHQ 5023”: OH HO PPAM°C180 >Lo I CAN 3)4- K2603. $0 I :\>-2 1 .4-Dioxane reflux 0,8 >—SOZCH3 >Lo QUEE- SO;CH3 O U‘OT‘I [Hydrogenation[Deprotecfion IPA DIPEA/T $02043 SOZCHa {177] Scheme 6: This scheme provides a method for the ation of a compound of formula (B-II) wherein L; and Lg are absent, X is N, D is CH, E is N, Z is O and other variables such as Re", X1, X2 and X4 are the same as described above in relation to formula (B-II).
Scheme6 Hal X4 XH Hat YXI:‘>~ArX4 \Xlr / + Ar—COOH 2‘x‘ OH PPA 180°C 5 6 Suzuki coupling RI Rk RRil Pd(PPh3)4, K2003, Pg~N ‘ [5 X4 X 1,4-Dioxane, reflux ([3 H \I I \ h—fl— \ O)— X Ar I k 0 R R \ Rh RQRiRe X2~X/ R] RI 1 81.?“ :>"Ar ll ‘ 8a LgO ' N—Pg Re R“ FI’ as i. Deprotection X D H \W ID a X} —,,_~.._ I 1 Ar \ Ar W \I/ :[\>—u ii. Coupling HRQR‘R" X2~ / Z Iliustration: Br/[N/‘ENHC)H234:; < ::> F Bl’UO’B 5h, reflux BrUN>_©_ _._+ NJ\©\POCI3UCF Pd cat. 105°C fi£5E.
BocaN Boc«30.,o '72419'72:\L/:EB % Pd/C stirr under H2 pressure Boca N O A compound of a (1c) wherein I-Ial 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 compound of formula (6d). The compound 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 nd of formula (83). The compound of a (83) can then be subjected to hydrogenation to give the nd of formula (93). The nd of formula (93) can then be tie-protected followed by coupling with a compound of formula RS-Lg wherein Lg is 21 leaving group to give the desired compounds of formula (3-II). {179] Similar ologies with certain ations 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-IIIA), (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) or (B) using suitable intermediates and reagents.
EXPERIMENTAL Unless otherwise mentioned, work—up refers to distribution of a reaction mixture between the aqueous and organic phases indicated within hesis, separation and drying over NaZSO4 of the organic layer and evaporating the solvent to give a residue. Unless otherwise 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 e or dichloromethane and methanol of suitable polarity as the mobile phases. RT generally refers to ambient temperature (ZS-28°C).
Intermediates ediate 4 Intermediate 1 Intermediate 3 awe {1:}wa “gr:am amen Intermediate 5 Intermediate 6 Intermediate 7 Intermediate 8 09—CNH B! N N O‘)—-<:/\N-Bac Intermed'ate91 F Intermediate 12 Intermediate 17 Intermediate 20 Intermediate 24 Intermediate 21 sonu ediate 28 Intermediate 25 Intermediate 26 Intermediate 27 72% F F = Er °‘§m%©—so;m \ N F O I \ SOzMe sone O 3 8r NH Intermediate 29 F Intermediate 32 Intermediate 30 F F F S Br some U/ Br H SOzMe N /' Br:w N SOZME Intermediate 33 Intermediate 34 8r 0 Intermediate 35 IntermeFdiate 36 Q@5025“ .249 F Br Br F 0 NH U\N scams .B \ N \CC , sozno 3 N Br 5 Intermediate 38 5 F: Intermediate 40 Intermediate 39 Intermediate 37 fimwow Brf): HDWS0N ediate 41 Intermediate 43 Intermediate 44 Intermediate 42 BrU/>—©—-CHF2N0 i"m‘w Intermediate 46 Intermediate 48 Intermediate 47 Intermediate 45 806‘ £5th Boc‘N BomN i\/\(:EIZ> QN g N N \>—NH2 N‘>'-NH; 0)—\ 8r Intermediate 49 0 0 Intermediate 50 Intermediate 51 Intermediate 52 BrUOHNH SrUa}N0 724?.E0 twoo Oin Intermediate 54 N CF, Intermediate 55 ediate 56 Intermediate 53 Intermediate 57 ediate 58 Intermediate 1: o(piperidinyl)-1H-benzo[d]imidazole: 4- bromobenzene—1,2—diamine (1.43 g, 7.64 mmol) and piperidinecarb0xylic acid (0.99 g, 7.64 11111101) were dissolved in poiyphosphoric acid (20 g). This mixture 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 14. Solid was filtered, washed with methanol and dried to obtain the title compound (1 g) as a dark brown solid.
Intermediate 2: S-Bromo-Z-(l-(5-ethylpyrimidin-2~yl)piperidinyl)-1H- benzo[d]imidazole: Intermediate 1 (500 mg, 1.69 mmol) and 2-chloro-5—ethylpyrimidine (264 mg, 1.86 mmol) were dissolved in propanoi (25 ml). T0 this mixture N,N- Diisopropylethyl amine (1.8 mi, 10.1 mmol) added and stirred at 90 0C for 12 h. After completion of the reaction, propan—2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of ACOET and Petethcr ) as eluent to afford the titled compound (0.2 g) as a pale-yellow solid. ediate 3: 2-[2~Fluoro(methylsulfonyl)phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane:1~bromo—2-fluoro—4-(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.CHzC12 (85 mg, 0.1 mmol). This mixture stirred at 105 0C for 12 11. 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 ) to afford the titled compound (900 mg) as a white solid. lH—NMR (3 ppm, CDClg, 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 4-(5-bromo-1H—benzo[d]imidazol yl)piperidine-l-carboxylate: 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 O 0C for 2 h. After tion of the reaction, reaction mixture washed with water, DCM layer dried over NagSO4 and removal of DCM afforded the crude. Crude was purified by combiflash using AcOEt and Petether (35: 65) as eluent to afford the titled nd (60 mg) as a brown solid. ediate 5: o~2-(piperidin-4~yl)benzo[d]oxazole: 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 mixture 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/HZO) followed removal of AcOEt afforded the titled compound (0.8 g) as a pale-yellow gummy solid.
Intermediate 6: S-Bromo-Z-[l-(5-ethylpyrimidin-Z-priperidin yl]benzo[d]0xazole: Intermediate 5 (800 mg, 2.85 mmol) and 2-chloro-5~ethylpyrimidine (447 mg, 3.14 mmol) were dissolved in oi (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, propan-2~ol was removed to obtain the crude. Crude was purified by combiflash using a e of AcOEt and er (8:92) as eluent to afford the titled compound (80 mg) as a paie~yellow solid. lH—NMR (6 ppm, CDCl3, 400 MHZ): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 11-1), 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), 2.02-1.90011, 2H), 1.19 (t, J 7.6, 3H).
Intermediate 7: Tert-butyi 4-(5-bromobenzo[d]oxazolyl) piperidine-1~ carboxylate: Intermediate 5 (500 mg, 1.78 mmol) was ved 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 d at 0 0C for 1 h. After tion 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 off-white solid.
Intermediate 8: tert-butyl 4-(5-(4,4,5,S-tetramethyl-I,3,2-di0xaboroian yl)benzo[d] oxazol-Z-yl)piperidine-l-carhoxylate: ediate 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 mmoi) and potassium acetate (2.1 g, 21.8 mmol) were dissolved in dioxane (20 mi) under N3 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppt)2Clg.CI-12Clz (210 0.26 mmol). Reaction mixture was stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (ACOEt/I‘IQO) afforded the (nude. Crude was ed 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: G-bromo-Z-(piperidin-d-ylmenzo[d]oxazole: 2-amino—5- bromophenoi (1.3 g, 6.9 mmol) and isonipecotie 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 rt 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 r0mobenzoidloxazol-Z-yl)piperidine-lcarboxyiate : Intermediate 9 (500 mg, 1.77 mmol) was dissolved in DCM 01), cooled to 0 OC and added TEA (0.25 ml, 1.77 mmol). To this mixture (Boc)20 (0.41111, 1.77 mmol) was added and stiired 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 combiflash using EtOAc and Pctethcr (7.5%) as eluent to obtain the title compound (500 mg). ll-I-NMR (8 ppm, CDClg, 400 MHz): 7.65 (d, J 1.6, 11-1), 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), 2.20208 (m, 2H), 1.96- 1.82 (in, 2H), 1.47 (s, 9H).
Intermediate 11: S-bromofluoro(piperidin-4—yl)benzo[d]oxazole: 2- 4—bromo—6-fluorophenol (1.7 g, 8.24 mmol) and isonipecotic acid (1.06 g, 8.24 11111101) were dissolved in polyphosphoric acid (28 g). This mixture was heated to 195 0C for 3 h.
After 3 h, reaction mixture cooled to rt and d with aqueous NaOI—I solution to pH 14.
Solid that obtained was d and dried to obtain the title compound (1.3 g) as a brown solid.
Intermediate 12: Tert-butyl romofluorobenzo[d]oxazoI-Z-yl) piperidine-l-carboxylate: Intermediate 11 (1.3 g, 4.36 mmol) was dissolved in DCM (40 11101), cooled to 0 0C and added TEA (1.2 ml, 8.72 mmol). To this mixture (Boc)20 (950 mg, 4.36 11111101) was added and stirred at It for 3 h. At this stage reaction mixture diluted with water and ted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash 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]oxazol-2~yl)piperidine—1- carboxylate: Intermediate 5 (980 mg, 3.31 mmol) was dissolved in DCM (5011101) and added TEA (0.45 ml, 3.31 mmol). Reaction mixture cooled to 0 0C, isopropylchloro fonuate (2.7 ml, 6.62 mmol) was added and stirred the reaction mixture for 3 h at 11. Work up (DCM/1120) followed by column purification on 60120 mesh silica gel using EtOAc and Petether (15: 85) as eluent afforded the titled compound (500 mg) as a pale-red solid.
Intermediate 14: Isopropyi 4-(S-(4,4,5,5-tetramethyi—1,3,2—di0xab0rolan- 2-yi)benzeId]oxazoIyl)piperidine-l-carboxylate: 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 dioxane (20 1111) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Clz.CHzClz (31 mg, 0.04 mmol). Reaction mixture was stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (AcOEt/HZO) ed the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and Petether (20:80) as eluent to afford the titled compound (0.3 g) as a pale-red solid.
Intermediate 15: Isopropyl 4-(6-bromobenzo[d]oxazoiyl)piperidine carboxylate: Intermediate 9 (1.3 g, 4.4 mmol) was dissolved in DCM (50 mol) and added TEA (1.22 ml, 8.8 mmol). Reaction e cooled to O 0C, isopropylchloro e (2.6 ml, 6.6 mmol) was added and stirred the reaction mixture for 3 h at It. Work up (DCM/1130) followed by purification on combifiash using nt mixture of EtOAc and Pctethcr (15: 85) as eluent afforded the titled compound (510 mg) as a brown viscous liquid.
Intermediate 16: Isopropyl 4-(6-(4,4,5,S~tetramethyl-1,3,Z-dioxaborolan- 2-y1)benzoId]oxazol-Z-priperidine-l-earboxylate: Intermediate 15 (0.51 g, 1.4 mmol), 4,4,4‘,4‘,5.5,5‘,5‘-octamethy1—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)2Clg.CI-12Clg (45 mg, 0.05 mmol). Reaction e was stirred at 105 0C for 12 11. Reaction mixture diluted with water and work up (AcOEUHgO) afforded the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and er (15:85) as eluent to afford the titled compound (0.36 g) as a brown viscous liquid.
Intermediate 17: 5-(4-bromoi1uorophenyl)-1H-tetrazole: ro-4— bronrobenzonitrile (300 mg, 1.5 mmol) dissolved in EtOH. added sodium azide (320 mg, 4.9 mmol), Zinc chloride (240 mg, 1.8 mmol). This mixture was stirred refluxed for 38 h. Work up (EtOAc/HZO) afforded the crude. Crude was washed with petether to obtain the titled compound (120 mg) as a white solid. IH-NMR (8 ppm, lg, 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). ediate 18: S-Bromo-Z-[1-(5~fluoropyrimidinyl)piperidin yl]benzo[d]oxazole: Intermediate 5 (1 g, 3.4 mmol) and 2—Chloro—5~fluoropyrimidine was dissolved in i30propanol (20 ml) and added MN-diisopropylethyl amine (2.4 ml). This mixture was stirred at 90°C for 90 mins. Isopropanol was removed on rotavapour to obtain a residue. Work up (EtOAc/H20) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (7:93) as eluent afforded the titled compound as a pink solid.
Intermediate 19: 2-[1-(S-Fluoropyrimidinyl)piperidinyl](4,4,5,S- tetramethyl—1,3,2-dioxaborolanyl)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-di0xaborolane) (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(dppt)2C12.CHgC12 (24 mg, 0.03 mmol). Reaction mixture was stirred at 105 0C for 12 h.
Reaction e diluted with water and work up (AcOEtlI-IZO) afforded the crude. Crude was purified by column chromatography on 60-120 mesh silica gel using a gradient e 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)fluorobenzamide: Following the general ure—1 the titled compound (200 mg) was obtained from S-Bromobenzofuran (200 mg, 1 mmol) and 2-fiuoro(4,4,5,5-tetramethyl—l,3,2-dioxaborolany})benzamide (320 mg, 1.2 mmol) as a brown solid. lHNMR (8 ppm, DMSO-(Zg, 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-carbamoyl-S-fluorophenyl)benzofuran-Z-ylboronic acid: ediate 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 stirred at same temperature for 20 mins. Reaction mixture warmed to 0°C and stirred for 2 hrs. After that triSOpropyl borate (88 mg, 0.47 mmol) was added and d 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: l-Benzyl—N-(S-bromohydr0xyphenyl)piperidine carboxamide: 1-Benzylpiperidine—4-carboxylic 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 rt for 2 h. After 2 11, DCM d on rotavapour and co-distilled the residue two times with DCM to obtainl—benzylpiperidinecarbonyl de quantitatively. 2—Amino-4—bromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at it for 30 mins and added i-benzylpiperidine—4-carbonyl 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 t further purification. ediate 23: 2-(1-Benzylpiperidinyl)-S~br0mobenzo[d]oxazole: 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 condenser. Xylene was removed and pH of the residue was adjusted to 9 using aq NaI-IC03 solution. Work up (EtOAc/I-I20) afforded the crude. Crude was purified by column on 60-120 mesh gel using a gradient e of EtOAc and Petether (10:90) as eluent to afford the titled compound (11 g) as brown solid.
Intermediate 24: 4-(2-(1-benzylpiperidinyl)benzoid]oxazol~5~yl) fluorobenzamide: Following the general procedure—3, the titled compound (4.8 g) was prepared from intermediate 23 (6g, 16.2 mmol) and 2-fluoro-4«(4,4,5,5-tetramethyi-l,3,2- dioxaborolanyl)benzamide (4.7 g, 17.8 mmol) as a brown solid.
Intermediate 25: 2-Fluoro(2-(piperidinyl)benzo[d]oxazol yl)benzamide: Intermediate 24 (100 mg, 0.23 mmol) dissolved in MeOI—I (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 h celite and celite was washed with MeOI-I.
MeOH was d on rotavapour to obtain the titled compound (80 mg) as an off-white solid. {208] Intermediate 26: 5-Bromo[2-fluoro—4-(methylsult‘onyl)phenyl]-1H- benzo[d]lmidazole: 4-bron10benzenew1,2~diamine (1.75 g, 9.39 mmol) and 2—f1uoro (methylsulfonyl)benzoic acid (2 g, 9.39 mmol) were dissolved in polyphosphoric acid (70 g).
This mixture was heated at 195 0C for three and half hours. on mixture cooled to rt and diluted with ice water (100 mi). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/1120) followed by removal of EtOAc afforded the crude. Crude was purified on combiflash with a gradient e of EtOAc and Petether ) to obtain the titled compound (1.5 g) as an off-white solid.
