CN101111486A - antidiabetic bicyclic compounds - Google Patents

Abstract

Bicyclic compounds containing a phenyl or pyridyl ring fused to a cycloalkyl or heterocyclic ring, to which is attached a 5-membered heterocyclic ring, including pharmaceutically acceptable salts and prodrugs thereof, are agonists of G-protein coupled receptor 40 (GPR40) and are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Description

antidiabetic bicyclic compounds

field of invention

The present invention relates to bicyclic compounds containing a phenyl ring fused to a carbocyclic or heterocyclic ring, including pharmaceutically acceptable salts and prodrugs thereof, which are G protein-coupled receptor 40 (GPR40) agonists and can Useful as a therapeutic compound, especially in the treatment of type 2 diabetes and the conditions often associated with these diseases, including obesity and lipid disorders.

Background of the invention

Diabetes mellitus is a multifactorial disease characterized by elevated plasma glucose levels (hyperglycemia) in the fasted state or after administration of glucose during an oral glucose tolerance test. There are generally two recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), the patient produces little or no insulin, the hormone used to regulate glucose. In type 2 diabetes, or non-insulin-dependent diabetes mellitus (NlDDM), the body still produces insulin. Patients with type 2 diabetes are resistant to the action of insulin to stimulate insulin and lipid metabolism in the main insulin-sensitive tissues (muscle, liver and adipose tissue). These patients usually have normal levels of insulin and may have hyperinsulinemia (elevated plasma insulin levels) as they compensate for the lowering effects of insulin by secreting increased amounts of insulin. The reduced number of insulin receptors is not the main cause of insulin resistance, mainly due to post-insulin receptor binding defects, which is not fully understood. This lack of response to insulin results in insufficient insulin-mediated activation of glucose uptake, oxidation, and storage in muscle, as well as in insulin-mediated inhibition of lipolysis in adipose tissue and on glucose production and secretion in the liver Insufficient suppression.

Persistent or uncontrolled hyperglycemia that accompanies diabetes is associated with increased and premature morbidity and mortality. In general, abnormal glucose homeostasis is directly or indirectly linked to obesity, hypertension, and changes in lipid, lipoprotein, and adipoprotein metabolism, as well as other metabolic and hemodynamic diseases. Patients with type 2 diabetes are at significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension is crucial in the clinical management and treatment of diabetes.

Patients with insulin resistance often have several symptoms collectively known as Syndrome X or Metabolic Syndrome. According to one definition that is widely used, patients with metabolic syndrome are characterized by having three or more symptoms selected from the following five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which can also be characteristic of type 2 diabetes if the patient is also diabetic. These symptoms are clinically defined in Third Report of the National Cholesterol Education Program Expert Panelon Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel HI, or ATP TS), National Institutes of Health, 2001, N1H Publication 3 7 No.0 . Patients with the metabolic syndrome, regardless of whether they have or manifest symptoms of diabetes, are at increased risk of developing the macrovascular and microvascular complications that occur with type 2 diabetes, such as atherosclerosis and coronary heart disease.

There are several methods available for treating type 2 diabetes, each with its own limitations and potential dangers. Physical activity and reducing dietary calorie intake often significantly improve the diabetic condition and are the recommended first-line therapy often used for type 2 diabetes and prediabetic conditions associated with insulin resistance. Compliance with this therapy is very poor due to a habitual lifestyle that is not easily changed and excessive consumption of foods, especially foods high in fat and carbohydrates. Pharmacological treatments focus on three pathophysiological areas: (1) hepatic glucose production (biguanides), (2) insulin resistance (PPAR agonists), and (3) insulin secretion.

Biguanides are a class of drugs widely used to treat type 2 diabetes. The two best known biguanides, phenformin and metformin, allow some correction of hyperglycemia. Biguanides work primarily by inhibiting hepatic glucose production, and they are also thought to mildly improve insulin sensitivity. Biguanides can be used alone or in combination with other antidiabetic drugs (such as insulin or insulin secretagogues) without increasing the risk of hypoglycemia. However, phenformin and metformin can induce lactic acidosis and nausea/diarrhea. Metformin has a lower risk of side effects than phenformin and is therefore widely prescribed for the treatment of type 2 diabetes.

The glitazones (ie, 5-benzylthiazolidine-2,4-dione) are a newer class of compounds that can improve hyperglycemia and other symptoms of type 2 diabetes. The currently marketed glitazones (rosiglitazone and pioglitazone) are agonists of the peroxisome proliferator-activated receptor (PPAR) gamma subtype. PPAR-γ agonists significantly enhance insulin sensitivity in muscle, liver, and adipose tissue in several animal models of type 2 diabetes, thereby partially or completely normalizing elevated plasma glucose levels without hypoglycemia. The mechanism of PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization observed in human patients treated with glitazones. New PPAR agonists are currently being developed. Many of the newer PPAR compounds are agonists of one or more of the PPAR alpha, gamma, and delta subtypes. Also as PPAR

Compounds that are agonists of the α and PPAR γ subtypes (PPAR α/γ binary agonists) are promising because they can both reduce hyperglycemia and improve lipid metabolism. Currently commercially available PPARγ agonists have modest effects in lowering plasma glucose and hemoglobin AlC. Currently marketed compounds do not greatly improve lipid metabolism and may in fact have a negative impact on lipid profile. Thus, PPAR compounds represent an important improvement in diabetes therapy, but still need to be further refined.

Another widely used drug therapy involves the administration of insulin secretagogues, such as sulfonylureas (eg tolbutamide and glipizide). These drugs increase plasma insulin levels by stimulating the pancreatic β-cells to secrete more insulin. Insulin secretion in pancreatic β-cells is tightly regulated by glucose and a series of metabolic, neural and hormonal signals. Glucose is metabolized to form ATP and other signaling molecules to stimulate insulin formation and secretion, while other extracellular signals act as potentiators or inhibitors of insulin secretion through the presence of GPCRs on the plasma membrane. Sulfonylureas and related insulin secretagogues act by blocking ATP-dependent K ⁺ channels in β-cells, which depolarizes the cells and opens voltage-dependent Ca2 ⁺ channels, simultaneously stimulating insulin release. This mechanism is insulin-independent, whereby insulin secretion can exist regardless of surrounding glucose levels. This can cause insulin to be secreted even when glucose levels are low, leading to hypoglycemia, which can be fatal in severe cases. Therefore, the dosing of insulin secretagogues must be carefully controlled. Insulin secretagogues are often used as first-line drugs in the treatment of type 2 diabetes.

The focus has now been refocused on Isle of Langerhans-based insulin secretion controlled by glucose-dependent insulin secretion. This approach can potentially be used to stabilize and restore β-cell function. In this regard, several orphan G protein-coupled receptors (GPCR's), which are preferentially expressed in β-cells and are involved in glucose-stimulated insulin secretion (GSIS), have recently been identified. GPR40 is a cell surface GPCR highly expressed in human (and rodent) pancreatic islets as well as insulin-secreting cell lines. Several naturally occurring long-chain fatty acids (FA's) as well as mediators of synthetic compounds, including several thiazolidinediones PPARγ agonists have recently been identified as GPR40 ligands (Itoh, Y. et al., Nature.422 : 173 [20031; Briscoe, CP. et al., J. Biol. Chem. 278: 11303 [2003]; Kotarsky, K. et al., Biochem. Biophys. Res. Comm. 301: 406 [2003]). GPR40 agonists enhance insulin release from islet cells under hyperglycemic conditions. The specificity of this response was suggested by the results showing that siRNA attenuates GPR40 activity inhibition by FA-induced amplification of GSIS. These findings suggest that, in addition to the intracellular formation of fat-derivatives of FA's thought to promote insulin release, FA's (and other synthetic GPR40 agonists) may also act as Binds the extracellular ligand of GPR40. GPR40 has several possible advantages as a potential target for the treatment of type 2 diabetes. First, because GPR40-mediated insulin secretion is glucose-dependent, there is little or no risk of hypoglycemia. Second, the limited tissue distribution of GPR40 (mainly in pancreatic islets) suggests that side effects associated with GPR40 activity in other tissues are less likely. Third, GPR40 agonists active in islets have the potential to restore or preserve islet function. This would be very advantageous because long-term diabetes treatment often results in a gradual decrease in islet activity such that following long-term treatment, daily insulin injections are often required to treat patients with type 2 diabetes. By restoring or maintaining islet function, GPR40 agonists can delay or prevent the decrease and loss of islet function in patients with type 2 diabetes.

