BRPI0812185B1 - NEW COMPOUNDS - Google Patents

Abstract

Novel Compounds The present invention discloses novel thyroid-like compounds of formula (I), wherein r1, r2, r2, r4 and z are as defined in the specification, a method for their preparation, composition containing such compounds and use of such compounds and composition as a medicine. furthermore, compounds of formula (I) have significantly low binding affinity for thyroid receptors and thus are considerably devoid of thyrotoxic effects. The invention also relates to the use of the compound of formula (I) for the preparation of a medicament for treating various disease conditions, such as obesity, dyslipidemia, metabolic syndrome and metabolic syndrome associated comorbidities.

Description

COMPOUNDS

FIELD OF THE INVENTION

The present thyroid-like invention of formula as prepared, refers to new compounds

R ¹ ,

R ² , R ³ , R ⁴ and Z do are defined here to a composition compounds and compounds of formula (I) thyroid receptors devoid of effects referring to the use of a diseased medicine, such as metabolic metabolic.

BACKGROUND OF THEN, to a method for its containing such compounds and to the compositions in which they have an affinity for and, thus, thyrotoxic.

formula compound for treatment are therapy use. Still, low connection for considerably

The invention (I) for several such as obesity, dyslipidemia, associated comorbidities

INVENTION also if preparation of conditions syndrome syndrome

Obesity is a condition of an excessive accumulation of energy in the body, in which the reserve of natural energy, stored in the fatty tissue of humans and other mammals, is increased to a point where it is associated with certain health conditions or increased mortality . Obesity develops from an imbalance between energy expenditure and fat intake and the physiological approach to treating obesity is to achieve a negative balance of energy and fat. In fact, weight loss through the diet is effective for most of the 10 patients, although very few manage to maintain their initial weight loss over time.

Obesity has reached epidemic proportions globally, with more than 1.6 billion overweight adults - at least 400 million of them clinically obese - and is a major contributor to the global burden of chronic disease and disability (WHO data sheet, 2006 ). WHO still estimates that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese. At least 20 million children at the age of 5 were overweight globally in 2005.

Obesity and overweight impose a great risk of serious chronic diseases, including type II diabetes, cardiovascular disease, hypertension, dyslipidemia, metabolic syndrome, stroke and certain forms of cancer. The health consequences range from an increased risk of premature death to chronic conditions of global quality of life.

Although obesity has been severe that has long been associated with serious health problems, it has only recently been considered a disease in the sense of being a specific target for medical therapy. Consequently, the development of obesity treatments that target new avenues is an increasing focus for the biopharmaceutical and medical device industries (Melnikova I. &

Wages D Nature Reviews

Drug Discovery (2006); 5: 369-370).

The therapies available for treating obesity have proven to be of limited value because of inadequate efficacy or because of the higher rate of adverse effects and, consequently, there is a need for a better approach with desired efficacy having low side effects.

Many of the compounds that use several new therapeutic approaches, such as NPY receptor antagonists, beta3 agonists, etc., are in an early stage of development. Recently, selective thyroid receptor ligands are also being explored for the treatment of obesity.

Evidence epidemiological data reveal clearly The relationship between the metabolism changed from carbohydrate and lipid, accumulation of fat body and cholesterol and

of subsequent cardiovascular risk diseases, such as atherosclerosis, hypertension, etc. Atherosclerosis, a disease of the arteries, is considered to be a cause of death worldwide. Epidemiological evidence has clearly established hyperlipidemia as a primary risk factor leading to cardiovascular disease due to atherosclerosis. In recent years, the medical fraternity has imposed renewed emphasis on lowering plasma cholesterol levels and, more particularly, low-density lipoprotein cholesterol, as an essential step in preventing cardiovascular disease. Maximum normal limits are now known to be significantly less than what has been appreciated so far. As a result, large segments of populations are now considered to be at a particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension and being male. Cardiovascular disease is more prevalent among diabetic individuals, at least in part because of the existence of multiple independent risk factors in this population. The successful treatment of dyslipidemia in the general population and in diabetic individuals in particular, therefore, is of paramount clinical importance.

Hypertension is a condition that occurs in the human population as a symptom secondary to several other disorders. However, hypertension is also evident in many patients in whom the causal factors are unknown. Although such essential hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been well established. Many patients also show symptoms of high blood pressure in the complete absence of any other signs of illness or disorder. It is known that hypertension can directly lead to various complications, such as heart failure, kidney failure and stroke (cerebral hemorrhage). Hypertension can also contribute to the development of atherosclerosis and coronary heart disease. Hypertension rarely manifests itself, but it usually adds to other cardiovascular risk factors, such as insulin resistance, visceral obesity and dyslipidemia.

These conditions gradually weaken a patient and can lead to death. Although effective blood pressure control is generally considered to be the most important intervention to reduce long-term complications of hypertension, treatment guidelines are now beginning to incorporate the concept of global cardiovascular risk management to improve outcomes for patient.

Metabolic syndrome, a group of metabolic abnormalities, is a combination of insulin resistance, dyslipidemia, obesity and hypertension, which leads to morbidity and mortality through cardiovascular disease (CVD). In the general population, the metabolic syndrome increases the risk of CVD by a factor of 1.65. The presence of metabolic syndrome predicts an increased risk of cardiovascular and total mortality (Eberhard Ritz, Am. J Cardiol (2007); 100 [Supl]: 53-60). In one study, the metabolic syndrome is estimated to be present in more than 20% of the adult population of the U.S. (Young-Woo Park et al., Arch intern Med (2003); 163: 427-436).

In type II diabetes, obesity and dyslipidemia are also highly prevalent and about 70% of people with type 2 diabetes additionally have hypertension, plus / J since leading to increased cardiovascular disease mortality.

Metabolic disorders that affect glucose and lipid metabolism, such as hyperlipidemia, obesity, diabetes, insulin resistance, hyperglycemia, glucose intolerance and hypertension have long-term health consequences, leading to chronic conditions, including cardiovascular disease and premature morbidity . Such metabolic and cardiovascular disorders can be interrelated, aggravating or triggering each other and generating feedback mechanisms, which are still unclear.

As a result, multifactorial intervention is crucial in preventing type II diabetes and reducing the overall cardiovascular risk associated with metabolic syndrome (Richard Ceska, Diabetes and Vascular Disease Research (2007); 4 (suppl): S2-S4). In addition, it has been proven that multifactorial intervention is more beneficial than reducing the individual risk factor for overall reduction in cardiovascular risk. Currently, there is no single treatment that addresses the multiple components of the metabolic syndrome simultaneously.

The thyroid gland, in response to stimulation by

TSH, produces T4,

T3 and rT3. Although T4, T3 and rT3 are generated within the thyroid gland, ο T4 is quantitatively the main by-product.

T3 and rT3 production within the thyroid is regulated in significant amounts converted to deamination or

T4 produced very small and is not considered compared to peripheral production. Ο T4 is

T3 or rT3 or eliminated through decarboxylation. It is estimated that over 70% of the deiodinated in the peripheral tissues in the thyroid is eventually conjugated to form T3 or rT3. Although some T3 is produced, in the thyroid, approximately generated outside the thyroid, of T4 in the liver and kidney.

results in the formation of

80-85% are primarily through

Additional degradation of T3 & rT3 conversion several different diiodothyronines:

3,5-T2, 3,3'-T2 and 3,5'-T2 (Kelly GS. Altern Med Rev (2000);

5 (4): 306-333) main thyroid and behavior

Structurally, all be divided into two unpredictable effect and 5- non-main ring on respectively (Burger,

565). Ο T3 is considered rings, and its the main ring

6th edition, vol hormones i.e., ring

SAR suggests substituents in and non-principal,

3, pages 564 as the most metabolically active thyroid hormone. Various experimental evidence suggests that the main effects of thyroid hormone are mediated by T3. Thyroid hormones affect the metabolism of virtually every cell in the body. At normal levels, these hormones maintain body weight, metabolic rate, body temperature and mood and influence serum low-density lipoprotein (LDL) levels. Thus, in hypothyroidism, there is weight gain, high levels of LDL cholesterol and depression. In excess, in hyperthyroidism, these hormones lead to weight loss, hypermetabolism, decreased serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women and anxiety (W0200703419). The brain is also an important target for thyroid hormone, mainly during development, but also in adult animals. Severe neonatal hypothyroidism is associated with changes in the cerebellum, especially on granular and Purkinje cells, which exhibit impaired differentiation and migration; Purkinje cells are hypoplastic, and granular cells fail to migrate from the outer germ layer to the inner granular layer properly.

Interestingly, it is known that the thyroid hormone known as thyroxine (T4) is converted to thyronine (T3) in human skin by deiodinase I, a selenoprotein.

Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodinase I activity; this reduction in T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of T4 administration. In addition, T3 and T4 have been the subject of several patent publications regarding the treatment of hair loss including, for example, Patent Application Publication No. WO 00/72810 and WO 00/72811.

The use of thyroid hormones is currently limited as a replacement therapy for patients with hypothyroidism. However, replacement therapy, particularly in elderly individuals, is limited by certain adverse effects of thyroid hormones. Some effects of thyroid hormones can be therapeutically useful in disorders unrelated to the thyroid, if the adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, lowering cholesterol to treat hyperlipidemia, relief of depression and stimulation of bone formation in osteoporosis (Liu Ye et al., JMC (2003); 46: 1580-88). Hypothyroidism has been found to be associated with a low level of total cholesterol in the serum, which is attributed to the thyroid hormone increasing the expression of the hepatic LDL receptor and stimulating cholesterol metabolism in bile acids (Abrams JJ et al., J Lipid Res. (1981); 22: 323-38). Hypothyroidism, in turn, has been associated with hypercholesterolemia and thyroid hormone replacement therapy is known to lower total cholesterol (Aviram M. et al., Clin. Biochem. (1982); 15: 62-66; Abrams JJ and collaborators, J. Lipid Res. (1981); 22: 323-38). It has been shown in animal models that thyroid hormone has the beneficial effect of raising HDL cholesterol and improving the ratio of LDL to HDL by increasing the expression of apo A-1, one of the main HDL apolipoproteins (Ness GC. and collaborators, Biochemical Pharmacology, (1998); 56: 121-129; Grover GJ. and collaborators, Endocrinology (2004); 145: 1656-1661; Grover GJ. and collaborators, Proc. Natl. Acad. Sci. USA (2003 ); 100: 10067-10072). Through its effects on LDL and HDL cholesterol, it is possible that thyroid hormones may also decrease the risk of atherosclerosis and other cardiovascular diseases. Additionally, there is evidence that thyroid hormones decrease lipoprotein (a), an important risk factor that is elevated in patients with atherosclerosis (Paul Webb. Expert Opin. Investig. Drugs, (2004); 13 (5): 489 -500; de Bruin et al., J. Clin. Endo. Metab., (1993); 76: 121-126).

Previous attempts to use thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, by cardiovascular toxicity (thyrotoxicosis) (Liu Ye et al., JMC (2003); 46: 1580-88).

Thyroid hormone exerts effects through thyroid receptors. There are two main subtypes of thyroid receptors located within the nucleus (Genomic effect): TRa and TRp. The TRal, TRpi, TR32 isoforms bind to the thyroid hormone and act as ligand-regulated transcription factors. The TRa2 isoform is prevalent in the pituitary and other parts of the CNS, does not bind to thyroid hormones and acts, in many contexts, as a transcriptional repressor. TRal is also widely distributed. The literature suggests many or most of the effects of thyroid hormones on the heart and, in particular, heart rate and rhythm are mediated through the TRal isoform. On the other hand, most of the actions of hormones on the liver and other tissues are mediated more through β-receptor forms (Liu Ye and colleagues,

JMC (2003); 46: 1580-88).

Thyroid hormone has been shown to modulate the behavior of many metabolic pathways potentially relevant to the basal metabolic rate. In general terms, the main candidate mechanisms include decoupling the cellular metabolism from the synthesis of adenosine triphosphate (ATP) or changes in the efficiency of metabolic processes downstream of the mitochondria. Therefore, efforts have been made to synthesize selective beta and / or tissue-selective compounds of thyroid hormone for the treatment of metabolic disorders, which are devoid of thyrotoxic side effects mediated by TRa receptors.

Thus, in an effort to make specific TRp thyroid ligands, many researchers have attempted to synthesize thyroid mimetics in which the effect of various main and non-main rings and the substituents on them are studied, as disclosed in US20050085541, US20040039028, WQ2007003419 , W02006128056,

W0200709913, US20010051645, US20020049226 and US20030040535, all of which are incorporated herein by reference.

Until recently, it was discovered that ο T3 is more biologically active than T4 ο and is currently believed to be the predominant activator of the thyroid hormone receptors (Burger, 6th edition, vol. 3, pages 564-565). In the last decade or so, evidence has accumulated that other naturally occurring iodothyronines other than T3 have biological effects. Among these, 3,5 diiodothyronine appears to be responsible for the rapid, short-term effects on cell oxidative capacity and respiration rate through direct interaction with mitochondrial binding sites. The accumulated evidence allows the conclusion that the action of T2 does not simply imitate that of T3, but rather, it is a specific action

exercised through mechanisms that are independent of those triggered by T3 through radio receivers

thyroid hormone (A. Lombardi. Immun Endoc and Metab

Agents in Med Chem (2006); 6: 255-65; W0200509433).

The growing body of evidence now suggests that 3,5 diiodothyronine may induce metabolic inefficiency, possibly by stimulating energy loss via a mechanism involving the mitochondrial apparatus rather than nuclear receptors. Such action of T2 can potentially result in reduced adiposity and less body weight gain without inducing a clinical syndrome related to the thyrotoxic state, by increasing the influx of fatty acid into the mitochondria and fatty acid oxidation (A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6: 255-65; Horst C, Biochem J. (1989); 261: 945-950). From a clinical point of view, a scenario involving a high level of fatty acid oxidation, reduced fat storage, reduced serum triglycerides and cholesterol levels, reduced liver steatosis, reduced body weight gain without a reduction in calorie intake / fat is an attractive prospect for intractable obesity (A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6: 255-65).

W02005 / 009433 discloses the composition of 3.5 T2 in therapeutically effective doses mainly for use in obesity, fatty liver and dyslipidemia. In summary, thyroid hormones and other iodothyronines, together or alone, influence the metabolism of virtually every cell in the body. These hormones play an important physiological role, such as maintaining body weight, metabolic rate, body temperature and mood and influencing serum low-density lipoprotein (LDL) levels, etc. Thus, thyroid hormones (T4, T3) can cause weight loss via an increased metabolic rate and a reduction in LDL cholesterol through an over-regulation of LDL receptors and increased cholesterol metabolism. However, thyroid hormone does not have a sufficiently wide therapeutic window, particularly with regard to cardiac acceleration, to be useful for the treatment of disorders such as obesity and lipid disorders. Very recently, it has been reported that selective TRp agonists could be explored as a therapeutically effective way to decrease plasma weight and cholesterol without stimulating harmful cardiac effects. However, recently it was also discovered that the selective TRP agonist induces a proliferative response, in order to lead to the proliferation of hepatocytes and also induced the proliferation of pancreatic acinar cells (Amedeo Columbano. Endocrinology (2006); 147 (7): 3211-8). There are also reports that ο T3 increases the consumption of low-dose food in animals, regardless of its nuclear effects (Wing May Kong et al., Endocrinology (2004); 145: 5252-5258) and the increase in energy intake was also shown for T2 (Horst et al., J Endocrinology (1995); 145: 291-297) which can be compensatory in the treatment of obesity.

Thus, there is a need for new thyroid-like compounds which are useful for the treatment of metabolic disorders, such as obesity, insulin resistance, diabetes, dyslipidemia, fatty liver, metabolic syndrome and disorders of altered thyroid function, without having effects undesirable effects, such as thyrotoxicosis and increased food consumption.

Consequently, the inventors of the present invention have discovered new thyroid-like compounds which are expected to demonstrate a utility for the treatment or prevention of diseases or disorders associated with inappropriate thyroid hormone activity, for example: 1) the condition associated with a disease or disorder associated with excessive fat accumulation, altered mitochondrial function,

2) obesity, 3) lipid disorders caused by an imbalance in blood or tissue lipid levels, such as dyslipidemia, atherosclerosis, 4) impaired glucose tolerance, 5) type II diabetes, 6) replacement therapy, 7) depression , 8) cardiovascular diseases and 9) skin disorders and significantly devoid of undesirable effects, such as thyrotoxicosis and increased food consumption.

W02007027842 refers to anilinopyrazole compounds useful for the treatment of diabetes and related disorders. US2004110816 discloses certain pyrazole derivatives reverse transcriptase inhibitors useful for the treatment of HIV and W09716422 discloses certain chromanyl and thiocromanyl compounds having retinoid-like activity.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 provides a graphical representation of the effect of test compound B on OGTT (oral glucose tolerance test).

SUMMARY OF THE INVENTION

One embodiment of the present invention is a compound of formula (I):

on what:

R ¹ and R ³ are the same or different and are independently selected from H, (Ci-Cô) alkyl, (C ₃ C ₇ ) cycloalkyl, halo, CN, CF ₃ , -O- (Ci-C ₆ ) alkyl, -CO ₂ - (C _x C ₆ ) alkyl, COOH, -CONH- (C 1 -C ₆ ) alkyl, -CONH-aryl, -NH ₂ ,

CONH-R ⁶ , -CONR ⁵ ,

-Ci-C ₃ alkyl-aryl, - (C _x -C ₃ ) alkyl-R ⁶ , -NH (C1-C6) alkyl,

R ⁷ , where

C 1 -C ₆ alkyl and

C ₃ -C ₇ cycloalkyl are optionally substituted by one or more substituents selected from (C 1 -C ₆ ) alkyl, halo, cyano, -OH, oxo,

COOH, -O- (C1-C ₆ ) alkyl, -0-benzyl, -COO- (C1-C ₆ ) alkyl, CONH- (C1-Cg) alkyl, -CONR ⁵ , -CONH-aryl, -CONH- heteroaryl or -CH ₂ NR ⁵ ;

R ² is selected from (Ci-Cg) alkyl, (C ₃ C ₆ ) cycloalkyl, (C ₃ -C ₆ ) alkenyl, (C ₃ -Cg) alkynyl, -C (O) (C1-C3) alkyl-COOH , - (Ci ~ C ₃ ) alkyl-COOH, -C (O) - (Ci ~

C ₃ ) alkyl-COO-alkyl, -C (O) -C (O) O- (C 1 -C ₆ ) alkyl, -C (O) -

optionally

more substituents

selected from perhaloalkyl, Oxo,

C (O) OH, -C (O) -O- (C _x -C ₃ ) alkyl, -C (O) -O- (C 1 -C ₃ ) alkyl-aryl,

-C (O) -O- (C1-C3) alkyl-R ⁶ , -CONH ₂ , -CONH (C 1 -C ₃ ) alkyl,

C (O) NH-aryl, -C (O) NH-R ⁶ , -CONR ⁵ -CONHNH2, -C (= NH) NH- (C1-C6) alkyl, -C (= NH) NH2, C (= NH) NHOH, -C (O) -R ⁸ , C (O) NHSO2 (C _x C ₆ ) alkyl, -C (O) NHSO ₂ -aryl, -C (O) NHOH, -C (O) NHSO ₂ -R ⁶ , C (O) NHNH- (C 1 -C ₆ ) alkyl,

-C (O) NHNH-aryl,

-CONH- (C1 ₂ ) alkyl-aryl, -C (O) NH- (C1-C ₂ ) alkyl-R ⁶ , -CH2NR ⁵ , -NH2,

C ₃ ) alkyl,

-NHC (O) -aryl, -NHC (O) - (C 1 -C ₃ ) alkylaryl,

NHC (O) -R ⁶ ,

C ₆ ) alkyl,

-NHSO ₂ (C 1 -C ₆ ) alkyl, -NH-SO ₂ -aryl, -NH-SO ₂ -R ⁶ , halo, cyano, -OH, -O- (C 1 -C ₆ ) alkyl, -O-aryl , -0 heteroaryl, -O- (C1-C ₂ ) alkyl-aryl, -SO ₃ H, -SO ₂ NH-aryl, SO ₂ NH-R ⁶ or -SO2NH- (Ci-Ce) alkyl, R ⁶ or R ⁷ ;

R ⁵ , together with the nitrogen atom to which it is attached, forms a saturated or unsaturated ring of (C ₃ -C ₆ ) elements, which may also contain 1-2 10 heteroatoms selected from O, N or S and the which can be optionally substituted by one or more substituents selected from oxo, -COOH, halo, -OH, -O- (C 1 -C ₆ ) alkyl, or - (C 1 ₆ ) alkyl;

R ⁶ is selected from phenyl or heteroaryl of 5-8 elements containing 1-4 heteroatoms selected from O, N or

S, wherein said heteroaryl or phenyl ring is optionally substituted by one or more substituents selected from halogen, -OH, -O- (C 1 -C ₆ ) alkyl, perhaloalkyl, - (C 1 -C ₆ ) alkyl, - ( C3-C6) cycloalkyl,

SO ₂ (C 1 -C ₆ ) alkyl, cyano, -COOH, -C (O) O- (C 1 -C ₆ ) alkyl,

C (O) O-CH ₂ -aryl, -C (O) 0-aryl, -CONH (C1-C3) alkyl, nitro, NH ₂ , -NH- (C 1 -C ₆ ) alkyl, -NHC (O) - _(Ci-C,) alkyl, -NHC (O) aryl, -NHSO ₂ (C ₆ -C?) alkyl, -CONH _2, -SO ₂ - _(C-C6) alkyl, NHSO ₂ (C -C ) alkyl or -COR ⁸ ;

R ⁷ is a 3-6 element heterocyclic ring containing 1-4 heteroatoms selected from O, N or S and said heterocyclic ring is optionally substituted by one or more substituents selected from oxo, halogen, -O- (Ci ~ C ₆ ) alkyl, -OH, -CF3, (C 1 -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, cyano, -COOH, -C (O) O- (Ci-Οδ) alkyl, -C (O) O-CH ₂ -aryl,

C (O) O-aryl, -NH ₂ , -NH- (C 1 -C ₆ ) alkyl, -NHC (O) - (C 1 -C ₆ ) alkyl, -NHC (O) -aryl, -CONH ₂ , - SO ₂ -aryl- (C _x Cô) alkyl, -SO ₂ - (C 1 -C 6) alkyl, -NHSO ₂ (C 1 -C ₆ ) alkyl or COR ⁸ ;

R ⁸ is an amino acid which is linked through its nitrogen atom;

Z = O, CH ₂ or NH;

R ⁴ is selected from P, Q or T:

Ρ

R ⁹ is selected from -OH, -O-alkyl, -OSO3H, halogen, -C (0) 0- (C1-C6) alkyl, -C (O) NHR ⁸ , -OC (O) - (C1C5) alkyl , -O-perhaloalkyl, -0C (0) 0- (0χ-0 ₆ ) alkyl,

CONR ⁵ , -NHCO- (C 1 -C ₆ ) alkyl, -NHC (0) -O- (C 1 -C ₆ ) alkyl,

NHC (0) -0-aryl,

-NHSO2- (C1-C ₆ ) alkyl, -NHSO ₂ -aryl,

NHCONR ⁵

alkoxy, aryloxy, -NHCO- (Οχ-Οβ) alkyl, -NHSO2 _(Ci-C6) alkyl or -NH-S02-aryl;

R ¹¹ is -CO- (Οχ-Οβ) alkyl, -S0 ₂ - (Cx ~ C ₆ ) alkyl or -SO ₂ aryl;

G 'is selected from H, halogen or (Οχ-Οβ) alkyl;

G is selected from hydrogen, (Οχ-Οε) alkyl, (C3C ₆ ) cycloalkyl, aryl, halogen, perhaloalkyl, CN, CHO,

- (C1-C3) alkylaryl, - (C1-Cg) alkyl-0- (Cx-Cg) alkyl, -CH ₂ R ⁹ ,

-CH ₂ aryl, -CH ₂ NR ⁵ , -COOH, -C (O) O (C 1 -C 6) alkyl, -CONH- (C 1 -C 6) alkyl, -CONR ⁵ , -SO2NR ⁵ , -SO ₂ NH- (C 1 -C ₆ ) alkyl, -SO ₂ NHaryl;

n can be one or two;

including their pharmaceutically acceptable salts and their hydrates, solvates, atropisomers, regioisomers, enantiomers, diastereomers, tautomers, polymorphs and prodrug thereof, provided that:

when R ⁴ is Q, then

R ² is other than R ⁶ and R ⁷ .

In another embodiment, the present invention relates to a compound as above, however, only including pharmaceutically acceptable salts thereof.