Intermediate 27: 2-[2-Fluoro(methyisulfonyl)phenyl]-S-(4,4,5,S- tetramethyi-I,3,2~dioxaborolanyl)~1H-benzo[d]imidazole: Intermediate 26 (1.5 g, 4.1 11111101), 4,4,4‘,4',5,5,5’,5'-octamethy1~2,2‘~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 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppi)zClg.CI-I2Clz (133 mg, 0.16 11111101). This mixture stirred at 105 0C for 12 11. 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~4- (methylsulfonyl)phenyl]benzo[dloxazole: 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 rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide s to pH 9. Work up (EtOAc/1120) followed by evaporation of EtOAc ed the crude. Crude was purified on ash with a nt mixture of EtOAc and Petether (33:67) to obtain the titled compound (2.8 g) as an off—white solid.
Intermediate 29: 2-[2-Fluoro~4-(methylsulfonyl)phenyl](4,4,5,S- tetramethyL1,3,2-dioxaborolanyl)benzo[d}oxazole: Intermediate 28 (2.8 g, 7.6 mmol) 4,4,4‘,4',5,5,5',5'-octamelhyl—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 e (150 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dPP02C12.CI-12Clg (248 mg, 0.3 nunol). This e stirred at 105 0C for 12 h. Reaction e d with water and work up (AcOEt/HgO) afforded the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and Petether (33:67) to afford the titled compound (1 g) as an off—white solid.
Intermediate 30: S-Bromofluoro[2-f1uoro (methylsulfonyl)phenyl]benzo[d]oxazole: 2—Amino-4—bro111ofluorophenol (2.6 g, 9.7 mmol) and 2-fluoro(n1et11ylsulfonyl)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 1111). s layer basified with sodium ide pellets to pH 9. Work up (EtOAc/Hzo) followed by evaporation of EtOAc afforded the c1ude. Crude (3.1 g) was used in the next step without further purification.
Intermediate 31: 7-Flu0r0[Z-fiuoro~4-(met11y1su1fonyl)phenyl] (4,4,5,5-tetramethy1-I,3,2-dioxahorolan-2~y1)benzo[d]oxazole: Intermediate 30 (1.5 g, 3.87 11111101) 4,4,4',4',5,5,5‘,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.28 g, 5 11111101) and potassium acetate (1.25 g, 12.8 11111101) were dissolved in dioxane (20 1111) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2C12.CHgC1g (126 mg, 0.15 11111101). This mixture mined at 105 0C for 1.2 h. on mixture diluted with water and work up (AcOEt/HgO) ed the crude. Crude was purified by combiflash using a gradient mixture of AcOEt and er (18:82) as eluent to afford the titled compound (620 mg) as an off-white solid.
Intermediate 32: N-(4-Bromo-Z-fluorophenyl)fluoro (methylsulfony1)benzamide: 2-F1u01'o(met11ylsu1fonyl)benzoic acid (2 g, 9.2 ) dissolved in DCM (10 1111), cooled to 0 0C and added oxalyl chlon'de (1.2 1111, 13.8 11111101). tic amount of DMF was added to this mixture and strirred at rt for 30 mins. After 30 mins, DCM ren10ved on notavapour and co—distilled the residue two times with DCM to obtain 2-11u0ro—4—(methylsulfonthenzoyl chloride quantitatively. 4-Br01110fluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 11111101) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-11uoro-4— (methylsulfony1)benzoyl de (2.08 g, 8.84 mmol). After uing stirring at It for 15 mins, reaction mixture diluted with water and extracted with DCM. DCM layer washed with aq. NaI-IC03 and DCM removed on rotavapour to obtain the $0111. Solid was triturated with Eth and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid.
Intermediate 33: N-(4—BromofluorophenyI)fluoro (methylsulfonyl)benzothioamide: ediate 32 (1 g, 2.56 mm01) dissolved in toluene (10 ml) and added P285 (0.57 g, 2.56 11111101). This mixture was refluxed for 18 h. Toluene removed on rotavapour to obtain the crude. Crude was purified by column chromatography on 60- 120 mesh silicagel using EtOAc and Petether ) as eluent to afford the title compound (500mg) as a yellow solid. II-I-NMR (5 ppm, DMSO-d6, 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, SH).
Intermediate 34: 6-Bromo-2—[2-fluoro (methylsulfonyl)phenyl]benzo[d]thiazole: Intermediate 33 (600 mg, 1.47 mmol) dissolved in DMF (7 ml) and added Na2C03 (156 mg, 1.47 mmol). This mixture stirred at 110 0C for 17 11. Work up (EtOAc/I’IgO) afforded the crude. Crude was triturated with Petether and dried to obtain the titled compound (360 mg) as a white solid. lI-I—NMR (6 ppm, CDClg, 400 MHZ): 8.71865 (m, 1H), 8.13 (d, J 1.9, 1H), 8.01 (d, .l 8.7, 1H), 7.91—7.83 (m, 2H), 7.66 (dd, J 1.9, 8.7, 11-1), 3.12 (s, 31-1).
Intermeidate 35: 2-[2-Fluoro(methylsulfony!)phenyl](4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)benzo[d]thiazolez Intennediate 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 dissolved in e (10 ml) under N2 atmosphere. This mixture was degassed with en for 30 mins and added i‘)2Clg.CHzClz (30 mg, 0.04 mmol). This mixture stined at 105 0C for 12 h. Reaction mixture d with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combifiash using a mixture of AcOEt and Petether (12:88) as eluent to afford the titled compound (300 mg) as an off-white solid. 1I-I—NMR (8 ppm, CDCI3, 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, 11-1), 7.91-7.83 (m, 2H), 3.12 (s, 3H), 1.38 (5, 121-1).
Intermediate 36: N-(2,5-Dibromophenyl)f1Hero (methylsulfonyl)benzamide: 2-Fluoro-4—(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).
Catalytic amount of DMF was added to this mixture and strirred at rt for 30 mins. After 30 mins, DCM removed on totavapour and co-distilled the e two times with DCM to obtain 2-fluoro—4-(methylsulfonyl)benzoyl chloride quantitatively. 2,5«Dibromoaniline (0.9 3.59 mmol) dissolved in DCM (10 ml) and added Pyridine (0.34 g, 4.30 mmol) under nitrogen atmosphere. This mixture stirred at It for 30 mins and added 2-fiuoro (methylsulfonyDbenzoyl chloride (1.01 g, 3.59 mmol). After uing stirring at it for 15 ruins, 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 Et20 and Petether mixture (4: 1) to obtain the titled compound (1.6 g) as a brown solid. IH-NMR (6 ppm, DMSO-dg, 400 MHZ): 10.34 (s, 1H), .99 (111, 1H), 7.98—7.93 (m, 2H), 7.92789 (m, 1H), 7.68 (d, J 8.6, 1H), 7.43 (dd, J 2.4, 8.6, 1H), 3.33 (s, SH).
Intermediate 37: N-(2,5«Dibromophenyl)fluoro~4— (methylsulfonyl)benzothioamide: Intermediate 36 (1.5 g, 3.34 mmol) dissolved in toluene (20 ml) and added P2S5 (0.74 g, 3.34 mmol). This mixture was refluxed for 18 h. Toluene removed on pour to obtain the crude. Crude was d by column chromatography on 60-120 mesh silicagel using EtOAc and er (20:80) as eluent to afford the title compound (480 mg) as a yellow solid. lH-NMR (6 ppm, g, 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, 11-1), 3.32 (5, 31-1). {220] Intermediate 38: 5-Bromo[2-fluoro (methylsulfonyl)phenyl]benzo[d]thiazole: Intermediate 37 (0.48 g, 1.03 mmol) dissolved in N-Methylpyrroiidinone (0.97 ml) and added NaH (52 mg, 2.2 mmol). This mixture was stirred at 140 0C for 3 h. Reaction mixture cooled to rt 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. IH-NMR (8 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, SH).
Intermediate 392 2-[2-Fluor0—4-(methylsulfonyl)phenyl]-S-(4,4,5,S— ethyi-1,3,2-dioxaborolanyl)benzo[d]thiazole: ediate 38 (360 mg, 0.94 mmol) 4,4,4’,4‘,5,5,5',5'-octan1ethyl~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(dpp02C12.CHgCl2 (22 mg, 0.03 mmol). This mixture stirred at 105 0C for 12 h. Reaction e diluted with water and work up (AcOEt/Hgo) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (12:88) as eluent to afford the titled compound (230 mg) as a yellow solid. lH—NMR (5 ppm, CDClg, 400 MHZ):8.73-8.67 (m, 1H), 8.62 (5, 11-1), 7.98 (d, J 8, 1H), 7.90—7.81 (m, 3H), 3.12 (s, 3H), 1.39 (s, 12 H).
Intermediate 40: 6-Bromo[2-fluoro-4— (methylsulf011yl)phenyl]benzo{d]oxazole: o—5-bro1nophenol (1.72 g, 9.2 mmol) and ro—4-(111ethylsulfonyl)benzoic acid (2 g, 9.2 mmol) were dissolved in polyposphoric acid (30 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. 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 nd (450mg) as a dark brown solid.
Intermediate 41: uoro(methylsulfouyl)phenyl]—6-(4,4,55- tetramethyi-1,3,2~dioxaborolanyl)benzo[d]oxazole: Intermediate 40 (1.5 g, 4.1 mmol) 4,4,4',4‘,5,5,5’,5’-octa111ethyl—2,2‘—bi(1,3,2-di0xaborolane) (1.35 g, 5.29 11111101) and potassium acetate (1.32 g, 13.45 11111101) were dissolved in dioxane (10 1111) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppl‘)2C12.CHgClg (133 0.16 11111101). This e stirred at 105 0C for 12 h. Reaction mixture diluted with water and work up (AcOEt/l-lgO) 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. [224} Intermediate 42: N-(S-Bromo-Z-hydroxyphenyD (trifluoromethyDbenzamide: 4-(T11fluoromethyl)benzoic acid (1 g, 5.3 mmol) dissolved in DCM (10 1111), cooled to 0 0C and added oxalyl chloride (0.7 1111, 7.9 11111101). 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— uoromethyl)benzoyl chloride quantitatively. o-4—br01110phenol (0.8 g, 4.25 11111101) dissolved in DCM (20 ml) and added Pyridine (0.4 ml, 5.1 11111101) under nitrogen atmosPhere.
This mixture stirred at rt for 30 111ins and added 4—(trifluoromethyl)benzoyl chloride (1.06 g, .1 mmol). After uing ng at It for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaI-IC03 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. IH—NMR (6 ppm, , DMSO-dg, 400 MHz): .15 (bs, 1H), 9.75 (s, 1H), 8.13 (d, I 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: 5-bromo-Z—[4-(trifluoromethyl)phenyllbenzo[djoxazolez Intermediate 42 (l g, 2.77 mmol) was dissolved in 1,4~Dioxane and added Phosphorus oxychloride (0.76 ml, 8.3 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 ed and dried to obtain the titled compound (630 mg) as an off-white solid. lH—NMR (8 ppm, , CDC13, 400 MHz): 8.35 (d, J 8.2, 2H), 7.93 (d, I 1.5, 1H), 7.79 (d, J 8.3, 2H). 7.52« 7.49 (H1, 211).
Intermediate 44: 5—(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-Z-yl)(4- (trifluoromethyl)phenyi)benzo[d]oxazole: Intermediate 43 (630 mg, 1.84 mmol), 4,4,4‘,4‘,5,5,5‘,5'«octa111ethyl—2,2'-bi(1,3,2-dioxab0rolane) (600 mg, 2.4 11111101) and ium acetate (590 mg, 6.1 11111101) were dissolved in 1,4—dioxane (10 1111) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppi)gClz.CHzClz (60 mg, 0.08 mmol). This e stirred at 105 0C for 12 11. Reaction mixture diluted with water and work up (AcOEt/IlgO) afforded the crude. Crude was purified by comhiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (400 mg) as a yellow solid. lH-NMR (5 ppm, CDC13, 400 MHz): 8.38 (d, J 8.1, 2H), 8.25 (s, 1H), 7.86 (dd,l 1, 7.9, 11-1), 7.78 (d, J 8.3, 2H), 7.59 (d, J 8.6, 1H), 1.38 (s, 1211).
Intermediate 45: N-(4-Bromo-Z-hydroxyphenyl)-4~ (difluoromethyl)benzamide: 4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0 0C and added oxalyi chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and str'ured at It for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4- romethyl)benzoyl chloride quantitatively. 2-A111ino-S—bromophenol (0.64 g, 3.411111101) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 11111101) under en atmosphere. This mixture d at It 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 d 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 Eth and Petether mixture (421) to obtain the titled compound (0.5 g) as a yellow solid. lH-NMR (5 ppm, DMSO-(lg, 400 MHz): 10.27 (s, 1H), 9.62 (3, 11-1), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 11-1), 7.12 (t, J 55.7, 111), 7.07 (d, l 2.2, 1H), 7.03-6.94 (111, 11-1).
Intermediate 46: 6«Bromo[4-(difluor0methyl)phenyljbenzo[dloxazolez N—(4-Bromohydroxypheny1)—4-(difluoromethyl)benzamide (0.5 g, 1.5 mmol) was dissolved in 1,4~Dioxane (10 ml) and added Phosphorus oxychloride (0.4 1111, 4411111101). This mixture was refluxed for 2 h. oxane d 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 off-white solid. lH-NMR (5 ppm, CDC13, 400 MHz): 8.28 (d, .1 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: 2-{4-(Difluoromethyl)pheny1](4,4,5,S-tetramethyl- 1,3,2-dioxahorolanyl)benzo[d]oxazole: Intermediate 46 (130 mg, 0.4 mmol) 4,4,4‘,4’,5,5,5',5'-0ctamethyl—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 1111) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2C1g.Cl-12Clz (13 mg, 0.02 mmol). This e stirred at 105 0C for 4 11. on mixture diluted with water and work up (AcOEt/l-lgO) afforded the crude. Crude was purified by combil‘lash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled nd (100 mg) as a yellow solid.
Intermediate 483 Tert-butyl 4-{2—[4- (difluoromethyl)phenyl]benzo[d]oxazolyl}-S,6-dihydropyridine-H2H)-carboxylate: Following the general procedure-2, the titled compound was prepared from intermediate 47 (0.1 g, 0.27 mmol) and tert-butyl 4-(trifluorometl1ylsulfonyloxy)-5,6-dihydropyridine~1(2H)- ylate (89 mg, 0.27 11111101) as an off-white solid. lH-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, 11-1), 6.12 (bs, 1H), 4.12 (d, J 2.7, 2H), 3.68 (t, J 5.6, 2H), 2.60 (135, 2H), 1.50 (s, 9H).
Intermediate 49: tert—butyl 4-(2—p-tolylbenzo[dloxazol-G-yl)piperidine-l- 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 hydrogen pressure for 15 11 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 tn’turated with er to obtain the titled compound (40 mg) as an off—white solid. MS (m/z): 393.2 [M+1-l]+, Intermediate 50: Tert~butyi 4-(2-aminobenzoId]oxazolyl)-5,6- dihydropyridine-l(ZID-carboxylate: obenzo[([]oxazoi-2~amine (824 mg, 3.9 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyn'dine-1(2H)-carboxylate (1.8 g, .8 mmol), ium fluoride (674 mg, 11.61 mmol) were dissolved in DMF under N2 atmosphere. This e was purged with N2 for 30 mins. f)2ClZ.CHgCl2 (252 mg, 0.3 mmol) was added to the above mixture and again purged with N; for 30 mins. The reaction mixture was stirred at 90°C for 12 h. Work up (EtOAc/HZO) followed by column cation on combiflash using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded the titled compound (550 mg) as an off—white solid. IH-NMR (6 ppm, g, 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: Tert-butyl 4-(2-aminobenzo[d]oxazol-S-yl)piperidine-1~ 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 hydrogen 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 MeOI—I. MeOI—I was removed on rotavapour to obtain the residue.
Residue was uiturated with petether to obtain the titled compound (400 mg) as an off-white solid.
Intermediate 52: Tert~butyl romobenzo[d]oxazol-S-yl)piperidine-l- carboxylate: Intermediate 51 (400 mg, 1.3 mmol) was dissolved in acetonitrile (50 ml) and added CuBrz (563 mg, 2.5 mmol). This mixture stirred at it for 15 mins. Tert-Butyl nitrite (259 mg, 2.5 mmol) was added to the above mixture for 5 mins and stirred at 45°C for 2 h.
Work up (DCM/HZO) 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. lH—NMR (6 ppm, CDCla, 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, 111-1).