Summary of the invention

The compounds described herein are a new class of GPR40 agonists. These compounds are useful in the treatment of diseases modulated by GPR40 agonists, including type 2 diabetes and hyperglycemia that may be associated with type 2 diabetes or pre-diabetic insulin resistance and obesity.

The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, including its single diastereoisomer and enantiomer and a mixture of its diastereoisomers and/or enantiomers:

Wherein A is independently selected from -CH- and -N-;

B is selected from -S-, -O-, -NH-, -C(=O)- and _-CH2- ;

D is selected from -C(=O)-, -C(=S)-, -C(=NH)-, -O- and -NH-;

W and Z are independently selected from -CH ₂ -, -CF ₂ -, -CH ₂ CH ₂ - and -CH ₂ CH ₂ CH ₂ -, and one of W and Z may optionally be selected from -O-, -C(=O)-, -NR ⁶ -, -S-, -SO- and -SO ₂ -;

Y is selected from =CH- and =N-;

The heterocycle is a 5-6 membered saturated or partially saturated monocyclic heterocycle with 1-3 heteroatoms independently selected from O, N and S;

Heteroaryl is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from O, N and S;

R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, halogen, -CN, -NO ₂ , -C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -N(R ⁶ )(R ⁶ ), -N(R ⁶ )C(=O)C ₁ -C ₆ alkyl, -N (R ⁶ )S(O) ₂ C ₁ -C ₆ alkyl, -C(=O)H, -C(=O)OH, -C(=O)OC ₁ -C ₆ alkyl, -C( =O)C ₁ -C ₆ alkyl, -C(=O)N(R ⁶ )(R ⁶ ), -C(=O)phenyl, -C(=O)naphthyl, -C(=O ) heterocycle, heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl, phenyl and naphthyl;

Wherein -C ₁ -C ₆ alkyl and -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -N(R ⁶ )C( =O)C ₁ -C ₆ alkyl, -N(R ⁶ )S(O) ₂ C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, and -C(=O)C The alkyl of ₁ -C ₆ alkyl is optionally substituted by 1-5 halogens and is also optionally substituted by 1-2 groups independently selected from -OH, -OC ₁ -C ₃ alkyl, so The -OC ₁ -C ₃ alkyl is optionally replaced by 1-5 halogen, -CF ₃ , -S(O) ₂ C ₁ -C ₃ alkyl, -C(=O)C ₁ -C ₃ alkyl , -OC(=O)C ₁ -C ₆ alkyl, -NHC(=O)CH ₃ , -NHC(=O)OC ₁ -C ₆ alkyl, -NHS(O) ₂ CH ₃ , -N( R ⁶ )(R ⁶ ), heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl, phenyl and naphthyl substitution;

where -C(=O)phenyl, -C(=O)naphthyl, -C(=O)heterocycle, heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl, phenyl and naphthyl As R ¹ , R ² , R ³ , R ⁴ , or as a substituent on R ¹ , R ² , R ³ and R ⁴ , optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, -CF ₃ , -OCF ₃ , -CN, -NO ₂ , -OH, -C ₁ -C ₃ alkyl, -C(=O)C ₁ -C ₃ alkyl, -S(O) ₂ C ₁ - C ₃ alkyl and -OC ₁ -C ₃ alkyl, wherein said -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl and - The C(=O)C ₁ -C ₃ alkyl substituent is optionally substituted with 1-3 halogens; and wherein

Alternatively - a pair selected from (R ¹ -R ² ), (R ² -R ¹ ), (R ² -R ³ ), (R ³ -R ² ), (R ³ -R ⁴ ) and (R ⁴ The ortho substituents of -R ³ ) can be linked together to form a divalent bridging group with a length of 3-5 atoms, wherein the divalent bridging group is selected from -CH ₂ CH ₂ CH ₂ -, - CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ CH ₂ -, -OCH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ OCH ₂ CH ₂ -, -CH ₂ OCH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ OCH ₂ CH ₂ -, and -SCH ₂ CH ₂ -, wherein the bridging group The group is optionally replaced by 1-3 independently selected from halogen, -OH, -CN, -NO ₂ , -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkane Substituents of group, -S(O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and -OCF ₃ ; and wherein

Alternatively the pair of ortho substituents R ¹ -R ² may be linked via a 4-carbon chain -CH=CH-CH=CH-, thereby forming a fused benzene at the R ¹ and R ² positions A base ring, or through a 4-atom chain -CH=CH-CH=N-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-, - _CH2CH2CH2C (=O) or _{-C (} =O) _CH2CH2CH2- is attached to _form a fused pyridyl ring or a fused _cyclohexane at the ^R1 and ^R2 positions Ketone ring, wherein said fused phenyl ring, said fused pyridyl ring and said fused cyclohexanone ring are optionally selected from 1-3 independently selected from halogen, -OH, -CN , -NO ₂ , -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and - Substituent substitution of OCF ₃ ; and wherein

Alternatively, the pair of ortho substituents R ¹ -R ² can pass through a 3-atom chain -CH=CHO-, -OCH=CH-, -CH=CH-S-, -SCH=CH-, -CH=CHN(R ⁶ )-, -N(R ⁶ )CH=CH-, -CH ₂ CH ₂ C(=O)- and -C(=O)CH ₂ CH ₂ - are linked so that at R ¹ and ^R2 positions form a five-membered ring fused to the phenyl ring, wherein the fused five-membered ring is optionally composed of 1-3 independently selected from halogen, -OH, -CN, -NO _2. -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and -OCF ₃ substituted by a substituent; and

R ⁶ is selected from H and -C ₁ -C ₆ alkyl.

In the definitions above and below, unless otherwise stated, an alkyl group may be a straight-chain or branched-chain alkyl group.

In closely related embodiments, R ¹ , R ² , R ³ and R ⁴ are as defined above, except when R ¹ , R ² , R ³ or R ⁴ is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -N(R ⁶ )C(=O)C ₁ -C ₆ alkyl, -N(R ⁶ ) When S(O) ₂ C ₁ -C ₆ alkyl, -C(=O)OC ₁ -C ₆ alkyl or -C(=O)C ₁ -C ₆ alkyl, then C ₁ -C ₆ Alkyl is optionally substituted with 1-5 halogens, and is optionally substituted with 1-2 independently selected from -OH, -OC ₁ -C ₃ alkyl, -CF ₃ , -OCF ₃ , -S(O ) ₂ C ₁ -C ₃ alkyl, -C(=O)C ₁ -C ₃ alkyl, -NHC(=O)CH ₃ , -NHS(O) ₂ CH ₃ , heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl, phenyl and naphthyl, wherein the substituents on heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl, phenyl and naphthyl are as above are defined; and all other substituents and groups are as defined above.