In another embodiment, the present invention includes the use of a compound of formula (IA) for the treatment of an unhealthy condition associated with inappropriate thyroid hormone activity selected from obesity, insulin resistance, dyslipidemia, metabolic syndrome, type II diabetes , replacement therapy in elderly individuals with hypothyroidism, depression, cardiovascular disease and skin disorders by administering a therapeutically effective amount of a compound to a living mammalian organism, including a human:

4

and are independently selected from H, (C 1 -C ₆ ) alkyl, (C ₃ Cg) alkyl, COOH,

-CONH- (C 1 -C ₆ ) alkyl, -CONH-aryl, -NH ₂ ,

CONH-R ⁶ , -CONR ⁵ ,

-NHaryl, -NH-SO ₂ - (C 1 -C ₆ ) alkyl, -CH ₂ -NH (C 1 -C ₆ ) alkyl, —CH ₂ —O— (Cx-C ₆ ) alkyl, -CxC 3 alkyl-NR ⁵ , R ⁶ ,

R ⁷ , where Cx-C ₆ alkyl and C ₃ -C7cycloalkyl is optionally substituted by one or more substituents selected from cyano, -OH, oxo,

-COOH, -O- (CiC ₆ ) alkyl,

-O-benzyl, -COO- (Cx-Cg) alkyl, -CONH- (CxC ₆ ) alkyl,

-CONR ⁵ , -CONH-arila,

-CONH-heteroaryl or

CH ₂ NR ⁵ ;

R ² selected from (Ci-Cê) alkyl, (C ₃ Cg) cycloalkyl, (C3-C6) alkenyl, (C ₃ -C ₆ ) alkynyl,

-C (O) (C1-C3) alkyl-COOH,

- (C1-C3) alkyl-COOH,

C ₃ ) alkyl-COO-alkyl, -C (O) -C (O) O- (Cx-Cê) alkyl

-C (O) 15 (C _x -C ₃ ) alkyl-NH- (C _x -C ₆ ) alkyl, -C (O) -O- (C _x -Cg) alkyl, C (O) NR ⁵ , - C (O) NH- (Ci-Ce) alkyl, -C (O) - (Cx-C3) alkylaryl, C (O) - (Cx-C3) alkyl-R ⁶ , R ⁶ , R ⁷ , where the said (CxC ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) alkenyl, (C ₃ C ₆ ) alkynyl are optionally substituted by one or more substituents selected from perhaloalkyl, Oxo, -C (O ) OH, -C (O) -O- (C _X _C ₃ ) alkyl, -C (O) -O- (C _x -C ₃ ) alkyl-aryl, -C (O) O- (Ci-Cs) alkyl-R ⁶ , -CONH2, -CONH (Cx-C3) alkyl, -C (O) NHaryl, -C (O) NH-R ⁶ , -CONR ⁵ -CONHNH2, C (= NH) NH- (C _x -C ₆ ) alkyl, -C (= NH) NH ₂ , C (= NH) NHOH, -C (O) -R ⁸ , C (O) NHSO2 (C1-C6) alkyl, -C (O) NHSOz- aryl, -C (O) NHOH, -C (O) NHSO2-R ⁶ , -C (O) NHNH- (CxC ₆ ) alkyl, -C (O) NHNH-aryl, -CONH- (C _x -C ₂ ) alkyl-aryl,

C (O) NH- (C _x -C ₂ ) alkyl-R ⁶ , -CH2NR ⁵ , -NH2, -NH- (C _x -C ₆ ) alkyl, NH-C (O) -O- (C1-C3 ) alkyl, -NH-C (O) - (C _x -C ₃ ) alkyl, -NHC (O) aryl, -NHC (O) - (C _x -C ₃ ) alkylaryl, -NHC (O) -R ⁶ , -NH-C (O) NR ⁵ , -NH-C (O) NH-aryl, -NHC (O) NH- (Cx-C6) alkyl, -NHSO2 (CxC6) alkyl, -NH-SO2-aryl, -NH-SO2-R ⁶ , halo, cyano, -OH, -O (Cx-C ₆ ) alkyl, -O-aryl, -O-heteroaryl, -O- (C _x -C ₂ ) alkylaryl, -SO ₃ H, -SO ₂ NH-aryl, -SO ₂ NH-R ⁶ or -SO ₂ NH- (C _x C ₆ ) alkyl, R ⁶ or R ⁷ ;

R ⁵ , together with the nitrogen atom to which it is attached, forms a ring of elements (C ₃ -C ₆ ) saturated or unsaturated, which may also contain 1-2 heteroatoms selected from O, N or S and which it can be optionally substituted by one or more substituents selected from oxo, -COOH, halo, -OH, -0- (C1-C6) alkyl or - (Cx-C6) alkyl;

R ⁶ is selected from phenyl or heteroaryl of 5-8 elements containing 1-4 heteroatoms selected from 0, N or

S, wherein the optionally referred heteroaryl or phenyl ring is replaced by one or more substituents selected from perhaloalkyl, ~ (C ₁ -C ₆ ) alkyl, - (C ₃ -C ₆ ) cycloalkyl, cyano, -COOH, -C (0 ) 0- (Cx-Cg) alkyl,

C (0) 0-CH ₂ -aryl, -C (0) 0-aryl, -CONH (C1-C3) alkyl, nitro,

NH ₂ , -NH- (C 1 -C ₆ ) alkyl, -NHC (O) - (C 1 -C ₆ ) alkyl, -NHC (O) aryl, -NHSO ₂ (C 1 -C ₆ ) alkyl, -CONH ₂ , -S0 ₂ - (C 1 -C ₆ ) alkyl, NHSO 2 (C 1 -C ₆ ) alkyl or -COR ⁸ ;

R ⁷ is a 3-6 element heterocyclic ring containing 1-4 heteroatoms selected from O, N or S and said heterocyclic ring is optionally substituted by one or more substituents selected from oxo, halogen, -0- (Ci ~

C ₆ ) alkyl, -OH, -CF3, (C 1 -C ₆ ) alkyl, (C ₃ -Cg) cycloalkyl, cyano, -COOH, -C (0) 0- (C 1 -C 6) alkyl, -C (0 ) 0-CH ₂ -aryl,

C (O) 0-aryl, -NH ₂ , -NH- (C _x -C ₆ ) alkyl, -NHC (O) - (CiC ₆ ) alkyl, -NHC (0) -aryl, -CONH ₂ , -S0 ₂ aryl (C 1 -C 6) alkyl, SO ₂ - (C _x -C ₆ ) alkyl, -NHSO ₂ (C _x -C ₆ ) alkyl or -COR ⁸ ;

nitrogen atom;

selected, CH ₂ or NH;

R ⁸ is an amino acid

selected

-O-alkyl,

-OSO ₃ H,

C (O) O- (Ct-Cs) alkyl, -C (O) NHR ⁸ , -OC (O) - (Ci-

halogen,

Perhaloalquila -O-, -OC (O) O- _(Ci-C6) alkyl,

CONR ⁵ , -NHCO- (C 1 -C ₆ ) alkyl, -NHC (O) -O- (C 1 -C ₆ ) alkyl,

NHC (O) -O-aryl, -NHSO ₂ - (C 1 -C ₆ ) alkyl, -NHSO ₂ -aryl,

NHCONR ⁵ or:

R ¹⁰ alkoxy,

is selected

Halogen, aryloxy, -NHCO- (C 1 -C ₆ ) alkyl,

C ₆ ) alkyl or -NH-SO ₂ -aryl;

(Ci-C ₆ ) alkyl, —NHSO ₂ - (CiR ¹¹ is

Cg) alkyl or -SO ₂ -aryl;

G 'is selected from H, halogen or (Οχ-Οθ) alkyl;

G is selected from hydrogen, (Ci ~ C _s ) alkyl, (C ₃ Cô) cycloalkyl, aryl, halogen, perhaloalkyl, CN, CHO, - (C1-C3) alkylaryl, - (Ci-C ₆ ) alkyl-O- (C 1 -C ₆ ) alkyl, -CH ₂ R ⁹ , -CH ₂ aryl, -CH ₂ NR ⁵ , -COOH, -C (O) O (C 1 -C 6) alkyl, -CONH- (CiC ₆ ) alkyl, -CONR ⁵ , -SO2NR ⁵ , -SO2NH- (C 1 -C ₆ ) alkyl, -SO ₂ NHaryl;

n can be one or two;

including their pharmaceutically acceptable salts and their hydrates, solvates, atropisomers, regioisomers, enantiomers, diastereomers, tautomers, polymorphs and prodrugs thereof.

In another embodiment, the present invention includes synthetic intermediates that are useful in the preparation of the compounds of formula (I) and a process for the preparation of such intermediates.

Another embodiment of the present invention is a method for preparing a compound of formula (I), as described herein in Schemes 1, 2 and 3.

Another embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I) optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Another embodiment of the present invention is a method for treating obesity by administering a compound of formula (I) to a mammal that needs it.

Another embodiment of the present invention is a method of relieving insulin resistance and / or preventing or delaying the progression of diabetes by administering a compound of formula (I) to a mammal that needs it.

Another embodiment of the present invention is a method for preventing and treating dyslipidemia by administering a compound of formula (I) to a mammal that needs it.

Another embodiment of the present invention is a method for preventing and treating metabolic syndrome by administering a compound of formula (I) to a mammal that needs it.

Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for treating obesity.

Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament to relieve insulin resistance and / or prevent or delay the progression of diabetes.

Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for the prevention and treatment of dyslipidemia.

Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for the prevention and treatment of metabolic syndrome.

In yet another embodiment, the present invention provides a method of treating an unhealthy condition associated with inappropriate thyroid hormone activity without significantly affecting appetite by administering a therapeutically effective amount of a thyroid-like compound.

In yet another embodiment, the present invention provides a method of treating an unhealthy condition associated with inappropriate thyroid hormone activity without significantly affecting appetite by administering the therapeutically effective amount of the compound of formula (IA).

DETAILED DESCRIPTION OF THE INVENTION

Definitions.

The following definitions apply to terms as used throughout this specification, unless otherwise limited in specific cases.

The term thyroid-like compound (s), as used here, denotes compounds structurally similar to diiodothyronine, which probably act in a similar way to thyroid hormone, but are significantly devoid of the toxic effects of thyroid hormone.

The term thyroid receptor ligand or thyroid ligand, as used here, encompasses any substance which can bind to a thyroid receptor. The ligand can act as an antagonist, agonist, partial antagonist or partial agonist.

The term thyroid receptor, as used here, represents a molecule that receives a thyroid hormone and allows it to anchor over the nucleus of a cell and to function as a hormone-activated transcription factor and act through modulation of the expression of genes. THRs bind to DNA in the presence of a hormone, usually suppressing gene transcription. Hormonal binding involves a conformational change in the receptor that causes it to activate transcription.

use of the terms one and one and the and and similar referents in the context of describing the invention (especially in the context of the following claims) must be constructed to encompass the singular and the plural, unless otherwise indicated here or clearly contradicted by the context.

The term compound, used here, refers to any compound covered by the generic formula disclosed here. The compounds described herein can contain one or more double bonds and, therefore, can exist as stereoisomers, such as double bonded isomers (i.e., geometric isomers). Consequently, the chemical structures represented here encompass all possible stereoisomers of the compounds illustrated, including stereoisomerically pure form (e.g., geometrically pure) and stereoisomeric mixtures. The compounds can also exist in various tautomeric forms, including the enol form, the keto form and mixtures thereof. Consequently, the chemical structures represented here encompass all possible tautomeric forms of the compounds illustrated. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include, but are not limited to, Η, H, C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O. The compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses considered herein and are intended to be within the scope of the present invention.

The term regioisomer is a term known to those skilled in the art and is defined in textbooks, such as Organic Synthesis, Smith, M., (McGraw Hill), which defines a regioisomer as two or more molecules with the same empirical formula, but with a different fixation of the atoms (different connectivity).

Atropisomer, as used here, refers to a stereoisomer where the chirality element is located on a plane or molecular axis.

Furthermore, it should be understood that when partial structures of the compounds are illustrated, a dash (-) or indicates the point of attachment of the partial structure to the rest of the molecule. The nomenclature of the compounds of the present invention, as indicated here, is according to the CDM

ISIS® Draw Version 2.2.

Pharmaceutically acceptable salts include derivatives of the disclosed compounds, wherein the parent compound is modified by making non-toxic acid or base addition salts thereof and further refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues, such as amines; alkaline or organic addition salts of acid residues, such as carboxylic acids; and the like and combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable salts include non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts, such as sodium salt, potassium salt, cesium salt and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt and the like and combinations comprising one or more of the preceding salts. Pharmaceutically acceptable organic salts include salts prepared from organic acids, such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxylic, phenylacetic, glutamic, benzoic, salicylic, benzoic, salicylic, benzoic, salicylic. , mesyl, esyl, besyl, sulphanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, disulfonic, oxalic, isethionic ethane, HOOC - (CH ₂ ) _n ~ ^_ COOH where n is 0-4 and the like; organic amine salts, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'dibenzylethylenediamine salt and the like; and salts of amino acids, such as arginate, asparginate, glutamate and the like; and combinations comprising one or more of the preceding salts.

The term alkyl, used alone or in attachment with another group, refers to a saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms and which is unsubstituted or optionally substituted. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that group can contain. For example, a C 1 -C ₆ alkyl will refer to any alkyl group containing one to six carbons in the structure. Alkyl may be a straight chain or a branched chain.

The term alkenyl, used alone or in connection with another group, refers to an unsaturated aliphatic hydrocarbon radical (=) having the indicated number of carbon atoms and which is unsubstituted or optionally substituted. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that group can contain. For example, a C ₃ -C ₆ alkenyl will refer to any alkenyl group containing three to six carbons in the structure. Alkenyl can be straight or branched.

The term alkynyl, used alone or in connection with another group, refers to an unsaturated aliphatic hydrocarbon radical (ξ) having the indicated number of carbon atoms and which is unsubstituted or optionally substituted. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that group can contain. For example, a C3-C6 alkynyl will refer to any alkynyl group containing three to six carbons in the structure. Alquinyl can be straight or branched.

The term cycloalkyl refers to a saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms and which is unsubstituted or optionally substituted. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that group can contain. For example, a C ₃ -Cs cycloalkyl will refer to any cycloalkyl group containing three to six carbons in the structure.

0 term ari there if refers to a group aromatic, per example, the what is one system of ring monocyclic or bicyclic with 6 The 10 elements, the what Can be no

replaced or replaced. Representative aryl groups can be phenyl, naphthyl and the like. When said ring is replaced, the substituents are selected from halogen (for example, F, Cl, Br, I), hydroxy, alkoxy, nitro, carboxylic acid, CF ₃ , NHSO ₂ alkyl, NHCOalkyl, alkyl, alkenyl, alkynyl, cycloalkyl and acyl.

The term heteroaryl, as used here, refers to an aromatic group, for example, which is a 5- to 10-element monocyclic or bicyclic ring system, which has a ring containing at least one heteroatom and at least one carbon. The heteroaryl group can be attached to any available nitrogen or carbon atom in any ring.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl furanyl, thienyl, oxadiazolyl, tetrazolyl, triazolyl, pyridyl, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, cinolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopiridinyl and the like.

The term alkoxy refers to an alkyl group, as defined above, attached to the precursor molecular moiety through an oxygen bridge.

Representative alkoxy radicals include methoxy, ethoxy, npropoxy, n-butoxy, n-pentyloxy, n-hexyloxy, sec-butoxy, tert-butoxy, tert-pentyloxy and the like.

As used here, the term halo or halogen denotes a fluorine, chlorine, bromine or iodine group.

All substituents (R ¹ , R ² ....) And their other substituents described here can be attached to the main structure in any heteroatom or at least which results in the formation of a stable compound.

As used herein, the term mammal means a human or animal, such as monkeys, primates, dogs, cats, horses, cows, etc.

As used here, the term polymorphs refers to compounds having the same chemical formula, the same type of salt and having the same hydrate / solvate form, but having different crystallographic properties.

As used on here, the term hydrates refers to one compound having a number of water molecules attached The molecule. As used on here, the term solvates refers to one

compound having a series of solvent molecules attached to the molecule.

The present invention also encompasses prodrugs of compounds of the invention, that is, secondary compounds which are converted to the first compounds in vivo.

In vivo cleavable esters are just one type of prodrug of the precursor molecule. An in vivo hydrolyzable (or cleavable) ester of a compound of the present invention that contains a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the precursor acid.

Pharmaceutically acceptable esters for carboxy include

Ci-Cg alkoxymethyl esters, for example, methoxymethyl, Ci-Cg alkanoyloxymethyl ester, for example, pivaloyloxymethyl;

ftalidyl esters;

C ₃ ^- Cg cycloalkoxycarbonyloxy-C 1 -C 6 alkyl esters, for example,

1-cyclohexylcarbonyloxyethyl; 1,3dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3, 3dioxolen-2-onylmethyl;

Ci-Ce alkoxycarbonyloxyethyl esters, for example,

1-methoxycarbonyloxymethyl; and can be formed on any carboxy group in the compounds of the present invention.

In the context of the present specification, the term treat or treatment also includes prophylaxis, unless there are specific indications to the contrary.

The term treat or treatment, within the context of the present invention, further encompasses administering a therapeutically effective amount of a compound of the present invention to alleviate a pre-existing sick, acute or chronic condition or condition. This definition also covers prophylactic therapies for preventing the reoccurrence of a condition and ongoing therapy for chronic disorders.

The phrase a therapeutically amount means the amount of a compound which, effective when administered to a patient for treating a disease, is sufficient to carry out such treatment for the disease. The therapeutically effective amount will vary depending on the compound, mode of administration, the disease and its severity and age, weight, etc. of the patient to be treated.

When used, the terms understand and comprising denote include and including, but not limited to. Thus, other ingredients, vehicles and additives may be present.

In one embodiment, the present invention provides a compound of formula (I):

I where, R ¹ , R ² , R ³ , Z and R ⁴ are as defined above.

The invention also provides pharmaceutically acceptable salts and their hydrates, solvates, atropisomers, regioisomers, enantiomers, diastereomers, tautomers, polymorphs and prodrugs thereof.

A preferred embodiment of the present invention is a compound of formula (I) mentioned above, wherein R ¹ , R ² , R ³ and Z are as defined above and R ⁴ is selected from P or T.

Pharmaceutical Composition.

In another embodiment of the invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of one or more of a compound of formula (I). Although it is possible to administer a therapeutically effective amount of compounds of formula

(I) individually or in combination directly without any formulation, is common practice administer the compounds in the form in pharmaceutical dosage forms

comprising pharmaceutically acceptable excipient (s) and at least one active ingredient. These dosage forms can be administered via a variety of routes, including oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, pulmonary, etc.

Oral compositions can be in the form of a solid or liquid dosage form. Solid dosage forms may comprise pellets, envelopes, sachets or discrete units, such as tablets, multi-particle units, capsules (soft & hard gelatine), etc. Liquid dosage forms can be in the form of elixirs, suspensions, emulsions, solutions, syrups, etc. The composition intended for oral use can be prepared according to any method known in the art for the manufacture of the composition of such pharmaceutical compositions. They may contain, in addition to active ingredients, excipients, such disintegrating agents, binders, such as diluents, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavors, sweeteners, colors, etc.

Some examples of suitable excipients include lactose, cellulose and its derivatives, such as microcrystalline cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, phosphate, dicalcium, mannitol, starch, gelatin, polyvinyl pyrrolidone, various gums, such as acacia, tragacanth, xanthan, alginates and their derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide, mineral oil, glyceryl monostearate, glyceryl beate, sodium starch glycolate, cross-linked povidone, cross-linked carboxymethyl cellulose, various emulsifiers, such as polyethylene glycol, sorbitol, fatty acid, esters, polyethylene glycol alkyl ethers, sugar esters, polyoxyethylene / polyoxypropylene block copolymers, polyethoxylated fatty acid monoesters, diesters and mixtures thereof.

Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle, such as water for injection, N-methyl-2-pyrrolidone, propylene glycol and other glycols, alcohols, an oil naturally occurring vegetable, such as sesame oil, coconut oil, peanut oil, cottonseed oil or a synthetic fatty carrier, such as ethyl oleate or the like. Buffers, anti-oxidants, preservatives, complexing agents, such as cellulose derivatives, peptides, polypeptides and cyclodextrins and the like can be incorporated, as required.

The dosage form can have a slow, delayed or controlled release of active ingredients, in addition to dosage forms with immediate release.

The amount of active ingredient which, to obtain a therapeutic effect, of course, will be required will vary with the particular compound, the route of administration, the individual being treated and the particular disorder or disease being treated. The compounds of the invention can be administered orally or parenterally in a dose of

0.001 to 1500 mg / kg per day, preferably from 0.01 to 1500 mg / kg per day, more preferably from 0.1 to 1500 mg / kg per day, more preferably from 0.1 to 500 mg / kg per day . The dose range for adult humans is generally 5 mg to 35 g per day and preferably 5 mg to 2 g per day. Tablets or other presentation dosage forms provided in separate units may conveniently contain an amount of compounds of the invention which is effective at such a dosage or as a multiple thereof, for example, units containing 5 mg to 500 mg.

Although a compound of the invention can be used as the only active ingredient in a drug, it is also possible that the compound is used in combination with one or more other active agents. These other active agents can be other compounds according to the invention or they can be different therapeutic agents, for example, an anti-obesity agent or an anti-dyslipidemic agent or other pharmaceutically active agent.

The compounds of the present invention can be used in combination with one or more other suitable therapeutic agents selected from the group consisting of hypolipidemic agents, anti-atherosclerotic agents, anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, anti-anxiety agents , anti-depressants, anti-hypertensive agents, cardiac glycosides, appetite suppressants, growth-promoting agents, agents for the treatment of skin disorders, bone resorption inhibitors and thyroid mimetics.

Examples of hypolipidemic agents suitable for use in combination with the compounds of the present invention include, but are not limited to, an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthase inhibitor, a fibric acid derivative, a ACAT inhibitor, lipoxygenase inhibitors, cholesterol absorption inhibitor, Na + ileal / bile acid co-transporter inhibitor, LDL receptor super-regulators, cholesteryl ester transfer protein (CETP) inhibitor, a trap of bile acid, a peroxisome-activator-proliferator-receptor-agonist (PPAR) alpha, a peroxisome-activator-proliferator-receptor (PPAR) -delta agonist, a peroxisome-activator-proliferator-receptor (PPAR) agonist - gamma / delta, a double agonist of the peroxisome activator-proliferator receptor (PPAR) -alpha / delta and / or nicotinic acid and its derivatives or a pharmaceutically acceptable salt thereof.

Examples of antidiabetic agents suitable for use in combination with the compounds of the present invention include, but are not limited to, a biguanide, such as metformin, phenformin, a sulfonylurea, such as gliclazide, an alpha glycosidase inhibitor, an agonist of PPARy such as thiazolidinediones, a PPARa agonist such as fibric acid derivatives, an alphaamylase inhibitor, a fatty acid oxidation inhibitor, an A2 antagonist, a PPARô agonist or antagonist, a PPARa / γ double agonist, an aP2 inhibitor, a dipeptidyl peptidase IV (DP4) inhibitor, an SGLT2 inhibitor, a glycogen phosphorylase inhibitor, a glucagon-like peptide-1 (GLP-1) and its analogs, a glycokinase activator, an agonist VPAC2 receptor, a PTP-1B inhibitor (protein tyrosine phosphatase-ΐβ), an Ιΐβ-HSD inhibitor (Ιΐβ-hydroxy-steroid dehydrogenase 1), meglitinide, a glucocorticoid (GR) antagonist, as well as insul or a pharmaceutically acceptable salt thereof.

Examples of anti-osteoporosis agents suitable for use in combination with the compounds of the present invention include, but are not limited to, alendronate, risedronate

PTH, fragment of

PTH, raloxifene calcitonin, RANK ligand antagonists, calcium perception receptor antagonists, TRAP inhibitors, selective estrogen receptor modulators (SERM) and AP-1 inhibitors or a pharmaceutically acceptable salt thereof.

Examples of anti-obesity agents suitable for use in combination with the compounds of the present invention include, but are not limited to, a transporter inhibitor.

5HT a transporter inhibitor

NE (norepinephrine), a reverse antagonist / agonist of

CB-1 (cannabinoid-1 receptor), a ghrelin antagonist, an H3 antagonist / inverse agonist (histamine H3), an NPY1 antagonist (neuropeptide Y1), an NPY2 agonist (neuropeptide Y2), an antagonist of

NPY5 (neuropeptide

Y 5), a leptin or its derivative, an opioid antagonist, an orexin antagonist, a BRS3 agonist (subtype 3 bombesin receptor), a CCK-A (cholecystokinin-A) agonist, a CNTF (neurotrophic factor a derivative of

CNTF, an agonist of growth hormone secretagogue), an agonist of

5HT2c (receiver

Serotonin 2c), a Mc3r agonist (melanocortin receptor 3), a Mc4r agonist (melanocortin receptor 4), a monoamine reuptake inhibitor, a β3 inhibitor (adrenergic beta 3 receptor), a DGAT1 inhibitor ( diacylglycerol acyltransferase 1), a DGAT2 inhibitor (diacylglycerol acyltransferase 2), an FAS inhibitor (fatty acid synthase), a PDE inhibitor (phosphodiesterase), a β thyroid hormone agonist, a UCP-1 activator (decoupling protein 1, 2 or 3), a glucocorticoid antagonist, an SCD-1 inhibitor (stearoyl-CoA desaturase-1), a lipase inhibitor, a fatty acid transporter inhibitor, a transporter inhibitor dicarboxylate, an anoretic agent, such as dexamphetamine, phentermine, phenylpropanolamine or mazindole or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be combined with growth-promoting agents such as, but not limited to, HRT, diethylstilbesterol, theophylline, E-series prostaglandin encephalins or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can also be used in combination with growth hormone secretagogues, such as GHRP-6, GHRP-1, GHRP-2 or with growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins, including IGF-1 and IGF-2 or with alpha-adrenergic agonists, such as clonidine or 5-HT.sub.D serotonin agonists, such as sumatriptan or agents that inhibit somatostatin or its release, such as physostigmine and pyridostigmine. Another use of the disclosed compounds of the invention is in combination with parathyroid hormone, PTH (1-34) or bisphosphonates, such as MK-217 (alendronate).

Examples of anti-anxiety agents suitable for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam and hydroxyzine pamoate and the like.

Examples of anti-depressants suitable for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline, paroxetine and the like.

Examples of antihypertensive agents suitable for use in combination with the compounds of the present invention include, but are not limited to, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, a beta-adrenergic receptor blocker, a alpha-adrenergic receptor blocker, calcium channel blocker, potassium channel activator, potassium channel activator, aldosterone synthesis inhibitor, neutral endopeptidase inhibitor (NEP), double conversion enzyme inhibitor angiotensin / neutral endopeptidase (ACE / NEP), an endothelin receptor antagonist, a double angiotensin / endothelin receptor antagonist (DARA), a diuretic or a pharmaceutically acceptable salt thereof.

Examples of cardiac glycosides suitable for use in combination with the compounds of the present invention include digitalis and ouabain.