Intermediate 53: N—(4-bromohydroxyphenyl) (trifluoromethyl)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 30mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4— oromethyl)benzoyl chloride quantitatively. 2-Aminobromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 mi, 4.1 11111101) under nitrogen atmosphere. This mixture d at It for 30 mins and added 4-(trifluoromethy1)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stim'ng 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 Etgo and Petether mixture (4:1) to obtain the titled compound (0.6 g) as a yellow solid.
Intermediate 54: 6-bromo-Z-(4-(trifluoromethyl)pheny1)benzo[d]oxazole: Intermediate 53 (940 mg, 2.6 mmol) was dissolved in xylene (25 ml) and added p- Toluenesuiphonic acid (991 mg, 5.22 11111101). This mixture was refluxed to 160°C for 12 11 under a dean-Stork condenser. Xylene removed from the reaction mixture and basified the residue with aq. NaI-IC03 (30 1111). Work up (EtOAc/HZO) followed by cation with combiflash using a gradient mixture of EtOAc and Petether (5:95) as eluent to afford the titled compound (650 mg) as an Off-White solid.
Intermediate 55: 6-(4,4,5,5-tetramethy1-l,3,2-dioxab0r013ny1){4— (trifluoromethyl)phenyl]benzo[d}oxazole: Intermediate 54 (630 mg, 1.84 11111101) 4,4,4',4',5,5,5',5'-octa111ethyl-2,2‘-bi(1,3,2-dioxaborolane) (600 mg, 2.4 mmol) and potassium acetate (590 mg, 3.3 11111101) were dissolved in 1,4-dioxane (30 1111) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added 02Clg.CHgC12 (60 mg, 0.074 11111101). This mixture stirred at 105 0C for 17 11. Reaction mixture diluted with water and work up (AcOEt/HZO) ed the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (20:80) as eluent to afford the titled compound (420 111g) as an off-white solid. lI-I—NMR (6 ppm, CDC13, 400 MHZ): 8.39 (d, J 8.1, 2H), 8.05 (s, 1H), 7.84 (dd, J 0.8, 8, 11-1), .76 (111, 31-1), 1.38 (s, 12 H). ediate S6: romo-Z-hydrexypyridin—3-yl) uoromethyl)benzamide: 4-(T1'ifluoromethyl)benzoic acid (2.45 g, 12.9 11111101) dissolved in DCM (30 1111), cooled to 0 0C and added oxalyl chloride (3.4 n11, 38.6 mmol).
Catalytic amount of DMF was added to this mixture and stri1red at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4—(tn‘fluor0111ethy1)benzoy1 chloride quantitatively. 2-I-Iydroxyamino—5- bron10pyridine (2.4 g, 11.1 11111101) dissolved in DCM (15 1111) and added Pyridine (1.74 g, 22 01) under nitrogen here. This mixture stilred at rt for 30 mins and added 4— (trifluoromed1y1)benzoyl chloride (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 MeOI-I and DCM (2:98) as eluent to afford the titled compound (2.1 g) as a brown solid. lH-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, J82, 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 e (30 ml) and added POCi3 (1.5 ml). This mixture was refluxed for 5 h. After 5 h, dioxane was removed on rotavapour to obtain the residue. Work up /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). lI-I-NMR (6 ppm, CDClg, 400 MHZ): 8.46 (d, J 2.1, 1H), 8.41 (d, J 8.2, 2H), 8.24 (d, 12.1, 1H), 7.83 (d, J 8.2, 2H).
Intermediate 58: 6-(4,4,5,5~tetramethyl-1,3,2-dioxaborolanyl)[4- (trilluoromethyi)phenyl]oxazolo[S,4~b]pyridine: Intermediate 57 (1.2 g, 3.5 mmoi) 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 oxane (40 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppflzClg.CHgC12 (113 mg, 0.14 mmol). This mixture stirred at 105 0C for 15 h. Reaction mixture diluted with water and work up (AcOEt/HZO) afforded the crude. Crude was purified by combiflash using a gradient e of AcOEt and Petether (5:95) as eluent to afford the titled compound ( 1.2 g) as an off-white solid. I1—1—NMR (6 ppm, CDC13. 400 MHZ): 8.77 (d, J 1.5, 1H), 8.46 (d, J 1.5, 1H), 8.41 (d,J 81,211), 7.80 (d, J 8.1, 2H), 1.38 (s, 12H).
General ure-1 for Suzuki coupling: Aryl bromide (1 eq.) was dissolved in e and water (5:1) and added arylboronic acid (1.3 eq), Pd(PPh3)4 (0.08 eq) and Na2C03 (3.3 eq). Reaction mixture degassed with N; for 30 mins and refluxed until both the starting materials disappeared.
Work-up (I-IZO/ACOEt) and purification gave the desired product.
General Procedure-2 for Suzuki coupling: {242] Aryl bromide (1 eq), arylboronic acid (1 eq.), Sodium carbonate (3 eq) dissolved in DMF and water (4:1) and ed with N; for 15 mins. To this mixture Pd(dppf)2C12.CH2C12 (0.08 eq) was added and ed again with N2 for 15 mins. This mixture was inadiated in micro wave for 105 mins, at 80 0C. Work-up (HgO/ACOEt) and purification gave the desired product.
General Procedure-3 for Suzuki coupling: Same as General Procedure-2 except that KF was used instead of Na2C03_ General Procedure-4 for Suzuki coupling: Same as General Procedure-2 except that Dioxane was used instead of DMF.
Examplel 2-{1-(5-Ethylpyrimidin-Z-yl) piperidin-4—yl]—5—[2-fluoro~4-(methylsulfonyl)pl1enyl]-1H- benzo[d}imidazole Following the General ure-1, the titled nd (25 mg) was prepared from Intermediate 2 (80 mg, 0.199 mmol) and Intermediate 3 (79 mg, 0.26 mmol) as a yellow solid. M.P.: 186.5»190 OC. II-I—NMR (8 ppm, DMSO-(ls, 400 MHz): 12.41 ((1, J 4, 11-1), 8.26 (s, 2H), 7.90-7.80 (m, 3H), 7.79-7.50 (111, 21-1), .32 (111, 11-1), 4.66 (d. J 13.1, 21-1), 3.29 (s, 3H), 3.21 (t, J 8.3, 1H), 3.09 (t, J 11.7, 21-1), 2.43 (q, 3 7.73, 21-1), 2.06 (d, J 12.5, 21-1), 1.82-1.71 (m, 2H), 1.13 (t, J 7.5, 3H).
Examplez Tert-butyl 4-{5-[2-11uoro(methylsulfonyl) phenyl]-1H~benzo[d]imidazol yl}piperidine-l-carboxylate [246} Following the General Procedure-1, the titled compound (40 mg) was prepared from Intermediate 4 (100 mg, 0.25 mmol) and ediate 3 (98 mg, 0.33 mmol) as a yellow solid. M.P.: 88—92 00. 1H—NMR (8 ppm, DMSO-de, 400 MHz): 12.39 (3, 11-1), 7.89—7.81 (at, 31-1), 7.69—7.58 (m, 2H), 7.40-7.32 (m, 11-1), 4.01 (d, J 12.5, 2H), 3.30 (s, 3H), 3.12305 (m, 1H), 3.00-2.88 (m, 2H), 2.00 (d, J 11.8, 2H), 1.76-1.55 (m, 21-1), 1.41 (s, 9H).
Example3 2-[l~(5-ethylpyrimidin-Z-yl) dinylj[2-fluoro(methylsulfouyl)phenyl] benzo[d]oxazole Following the General ure—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 off—white solid. MR: 247-250 0C. lH-NMR (6 ppm, CDC13, 400 MHZ): 8.20 (s, 2H), 7.86 (5, 111), 7.8001), 111), 779—774(11), 11-1), 7.66 (t, I 7.5, 1H), 7.59 (d, J 8.4, 11-1), 7.50 (d, J 8.5, 1H), 4.75 (d, J 13.4, 21-1), 3.35-3.15 (m, 3H), 3.11 (s, 3H), 2.47 (q, I 7.6, 2H), 2.31-2.22 (m, 2H), 2.09—1.94 (111, 21-1), 1.20 (t, J 7.6, 311).
Example 4 tert-butyl 4-{5-[2-f1u0ro~4-(metllylsulfonyl)phenyl]benzo[dloxazol-Z-yl}piperidine carboxylate Following the l Procedure-1, the titled compound (40 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and Intermediate 3 (154 111g, 0.51 11111101) as an off-white solid. M.P.: 144—147 0C. lI-I-NMR (8 ppm, CDC13, 400 MHZ): 7.87 (s, 11-1), 7.82 (d, .1 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 (111, 41-1), 3.00 (1,1 11.3, 21-1), 2.21-2.12 (n1, 2H), 2.00- 1.88 (111, 2H), 1.48 (s, 9H).
Example 5 Tert-butyl 4—{5—[2-fluoro(methylsu1fonyl)pheny1]methyl-1H»benzo{d]imidazol-Z- yl}piperidine-l-carboxylate: Tert-buty] 4-{5—[2»fluoro(n1ethyisulfony1)pheny1]~1H—benzo[d]i11iidazol y]}piperidine~l-carboxylate (85 mg, 0.17 11111101) dissolved in TI~IF (15 1111) and cooled to 0 0C.
Sodium hydride (9 111g, 0.342 01) added to the above mixture and stirred at the same temperature for 30 mins. To this mixture methyl iodide (48 mg, 0.342 11111101) added at same temperature and stirred the reaction mixture at rt for 3 h. Reaction mixture diluted with ice and worked up (ELOAc/I-IZO). Crude was purified by column tography on 60-120 mesh silica gel using EtOAc: Petether (3:1) as eluent to afford the title compound (50 111g) as an orange solid. M.P.: 85-88 0C. lH—NMR (5 ppm, CDC13, 400 MHZ): 7.85-7.75 (n1, 2H), 7.73- 7.64 (111, 2H), 7.56-7.51 (111, 1H), 7.50—7.45 (111, 1H), 4.39-4.21 (111, 21-1), 3.82 (s, 3H), 3.11 (8, 31-1), 3.10—3.00 (111, 2H), 3.00—2.88 (111, 21-1), 2.05-1.93 (m, 3H), 1.48 (s, 9H).
Example 6 Tert-butyl 2-f1uoro(methylsulfony11phenyl]benzo{clJoxazol-Z-y1}piperidine ylate: Following the General Procedure-l, the titled compound (21 mg) was ed from Intermediate 10 (100 mg, 02611111101) and Intermediate 3 (102 mg, 0.34 mmol) as an ite solid. M.P.: 174-1783 oC. 'l-l-NMR (5 ppm, CDC13, 400 MHz): 7.85-7.75 (n1, 3H),7.73-7.64(111,2I-1), 7.50 (d, J 8.2, 1H), 4.15 (d, J 12.4, 2H), 3.20-3.10 (111,411), 3.0 (t, J 12.5, 2111), 2.20-2.12 (111, 2H), 2.00—1.85 (111, 2H), 1.48 (s, 911).
Example 7 Isopropyl 4-{5-[2-fluoro(met11y1su1f0ny1)phenyl]benzo[d}oxazol~2—yl}piperidine carboxylate: [25 1] Tert-butyl 4-{ 5-[2-f1u01'0(methylsulfonyl)pl1enyl]benzo[d]oxazol-Z— eridinecarboxy1ate (200 mg, 0.42 11111101) dissolved in DCM and added Trifluoroacetic acid (0.75 ml). This e was d at it for 2 h. DCM removed from the reaction mixture to obtain 5-(2-fluoro(methylsulfonyl)pheny1)(piperidin—4- y1)benzo[d]oxazole 2,2,2~trif1uoroacetate (190 mg). 5-(2-fluoro(metl'lylsu1fonyl)phenyl)—2— (pipefidin—4—yl)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 ash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (120 mg) as a pale-yellow solid. M.P.: 965-1012 0C. lH-NMR (8 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 (in, 1H), 3.12 (s, 3H), 3.04 (t, J 10.9, 21-1), 2.22-2.14 (111, 21-1), 2.00—1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 8 Tert-butyl 4-{7-fluoro[2-11now(methylsulfonyl)pheny1]benzo[d]oxazol y1}piperidine-l-carboxylate: [252} Following the General Procedure-1, the titled compound (50 mg) was ed from Intermediate 12 (200 mg, 05011111101) and Intermediate 3 (151 mg, 0.50 mmol) as an off-white solid. M.P.: 1553-1584 0C. iH-NMR (6 ppm, CDC13, 400 MHz): 7.82 (dd, J 1.8, 8.1, 11-1), 7.78 (dd, J 1.7, 9.4, 1H), 7.69-7.63 (m, 2H), 7.29 (td, 1.3, 10.6, 11-1), 4.16 (d, J 11.2, 21-1), 3.22- 3.16 (m, 1H), 3.11 (3, 31-1), 3.00 (t, J 13.3, 21-1), 2.21-2.14 (m, 21—1), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Example 9 Tert-butyl 4-[5-(4-eyanophenyl)benzo[d]oxazoly1]piperidine-l-carboxylate: {253] 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. 'H-NMR (5 ppm, C1303, 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, 911). e 10 Tert-butyl 4-{5-[3-flu0r0(methylsu1fonyl)phenyl]benzo[d]0xazolyl}piperidine carboxylate: Following the General Procedure-1, the titled compound (30 mg) was ed from ediate 8 (100 mg, 0.23 mmol) and 4-biomofluoro(methylsu1fonyl)benzene (70 0.37 mmol) as an off-white solid. M.P.: 1743—1775 0C. 'H—NMR (5 ppm, CDC13, 400 MHz): 8.03 (t, J 7.9, 1H), 7.88 (d, I 1.6, 1H), .51 (m, 3H), 7.46 (dd, J 1.6, 11.1, 1H), 4.15 ((1.3 11.2, 21-1), 3.26 (s, 3H), 3.20—3.11 (m, 11-1), 3.00 (1,} 12.2, 2H), 2.20-2.12 (m, 21-1), 1.98-1.84 (m, 2H), 1.48 (s, 9H).
Example 11 Tert-butyl 4-{5-[4-(lH-tetrazolyl)phenyl}benzo[d]oxazolyl}piperidine—1- ylate: {255] ing the General Procedure-1, the titled compound (80 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromopheny1)-lH-tetrazole (100 mg, 0.44 mmol) as a brown solid. MR: 207—211 0C. 111.101412 (5 ppm, CD013, 400 MHz): 9.02 (s, 1H), 7.91 (a, J 1.2, 1H), 7.82-7.79 (m, 4H), 7.62-7.55 (111, 21-1), 4.16 (d, J 10.6, 2H), 3.21-3.12 (111, 11-1), 3.00 (t, J 12.3, 2H), 2.20—2.14(m, 2H), 2.00—1.88 (m, 2H), 1.48 (3, 91-1).
Example 12 Tert-hutyl 4~{5-[Z-fiuoro(IH-tetrazo[yl)phenyllbenzo[dloxazolyl}piperidine carboxylate: Following the General Procedure-1, the titled compound (10 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4—bromo—3-fluoropheny1)-II-I-tetrazole (110 mg, 0.45 mmol) as a brown solid. M.P.: 203-207 0C. lH—NMR (6 ppm, CDC13, 400 MHZ): 9.04 (s, 1H), 7.88 (s, 1H), 7.71-7.58 11), 7.52 (td, 1.6, 8.4, 1H), 4.16 (d, J 10.8, 21-1), 3.21-3.12 (m, 1H), 3.00 (t, J 12.2, 2I-I),2.21—2.13(111,21‘1),2.00-1.85 (111,211), 1.48 (5, 91-1).
Example 13 Tert-butyl 4-{5—[4-(trifluoromethyl)phenyl]benzo[d]0xazolyl}piperidine carboxylate: Following the General Procedure-1, the titied compound (40 mg) was ed from Intermediate 7 (150 mg, 0.4 mmol) and 4-(t1'ifluoromethyl)phenyiboronic acid (74 mg, 0.39 mmol) as an off—white solid. M.P.: 166-169 0C. lH-NMR (6 ppm, CDCI3, 400 MHZ): 7.88 (d, J 1.2, 1H), 7.73767 (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 (111, 21-1), 1.99-1.86 (m, 2H), 1.48 (s, 9H).