In another closely related embodiment, R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, halogen, -CN, -NO ₂ , -C ₁ -C ₆ alkyl, -OC ₁ - C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -N(R ⁶ )(R ⁶ ), -N(R ⁶ )C(=O) C ₁ -C ₆ alkyl, -N(R ⁶ )S(O) ₂ C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl, -C(=O)N(R ⁶ ) (R ⁶ ), -C(=O)phenyl, -C(=O)naphthyl, -C(=O)heterocycle, heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl , phenyl and naphthyl;

Wherein -C ₁ -C ₆ alkyl and -OC ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -N(R ⁶ )C( The alkyl of =O)C ₁ -C ₆ alkyl, -N(R ⁶ )S(O) ₂ C ₁ -C ₆ alkyl and -C(=O)C ₁ -C ₆ alkyl is optionally represented by substituted by 1-5 halogens, and optionally substituted by 1-2 groups independently selected from: -OH, -OC ₁ -C ₃ alkyl, -CF ₃ , -OCF ₃ , -S( O) ₂ C ₁ -C ₃ alkyl, -C(=O)C ₁ -C ₃ alkyl, -NHCOCH ₃ , -NHS(O) ₂ CH ₃ , heterocycle, heteroaryl, C ₃ -C ₇ - cycloalkyl, phenyl and naphthyl;

where -C(=O)phenyl, -C(=O)naphthyl, -C(=O)heterocycle, heterocycle, heteroaryl, C ₃ -C ₇ -cycloalkyl, phenyl and naphthyl As R ¹ , R ² , R ³ , R ⁴ or as substituents on R ¹ , R ² , R ³ and R ⁴ , optionally 1-4 independently selected from halogen, -CF ₃ , -OCF ₃ , -CN, -NO ₂ , -OH, -C ₁ -C ₃ alkyl, -C(=O)C ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl and - The substituent of OC ₁ -C ₃ alkyl is substituted, wherein said -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl and -C( =O) C ₁ -C ₃ alkyl substituents are optionally substituted with 1-3 halogen.

All other substituents in the above embodiments are as previously described, including other definitions for R ¹ , R ² , R ³ and R ⁴ , wherein the R ¹ , R ² , R ³ and R ⁴ groups ortho to each other can be determined by The bridging group connects to form an additional fused ring. In the above specification, it is drawn that the bridging group connecting a pair of groups R ¹ , R ² , R ³ and R ⁴ adjacent to each other can be attached to the ring in a left-to-right or right-to-left manner .

Detailed description of the invention

The invention has various embodiments outlined below. The compounds shown in the present invention also include single diastereomers, enantiomers and epimers of the compounds and mixtures of diastereomers and/or enantiomers. The present invention also includes pharmaceutically acceptable salts of said compounds, and pharmaceutical compositions comprising said compounds and pharmaceutically acceptable carriers. The compounds are particularly useful in the treatment of insulin resistance, type 2 diabetes and dyslipidemia associated with type 2 diabetes and insulin resistance.

A subgroup of compounds of formula I includes compounds, including pharmaceutically acceptable salts thereof, wherein R ¹ , R ² , R ³ and R ⁴ are independently selected from (1) H; (2) halogen; (3) -NO ₂ (4)-CN; (5)-C _1-6 alkyl, which is optionally substituted by 1-5 halogen and optionally also 1-2 independently selected from -OH, -CF ₃ , -C(=O)C ₁ -C ₃ alkyl and substituents of -OC ₁ -C ₃ alkyl optionally substituted with 1-3 halogens; (6) -OC _1-6 alkyl, which optionally substituted by 1-5 halogens, and also optionally substituted by 1-2 groups independently selected from _-CF3 and -C(=O) _C1 - _C3alkyl ; (7) -C(=O)C ₁ -C ₃ alkyl, which is optionally substituted by 1-5 halogens, and is also optionally substituted by 1-2 groups independently selected from -CF ₃ ; and ( 8) C ₃ -C ₇ cycloalkyl, phenyl or heterocycle, each of which is optionally selected from 1-3 independently selected from halogen, -OH, -OC _1-3 alkyl, CF ₃ and -C( =O) Substituents of C ₁ -C ₃ alkyl.

In a subgroup of compounds of formula I or pharmaceutically acceptable salts thereof, R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH ₂ OH, -CH(OH)CH ₃ , -C(O)H, -C(=O)OH, -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, -CN, -OCH ₃ , -OCF ₃ , -NO ₂ , CH(CH ₃ ) ₂ , nC ₃ H ₇ , nC ₅ H ₁₁ , -C ₂ F ₅ , -CHFCH ₃ , -CHFCF ₃ , -CF ₂ CH _3. -CHF ₂ , -CH ₂ F, -OCHF ₂ , -OCH ₂ F, -OCH ₂ phenyl, -C(=O)OCH ₃ , -S(O) ₂ CH ₃ , -C(=O) NH ₂ , -CH ₂ OC(=O)CH ₃ , -NH ₂ , -CH ₂ NH ₂ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHC(=O)OC(CH ₃ ) ₃ , - CH ₂ (1-pyrrolidinyl) and -C(=O)(3,3-difluoro-1-azetidinyl).

In a subgroup of compounds of formula I or pharmaceutically acceptable salts thereof, R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , —CH( OH) _{CH3 ,} -C(=O) _CH3 , _-CH2CH3 , _-CH2CF3 , cyclopropyl, -CN, _{-OCH3 , -OCF3} , and _-NO2 . In other subgroups of compounds of formula I or pharmaceutically acceptable salts thereof, R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH ₂ OH, -CH(OH)CH ₃ , -C(=O)H, -C(=O)OH, -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropane group, -CN, -OCH ₃ , -OCF ₃ and -NO ₂ .

A subgroup of compounds of formula I includes the following compounds and pharmaceutically acceptable salts thereof, wherein R and ^R are linked by a 4-carbon chain -CH=CH-CH=CH- ^, so that at the R ^{and R} positions Forming a fused phenyl group, wherein the fused phenyl group is optionally replaced by 1-3 independently selected from halogen, -OH, -CN, -NO ₂ , -C ₁ -C ₃ alkyl, -OC Substituents of ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and -OCF ₃ are substituted.

A subgroup of compounds of formula I includes compounds wherein R ¹ and R ² are selected from the group consisting of -CH=CH-CH=CH-, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ C(=O) and - The -3- or 4-carbon chain of C(=O)CH ₂ CH ₂ is linked to form a fused phenyl, cyclopentyl or cyclohexanone ring at the R ¹ and R ² positions, wherein the fused The combined phenyl, cyclopentyl and cyclopentanone rings are optionally selected from 1-3 independently selected from halogen, -OH, -CN, -NO ₂ , -C ₁ -C ₃ alkyl, -OC ₁ - Substituents of C ₃ alkyl, -SC ₁ -C ₃ alkyl, -S(O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and -OCF ₃ are substituted.

In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof has a Z group that is -CH ₂ - and is -CH ₂ -, -CF ₂ -, -CH ₂ CH ₂ -, -O- Or the group W of -S-.

In another embodiment, the compound of formula I or its pharmaceutically acceptable salt has group A, which is -CH- or -N-; group B, which is -S-, -O-, -NH- or - _CH2- ; and the group D, which is -C(=O)-.

Additional embodiments include compounds of formula I and pharmaceutically acceptable salts thereof, wherein R ¹ and R ² are selected from -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ - ^, -CH ₂ CH ₂ S-, and -SCH ₂ CH ₂ - ^divalent bridging groups to form a fused to 5- or 6-membered ring of phenyl ring.

In a preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH ₂ OH, -CH(OH)CH ₃ , -C(=O)H , -C(=O)OH, -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, -CN, -OCH ₃ , -OCF ₃ and -NO ₂ , where R ^and R may ^{alternatively} be linked via a 4-carbon chain -CH=CH-CH=CH-, forming a fused phenyl group at the R ^{and R} positions;

Y is selected from =CH- and =N-;

W is selected from -O-, -S- and _CH2 ;

Z is selected from -CH ₂ - and -CH ₂ CH ₂ -;

A is -CH- or -N-;

B is selected from -S-, -O- and _-CH2- ; and

D is -C(=O).

Additional embodiments of the invention include compounds of formula Ia and pharmaceutically acceptable salts thereof, wherein

R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH(OH)CH ₃ , -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, -CN, -OCH ₃ , -OCF ₃ and -NO ₂ ;

Or R ¹ and R ² are connected through a 4-carbon chain -CH=CH-CH=CH-, thereby forming a fused phenyl group at the R ¹ and R ² positions;

Y is selected from =CH- and =N-;

W is selected from -CH ₂ -, -CF ₂ -, -CH ₂ CH ₂ -, -O- and -S-;

A is -CH- or -N-; and

B is selected from -S-, -O-, -NH- and _-CH2- .