Examples of thyroid mimetics suitable for use in combination with the compounds of the present invention include, but are not limited to, KB-2115, MB07811 or a pharmaceutically acceptable salt thereof.

For the treatment of skin disorders or diseases as described above, the compounds of the present invention can be used alone or optionally in combination with a retinoid, such as tretinoin or a vitamin D analog.

The other therapeutic agents above, when used in combination with the compounds of the present invention, can be used, for example, in those amounts indicated in the Physiciãns' Desk Reference (PDR) or as otherwise determined by those skilled in the art.

Where the compounds of the invention are administered in the form of a combination with one or more other therapeutic agents, they can be administered concurrently, sequentially or in a fixed unit dosage form.

Abbreviations:

TSH - Thyroid-stimulating hormone, also known as thyrotropin.

T4 - Thyroxine.

T3 - Triiodothyronine.

T2 - Diiodothyronine.

rT3 - T3 Reverse.

SAR - List of structural activity.

NPY - Neuropeptide Y.

Reaction schemes for the synthesis of compounds of the invention.

In the following, reaction schemes are provided for compounds according to another embodiment of the present invention.

Scheme 1:

A. (CH ₃ ) ₃ SiCl, tetrabutylammonium bromide, DMSO, acetonitrile.

B. R ⁴ OH (XII, XIV, XVI, XVII) or R ⁴ NH ₂ .

C. 1. R ⁴ CHO (XIII), AcOH-piperidine, toluene.

2.Pd / BaSO ₄ , H ₂ , 50 psi.

D. R ⁴ CH ₂ Y (XV), NaH, THF.

E. NH ₂ NH ₂ .H ₂ O, ethanol.

F. R ² Y, base, THF.

G. R ² NHN ₂ , ethanol, AcOH.

H. Bromine, HBr, methanol or CC1 ₄ .

I. R ⁴ OH (XII, XIV, XVI, XVII) or R ⁴ NH ₂ , K ₂ CO ₃ , acetone or DMF.

J. R ³ COOEt or R ³ COC1, KO'Bu, THF.

K. DMF-DMA, 80 ° C.

L. NaCN, DMF.

where R ¹ , R ² , R ³ , R ⁴ and Z are as defined above and Y is halo or any other driving group.

In a specific embodiment, the compounds of formula (I) are obtained from the pyrazole derivatives of formula (II) or dicet derivatives of formula (III), as shown in scheme 1.

The derivatives of formula (II) are reacted with substituted alkyl halide or any other alkyl derivative containing a suitable conduction group in the presence of a selected base of metal hydride or metal carbonate, in a polar aprotic solvent, such as tetrahydrofuran , to provide the compounds of formula (I).

Similarly, the diceto derivative of formula (III), when reacted with hydrazine derivatives substituted in alcoholic solvent, provides the compound of formula (I).

The compounds of formula (II) are obtained by treating the compounds of formula (III), as shown in Scheme 1, with hydrazine hydrate under the condition known in the literature. The compound of formula (III) is prepared from the compound of formula (IV) by reacting it with substituted hydroxyls of formula (XII), (XIV), (XVI) or (XVII) or with hydroxyl-substituted indoles. in the presence of a base, such as metal hydride or metal carbonate, in a polar aprotic solvent, such as tetrahydrofuran. The compounds of formula (IV) can be obtained from the dicet derivative of formula (V) by dissolving it in an appropriate solvent, such as acetonitrile, in the presence of a suitable reagent, such as trimethylsilyl chloride and dimethyl sulfoxide.

Alternatively, the compounds of formula (III) are directly obtained by reacting the compounds of formula (V) with aldehyde derivatives of formula (XIII) in the presence of piperidine-acetic acid, followed by hydrogenation in the presence of a catalyst, such as Pd / BaSO4, under a hydrogen atmosphere or with a chlorine derivative of formula (XV) in the presence of metal hydride or metal carbonate.

In an alternative process, the compound of formula (III) can also be prepared from the compound of formula (VI) by reacting it with the appropriate acid chloride or ethyl ester in the presence of a base, such as metal hydride or metal alkoxide. The compound of formula (VI) is obtained from the compound of formula (VII) by reacting it with hydroxy or suitable indane amino of formula (XII), (XIV), (XVI) or (XVII) or indole derivatives in the presence of a base, preferably selected from metal hydride or metal carbonate. The compound of formula (VII), as shown in scheme 1, is obtained by bromination of methyl ketone of formula (VIII) in an appropriate solvent, such as methanol.

The compounds of formula (II) and formula (I) can be prepared from the keto derived from formula (IX) or the cyano derivative of formula (X) by reacting the compounds of formula (IX) with a substituted hydrazine or unsubstituted appropriate in the presence of alcoholic solvent to provide compounds of formula (I) and formula (II), respectively. The compound of formula (IX) is obtained by reacting the compound of formula (VI) with dimethylformamide / diethyl acetal.

Alternatively, the compounds of formula (X) are reacted with compounds of formula (XV) in the presence of a base, such as metal hydride, followed by treatment with appropriate substituted or unsubstituted hydrazine in the presence of an alcoholic solvent to obtain compounds of formula (I) and formula (II), respectively.

As shown in scheme 1, the cyano derivative of formula (X) is obtained from the compound of formula (VII) by dissolving it in an organic solvent, such as dimethylformamide, in the presence of sodium cyanide. The compound of formula (I), as obtained through scheme 1, is the final compound or can be converted to formula (I) by converting the appropriate functional group or using conventional methods known in the art.

The intermediates of formula (XII), (XIII), (XIV) and (XV) can be obtained as shown in scheme 2, as shown here below.

SCHEME 2

where G = hydrogen / lower alkyl / halogen / CF ₃ , cyan / aldehyde / ester / aryl / arylalkyl; Y = Br / Cl

A. 1. Paraformaldehyde, MgCl ₂ , TEA, THF.

2. Pd-C, H ₂ , methanol.

B. N-halo succinimide, diisopropylamine, THF.

C. A1C1 ₃ , 170-180 ° C.

D. Triethylsilane, TFA.

E. Hexamine, TFA.

F. Nitric acid, AcOH-water.

G. 1. Honey, K ₂ CO ₃ , DMF.

2. NaBH ₄ , methanol.

H. PPh ₃ , CBr ₃ , THF.

I. Thionyl chloride, THF.

As shown in Scheme 2, intermediates (XII) are obtained from substituted dihydrocoumarine XI or 4-hydroxyindane. In a specific embodiment, the substituted dihydrocoumarins of formula (XI) are heated with aluminum trichloride, followed by reduction of the keto group of indanone with triethylsilane in trifluoroacetic acid to obtain the compound of formula (XII). The reduction of indanone can also be carried out using the method disclosed in US2005 / 0037925, W09943647 and

US2002 / 0040016. Alternatively, 4-hydroxyindane is reacted with paraformaldehyde to obtain the substituted aldehyde compound, which is reduced to the methyl group, in the presence of a suitable agent, such as NH2NH2-KOH-ethylene glycol or Pd / C under an atmosphere of hydrogen or a acid through oxidation of the aldehyde using the mild oxidizing agent, such as sulfamic acid and sodium chlorite. The acid group thus obtained is in the presence of acid a suitable amine and carbodiimide to be further reacted with an appropriate mineral alcohol to obtain the ester or using a selected coupling reagent to obtain the amide. In addition, the aldehyde group of formula (XII) cyano using an alternative, os is also used to obtain the derivative of conventional method. In another process, substituted halo hydroxyindane derivatives of formula (XII) are also prepared by reacting 4-hydroxyindane with N-halo-succinimide in the presence of a catalytic amount of diisopropylamine in solvents, preferably tetrahydrofuran or dihaloalkane (G = halogen) or through treatment with

The compound of formula (XII) or 4-hydroxy indane (G = H) is treated with hexamine in trifluoroacetic acid to obtain the compound of formula (XIII).

In yet another specific modality, the compost of formula (XV) can be obtained from the compost of formula (XIII) by reacting it with methyl iodide in the presence of a base followed by reduction in the presence of a reducing agent, such as borohydride sodium and additional reaction of the intermediate thus obtained with carbon tetrabromide and triphenyl phosphine or chloride from an alternative process, the one also obtained from

4-hydroxy indane through

thionyl, respectively. In compound in formula (XIV) is compound in formula (XII) or

treatment of it with nitric acid in the presence of acetic acid.

The intermediates of formula (XVI) and (XVII) can be obtained as shown in

Scheme 3, as shown here below.

SCHEME 3

Pd-C, H ₂ , methanol.

BBr ₃ , MDC.

Paraformaldehyde, MgCl ₂ , TEA, THF.

It = halogen / cyan / aldehyde / ester / amide

Triethylsilane, TFA or Pd-C, H ₂ .

N-halo succinimide, diisopropylamine, THF.

The intermediate of formula (XVI) is obtained from dimethoxy indanone, by reducing the keto group of indanone, using triethylsilane or Pd-C, followed by reaction with boron tribromide.

For the compound of formula (XVII), when G = methyl, it is obtained by treating 7-methoxy-indan-4-ol (XVI) with paraformaldehyde and then reducing the intermediate through a catalytic reducing agent, such as Pd / C, under a hydrogen atmosphere, in the presence of a suitable alcoholic solvent selected from methanol. Alternatively, for the compound of formula (XVII), when G = ester or amide, the compound of formula (XVI) is reacted with paraformaldehyde which, when further oxidized under mild condition, as described here above, can be converted to G = acid. In addition, the acid group can be reacted with an appropriate alcohol in the presence of mineral acid to obtain an ester or with the use of a suitable amine and a coupling reagent selected from carbodiimide to obtain the amide. For G = cyan in the formula (XVII), it can be obtained by appropriate selection of cyano-substituted indanone or by converting the amide derivative to cyan using conventional methods.

Alternatively, the halo-substituted compound of formula (XVII) is obtained by reacting 7-methoxyindan-4-ol (XVI) with N-halo-succinimide in the presence of a catalytic amount of diisopropylamine in selected tetrahydrofuran solvents or through treatment with sulfuryl chloride (G = Cl).

Preparatory Examples.

The present invention is further illustrated by the following non-limiting examples. The examples illustrate the preparation of the compounds of formula (I) and, as such, should not be considered or construed as limiting the scope of the invention presented in the appended claims.

Example 1: (Compound No. 1).

3- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-pyrazol-lil] -propionic acid.

STEP I: Preparation of 4,7-dimethoxy indane.

To the cold, stirred suspension of 4,7-Dimethoxyindan-l-one (35 gm, 0.182 moles) in triethyl silane (105.7 gm, 0.909 moles) was added trifluoroacetic acid (350 ml) at 1015 ° C. Stirring was continued at room temperature for 2 hours and dissipated in water. It was extracted with ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated to provide a crude mass which was purified by column chromatography using 5% ethyl acetate in hexane (22.5 gm ). Yield:

69.3% ^X H-NMR (400 MHz, CDCI ₃ ): δ 6.67 (2H, s), 3.70 (6H, s),

2.74-2.78 (4H, m), 1.95-2.02 (2H, m).

STEP-II: Preparation of 7-methoxyindan-4-ol.

To the clear solution of 4,7-Dimethoxyindane (22.5 gm, 0.126 moles) in methylene chloride (400 ml) was added boron tribromide (12.27 ml, 0.13 moles) at 0 ° C. After 2 hours of stirring at 0-10 ° C, water (100 ml) was added and then the reaction mixture was extracted with methylene chloride. The methylene chloride layer was dried over sodium sulfate and distilled to provide a crude mass, which was purified by column chromatography using 7% ethyl acetate in hexane (9.0 gm).

Yield: 43.4%.

^x H-NMR (400 MHz, DMSO-d ₆ ): δ 8.66 (1H, s), 6, 493-6, 558 (2H, m), 3.66 (3H, s), 2.71 2.75 (4H, m), 1.92-2.00 (2H, m). STEP-III: Preparation of 4- (7-Methoxy-indan-4-yloxy) -3,5dimethyl-1H-pyrazole.

The suspension of 60% sodium hydride (2.0 gm, 0.051 moles) in tetrahydrofuran (20 ml) was added a solution of 7-Methoxyindan-4-ol (7.0 gm, 0.042 moles) in tetrahydrofuran (30 ml ) at room temperature. After one hour of stirring, a solution of 3-Chlorine 2,4-pentanedione (9.0 ml, 0.075 moles) in tetrahydrofuran (20 ml) was added, followed by the addition of potassium bromide (3.0 gm, 0.025 moles) ). The reaction mixture was stirred at 70 ° C for 6 hours. The water was added and extracted with diethyl ether. The ether layer was separated and distilled to provide an oily mass, which was partially purified through a column using 2% ethyl acetate in hexane to provide a crude mass (2.7 gm). The obtained crude mass was stirred with hydrazine hydrate (1 ml) in 20 ml of ethanol at 10 ° C. The ethanol was evaporated to dryness. The residue obtained was divided between water and ethyl acetate. The separated ethyl acetate layer was dried over sodium sulfate and distilled to provide the desired product (2.0 gm). Yield: 18.1% (in two stages).

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 2.12 (1H, s), 6.61 (1H,

d), 6.29 (1H, d), 3.69 (3H, s), 2.88 (2H, t), 2.80 (2H, t), 2.00-2.07 (5H, m ), 1.91 (3H, s).

STEP-IV: Preparation of 3- [4- (7-Methoxyindan-4-yloxy) -3,5-dimethyl-pyrazol-1-yl] -propionic acid ethyl ester.

The suspension of 60% sodium hydride (0.372 gm 0.0093 moles) in 10 ml of tetrahydrofuran, was added a solution of pyrazole derivative obtained in step III (2.0 gm, 0.00775 moles) in 10 ml of tetrahydrofuran under a nitrogen atmosphere at room temperature. After 1 hour of stirring at room temperature, a solution of 3-chloro ethyl propionate (1.15 gm, 0.0084 moles) in 10 ml of tetrahydrofuran was added to the reaction mixture. It was stirred at room temperature for 4 hours. The reaction mixture was poured into water, extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and distilled. The obtained crude mass was purified by column chromatography using 20% ethyl acetate in hexane to provide the desired product (0.850 gm). Yield: 30.6%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.60 (1H, d), 6.26 (1H,

d), 4.15 (2H, t), 4.05 (2H, q), 3.69 (3H, s), 2.88 (2H, t), 2.78-2.83 (4H, m ), 1.99-2.08 (5H, m), 1.89 (3H, s), 1.16 (3H, t).

STEP-V: Preparation of 3- [4- (7-Hydroxy-indan-4-yloxy) 3,5-dimethyl-pyrazol-1-yl] -propionic acid.

To a clear solution of the ethyl ester derivative obtained in step-IV (0.85 gm, 0.0023 moles) in 15 ml of methylene chloride, was added a solution of boron tribromide (1.0 ml, 0.0105 moles) in 15 ml of methylene chloride at 0 ° C. The reaction mixture was stirred for 2 hours at room temperature; 10 ml of water was added and extracted with ethyl acetate. The acetate layer

ethyl was dried on sulfate sodium and distilled for provide a 0, solid product > (230 mg) . Yield: 30, 6 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.27 l : ih, bs), 8.77 (1H, bs), 6.42 (1H, d), 6.15 (1H, d), 4.10 (2H, t), 2.84 (2H,

t), 2.71-2.78 (4H, m), 1.98-2.04 (5H, m), 1.88 (3H, s).

Mass: 315 (M ⁺ -l).

Example 2: (Compound No. 7).

3- [4- (7-Hydroxy-indan-4-yloxy) -3-thiophen-2-yl-pyrazol1-yl] -propionic acid and 3- [4- (7-Hydroxy-indan-4-yloxy) acid -5thiophen-2-yl-pyrazol-1-yl] -propionic.

STEP-I: Preparation of 2- (7-Methoxy-indan-4-yloxy) -1-thiophen-2yl-ethanone.

To a clear solution of 4-Hydroxy-7-methoxy indane (2.0 gm, 0.0121 moles) in acetone (20 ml), potassium carbonate (2.52 gm, 0.0182 moles) was added at room temperature and stirred for 1.5 hours. A solution of 2Bromo-1-thiophene-2-yl-ethanone (3.75 gm, 0.0181 moles) in acetone (10 ml) was added at 0 ° C and stirred for 8 hours at room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 X 100 ml). The ethyl acetate layer was dried over sodium sulfate and evaporated to a crude product, which was purified by column chromatography using 2% ethyl acetate in hexane as a mobile phase. The collected eluent was evaporated to provide the desired product (2.1 gm) as a viscous oil. Yield: 59.8%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 8.12 (1H, dd), 8.09 (1H, dd), 7.29-7.31 (1H, m), 6.63 ( 2H, s), 5.33 (2H, s), 3.70 (3H, s), 2.87 (2H, t), 2.78 (2H, t), 1.98-2.06 (2H , m). STEP-II: Preparation of 3-Dimethylamino-2- (7-Methoxy-indan-4yloxy) -1-Thiophen-2-yl-propenone.

The compound obtained in step-I of Example 2 (2.0 gm,

0.0059 moles) was added in 5 ml of N, diethylacetal Ndimethylformamide at room temperature and stirred at 90 ° C for 2 hours. The reaction mixture was poured into chilled water (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated to provide an oily product (1.9 gm). It was used for the next step. Yield: 79.5%.

STEP-III: Preparation of 4- (7-Methoxy-indan-4-yloxy) -3-thiophen-2-yl-1H-pyrazole and 4- (7-Methoxy-indan-4-yloxy) -5-thiophen-2yl- lH-pyrazole

To a clear solution of the compound obtained in step-II of Example 2 (1.9 gm, 0.0055 moles) in ethanol (30 ml), hydrazine hydrate (0.5 ml, 0.0102 moles) was added and stirred at 60 ° C for 4 hours. Ethanol was evaporated in vacuo and water was added to the reaction mixture. It was extracted with ethyl acetate (2 x 50 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo giving a crude product, which was purified by column chromatography using ethyl acetate in hexane (20:80) as a mobile phase. The collected eluent was evaporated under vacuum resulting in 1.0 gm of the desired product. Yield: 58.13%.

^X H-NMR (400 MHz, DMSO-d ₆ ): For the main isomer 012.82 (1H, s), 7.67 (1H, d), 7.43 (1H, d), 7.24 (1H , d), 7.02-7.08 (1H, m), 6.65 (1H, d), 6.56 (1H, d), 3.70 (3H, s), 2.92 (2H, t), 2.82 (2H, t), 2.03-2.10 (2H, m).

STEP-IV: Synthesis of 3- [4- (7-Methoxyindan-4-yloxy) -3-thiophen-2-yl-pyrazol-1-yl] -propionic acid ethyl ester 3- [4 - (7-Methoxy-indan-4-yloxy) -5-thiophen2-yl-pyrazol-l-yl] -propionic

It was prepared using the same method as described for step-IV of Example 1. Yield: 45.4%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): For the main isomer: δ

7.64 (1H, s) , 7.45 (1H, dd), 7.26 (1H, dd), 7.03-7.07 (1H, m), 6, 67 (1H, d), 6, 62 (1H, d), 4.30 (2H, t), 4.01-4.09 (2H, m), 3.72 (3H, s) , 2.78-2.90 (6H, m), 2.04-2.07 (2H, m), 1.13 (3H, t).

STEP-V: Preparation of 3- [4- (7-Methoxy-indan-4-yloxy) -3thiophen-2-yl-pyrazol-1-yl] -propionic acid and 3— [4— (7— Methoxy- indan-4-yloxy) -5-thiophen-2-yl-pyrazol-1-yl] propionic.

To a clear solution of the compound obtained in step-IV (0.6 gm, 0.0014 moles) in methanol (5.0 ml), a solution of sodium hydroxide (0.12 gm, 0.0029 moles) in water (25 ml) was added and stirred for 2 hours at room temperature. Methanol was vacuum distilled completely. The residual aqueous layer was washed with ether (20 ml), acidified with dilute hydrochloric acid and extracted with ethyl acetate (2 X 50 ml). The separated ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide the acid derivative (440 mg) as a solid. Yield: 78.7%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): For the main isomer: δ 12.42 (1H, bs), 7.64 (1H, s), 7.44 (1H, d), 7.26 (1H, d), 7.05 (1H, dd), 6.66 (1H, d), 6.62 (1H, d), 4.26 (2H, t),

3.72 (3H, s), 2.78-2.90 (6H, m), 2.01-2.06 (2H, m).

STEP-VI: Preparation of 3- [4 - (7-Hydroxy-indan-4-yloxy) 3-thiophen-2-yl-pyrazol-1-yl] -propionic acid and 3— [4— (7—

Hydroxy-indan-4-yloxy) -5-thiophen-2-yl-pyrazol-1-yl] propionic.

To a clear solution of the compound obtained in step-V of Example 2 (0.44 gm, 0.00118 moles) in methylene chloride (20 ml), a solution of boron tribromide (0.35 ml, 0.0037 moles) ) in methylene chloride (5 ml) was added at 010 ° C dropwise and stirred for 2 hours at room temperature (25-28 ° C). Water (10 ml) was slowly added to the reaction mixture and extracted with methylene chloride (2 X 30 ml). The separated methylene chloride layer was dried over sodium sulfate and distilled in vacuo to provide the desired product (200 mg) as a solid.

Yield: 47.1%. DMSO-dg): For the main isomer: ^X H-NMR (400 MHz, 812.41 (1H , s), 9.00 (1H, s) , 7.55 (1H, s), 7.44 (1H, d), 7.29 (1H, d), 7.04-7 , 06 (1H, m), 6.46-6.54 (2H, m), 4.24 (2H, t), 2.73-2.84 (6H, m), 1.96-2.06 (2H, m). PASTA:

369 (M ⁺ -1).

Example 3: (Compound No. 3).

7- [3,5-Dimethyl-1- (1H-tetrazol-5-ylmethyl) -1H-pyrazol-4yloxy] -indan-4-ol.

STEP-I: Preparation of [4- (7-Methoxy-indan-4-yloxy) -3,5dimethyl-pyrazol-1-yl] -acetonitrile

It was prepared using a similar method as described for step-IV of Example 1 using bromoacetonitrile instead of ethyl 3-chloropropionate. Yield: 96.7%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.63 (1H, d), 6.31 (1H,

d), 5.35 (2H, s), 3.70 (3H, s), 2.89 (2H, t), 2.80 (2H, t), 2.10 (3H, s), 1, 98-2.07 (2H, m), 1.93 (3H, s).

STEP-II: Preparation of 5- [4- (7-Methoxy-indan-4-yloxy) -3,5dimethyl-pyrazol-1-ylmethyl] -ΙΗ-tetrazole.

To a stirred solution of [4- (7-Methoxy-indan-4-yloxy) 3,5-dimethyl-pyrazol-1-yl] -acetonitrile (3.0 gm, 0.0101 moles) in dimethylformamide (30 ml) , sodium azide (1.2 gm, 0.0185 moles) and triethylamine hydrochloride (4.0 gm, 0.0303 moles) were added at room temperature (27-30 ° C). The reaction mixture was stirred at 90-100 ° C for 4 hours. The reaction mixture was cooled and poured into dilute hydrochloric acid (100 ml) and stirred for 30 minutes. The separated solid was filtered and dissolved in ethyl acetate (100 ml). The ethyl acetate layer was dried over sodium sulfate and distilled under vacuum to provide 1.5 gm of product

72 desired as a solid. Yield: 43.7%.

¹ H-NMR (400 MHz, DMSO-dg): δ 6.62 (1H, d), 6.32 (1H,

d), 5.57 (2H, s), 3.70 (3H, s), 2.89 (2H, t), 2.80 (2H, t), 2.11 (3H, s), 2.03-2.09 (2H, m), 1.89 (3H, s). STEP-III: 7- [3,5-Dimethyl-1- (1H-tetrazol-5-ylmethyl) -1H-

pyrazol-4-yloxy] -indan-4-ol.

It was prepared using a similar method as described for step-VI of Example 2. Yield: 31.3%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 8.85 (1H, s), 6.44 (1H,

d), 6.21 (1H, d), 5.55 (2H, s), 2.84 (2H, t), 2.76 (2H, t), 2.11 (3H, s), 2.00-2.06 (2H, m), 1.88 (3H, s). Mass: 325

(M ⁺ -l).

Example 4: (Compound No. 10).

5- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-pyrazol-lilmethyl] -1H-pyrazol-3-ol.

STEP-I: Preparation of 4- [4- (7-Methoxyindan-4-yloxy) -3,5-dimethyl-pyrazol-1-yl] -3-oxo-butyric acid ethyl ester

It was prepared using a similar method as described for step-IV of Example 1 using 4-chloro-3-oxo-butyric acid ethyl ester as an alkylating agent instead of ethyl 3-chloropropionate. Yield: 35.7%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 6.64 (1H, d), 6.33 (1H,

5.11 (2H, s), 4.11 (2H, q), 3.69-3.70 (5H, m) , 2.87- (2H, m), 2.80 (2H, t), 2.02-2.07 (2H, m), 1, 92 (3H, 1.90 (3H, s), 1.19 ( 3H, t).

STEP-II: Preparation of 5- [4- (7-Methoxy-indan-4-yloxy) -3,5dimethyl-pyrazol-1-ylmethyl] -1H-pyrazol-3-ol.

To a stirred solution of the keto ester from step-1 of

Example 4 (0.8 gm, 0.00207 moles) in Methanol (20 ml), a solution of hydrazine hydrate (0.11 ml, 0.00227 moles) in methanol (5 ml) was added at 0-10 ° Ç. The reaction mixture was heated to 75-80 ° C and stirred for 12 hours. The methanol was distilled in vacuo and the obtained solid was stirred in ethyl acetate (5 ml). It was further filtered, suction dried to provide 380 mg of the desired product as a solid. Yield: 51.8%.