Example 14 Impropyl 4-{5-[2-fluero(lH—tetrazolyl)phenyl]benzolfloxazol-Z—yl}piperidine—1- carboxylate: Terr—butyi 4-{5-[2—fluoro(IH-tetrazoI—l-yl)phenyl]benzo[(ljoxazoIy1}piperidine- oxylate (120 mg, 0.26 mmol) dissolved in DCM and added Trifluoroacetic acid (0.5 ml).
This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5—(2- fluoro-4—(1H-tetrazol-1~y1)phenyl)(piperidin—4-yl)benzo[d]oxazole 2,2,2~tiifluoroacet11te (150 mg). 5-(2—fluoro-4—(1H-tetrazol—1-yl)phenyI)(piperidin—4—yl)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 iSOpIOpyl chlorofonnate in toluene (42 mg, 0.34 mmol). After 1 1), on mass diluted with water and extracted with DCM. Removal of DCM ed crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eiuent to afford the titled compound (30 mg) as an off-white solid. M.P.: 168-171 0C. 1H~NMR (5 ppm, CDC13, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), .58 (m, 31-1), 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), .15 (m, 2H), 2.00—1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 15 Tert-butyl 4-{5-[3~fluoro(1H-tetrazol-l-yl)phenyl}benzo[dioxazol-Z-yl}piperidine—1- carboxylate: Following the General Procedure-3, the titled compound (22 mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and 1-(4-bromol'luorophenyl)—1H-tetrazole (56 mg, 0.23 mmol) as a pale—yellow solid. M.P.: 154-159 0C. lI-I-NMR (6 ppm, CDC13, 400 MHz): 9.14 (d, J 2.5, 11-1), 8.04 (t, .1 7.8, 1H), 7.91 (d, J 3.9, 11-1), 7.64-7.54 (m, 4H), 4.16 (d, J 10, 2H), 3.21- 3.13011, 1H), 3.01 (t, J 11.9, 2H), .12(m,2H),2.00-1.87(111,211), 1.48 (s, 9H).
Example 16 2-[1-(5-ethylpyrimidin-Z-yl)piperidinyl][2-fluoro(lH-tetrazol yl)phenyl]benzold]oxazole: Tert-butyl 4-{5—[2-fluoro—4—(lH-tetrazol—1-y1)phenyl]benzo[(Hoxazoly1}piperidine- l-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 mi) 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—tetrazol-1—yl)phenyl]—2-(piperidin-4~yl)benzo[(floxazole 2,2,2- trifluoroacetate (150 mg). 5—[2-fluoro(lH—tetrazol—1—yl)pheny1](piperidin-4— yl)benzo[d]oxazole 2,2,2—trifluoroacetate (70 mg, 0.15 mmol) was dissolved in IPA (10 ml), added DiPEA (0.25 mi, 1.2 mmol) and stirred at rt for 30 mins. 2-Chloro-5~ethy1pipen‘dine was added to the above reaction mixture and heated the reaction mixture to 90 0C for ght.
After completion of the reaction, work-up (EtOAc/HgO) followed by purification on combiflash using the gradient e of ethyl acetate and petether (1:1) as eluent afforded the titled compound (20 mg) as an off-white solid. M.P.: 188-192 0C. lH-NMR (8 ppm, CDClg, 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 (111, 31—1), 7.54-7.49 ((m, 1H), 4.80-4.70 (m, 2H), 3.33-3.23 (m, 1H), 3.22 (t, J 14, 21-1), 2.48 (q, I 7.6, 2H), 2.30-2.22 (m, 2H), 2.07-1.95 (m, 2H), 1.20 (t, J 7.6, 3H).
Example 17 utyl 4-[5-(4¢cyanofluorophenyl)benzo[d]oxazol-Z-yllpiperidine-l-carboxylate: Following the General Procedure-2, the titled compound (70 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromofluorobenzonitrile (70 mg, 0.35 mmol) as a white solid. M.P.: 138-142 0C. lH-NMR (5 ppm, CDCla, 400 MHz): 7.87 (d, J 1.6, 11-1), 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, 21-1), 3.20-3.11 (m, 1H), 3.00 (t, J 11.8, 2H), 2.2-2.12(m, 2H), .86 (111, 21-1), 1.56 (S, 9I-I).
Example 18 Isopropyl 4-{5~[3»fluoro(1H-tetrazolyl)phenyllbenzo[d]oxazolyl}piperidine carboxylate: {262] Tert-butyl 4- { 5-[3-fluoro-4—(1H-tetrazolyl)phenyl]benzo[dloxazol-2—y1}piperidine- l-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Tiil’luoroacetic acid (0.5 ml). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain 5—[3-fluoro(1H—tetrazoly1)phenyl](piperidinyi)benzo[(floxazole 2,2,2- trifluoroacetate (120 mg). 5-[3-fluoro(1H-tetrazolyl)phenyl]~2-(piperidin yl)benzo[d]0xazole 2,2,2-u-ifluoroacetate (120 mg, 0.25 mmol) was dissolved in DCM (15 ml) and added TEA (0.27 ml, 2 mmol). This mixture stirred at It for 30 mins and added isopropyl chloroformate in toluene (61 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 compound (20 mg) as an off~white solid. M.P.: 187—191 0C. lH—NMR (5 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), .55 (m, 4H), 4.95 (septet,J 6.2, 11-1), 4.20 (d, J 11.2, 21-1), 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-fluoro(1H-tetrazol-S-yl)pheny!]benzo[d]oxazolyl}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. lH-NMR (6 ppm, CDCls, 400 MHz): 8.15 (s, 1H), 8.11 (t, J 8, '11-1), 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), .06 (m, 2H), 1.7616401], 2H), 1.41 (s, 9H).
Example 20 utyl 4-[S-(4-carbamoyl-3—chlorophenyl)benzo[d]0xazolyl]piperidine carboxylate: [264} 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.: 1 0C. lH—NMR (5 ppm, DMSO-dg, 400 MHZ): 8.03 (3, 11—1), 7.87 (bs, 1H), 7.82-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.59 (bs, 1H), 7.52 (d, J 7.9, 1H), 3.94 (d, J 12.9, 21-1), 2(11), 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-carbam0ylfluorophenyl)benzo[d]0xazolyl]piperidine carboxylate: 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. ’H-NMR (5 ppm, DMSO—(Zg, 400 MHZ): 8.22 (t, J 3.3, 1H), 7.89 (s, 1H), 7.59—7.49 (111, 31-1), 7.37 (dd,J 1.6, 13.24, 111), 6.71 (d, J 9.5, 11-1), 5.85 (s, 1H), 4.15 (d, J 10.7, 21-1), 3.20-3.10 (m, 1H), 3.00 (t, J 11.8, 21-1), .12 (m, 21-1), 1.99-1.85 (111,2H), 1.48 (s, 9H). e 22 Tert-butyl 4-[5-(3~11uoroisopropoxyphenyl)beuzoldloxazol—Z—yl]piperidine carboxylate: Following the General Procedure—3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2—fluoroisopropoxybenzene (81 mg, 0.35 mmol) as a white solid. M.P.: 124-128 0C. lH-NMR (5 ppm, CDCl3, 400 MHZ): 7.81 (d, J 1.4, 1H), 7.53-7.45 (111,211),7.35-7.27(m, 21-1), 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, 21-1), 1.97-1.86 (m, 2H), 1.56 (s, 9H), 1.39 (d, J 6.1, 6H).
Example 23 Cyclobutyl 4—{5-[2-fluoro-4—(1H—tetrazolyl)phenyl]benzo[d]oxazolyl}piperidine carboxylate: Tert-butyl 4—{ uoro(1H—tetrazol—l—y1)pheny1]benzo[d]oxazoly1}piperidine- l—carboxyiate (300 mg. 0.65 mmol) ved in DCM (15 ml) and added Trifluoroacetic acid (1.5 111]). This mixture was stirred at It for 2 h. DCM removed from the reaction mixture to obtain S-[2-fluoro(1H-tetrazoly1)phenyl](piperidinyl)benzo[(floxazole 2,2,2- trifluoroacetate (300 mg). 5—[2-fluoro-4—(1H—tetrazoiy1)pl1enyl]~2—(piperidin yl)benzo[d]oxazole 2,2,2—trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added [VIN-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added cyclobutanol (0.05 ml, 0.63 mmol) and TEA (0.13 In}, 0.94 mmol) and stirred at 60 0C for overnight. Work up /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. lI-I-NMR (5 ppm, CDC13, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.72—7.58 (m, 4H), 7.55-7.50 (m, 1H), 4.96 (septet, J 7.8, 11-1), 4.20 (d, J 12.4, 2H), 3.22—3.13 (111, 11-1), 3.06 (t, J 9.8, 2H), 2.40-2.30 (m, 2H), 2.24—2.15 (111,211.), 2.15-2.02 (m, 2H), ZOO—1.90011, 2H), 1.78 (q, J 10, 2H).
Example 24 Sec-butyl 4-{S-[Z-fluoro-4—(1H-tetrazolyi)phenyl]benzo[d]oxazol~2—yl}piperidine carboxylate: Tert-buty] 4—{ 5-[2-fluoro(1H-tetrazol—1—yl)phenyl]benzo[(Z]oxazolyl }piperidine- 1-carboxyiate (250 mg, 0.54 11111101) dissolved in DCM (15 111]) and added Trifluoroacetic acid (1 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain -[2-1'1u0ro(1H—tetrazol-i-y1)phenyi}—2—(piperidin—4—yl)benzo[d]oxazole 2,2,2-trifluoro acetate (260 mg). 5-[2—fluoro—4—(lH-tetrazol—1—y1)phenyl]~2-(piperidiny1)benzo[d}oxazole trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N— Carbonyl azole (101 mg, 0.63 mmol) and stirred at It 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 /HZO) and purification of the cmde by combiflash with nt e of ethyl acetate and er (1:1) as eIuent afforded the titled compound (30 mg) as an off-white solid. M.P.: 118—122 0C. lH—NMR (6 ppm, CDCI3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72- 7.58 (m, 4H), 7.55-7.50 (n1, 1H), 4.82-4.73 (111, 11-1), 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).
Example 25 Pentan—s-yl 4-{5-{2-fluoro(1H-tetrazol—1-yl)pheny1]benzo[d]oxazolyl}piperidine-l- carboxylate: Terr-butyl 4—{5-{2—fluoro-4—(1H-tetrazol—1—y1)pheny]]benzo[d]oxazoi~2-y1}piperidine— l-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 luoro(1H—tetrazolyl)pheny1]—2-(piperidinyl)benzo[dloxazole 2,2,2- trifluoroacetate (260 mg). 5-[2-fluoro-4—(1H—tetrazolyl)phenyl]—2-(piperidin y1)benzo[d]oxazole 2,2,2-tfifluoroacetate (150 mg, 0.31 11111101) was dissolved in DMF (2.6 ml) and added BAN-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added 3—pentan01 (46 mg, 0.63 mmol) and TEA (0.13 m], 0.94 mmol) and stirred at 60 0C for overnight. Work up (EtOAC/I‘IQO) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (20 mg) as an ite solid. M.P.: 114-117 0c. *H-NMR (5 ppm, 0130],, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.54-7.50 (m, 1H), 4.69 (quintet, J 6, 1H), 4.23 (d, J 13.5, 21-1), 3.25-3.15 (m, 1H), 3.07 (t, J 11.9, 211), 2.21-2.17 (111, 21-1), .88 (m, 2H), 1.65-1.50 (111, 41-1), 0.91 (t, J 7.4, 6H).
Example 26 -[2-fluoro(IH-tetraon-yl)phenyl](piperidinyl)benzo[d]oxazole: '1uoro(1H-tetrazoly1)pheny1](piperidiny1)benzo[(ljoxazole 2,2,2— trifluoroacetate (50 mg) was dissolved in DCM (15 ml) and added TEA (0.3 1111). This mixture stirred for 3 11 at rt. Work up (DCM/H20) followed by purification of the crude by preparative 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. IH-NMR (5 ppm, DMSO-(lg, 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), 3.27-3.13 (m, 1H), 3.07 (d, J 12.4, 21-1), 2.70 (t, J 11.2, 2H), 2.06 (d, J 11.1, 2H), 1.82—1.70 (m, 211).
Example 27 pyl 4-{5-[4-(trifluoromethyl)phenyl]benzoId]oxazol~2-yl}piperidine ylate: Following the General ure-1, the titled compound (100 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(trifluoromethy1)phenylboronic acid (124 mg, 0.65 11111101) as an off-white solid. M.P.: 6 0(3. 'H-NMR (5 ppm, 0001,, 400 MHz): 7.88 (a, J 1, 1H), 7.72-7.68 (111, 4H), .53 (n1, 2H), 4.95 (septet, J 6.3, 1H), 4.20 (d, J 13.3, 2H), 3.22-3.12 (111, 11-1), 3.04 (t, J 11.3, 21-1), 2.17 (dd, J 2.6, 13.2, 2H), 2.00—1.88 (111, 21-1), 1.26 (d, J 6.2, 6H).
Example 28 Isopropyl 4-[5-(4-formylphenyl)benzo{d]0xazoly|]piperidine-l-carboxylate: Following the General Procedure-1, the titled compound (100 mg) was prepared from Intermediate 13 (270 mg, 0.73 mmol) and 4-fon11ylphenylboronic acid (132 mg, 0.88 11111101) as an off-white solid. MR: 167-170 0C. lH—NMR (6 ppm, CDC13, 400 MHz): 10.07 (8, 1H), 7.96 (dd, J 1.7, 6.6, 2H), 7.93 (s, 1H), 7.76 (d, J 8.2, 2H), 7.58 (3, 21-1), 4.95 (septet, J 6.2, 1H), 4.20 (11,1 11.1, 211), 3.22-3.13(111, 11-1), 3.04 (t, J 11.3, 21-1), 2.18 (dd, J 2.8, 13.3, 21-1).
Example 29 Isopropyl 4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidine-l-carboxylate: Isopropyl 4-[5-(4-fom1ylphenyl)benzo[d]oxazol—2-yl]piperidine~1-carboxy1ate (100 mg, 0.25 11111101) dissolved in DCM and added DAST (123 mg, 0.76 11111101) and d the reaction mixture at 55 0C. Work up (DCM/HZO) followed by purification on combiflash with a gradient mixture of EtOAc and Peteiher (1:4) as eluent afforded the titled compound (35 mg) as an off-white solid. M. P.: 151-154 0C. \1MR (5 ppm, CDCI3, 400 MHz): 7.88 (s, 1H), 7.68 (d, J 8.2, 2H), 7.60 (d, J 8.2, 2H), 7.58—7.52 (111, 21-1), 6.70 (t, J 56.5, 11-1), 4.95 (septet, J 6.2, 11-1), 4.19 (d, J 11.1, 21-1), 3.21313 (111, 11-1), 3.04 (t,J 11.4, 21-1), 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-carbamoylchlorophenyl)benzoId]oxazol-2—yl]piperidine carboxylate: Following the General Procedure-2, the titled compound (30 mg) was prepared from Intermediate 13 (150 mg, 0.41 11111101) and 2-chloro(4,4,5,5—tetra111ethyl—1,3,2-dioxaborolan- 2-y])benzamide (110 mg, 0.41 mmol) as a ellow solid. M.P.: 178-181 0C. 1H-NMR (5 ppm, DMSO-(lfi, 400 MHZ): 8.04 (d, J 1.7, 11-1), 7.88 (bs, 1H), 7.80 (d, J 1.7, 1H), 7.77 (d, J 8.5, 1H), 7.73-7.68 (111, 2H), 7.62-7.58 (n1, 1H), 7.52 (d, J 8, 1H), 4.78 (septet, J 6.2, 1H), 3.97 (d, J 13.2, 21-1), 3.34-3.24 (n1, 1H), .00 (m, 2H), .05 (n1, 2H), 1.75-1.65 (m, 2H), 1.19 (d, J 6.2, 61-1).
Example 31 Isopropyl 4-[5-(4-carbamoylf1uorohenyl)benm{d10xazolyl]piperidine carboxylate: [275} Following the l Procedure-2, the titled compound (30 mg) was prepared from Intermediate 14 (300 mg, 0.72 mmol) and 4-bromo-2—fluorobenzamide (157 mg, 07211111101) as an off-white solid. M.P.: 184-187 °c. IH-NMR (5 ppm, DMSO-dé, 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 (111, 21-1), .64 (m, 2H), 1.19 (d, J 6.2, 6H).