Preferred embodiments include compounds of formula Ia and pharmaceutically acceptable salts thereof, wherein

R ¹ is H, F, Br, Cl, CH ₃ , CF ₃ or -CH ₂ CH ₃ ;

R ² is H, CH ₃ , CF ₃ , -CH ₂ CH ₃ or -OCF ₃ ;

Or R ¹ and R ² are connected through a 4-carbon chain -CH=CH-CH=CH-, thereby forming a fused phenyl group at the R ¹ and R ² positions;

R ³ is H, Cl, CH ₃ , CF ₃ , -CN or -NO ₂ ;

R ⁴ is H or -CH ₃ ;

Y is =CH- or =N-;

W is -CH ₂ -, -CH ₂ CH ₂ - or -S-;

A is -CH- or -N-; and

B is -S-, -O- or -CH ₂ -.

Other preferred embodiments have Formula Ib, including pharmaceutically acceptable salts thereof:

In these compounds, R ¹ , R ² , R ³ , R ⁴ , Y, W, Z, A and B are as defined in the previous embodiments. It should be noted that formula Ib is a stereoisomer. Compounds having the stereochemistry of formula Ib are generally more reactive than epimers of the compounds. In the case where A=CH, a diastereomeric mixture is obtained. Less active epimers have some therapeutic activity, and less active epimers and other stereoisomers can be used as research tools to study receptor steric requirements and receptor mechanism of action.

In a more preferred embodiment, the compound of formula Ib or a pharmaceutically acceptable salt thereof has the following definitions:

R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH(OH)CH ₃ , -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, -CN, -OCH ₃ , -OCF ₃ and -NO ₂ ;

Y is selected from =CH- and =N-;

W is selected from -CH ₂ -, -CF ₂ -, -CH ₂ CH ₂ -, -O- and -S-;

Z is -CH ₂ -;

A is -CH- or -N-; and

B is selected from -S-, -O-, -NH- and _-CH2- .

Other preferred subgroups include compounds of formula Ic or pharmaceutically acceptable salts thereof, wherein

R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH ₂ OH, -CH(OH)CH ₃ , -C(=O)H , -C(=O)OH, -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, -CN, -OCH ₃ , -OCF ₃ and -NO ₂ ;

wherein R ¹ and R ² can alternatively be linked via a 4-carbon chain -CH=CH-CH=CH-, thereby forming a fused phenyl group at the R ¹ and R ² positions, wherein the fused phenyl The group is optionally selected from 1-3 independently selected from halogen, -OH, -CN, -NO ₂ , -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkane Substituents of group, -S(O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and -OCF ₃ ;

Y is selected from =CH- and =N-;

W is selected from -O- and -S-;

A is -CH- or -N-; and

B is selected from -S-, -O-, -NH- and _-CH2- .

Other preferred subgroups have the formula Id, including pharmaceutically acceptable salts thereof, wherein

R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, F, Br, Cl, CH ₃ , CF ₃ , -CH ₂ OH, -CH(OH)CH ₃ , -C(=O)H , -C(=O)OH, -C(=O)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, -CN, -OCH ₃ , -OCF ₃ and -NO ₂ , where R ^and R may ^{alternatively} be linked via a 4-carbon chain -CH=CH-CH=CH-, forming a fused phenyl group at the R ^{and R} positions; and

B is selected from -S- and -O-;

Other preferred groups of compounds, including their pharmaceutically acceptable salts, have the following structures, for substituent groups their previous definitions apply. They all have the same stereochemistry as described above for the intermediate ring of formula Ib:

(1)

Wherein R ¹ , R ² , R ³ , R ⁴ , A, B, Y and W are each as previously defined, and their definitions are independent of other groups, including pharmaceutically acceptable salts thereof.

(2)

Wherein R ¹ , R ² , R ³ , R ⁴ and W are each as previously defined, and their definitions are independent of other groups, including pharmaceutically acceptable salts thereof.

(3)

Wherein R ¹ , R ² , R ³ , R ⁴ and W are each as previously defined, and their definitions are independent of other groups, including pharmaceutically acceptable salts thereof.

(4)

Wherein R ¹ , R ² , R ³ , R ⁴ , Y and W are each as previously defined, and their definitions are independent of other groups, including pharmaceutically acceptable salts thereof.

(5)

Wherein R ¹ , R ² , R ³ , R ⁴ , A, B, Y and W are each as previously defined, and their definitions are independent of other groups, including pharmaceutically acceptable salts thereof. In the preferred embodiments of Figures Ie and Ij, A is -CH-; and B is -S- or -O-.

In embodiments wherein adjacent pairs of R ¹ , R ² , R ³ and R ⁴ groups are optionally linked by a bridging group to form a 5- or 6-membered ring, the bridging group is optionally 1-3 independently selected from halogen, -OH, -CN, -NO ₂ , -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -S Substituents of (O) ₂ C ₁ -C ₃ alkyl, -CF ₃ and -OCF ₃ .

While the specific stereochemistry described above is preferred, all other stereoisomers, including their diastereomers, enantiomers, epimers, and mixtures thereof, may also be used in the treatment of GPR40-mediated disease. Inactive or less active diastereomers and enantiomers can be used in scientific studies related to receptors and activation mechanisms.

The structures of specific compounds and synthetic methods used to prepare the compounds are disclosed in the Examples. Some examples and analytical information are disclosed in the tables of the specification. Information on how the compounds in the tables were prepared is found in the instructions. When a stereochemical center is not defined (such as A in Figure 1, where A is -CH-), the compound is a mixture of stereoisomers at that center. For said compounds, single stereoisomers thereof, including enantiomers, diastereomers and mixtures thereof, are likewise compounds of the invention. The compounds of the present invention also include their pharmaceutically acceptable salts.

The compound of the present invention can be used in a pharmaceutical composition comprising (a) the compound or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compounds of the invention may be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients. The compounds of the present invention may also be used in pharmaceutical compositions in which the compound of formula I or a pharmaceutically acceptable salt thereof is the sole active ingredient.

The compound of formula I or its pharmaceutically acceptable salt can be used in the manufacture of medicines for treating type 2 diabetes in human or other mammal patients.

The method for treating type 2 diabetes comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing said compound to a patient in need of treatment. Other medical uses of the compounds of formula I are described below.

definition

"Ac" is acetyl, which is _CH3C (=O).

"Alkyl" means a saturated carbon chain which may be straight or branched or combinations thereof, unless otherwise defined for carbon chain. Other groups having the prefix "alk", such as alkoxy and alkanoyl, may also be straight or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl and nonyl, and the like.

"Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and which may be straight or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, etc. wait.

"Alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, and which may be straight or branched or combinations thereof. Examples of alkynyl include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

"Cycloalkyl" means a saturated carbocyclic ring having the indicated number of carbon atoms. The term can also be used to describe carbocycles fused to aryl groups. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Cycloalkenyl rings contain double bonds in the ring.

"Aryl" is generally used to refer to carbocyclic aromatic structures. The most common aryl groups are phenyl and naphthyl. Usually the most preferred aryl is phenyl.

"Heterocycle" means a fully or partially saturated ring or ring system containing at least one heteroatom selected from N, S and O, wherein the number of heteroatoms and ring size are as defined herein. Examples of heterocycles include tetrahydrofuran, piperazine, piperidine and morpholine.

"Heteroaryl" means an aromatic ring or two fused aromatic rings containing at least one ring heteroatom selected from N, O, and S (including SO and _SO2 ), as more specifically defined herein. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, Azolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuran benzothienyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolinyl, indolyl, isoquinolyl, quinazolinyl and diphenyl And furyl and so on.

"Halogen" includes fluorine, chlorine, bromine and iodine.

"Me" means methyl.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, substances, compositions, salts and/or compounds that are safe and suitable for the human or animal to which they are administered, using sound medical judgment and in compliance with all applicable governmental regulations. or dosage form.