¹ H-NMR (400 MHz, DMSO-dg) : O 11.81 (1H, bs), 9, 57 (1H, bs), 6.61 (1H, d), 6.28 (1H, d), 5.27 (1H, bs), 5.03 (2H, bs), 3.69 (3H, s), 2.88 (2H, t) , 2.80 (2H, t), 2.01-2.08

(5H, m), 1.90 (3H, s).

STEP-III: Preparation of 5- [4- (7-Hydroxy-indan-4-yloxy) -3,5dimethyl-pyrazol-1-ylmethyl] -H-pyrazole-3-ol.

It was prepared using a similar method as described for step-VI of Example 2. Yield: 60.4%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.82 (1H, bs), 6.41 (1H,

d), 6.15 (1H, d), 5.22 (1H, s), 5.01 (2H, s), 2.82 (2H, t), 2.74 (2H, t), 1, 93-2.06 (5H, m), 1.84 (3H, s). Mass: 339 (M ⁺ -l).

Example 5: (Compound No. 19).

[3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4-ylmethyl) pyrazol-1-yl] -acetic acid.

STEP-1: Preparation of 7-Chloromethyl-4-methoxy-5-methyl-indane.

To a stirred solution of 7-Methoxy-6-methyl-indan-4carboxaldehyde (39 gm, 0.205 moles) in methanol (200 ml), sodium borohydride (9.5 gm, 0.225 moles) was added gradually at 10-20 ° C and stirred at room temperature for 2 hours. The reaction mixture was poured into water (200 ml) and acidified with hydrochloric acid to a pH of

6. The reaction mixture was subjected to vacuum distillation and then extracted with ethyl acetate (2 X 200 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide 38 gm of a viscous oil. To a clear solution of viscous oil (38.0 gm) in methylene chloride (160 ml), thionyl chloride (29.07 ml, 0.396 moles) was added at 10-15 ° C and stirred at 20-25 ° C for 2 hours. The reaction mixture was poured into water (200 ml). The separated organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, vacuum distilled to provide the crude product as a solid. The crude solid was dissolved in hexane, filtered, and then the filtrate was distilled to provide the desired compound (36.0 gm) as a solid.

Yield: 83.5%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.95 (1H, s), 4.66 (2H, s), 3.70 (3H, s), 2.85-2.98 ( 4H, m), 2.15 (3H, s), 1.99-2.05 (2H, m).

STEP-II: Preparation of 3,5-Diethyl-4- (7-methoxy-6-methyl-indan4-ylmethyl) -ΙΗ-pyrazole.

To a stirred suspension of 3,5-heptanedione (8.7 ml, 0.0642 moles) and potassium carbonate (15.0 gm, 0.1086 moles) in dimethylformamide (50 ml), the solution of 7-chloromethyl-4- methoxy-5-methyl-indane (15.0 gm, 0.0714 moles) in dimethylformamide (25 ml) was added slowly and stirred for 2.5-3 hours at 40-45 ° C. To the reaction mixture, water (500 ml) was then added, acidified with dilute hydrochloric acid and extracted with ethyl acetate (2 X 500 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide 20 gm of the dicet derivative as a viscous oil. To a clear solution of the viscous oil obtained in isopropyl alcohol (80 ml), a 99% hydrazine hydrate solution (3.3 ml,

0.066 moles) in isopropyl alcohol (20 ml) was added slowly at 15-20 ° C. The reaction mixture was heated to 80-85 ° C and stirred for 1 hour. Acetic acid (7.5 ml) was added and heating was continued for an additional 11-12 hours. The isopropyl alcohol was distilled and the residue was divided between aqueous sodium bicarbonate (200 ml) and ethyl acetate (2 X 200 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide a solid. The obtained solid was stirred in hexane (50 ml), filtered and dried under vacuum to provide

9.3 gm of the desired pyrazole. Yield: 43.7%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 12.02 (1H, s), 6.46 (1H,

S) , 3.64 (3H, s), 3, 51 (2H, s), 2.84-2, 88 (2H, m), 2.75 (2H, t), 2.36-2.40 (4H, m), 2.06 (3H, s ), 1.96-2.04 (2H, m), 1.00-1.04 (6H, m). STEP-III: Preparation ethyl ester of acid [3,5-Diethyl-4- (7-

methoxy-6-methyl-indan-4-ylmethyl) -pyrazol-1-yl] -acetic.

To a stirred solution of the pyrazole derivative obtained in step-11 of Example 5 (9.0 gm, 0.0302 moles) and bromine ethyl acetate (6.7 ml, 0.0604 moles) in dimethylformamide (50 ml), cesium carbonate (14.7 gm, 0.0453 moles) was added and stirred for 16 hours at room temperature (25-30 ° C). The reaction mixture was poured into water (400 ml). The separated solid was filtered and washed well with water (50 ml) and dried with suction. The solid cake was dissolved in ethyl acetate (200 ml) and washed with water. The ethyl acetate layer was dried over sodium sulfate and vacuum distilled to provide the crude solid. The crude solid was stirred in hexane (50 ml) for 2 hours, filtered, washed with hexane (10 ml) and dried under vacuum to give the white product (9.0 gm). Yield:

^X H-NMR (400 MHz, DMSO-d ₆ desired as a solid

O.

s) , 4.12 (2H, q) ' 3.64 (3H, (2H, m), 2.73 -2.77 (2H, m), 2.06 (3H, s) , 1. 96- -2.04 (2H, t), 0.89 (3H, t).

STEP-IV: Preparation of acid [3

: δ 6, 47 (1H, s), 4.90 (2H, s) , 3.54 (2H, s), 2.85- • 2.89 2.44 (2H, q), 2.30 (2H, q) λ m), 1.19 (3H, t), 1.00 (3H,

5-Diethyl-4- (7-methoxy-6-methylindan-4-ylmethyl) -pyrazol-1-yl] -acetic.

To a stirred solution of [3,5— Diethyl-4- (7-methoxy-6-methyl-indan-4-ylmethyl) -pyrazol-1-yl] acetic acid ester from step-III (9.0 gm , 0.0234 moles) in tetrahydrofuran (40 ml) and methanol (20 ml), a solution of sodium hydroxide (1.87 gm, 0.0468 moles) in water (75 ml) was added at 20-30 ° C and stirred for 1.5-2 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 X 200 ml). The residual aqueous layer was acidified with dilute hydrochloric acid. The separated solid was filtered, washed well with water (50 ml) and dried under vacuum at 60-65 ° C to provide the desired product as a white solid (6.3 gm). Yield: 75.5%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.80-13.00 (1H, bs),

6.48 (1H, s) , 4.79 (2H, s), 3.64 (3H, s), 3.54 (2H, s), 2.85- -2.89 (2H, m), 2.74-2.78 (2H, m), 2.44 (2H, q), 2.30 (2H, q), 2.06 (3H, s), 1.96- -2.04 (2H, m), 1.00 (3H, t), 0.90 (3H, t).

STEP-V: Preparation of [3,5-Diethyl-4- (7-hydroxy-6-methylindan-4-ylmethyl) -pyrazol-1-yl] -acetic acid.

To a stirred suspension of [3,5-Diethyl-4- (7methoxy-6-methyl-indan-4-ylmethyl) -pyrazol-1-yl] -acetic acid (6.0 gm, 0.0168 moles) in chloride methylene chloride (100 ml), a solution of boron tribromide (4.2 ml, 0.0442 moles) in methylene chloride (20 ml) was added at 0-5 ° C and stirred for 2-3 hours at 20- 30 ° C. Water (250 ml) was charged to the reaction mixture and stirred for 1 hour. The separated solid was filtered under vacuum, washed with water. The obtained solid was dissolved in ethyl acetate (2.0 liters) and washed with water (1 liter). The ethyl acetate was distilled in vacuo and the solid thus obtained was stirred in diethyl ether (50 ml), filtered and dried at 55-60 ° C under vacuum to provide 4.5 gm of the desired product. Yield: 78.3%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 8.14 (1H, s), 6.39 (1H, s), 4.77 (2H, s), 3.48 (2H, mixed with peak water present in DMSO-d6), 2.68-2.77 (4H, m), 2.43 (2H, q), 2.30 (2H, q), 1.94-2.01 (5H , m), 1.00 (3H, t), 0.90 (3H, t).

¹ H-NMR (400 MHz, CD ₃ OD): δ 6.66 (1H, s), 4.83 (2H, s),

3.59 (2H, s), 2.75-2.83 (4H, m), 2.51 (2H, q), 2.42 (2H, q), 1.91-2.07 (5H, m), 1.05 (3H, t), 0.97 (3H, t). Mass: 341 (M ⁺ -l).

Example 6: (Compound No. 33).

3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -N-isopropyl-propionamide.

STEP-1 Preparation of 3- [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -propionic acid.

It was prepared using a similar method as described for step-IV of Example 5. Yield: 54.0%.

^X H-NMR (400 MHz, DMSO-d6): δ 12.29 (1H, bs), 6.49 (1H,

s), 4.10 (2H, t), 3.64 (3H, s), 3.48 (2H, s), 2.86 (2H, t), 2.68-2.75 (4H, m ), 2.10 (3H, s), 2.08 (3H, s), 1.96-2.03 (2H, m), 1.92 (3H, s).

STEP-II: Preparation of N-isopropyl-3- [4- (7-methoxy-6-methylindan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -propionamide.

To the solution of 3- [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -propionic acid (1.0 gm, 0.00292 moles) in tetrahydrofuran (20 ml), carbonyldiimidazole (0.62 gm, 0.0038 moles) was added at 2030 ° C. The reaction mixture was heated and stirred for one hour at 70-75 ° C. A solution of isopropyl amine (0.3 ml, 0.00367 moles) in tetrahydrofuran (5 ml) was added at 20-30 ° C. The reaction mixture was further stirred at 70 ° C for 4 hours. The reaction mixture was cooled and poured into water (50 ml) and extracted with ethyl acetate (2 X 100 ml). The ethyl acetate layer was dried over sodium sulfate, distilled in vacuo to provide a crude product, which was stirred in hexane (20 ml) and filtered to provide 810 mg of the desired product as a solid. Yield: 72.8%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 7.77 (1H, d), 6.49 (1H,

s), 4.10 (2H, t), 3.77 (1H, m), 3.64 (3H, s), 3.47 (2H, s), 2.86 (2H, t), 2, 73 (2H, t), 2.49 (2H, mixed with DMSO-d ₆ peak), 2.08 (6H, s), 1.95-2.03 (2H, m), 1.92 (3H , s) ,

0.98 (6H, d).

STEP-III:

Preparation of 3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -N-isopropyl propionamide.

It was prepared using a similar method as described for step-VI of Example 2. Yield: 51.9%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 8.11 (1H, s) , 7.76 (1H, d), 6.40 (1H, s), 4.08 (2H, t), 3.76-3.81 (1H, m), 3.42 (2H, s) , 2.75 (2H, t), 2.69 (2H, t), 2.51 (2H, mixed with peak DMSO-d ₆ ), 2.07 (3H , s) , 2.02 (3H, s) , 1.90-1.99

(5H, m), 0.98 (6H, d). Mass: 370 (M ⁺ + 1).

Example 7: (Compound No. 42).

5- [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4-ylmethyl) pyrazol-1-ylmethyl] -3H- [1,3,4] oxadiazole-2-one.

STEP-I: Preparation of [3,5-Diethyl-4- (7methoxy-6-methyl-indan-4-ylmethyl) -pyrazol-1-yl] -acetic acid hydrazide.

The stirred suspension of [3,5-Diethyl4- (7-methoxy-6-methyl-indan-4-ylmethyl) -pyrazol-1-yl] -acetic acid ethyl ester (3.3 gm, 0.0085 moles) and 99% hydrazine hydrate (33 ml) was heated to 60-65 ° C for 3 hours. The reaction mixture was poured into water (200 ml), stirred for one hour and then filtered. The obtained solid was stirred in methanol (10 ml), filtered and dried to provide 2.9 gm of desired product as a solid. Yield: 91.4%.

^X H-NMR (400 MHz, DMSO-d6): δ 9.23 (1H, s), 6.51 (1H,

s) , 4.58 (2H, s), 4.29 - 4.30 (2H, d), 3.64 (3H, s), 3.52 (2H, s) , 2.87 (2H, t), 2.76 (2H, t), 2.47 (2H, mixed with peak DMSO-Ó6), 2.30 (2H, q), 2.07 (3H, s), 1.97-2.04 (2H, m), 1.00 (3H, t), 0.90 (3H, t).

STEP-II: Preparation of 5- [3,5-Diethyl-4- (7-methoxy-6-methylindan-4-ylmethyl) -pyrazol-1-ylmethyl] -3H- [1,3,4] oxadiazole-2one .

To a stirred solution of [3,5 - Diethyl-4- (7-methoxy-6-methyl-indan-4-ylmethyl) -pyrazol-1-yl] acetic acid hydrazide (1.5 gm, 0.0041 moles ) in 1,4-Dioxane (70 ml), carbonyl-diimidazole (2.0 gm, 0.0121 moles) was added at 20-30 ° C. The reaction mixture was stirred for 8 hours at 90-95 ° C. The reaction mixture was cooled and poured into water (200 ml), stirred for 2 hours and then the separated solid was filtered. The solid was further stirred in diethyl ether (25 ml) and filtered, dried to give 900 mg of desired product as a solid. Yield: 56.2%.

^L H-NMR (400 MHz, DMSO-d ₆ ): δ12,28 (1H, bs), 6.45 (1H 5.20 (2H, s), 3, 64 (3H, s), 3.54 (2H, s) , 2.87 (2H, t) (2H, t), 2.54 (2H, q), 2.31 (2H, q), 2.06 (3H, s)

1.98-2.01 (2H, m), 1.00 (3H, t), 0.92 (3H, t).

STEP-III: Preparation of 5- [3,5-Diethyl-4- (7-hydroxy-6-methylindan-4-ylmethyl) -pyrazol-1-ylmethyl] -3H- [1,3,4] oxadiazole-2 ona.

It was prepared using a similar method as described for step-VI of Example 2. Yield: 70.7%.

^X H-NMR (400 MHz, DMSO-dg): δ 12.41 (1H, s), 8.14 (1H,

s) , 6, 37 (1H, s), 5.20 (2H, s), 3.49 (2H, s), 2.69-2.77 (4H, m), 2.53 (2H, mixed with peak DMSO-d6), 2.31 (2H, q), 1.91-2.01 (5H, m), 0, 99 (3H, t) , 0.92 (3H, t).

Mass: 383 (M ⁺ + 1).

Example 8: (Compound No. 45).

6- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-ylmethyl] -2-methyl-3H-pyrimidine-4-one.

STEP-I: Preparation of 4- [4- (7-Methoxy-6methyl-indan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -3-oxobutyric acid ethyl ester.

It was prepared using a similar method as described for step-IV of Example-1 using 4-chloro-3-oxo-butyric acid ethyl ester as an alkylating agent instead of ethyl 3-chloropropionate. Yield: 47.1%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 6.53 (1H, s), 5.07 (2H, s), 4-4.08 (2H, q), 3.64 (3H, s), 3.63 (2H, s), 3.51 (2H, s), 2.86 (2H, t), 2.74 (2H, t), 2.09 (3H, s), 1, 97 - 2.05 (5H, m), 1.92 (3H, s), 1.18 (3H, t).

STEP-II: Preparation of 6- [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-ylmethyl] -2-methyl-3Hpirimidin-4-one.

To 4- [4- (7-Methoxy-6methyl-indan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -3-oxobutyric acid ethyl solution (1.0 gm, 0, 0025 moles) in ethanol (60 ml), acetamide hydrochloride (0.71 gm, 0.0075 moles) was added. In addition, sodium ethoxide (0.51 gm, 0.0075 moles) was added at 5-10 ° C and then stirred at 70-75 ° C for 2 hours. The ethanol was distilled in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). In addition, the aqueous phase was extracted with ethyl acetate (2 X 100 ml). The combined volume of the ethyl acetate layer was reduced to 20 ml and then filtered to provide 800 mg of the desired product. Yield: 81.3%.

¹ H-NMR (400 MHz, DMSO-d6): δ 12.42 (1H, bs), 6.50 (1H,

s), 5.16 (1H, s), 4.97 (2H, s), 3.64 (3H, s), 3.55 (2H, s), 2.87 (2H, t), 2, 74 (2H, t), 2.27 (3H, s), 2.09 (3H, s),

2.05 (3H, s), 1.98-2.02 (2H, m), 1.95 (3H, s).

STEP-III: Preparation of 6- [4- (7-Hydroxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-ylmethyl] -2-methyl-3Hpirimidin-4-one

It was prepared using a similar method as described for step-VI of Example 2. Yield: 58.4%.

¹ H-NMR (400 MHz, DMSO-dg): δ 12.41 (1H, s), 8.12 (1H, s), 6.42 (1H, s), 5.13 (1H, s), 4.95 (2H, s), 3.49 (2H, s), 2.67-2.77 (4H, m), 2.26 (3H, s), 2.03 (6H, s), 1 , 94-1.99 (5H, m). Mass: 379 (M ⁺ + 1).

Example-9: (Compound No. 46).

3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-ylmethyl] - [1,2,4] oxadiazole-5-ol.

STEP-I: Preparation of [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) 3,5-dimethyl-pyrazol-1-yl] -acetonitrile.

It was prepared using a similar method as described for step-IV of Example-1 using bromoacetonitrile as an N-alkylating agent instead of ethyl 3-chloropropionate. Yield: 52.8%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.51 (1H, s), 5.31 (2H,

s), 3.64 (3H, s), 3.52 (2H, s), 2.87 (2H, t), 2.73 (2H, t), 2.15 (3H, s), 2, 09 (3H, s), 1.92-2.03 (5H, m).

STEP-II: Preparation of N-Hydroxy-2- [4- (7-methoxy-6-methylindan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -acetamidine.

To a stirred solution of [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -acetonitrile (2.0 gm

0.00647 moles) in methanol (50 ml), a suspension of hydroxylamine hydrochloride (2.29 gm, 0.033 moles) and potassium carbonate (4.37 gm, 0.0317 moles) in water (20 ml) was added. The reaction mixture was stirred for 30-36 hours at 70 ° C, cooled and then filtered. The obtained solid was washed with water (10 ml) and, finally, as hexane and dried under vacuum to provide 1.8 gm of the desired product. Yield: 81.4%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.20 (1H, bs), 6.52 (1H,

s), 5.24 (2H, s), 4.51 (2H, s), 3.64 (3H, s), 3.49 (2H, s), 2.86 (2H, t), 2, 74 (2H, t), 2.09 (6H, s), 1.98-2.05 (2H,

m), 1.94 (3H, s).

STEP-III: Preparation of 3- [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-ylmethyl] - [1,2,4] oxadiazole-5ol.

The N-Hydroxy-2- [4- (7-methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -acetamidine solution (2.4 gm, 0.00701 moles ) in pyridine (50 ml), ethyl chloroformate (1.5 ml, 0.0157 moles) was added at 0-5 ° C. The reaction mixture was stirred for 15 minutes and the pyridine was distilled in vacuo. To the obtained residue, the mixture of water and tetrahydrofuran (1: 1) 40 ml and 1M sodium hydroxide solution (10 ml) were added and stirred at 75 ° C for one hour and continued for 24 hours at 25-28 ° Ç. The reaction mixture, 2M hydrochloric acid (200 ml) was added and extracted with ethyl acetate (2 X 100 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide 2.0 gm of a solid. The obtained solid was taken up in a mixture of tetrahydrofuran (5 ml) and 1M sodium hydroxide (50 ml) and refluxed for 24 hours. The reaction mixture was cooled and 2N hydrochloric acid (100 ml) was added. The separated solid was filtered, washed with water (20 ml) and dissolved in ethyl acetate (100 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide 880 mg of the desired product as a solid. Yield: 34.10%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.52 (1H, s), 5.14 (2H, s), 3.64 (3H, s), 3.51 (2H, s) , 2.86 (2H, t), 2.74 (2H, t), 2.13 (3H, s), 2.08 (3H, s), 1.95-2.03 (2H, m), 1.94 (3H, s).

STEP-IV: Preparation of 3- [4- (7-Hydroxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-ylmethyl] - [1,2,4] oxadiazole-5ol.

It was prepared using a similar method as described for step-VI of Example 2. Yield: 79.5%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.15 (1H, s), 6.44 (1H, s), 5.14 (2H, s), 3.46 (2H, s) , 2.68-2.77 (4H, m), 2.13 (3Η, s), 2.03 (3H, s), 1.87-1, 99 (5H, m). Mass: 353 (M ⁺ 1) ·

Example-10: (Compound No. 66).

Propane-2-sulfonic acid {3- [4- (7-methoxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -propionyl} -amide.

The suspension of 60% sodium hydride (76 mg, 0.0019 moles) in tetrahydrofuran (2 ml), the solution of 3- (4- (7Methoxy-6-methyl-indan-4-ylmethyl) -3.5 -dimethyl-pyrazol-1-yl] propionamide (500 mg, 0.00146 moles) in tetrahydrofuran (5 ml) was added at room temperature and stirred for 20 minutes A solution of isopropyl sulfonyl chloride (0.18 ml, 0 .0016 moles) in tetrahydrofuran (3 ml) was added at 0-5 ° C and stirred at 15-25 ° C for 3 hours The tetrahydrofuran was distilled in vacuo, dilute hydrochloric acid (20 ml) was added to the reaction mixture and extracted with ethyl acetate (50 ml). The ethyl acetate layer was dried over sodium sulfate and distilled in vacuo to provide a crude product, which was purified by column chromatography using ethyl acetate as the mobile phase. The fractions were distilled to provide 80 mg of the desired compound as a solid Yield: 12.2%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 11.50 (1H, bs), 6.49 (1H,

s) , 4.12 (2H, t), 3.64 (3H, s) , 3.51-3.55 (1H, m), 3.47 (2H, s) , 2.80-2.88 (4H, m), 2.73 (2H, t), 2.09 (3H, s), 2.08 (3H, s), 1.96 · -2.03 (2H, m), 1.91 (3H, s), 1.20 (6H,

d). Mass: 446 (M ⁺ -l).

Example-11: (Compound No. 12).

7- [1- (2-Hydroxy-ethyl) -3,5-dimethyl-1H-pyrazol-4-ylmethyl-3-5methyl-indan-4-ol.

STEP-I: Preparation of 3- (7-Methoxy-6-methyl-indan-4-ylmethyl) pentane-2,4-dione.

The solution of 7-Methoxy-6-methyl-indan-4-carbaldehyde (8.0 gm 0.042 moles) and acetyl acetone (4.63 gm, 0.046 moles) in toluene (80 ml), piperidine (0.5 ml) and acetic acid (0.5 ml) were added. The reaction mixture was refluxed over a 3Å molecular sieve using a Dean Stark apparatus for 24 hours. Toluene was distilled under vacuum to provide a crude product, which was purified by column chromatography using ethyl acetate in 5% hexane. The fractions were distilled to provide 3.0 gm of condensed product. It was dissolved in methanol (60 ml) and hydrogenation was carried out over palladium on 5% w / w barium sulfate (350 mg) at 40-50 psi. using hydrogen gas at 2590

30 ° C. The reaction mixture was filtered through a bed

Hyflow and vacuum distilled to provide 2.9 gm of desired compound as a viscous oil. Yield: 25.1%.

Mass: 274 (M ⁺ -l).

STEP-II: Preparation of 2- [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -ethanol.

To a stirred solution of 3- (7-Methoxy-6-methyl-indan-4ylmethyl) -pentane-2,4-dione (1.0 gm 0.0036 moles) in ethanol (15 ml), a solution of 2- hydrazino-ethanol (0.33 gm, 0.0043 moles) in ethanol (5 ml) was added at 25-30 ° C and the reaction mixture was heated to 70 ° C for one hour. Acetic acid (2 ml) was added. In addition, the reaction mixture was stirred at 70 ° C for 3 hours. Ethanol was distilled under vacuum to provide a residue which was partitioned between ethyl acetate (50 ml) and water (25 ml). Ethyl acetate was distilled in vacuo to give a crude product. The crude product was solidified after stirring in diethyl ether (10 ml). The solid was filtered under vacuum and dried to provide 700 mg of the desired compound as a solid. Yield: 61.4%. Mass: 315 (M ⁺ + 1).

STEP-III: Preparation of 7- [1- (2-Hydroxy-ethyl) -3,5-dimethyl-1Hpyrazol-4-ylmethyl] -5-methyl-indan-4-ol.

It was prepared using a similar method as described for step-VI of Example 2. Yield: 45.4%.

^X H-NMR (400 MHz, DMSO-d6): δ 8.11 (1H, s), 6.43 (1H,

s), 4.80 (1H, t), 3.95 (2H, t), 3.63 (2H, q), 3.43 (2H, s), 2.69-2.77 (4H, m ), 2.08 (3H, s), 2.03 (3H, s), 1.92-1.99 (5H, m). Mass: 301 (M ⁺ + 1).

The following is a process for preparing intermediates which were used to prepare the compounds mentioned in Table 1:

Preparation of Intermediates.

1: Preparation of 7-Methoxy-6-methyl-indan-4-carbaldehyde. Method-1.

STEP-I: Preparation of 8-Methyl coumarin

The suspension of 2-hydroxy-3-methyl benzaldehyde (30 gm, 0.220 moles) and anhydrous sodium acetate (45 gm, 0.55 moles) in acetic anhydride (45 gm, 0.44 moles) was heated to 175180 ° C for 6 hours. The reaction mixture was cooled; water (150 ml) and hexane (60 ml) were added. It was stirred for an hour and filtered. The obtained solid was stirred with diethyl ether (30 ml). Finally, the suspension

was filtered and dried to provide 19 product gm wanted. Yield: 85%. ^X H-NMR (400 MHz, CDCI3): δ 7.69 (1H, d), 7.35-7.37 (1H, m), 7.30-7.32 (1H, m), 7.16 (1H, t), 6.39 (1H, d),

2.44 (3Η, s).