Example 32 1-{4-[5-(2-l'luoro-4~(lH-tetrazol-I-yl)phenyl)benzo[d]oxazol—2—yl]piperidin-l-yl} methylpropan-l-one: Tert-butyl 4- { 5—[2-fluoro(lH-tetrazoly1)phenyl]benzo[(noxazol-Z-yl }piperidine- l—carboxylate (100 mg, 0.22 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (0.4 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 5~{2-fluoro(lH-tetrazol-l- yl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2-trifluoroacetate (100 mg). 5~[2-fluoro trazoly1)phenyl]-2—(pipen'din—4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (100 mg, 0.21 mmol) was ved in EMF (3 ml) and added isobutyric acid (202 mg, 0.23 mmol), EDCHCI (99 mg, 0.52 mmol), HOBt (33 mg, 0.25 mmol) and TEA (0.23 ml, 1.7 mmol). After completion of the reaction, work up (EtOAc/HgO) followed by purification on combiflash 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. lI-I-NMR (6 ppm, CDCIz, 400 MHz): 9.04 (3, 11-1), 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, 11-1), 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), 2.0517201], 21-1), 1.16 (d, J 6.8, 611)..
Example 33 Isopropyl 4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazolyl}piperidine—l~carboxylate: [277} Following the General Procedure-l, pyl 4-[6-(4-formylphenyl)benzo[dloxazol— 2—yl]piperidine~1-carboxylate (140 mg) was prepared from Intennediate 15 (300 mg, 0.82 mmol) and 4-fon11ylphenylboronic acid (146 mg, 0.98 mmol) as an ite solid. Isopropy14— formylphenyl)benzo[djoxazolyljpiperidinecarboxylate (100 mg, 0.25 mmol) was dissolved in DCM (5 ml) and added DAST (0.1 ml, 0.76 11111101). This mixture stirred at reflux for 2 11. Work up (DCM/1120) followed by the purification of the crude on combiflash using gradient mixture of EtOAc and Petelher (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]benzo[d]oxazol-5~yl}nicotinic acid: Following the General Procedure-2, Methyl 6-{2-(l-(isopropoxycarbonyl)pipcridin-4— yl)benzo[djoxazol-S-y]]nicotinate (50 mg) was prepared from Intermediate 14 (400 mg, 0.97 11111101) and methyl 6-c1110ronicotinate (166 mg, 0.97 mmol) as a brown solid. Methyl 6-{2-(1— (isoprop0xycarbonyl)piperidin—4-y1)benzo[d]oxazolyl]nicotinate (35 mg, 0.08 11111101) was dissolved in MeOH (5 ml) and added K2C03 (22 mg, 0.17 11111101). This mixture was stirred at reflux for overnight. MeOH removed on rotavapour and pH adjusted to 6 using acetic acid to obtain a solid. Solid was filtered and dried to obtain the titled compound (20 mg) as a grey solid. M. P.: 239—242 0C. MS (in/z): 410.4 [M+I-I]+, Example 35 -[2-fluoro(1H-tetrazol~1-yl)phenyl][1-(methylsulfonyl)piperidin yl]benzo[d]oxazole: [279} 5-[2-fluoro( lH-tetrazol-l-yl)pheny1](piperidin—4-yl)benzo[d] oxazole 2,2,2- trii‘luoroacetate (30 mg, 0.06 mmol) was dissolved in DCM (5 ml) and added TEA (60mg, 0.6 11111101) and stirred the mixture at It for 30 mins. To this mixture added methanesulphonyl chloride (14 mg, 0.12 mmol) and stirred at rt for 2 h. Work up (DCM/HzO) followed by cation on combii‘lash using a nt mixture of EtOAc and Petether (7:3) as eluent afforded the titled compound (17 mg) as a brown solid. M. P.: 209-212 0C. MS (in/z): 443.2 [M+I-I]+_ e 36 lsopropyl 4-[5—(S—carbamoylpyridiny1)benzo[d]oxazoly1]piperidinecarboxylate: Following the l 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 , e 37 pyl 4~[5-(4-carbamoylfluorophenyl)benzo[d]oxazol-Z-yUpiperidine-1 - ylate: Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromofluor0benzamide (105 mg, 0.48 mmol) as an off—white solid. M.P.: 194-197 0C. MS (m/z): 426.0 [Ma-HT“.
Example 38 lsopropyl 4-carbamoyl-Z-chlorophenyl)benzo{d]oxazolyl}piperidine-l- carboxylate: [282} Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromoclflorobenzamide (105 mg, 0.48 mmol) as a brown solid. M.P.: 178-182 0c. MS (in/Z): 442.0 [M+H]+_ Example 39 2-Fluoro{2-[1-(3-methylbutanoyl)piperidinyl]benzo[d]oxazolyl}henzamide: Tert-butyl 4-[5«(4-carbamoyl-3—fluorophenyl)benzo{d}oxazolyl]piperidine-l - carboxylate (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (1 ml). This mixture d at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fiuoro(2-(pipen'din-4— y])benzo{d]oxazolyl)benzamide t1‘ifluoroacetate (140 mg). 2-Fluoro(2-(pipe1idin-4~ yl)benzo[d]oxazol-S-yl)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), EDGHCI (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+I—I]+_ Example 40 1-{4-[5-(2-fluoro(1H-tetrazolyl)phenyl]benzo[dioxazolyl]piperidin~1-yl}~3- methylbutan-l-one: 5-[2—fluoro(lH-tetrazol-l~yl)phenyl]—2-(piperidinyl)benzo[(lioxazole 2,2,2- trifluoroacetate (140 mg, 0.29 mmol) was dissolved in DMF (4 ml) and added isovaleric acid (38 mg, 0.37 mmol), EDCHCI (147 mg, 0.73 mmol), HOBt (47 mg, 0.35 mmol) and TBA (88 mg, 0.88 mmol). After tion of the reaction, work up (BtOAc/I-lgO) followed by purification of crude on combiflash using a gradient mixture of EtOAc and Petether (7:3) as eluent afforded the titled nd (100 mg) as a pale-yellow solid. M.P.: 168-172 0C. MS (m/z): 449.1 , Example 41 -[2-fluoro(1H~tetrazolyl)phenyl]—2-[1~(2-methoxyethyl)piperidin yl]benzo[d]oxazole: 5—[2-fluoro—4-(lH—tetrazolyl)phenyl](piperidinyl)benzo[d]oxazole 2,2,2- trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DMF (2 ml) and added K2C03 (40 mg, 0.29 mmol) and stirred the e at It for 15 mins. To this mixture added 2-methoxyethyl methanesulfonate (45 mg, 0.29 mmol) and stirred at rt for 17 11. Work up (EtOAc/Hgo) 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 Isopropyl 3-flu0ro(methylcarbamoyl)phenyl]benzo[floxazol—Z-yl}piperidine carboxylate: Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4«br0mo-2«fluoro—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-Fluoro[2-(1-isobutyrylpiperidin—4~yl)benzo[d]oxazolyl]beuzamide: utyl 4-[5-(4-carbamoylflurophenyl)benzo[(floxazol-Q-yl]pipe1idine carboxylate (190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added trifluoroacetic acid (15 ml). This mixture stirred at it for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2—fluoro—4-(2-(pipe1idin-4— yl)benzo{d]oxazol—5-yl)benzamide 2,2,2—trifluoroacetate (190 mg). 2-Fluoro(2-(piperidin—4- yl)benzo[d]oxazoly])benzamide 2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was dissolved in DMF (7 ml) and added yric acid (47 mg, 0.46 mmol), EDCHCI (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 tilled 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-carbamoylfluorophenyl)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-bromo-?.-fluorobenzamide (190 mg, 0.87 mmol) as an ite solid. M.P.: 1 °c. MS (tn/7.): 425.45 , Example 45 Isopropyl 4—{5-[3-fluoro(2~hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol yl}piperidine-l—carboxylate: Following the l Procedure-3, the titled compound (65 mg) was ed from Intermediate 3.4 (200 mg, 0.54 11111101) and 4-bromo-2—flu0ro-N-(2-hydroxyethyDbenzamide (l 10 mg, 0.43 mmol) as a brown solid. M.P.: 145-147 0C. MS ): 470.4 [M+H]+ Example 46 Isopropyl 4-{5-[3-flu0r0(isopropylcarbamoyl)phenyl]benzo[d]oxazolyl}piperidine- l-carboxylate: ing the General Procedure-3, the titled compound (45 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 3—fluoro(isopmpylcarbamoyl)phenylboronic acid (120 mg, 05411111101) as a grey solid. M.P.: 147-150 0C. MS (111/2): 468.4 [M+H}+.
Example 47 Isopropyl 4-{5—[4-(N-methylsulfamoyl)phenyl]benzoEd]oxazol-2—yl}piperidine carboxylate: {291]Following the General Procedure-3, the titled compound (35 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(N-methy]sulfa111oyl)pl1enylboronic acid (120 0.54 11111101) as a white solid. M.P.: 179—181 00. MS (111/2): 458.3 {Ml-HT.
Example 48 Isopropyl 4-{5-[6-(methylcarbamoyl)pyridinyl]benzo[d]oxazolyl}piperidine carboxylate: Following the General Procedure—1, the titled compound (20 mg) was prepared from Intermediate 13 (300 mg, 0.82 mmol) and N~methyl~5-(4,4,5,5-tetra111etl1yl-l,3,2— dioxaborolan—Q—yl)picolinamide (256 mg, 0.98 11111101) as a brown solid. M.P.: 158-161 0C.
MS (In/7.): 423.5 ]+_ Example 49 Isopropyl 4-{5~[3-methyl(methylcarbamoyl)phenyl]benzo{d]oxazolyl}piperidine- l—carboxylate: ing the General Procedure-3, the titled compound (30 mg) was prepared from Intermediate 13 (250 mg, 0.68 mmol) and N,2—di111ethyl(4,4,5,5—tet1'amethyl~13,2- dioxaborolan-Q—yl)benzamide (187 mg, 0.68 mmol) as an offiwhite solid. M.P.: 151-154 0C.
MS (m/z): 436.5 [Ml—HT, Example 50 Isopropyl 4-{5-[4~(cyclopropylcarbamoyl)fiuorophenyl]benzoldloxazol-Z- yl}piperidine-I-carboxylate: [294} Following the General Procedure-3, the titled compound (20 mg) was prepared from Intermediate 14 (250 mg, 0.61 mmol) and 4-bromo-N—cyelopropyl-Q-fluorobenzamide (156 mg, 0.61 mmol) as an ite solid. M.P.: 5 0C. MS (m/z): 466.3 [M+H]+, Example 51 2-Flu0ro-4~{2-[l-(5-fluoropyrimidin-Z-yl)piperidinyl]benzo[dloxazol-S- yl}benzamide: Following general procedure-3 and using DMF as solvent titled compound (40 mg) was obtained from intennediate 19 (150 mg, 0.35 mmol) and 4-bromofluorobenzamide (77 mg, 0.35 mmol) as a brown solid. M.P.: 226-229 0C. MS (m/z): 436.5 [M+I—I]*.
Example 52 Tert-butyl 4-[5-(4-carhamoyl-3fluorophenyl)benzofuran-Z-yII-S,6-dihydropyridine- 1(2H)-carboxylate: Following the general procedure-4, the titled compound (370 mg) was ed from intermediate 21 (1.5 g, 5.02 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6- dihydr0pyridine—1(2H)-carboxylate (1.99 g, 6 mmol) as a white solid. M.P.: 100 1H- NMR (8 ppm, DMSO'dG, 400 MHZ): 7.95 (5, 11-1), 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~fluoro~4-{2-[1-(propylsulfonyl)piperidinyl}benzo[dloxazol-S-yl}benzamide: Intermediate 25 (80 mg, 0.24 mmol) was dissolved in DCM (10 ml) and added TBA (35 mg, 0.35 mmol). This mixture was stirred at It for 15 mins. Reaction mixture cooled to 0°C and added propane-l-sulphonylchlon'de (33 mg, 0.23 mmol). Reaction mixture d at rt 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 gradient 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~d6, 400 MHz): 8.09 (d, J 1.3, 1H), 7.82-7.72 (m, 3H), .61 (m, 4H), 3.67—3.58 (m, 2H), 3.30-3.22 (m, 2H), .99 (m, 2H), 2.25-2.16 (m, 2H), 1.92—1.79 (m, 2H), 1.69 (hextet, J 7.6, 2H), 0.98 (t, J 7.4, 311).
Example 56 Tert-butyl 4-{2~[2—fluoro(methyisuifonyl)phenyl]-1H-benzo[d]imidazol-S-yl}»5,6~ dihydropyridine-l(2H)-carboxylate: 2fluoro(methylsulfonyl)phenyl](4,4,5,5-tetramethyl-l,3,2-dioxa borolan—Z- yl)-lH—benzo[d]imidazole (880 mg, 2.12 mmol), lert-butyl 4-(triiluoromethylsulfonyloxy)-5,6— dihydropyiidine-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(dpp1)zClg.CH2Cig (138 mg, 0.17 mmol). This mixture stirred at 80 DC for 90 mins in microwave. Reaction mixture diluted with water and work up (AcOEl/Hgo) 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. ll-I-NMR (8 ppm, DMSO-(lo, 400 MHz): 12.80 (s, 1H), 8.49 (t, J 7.5, 1H), 8.02 (d, J 10.4, 11-1), 7.92 (d, J 8.2, 1H), 7.88-7.67 (in, 11-1), 7.66-7.54 (111,114), 7.48-7.39 (m, 1H), 6.18 (bs, 1H), 4.02 (bs, 21-1), 3.57 (bs, 2H), 3.34 (s, 31-1), 2.60-2.55 (111,211), 1.43 (s, 9H).
Example 57 Tert—butyl 4-{2-[2-f1uoro(methyisulfony1)phenyl]—lH-benzo[d]imidazol yi}piperidine-l-carboxylate: Example 56 (240 mg, 0.51 mmol) was dissolved in MeOH (25 ml) and added % Pd/C (100 mg). This e 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 ol. 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-da, 400 MHZ): 12.71 (s, 1H), 8.47 (t, J 7.7, 1H), 8.01 (d, J 10.4, 111), 7.91 (dd, J 1.4, 8.2, 1H), 7.65- 7.40 (111, 21-1), 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 S-[l-(S-ethylpyrimidin-Z-yl)piperidinyl][2-fluoro(methylsulfonyl)phenyl]-1H- benzo[d]imidazole: Example 57 (150 mg, 0.3 mmol) dissolved in DCM (12 1111) and added TFA (0.45 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-f1more—4—(methylsulfonyl)phenyl]-5—(piperidin—4-yl)-1H- d]imidazole trif1uoroacetate (150 mg). 2-[2-fluoro(111ethyisulfony1)phenyl]~5— (piperidin—4-yl)-1H—benzoldjimidazole 2,2,2—trifluoroacetate (150 mg, 0.4 11111101) and 2— chloro-S-ethylpyrimidine (60 mg, 0.4 mmol) were dissolved in propan—2-ol (10 mi) and added DiPEA (0.6 ml, 3.2 mmol). This mixture was refluxed at 90 0C for 12 h. After 12 h, propan01 removed on rotavapor to obtain the residue. Residue was purified on ash using Ethyl acetate and Petether (1:1) as eluent to afford the titled compound (50 mg) as a white solid. M.P.: 220-2235 0C. lH—NMR (5 ppm, , DMSO—dg, 400 MHz): 12.69 ((1, J 12.8, 1H), 8.49—8.45 (m, 1H), 8.24 (s, 2H), 8.00 (dd, J 1.5, 10.4, 11-1), 7.91 ((1,! 8.3, 1H), 7.67—7.56 (111, 1H), 7.55-7.40 (n1, 1H), 7.22—7.12 (m, 1H), 4.80 (d, J 12.6, 21-1), 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 (111, 2H), 1.13 (t, J 7.6, 3H).