The term "composition", as used in pharmaceutical composition, is intended to include a product comprising an active ingredient and an inert ingredient constituting a carrier, as well as any combination, complex or aggregation of any two or more ingredients resulting directly or indirectly product, or any product resulting from the decomposition of one or more components, or from any other type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The substituent "tetrazole" refers to a 2H-tetrazol-5-yl substituent and tautomers thereof.

Optical isomers - diastereoisomers - geometric isomers - tautomers

Compounds of formula I may contain one or more asymmetric centers and thus may be racemates, racemic mixtures, single enantiomers, single diastereomers and diastereomers and and/or as a mixture of enantiomers. The present invention is intended to include all such isomeric forms of the compounds of formula I. Specifically, the compounds of the invention possess at least one asymmetric center located on the ring fused to the phenyl ring, at the point of attachment to the heterocycle. A second asymmetric center may also be present in the heterocycle. Other centers of asymmetry may exist depending on the nature of the various substituents on the molecule. Each of said asymmetric centers will independently form two optical isomers, and it is intended that all possible optical isomers and diastereomers as mixtures or as pure or partially pure compounds are included within the scope of the present invention (i.e. , is the combination of all possible asymmetric centers of a pure compound or a mixture).

Some of the compounds described herein may contain olefinic double bonds and, unless expressly stated otherwise, are meant to include both E and Z geometric isomers thereof.

Some of the compounds described herein can exist at different points of attachment of hydrogen, known as tautomers. An example is a ketone and its enol form, commonly known as keto-enol tautomers. Both single tautomers and mixtures thereof are included in the compounds of formula I.

Compounds of formula I having one or more asymmetric centers may be separated into diastereomers, enantiomers and the like by methods well known in the art.

Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereoselective synthesis using optically pure starting materials and/or reagents of known configuration.

Salt

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic or organic bases and inorganic or organic acids). Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salt and more. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amine salts, secondary amine salts, tertiary amine salts, substituted amine salts (including naturally occurring substituted amine salts), cyclic amine salts and cationic ion exchange resin salts, Such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine , polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine, etc. salts.

When the compound of the present invention is basic, or when it has basic substituents in its structure, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, Tonic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid, etc. Particular preference is given to citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids. It should be understood that, as used herein, references to compounds of formula I are also meant to include pharmaceutically acceptable salts.

metabolite-prodrug

Therapeutically active metabolites in which the metabolite itself falls within the scope of the invention of the claims are likewise compounds of the invention. Prodrugs, compounds which are converted into the claimed compounds when or after administration to a patient, are likewise compounds of the invention. The claimed chemical structures for these applications can sometimes themselves be prodrugs.

Practicality

The compounds of the present invention are potent agonists of the GPR40 receptor. The compounds of the present invention and their pharmaceutically acceptable salts are effective in the treatment of diseases modulated by GPR40 ligands and agonists. These diseases are described below.

One or more of the following diseases can be treated by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of treatment. At the same time, the compounds of the present invention can be used in the manufacture of medicines for the treatment of one or more of the diseases:

(1) Non-insulin-dependent diabetes mellitus (type 2 diabetes);

(2) hyperglycemia;

(3) Metabolic syndrome;

(4) Obesity;

(5) Hypercholesterolemia;

(6) Hypertriglyceridemia (elevated triglyceride-rich lipoprotein levels);

(7) Mixed or diabetic dyslipidemia;

(8) Low HDL cholesterol;

(9) High LDL cholesterol;

(10) hyperlipoprotein B hyperlipidemia; and

(11) Atherosclerosis.

A preferred use of the compounds of the invention is in the treatment of one or more of the following diseases by administering a therapeutically effective amount of the compound to a patient in need thereof. The compounds of the present invention can be used in the manufacture of medicaments for the treatment of one or more of the following diseases:

(1) Type 2 diabetes mellitus, and specifically hyperglycemia;

(2) Metabolic syndrome;

(3) Obesity; and

(4) Hypercholesterolemia.

Compounds of the invention are expected to be effective in lowering glucose and fat in diabetic patients and non-diabetic patients with impaired glucose tolerance and/or in pre-diabetic conditions.

The compounds of the present invention can alleviate the hyperinsulinemia commonly present in diabetic or prediabetic patients by modulating the fluctuations in serum glucose levels normally present in these patients. The compounds are also effective in treating or reducing insulin resistance. The compound can effectively treat or prevent gestational diabetes. The compounds, compositions and medicaments described herein are also effective in reducing the risk of adverse sequelae associated with metabolic syndrome, reducing the risk of developing atherosclerosis, delaying the onset of atherosclerosis and/or reducing the risk of atherosclerosis Risk of sequelae of sclerosis. Sequelae of atherosclerosis include angina, claudication, heart attack, stroke, etc. The compounds are also effective in delaying or preventing vascular restenosis and diabetic retinopathy by maintaining control of hyperglycemia.

The compounds of the invention may also be used to improve or restore beta-cell function, making them useful in the treatment of type 1 diabetes or in delaying or preventing type 2 diabetes requiring insulin therapy. The compounds of the present invention are generally effective in the treatment of one or more of the following disorders: (1) type 2 diabetes (also known as non-insulin-dependent diabetes mellitus, or NIDDM), (2) hyperglycemia, (3) impaired glucose tolerance, (4) Insulin resistance, (5) Obesity, (6) Lipid disease, (7) Dyslipidemia, (8) Hyperlipidemia, (9) Hypertriglyceridemia, (10) Hypercholesterolemia syndrome, (11) low HDL level, (12) high LDL level, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) abdominal obesity, (16) retinopathy, (17) ) metabolic syndrome, (18) hypertension, and (19) insulin resistance.

One aspect of the present invention provides for the treatment and management of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia and/or hypertriglyceridemia A method comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment. Said compounds may be used alone or may advantageously be combined with cholesterol biosynthesis inhibitors, especially HMG-CoA reductase inhibitors, such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, albino Vastatin, rivastatin, itastatin or ZD-4522 were administered together. The compounds may also be advantageously combined with other lipid-lowering drugs, such as cholesterol absorption inhibitors (e.g., phytosterol esters, phytosterol glycosides (such as tiquine) and azetidinones (such as ezetimibe)) , ACAT inhibitors (such as avasimibe), CETP inhibitors (such as torchamp), niacin and niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile Acid reuptake inhibitors are used in combination. These combination treatments can effectively treat or control one or more diseases associated with hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL and low HDL. situation.

Administration and Dose Range

To provide an effective amount of a compound of the invention to a mammal, especially a human, any suitable route of administration may be used. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc. routes of administration may be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Oral administration of compounds of formula I is preferred.

The effective dosage of active ingredient employed may vary depending upon the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by those skilled in the art. When treating or controlling diabetes and/or hyperglycemia or hypertriglyceridemia or other diseases that require the compound of formula I, when the compound of the present invention is administered at a daily dose of about 0.1 mg to about 100 mg/kg of animal body weight Satisfactory results can usually be obtained when the drug is administered preferably in a single dose or divided into 2 to 6 doses per day, or in a sustained release form. For most mammals, the total daily dosage will be from about 1.0 mg to about 1000 mg. In the case of a 70 kg human adult, the total daily dosage will generally be from about 1 mg to about 500 mg. For particularly potent compounds, the adult dose may be reduced to 0.1 mg. Dosage regimens can be adjusted within this range, or even outside this range, to provide the optimum therapeutic response.

Oral administration is usually performed using tablets or capsules. Examples of dosages in tablets and capsules are 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg and 500 mg. Other oral forms may also have the same or similar dosages.

pharmaceutical composition

Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention comprises the compound of formula I or a pharmaceutically acceptable salt as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or acids and organic bases or acids). If a prodrug is administered, the pharmaceutical composition may also contain the prodrug or a pharmaceutically acceptable salt thereof.