STEP-11: Preparation of 8-Methyl dihydrocoumarin

To a solution of 8-Methyl coumarin (16.2 gm) in ethyl acetate (160 ml), 10% w / w palladium-charcoal (1.62 gm) was added. Hydrogenation was carried out for 5 hours at 55-60 ° C in an autoclave at 240-250 psi. using hydrogen gas. The reaction mixture was filtered through a Hyflow bed and distilled under vacuum to provide 14.5 gm of the compound as a white solid. Yield: 90%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.10-7.14 (2H, m), 7.01 (1H, t), 2.93-2, 97 (2H, m), 2.73-2.76 (2H, m), 2.21 (3H,

s) .

STEP-III: Preparation of 4-Hydroxy-5-methyl-indan-1-one.

The mixture of 8-Methyl dihydrocoumarin (20 gm, 0.123 moles) and aluminum trichloride (49.3 gm, 0.370 moles) was stirred for 2 hours at 175-180 ° C. The reaction mixture, water (250 ml) was added slowly and stirred for one hour. It was further filtered and the obtained solid was stirred in methanol (60 ml). Finally, the suspension was filtered and the obtained solid was dried under vacuum to provide 13.5 gm of the desired product as a solid. Yield: 67.5%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.22 (1H, s), 7.15 (1H,

d), 7.04 (1H, d), 2.96 (2H, t), 2.59 (2H, t), 2.24 (3H, s). STEP-IV: Preparation of 5-Methyl-indan-4-ol.

To a suspension of 4-Hydroxy-5-methyl-indan-1-one (8 gm) in methanol (80 ml), 10% w / w Pd-C was added. Hydrogenation was carried out for 5 hours at 5560 ° C in an autoclave at 200-250 psi using hydrogen gas. The reaction mixture was filtered through a Hyflow bed and the filtrate was distilled under vacuum to provide 6.0 gm of the desired product as a white solid. Yield: 82.2%.

^ -NMR (400 MHz, DMSO-d ₅ ): δ 8.36 (1H, s), 6.82 (1H, d), 6.58 (1H, d), 2.73-2.79 (4H , m), 2.10 (3H, s), 1,921.99 (2H, m).

STEP-V: Preparation of 7-Hydroxy-6-methyl-indan-4-carbaldehyde

To a clear solution of 5-Methyl-indan-4-ol (6 gm, 0.0405 moles) in 30 ml of trifluoroacetic acid, hexamine (5.7 gm, 0.0405 moles) was added at 25-28 ° C. The reaction mixture was heated and stirred at 85-90 ° C for 6 hours. The cold reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate (2 X 200 ml). The organic layer was dried over sodium sulfate and distilled under vacuum to provide a crude product, which was purified by column chromatography using ethyl acetate: hexane (10:90) as a mobile phase. The fractions collected were

distilled for provide 5.4 product gm wanted like a solid. Yield: 76%. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.87 (1H, s) , 9.63 (1H, bs), 7.44 (1H, s), 3.14 (2H, t), 2.79 (2H, t), 2.18 (3H,

s), 1.99-2.08 (2H, m).

EΤΑΡΑ-VI: Preparation of 7-Methoxy-6-methyl-indan-4-carbaldehyde.

To a stirred suspension of 6-Methyl-7-hydroxy-indan-4carbaldehyde (5 gm, 0.0284 moles) and potassium carbonate (4.7 gm, 0.0340 moles) in dimethyl formamide, methyl iodide (2, 2 ml, 0.0312 moles) was added at 0 ° C. The reaction mixture was stirred at 25-30 ° C for 4 hours, then water (200 ml) was added and extracted with ethyl acetate (2 X 100 ml). The ethyl acetate layer was dried over sodium sulfate and evaporated to provide a crude mass, which was purified by column chromatography using ethyl acetate: hexane (10:90) as a mobile phase. The fractions were vacuum distilled to provide 4.8 gm of the desired product as a viscous oil. Yield: 88.9%.

1H-NMR (400 MHz, DMSO-d ₆ ): δ 9.97 (1H, s), 7.50 (1H,

s), 3.84 (3H, s), 3.14 (2H, t), 2.96 (2H, t), 2.22 (3H, s),

2.01-2.08 (2Η, m). MASS: 191 (M ⁺ + 1).

Method-2

STEP-I: Preparation of 4-Hydroxy-indan-5-carbaldehyde

To a stirred suspension of magnesium chloride (71.0 gm, 0.745 moles) and para-formaldehyde (33.6 gm, 1.12 moles) in tetrahydrofuran (200 ml), triethylamine (104 ml, 0.745 moles) was added in at room temperature and stirred for 35 minutes. The reaction mixture, the solution of indan-4-ol (50 gm, 0.373) in tetrahydrofuran (100 ml) was added at room temperature and heated to 70-

75 ° C for 6 hours. The mixture in reaction, acid hydrochloric to 2N (600 ml) was added and extracted with acetate ethyl (2 X 500 ml). The layer of acetate ethyl was washed

with water (300 ml), dried over sodium sulfate and was further distilled in vacuo to provide a viscous oil (52.0 gm), which became solid upon standing. Yield: 86.0%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (1H, s), 10.04 (1H, s), 7.55 (1H, d), 6.95 (1H, d) , 2.91 (2H, t), 2.83 (2H, t), 2.02-2.09 (2H, m).

STEP-II: Preparation of 5-Methyl-indan-4-ol.

To a solution of 4-Hydroxy-indan-5-carbaldehyde (5 gm) in methanol (80 ml), 10% w / w palladium-carbon (500 mg) was added. Hydrogenation was carried out for 8 hours at 55-60 ° C in an autoclave at 240-250 psi using hydrogen gas. The reaction mixture was filtered through a Hyflow bed and distilled under vacuum to provide 4.0 gm of the title compound as a solid. Yield: 88.0%. STEP-III: Preparation of 7-Hydroxy-6-methyl-indan-4carbaldehyde.

It was prepared using the same procedure as described for step-V of method 1 to prepare intermediate 1.

STEP-IV: Preparation of 7-Methoxy-6-methyl-indan-4-carbaldehyde.

It was prepared using the same procedure as described for step-V of method 1 to prepare intermediate 1.

2: Preparation of 7-Methoxy-6- (4-methyl-benzyl) -indan-4carbaldehyde.

STEP-I: Preparation of 4-Methoxy-indan-5-carbaldehyde.

To a stirred suspension of 4-Hydroxy-indan-5carbaldehyde (52.0 gm, 0.320 moles) and potassium carbonate (57.2 gm, 0.414 moles) in solution in dimethylformamide (200 ml) of methyl iodide (22 ml, 0.351 moles) in 60 ml of dimethylformamide was added at 0-5 ° C. The reaction mixture was stirred at 25-28 ° C for 4 hours and then poured into water (200 ml). It was also extracted with ethyl acetate (2 X 500 ml). The organic layer was dried over sodium sulfate, vacuum distilled to provide the crude product, which was purified by column chromatography using ethyl acetate: hexane (3:97) as a mobile phase. The collected fractions were distilled under vacuum to provide 30 gm of the desired product as a viscous oil. Yield: 53.0%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 10.26 (1H, s), 7.54 (1H, d), 7.12 (1H, d), 3.92 (3H, s) , 3.01 (2H, t), 2.91 (2H, t), 2.03-2.10 (2H, m).

STEP-II: Preparation of 4-Methoxy-5- (4-methyl-benzyl) -indane.

To a stirred suspension of magnesium gyrate (1.36 gm, 0.056 moles) in 60 ml of diethyl ether, 4Bromo toluene (8.7 ml, 0.071 moles) in 20 ml of diethyl ether was added at 30-40 ° C under a nitrogen atmosphere. It was further stirred at 30-40 ° C for 45 minutes. The solution of 4-methoxy-indan-5-carbaldehyde (5.0 gm, 0.0284 moles) in 20 ml of diethyl ether was added to the reaction mixture at room temperature. After one hour of stirring at room temperature, dilute hydrochloric acid was added and extracted with ethyl acetate (2 X 100 ml). The organic layer was dried over sodium sulfate, vacuum distilled to provide 8.0 gm of crude alcohol, which was taken up with triethyl silane (40.0 ml, 0.250 moles) and trifluoroacetic acid (80 ml) was added at 0 -5 ° C. After stirring at 70 ° C for 5 hours, the reaction mixture was

spilled in solution saturated in bicarbonate sodium and extracted with acetate in ethyl (2 X 100 ml). The layer in acetate in ethyl was dry on sulfate sodium and

distilled to provide a crude mass, which was purified by column chromatography using ethylazhexane acetate (3:97) as the mobile phase. The fractions were distilled to provide 5.6 gm of pure product as a viscous oil. Yield: 78.2%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 7.05-7.07 (4H, s), 6.90 (1H, d), 6.87 (1H, d), 3.82 ( 2H, s), 3.62 (3H, s), 2.88 (2H, t), 2.79 (2H, t), 2.23 (3H, s), 1.95-2.01 (2H , m).

STEP-III: Preparation of 7-Methoxy-6- (4-methyl-benzyl) -indan-4carbaldehyde.

It was prepared using the same procedure as described for step-V of method-1 to prepare intermediate 1. Yield: 21%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 9.97 (1H, s), 7.49 (1H,

s), 7.07 (4H, s), 3.89 (2H, s), 3.78 (3H, s), 3.16 (2H, t), 2.97 (2H, t), 2, 24 (3H, s), 2.02-2.09 (2H, m). MASS: 281 (M ⁺ + 1).

3. Preparation of 7-Methoxy-3,6-dimethyl-indan-4-carbaldehyde.

STEP-I: Synthesis of 4-Methoxy-5-methyl-indan-l-one

To a suspension of 4-Hydroxy-5-methyl-indan-1-one (50.0 gm, 0.308 moles) and potassium carbonate (127.0 gm, 0.928 moles) in dimethylformamide (250 ml), dimethyl sulfate ( 90 ml, 0.928 moles) was added at 0 ° C. The reaction mixture was heated to 60-65 ° C and stirred for 16 hours. The reaction mixture was poured into water (1 liter) and extracted with ethyl acetate (3 X 250 ml). The organic layer was dried over sodium sulfate and vacuum distilled to provide 10.0 gm of crude product, which was purified by column chromatography using hexane as a mobile phase. The collected fractions were distilled under vacuum to provide 45.0 gm of the desired product as a viscous oil. Yield: 82.5%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 7.30 (1H, d), 7.27 (1H, d), 3.84 (3H, s), 3.12 (2H, t) , 2.60-2, 63 (2H, m), 2.31 (3H, s).

STEP-II: Synthesis of 4-methoxy-1,5-dimethyl-indane

To a spinning suspension of magnesium (2.72 gm, 0.113 moles) in diethyl ether (40 ml), a solution of methyl iodide (13.7 ml, 0.219 moles) in diethyl ether (10 ml) was

100 added slowly at 30-35 ° C under a nitrogen atmosphere. The reaction mixture was stirred for one hour at room temperature and then a solution of 4 Methoxy-5-methyl-indan-l-one (10.0 gm, 0.0568 moles) in diethyl ether (30 ml) was added at 0 ° C. The reaction mixture was stirred for one hour at room temperature and then dilute hydrochloric acid (50 ml) was added. It was extracted with ethyl acetate (3 X 50 ml). The organic tf layer was dried over sodium sulfate, vacuum distilled to provide 10.0 gm of crude alcohol. The obtained alcohol was taken up with triethyl silane (41.3 ml, 0.258 moles) and trifluoroacetic acid (100 ml) was added at 0 ° C. The reaction mixture was stirred at 65-70 ° C for 4 hours and poured into saturated sodium bicarbonate solution. It was extracted with ethyl acetate (2 X 100 ml), dried over sodium sulfate, distilled in vacuo to provide a crude mass, which was purified by column chromatography using hexane as a mobile phase. The collected fractions were vacuum distilled to provide 5.0 gm of the desired product as a viscous oil. Yield: 50%.

^X H-NMR (400 MHz, DMSO-d6): δ 6.96 (1H, d), 6.81 (1H,

d), 3.69 (3H, s), 3.04-3.10 (1H, m), 2.87-2, 94 (1H, m),

101

2.73-2.81 (1Η, m), 2.21-2.28 (1H, m), 2.15 (3H, s), 1,461.55 (1H, m), 1.20 (3H, d).

STEP-III: synthesis of 7-Methoxy-3,6-dimethyl-indan-4carbaldehyde.

It is prepared using the same procedure as described for step-V of method 1 for preparation of intermediate 1. Yield: 43.1%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.98 (1H, s), 7.52 (1H,

s), 3.86 (3H, s), 3.76-3.79 (1H, m), 2.89-3.08 (2H, m),

2.12-2.21 (4H, m), 1.79-1.84 (1H, m), 1.12 (3H, d).

4: Preparation of 7-Methoxy-6-methyl-2- (4-nitro-phenoxy) -indan-4carbaldehyde.

Step-I: synthesis of 2-Bromo-4-methoxy-5-methyl-indan-1-one.

To a stirred solution of 4-Methoxy-5-methyl-indan-l-one (5.0 gm, 0.0284 moles) in acetic acid (65 ml) and hydrobromic acid (1 ml), a bromine solution (1 , 47 ml, 0.0284 moles) in 5 ml of acetic acid was added at 10-20 ° C. The reaction mixture was stirred at 20-25 ° C for one hour. Then, it was poured into a saturated sodium bicarbonate solution and extracted with diethyl ether (3 X 100 ml). The organic layer was dried over sodium sulfate, distilled in vacuo to provide a crude product, which was purified on a chromatographic column using

102 ethyl acetate: hexane (5:95) as a mobile phase. The collected fractions were distilled to provide 3.2 gm of the desired product as a viscous oil. Yield:

44.2%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.44 (1H, d), 7.38 (1H, d), 5.00-5, 03 (1H, m), 3.89- 3.97 (1H, m), 3.84 (3H, s), 3,313.36 (1H, mixed with water peak present in DMSO-do), 2.33 (3H, s).

STEP-II: synthesis of 4-Methoxy-5-methyl-2- (4-nitro-phenoxy) indan-l-one.

To a stirred solution of 2-Bromo-4-methoxy-5-methylindan-l-one (2.0 gm, 0.0078 moles) in dimethylformamide (15 ml), 4-nitrophenol sodium salt (1, 27 gm, 0.0078 moles) at 10-15 ° C. After 2 hours of stirring at 2528 ° C, the reaction mixture was poured into water (50 ml). The separated solid was filtered, washed with hexane and dried in vacuo to provide 1.8 gm of desired product as a solid. Yield: 73.4%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.26 (2H, d), 7.30-7.43 (4H, m), 5.58 (1H, dd), 3, 89- 3.95 (1H, m), 3.85 (3H, s), 3.10-3.15 (1H, m), 2.34 (3H, s).

STEP-III: Synthesis of 4-Methoxy-5-methyl-2- (4-nitro-phenoxy) indane.

103

To a mixture of 4-Methoxy-5-methyl-2- (4-nitro-phenoxy) indan-l-one (1.8 gm, 0.0057 moles) and triethyl silane (9.0 ml, 0.0564 moles ), trifluoroacetic acid (18 ml) was added at 20-25 ° C. The reaction mixture was heated to

- 65 ° for 3 hours and then poured into saturated sodium bicarbonate solution. It was extracted with ethyl acetate (2 X 100 ml), dried over sodium sulfate, distilled in vacuo to provide a crude product, which was purified by column chromatography using ethyl acetate: hexane (2:98) as a mobile phase. The collected fractions were vacuum distilled to provide 1.2 gm of desired product as a solid. Yield: 69.7%.

¹ H-NMR (400 MHz, DMSO-d6): δ 8.22 (2H, d), 7.18 (2H, d), 7.02 (1H, d) , 6.91 (1H, d), 5.40- 5.43 (1H, m), 3.71 (3H, s), 3.38-3, 51 (2H, m), 2.99- • 3, 10 (2H, m), 2.18 (3H,

s) .

STEP-IV: Synthesis of 7-Methoxy-6-methyl-2- (4-nitro-phenoxy) indan-4-carbaldehyde.

It was prepared using the same procedure as described for step-V of method 1 for preparation of intermediate 1. Yield: 93.1%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 9.95 (1H, s), 8.19 (2H,

104

d), 7.61 (1H, s) , 7.19 (2H, d), 5.47- • 5.50 (1H, m), 3.88 (3H, s) , 3.55 -3, 70 (2H, m), 3.42 -3.46 (1H, m), 3.17-3.21 (1H, m), 2.25 (3H, s). PASTA: 328 (M ⁺ + l) • 5: Preparation in 7-Methoxy-2, 2, 6-trimethyl-indan-4-

carbaldehyde.

STEP-I: Preparation of 4-Methoxy-2,2,5-trimethyl-indan-1-one.

To a 60% sodium hydride suspension (2.72 gm,

0.068 moles) in 30 ml of tetrahydrofuran, a solution of 4-Methoxy-5-methyl-indan-l-one (10.0 gm, 0.0568 moles) in tetrahydrofuran (30 ml) was added at 0-5 ° C ; still, to that, methyl iodide (9.09 ml, 0.146 moles) was added at 0 ° C. The reaction mixture was stirred for 2 hours, then water (100 ml) was added and extracted with ethyl acetate (2 X 100 ml). The ethyl acetate layer was dried over sodium sulfate and evaporated to provide a crude mass, which was purified by column chromatography using ethyl acetate: hexane (3:97) as a mobile phase. The fractions were vacuum distilled to provide 3.0 gm of the desired product as a viscous oil. Yield: 25.88%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 7.31 (1H, d), 7.29 (1H,

d), 3.83 (3H, s), 3.03 (2H, s), 2.30 (3H, s), 1.14 (6H, s). STEP-11: Preparation of 4-Methoxy-2,2,5-trimethyl-indan.

105

It was prepared using the same procedure as described for step-III of preparation of intermediate 4. Yield: 92.3%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.99 (1H, d), 6.79 (1H,

d), 3.68 (3H, s), 2.70 (2H, s), 2.62 (2H, s), 2.14 (3H, s),

1.10 (6H, s).

STEP-III: Preparation of 7-Methoxy-2,2,6-trimethyl-indan-4carbaldehyde.

It is prepared using the same procedure as described for step-V of method 1 of preparing intermediate 1. Yield: 50.8%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 9.95 (1H, s), 7.51 (1H,

s), 3.83 (3H, s), 2.98 (2H, s), 2.80 (2H, s), 2.21 (3H, s), 1.12 (6H, s).

6: Preparation of 7-Methoxy-6- (pyrrolidine-1-carbonyl) -indan-4carbaldehyde.

STEP-I: Preparation of 4-Methoxy-indan-5-carboxylic acid.

To a clear solution of 4-Methoxy-indan-5-carbaldehyde (11.5 gm, 0.065 moles) in dichloromethane (100 ml), sulfamic acid (19.0 gm, 0.196 moles) was added at 25-28 °. A solution of sodium chlorite (15.28 gm, 0.169 moles) in water (50 ml) was added at 5-10 ° C. The reaction mixture was stirred for 5 hours at 25-28 ° C. Finally, the

106 reaction mixture was poured into water (200 ml) and extracted with dichloromethane (2 X 200 ml). The organic layer was dried over sodium sulfate, distilled in vacuo to provide 12.0 gm of the desired product as a viscous oil. Yield: 96.0%. MASS: 191 (M ⁺ -l).

STEP-II: Preparation of (4-Methoxy-indan-5-yl) -pyrrolidin-1-ylmethanone.

To a clear solution of 4-Methoxy-indan-5-carboxylic acid (12.0 gm, 0.0625 moles) in tetrahydrofuran (60 ml), carbonyl-diimidazole (13.24 gm, 0.0812 moles) was added at 25- 28 ° C. The reaction mixture was heated to 65-70 ° C and stirred for 2 hours. The reaction mixture, a solution of pyrrolidine (5.74 ml, 0.0687 moles) in tetrahydrofuran (20 ml) was added at 10-15 ° C. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (200 X 100 ml). The organic layer was dried over sodium sulfate, distilled in vacuo and purified by column chromatography using ethyl acetate: hexane (20:80) as a mobile phase. The fractions were vacuum distilled to provide 6.0 gm of the desired product as a viscous oil. Yield: 39.2%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.98 (2H, s), 3.74 (3H, s), 3.44 (2H, t), 3.13 (2H, t) , 2.85-2.94 (4H, m), 2.01107

2.06 (2Η, m), 1.75-1.88 (4H, m).

STEP-III: Preparation of 7-Methoxy-6- (pyrrolidine-1-carbonyl) indan-4-carbaldehyde.

It was prepared using the same procedure as described for step-V of method 1 to prepare intermediate 1. Yield: 71.7%.

^X H-NMR (400 MHz, DMSO-dg): δ 10.0 (1H, s), 7.60 (1H,

s), 3.88 (3H, s), 3.46-3.49 (2H, m), 3.16-3.24 (4H, m),

2.97 (2H, t), 2.05-2.13 (2H, m), 1.80-1.92 (4H, m). PASTA:

298 (M ⁺ + 1).

7: Preparation of 7-Methoxy-6- (4-methoxy-phenyl) -indan-4carbaldehyde.

STEP-I: Preparation of 6-Bromo-7-methoxy-indan-4-carbaldehyde.

To a solution of 4-Hydroxy-indane (10.0 gm, 0.0746 moles) and diisopropylamine (1 ml) in dichloromethane (100 ml), N-Bromo succinimide (13.28 gm, 0.0746 moles) was added slowly at 5-15 ° C. The reaction mixture was stirred for 20 hours. Dichloromethane was distilled and the residue was partitioned between water (100 ml) and diethyl ether (200 ml). Diethyl ether was distilled in vacuo to provide a crude solid (14.4 gm). The solid was dissolved in trifluoroacetic acid (100 ml) and hexamine (8.4 gm, 0.06 moles) was added at 25 - 28 ° C. In addition, the reaction mixture was

108 heated to 85-90 ° C for 4 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 100 ml). The organic layer was dried over sodium sulfate, distilled in vacuo to provide a crude mass, which was purified by column chromatography using ethyl acetate: hexane (3:97) as the mobile phase. The collected fractions were distilled to provide 7.34 gm of aldehyde. Finally, the solution of the obtained aldehyde (7.34 gm, 0.0304 moles) in dimethylformamide (30 ml), potassium carbonate (6.3 gm, 0.0463 moles) was added and stirred for one hour. To the reaction mixture, methyl iodide (2.9 ml, 0.0463 moles) was added at 0-5 ° C and stirred at 20-25 ° C for 4 hours. Then, water (100 ml) was added and extracted with diethyl ether (3 X 100 ml). The diethyl ether was dried over sodium sulfate and distilled to provide a crude product, which was purified by column chromatography using ethyl acetate: hexane (2:98). The fractions were vacuum distilled to provide 1.06 gm of the title compound as a solid. Yield: 5.5%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 9.97 (1H, s), 7.91 (1H, s), 3.91 (3H, s), 3.16 (2H, t) , 3.03 (2H, t), 2.04-2.12

109 (2Η, m).

STEP-II: Preparation of 7-Methoxy-6- (4-methoxy-phenyl) -indan-4carbaldehyde.

To a suspension of 6-Bromo-7-methoxy-indan-4carbaldehyde (0.2 gm, 0.00078 moles), 4-methoxyphenyl boronic acid (0.122 gm, 0.0008 moles) and potassium carbonate (0.27 gm , 0.0019 moles) in toluene (5 ml) and water (5 ml), tetrakis (triphenylphosphine) palladium (O) (2 mg) was heated to 85-90 ° C and stirred for 6 hours. Toluene was distilled and the residue obtained was dissolved in diethyl ether (50 ml). In addition, it was washed with water (20 ml) and the ether was distilled under vacuum to provide a crude mass, which was purified by column chromatography using ethyl acetate: hexane (1:99) as a mobile phase. The fractions were distilled to provide 50 mg of the desired product as a solid. Yield: 22.7%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 10.05 (1H, s), 7.65 (1H,

s), 7.45 (2H, d), 7.01 (2H, d), 3.80 (3H, s), 3.61 (3H, s),

3.22 (2H, t), 2.99 (2H, t), 2.07-2.15 (2H, m). MASS: 283 (M ⁺ + 1).

8: Preparation of 6-Chlorine-7-methoxy-indan-4-carbaldehyde.

STEP-I: Preparation of 5-Chloro-indan-4-ol.

To a clear solution of indan-4-ol (40.0 gm, 0.297

110 moles) and diisopropylamine (4.29 ml, 0.029 moles) in dichloromethane (140 ml), a solution of sulfuryl chloride (21.76 ml, 0.267 moles) in dichloromethane (20 ml) was added at 0-5 ° C . The reaction mixture was stirred for 15 hours at 20-25 ° C and spilled into water (200 ml). In addition, it was extracted with ethyl acetate (2 X 200 ml). The organic layer was dried over sodium sulfate, vacuum distilled to provide a crude solid, which was purified by column chromatography using ethyl acetate: hexane (2:98) as the mobile phase. The collected fractions were distilled to provide 5.7 gm of the desired product as a solid. Yield: 11.4%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.28 (1H, s), 7.08 (1H,

d), 6.80 (1H, d), 2.79-2.83 (4H, m), 1.97-2.04 (2H, m). STEP-II: Preparation of 6-Chloro-7-hydroxy-indan-4-carbaldehyde.

It was prepared using the same procedure as described for step-V of method 1 for the preparation of intermediate 1. Yield: 81.2%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.85 (1H, s), 7.67 (1H,

s), 3.14 (2H, t), 2.81 (2H, t), 1.99-2.04 (2H, m).

STEP-III: Preparation of 6-Chlorine-7-methoxy-indan-4-carbaldehyde.

It is prepared using the same procedure as described for step-VI of method 1 for preparing the

111 intermediate 1. Yield: 55.7%.

^ -NMR (400 MHz, DMSO-d ₆ ): δ 10.04 (1H, s), 7.84 (1H, s), 3.98 (3H, s), 3.24 (2H, t), 3.08 (2H, t), 2.11 - 2.19 (2H, m). MASS: 211 (M ⁺ + 1).