Example 59 Tert-butyl 4-{2-[2-fiuoro(methylsulfonyl)phenyl]benzo{d]oxazol-S-yl}-5,6- dihydropyridine-I(zm-carboxylate: 2-[2-1‘luoro~4-(methylsulfony1)pheny1]—5—(4,4,5,5-tetramethy1-1,3,2-dioxa borolan-Z-yl)benzo[(floxazoie (50 mg, 0.12 11111101), tert-butyi 4-(trifluoromethy1suIfonyloxy)- ,6—dihydi‘opyridine-1(2H)-carboxylate (39 mg, 0.12 mmol) and sodium carbonate (38 mg, 0.36 11111101) were dissolved in DMF (2 1111) under N2 atmosphere. This mixture was ed with nitrogen for 30 mins and added Pd(dpp02Clg.CHzC12 (10 mg, 0.009 01). This mixture stirred at 80 0C for 90 mins in microwave. Reaction mixture diluted with water and work up (AcOEtlHZO) ed the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (27:73) to afford the titled nd (25 mg) as an off—white solid.
M.P.: 149-151 0C. IH—NMR (6 ppm, CDC13, 400 MHZ): 8.47 (t, J 7.4, 1H), 7.93-7.80 (m, 3H), 7.65-7.57 (111, 1H), 7.53-7.45 (m, 1H), .02 (m, 1H), 4.12 (bs, 2H), 3.68 (t, J 5.3, 2H), 3.13 (s, 3H), 2.65-2.55 (n1, 2H), 1.50 (s, 9H).
Example 60 Tert-butyl 4-{2—[2-fiu0ro~4-(methylsulfonyl)phenyl]benzofd]oxazolyl}piperidine carboxylate: Example 59 (300 mg, 0.64 mmol) was dissolved in MeOH (25 1111) 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 ed through a pad of celite and celite washed thoroughly with ol. Methanol removed on rotavapour to obtain the titled compound (200 mg) as an off—white solid. M.P.: 168-171 0C. iH—NMR (5 ppm, CDCIa, 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 (111, 21-1), 3.13 (s, 3H), 2.90-2.75 (m, 31—1), 1.90 (d, J 12.6, 2H), .74 (m, 2H), 1.49 (s, 9H).
Example 61 2—[2-fluoro(methylsulforiyl)phenyl](piperidinyl)benz0{d]oxazole 2,2,2- trifluoroacetate: {303] Example 60 (170 mg, 0.36 mmol) dissolved in DCM (15 ml) and added TFA (0.6 ml). This mixture stirred at It for 3 h. After 3 h, DCM removed on rotavapour and co- distilled with DCM to obtain 2-[2-fluoro(methylsulfonyl)phenyl](piperidin-4— yl)benzo[d}oxazole 2,2,2-tfifluoroacetate (180 mg). M.P.: 223-227 0C. lH-NMR (6 ppm, DMSO-(lg, 400 MHz): 8.61 (133, 11-1), 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 (cl, J 12.9, 21-1), 1.93—1.80 (m, 21-1).
Example 62 -[1-(5-ethylpyrimidiny1)piperidin~4-yl][2-flu0ro (methylsulfonyl)phenyl]benzo[d]oxazole: Example 61 (150 mg, 0.31 mmol) and 2—chloro-S—ethylpyrimidine (48 mg, 0.34 mmol) were dissolved in propan-Z-ol (20 ml) and added DiPBA (0.4 ml, 2.45 mmol).
This e was refluxed at 90 0C for 12 h. After 12 h, propan01 removed on rotavapor to obtain the e. Residue was purified on comhiflash 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. lI-I-NMR (5 ppm, , CDC13, 400 MHZ): 8.49-8.43 (m, 1H), 8.20 (8, 21-1), 7.90-7.84 (m, 2H), 7.71 (s, 1H), 7.57 (d, J 8.4, IH), 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 (in, 2H), 1.20 (t, J 7.6, 31-1).
Example 63 Terr-butyl 4-{7-fluoro£2-flu0ro—4-(methylsnlfonyl)phenyl]benzo[d}0xazol y!}piperidine—l-carboxylate: Following the general ure-1 Tert-butyl 4-{7—fluoro[2—fluoro-4— (methylsulfonyl)phenyl]benzo[d]oxazol—5—yl] —5,6-dihydropyridine-1(2H)-carboxylate (180 mg) obtained from intermediate 31 (600 mg, 1.38 mmol) and tert—butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydr0pyridine—1(2H)-carboxylate (456 mg, 1.38 mmol).
Tert-butyl 4-{7-f1uoro-2—[2-fluoro—4~(methylsu1fonyl)phenyl1benzo{d]oxazol~5—y1}-S,6~ dihydropyridine— carboxylate (150 mg, 0.30 mmol) dissolved in MeOH and added Pd/C (71 mg). This e was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 11.
Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the titled nd (100 mg) as a brown solid. M.P.: 188- 192.41 “C. ’H-NMR (5 ppm, , CDC13, 400 MHz): 8.47 (t, J 7.12, 11-1), 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 (111, 31-1), 1.95—1.85 (in, 2H), 1.72-1.56 (111, 21-1). 1.49 (s, 9H).
Example 64 Isopropyl 4-{2-[2-flu0ro(methylsulfonyl)phenyl]benzo[d]oxazolyl}piperidine-l- carboxylate: Example 61 (100 mg, 0.20 mmol) was dissolved in DCM (10 ml) and added TEA (1.4 ml). This mixture was stirred at rt for 30 mins. ISOpIOpyl chloroformate in toluene (50 mg, 0.41 mmol) added to the above mixture and stirred at rt for 1 h. on mixture diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash with EA and Petehter (35:65) as eluent to afford the title compound (50 mg) as an off-white solid. M.P.: 1514—1565 0C. lH—NMR (8 ppm, g, 400 MHz): 8.47 (t, J 7.8, 11-1), 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 (111, 21-1), 1.65-1.55 (m, 2H), 1.20 (d, J 6.2, 6H).
Example 65 Tert-butyl 4-{2-[2-fluoro(methylsulfonyl)pllenyl]benzo[d]thiazolyl}-5,6— dihydropyridine-I(ZED-carboxylate: Following the general procedure-1, the titled compound (140 mg) was obtained from intemlediate 35 (300 mg, 0.69 mmol) and tert—butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine»l(2I-1)—carboxylate (230 mg, 0.69 mmol) as a brown solid. M.P.: 1599-1635 0c. 'H-NMR (6 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), 7.90-7.82 (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-fluoro(methylsulfonyl)phenyl]benzo[d]tlliazolyl}-5,6- dillydropyridine-l(2H)-carboxylate: ing the l procedure-1, the titled compound (120 mg) was obtained from intermediate 39 (230 mg, 0.53 mmol) and tert—butyl 4- uoromethylsulfonyloxy)-5,6-dihydropyridine-l(2I-I)-carboxylate (175 mg, 0.53 mmol) as an yellow solid. M.P.: 170-1743 0C. ‘H—NMR (3 ppm, , CDCl3, 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), .60 (m, 2H), 1.51 (s, 9H).
Example 67 Tert-butyl 4—{2-[2-fluoro(methylsulfonyl)phenyl}benzo[d}oxazolyl}piperidine-1— carboxylate: {309] Following the general procedure—1 Terz-butyl 4-{2-[2-fluoro (lllethylsulfonyl)pheny]}benzo[d]oxazolyl} ‘5 ,6—dihydropyridine- l (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 [clloxazolyl ]-5,6- dihydropyridine-1(2H)-cal'boxylate (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 11. on e filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the crude. Crude was purified 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 0(3. ‘H—NMR (6 ppm, , coca, 400 MHz): .46 (m, 1H), 7.91- 7.83 (m, 2H), 7.73 (d, J 8.3, 1H), 7.49 (s, 1H), 7.33—7.25 (m, 1H), 4.35—4.20 (111, 2H), 3.13 (s, 3H), 2.90-2.75 (111, 31—1), 1.95-1.85 (111,211), 1.75-1.60 (111, 21-1), 1.49 (s, 911).
Example 68 {2-[2-fluoro(methylsulfonyl)phenyl}benzo[d]thiazol-S-yi}piperidine-l-carboxylate: Tert~butyl 4- { 2—[2-fluoro—4-(1nelhylsulfonyl)pheny1]benzo[d] Lhiazol-S- yl}pipe1idinecarboxy1ate (30 mg, 0.06 11111101) dissolved in MeOH and added Pd/C (30 mg). This mixture was stirred in an auto clave under en atmosphere at 55 Psi for 87 h.
Reaction mixture filtered through celite and washed the cetile with MeOl—l. Methanol was removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (20:80) as eluent to obtain titled nd (12 mg) as a pale-yellow solid. M.P.: 1733-1781 0C. lH-NMR (6 ppm, , CDCIg, 400 MHZ): 8.71-8.65 (m, 1H), 7.99 (s, 1H), 7.93~ 7.82 (111, 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), 1.96188 (111, 21-1), 1.80-1.68011, 21-1), 1.50 (s, 9H).
Example 69 Ethyl 4-{2-[2-flu0r0-4~(metllylsulfonyl)phenyl]benzo[d}oxazoI-S-yl}piperidine carboxylate: [3 1 l] 2-[2-fluoro-4—(methylsulfonyl)phenyl](piperidin-4—yl)benzo[(l]oxazole 2,2,2—trifluoroacetate (80 mg, 0.16 mmol) ved in DCM (10 ml) and added TEA (0.12 ml, 0.8 mmol). This mixture was stirred at It for 30 mins. Ethylchloro formate (35 mg, 0.33 11111101) was added to the above mixture and stirred at It for 30 mins. Reaction mixture extracted with DCM. DCM removed on pour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether ) as eluent to afford the titled compound (20 mg) as an off-white solid. M.P.: 8 0C. lH-NMR (8 ppm, , CDC13, 400 MHZ): 8.49— 8.44 (m, 11-1), 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), 2.95279 (m, 3H), 1.96—1.88 (m, 2H), 1.75-1.65 (m, 2H), 1.29 (t, 3 7.1, 3H).
Example 70 Tert-butyi 4-{2-{4-(trifluoromethyl)phenyl]benzo[d]oxazol-5—yl}piperidine-l- carboxylate: [3 12] Following the general procedure- 1, Tert-butyl 4- { 2-[4- (trifluoromethyl)phenyl]benzo[(onazol—S-y1 } -5 ,6—dihydropyridine-1(2I-I)—carboxylate (90 mg) ed from intermediate 44 (200 mg, 0.51 mmol) and Terr-butyl 4— (trifluoromethylsulfonyloxy)~5,6-dihydropyridine-1(2H)-carboxy1ate (170 mg, 0.511 mmol).
Tert—butyl 4- { 2— [4—(trifluoromethyl)pheny1]benzo[d]oxazolyl } -5 ,6-dihydr0pyridine- 1(2H)— carboxylate (90 mg, 0.2 mmol) dissolved in MeOH (30 ml) and added MIC (90 mg). ”[1115 mixture was stirred in an auto clave in hydrogen here at 55 Psi for 12 11. Reaction mixture filtered through celite and washed the cetile with . 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, CDC13, 400 MHz): 8.36 (d, J 8.2, 2H), 7.78 (d, J 8.4, 2H), 7.63 (d, J 1.5, 11-1), 7.53 (d, J 8.4, 1H), 7.26-7.20 (m, 1H), 4.34-4.20 (m, 2H), 2.90-2.75 (m, 3H), 1.93-1.84 (m, 21-1), 1.74-1.62 (m, 2H), 1.49 (s, 9H).
Example 71 Isopropyl 4-{2-[2-fluoro—4—(methylsuifonyl)phenyl}benzo[d]oxazoIy1}piperidine carboxylate: utyl 4-{2-[2-fluoro(melhylsulfonyl)phenyl]benzo[(1]oxazol yl}pipen‘dine—1-carboxylate (270 mg, 5.7 mmol) dissolved in THF (5 ml) and added Et20.1-IC1 (10 ml). Reaction mixture stirred at it for 3 h. Ether removed on rotavapour to obtain crude. Crude was ated with ether to obtain 2fluoro—4- (methylsulfonyl)phenyl}~6-(piperidin—4-yl)benzo[cfloxazole hydrochloride (225 mg). 2-[2- fluoro(methylsulfonyl)phenyl]—6-(piperidin—4~yl)benzo[(floxazole hydrochloride (70 mg, 0.17 mmol) was dissolved in DCM (5 ml) and added TEA (0.11 ml, 0.85 mmol). This mixture stirred at rt for 30 mins and added isopropylchloro formate in toluene (42 mg, 0.34 mmol). After 30 mins reaction mixture quenched with water and ted 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. lH-NMR (3 ppm, , CDC13, 400 MHZ): .44 (m, 1H), 7.90783 (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, 11-1), 4.40- 4.28 (m, 2H), 3.13 (s, 3H), 2.92-2.80 (n1, 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-4~(methyisulfonyl)phenyl]benzo[dloxazol-G-yl}piperidine—1- carboxylate: [3 14] 2~{2-fluoro-4—(methylsulfonyl)pheny]](piperidin—4—yi)benzo[d]oxazole hydrochloride (70 mg, 0.17 11111101) from Example 71 was dissolved in DCM (10 ml) and added TEA (0.12 ml, 0.83 11111101). This mixture stirred at rt for 30 ruins and added Ethylchloro fonnate (35 mg, 0.34 11111101). After 30 mins reaction e 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. Il-leMR (8 ppm, , CDClg, 400 MHz): 8.49-8.43 (m, 1H), 7.90—7.82 (111, 21—1), 7.78 (d, J 8.3, 11-1), 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, 31-1), 2.95-2.80 (111, 3H), 1.96-1.88 (111, 2H), 1.75-1.65 (111, 211), 1.29 (t, J 7.1, 3H).
Example 73 Ethyl 4-{2-[2-fluoro(methylsulfonyhenyl]beuzo[d]oxazol-G-yl}piperidine~1a carboxylate: Tert-butyl 4- { 2-[2-fluoro(methy]sulfonyl)phenyl]benzo[d]thiazol yl}pipe11‘dine-l-carboxylate (130 mg, 0.27 11111101) ved in DCM (5 ml) and added TFA (0.5 ml). Reaction mixture stirred at rt for 3 h. DCM removed on rotavapour to obtain elude.
Guide was tn'turated with ether to obtain 2—[2—flu0r0(methylsulfonyl)pl1enyl]~5-(piperidin— 4-yl)benzo[([]thiazole 2,2,2—trifluoroacetate (150 mg). 2-[2-fluoro~4-(methylsulfonyl) phenyll—S-(pipen'din—4-yl)benzo[d]tl1iazole 2,2,2—ti'iflu01'oacetate (105 mg, 0.21 01) was dissolved in DCM (20 ml) and added TEA (0.23 ml, 1.66 11111101). This mixture stirred at It for mins and added isopr0pylcl1loro formate in toluene (51 mg, 0.42 11111101). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by ash using EtOAc and er (1:3) as eluent to afford the titled nd (60 mg) as a grey solid. M.P.: 174-177 0C. 1H— NMR (5 ppm, , CDCla, 400 MHz): 871865 (m, 1H), 8.00 (d, J 1.2, 1H), 7.93-7.81 (111, 3H), 7.35 (dd, J 1.6, 8.4, 1H), 4.96 (septet, J 6.2, 1H), 4.40-4.22 (I11, 2H), 3.12 (s, 3H), 2.95-2.82 (111, 3H), 2.0-1.90 (n1, 211), 1.80—1.64 (11], 2H), 1.28 (d,.1 6.3. 6 H).
Example 74 Benzyl 4-{2-[2-fluoro(methylsuifonyl)pheny1}benzo[d]oxazo1—5~yl}piperidine-1— ylate: [3 16] 2»[2-fluor0-4~(11lethyisulf0nyl)phenyl]—5—(piperidin-4~y1)benzo [(11011azole 2,2,2-uifluoroacetate (Example 61) (70 mg, 0.14 11111101) dissolved in DCM (10 1111) and added TEA (0.1 ml, 0.72 11111101). This mixture d at rt for 30 mins and added benzy] carbonochloridale in toluene (48 mg, 0.28 11111101). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by ash using EtOAc and Petether (1:2) as eluent to afford the titled nd (30 mg) as an off-white solid. M.P.: 172-175 0C. IH-NMR (6 ppm, , CDClg, 400 MHZ): 8.49-8.43 (111, 1H), 7.90-7.84 (111, 21-1), 7.68 (d, J 1.4, 1H), 7.57 (d,1 8.5, 1H), 7.42- 7.22 (m, 6H), 5.17 (s, 2H), 4.42-4.25 (bs, 21-1), 3.13 (s, 3H), 3.00-2.78 (111, 3H), .88 (111, 2H), 1.80-1.65 (111, 2H).