Compositions of the present invention include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ophthalmic (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, In any given case, however, the most suitable route will depend upon the nature and severity of the condition being treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practical application, the compound of formula I as an active ingredient and a pharmaceutical carrier can be mixed into an intimate mixture according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the desired form of preparation for administration (eg, oral, parenteral (including intravenous)). In preparing oral dosage form compositions, any of the usual pharmaceutical media may be used, such as, for example, water, glycols, Oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations (such as, for example, powders, hard and soft capsules, and tablets), carriers such as starch, sucrose , large crystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents, etc., while solid oral preparations are preferably liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers obviously are employed. Tablets may be coated, if desired, by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of active compound. In these compositions the percentage of active compound may of course vary, but is desirably from about 2% to about 60% by weight of the unit dosage form. The amount of active compound in said therapeutically effective compositions is such that an effective dosage is obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.

The tablets, pills, capsules, etc. may also contain binders, such as gum tragacanth, gum arabic, corn starch or gelatin; excipients, such as calcium hydrogen phosphate; disintegrants, such as corn starch, potato starch , alginic acid; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

In some cases, depending on the solubility of the compound or salt to be administered, it may be advantageous to use an oil (such as a triglyceride of one or more medium-chain fatty acids), a lipophilic solvent (such as triacetin, ), a hydrophilic solvent (for example, propylene glycol) or a mixture of two or more of the above substances to formulate the compound or salt into a liquid, which also optionally contains one or more ionic or nonionic surfactants, Examples include sodium lauryl sulfate, polysorbate 80, polyglycolic acid triglyceride, and mono- and/or diglycerides of one or more medium-chain fatty acids. Liquid formulations containing surfactants (especially two or more surfactants) will form emulsions or microemulsions upon contact with water. The compounds can also be formulated in water soluble polymers that have been dispersed into an amorphous phase by methods such as hot melt extrusion and spray drying, including HPMCAS, HPMCS and polyvinyl pyrrolidone.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with dextrose shellac, sucrose, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

Compounds of formula I may also be administered parenterally. Liquids or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

combination therapy

The compounds of formula I may be used in combination with other drugs which are also useful in the treatment or amelioration of the diseases or conditions for which the compounds of formula I are used to treat or ameliorate. Said other drugs may be administered simultaneously or sequentially with the compound of formula I by the routes and dosages usually used therefor. In the treatment of people with type 2 diabetes, insulin resistance, obesity, metabolic syndrome and the concomitant conditions that accompany these diseases, more than one drug is usually administered. The compounds of the invention can generally be administered to patients already receiving one or more other drugs for the condition.

When the compound of formula I is used simultaneously with one or more other drugs, a pharmaceutical composition containing said other drugs and the compound of formula I in a unit dosage form is preferred. However, the combination therapy may also include therapy in which the compound of formula I and one or more other drugs are administered on different overlapping schedules.

It is also contemplated that when used in conjunction with one or more other active ingredients, the compounds of the invention and the other active ingredients may be administered at lower dosages than when each is used alone. Accordingly, in addition to the compound of formula I, the pharmaceutical composition of the present invention also contains one or more other active ingredients.

Examples of other active ingredients that may be administered in conjunction with a compound of formula I and either alone or in the same pharmaceutical composition include, but are not limited to: (a) PPAR gamma agonists and partial agonists, including glitazones and non- Glitazones (eg, troglitazone, pioglitazone, emglitazone, MCC-555, rosiglitazone, balaglitazone, naglitazone, T-131, LY-300512, and LY-818); (b) biguanides , such as metformin and phenformin;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors such as sitagliptin, saxagliptin and vildagliptin;

(e) insulin or insulin mimics;

(f) sulfonylureas, such as tolbutamide, glimepiride, glipizide and related substances;

(g) α-glucosidase inhibitors (such as acarbose);

(h) Agents that improve the patient's lipid profile, such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, ravastatin, statins, ivastatin, ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine, colestipr and dialkylaminoalkyl derivatives of cross-linked dextran), (iii) Nicotinic acid receptor agonists, nicotinic acid, nicotinic acid or its salts, (iv) PPARa agonists, such as fenofibric acid derivatives (xylene heptanoic acid, clofibrate, fenofibrate and benzalkonate) fibrates), (v) cholesterol absorption inhibitors, such as ezetimibe, (vi) fatty acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, such as avasimibe, (vii) CETP Inhibitors, such as torchep, and (viii) phenolic antioxidants, such as probucol;

(i) PPAR α/γ binary agonists such as mogestazol, tesaglitazar, faglitazone and JT-501;

(j) PPAR delta agonists, such as those disclosed in WO97/28149;

(k) Anti-obesity compounds such as phenfluramine, dexfenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4r agonists, cannabinoid receptor 1 (CB-1) Antagonists/inverse agonists and β3-adrenoceptor agonists;

(l) ileal bile acid transporter inhibitors;

(m) Agents for inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, and cyclooxygenase 2 selective inhibitors;

(n) glucagon receptor antagonists;

(o) GLP-1,

(p) GP-1,

(q) GLP-1 analogues such as insulin exocrines such as exenatide (Byetta), and

(r) Hydroxysterol dehydrogenase-1 (HSD-1) inhibitors.

The above-mentioned compositions include not only combinations of the compound of the present invention with one other active compound, but also combinations with two or more other active compounds. Non-limiting examples thereof include compounds of formula I in combination with two or more compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors and Compositions of anti-obesity compounds.

biological assay

Formation of GPR40-expressing cells

Human and murine GPR40 stable cell lines were developed in CHO cells stably expressing NFAT BLA (β-lactamase). Human GPR40 stable cell lines were developed in HEK cells stably expressing aequorin expressing the reporter. Expression plasmids were transfected using lipofectamine (Life Technologies) following the manufacturer's instructions. Following drug selection, stable cell lines were formed.

FLIPR assay

A FLIPR (Fluorescent Imaging Plate Reader, Molecular Devices) assay was performed to measure agonist-induced calcium mobilization of stable clones. For the FLIPR assay, GPR40/CHO NFAT BLA cells were seeded in black-walled clear bottom 384-well plates (Costar) at 1.4×10 ⁴ cells/20 μl medium/well the day before the assay. Cells were incubated with 20 μl/well of assay buffer (HBSS, 0.1% BSA, 20 mM HEPES, 2.5 mM probenecid, pH 7.4) containing 8 μM fluo-4, AM, 0.08% pluronic acid for 100 h at room temperature. minute. Fluorescence output was measured using FLIPR. Compounds were dissolved in DMSO and diluted to desired concentrations with assay buffer. Compound solutions were added thereto at 13.3 µl/well.

Inositol phosphate turnover assay

The assay was performed on 96-well plates. HEK cells stably expressing human GPR40 were plated to be 60-80% confluent within 72 hours. After 72 hours, plates were aspirated and cells were washed with inositol-free DMEM (ICN). Replace the washing medium with 150uL 3H-inositol-labeled medium (inositol-free medium containing 0.4% human albumin or 0.4% murine albumin, IX pen/strep antibiotics, glutamine, 25mM HEPES, to which 3H - Inositol NEN #_NET114A 1mCi/mL, diluted to 25Ci/mmol 1:150 in loading medium, final specific activity is 1uCi/150uL). Alternatively, human and mouse albumin can be added after the overnight labeling step, prior to the addition of LiCl.

Typically after the 18 hour mark, the assay was run the next day. On the day of the assay, 5uL of 300mM LiCl was added to all wells and incubated at 37°C for 20 minutes. 0.75uL of 200X compound was added and the cells were incubated for 60 minutes at 37°C. The medium was then aspirated and the assay was terminated by adding 60 uL of 10 mM formic acid. Cells were lysed for 60 min at room temperature. In clear bottom Isoplates, 15-30 uL of lysate was mixed with 70 uL/1 mg YSi SPA beads (Amersham). The plate was shaken for 2 hours at room temperature. Beads were allowed to settle and plates were counted in a Wallac Microbeta.

in vivo studies

Male C57BL/6N mice (7-12 weeks old) were housed 10 per box and had access to normal chow chow and ad libitum water supply. The above mice were randomly divided into treatment groups and fasted for 4-6 hours. The baseline blood glucose concentration of the tail-scratched blood was determined by a saccharometer. The animals were then treated with vehicle (0.25% methylcellulose) or test compound orally. Blood glucose concentrations were measured at set time points of treatment (t=0 min), after which mice were treated intraperitoneally with glucose (2 g/kg). A group of vehicle-treated mice was treated with saline as a negative control. Glucose levels were measured in tail blood at 20, 40 and 60 minutes after glucose treatment. For each treatment, the glucose excursion profile from t=0 to t=60 min was used to integrate the area under the curve (AUC). The percent inhibition for each treatment was obtained by normalizing the AUC data to the saline-treated control.