9: Preparation of 7-Methoxy-6-methyl-indan-4-ol.

To a stirred solution of 7-methoxy-6-methyl-indan-4carbaldehyde (1.0 gm, 0.0060 moles) in methanol (20 ml), sulfuric acid (0.6 ml) was added at room temperature. To the reaction mixture, 30% hydrogen peroxide (1.6 ml) was added and stirred for 1 hour at 0 ° C.

Methanol was distilled in vacuo and the residue was dissolved in ethyl acetate (50 ml). In addition, the ethyl acetate layer was washed with water and evaporated to provide a crude product which, when triturated with hexane, provides 600 mg of the title compound as a solid. Yield: 56%.

^X H-NMR (400 MHz, DMSO-d ₆ ): δ 8.78 (1H, s), 6.37 (1H,

s), 3.58 (3H, s), 2.81 (2H, t), 2.69 (2H, t), 2.09 (3H, s), 1.95-1.98 (2H, m ).

MASS: 177 (M ⁺ -l).

The following compounds were prepared using the procedure mentioned in the reaction diagram, as shown above.

112

Table 1:

At the. Comp. NAME ¹ H-NMR (400 MHz, DMSO-dg) PASTA IR (KBr, CM ^-1 ) 1 Acid 3- [4- (7- Hydroxy-indan-4yloxy) -3,5dimethyl-pyrazol1-yl] -propionic δ 12.27 (1H, bs), 8.77 (1H, bs), 6.42 (1H, d), 6.15 (1H, d), 4.10 (2H, t), 2.84 ( 2H, t), 2.71 2.78 (4H, m), 1.98- 2.04 (5H, m), 1.88 (3H, s). 315 (M ⁺ -l) 3215, 1702, 1653, 1599 2 3- [4- (1Hindol-5ylmethyl) -3,5dimethyl-pyrazol1-yl] -propionic acid δ 12.33 (1H, bs), 10, 93 (1H, S), 7.21-7.27 (3H, m), 6.85 (1H, dd), 6.31 (lH, t), 4.10 (2H, t), 3.69 (2H, s), 2.71 (2H, t), 2.17 (3H, s), 1.99 (3H, s). 298 (M ⁺ -l) 3392, 1710, 1558, 1507 3 7- [3,5-Dimethyl1- (1H-tetrazol5-ylmethyl) -1Hpyrazol-4yloxy] -indan-4ol δ 8.85 (1H, s), 6.44 (1H, d), 6.21 (1H, d), 5.55 (2H, s), 2.84 (2H, t), 2.76 (2H, t), 2.11 (3H, s) , 2.00-2.06 (2H, m), 1.88 (3H, s). 325 (M ⁺ -l) 3313, 1589, 1553, 1484 4 7- {3,5-Dimethyl- 1- [2- (1Htetrazol-5-yl) ethyl] -1Hpyrazol-4- δ 8.74 (lH, bs), 6.42 (1H, d), 6, O9 (1H, d), 4.33 (2H, t), 3.37 (2H, t), 2.74-2.82 (4H, m), 2.012.05 ( 2H, m), 1.89 (3H, 339 (M ⁺ -l) 3310, 1646, 1553, 1486

113

iloxy} -indan-4- hello s), 1.87 (3H, s). 5 Acid {2- [4- (7- Hydroxy-indan-4yloxy) -3,5dimethyl-pyrazole- 1-yl] acetylamino} acetic δ 12.65 (1H, bs), 8.82 (1H, S), 8.26 (1H, t), 6.43 (1H, d), 6.21 (1H, d), 4.69 (2H, s), 3.79 (2H, d), 2.85 (2H, t), 2.76 (2H, t), 1.99-2.06 (5H, m), 1.83 (3H, s). 358 (M ⁺ -l) 3346, 1660, 1553, 1491 6 2- [4- (7-Hydroxyindan-4-yloxy) - 3,5-dimethylpyrazol-1-yl] -N (1H-tetrazol-5yl) -acetamide δ 12.48 (lH, bs), 8.80 (lH, bs), 6.44 (1 H, d), 6.21 (lH, d), 5.03 (2H, s), 2.87 (2H, t), 2.77 (2H, t), 1.992.07 (5H, m), 1.89 (3H, s). 368 (M ⁺ -l) 3226, 1712, 1620, 1555 7 Acid 3- [4- (7- Hydroxy-indan-4yloxy) -3-thiophen2-yl-pyrazol-lil] -propionic e 3- [4- (7hydroxy-indan-4yloxy) -5-thiophen2-yl-pyrazol-lil] -propionic acid For the main isomer δ 12.41 (1H, s), 9.00 (1H, S), 7.55 (1H, s), 7.44 (lH, d), 7.29 (lH, d), 7.04-7.06 (1H, m), 6.46-6.54 (2H, m), 4.24 (2H, t), 2.73-2.84 (6H, m), 1,962.06 (2H, m). 368.99 (M ⁺ -l) 3108, 1708, 1564, 1486 8 7- [1- (1H- For the isomer 379 3243,

114

tetrazol-5ylmethyl) -3tiophen-2-yl-1Hpyrazol-4yloxy] -indan-4ol and 7- [1- (1H- Tetrazol-5ylmethyl) -5thiophen-2-yl-1Hpyrazol-4yloxy] -indan-4ol main δ 9.07 (1H, s), 7.69 (1H, S), 7.47 (1H, dd), 7.35 (1H, dd), 7.06-7.08 (1H, m), 6.63 (1H, d), 6.53 (H, d), 5.67 (2H, s), 2.77-2.86 (4H, m), 1.99-2.06 (2H, m). (M ⁺ -l) 1732, 1550, 1483 9 Acid 3- [4- (7- Hydroxy-6-methylindan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -propionic δ 12.31 (1H, bs), 8.11 (1H, s), 6.41 (1H, s), 4.09 (2H, t), 3.43 (2H, s), 2.68-2.77 (6H, m), 2.09 (3H, s), 2.03 (3H, s), 1.94- 1.99 (2H, m), 1.91 (3H, s). 327 (M ⁺ -l) 3388, 1686, 1616, 1489 10 5- [4- (7-Hydroxyindan-4-yloxy) - 3,5-dimethylpyrazol-1ylmethyl] -1Hpyrazol-3-ol δ 8.82 (lH, bs), 6.41 (1H, d), 6.15 (1H, d), 5.22 (1H, s), 5.01 (2H, s), 2.82 (2H, t), 2.74 (2H , t), 1.93-2.06 (5H, m), 1.84 (3H, s). 339 (M ⁺ -l) 3143, 1581, 1546, 1483 11 Acid 2— [4— (7— Hydroxy-6-methyl- δ 12.86 (1H, bs), 312.9 (M ⁺ -l) 3392, 1730,

115

indan-4ylmethyl) -3,5dimethyl-pyrazoll-yl] -acetic 8.13 (1H, s), 6.44 (1H, s), 4.81 (2H, s), 3.45 (2H, s), 2.69-2.77 (4H, m), 1.89-2.03 (HH, m). 1569, 1485 12 7- [1- (2-Hydroxyethyl) -3,5dimethyl-1Hpyrazol-4ylmethyl] -5methyl-indan-4-ol δ 8.11 (1H, s), 6.43 (lH, s), 4.80 (lH, t), 3.95 (2H, t), 3.63 (2H, q), 3.43 (2H, s), 2.69-2.77 (4H, m), 2.08 (3H, s), 2 , 03 (3H, s), 1.92-1, 99 (5H, m). 301 (M ⁺ -l) 3320, 3167, 1570, 1481 13 [4- (1Hlndol-5ylmethyl) -3,5dimethyl-pyrazoll-yl] -acetic acid δ 12.97 (lH, bs), 10.95 (1H, S), 7.25-7.27 (2H, m), 7.22 (lH, s), 6.86 (lH, dd), 6.31 (1H, S), 4.78 (2H, s), 3.71 (2H, s), 2.10 (3H, s), 1.99 (3H, s). 284 (M ⁺ -l) 3401, 1712, 1640, 1470 14 Acid 3- [4- (7- Methoxy-6-methyl- indan-4ylmethyl) -3,5dimethyl-pyrazoll-yl] -propionic δ 12.29 (1H, bs), 6.49 (1H, s), 4.10 (2H, t), 3.64 (3H, s), 3.48 (2H, s), 2.86 (2H, t), 2.68-2.75 (4H, m), 2.10 (3H, s), 2.08 (3H, s), 1. 96-2.03 (2H, m), 1.92 (3H, s). 342.9 (M ⁺ -l) 2941, 1729, 1557, 1475 15 7- [3,5-Dimethyl- 1- (lH-tetrazole- δ 8.13 (1H, bs), 6, 43 (1H, s), 5.53 (2H, s), 337 (M ⁺ -l) 3233, 1542,

116

5-ylmethyl) -1H- pyrazol-4ylmethyl] -5methyl-indan-4-ol 3.46 (2H, s), 2.75 (2H, t), 2.70 (2H, t), 2.17 (3H, s), 2.03 (3H, s), 1.91-1.99 (5H, m). 1488, 1453 16 7- [3,5- Diisopropyl-1- (1H-tetrazole-5- ylmethyl) -1Hpyrazol-4ylmethyl] -5methyl-indan-4-ol δ 8.12 (1H, s), 6.25 (1H, s), 5.56 (2H, s), 3.59 (2H, s), 3.19-3.20 (1H, m), 2.77-2.79 (4H, m), 2.65-2.68 (1H, m), 1.94-2.10 (5H, m), 1.07 (6H, d), 1.02 (6H, d) 393 (M ⁺ -l) 2962, 1668, 1599, 1478 17 3- [3,5Dicyclopropyl-4 (7-hydroxyindan-4-yloxy) pyrazol-l-yl] propionic acid δ 12.36 (1H, bs), 8.80 (1H, S), 6.43 (1H, d), 6.14 (1H, d), 4.22 (2H, t), 2.87 (2H, t), 2,752.79 (4H, m), 2.02-2.07 (2H, m), 1 , 67-1.71 (lH, m), 1.45-1.49 (lH, m), 0.72-0.76 (2H, m), 0.62-0.67 (6H, m). 367 (M ⁺ -l) 3213, 2949, 1702, 1482 18 Acid 3- [4- (7- Hydroxy-6-methylindan-4- ilmethyl) -3,5diisopropylpyrazol-l-yl] propionic δ 12.39 (1H, bs), 8.11 (1H, s), 6.23 (1H, s), 4.21 (2H, t), 3.55 (2H, s), 3.04-3.11 (1H, m), 2.69-2.79 (6H, m), 2.60-2.67 383 (M ⁺ -l) 2963, 1716, 1584, 1481

117

(1H, m), 1.93-2.03 (5H, m), l, 12 (6H, d), 1.04 (6H, d). 19 Acid [3,5- Diethyl-4- (7- hydroxy-6-methylindan-4- ilmethyl) pyrazol-l-yl] acetic δ 8.14 (1H, s), 6, 39 (1H, S), 4.77 (2H, s), 3.48 (2H, mixed with water peak present in DMSO-d6> 2.68-2 , 77 (4H, m), 2.43 (2H, q), 2.30 (2H, q), 1.94-2.01 (5H, m), 1.00 (3H, t), 0, 90 (3H, t), ^X H-NMR (400MHz, CD ₃ OD) δ 6.66 (1H, s), 4.83 (2H, s), 3.59 (2H, s), 2,752.83 ( 4H, m), 2.51 (2H, q), 2.42 (2H, q), 1,912.07 (5H, m), 1.05 (3H, t), 0.97 (3H, t). 341 (M ⁺ -l) 3398, 2931, 1718, 1476 20 Acid 3- [3,5- Diethyl-4- (7-hydroxy-6-methylindan-4- ilmethyl) pyrazol-l-yl] propionic δ 8.13 (1H, s), 6, 37 (1H, s), 4.12 (2H, t), 3.47 (2H, s), 2,722.76 (6H, m), 2.51 ( 2H, mixed with peak in DMSO-d6), 2.31 (2H, q), 1.97-2.01 (5H, m), 1.00 (3H, t), 0.93 (3H, t) , ¹ H-NMR (400MHz, CD3OD) δ 6.42 (lH, s), 4.26 (2H, t), 355 (M ⁺ -l) 3380, 2951, 1707, 1554

118

3.56 (2H, s), 2.79-2, 83 (4H, m), 2.75 (2H, t), 2.57 (2H, q), 2.42 (2H, q), 1.98-207 (5H, m), 1.04 (3H, t), 0.99 (3H, t). 21 7- [3,5-Diethyl-l- (1H-tetrazol-5ylmethyl) -1Hpyrazol-4ylmethyl] -5methyl-indan-4-ol Δ 8.14 (1H, bs), 6.39 (1H, S), 5.77 (2H, s), 3.49 (2H, s), 2,712.78 (4H, m), 2,582.61 ( 2H, q), 2.31 (2H, q), 1.92-2.07 (5H, m), 0.98 (3H, t), 0.92 (3H, t) 365 (M ⁺ -l) 3464, 2951, 1578, 1477 22 Acid [3,5- Dicyclopropyl-4 (7-hydroxyindan-4-yloxy) pyrazol-l-yl] acetic δ 8.82 (1H, s), 6.44 (1H, d), 6.16 (1H, d), 4.81 (2H, s), 2.88 (2H, t), 2.78 (2H, t), 1.99-2.07 (2H, m), 1.45- 1.58 (2H, m), 0.580.70 (8H, m). 355 (M ⁺ -l) 3305, 1718, 1579, 1483 23 3- [3,5Diethyl-4- (1Hindol-5ylmethyl) pyrazol-l-yl] propionic acid δ 12.35 (1H, bs), 10.94 (lH, s), 7,257.27 (2H, m), 7.21 (1H, s), 6.85 (lH, d), 6.31 ( 1H, s), 4.13 (2H, t), 3.73 (2H, s), 2.76 (2H, t), 2.59 (2H, q), 2.38 (2H, q), 1.03 (3H, t), 0.96 (3H, t). 326 (M ⁺ -l) 3347, 1706, 1554, 1441 24 2- [4- (lH-lndol- 5-ylmethyl) -3,5- δ 10.94 (1H, s), 7.25- 7.27 (2H, m), 270 (M ⁺ -l) 3229, 2924,

119

dimethyl-pyrazole- 1-yl] -ethanol 7.22 (1H, s), 6.86 (1H, d), 6.31 (lH, t), 4.82 (lH, t), 3.96 (2H, t), 3.70 (2H, s), 3.64 (2H, q), 2.16 (3H, s), 2.00 (3H, s). 1571, 1464 25 Acid [4- (7- Hydroxy-indan-4yloxy) -3,5dimethyl-pyrazol1 — i1] -acetic δ 8.84 (lH, bs), 6.44 (lH, d), 6.19 (lH, d), 4.70 (2H, s), 2.86 (2H, t), 2.77 ( 2H, t), 1.98- 2.06 (5H, m), 1.88 (3H, s). 301 (M ⁺ -l) 3219, 1732, 1594, 1479 26 Acid 3- [4- (6- Chlorine-7-hydroxyindan-4ylmethyl) -3,5diethyl-pyrazol1-yl] -propionic δ 12.33 (1H, bs), 9.04 (1H, S), 6.52 (1H, s), 4.14 (2H, t), 3.50 (2H, s), 2.73-2.83 (6H, m), 2.52 (2H, mixed with peak in DMSO-d6), 2.30 (2H, q), 1.97-2.04 (2H, m), 0.99 (3H, t), 0.93 (3H, t). 375 (M ⁺ -l) 3394, 1696, 1579, 1469 27 [4- (6chloro-7-hydroxyindan-4ylmethyl) -3,5diethyl-pyrazol1-yl] -acetic acid Ô 9.05 (1H, s), 6, 55 (1H, s), 4.80 (2H, s), 3.53 (2H, s), 2,762.84 (4H, m), 2.52 (2H, mixed with peak in DMSO-d6), 2.30 (2H, q), 1.97-2.05 ( 2H, m), 1.00 (3H, t), 0.91 (3H, t). 361 (M ⁺ -l) 3408, 2952, 1719, 1475 28 Acid 3— {4— [7— Hydroxy-6- ^X H-NMR (400MHz, CDC1 ₃ ) δ 11.03 (lH, bs), 410 (M ⁺ -l) 2958, 1711,

120

(pyrrolidine-1carbonyl) -indan4-ylmethyl] -3,5dimethyl-pyrazoll-yl} -propionic 6.71 (1H, S), 4.25 (2H, t), 3.51 (2H, s), 3.48- 3.52 (4H, m), 2,912.96 (4H, m), 2.84 (2H, t), 2.08-2.16 (8H, m), 1.861, 90 (4H, m). 1563, 1432 29 Acid 3- [4- (6- Chlorine-7-hydroxyindan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -propionic δ 9, 04 (1H, s), 6, 67 (1H, S), 4.11 (2H, t), 3.47 (2H, s), 2.80 (2H, t), 2.69-2.76 (4H, m), 2.11 (3H, s), 1.922.04 (2H, m), 1.92 (3H, s). 349 (M ⁺ -l) 2951, 1697, 1574, 1472 30 1- {2- [4 (7-Hydroxy-6methyl-indan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -acetyl} pyrrolidine-2carboxylic acid Ô 12.33 (1H, bs), 8.11 (1H, S), 6.45 (1H, s), 4.93 (2H, s), 4.22- 4.25 (1H, m), 3.58 (2H, t), 3.45 (2H, s), 2.69- 2.77 (4H, m), 1.83- 2.16 (15H, m). 410 (M ⁺ -l) 3250, 1732, 1575, 1473 31 7- [3,5-Dimethyl- 1- (1H-tetrazol5-ylmethyl) -1Hpyrazol-4yloxy] -5-methylindan-4-ol δ 8.08 (1H, bs), 6.14 (1H, s), 5.56 (2H, s), 2.77-2.82 (4H, m), 2.11 (3H, s), 1.972.09 (5H, m), 1.88 (3H, s). 341 (M ⁺ -l) 3153, 1556, 1487, 1421 32 Acid [4- (7- Hydroxy-6-methyl- indan-4- ilmethyl) -3.5- δ 12.80 (1H, bs), 8.19 (1H, s), 6.35 (1H, s), 4.95 (2H, s), 3.68 (2H, s), 369 (M ⁺ -l) 2965, 1733, 1550, 1483

121

diisopropylpyrazol-l-yl] acetic 2.96-3.06 (1H, m), 2.86- 2.95 (4H, m), 2.68- 2.77 (lH, m), 2.07- 2.15 (5H, m), 1.18 (6H, d), 1.13 (6H, d). 33 3- [4- (7-Hydroxy- 6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazole- 1-yl] -Nisopropylpropionamide δ 8.11 (1H, s), 7.76 (1H, d), 6.40 (1H, s), 4.08 (2H, t), 3,763.81 (1H, m), 3.42 (2H, s), 2.75 (2H, t) , 2.69 (2H, t), 2.51 (2H, mixed with peak in DMSO-d6), 2.07 (3H, s), 2.02 (3H, s), 1.90-1.99 (5H, m), 0.98 (6H, d). 370 (M ⁺ -l) 3293, 1743, 1641, 1560 34 Acid [4— (7— Hydroxy-6-methylindan-4-yloxy) - 3,5-dimethylpyrazol-1-yl] acetic Ô 8, 11 (1H, s), 6, 13 (1H, s), 4.78 (2H, s), 2.77-2.83 (4H, m), 1.99-2.05 (5H, m), 1.93 (3H, s), 1.89 (3H, s). 317 (M ⁺ -l) 3277, 1730, 1575, 1483 35 Acid 3- [4- (7- Hydroxy-6-methylindan-4-yloxy) - 3,5-dimethylpyrazol-l-yl] propionic δ 12.38 (lH, bs), 8.05 (lH, s), 6.08 (lH, s), 4.10 (2H, t), 2,772.81 (4H, m), 2.72 (2H, t), 1.97-2.08 (8H, m), 1.88 (3H, s). 331 (M ⁺ -l) 3398, 1717, 1580, 1486 36 4- [4- (7- Hydroxy-6-irLetyl- Ô 12.3 (lH, bs), 8.09 (1H, S), 6.40 (1H, s), 343 (M ⁺ -l) 3036, 1610,

122

indan-4- ilmethyl) -3.5- dimethyl-pyrazole- 1-yl] -butyrical 3.92 (2H, t), 3.44 (2H, s), 2.74 (2H, t), 2.69 (2H, t), 2.16 (2H, t), 2.05 (3H, s), 2.02 (3H, s), 1.83- 1.98 (7H, m). 1581, 1481 37 3- [4- (7-Hydroxy- 6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazole- 1-yl] -N- (1Htetrazol-5-yl) propionamide δ 11, 61 (lH, bs), 8.11 (1H, S), 6.39 (1H, S), 4.20 (2H, t), 3.42 (2H, s), 2.91 (2H, t), 2.72 (2H, t), 2.64 (2H, t), 2.10 (3H, s), 1.98 (3H, s), 1.87- 1.91 (5H, m). 396 (M ⁺ -l) 2918, 1711, 1484, 1402 38 5- [4- (7-Hydroxy- 6- methyl-indan-4ylmethyl) -3,5dimethyl-pyrazole- 1-ylmethyl] -1H- [1,3,4] oxadiazole -2-one δ 12.39 (1H, s), 8.14 (1H, S), 6.41 (1H, s), 5.17 (2H, s), 3.46 (2H, s), 2.74 (2H, t), 2.68 (2H, t), 2.12 (3H, s), 2.02 (3H, s), 1.91 - 1.99 (5H, m). 355 (M ⁺ -l) 3150, 1793, 1483, 1434 39 7- {3,5-Dimethyl- 1- [2- (1Htetrazol-5-yl) ethyl] -1Hpyrazol-4ylmethyl} -5methyl-indan-4-ol δ 6.34 (1H, s), 4.40 (2H, t), 3.43 (2H, s), 3.37 (2H, t), 2.74 (2H, t), 2.63 ( 2H, t), 2.04 (3H, s), 1.99 (3H, s), 1.91 1.96 (5H, m). 353 (M ⁺ -l) 3330, 1599, 1548, 1441 40 Acid {2- [4- (7- Hydroxy-6-methylindan-4- ilmethyl) -3.5- δ 12.64 (lH, bs), 8.20 (lH, t), 8, ll (lH, s), 6.44 (1H, s), 4.67 (2H, s), 370 (M ⁺ -l) 3283, 2946, 1667, 1562

123

dimethyl-pyrazole- 1-il] - acetylamino} acetic 3.78 (2H, d), 3.45 (2H, s), 2.69-2.77 (4H, m), 2.03 (6H, s), 1.91 1.99 (5H, m). 41 5- [4- (7-Hydroxy- 6- methyl-indan-4- ilmethyl) -3,5dimethyl-pyrazol1-ylmethyl] -1Hpyrazol-3-ol δ 9.43 (lH, bs), 8.12 (1H, S), 6.40 (1H, s), 5.14 (1H, s), 4.99 (2H, s), 3.44 (2H, s), 2.74 (2H, t), 2.69 (2H, t), 2.08 (3H, s), 2.02 (3H, s), 1.91 1.98 (5H, m). 353 (M ⁺ -l) 2948, 1589, 1476, 1442 42 5- [3,5-Diethyl-4 (7-hydroxy-6methyl-indan-4ylmethyl) pyrazol-1ylmethyl] -3H [1,3,4] oxadiazole -2-one δ 12.41 (1H, s), 8.14 (1H, S), 6.37 (1H, s), 5.20 (2H, s), 3.49 (2H, s), 2.69-2.77 (4H, m), 2.53 (2H, mixed with peak in DMSO-d6), 2.31 (2H, q), 1.912.01 (5H, m), 0.99 ( 3H, t), 0.92 (3H, t). 383 (M ⁺ -l) 3475, 2968, 1799, 1444 43 5- {2- [4- (7- Hydroxy-6-methylindan-4ylmethyl) -3,5dimethyl-pyrazoll-yl] -ethyl} -3H [1,3,4] oxadiazole -2-one δ 12.09 (1H, s), 8.10 (1H, s), 6.39 (1H, s), 4.21 (2H, t), 3.42 (2H, s), 2.97 (2H, t), 2.74 (2H, t), 2.66 (2H, t), 2.08 (3H, s), 2.05 (3H, s), 1.89- 1.99 (5H, m). 369 (M ⁺ -l) 3370, 2958, 1788, 1580 44 Acid {2- [3,5- δ 8.20 (2H, m), 6.40 400 3363,

124

Diethyl-4- (7- hydroxy-6-methylindan-4- ilmethyl) pyrazol-l-yl] acetylamino} acetic (1H, S), 4.79 (2H, s), 3.81 (2H, d), 3.49 (2H, s), 2.71-2.78 (4H, m), 2.47 ( 2H, mixed with peak in DMS0-d6), 2.32 (2H, q), 1.852.01 (5H, m), 1.01 (3H, t), 0.92 (3H, t). (M ⁺ -l) 1707, 1676, 1552 45 6- [4- (7-Hydroxy- 6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazole- 1-ylmethyl] -2- methyl-3Hpiriinidin-4 - one δ 12.41 (1H, s), 8.12 (1H, S), 6.42 (1H, s), 5.13 (1H, s), 4.95 (2H, s), 3.49 (2H, s), 2,672.77 (4H, m) , 2.26 (3H, s), 2.03 (6H, s), 1.94- 1.99 (5H, m). 379 (M ⁺ -l) 2928, 1694, 1610, 1573 46 3- [4- (7-Hydroxy6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazolylmethyl] - [1,2,4] oxadiazole -5-01 δ 8.15 (1H, s), 6.44 (1H, S), 5.14 (2H, s), 3.46 (2H, s), 2,682.77 (4H, m), 2.13 (3H, s), 2.03 (3H, s) , 1.87- 1.99 (5H, m). 353 (M ⁺ -l) 3424, 1751, 1491, 1443 47 7- (1-Benzyl-3,5dimethyl-1Hpyrazol-4ylmethyl) -5methyl-indan-4-ol δ 8.12 (1H, s), 7.22- 7.33 (3H, m), 7.027.04 (2H, m), 6.40 (1H, s), 5.20 (2H, s), 3.47 (2H, s), 2.74 (2H , t), 2.68 (2H, t), 2.02 (3H, s), 2.00 (3H, s), 1.91 - 1.99 (5H, m). 347 (M ⁺ -l) 2944, 1608, 1569, 1484