Examp1e 75 Isobutyl 4-{2-[2-[1uoro(methylsulfonyl)phenyl]benzo[d]oxazol-S-yl}piperidine-l-carboxyiate: [3 17] 2-[2-fluoro(111ethy1sulfony1)phenyi]—5-(pipe1'idin-4—yl)benzo[(floxazole 2,2,2—trifluoroacetate (Example 61) (140 mg, 0.29 11111101), anol (42 mg, 0.58 111n101), N,N~Carbony1 diimidazole (82 mg, 0.50 11111101) and TEA (0.2 1111, 1.26 11111101) were dissolved in DMF (2.41111). Reaction mixture heated to 60 0C for 18 11. Work up (EtOAc/Hgo) 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. lH-NMR (5 ppm, , 01101;, 400 MHz): 8.49-8.43 (111, 1H), 7.83-7.90 (111, 211), 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 (111, 3H), .88 (111, 3H), 1.80-1.65 (m, 2 H), 0.96 (d, J 6.7, 6H).
Example 76 ISOpI‘Opyl 4-{2-{2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazolyl}piperidine carboxylate: Tert-butyl 4- { 2-[2-fluoro(methylsulfonyl)phenyl]benzo[d]thiazol yl}piperidinecarboxylate (190 mg, 0.38 mmol) dissolved in DCM, cooled to O 0C, oroacetic acid (0.8 ml) was added and stirred the reaction mixture at rt for 3 h. DCM and tn‘fluoroacetic acid was removled on rotavapour to obtain the crude. Crude was washed with er to obtain 2-[2—fluoro—4—(methylsulfonyl)pheny1]—6—(piperidin-4—yl)benzo[d]thiazole (190 mg) as an ite solid. 2-[2-fluoro(methy1sulfony1)phenyl]~6~(piperidin y1)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. Reaction mixture cooled to 0 0C and added isopropylchloro formate (92 mg, 0.75 mmol). This mixture was d at rt 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. lI-l-NMR (5 ppm, CDCI3, 400 MHZ): Example 77 Isopropyl 4-{2—[4-(trifluoromethyl)phenyl]benzo[d}oxazolyl}piperidine-l- carboxylate: Terr-butyl 4- { 2-[4-(trifluoromethy1)phenyl]benzo[(floxazol-S-yl }-5 ,6— opyridine—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 mixture at It for 3 h.
DCM and uifluoroacetic acid was removed on rotavapour to obtain the crude. Guide was washed with petether to obtain 5-(piperidin-4—yI)(4— (trifluoromethyl)phenyl)benzo[d}oxazole t1'ifluoroacetate (90 mg) as an off-white solid.
S—(piperidinyl)—2—(4-(trifluoromethyl)pheny])benzo{d]oxazole 2,2,2-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 mixture at rt for 30 mins. Reaction e cooled to O 0C and added isopropylchloro formate (46 mg, 0.38 mmol). This mixture was stin‘ed at It for 30 mins.
Work up (DCM/£120) followed by evaporation of the DCM on rotavapour afforded crude.
Crude was purified with combiflash using a gradient mixture of ethylacetate and petether (15:85) as eluent to afford the titled nd (30 mg) as an off-white solid. M.P.: 145-148 “C. ‘H-NMR (5 ppm, CDC13, 400 MHz): 8.36 (d, J 8.1, 2H), 7.78 (d, J 8.3, 21-1), 7.62 (a, 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).
Example 78 Isopropyl 4-(2—p-tolylbenzo[dloxazolyl)piperidine~1-carl)oxylate: Intermediate 49 (40mg, 01411111101) was dissolved in DCM (10 ml) and added trifluooroacetic acid (0.15 ml) at 0°C. This mixture was stirred at rt for 3 h. After 3 h DCM was removed on rotavapour and the residue that ed was washed with diethyl ether to obtain 6-(piperidiny1)p-tolylbenzo[d]oxazole trifluoroacetate (40 mg). 6- (piperidinyl)p-tolylbenzo[d]oxazole 2,2,2-trifluoroacetate (40 111g, 0.1 11111101) was dissolved in DCM (10 ml) and added TEA (0.1 ml, 0.79 inmol) at 0°C. To the above mixture iSOpIOpylchloro fonnate (24 mg, 0211111101) was added and stirred at rt for 15 mins. Workup (DCM/1120) followed by column cation 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. Jl-l-NMR (6 ppm, , CDC13, 400 MHz): 8.12 (d, J 8.2, 21-1), 7.66 (d, l 8.2, 1H), 7.40 (d, J 1.2, 111), 7.32 (d, l 8, 21-1), 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-[1uoro(methylsulfonyl)phenyl)benzo[d]oxazoIyl]-S,6-dihydropyridin- 1(2H)-ylsulfonyl}propan—l~ol: Example 59 (200 mg, 0.42 11111101) was dissolved in DCM (30 ml) and added TFA (1.5 ml, 9.2 11111101). This mixture was stirred 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— (mctl1y1sulfonyl)phenyl)(1,2,3,6—tetrahydropyridin—4-yl)bcnzo[d]0xazole 2,2,2— tiifluoroacetate (210 mg). 2-(2~fluoro-4~(n1ethy13ulfonyl)phenyl)(1,2,3,6- tetrahydropyridin—4-yl)benzo[d]oxazole trifluoroacetate (200 mg, 0.4 11111101) was dissolved in DCM (10 1111) and added TEA (0.46 ml, 3.3 11111101). This mixture was stirred at rt for 30 mins. After 30 mins reaction mixture cooled to 0°C and added ethyl 3— osulfony1)propanoate (164 mg, 0.4 01). This reaction continued for 30 mins at it.
Work up (I-IzO/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-fluor0 (mathylsulfonyl)phenyl]benzoldloxazol-5~yl}-5,6-dihydropyridin~1(2PD-ylsu1fonyl)acetate (120 mg). Ethyl 2-{4—{2—(2-fluoro(methylsulfonyl)phenyl]benzo[(floxazol—S—yl}-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 0°C. This mixture was stirred at same temperature for 90 mins. After completion of the reaction, reaction mass quenched with 1N 11C] (7 ml). Work up 120) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (80:20) as eluent afforded the titled compound (40 mg) as a white solid. M.P.: 184-186 0c. ‘H—NMR (5 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 (5, 11-1), 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 (111, 21-1), 1.88—1.80 (111, 21-1).
Example 80 3-{4-[2-(2-fl uoro(methylsulfonyl)pheny1)benzo[d]oxazol-5~yllpiperidin ylsulfonyl}propanol: Example 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 rt for 30 mins. After 30 mins on mixture cooled to 0°C and added ethyl 3-(chlorosulfonyl)propanoate (245 mg, 1.2 mmol). This reaction continued for 30 mins at rt. Work up (I-le/DCM) followed by column purification on combiflash using a gradient mixture of EtOAc and er ) as eluent afforded ethyl 2-{4-[2-(2-fluoro(methylsulfonyl)pheny1)benzo[rlloxazol-S-yllpiperidin-l- ylsulfonyl } acetate. Ethyl 2- { 4-[2—(2—fluoro(methy1sulfonyl)pheny1)benzoldloxazol—S- y1]piperidinylsulfonyl}acetate (100 mg, 0.19 mmol) was dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg, 0.37 mmol) at 0°C. This mixture was stirred at same ature for 90 mins. After tion of the reaction, reaction mass quenched with 1N I-ICl (7 ml). Work up (DCM/[120) 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.: 204—206 °c 'H-NMR (5 ppm, , lg, 400 MHz): 8.47 (t, .1 8.03, 1H), 8.06 (dd, J 1.6, 10.1, 11-1), 7.97 (dd, J 1.6, 8.2, 11-1), 7.82-7.75 (111, 21-1), 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— 3.06011, 2H), 2.98-2.80 (111, 31-1), 1.96-1.90 (m, 2H), 1.88181 (111,211), 1.79-1.69 (m, 2H).
Example 81 3-{4-[2-(2-fluoro~4-(methylsu]fonyl)phenyl)benzo[d]0xazolyl]piperidin-l- ylsulfonyl}propanol: Example 61 (150 mg, and 0.31 mmol) and 2—Chlorofluoropyrimidine (44 mg, 0.34 11111101) were dissolved in isopropanol (20 1111). To this mixture DiPEA (0.45 ml) was added and heated to 90°C for 12 h. Isopropanoi was d on rotavapour to obtain a residue. Residue was purified by combiflash using a nt 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 (In/Z): 471.2 [M+H]*, e 82 Tert-butyl 4-[2-(4-carbamoylfluorophenyl)benzo[d]oxazol-S-yl]piperidine-l- carboxylate: Intermediate 52 (40 mg, 0.1 11111101), 2-fluoro-4—(4,4,5,5—tetramethy1-1,3,2- dioxaborolan-Z-yl)benzamide (30 mg, 0.12 mmol) and KF (18 mg, 0.3 11111101) were dissolved in a mixture of DMF (1 1111) and and water (0.4 1111). This mixture was purged with N2 for 30 mins. Pd(dppf)C12.CI-IZC12 was added to the above mixture and again purged with N2 for 30 mins. This on mixture was heated to 90°C for 1?. 11. Work up (EtOAc and 1120) followed by purification on combiflash using a gradient mixture of EtOAc and Petether ) as eluent afforded the titled compound (3 mg) as an Off—White solid. MS (In/z): 439.5 [M+H]+, Example 83 2-[2-fluoro(methylsulfonyl)phenyI}[4-(3-isopropy1-1,2,4-oxadiazoly1)piperidin- 1-yl]benzo[d10xazole: Intermediate 28 (150 mg, 0.41 mmol), ropyl(piperidinyi)»1,2,4— zole hydrochloride (96 mg, 0.5 11111101), K2C03 (59 mg, 0.43 mmol), CuCi (’2 mg, 0.02 11111101), acetyl acetone (5 mg, 0.05 mmol) were dissolved in NMP (1 1111). This reaction mixture was stirred at 130°C for 16 11 under N2 atmposphere. Work up (EtOAc/1120) 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— 20900. ll-I-NMR (5 ppm, , CD013, 400 MHz): 8.26 (d, J 3.2, 11-1), 7.97 (d, J 1.4, 1H), 7.69 (d, J 1.4, 1H), 7.63 (dd, .1 1.5, 8.2, 1H), 7.56-7.48 (111, 21-1), 3.49—3.39 (m, 2H), 3.15-3.04 (111, 5H), 3.03—2.93 (m, 2H), 2.25—2.16(m, 411), 1.36 (d, J 7, 6H).
Example 84 Terr-butyl 4-{2-[4-(trifluoromethyl)phenyl}benzo[d]oxazolyl}piperldine-l-carboxylate Following the general procedure, lerI-butyl 4~[2-(4- (trifluoromethyl)phenyl]benzo[d]oxazol-6—y1)-5,6-dihydropyridine-1(2H)-carboxy1ate (260 mg) was prepared from ediate 55 (420 mg, 1.08 01) and tert-butyl 4~ (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-l(2H)—carboxy1ate (358 mg, 1.08 mmol).
Iert~butyl 4—(trifluoromethyl)phenyllbenzo[d]oxazol—6—y1)-5,6-dihydropyridine-1(2H)- carboxylate (260 mg, 0.58 mmol) was dissolved in methanol (8 H11) and added Pd/C (5%) (520 mg). This e was stirred under H; pressure (6.5 kg) for 12 h. Combined methanol fractions were evaporated on rotavapour 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 (150 mg) as a white solid. M. P.: 174-17900 MS (m/z): 446.46 [M+1~1]+.
Example 85 pyl 4-{2-[2-fluor0(methylsulfonyl)phenyl}benzo[djoxazolyl}piperazine-l- carboxylate: [327} Intermediate 28 (490 mg, 1.32 mmol). N-Benzylpiprazine (280 mg, 1.6 mmol), K2CO3 (190 mg, 1.4 mmol). CuCl (6.5 mg, 0.05 mmol), acetyl e (17 mg, 0.12 mmol) were dissolved in NM? (2 ml). This reaction mixture was stirred at 130°C for 15 h under N2 atmposphere. Work up (EtOAc/l-IQO) 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- benzylpiperazin-i-y1)-2~[2-i'1uoro(methylsulfonyl)phenyl]benzo[(floxazole (250 mg) as a yellow solid. 5—(4-Benzy1piperazin-1~y1){2—f1uoro (methylsulfonyl)pheny1]benzo[(floxazole (130 mg, 0.28 mmol) dissolved in DCM (15 ml) and added isopropylchloro formate (102 mg, 0.84 mmol). This mixture was stirred at reflux for 18 h. Work up (DCM/HgO) followed by purification of the crude by column chromatography 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. MR: 231— 23400 xH-NMR (5 ppm, , CDCl3, 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 (111, 41-1), 1.26 (d, J 6.2, 611).
Example 86 Tert-hutyl 4-{2-{4-(trifluoromethyl)phenyljoxazolo[5,4~b]pyridinyl}-S,6- opyridine-1(2H)-carb0xylate: Following the general procedure-l, the titled compound (230 mg) was obtained from ediate 58 (500 mg, 1.28 mmol) and tert—butyl 4- (trifluoromethylsulfonyloxy)~5,6-dihydropyridine-l(2H)-carboxylate (467 mg, 14 mmol) as an off-white solid. M.P.: 207-212 0C. ll—I—NMR (3 ppm, , CD013, 400 MHz): .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 Tart-Duty! 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridinyl}piperidine-I- carboxylate: Tert~butyl 4- { 2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-é-yl] -5,6— dihydropyridine—1(2H)-carboxylate (170 mg, 0.38 mmol) was dissolved in methanol (10 ml) and added Pd/C (5%) (283 mg). This e was stirred under H; pressure (6.5 kg) for 12 h.
Combined methanol fractions were evaporated on rotavapour to obtain the crude. Crude was purified on combiflash using a nt mixture of BtOAc and l’etether (1:9) as eluent to afford the titled compound (35 mg) as a white solid. M. P.: 184-1880C. II-I-NMR (6 ppm, CDCls, 400 MHz): 8.40 (d, I 8.1, 2H), 8.27 (d, J 2, 1H), 7.93 (d, J 2, 1H), 7.81 (d, J 8.3, 21-1), 4.31 (d, J 13.5, 2H), 2.91-2.81 (m, 31-1), 1.91 (d, J l2.9, 2H), 1.78-1.62 (m, 2H), 1.50 (3, 91-1).
BIOLOGICAL ASSAY The biological 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 ified below.
A. In Vitro cvclic AMP Assav: {331] CAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio, Bedford, MA) according to the manufacmrer’s protocol. Briefly, I-IEK293 cells (0.2 x IDs/well) were plated in a 24 well plate and incubated overnight at 37°C. Cells were transfected with either empty vector DNA or human GPR119 expression plasmid DNA using Lipofectamine 2000 rogen). 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 trations of compounds and incubated for 60 min at room ature. Lysis buffer containing CAMP-d2 and cryptate conjugate were added and incubated for 1 h. HRTF ratio was ed on a late reader (BMG h., Germany) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 run with an integration time of 400 usecData were analyzed using Graphpad Prism (Graphpad software; San Diego CA) for ECso determination.