Example

The following examples serve to illustrate the invention and should not be construed as limiting the invention in any way. The scope of the invention is defined by the appended claims.

Several methods for preparing compounds of the invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be prepared by methods known in the literature or as shown in the schemes. The invention further provides processes for the preparation of compounds of formula I as defined above.

A general method of constructing the target compound I starting from formula (1-3) is, in the presence of a base, coupling phenol (1-1) and halogen-substituted ketones (1-2) or coupling halogenated aromatic hydrocarbons (1 -4) and hydroxyketones (1-5) (Scheme 1).

plan 1

In the presence of a base (such as sodium acetate or pyrrolidine), with or without a solvent, at elevated temperature, the ketone of formula (1-3) prepared according to Scheme 1 is reacted with 2,4-thiazolidinedione (2-1 ) for condensation. Reduction of the resulting unsaturated intermediate of formula (2-2) with a reducing agent such as lithium borohydride affords the desired product of formula I as a mixture of diastereoisomers (Scheme 2).

Scenario 2

To synthesize target compounds with indane (n=1) or tetralin (n=2) core structures, an alternative synthetic route was developed. Starting from methoxyindanone or tetralone (3-1), the unsaturated ester (3 -3). Further hydrogenation gives saturated ester (3-4) as enolate, which is silylated and brominated to give α-bromoester (3-5). The TZD ring (3-7) is then formed by treatment of the bromoester (3-5) with thiourea and subsequent hydrolysis of the resulting cyclic product (3-6). The obtained intermediate (3-7) is demethylated with boron tribromide or aluminum trichloride to obtain the key intermediate (3-8).

Option 3

When W is an oxygen atom, a slight modification of the above method is required. Reformasky condensation of benzyloxy substituted ketones (4-1, m=1, 2, 3) with bromoacetate (3-2) affords unsaturated esters (4-2). At the same time, the double bond of the above compound is saturated and debenzylated to obtain a hydroxylated saturated ester (4-3), which is protected again by benzylation of the hydroxyl group to obtain the intermediate (4-4 ). Following the same method as described in Scheme 3, TZD rings (4-6) were formed. Debenzylation by catalytic hydrogenation using a diamine-treated palladium catalyst affords intermediates (4-8).

Option 4

When W is a sulfur atom, the starting material (5-1) is used, and the thiophene ring is saturated with a triethylsilane/trifluoroacetic acid system. The resulting ester (5-2) was subjected to a reaction similar to that described in Scheme 2 to afford the key intermediate (5-6) (see Scheme 5).

Option 5

Finally, intermediates (3-8, 4-8, 5-6) were reacted with halogenated arenes in the presence of a base (such as cesium carbonate) with or without a catalyst (such as CuCl/N, N-dimethylglycine). (6-1) Condensation was carried out (Scheme 6).

Option 6

The substitution of TZD endcaps with 1,2,4-oxadiazolidine-3,5-dione can be achieved using different chemistries. For example, when A of formula I is a nitrogen atom and B is an oxygen atom, the target compound is prepared according to the following method (Scheme 7). The intermediate ketone (1-3) is converted to the oxime (7-1) with hydroxylamine. (7-1) can be selectively reduced to hydroxylamine intermediate (7-2) by sodium cyanoborohydride. After further conversion to the amide (7-3), the cyclic product was obtained in two steps: first, treatment of (7-3) with methyl chloroformate, followed by treatment of intermediate (7-4) with sodium hydride.

Option 7

Another method of replacing the TZD endcap with imidazoline-2,4-dione was performed in a similar manner (Scheme 8). Oxime (7-2) is hydrogenated to amine (8-1), which is then further converted to glycinate (8-2). Treatment of the resulting amino ester with trichloroacetyl isocyanate followed by hydrolysis under basic conditions affords intermediate (8-3). The deprotection and cyclization of the trichloroacetyl group to the final target compound in hot methanol, ethanol or other alcohols under basic conditions (such as potassium carbonate) can be performed in one kettle.

Option 8

Replacing the TZD endcap with 1,3-oxazolidine-2,4-dione (OZD) can be achieved according to the method shown in Scheme 9.

Option 9

Hydroxylation of ester (9-1) can be achieved by known methods (GM Rubottom and R. Marrero, Synth. Commun., 1981, 11(6), 505-511). Treatment of (9-1) with a base such as potassium, lithium, sodium bis(trimethylsilyl)amide or LDA followed by trimethylsilyl chloride affords alkyltrimethylsilanes Diethyl ketene acetal intermediate (9-2). In situ treatment of (9-2) with MCPBA in hexanes followed by treatment of the resulting crude reaction mixture with triethylammonium fluoride afforded the α-hydroxyester (9-3). Further conversion of (9-3) to the [alpha]-hydroxyamide (9-43) can be cyclized to OZD (9-5) by treatment with dimethyl carbonate. Demethylation of (9-5) with BBr ₃ gave the key intermediate (9-6), which was smoothly coupled with (6-1) to give the final compound.

After chiral resolution of the starting acid by chiral HPLC or according to published methods (WO 2004011446) by using chiral amines such as (R) or (S)-methylbenzylamine, In the same way, chiral intermediates (10-8) and (10-9) can be easily obtained. Chiral (10-8) and (10-9) are each a mixture of two diastereoisomers, the relative proportions of which are highly dependent on the ring size (from 3:1 for 5-membered rings to 3:1 for 6-membered rings) 6:1). The major diastereomer can be purified on HPLC. However, because the TZD ring rapidly undergoes epimerization in solution, it will again become a mixture of diastereomers upon standing or storage.

Scheme 10

The final chiral target compound was synthesized according to a method similar to that described in Scheme 6 (see Scheme 11).

Scenario 1 1

The following are representative procedures for the preparation of synthetic intermediates used in the Examples below.

In some cases, changes in the order in which the above reaction schemes are performed can be made to facilitate reactions or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only, and should not be considered as limiting the disclosure of the present invention.

Concentration of the solution is usually performed under reduced pressure on a rotary evaporator. Flash chromatography was performed on silica gel (230-400 mesh). MPLC refers to medium pressure liquid chromatography and, unless otherwise stated, is performed on a silica gel stationary phase. Unless otherwise stated, NMR spectra were obtained in _CDCl3 solution. Coupling constants (J) are expressed in hertz (Hz). Abbreviations: ether (ether), triethylamine (TEA), N,N-diisopropylethylamine (DIEA), saturated aqueous solution (sat'd), room temperature (rt), hour (h), minute (min ).

Intermediate 1

Step A:

To cooled (-78°C) ethyl [(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]acetate (2.34 g, 10mmol) in 20mL of anhydrous THF solution was added dropwise with sodium bis(trimethylsilyl)amide solution (1.0M, 12mL, 12mmol). The above mixture was stirred at -78°C for 30 minutes, then a solution of neat trimethylsilyl chloride (1.4 mL, 11 mmol) was added dropwise. The reaction was stirred for another 10 minutes, then solid NBS (2.0 g, 11 mmol) was added in one portion, the reaction was warmed to room temperature for one hour, quenched with water and extracted with ethyl acetate. The resulting organic phase was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give a crude oil which was used in the next step without further purification.