125

48 Acid 3— {4 - [7- Hydroxy-6- (4- methyl benzyl) - indan-4- ilmethyl] -3.5- dimethyl-pyrazole- 1-il} -propionic δ 12.33 (1H, bs), 8.22 (1H, s), 6.97- 7.03 (4H, m), 6.44 (1H, s), 4.06 (2H, t), 3.73 (2H, s), 3.41 (2H, s), 2.74 (2H, t), 2.64-2.69 (4H, m), 2.22 (3H, s), 2.03 (3H, s), 1.90-1.98 (2H, m), 1.86 (3H, s). 419 (M ⁺ -l) 3384, 2921, 1716, 1613 49 Acid 2- [4- (7- Hydroxy-6-methylindan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -propionic δ 12.77 (1H, s), 8.11 (1H, s), 6.43 (1H, s), 4.98 (1H, q), 3.45 (2H, s), 2.68-2.76 (4H, m), 2.05 (3H, s), 2.02 (3H, s), 1.91 1.98 (5H, m), 1.56 (3H, d). 327 (M ⁺ -l) 2949, 1708, 1650, 1579 50 Acid 3- [4- (7- Hydroxy-6isopropyl-indan- 4-ylmethyl) -3,5dimethyl-pyrazoll-yl] -propionic δ 8.11 (1H, bs), 6.58 (1H, s), 4.08 (2H, t), 3.45 (2H, s), 3,133.22 (1H, m), 2.74 ( 2H, t), 2.63-2.68 (4H, m), 2.10 (3H, s), 1.91 1.97 (5H, m), 1.07 (6H, d). 355 (M ⁺ -l) 3426, 2985, 1711, 1610 51 Acid {4 - [7 - Hydroxy-6- (4methyl-benzyl) indan-4ylmethyl] -3,5dimethyl-pyrazole- δ 8.23 (1H, s), 6.95- 7.01 (4H, s), 6.51 (1H, s), 4.69 (2H, s), 3.73 (2H, s), 3.44 (2H, s), 2.74 (2H, t), 2.68 (2H, t), 2.22 (3H, s), 1.91 - 1.97 (5H, m), 405 (M ⁺ -l) 2926, 1710, 1612, 1574

126

1-il} -acetic 1.87 (3H, s). 52 Acid 3- {4- [6- (4-Fluoro- benzyl) -7- hydroxy-indan-4- ilmethyl] -3.5- ilmethyl-pyrazole- 1-il} -propionic δ 8.29 (lH, s), 7.12- 7.16 (2H, m), 7.03 (2H, t), 6.45 (1H, s), 4.06 (2H, t), 3.77 (2H, s), 3.42 (2H, s), 2.75 (2H, t), 2.64- 2.69 (4H, m), 2.04 (3H, s), 1.91 - 1.99 (2H, m), 1.86 (3H, s). 423 (M ⁺ -l) 2949, 1703, 1604, 1569 53 Acid {4 - [6— (4 - Fluoro-benzyl) 7-hydroxy-indan- 4-ylmethyl] -3,5dimethyl-pyrazole- 1-il} -acetic δ 8.30 (1H, s), 7.13- 7.17 (2H, m), 7.03 (2H, t), 6.52 (1H, s), 4.59 (2H, s), 3.77 (2H, s), 3.42 (2H, s), 2.75 (2H, t), 2.69 (2H, t), 1.79-1.98 (8H, m). 407 (M ⁺ -l) 2943, 1711, 1603, 1575 54 4— [4 - (7-Hydroxy-6methyl-indan-4ylmethyl) -3,5dimethylpyrazol-l-yl] butyric acid sodium salt δ 6, 26 (1H, s), 3.86 (2H, t), 3.35 (2H, s), 2.60-2.66 (4H, m), 2.07 (3H, s), 1.92 (3H, s), 1.90 (3H, s), 1.74- 1.87 (6H, m). 341 (M ⁺ -l) 1650, 1554, 1469, 1410 55 3— [4— (7-Hydroxy-6methyl-indan-4ylmethyl) -3,5dimethyl-pyrazole- magnesium salt δ 8.16 (lH, bs), 6.40 (lH, s), 4.06 (2H, t), 3.40 (2H, s), 2,632.76 (4H, m), 2.47 ( 2H, mixed with peak in DMSO-d6), 2.07 (3H, s), 327 (M ⁺ -l) 1678, 1612, 1573, 1480

127

1-il] -propionic 2.01 (3H, s), 2.01 (3H, s), 1.90-1.97 (5H, m). 56 Sodium salt of 3- (4- (7Hydroxy-6-methylindan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -propionic acid δ 6.27 (1H, s), 4.00 (2H, t), 3.33 (2H, s), 2.61 - 2.68 (4H, m), 2.25 (2H, t), 2.06 (3H, s), 1.92 (6H, s), 1.76- 1.86 (2H, m). 327 (M ⁺ -l) 1650, 1575, 1470, 1410 57 3- {3,5Diethyl-4- [6- (4fluoro-benzyl) 7-hydroxy-indan- 4-imethyl] pyrazol-l-yl} propionic δ 12.2 (lH, bs), 8.29 (lH, s), 7,097.12 (2H, m), 7.01 (2H, t), 6.37 (lH, s), 4.09 ( 2H, t), 3.75 (2H, s), 3.45 (2H, s), 2.76 (2H, t), 2,672.72 (4H, m), 2.44 (2H, q), 2.23 (2H, q), 1.92l, 98 (2H, m), 0.93 (3H, t), 0.83 (3H, t). 451 (M ⁺ -l) 3377, 2970, 1715, 1603 58 Ethyl ester of 3- (4- (7Methoxy-6-methylindan-4ylmethyl) -3,5dimethyl-pyrazoll-yl] -3-oxopropionic δ 6.50 (1H, s), 4.07- 4.13 (4H, m), 3.66 (3H, s), 3.58 (2H, s), 2.87 (2H, t), 2.75 (2H, t), 2.43 (3H, s), 2.09 (3H, s), 1.97- 2.04 (5H, m), 1.15 (3H, t). 385 (M ⁺ -l) 1666, 1587, 1475, 1438 59 Acid hydrazide [3,5Diethyl-4- (7- δ 9.23 (1H, s), 6.51 (1H, S), 4.58 (2H, s), 371 (M ⁺ -l) 3290, 2952, 1661,

128

methoxy-6-methyl- indan-4ylmethyl) pyrazol-l-yl] acetic 4.29 - 4.30 (2H, d), 3.64 (3H, s), 3.52 (2H, s), 2.87 (2H, t), 2.76 (2H, t), 2.47 (2H, mixed with peak in DMS0-d6), 2.30 (2H, q), 2.07 (3H, s), 1.97-2.04 (2H, m), 1.00 (3H, t), 0.90 (3H, t). 1540 60 N-Hydroxy-2- [4- (7-methoxy-6methyl-indan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] acetamidine δ 9.20 (lH, bs), 6.52 (lH, s), 5.24 (2H, s), 4.51 (2H, s), 3.64 (3H, s), 3.49 ( 2H, s), 2.86 (2H, t), 2.74 (2H, t), 2.09 (6H, s), 1.98-2.05 (2H, m), 1.94 (3H, s). 343 (M ⁺ -l) 3468, 2947, 1666, 1587 61 Ethyl acid ester [4— (7 - Methoxy-6-methylindan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -oxoacetic δ 6.55 (1H, s), 4.39 (2H, q), 3.65 (3H, s), 3.62 (2H, s), 2.88 (2H, t), 2.75 (2H, t), 2.48 (3H, s), 2.09 (3H, s), 1.99- 2.05 (5H, m), 1.30 (3H, t), 0.92 (3H, t). 371 (M ⁺ -l) 1758, 1725, 1483, 1399 62 [4- (7-Methoxy-6methyl-indan-4ylmethyl) -3,5dimethyl-pyrazoll-yl] -morfolin4-yl-methanone δ 6.53 (1H, s), 3.63- 3.65 (7H, m), 3.53- 3.56 (6H, m), 2.87 (2H, t), 2.74 (2H, t), 2.22 (3H, s), 2.09 (3H, s), 1.96- 2.04 (5H, m). 384 (M ⁺ -l) 1688, 1590, 1481, 1431

129

63 1- (4-Chlorophenyl) -4- (7methoxy-6-methylindan-4ylmethyl) -3,5dimethyl-1Hpyrazole Ô 7.54 (4H, s), 6.59 (1H, s), 3.65 (3H, s), 3.60 (2H, s), 2.88 (2H, t), 2.79 (2H, t), 2.21 (3H, s) , 2.12 (3H, s), 1.98- 2.05 (5H, m). 381 (M ⁺ -l) 2949, 1590, 1566, 1503 64 2- (4-Methanesulfonyl-phenyl) 1- [4- (7-methoxy6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -ethanone δ 7.88 (2H, d), 7.60 (2H, d), 6.51 (1H, s), 4.58 (2H, s), 3.65 (3H, s), 3.60 (2H, s), 3.21 (3H, s) , 2.88 (2H, t), 2.76 (2H, t), 2.41 (3H, s), 2.10 (3H, s), 1.99-2.05 (5H, m). 467 (M ⁺ -l) 2941, 1723, 1596, 1483 65 Ethyl ester of 4- (7Methoxy-6-methylindan-4ylmethyl) -3,5dimethylpyrazole-1carboxylic acid δ 6.47 (1H, s), 4.35 (2H, q), 3.66 (3H, s), 3.57 (2H, s), 2.87 (2H, t), 2.75 (2H, t), 2.38 (3H, s) , 2.09 (3H, s), 1,932.04 (5H, m), 1.32 (3H, t). 343 (M ⁺ -l) 2947, 1738, 1605, 1484 66 {3- [4- (7-methoxy- 6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] propionyl} -propane-2- amide δ 11.50 (lH, bs), 6.49 (1H, s), 4.12 (2H, t), 3.64 (3H, s), 3.51- 3.55 (1H, m), 3.47 (2H, s), 2.80-2.88 (4H, m), 2.73 (2H, t), 2.09 (3H, s), 2.08 (3H, s), 1.96- 2.03 (2H, m), 1.91 (3H, s), 446 (M ⁺ -l) 2943, 1710, 1462, 1406

130

sulfonic 1.20 (6H, d). 67 Acid 3 - [5 - Epoxy-4- (7- methoxy-6-methyl- indan-4- ilmethyl) -3- methyl-pyrazole-1- il] -propionic or 3- [3- acid Epoxy-4- (7methoxy-6-methylindan-4ylmethyl) -5methyl-pyrazol-1yl] -propionic δ 6.57 (1H, s), 4.02 (2H, t), 3.92 (2H, q), 3.65 (3H, s), 3.49 (2H, s), 2.87 (2H, t), 2.64- 2.77 (4H, m), 2.09 (3H, s), 1.98-2.04 (2H, m), 1.91 (3H, s), 1.21 (3H, t). 373 (M ⁺ -l) 2926, 1731, 1577, 1479 68 Acid [4- (7- Hydroxy-3,6dimethyl-indan-4- ilmethyl) -3,5dimethyl-pyrazole- 1-il] -acetic δ 8.10 (1H, s), 6.33 (1H, s), 4.76 (2H, s), 3.52 (2H, d), 3.27 (1H, mixed with water peak present in DMSOd ₆ ), 2.74-2.78 (2H, m), 2.05-2.10 (1H, m), 2.00 (3H, s), 1.99 (3H, s), l, 90 (3H, s), 1,671.72 (1H, m), 1.09 (3H, d). 329 (M ⁺ -l) 3428, 2949, 1715, 1483 69 Acid 2- [4- (7- Hydroxy-6-methyl- indan-4- ilmethyl) -3.5- δ 12.33 (2H, bs), 8.09 (1H, s), 6.54 (1H, S), 4.12-4.17 (1H, m), 3.92- 3.97 (1H, m), 3.43 (2H, s), 399 (M ⁺ -l) 3367, 2957, 1734, 1483

131

dimethyl-pyrazole- 1-ilmethyl] - pentanedioic 2.81 - 2.86 (1H, m), 2.74 (2H, t), 2.68 (2H, t), 2.15-2.17 (2H, m), 2.06 (3H, s), 2.01 (3H, s), 1.89-1.98 (5H, m), 1.63- 1.69 (2H, m). 70 Acid [4 - (7 - Methoxy-2,2,6trimethyl-indan4-ylmethyl) -3,5dimethyl-pyrazol1-yl] -acetic δ 12.8 (lH, bs), 6.52 (1H, s), 4.77 (2H, s), 3.62 (3H, s), 3.47 (2H, s), 2.67 (2H, s), 2.57 (2H, s), 2.07 (3H, s), 2.03 (3H , s), 1.91 (3H, s), 1.10 (6H, s). 355 (M ⁺ -l) 2952, 1716, 1574, 1478 71 N- {2- [4- (7- Methoxy-6-methyl- indan-4ylmethyl) -3,5dimethyl-pyrazol1-yl] -ethyl} acetamide Δ 7.97 (1H, t), 6.51 (1H, S), 3.96 (2H, t), 3.64 (3H, s), 3.46 (2H, s), 3.31 ( 2H, mixed with water peak present in DMSO-d ₆ ), 2.86 (2H, t), 2.74 (2H, t), 2.09 (3H, s), 2.07 (3H, s) , 1.96-2.01 (2H, m), 1.93 (3H, s), 1.77 (3H, s). 356 (M ⁺ -l) 3316, 1644, 1544, 1478 72 N- {2- [4- (7Methoxy-6-methylindan-4- ilmethyl) -3,5dimethyl-pyrazol1-yl] -ethyl} methane- δ 7.19 (1H, t), 6.50 (1H, s), 4.00 (2H, t), 3.64 (3H, s), 3.49 (2H, s), 3.28 (2H, mixed with water peak present in DMSO-dg), 392 (M ⁺ -l) 3111, 1573, 1475, 1384

132

sulfonamide 2.86 (2H, t), 2.73- 2.79 (5H, m), 2.11 (3H, s), 2.08 (3H, s), 1.94- 2.03 (5H, m). 73 4- [4- (7-Methoxy- 6-methyl-indan-4ylmethyl) -3,5dimethyl-pyrazole- 1-yl] -1-toluene- 4-sulfonyl) piperidine ^X H-NMR (400MHz, CDC1 ₃ ) δ 7.68 (2H, d), 7.34 (2H, d), 6.47 (1H, s), 3.92-3.94 (2H, m) , 3,813.89 (1H, m), 3.73 (3H, s), 3.52 (2H, s), 2.94 (2H, t), 2.77 (2H, t), 2.42- 2.48 (5H, m), 2.28-2.38 (2H, m), 2.15 (3H, s), 2.05-2.11 (5H, m), 2.02 (3H, s), 1.90 - 1.93 (2H, m). 508 (M ⁺ -l) 2949, 1485, 1443, 1330 74 Acid {3,5- Diethyl-4- [6- (4-fluoro-benzyl) 7-hydroxy-indan- 4-ylmethyl] pyrazol-l-yl} acetic δ 8.29 (lH, s), 7,087.13 (2H, m), 6.99 (2H, t), 6.45 (lH, s), 4.73 (2H, s), 3.75 ( 2H, s), 3.45 (2H, s), 2.76 (2H, t), 2.70 (2H, t), 2.37 (2H, q), 2.26 (2H, q), 1.92l, 99 (2H, m), 0.94 (3H, t), 0.82 (3H, t). 437 (M ⁺ -l) 2974, 1734, 1604, 1506 75 Acid 3— {4— [7— Methoxy-6- (4methoxy-phenyl) indan-4ylmethyl] -3,5- 433 (M ⁺ -l) 2945, 1737, 1608, 1569

133

dimethyl- pyrazol-l-il} - propionic 76 2- [3,5-Diethyl-4 (7-hydroxy-6methyl-indan-4ylmethyl) pyrazol-l-yl] -Nisopropylacetamide δ 8.12 (1H, s), 7.73 (lH, d), 6.40 (lH, s), 4.58 (2H, s), 3,813.83 (lH, m), 3.48 ( 2H, s), 2.72-2.78 (4H, m), 2.44 (2H, q), 2.31 (2H, q), 1.93-2.02 (5H, m), 1.07 (3H, s), 1.05 (3H, s), 1.00 (3H, t), 0.90 (3H, t). 384 (M ⁺ -l) 3249, 2972, 1756, 1658 77 Methyl acid ester 3- [4- (7- Ethoxycarbonyloxy -6-methyl-indan- 4- ilmethyl) -3,5dimethylpyrazol-l-yl] propionic δ 6.58 (1H, s), 4.24 (2H, q), 4.16 (2H, t), 3.58 (3H, s), 3.55 (2H, s), 2.69-2.83 (6H, m), 2.12 (3H, s), 1.98-2.09 (5H, m), 1.94 (3H, s), 1.28 (3H, t). 415 (M ⁺ -l) 1743, 1618, 1564, 1473 78 Sodium salt of [3,5Diethyl-4- (7hydroxy-6-methylindan-4ylmethyl) pyrazol-l-yl] acetic acid δ 6.62 (1H, s), 4.28 (2H, s), 3.38 (2H, mixed with water peak present in DMSOd ₆ ), 2, 65-2.70 (4H, m), 2 , 38 (2H, q), 2.30 (2H, q), 1.85-1, 99 (5H, m), 1.00 (3H, t), 0.90 (3H, t). 381 (M ⁺ -l) 2936, 1738, 1486, 1393

134

79 Acid 3- [4- (7- Methoxy-6-methyl- indan-4ylmethyl) -3methyl-5- trifluoromethylpyrazol-l-yl] propionic and 3- [4- (7Methoxy-6-methylindan-4ylmethyl) -5methyl-3- acid trifluoromethylpyrazol-l-yl] propionic δ 6.52 (1H, s, for the main isomer), 6.38 (1H, s, for the main isomer), 5.04 (2H, s, for the minimum isomer), 5.03 (2H, s , for the main isomer), 3.69 (2H, s, for both isomers), 3.58 (3H, s, for both isomers), 2.88 (2H, t, for both isomers), 2.75 (2H, t, for both isomers), 2.24 (3H, s, for both isomers), 1,972.05 (5H, m, for both isomers). 80 Acid [4- (4-hydroxy-3-methyl- 5,6,7,8tetrahydro- naphthalen-1-methyl) -3,5-dimethyl-pyrazole- 1-il] -acetic δ 13.01 (1H, bs), 7.95 (1H, bs), 6.36 (1H, s), 4.80 (2H, s) 3.44 (2H, mixed with water peak present in DMSO-dg), 2.54- 2.58 (4H, m), 2.02 (3H, s), 1.98 (3H, s), 1.90 (3H, s), 1.65-1.70 (4H, m). 329 (M ⁺ -l) 2924, 1719, 1575, 1471 81 Acid [4- (7- For the isomer 373 2960,

135

Chloro-indan-4yloxy) -3-thiophen2-yl-pyrazol-lil] -acetic and Acid [4 - (7 - Chlorine-indan-4yloxy) -5-thiophen2-yl-pyrazol-lil] -acetic principal δ 7.82 (lH, s), 7.47 (lH, dd), 7.22 (lH, dd), 7.14 (lH, d), 7.05 (1H, dd), 6.63 (1H, d), 4.90 (2H, s), 3.04 (2H, t), 2.95 (2H, t), 2.10- 2.17 (2H, m). (M ⁺ -l) 1746, 1560, 1463 82 Acid {4— [7— Methoxy-6-methyl- 2- (4-nitrophenoxy) -indan-4ylmethyl] -3,5dimethyl-pyrazol1-yl} acetic δ 12.81 (1H, bs), 8.22 (2H, d), 7.18 (2H, d), 6.62 (1H, s), 5.40- 5.42 (1H, m), 4.74 (2H, s), 3.66 (3H, s), 3.45-3.52 (4H, m), 2.96- 3.07 (2H, m), 2.11 (3H, s), 2.02 (3H, s), 1.91 (3H, s). 464 (M ⁺ -l) 2944, 1732, 1595, 1503 83 Acid [5-Amino- 4- (7-methoxy-6methyl-indan-4ylmethyl) -3- (4 methoxy-phenyl) pyrazol-1-yl] acetic and [3-Amino4- (7-methoxy-6methyl-indan-4ylmethyl) -5- (4- For the main isomer δ 7.34 (2H, d), 6.95 (2H, d), 6.53 (1H, s), 4.88 (2H, s), 3.87 (3H, s), 3.65- 3.67 (5H, m), 2.90 (2H, t), 2.76 (2H, t), 1.99-2.05 (5H, m). 422 (M ⁺ -l) 3336, 2942, 1729, 1613

136

methoxy-phenyl) pyrazol-l-yl] - acetic 84 2- [3,5-Diethyl-4- (7-hydroxy-6methyl-indan-4ylmethyl) pyrazole- l-yl] -N- (1Htetrazol-5-yl) acetamide δ 15.98 (1H, bs), 12.42 (1H, s), 8.14 (1H, S), 6.41 (1H, S), 5.03 (2H, s), 3.50 ( 2H, s), 2.74-2.76 (4H, m), 2.50 (2H, mixed with peak in DMSO-d6), 2.31 (2H, q), 1.97-2.02 ( 5H, m), 1.00 (3H, t), 0.93 (3H, t). ¹ H- NMR (400MHz, CD ₃ OD) δ 6.49 (1H, s), 5.04 (2H, s), 3.60 (2H, s), 2.76-2.84 (4H, m ), 2.54 (2H, q), 2.43 (2H, q), 2.02-2.08 (5H, m), 1.06 (3H, t), 0.99 (3H, t) . 408 (M ⁺ -l) 3239, 2937, 1719, 1617 85 1 - Carboxymethyl-5 (5-chloro-thiophen-2-yl) -4- (7-methoxy-6-methylindan-4ylmethyl) -1Hpyrazole-3carboxylic acid and For the main isomer δ 7.04 (1H, d), 6.77 (1H, d), 6.28 (1H, s), 5.24 (2H, s), 4.10 (2H, s), 3.65 (3H, s), 2.91 (2H , t), 2.83 (2H, t), 2.00-2.09 (5H, m). 459 (M ⁺ -l) 3564, 2903, 1744, 1681

137

2- acid Carboxymethyl-5 (5-chloro-thiophen2-yl) -4- ΠπίθΙόχΐ-δ-ιηβϋΙindan-4ilmetil) -2Hpyrazola-3carboxylic

$ Average values are given for NMR.

The following compounds can also be prepared using the process mentioned above:

86. 3- [4- (1H-indol-5-yloxy) -3,5-dimethyl-pyrazol-1-yl] -propionic acid;

87. [4- (1H-indol-5-yloxy) -3,5-dimethyl-pyrazol-1-yl] acetic acid;

88. 2- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-pyrazol-1-yl] -propionic acid;

89. 1— {2— [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4ylmethyl) -pyrazol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid;

90. [3,5-Diethyl-4- (7-hydroxy-6-pyrrolidin-1-ylmethylindan-4-ylmethyl) -pyrazol-1-yl] -acetic acid;

91. 3- [3,5-Dietyl-4- (7-hydroxy-6-pyrrolidin-1-ylmethyl-indan-4-ylmethyl) -pyrazol-1-yl] -propionic acid;

92. 3- [3,5-Diethyl-4- (7-methoxy-6-methoxymethyl-indan-4138 ylmethyl) -pyrazol-1-yl] -propionic acid;

93. {3,5-Diethyl-4- [7-hydroxy-6- (pyrrolidine-1-carbonyl) -indan-4-ylmethyl] -pyrazol-1-yl} -acetic acid;

94. [3,5-Diethyl-4- (7-methoxy-6-methoxymethyl-indan-4ylmethyl) -pyrazol-1-yl] -acetic acid;

95. 3- {3,5-Diethyl-4- [7-hydroxy-6- (pyrrolidine-1-carbonyl) -indan-4-ylmethyl] -pyrazol-1-yl} -propionic acid; and

96. N- (4-Chloro-phenyl) -2- [3,5-diethyl-4- (7-hydroxy-6-methylindan-4-ylmethyl) -pyrazol-1-yl] -acetamide.

BIOLOGICAL ACTIVITY

Metabolically active thyroid-like compounds which have minimal or no effect on appetite, as well as less affinity for thyroid receptors, are considered to be more effective for the treatment of various metabolic disorders, such as obesity, dyslipidemia, atherosclerosis, resistance insulin and metabolic syndrome. The compounds of the present invention were tested for their effect on O ₂ consumption (metabolic effect), LDL cholesterol, glucose levels, insulin levels and food consumption (appetite stimulant) and also to evaluate the transcriptional activity of thyroid hormone receptor via a TRE reporter assay (thyroid receptor element)

139 in vitro for TRal and TRpl.

Effect of compounds on the transcriptional activity of thyroid hormone receptor (THR): THRal and THR βΐ Test procedure:

COS7 cells were transiently transfected with pGAL4 (beta galactosidase) / thyroid al or pGAL4 / thyroid βΐ and pLucPur. The cells were co-transfected with pLacZNorm to normalize the transfection efficiency. The transfected cells were then treated with different concentrations of compounds of the present invention or vehicle for 24 hours.

The cells were subjected to lysis and luciferase activity was monitored in all samples. The results were expressed as activation times when compared to vehicle control.