Results: The results are as given in Table I as % Induction@ 14M . Table H as % lnduction@ 10 “M and EC 50in nM B. In Vitro Mouse GPR 119 cyclic AMP Assay: CAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio, Bedford, MA) according to the manufacturer’s protocol. HEK293 Cells were stably transfected with Mouse GPR119 sion plasmid DNA using Lipofectamine 2000 (Invitrogen) and maintained in culture. Cells were harvested, counted and plated at 1000 cells/5 111 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. l-lRTF ratio was measured on a late 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 psec. Data were analyzed using Graphpad Prism (Graphpad re; San Diego CA) for ECSO determination.For example example 12 showed an EC 50 of < '25 nM C. In Vitro HIT-T15 cvclic AMP Assay: {333] CAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio, Bedford, MA) according to the manufacturer’s protocol. Briefly, HIT—T15 cells were harvested, counted and plated at 4000 cells/5 ul A solution in a black 384 welled small volume plate. Cells were d 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 ed on a microplate reader (BMG Labtech., Gemiany) 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 ECso determination. For instance example 12 showed an EC 50 of < 25 nM D. In Vitro HIT-T15 n Assav: Insulin measurements were done using a Ultra ive Insulin ELISA kit (Crystal Chem Inc, USA) according to the manufacturer’s protocol. Briefly, 2.5 x l05 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% FBS, 1% pen-strep and further incubated for 24 h. Cells were treated with desired concentrations of nds and incubated for 60 min at room temperature. Supernatant was collected, centrifuged and soup added to the pro-coated strips followed by ELISA. The absorbance was measured at 450 and 630 nM. Data were analyzed using Graphpad Pn‘sm (Graphpad software; San Diego CA) for EC50 determination.
Table I EXAMPLE-8 EJIm _-_—— EXAMPLE-15 --u EXAMPLE-43 “mil—IE“ EXAMPLE-18 __—IIJI ND EXAMPLE-21 EXAMPLE-32 EXAMPLE-50 EXAMPLE-25 __I§Eu__- __-_—- E28 —m-_- ND: Not done; A++2525 nM ; A+:> 25 to $50 nM;A : >50105 IOOnM; B COMPOUND EC50* COMPOUND W- : > 100 to S 500 nM; C : > 500 to 5 1000 nM; *Emax varies n 65 to 80 Table II __I_-A» _-_——m _-lnl_—lrul Mme-In- EXAMPLE-76 EXAMPLE-77 80.37 EXMLE-e mun-nu EXAMPLE-63m EXAMPLE-64 EXAMPLE-so _Inn ————_m EXAMPLE-66 —Ir_—-n_ EXAMPLE-6v E-84 —» EXAMPLE-69 EXAMPLE-70 EXAMPLE-86 Inn-n- —————m ND: Not done; ;A++ : S 2511M;A+:> 25 to 550 nM ; A :> 50 & < 250 11M; B : < 500 nM; C : > 500 to S 1000 nM; *Emax varies between 65 to 80 %.
E: Oral glucose nce test (OGTT) in C57BI/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 ping diabetes in the future.
After the quarantine period, 6 hr fasted animals were randomized and divided into s groups depending on their blood glucose levels. Test compounds or standard drug (sitagliptin) was prepared as a suspension in a vehicle consisting of 0.5% melhylcellulose and Tween 80 as a suspending agent. The standard drug, Compound A (example~64), Compound B le-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 e-treated control group. The results are shown in s land 2 and are discussed below.
Results: Compound A and Sitagliptin dosed as single agents lowered AUCg:ucosc by 24% and 59%, respectively, and nd B and sitagiiptin dosed as single agents lowered AUCg]ucosc by 22 and 50%, respectively.
F: Intraperitoneal glucose tolerance test (IPGTT) in CS7Bl/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 stered by oral gavage in a volume of 10mL/kg. 1 l1 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 intrapcritoneal administration of glucose solution of 2.0 g/kg of body weight. Food, but not water is to be withheld from the cages during the course of experiment. The area under curve (AUC) of experimental s will be compared with that of vehicle-treated control group.
G: Oral glucose tolerance test (OGTT) in Streptozotocin & nicotinamide induced type 2 diabetes in CD-1 mice: After the quarantine pen‘od, animals are to be randomized and divided into various groups depending on their body weights and s 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 logical saline. Two weeks later, the diabetic mice were grouped to e similar mean non-fasting blood glucose 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 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 e is to be administered by oral gavage in a volume of lOmL/kg. l h after drug or vehicle stration, 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 weight. 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.
H: Sub-acute treatment of test compound in Streptozotocin & nicotinamide induced type 2 es in (ID-1 mice: After the tine period, animals are to be randomized and divided into various groups depending on their body s 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 provide similar mean non- fasting blood glucose levels in each group, on day 0, fasted animals are to be randomized and divided into s groups depending on their blood glucose levels. Test compound or standard drug is to be prepared as a sion in a vehicle consisting of 0.5% methylcellulose in which Tween 80 as a suspending agent. The compound or vehicle is to be stered by oral gavage in a volume of lOmL/kg. i 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 weight. 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 e- treated control group. After conducting the OGT'I‘ on day 0, the treatment will be continued for 14 days, on day 14, 6 hr fasted animals will be used for the same OGTT procedure. After conducting the OGTT, blood samples will be collected from the animals and analysed for the lipid , insulin, and GLP-1 levels.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the t invention. It is therefore 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 dual publication or patent application was specifically and dually indicated to be incorporated herein by reference.

Claims (16)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1.-
1. A compound of formula (A-IA), (A-IIA), (B-IA), (B-IIA), A) or (B-IVA): X 1 X (R 6) p N R 5 X 4 O (A-IA) (A-IIA) N R 5 X 1 X X 4 X Ar G X 3 Ar G X 4 O X 2 X 1 O (R 6) p (R 6) p (B-IA) (B-IIIA) R 5 R 5 N N X 1 O X 4 O Ar G Ar G X 3 X 2 X 4 X X 1 X (R 6) p (R 6) p (B-IIA) (B-IVA) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt or N- oxide f, wherein Ar is G is independently selected from wherein variable R on substituent G is selected from substituted or tituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl and substituted or tituted cycloalkyl. X1 is CR1 or N, wherein R1 is H or halogen; X2 is CH; X3 is CH; X4 is CR4 or N, wherein R4 is H or halogen; X is CR, wherein R is 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 tituted 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-, or -NRaRb-NRaRb-; each occurrence of Y is independently selected from O, S, and NRa; each occurrence of q independently represents 0, 1 or 2; 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 l, tuted or unsubstituted alkynyl, tuted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted kyl, 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, -(=N-N(Ra)Rb), O)ORb, , - NRaC(O)Rb-, -NRaC(S)Rb –NRaC(S)NRaRb, -SONRaRb-, -SO2NRaRb-, -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, or any two of Ra and Rb which are ly bound to a common atom may be joined to form (i) an oxo (=O), thio (=S) or imino (=NRd), or (ii) a substituted or unsubstituted, ted or unsaturated 3-14 ed ring, which may optionally include one or more heteroatoms which may be the same or different and are ed from O, NRd or S, wherein each occurrence of Rd is ndently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, tuted or unsubstituted alkenyl, substituted or unsubstituted l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted 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; and R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, tuted or unsubstituted cycloalkylalkyl, substituted or unsubstituted lkenylalkyl, substituted or unsubstituted heterocyclyl, tuted 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, RaRb, -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, -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, 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 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 (=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; and n term “substituted” unless otherwise specified, refers to tution with any one or any ation of the following substituents and may be the same or different which one or more are selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, tuted or unsubstituted alkynyl, tuted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, tuted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or tituted 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’’, -(=NN (R’)R’’), - NR’C(O)OR’’, -NR’R’’, O)R’’-, -NR’C(S)R’’ –NR’C(S)NR’’R’’’, - SONR’R’’-, -SO2NR’R’’-, -OR’, -OR’C(O)NR’’R’’’, -OR’C(O)OR’’-, -OC(O)R’, - OC(O)NR’R’’,- C(O)R’’’, -R’OR’’, -R’C(O)OR’’, -R’C(O)NR’’R’’’, )R’’, - )R’’, -SR’, -SOR’, -SO2R’, -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 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, tuted 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 aryl, 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, NRd or S or form oxo (=O), thio (=S) or imino (=NR’, where R’ is defined above), and wherein the tuents in the aforementioned "substituted" groups cannot be further substituted.
2. A compound of formula (A-IIIA) or ) (A-IIIA) (A-IVA) wherein Ar, G, R5, X, X1-X4, R6, p and the term ‘substituted” are the same as defined in claim 1; with the provisos a) that for compound of formula (A-IIIA), wherein X4 is N or CR4 then Ar-G cannot be b) that for compound of formula (A-IVA) wherein X1 is N or CR1 then Ar-G cannot be wherein R1 and R4 is as defined above for compound of formula (A-IA) 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 selected from N, O, and S; R1a, at each occurrence, is independently hydrogen or )alkyl; R1 is optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, optionally substituted (C2-C6)-alkynyl, optionally substituted 2)-cycloalkyl, ally substituted (C1-C10)aryl, a 4 to bered optionally substituted heteroaryl, which ns 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.
3. A compound of claim 1 or claim 2, wherein R5 is selected from
4. A compound of claim 3, wherein R5 is -C(O)OC(CH3)3 or CH(CH3)2.
5. A compound of any one of claims 1 to 4, wherein p is 0 or 1.
6. A compound of any one of claims 1 to 5, wherein R6 is halogen, substituted or unsubstituted alkyl or -ORa; n Ra is substituted or tituted alkyl.
7. A compound of claim 6, n R6 is -F, -CH3, -CF3 or -OCH3.
8. A compound of any one of claims 1 to 7, wherein Ar-G is selected from
9. A compound of claim 8, wherein G is independently selected from
10. A compound of formula (A -IB) and (A-IIB) (A-IB) (A-IIB) or a tautomer, stereoisomer, enantiomer, diastereomer, pharmaceutically acceptable salt or N-oxide thereof, wherein Z is O or S; Ar1-G is wherein G is as d in claim 1; p is 0, 1-7 or 8; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N and X4 is CR4 or N; X is CR; each occurrence of R, R1, R2, R3 and R4 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, and substituted or unsubstituted C3-6 cycloalkenyl, , -ORa, -S(=O)q-Ra, - NRaRb, –C(=Y)-Ra, -CRaRb-C(=Y)-Ra, -CRaRb-Y-CRaRb-, -NRaRb-, -NRaRb-C(=Y)- NRaRb-, -S(=O)q-NRaRb-, -NRaRb-S(=O)q-NRaRb-, -NRaRb-NRaRb-; R5 is 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 tituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lkenyl, 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 tituted arylalkyl, –COORa, -C(O)Ra, -C(S)Ra, RaRb, -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-, -SO2NRaRb-, -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; R6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, 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, 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, NRaRb, -NRaRb, - NRaCONRaRb, -N(Ra)SORb, -N(Ra)SO2Rb, -(=N-N(Ra)Rb), -NRaC(O)ORb, , -NRaC(O)Rb-, - NRaC(S)Rb S)NRaRb, -SONRaRb-, -SO2NRaRb-, -ORa, 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 -SO2Ra, and -ONO2; each occurrence of Y is independently selected from O, S, and NRa; and each occurrence of q independently represents 0, 1 or 2; each ence of Ra and Rb may be same or different and are independently selected from hydrogen, nitro, y, cyano, n, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, tuted 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 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 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 lkylalkyl, and substituted or unsubstituted C3-6 cycloalkenyl; each occurrence of Rd is independently hydrogen, hydroxy, n, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, tuted or unsubstituted alkenyl, substituted or unsubstituted l, substituted or unsubstituted cycloalkyl, substituted 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 aryl, substituted or tituted arylalkyl, and -ONO2; and and wherein term “substituted” unless otherwise specified, refers to tution with any one or any combination of the following substituents and may be the same or different which one or more are selected from the groups such as hydrogen, y, halogen, yl, cyano, nitro, oxo (=O), thio (=S), 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 cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted 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’’, -(=N-N(R’)R’’), - NR’C(O)OR’’, -NR’R’’, -NR’C(O)R’’-, -NR’C(S)R’’ – NR’C(S)NR’’R’’’, -SONR’R’’-, -SO2NR’R’’-, -OR’, -OR’C(O)NR’’R’’’, -OR’C(O)OR’’-, - OC(O)R’, -OC(O)NR’R’’,- C(O)R’’’, -R’OR’’, -R’C(O)OR’’, -R’C(O)NR’’R’’’, - R’C(O)R’’, -R’OC(O)R’’, -SR’, -SOR’, , -ONO2 wherein R’, R’’ and R’’’ in each of the above groups can independently be hydrogen, hydrogen, hydroxy, n, carboxyl, cyano, nitro, oxo (=O), thio (=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or tituted 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, tuted 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, NRd or S or form oxo (=O), thio (=S) or imino (=NR’, where R’ is defined above), and wherein the substituents in the entioned "substituted" groups cannot be further substituted.
11. A compound of 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 wherein G is as defined in claim 1; p is 0, 1-7 or 8; R5, X1-X4, X, R6 and the term “substituted” are as defined in claim 10; with the o that a) that for nd 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 nd of formula (A-IA) 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 (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 bered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S.
12. A compound selected from Tert-butyl 4-carbamoylfluorophenyl)benzofuranyl]-5,6-dihydropyridine- carboxylate: and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition, comprising a compound of any one of claims 1-12 and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13, further comprising one or more additional therapeutic agents and mixtures thereof.
15. Use of a therapeutically effective amount of a compound of any one of claims 1- 12 and optionally an additional therapeutic agent in the manufacture of a medicament for modulating the activity of the GPR119 or in a mammalian subject.
16. Use of a therapeutically effective amount of at least one compound, of any one of claims 1-12, and optionally an additional therapeutic agent in the manufacture of a medicament for the treatment, prevention and/or amelioration of diseases or disorders associated with the GPR119 receptor in a mammalian subject wherein: (a) the diseases or disorders associated with the GPR119 receptor are selected from the group consisting of diabetes mellitus, type 1 es, type 2 diabetes, uate glucose nce, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, , syndrome X, ension, pancreatic beta-cell iciency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic pathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic ovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial tion, learning impairment, memory impairment, a neurodegenerative disorder, a ion ameliorated 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, traumatic brain injury, spinal cord injury, obesity, delayed wound healing, abnormal heart function, myocardial ischemia, low HDL, high LDL, non-cardiac ischemia, ar restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive ment and dementia, bone e, 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 agents, antiischemic agents, anti-hypertensive agents, anti-obesity , yslipidemic agents, antihyperlipidemic , 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.
NZ715471A 2011-06-09 2012-06-08 Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of gpr-119 NZ715471B2 (en)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
IN1958CH2011 2011-06-09
IN1958/CHE/2011 2011-06-09
IN2352CH2011 2011-07-11
IN2352/CHE/2011 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
IN3463/CHE/2011 2011-10-07
IN3462CH2011 2011-10-07
IN3462/CHE/2011 2011-10-07
IN82/CHE/2012 2012-01-09
IN82CH2012 2012-01-09
NZ617816A NZ617816B2 (en) 2011-06-09 2012-06-08 Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of GPR-119

Publications (2)

Publication Number Publication Date
NZ715471A NZ715471A (en) 2018-11-30
NZ715471B2 true NZ715471B2 (en) 2019-03-01

Family

ID=

Similar Documents

Publication Publication Date Title
EP2718279B1 (en) Novel compounds as modulators of gpr-119
AU2012267556A1 (en) Novel compounds as modulators of GPR-119
AU2009268527B2 (en) 4-phenoxymethylpiperidines as modulators of GPR119 activity
CA2753434C (en) Soluble guanylate cyclase activators
CA2693169C (en) N-linked heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
KR102566864B1 (en) Aryl- or heteroaryl-substituted benzene compounds
AU2015310662B2 (en) Therapeutic compounds as inhibitors of the orexin-1 receptor
EA037162B1 (en) 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as apj agonists
JP2011528362A (en) Pyridone and pyridazone analogues as GPR119 modulators
KR20140034787A (en) Substituted benzene compounds
CA2888485A1 (en) Phenyl linked quinolinyl modulators of ror.gamma.t
WO2021127337A1 (en) Trpml modulators
JP6883045B2 (en) Halo-substituted piperidine as an orexin receptor regulator
EP3609504A1 (en) Novel oxaborole analogs and uses thereof
NZ715471B2 (en) Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of gpr-119
DK2718279T3 (en) Novel compounds as modulators of gpr-119
AU2013355729A1 (en) Pyridone compound
NZ617816B2 (en) Novel 2,5- or 2,6-disubstituted bicyclic heteroaryl compounds as modulators of GPR-119
WO2022197647A1 (en) Pro drugs of pde10 compounds
WO2023220223A1 (en) Inhibitors of human respiratory syncytial virus and metapneumovirus