Results: Thyroid transactivation (αΐ / βΐ) in cells

COS 7

Table 2:

Compound Cone. (pm) al Activation times βΐ Activation times Vehicle (lOmM NaOH) Zero 1 1

140

T3 20 35 29 0.02 17 13 T2 20 20 27 2 14 16 0.2 7 4 0.02 1 2 1 20 1 1 2 20 1 1 3 20 1 1 4 20 1 1 5 20 1 1 6 20 1 1 7 20 3 1 8 20 3 1 9 20 2.5 2

The compounds of the present invention exhibited significantly less transcriptional activation of THR (al) or THR (βΐ) when compared to T3 and T2 under the 5 experimental conditions.

In vivo testing

Experiment 1: Effect of compounds on oxygen consumption, food consumption and heart weight.

Methodology:

C57BL6 mice (14-18 weeks of age), fed for 8-12 weeks on a high-fat diet

141 fat (45% kcal of fat) were used for the study. The mice were placed in an individual housing for one week. The mice were then kept in Oxymax cages for 48 hours for acclimatization. Baseline records of oxygen consumption and carbon dioxide production for each mouse were recorded with an indirect open circuit calorimeter (Oxymax, Columbus Instruments, USA (Ling fu et al., Endocrinology (2004); 145 (6); 2591-3 Based on body weight and oxygen consumption, the mice were randomly distributed and divided into two groups.

I) Vehicle treated group

II) Group treated with test compound

The mice were treated with vehicle and test compounds intraperitoneally for 7-15 days. On day 8, oxygen consumption was measured for individual mice 30 min after drug treatment and the% change with respect to the vehicle is calculated.

During the experiment, food consumption was monitored daily. At the end of the experiment, the animals were sacrificed and the heart weights were recorded. Results:

Table 3: Effect of test compounds on the consumption of

142 oxygen, food consumption, body weight and heart weight

Compound At the. Dose (μΜ / Kg) Increase in O ₂ consumption Increased food consumption with reference to the vehicle Increased heart weight with reference to the vehicle T2 0.05 T2 0.5 * * + + T2 2 * * ++ ++ T2 5 * * ++ + ++ 1 11 * No changes No changes 2 11 * No changes No changes 3 11 * * No changes No changes 6 11 * No changes No changes 7 11 * * No changes No changes 8 11 * * No changes No changes 9 11 * * No changes No changes 19 11 * * No changes No changes 20 11 * * No changes No changes 14 11 * No changes No changes

To change consumption ** = increase> 5%.

For change in consumption%, ++ = increase of 10-20%, of oxygen: * = increase <5%, of food: + = increase of 5-10 +++ increase of> 20%.

For change in heart weight: + = 10-15 increase

O.

The f

143 ++ = 15-20% increase, +++> 20% increase.

The test compounds of the present invention showed an increase in O ₂ consumption without significantly influencing food consumption.

Experiment 2: Effect of compounds on body weight, LDL cholesterol, OGTT, fasting glucose levels and fasting insulin.

Methodology:

Male C57BL6 mice were fed a high-fat diet (Research Diet, New Brunswick, NJ). The mice were housed 3 animals per cage in a temperature-controlled unit (22 + 2 ° C) with a 12-h light / dark cycle. The mice were fed a high-fat (45% kcal) diet for 8-12 weeks before drug treatment started. DIO (Diet-Induced Obese) mice were selected from the stock and randomly divided into three groups with 15 animals in each group, based on their body weight and age.

Group I: Vehicle (10 ml / kg)

Group II: Dose 1

Group III: Dose 2

Before monitoring baseline parameters, all

144 mice were acclimatized for treatment by administering a 0.02 disodium hydrogen phosphate vehicle

M, 10 ml / kg i.p., b.i.d) for about 2 weeks. Then, the animals were treated with test compound A or B of formula (I) in two different doses for 6-12 weeks.

The treatment was administered intraperitoneally b.i.d. The effect of the 6-12 week treatment on the change in body weight, body fat, LDL cholesterol, OGTT, fasting glucose and fasting insulin was monitored.

An insulin resistance index, that is, HOMA-IR, was calculated using the following formula:

HOMA-IR score - fasting serum insulin (μυ / ml) x fasting serum glucose (mmol / 1) / 22.5.

Results:

Parameter Comp. test Vehicle Dose 1 Dose 2 Glucose THE 217.6 + 5.4 185, 9 +5, 5 ** 214.3 +6.5 (mg / dL) B 240.51 + 8.7 224.85 +6.2 210.43 +11.5 ’ Insulin THE 0.83 +0.14 0.38 + 0.05 ** 0.53 + 0.05 * (ng / mL) B 0.90 +0.13 0.78 +0.08 0.74 +0.13 HOMA GO THE 2.26 +0.36 0.90 + 0.13 ** 1.35 + 0.14 * B 2.7 +0.4 2.3 +0.26 2 + 0.4 LDL-C THE 24.96 +1.13 15.18 + 1.6 # 13.73 + 0.9 # (MG / dl) B 30.0 +1.03 27.9 +1.05 26.5 + 0.9 * Accumulation THE 2.67 +0.26 1.65 + 0.17 ** 2.02 + 0.12 *

145

in B 3.56 + 0.44 2.33 + 0.24 * 1.9 + 0.18 ** body fat (g)

Ν = 12 to 15 / group; * P <0.05; ** P <0.01; #P <0.001

Conclusion:

The 6-12 week treatment with test compound A and B was found to be effective in significantly reducing body weight, body fat, LDL cholesterol, fasting plasma glucose, insulin and improved insulin resistance with respect to vehicle. Figure 1 also indicates that the test compound also showed improved glucose tolerance in experimental animals.

In general, it can be concluded that the compounds of the present invention are useful in various conditions of metabolic disease, such as dyslipidemia, insulin resistance, type II diabetes, obesity and metabolic syndrome.

References:

WHO fact sheet, 2006;

Melnikova I. & Wages D. Nature Reviews Drug Discovery (2006); 5: 369-370;

Eberhard Ritz, Am. J Cardiol (2007); 100 [Suppl]: 53-60; Young-Woo Park et al. Arch intern Med (2003); 163: 427-436;

146

Richard Ceska, Diabetes and Vascular Disease Research (2007); 4 (suppl): S2-S4 Kelly GS. Altern Med Rev (2000); 5 (4): 306-333;

Burger '6'h edition, vol 3, pp.564-565;

W0200703419;

Liu Ye et The! . , JMC (2003); 46: 1580-88 f Abrams JJ et. al. J. Lipid Res. (1981); 22: 323-38; Aviram M. et. al. CUn. Biochem. (1982); 15: 62—66;

Ness GC. et. al. Biochemical Pharmacology, (1998); 56: 121

-129;

Grover GJ. et. al. Endocrinology, (2004); 145: 1656-1661;

Grover GJ. et. al. Proc. Natl. Acad. Know. USA, (2003); 100: 10067-10072;

Paul Webb. Expert Opin. Investig. Drugs, (2004); 13 (5):

489-500;

de Bruin et. al. J. CUn. Endo. Metab., (1993); 76: 121-126;

A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6: 255-65;

Horst C., Biochem J. (1 989); 261: 945-950;

W0200509433;

Amedeo colum bano. Endocrinology (2006); 147 (7): 321 1-8;

Wing May Kong et al. Endocrinology (2004); 145: 5252-5258;

Horst et al., J Endocrinology (1995); 145: 291-297;

147

Ling fu et al., Endocrinology (2004); 145 (6): 2591-3.

Claims (13)

1. Compound of formula (I): characterized by R ² R ¹ and R ³ are the same or different, and are independently selected from H, (C 1 -C ₆ ) alkyl, (C ₃ C ₇ ) cycloalkyl, CF ₃ , -0- (C 1 -C ₆ ) alkyl, COOH, -NH ₂ and R ⁶ , where C 1 -C ₆ alkyl and C ₃ -C ₇ cycloalkyl are optionally substituted by (C 1 -C ₆ ) alkyl; R ² is selected from (C 1 -C 6) alkyl, - (C 1 -C 3) alkyl COOH, -C (0) - (C 1 -C 3) alkyl-COO-alkyl, -C (0) -C (0) 0- ( C1-6 alkyl, -C (0) -0- (C1-6) alkyl, -C (O) NR ⁵ , -C (0) - (C1- C3) alkyl-R ⁶ , R ⁶ and R ⁷ , in that said (C 1 -C 6) alkyl are optionally substituted by one or more substituents selected from oxo, -C (O) OH, -C (0) -0- (C 1 -C 3) alkyl, -CONH (C 1 -C 3) alkyl, -C (O) NH-R ⁶ , -CONR ⁵ , CONHNH2, C (= NH) NHOH, -C (O) -R ⁸ , C (O) NHSO ₂ (C 1 -C ₆ ) alkyl, NH- C (0) - (C 1 -C ₃ ) alkyl, -NHSO ₂ (C 1 -C ₆ ) alkyl, -OH, R ⁶ and R ⁷ ; R ⁵ , together with the nitrogen atom to which it is attached, forms a saturated or unsaturated ring of (C ₃ -C ₆ ) elements, which may also contain 1-2 heteroatoms selected from 0, N or S and which it can be optionally substituted by one or more of -COOH; R ⁶ is selected from phenyl or heteroaryl of 5-8 elements containing 1-4 heteroatoms selected from 0, N or Petition 870190058304, of 06/24/2019, p. 29/61 2/13 S, wherein said heteroaryl or phenyl ring is optionally substituted by one or more substituents selected from halogen, -OH, -0- (C 1 -C ₆ ) alkyl, - (C 1 ~ C ₆ ) alkyl, -S0 ₂ (C 1 -C ₆ ) alkyl and -S 0 ₂ - (C 1 -C ₆ ) alkyl; R ⁷ is a 3-6 element heterocyclic ring containing 1-4 heteroatoms selected from 0, N or S and said heterocyclic ring is optionally substituted by one or more substituents selected from oxo (C 1 -C ₆ ) alkyl and S ₂ aryl- (C 1 -C ₆ ) alkyl; R ⁸ is an amino acid which is linked through its nitrogen atom; Z = 0 or CH ₂ ; R ⁴ is selected from P or T: -OC (0) - (C 1 -C ₆ ) alkyl; R ¹⁰ is selected from H, (C 1 -C ₆ ) alkyl and aryloxy; G 'is H; G is selected from hydrogen, (Ci-C ₆ ) alkyl, aryl, halogen, - (Ci-C ₃ ) alkylaryl, - (Ci-C ₆ ) alkyl-0- (Ci ~ C ₆ ) alkyl, -CH ₂ NR ⁵ , and -CONR ⁵ ; n can be one or two; including their pharmaceutically acceptable salts and their hydrates, solvates, atropisomers, regioisomers, Petition 870190058304, of 06/24/2019, p. 30/61 3/13 enantiomers, diastereomers, tautomers and polymorphs thereof. 2. Compound, according to claim 1, characterized by the fact that it is selected from the group consisting of: 3- [4- (7-hydroxy-indan-4-yloxy) -3,5-dimethylpyrazol-1-yl] -propionic acid; 7- [3,5-dimethyl-1- (1H-tetrazol-5-ylmethyl) -1H-pyrazol-4yloxy] -indan-4-ol; 7- {3,5-dimethyl-1- [2- (1H-tetrazol-5-yl) -ethyl] -1Hpyrazol-4-yloxy} -indan-4-ol; {2- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethylpyrazol-1-yl] -acetylamino} -acetic acid; 2- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-pyrazol-1-yl] -N- (1H-tetrazol-5-yl) -acetamide; 3- [4- (7-Hydroxy-indan-4-yloxy) -3-thiophen-2-ylpyrazol-l-yl] -propionic acid and 3- [4- (7-Hydroxy-indan-4yloxy) -5 -thiophen-2-yl-pyrazol-1-yl] -propionic; 7- [1- (1H-Tetrazol-5-ylmethyl) -3-thiophen-2-yl-1Hpyrazol -4-yloxy] -indan-4-ol and 7- [1- (1H-Tetrazol-5ylmethyl) - 5-thiophen-2-yl-1H-pyrazol-4-yloxy] -indan-4-ol; 3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -propionic acid; 5- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-pyrazol-lilmethyl] -1H-pyrazol-3-ol; 2- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5 dimethyl-pyrazol-1-yl] -acetic acid; 7- [1- (2-Hydroxy-ethyl) -3,5-dimethyl-1H-pyrazol-4ylmethyl] -5-methyl-indan-4-ol; Petition 870190058304, of 06/24/2019, p. 31/61 4/13 3- [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -propionic acid; 7- [3,5-Dimethyl-1- (1H-tetrazol-5-ylmethyl) -1H-pyrazol-4ylmethyl] -5-methyl-indan-4-ol; 7- [3,5-Diisopropyl-1- (1H-tetrazol-5-ylmethyl) -1Hpyrazol-4-ylmethyl] -5-methyl-indan-4-ol; 3- [3,5-Dicyclopropyl-4- (7-hydroxy-indan-4yloxy) -pyrazol-1-yl] -propionic acid; 3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5 diisopropyl-pyrazol-1-yl] -propionic acid; [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4ylmethyl) -pyrazol-1-yl] -acetic acid; 3- [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4ylmethyl) -pyrazol-1-yl] -propionic acid; 7- [3,5-Diethyl-1- (1H-tetrazol-5-ylmethyl) -1H-pyrazol-4ylmethyl] -5-methyl-indan-4-ol; [3,5-Dicyclopropyl-4- (7-hydroxy-indan-4-yloxy) pyrazol-1-yl] -acetic acid; [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethylpyrazol-1-yl] -acetic acid; 3- [4- (6-Chloro-7-hydroxy-indan-4-ylmethyl) -3,5diethyl-pyrazol-1-yl] -propionic acid; [4- (6-Chloro-7-hydroxy-indan-4-ylmethyl) -3,5diethyl-pyrazol-1-yl] -acetic acid; 3- {4- [7-Hydroxy-6- (pyrrolidine-1-carbonyl) indan-4-ylmethyl] -3,5-dimethyl-pyrazol-1-yl} -propionic acid; 3- [4- (6-Chloro-7-hydroxy-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -propionic acid; Petition 870190058304, of 06/24/2019, p. 32/61 5/13 1— {2— [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid; 7- [3,5-Dimethyl-1- (1H-tetrazol-5-ylmethyl) -1H-pyrazol-4yloxy] -5-methyl-indan-4-ol; [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5diisopropyl-pyrazol-1-yl] -acetic acid; 3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -N-isopropyl-propionamide; [4- (7-Hydroxy-6-methyl-indan-4-yloxy) -3,5dimethyl-pyrazol-1-yl] -acetic acid; 3- [4- (7-Hydroxy-6-methyl-indan-4-yloxy) -3,5-dimethyl-pyrazol-1-yl] -propionic acid; 4- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5 dimethyl-pyrazol-1-yl] -butyric acid; 3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -N- (1H-tetrazol-5-yl) -propionamide; 5- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-ylmethyl] -3H- [1,3,4] oxadiazole-2-one; 7- {3,5-Dimethyl-1- [2- (1H-tetrazol-5-yl) -ethyl] -1Hpyrazol-4-ylmethyl} -5-methyl-indan-4-ol; {2- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -acetylamino} -acetic acid; 5- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol -1-ylmethyl] -1H-pyrazol-3-ol; 5- [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4-ylmethyl) pyrazol -1-ylmethyl] -3H- [1,3,4] oxadiazole-2-one; 5- {2- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -ethyl} -3H- [1,3,4] oxadiazole-2 -one; Petition 870190058304, of 06/24/2019, p. 33/61 6/13 {2- [3,5-Dietyl-4- (7-hydroxy-6-methyl-indan-4ylmethyl) -pyrazol-1-yl] -acetylamino} -acetic acid; 6 ^- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-ylmethyl] -2-methyl-3H-pyrimidin-4-one; 3- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-ylmethyl] - [1,2,4] oxadiazole-5-ol; 7- (1-Benzyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl) -5-methylindan-4-ol; 3- {4- [7-Hydroxy-6- (4-methyl-benzyl) -indan-4ylmethyl] -3,5-dimethyl-pyrazol-1-yl} -propionic acid; 2- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -propionic acid; 3- [4- (7-Hydroxy-6-isopropyl-indan-4-ylmethyl) - acid 3) 5-dimethyl-pyrazol-1-yl] -propionic; {4- [7-Hydroxy-6- (4-methyl-Benzyl) -indan-4ylmethyl] -3,5-dimethyl-pyrazol-1-yl} -acetic acid; 3- {4- [6- (4-Fluoro-Benzyl) -7-hydroxy-indan-4ylmethyl] -3,5-dimethyl-pyrazol-1-yl} -propionic acid; {4- [6- (4-Fluoro-Benzyl) -7-hydroxy-indan-4ylmethyl] -3,5-dimethyl-pyrazol-1-yl} -acetic acid; 4- [4- (7-Hydroxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -butyric acid sodium salt; 3- [4- (7-Hydroxy-6-methylindan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -propionic acid magnesium salt; Sodium salt of 3- [4- (7-Hydroxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -propionic acid; 3- {3,5-Diethyl-4- [6- (4-fluoro-benzyl) -7-hydroxyindan-4-ylmethyl] -pyrazol-1-yl} -propionic acid; Petition 870190058304, of 06/24/2019, p. 34/61 7/13 Ethyl ester of 3- [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -3-oxo-propionic acid; [3,5-Diethyl-4- (7-methoxy-6-methylindan-4-ylmethyl) -pyrazol-1-yl] -acetic acid hydrazide; N-Hydroxy-2- [4- (7-methoxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -acetamidine; [4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -oxo-acetic acid ethyl ester; [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -morpholin-4-yl-methanone; 1- (4-Chloro-phenyl) -4- (7-methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-1H-pyrazole; 2- (4-Methanesulfonyl-phenyl) -1- [4- (7-methoxy-6-methylindan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -ethanone; 4- (7-Methoxy-6-methyl-indan-4ylmethyl) -3,5-dimethyl-pyrazole-1-carboxylic acid ethyl ester; Propane-2-sulfonic acid {3- [4- (7-methoxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -propionyl} -amide; 3- [5-Ethoxy-4- (7-methoxy-6-methyl-indan-4-ylmethyl) - acid 3-methyl-pyrazol-1-yl] -propionic or 3- [3-Ethoxy-4- (7methoxy-6-methyl-indan-4-ylmethyl) -5-methyl-pyrazol-1-yl] propionic acid; [4- (7-Hydroxy-3,6-dimethyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -acetic acid; 2- [4- (7-Hydroxy-6-methyl-indan-4-ylmethyl) -3,5 dimethyl-pyrazol-1-ylmethyl] -pentanedioic acid; [4- (7-Methoxy-2,2,6-trimethyl-indan-4-ylmethyl) 3,5-dimethyl-pyrazol-1-yl] -acetic acid; Petition 870190058304, of 06/24/2019, p. 35/61 8/13 Ν- {2- [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -ethyl} -acetamide; N- {2- [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3,5dimethyl-pyrazol-1-yl] -ethyl} -methane-sulfonamide; 4- [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3,5-dimethylpyrazol-1-yl] -1- (toluene-4-sulfonyl) -piperidine; {3,5-Diethyl-4- [6- (4-fluoro-benzyl) -7-hydroxyindan-4-ylmethyl] -pyrazol-1-yl} -acetic acid; 3- {4- [7-Methoxy-6- (4-methoxy-phenyl) -indan-4ylmethyl] -3,5-dimethyl-pyrazol-1-yl} -propionic acid; 2- [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4-ylmethyl) pyrazol -1-yl] -N-isopropyl-acetamide; 3- [4- (7-Etoxycarbonyloxy-6-methylindan-4-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -propionic acid methyl ester; [3,5-Diethyl-4- (7-hydroxy-6methyl-indan-4-ylmethyl) -pyrazol-1-yl] -acetic acid sodium salt; 3- [4- (7-Methoxy-6-methyl-indan-4-ylmethyl) -3-methyl- 5-rifluoromethyl-pyrazol-1-yl] -propionic and 3— [4— (7— Methoxy-6-methyl-indan-4-ylmethyl) -5-methyl-3-rifluoromethylpyrazol-1-yl] -propionic; [4- (4-Hydroxy-3-methyl-5,66,7,8-tetrahydronaphthalen-1-ylmethyl) -3,5-dimethyl-pyrazol-1-yl] -acetic acid; [4- (7-Chloro-indan-4-yloxy) -3-thiophen-2-ylpyrazol-1-yl] -acetic acid and [4- (7-Chloro-indan-4-yloxy) -5thiophen-2 -yl-pyrazol-1-yl] -acetic; {4- [7-Methoxy-6-methyl-2- (4-nitro-phenoxy) -indan-4ylmethyl] - 3,5-dimethyl-pyrazol-1-yl} -acetic acid; [5-Amino-4- (7-methoxy-6-methyl-indan-4-ylmethyl) -3 (4-methoxy-phenyl) -pyrazol-l-yl] -acetic acid and [3-Amino-4Petition 870190058304 , of 06/24/2019, p. 36/61 9/13 (7-methoxy-6-methyl-indan-4-ylmethyl) -5- (4-methoxy-phenyl) pyrazol-1-yl] -acetic; 2- [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4-ylmethyl) pyrazol -1-yl] -N- (1H-tetrazol-5-yl) -acetamide; 1-Carboxymethyl-5- (5-chloro-thiophen-2-yl) -4- (7methoxy-6-methyl-indan-4-ylmethyl) -1H-pyrazola-3-carboxylic acid and 2-Carboxymethyl-5- (5-chloro-thiophen-2-yl) -4- (7-methoxy-6methyl-indan-4-ylmethyl) -2H-pyrazole-3-carboxylic; 2- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethylpyrazol-1-yl] -propionic acid; L- {2- [3,5-Diethyl-4- (7-hydroxy-6-methyl-indan-4ylmethyl) -pyrazol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid; [3,5-Diethyl-4- (7-hydroxy-6-pyrrolidin-1-ylmethylindan -4-ylmethyl) -pyrazol-1-yl] -acetic acid; 3- [3,5-Diethyl-4- (7-hydroxy-6-pyrrolidin-lilmetyl-indan-4-ylmethyl) -pyrazol-1-yl] -propionic acid; Acid 3- [3 _; 5-Diethyl-4- (7-methoxy-6-methoxymethyl-indan-4ylmethyl) -pyrazol-1-yl] -propionic; {3,5-Diethyl-4- [7-hydroxy-6- (pyrrolidine-1carbonyl) -indan-4-ylmethyl] -pyrazol-1-yl} -acetic acid; [3,5-Diethyl-4- (7-methoxy-6-methoxymethyl-indan-4ylmethyl) -pyrazol-1-yl] -acetic acid; 3- {3,5-Diethyl-4- [7-hydroxy-6- (pyrrolidine-1carbonyl) -indan-4-ylmethyl] -pyrazol-1-yl} -propionic acid; and N- (4-Chloro-phenyl) -2- [3,5-diethyl-4- (7-hydroxy-6-methylindan-4-ylmethyl) -pyrazol-1-yl] -acetamide. Pharmaceutical composition characterized by the fact that it comprises a therapeutically effective amount of one or more compounds according to claim 1 or 2, Petition 870190058304, of 06/24/2019, p. 37/61 10/13 optionally in combination with pharmaceutically acceptable salts, diluents or vehicles. 4. Use on one or more compounds, in wake up with the claim 1 or 2, characterized by fact that is for the manufacture on one medicine for O treatment of obesity in a living mammalian organism, including a being human. 5. Use on one or more compounds, in wake up with the claim 1 or 2, characterized by fact that is for manufacture one medicine for improvement gives resistance to insulin and / or prevention or delay of progression to diabetes in a living mammalian organism, including a being human. 6. Use on one or more compounds, in wake up with the claim 1 or 2, characterized by fact that is for manufacture a medicine for prevention and treatment in dyslipidemia in a living mammalian organism, including one human being. 7. Use in one or more compounds according to with The claim 1 or 2, characterized by the fact that what is to manufacture one medicine for prevention and treatment of syndrome metabolic in a mammalian organism alive, including one; to be human. 8. Use in one or more compounds according to with The claim 1 or 2, characterized by the fact that what is to manufacture one medicine for prevention and treatment of disease or disorder associated with inappropriate thyroid hormone activity in a living mammalian organism, including a human. Petition 870190058304, of 06/24/2019, p. 38/61 11/13 9. Use according to claim 8, characterized by the fact that the disease or disorder selected from: conditions associated with a disease or disorder associated with excessive fat accumulation, altered mitochondrial function; lipid disorders caused by an imbalance in blood or tissue lipid levels; impaired glucose tolerance; type ii diabetes; replacement therapy in elderly individuals with hypothyroidism; depression; cardiovascular diseases; skin disorders. 10. Process for the preparation of a compound, as defined in claim 1, characterized by the fact that it comprises: (i) reaction of a compound of formula (II): with a compound of formula: R ² -Y where Y is a driving group, preferably halogen, in the presence of a suitable base in a suitable solvent, or; (ii) reaction of formula (III) or (IX): Petition 870190058304, of 06/24/2019, p. 39/61 12/13 with hydrazine hydrate or properly substituted hydrazine of formula: R ² NHNH ₂ or; (iii) reaction of a compound of formula (XIII): R ⁴ -CHO XIII with a compound of formula (V): V in the presence of a suitable base in a suitable solvent, followed by reduction with a suitable reducing agent, or; (iv) reaction of a compound of formula (XV): R ⁴ -CH ₂ Y XV where Y is a group in driving, preferably halogen, with a composed of formula (V): R ¹ I Γ O THE R ’ CN V X in presence of a base proper in a solvent appropriate, or; Petition 870190058304, of 06/24/2019, p. 40/61 13/13 (v) reaction of a compound of formula (IV): with a compound R ⁴ OH or R ⁴ NH ₂ in the presence of a base; wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1. Petition 870190058304, of 06/24/2019, p. 41/61 1/1 Effect of compound B test on OGTT Glucose mg / dL 0 15 30 45 60 Time, minutes £ —o — Vehicle —a— Dose 1 · —Dose 2 * j