Step B:

The crude product from Step A (3.70 g) was treated with thiourea (0.76 g, 10 mmol) and sodium acetate (0.82 g, 10 mmol) in 50 mL of ethanol. The above mixture was refluxed for 13 hours, then it was cooled to room temperature. After adding 20 mL of diethyl ether and 20 mL of hexane, the resulting solid was collected by filtration and washed with hexane. The desired product (1.72 g) was obtained as an off-white solid. LC-MS: _Calcd . _{for C13H14N2O2S} : 262; found: ₂₆₃ (M+H). ¹ H NMR (400MHz, CD ₃ OD) δ7.11, 6.90 (dd, J = 8.1, 8.3Hz, ratio = 2:1, 1H), 6.58-6.76 (m, 2H), 5.03, 4.66 (dd, J =3.0, 2.8Hz, ratio=2:1, 1H), 3.95(m, 1H), 3.70(s, 3H), 2.92(m, 2H), 2.42, 2.05, 1.82, 1.70(mmmm, 2H).

Step C

The product from Step B was mixed with 50 mL of 2N aqueous HCl and 50 mL of ethanol. The above mixture was refluxed overnight (monitored by LC-MS until complete conversion was observed). Ethanol was removed under vacuum and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated and dried in vacuo to give a yellow solid. LC-MS: _Calcd . _{for C13H13NO3S} : 263 Found: 264 (M+H). ¹ H NMR (400MHz, CD ₃ OD) δ7.10, 6.96 (dd, J = 8.3, 8.4Hz, ratio = 3:1, 1H), 6.60-6.80 (m, 2H), 5.11, 4.76 (dd, J = 3.7, 4.1 Hz Ratio = 3:1, 1H), 4.0 (s, 1H), 3.72 (s, 3H), 3.0-2.7 (m, 2H), 2.40, 2.08, 1.90 (mmm, 2H).

Step D

To a stirred cooled (-78° C.) solution of the product from Step C (1.40 g, 5.3 mmol) in 10 mL of dichloromethane was added boron tribromide in dichloromethane (1.0 M, 15 mL, 15 mmol). Then, the above reaction was warmed to room temperature for 30 minutes, and then quenched with ice water. The resulting product was extracted twice with ethyl acetate. The organic phase obtained was washed twice with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was dried under high vacuum to give a beige solid which was used in the next step without further purification. LC-MS _: Calcd. _{for C12H11NO3S} : 249 Found: 250 (M+H). ¹ H NMR (400MHz, CD ₃ OD) δ7.0, 6.9 (dd, J = 8.2, 8.2Hz, ratio = 3:1, 1H), 6.50-6.62 (m, 2H), 5.08, 4.71 (dd, J =3.8, 4.2Hz ratio=3:1, 1H), 3.90(m, 1H), 3.72(s, 3H), 2.92-2.70(m, 2H), 2.38, 2.06, 1.86(mmm, 2H).

Intermediate 2

Step A:

To a stirred solution of racemic [6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid (69.4 g) in 1500 mL of acetone once prepared according to a published method (WO 20040011446) Add 38.7 mL of (S)-α-methylbenzylamine intermittently. The above mixture was stirred at room temperature for 30 minutes, then 1500 mL of hexane was added thereto. The above mixture was stirred at room temperature for one hour. The resulting solid was removed by filtration and washed with hexane/acetone (4:1 v/v), then dried in air to give the first crop of solid. The combined mother liquors were stored overnight at 0-5°C and the resulting solids were collected by filtration to give a second crop of solids. The above two crops of salt were combined and dissolved in hot acetone (500 mL). 750 mL of hexane was added thereto, and the resulting mixture was stirred at room temperature for one hour. The resulting solid was collected by filtration, washed with hexane/acetone (4:1 ) and dried in air to afford off-white crystals of the (R,S)-salt.

Step B

All mother liquors from Step A above were combined and concentrated to give a beige solid. 3N aqueous HCl was added to adjust the pH to <3, it was stirred with ethyl acetate (500 mL) and separated. The resulting organic phase was washed with 3N aqueous HCl, dried over sodium sulfate, filtered and evaporated to give a beige solid (32 g, 145 mmol, S-enriched acid). This solid was dissolved in 500 mL of acetone, (R)-(+)-α-methylbenzylamine (16.6 mL, 145 mmol) was added, and the resulting mixture was refluxed until all solids were dissolved, then cooled to room temperature. The resulting precipitate was collected by filtration and washed with acetone to give the salt (S,R) as a white solid. X-ray crystallography of the amides formed by treatment of the above salts with EDAC confirmed the (S)-absolute configuration of the resulting acids.

Step C:

The (S,R) salt (23.2 g) from Step B above was stirred with 200 mL of 3N HCl and 200 mL of ethyl acetate for one hour. The organic phase was separated, washed with 3N aqueous HCl (2 x 100 mL), dried over sodium sulfate, filtered and evaporated to give the desired (S)-acid as a beige solid.

Step D:

The (S)-acid (14 g) from Step C above was dissolved in 150 mL of ethanol and 19 mL of trimethylsilyl chloride was added. The above mixture was stirred overnight at room temperature, then evaporated and mixed with ethyl acetate (100 mL). The resulting organic phase was washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate and purified on FC (silica gel, 20% ethyl acetate/hexanes) to give the desired (S)-ester as a colorless oil . ¹ H NMR (400MHz, CDCl ₃ ) δ7.04(d, J=7.7Hz, 1H), 6.67(m, 1H), 6.60(m, 1H), 4.14(m, 2H), 3.74(bs, 3H) , 3.26 (m, 1H), 2.80-2.40 (m, 4H), 1.90-1.60 (m, 4H), 1.24 (m, 3H).

Step E:

To cooled (-78°C) ethyl [(1S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetate (7.45 g, 30 mmol ) in 50 mL of anhydrous THF solution was added dropwise with sodium bis(trimethylsilyl)amide solution (1.0 M, 36 mL, 36 mmol). The above mixture was stirred at -78°C for 30 minutes, then a solution of neat trimethylsilyl chloride (4.22 mL, 33 mmol) was added dropwise. The above reaction was stirred for an additional 10 minutes. Solid NBS (5.87 g, 33 mmol) was added in one portion. The reaction was warmed to room temperature over one hour, quenched with water and extracted with ethyl acetate. The resulting organic phase was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give a crude oil which was used in the next step without further purification.

Step F:

The crude product from Step E above was treated with thiourea (2.28 g, 30 mmol) and sodium acetate (2.46 g, 30 mmol) in 50 mL of ethanol. The above mixture was refluxed for 13 hours, then it was cooled to room temperature. After adding 20 mL of diethyl ether and 20 mL of hexane, the resulting solid was collected by filtration and washed with hexane. The desired product was obtained as an off-white solid. LC _- MS: _Calcd . _{for C14H16N2O2S} : 276; found: 277 (M+H).

Step G

The product from Step F was mixed with 50 mL of 4N aqueous HCl and 50 mL of ethanol. The above mixture was refluxed overnight (monitored by LC-MS until complete conversion was observed). Ethanol was removed under vacuum and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated and dried in vacuo to give a yellow solid. LC-MS: _Calcd . _{for C14H15NO3S} : 277. Found: 278 (M+H).

Step H

To a stirred solution of the product from Step G above (5.2 g, 18.7 mmol) in 50 mL of dichloromethane cooled (-78° C.) was added boron tribromide in dichloromethane (1.0 M, 57 mL, 57 mmol) . Then, the above reaction was warmed to room temperature for 30 minutes and quenched with ice water. The resulting product was extracted twice with ethyl acetate. The organic phase obtained was washed twice with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was dried under high vacuum to give a beige solid which was used in the next step without further purification. LC-MS: _Calcd . _{for C13H13NO3S} : 264 Found: 265 (M+H).

Intermediate 3

Step A:

The (R,S) salt (24.5 g) from Synthesis of Intermediate 2 Step A was stirred with 200 mL of 3N HCl and 200 mL of ethyl acetate for one hour. The organic phase was separated, washed with 3N aqueous HCl (2 x 100 mL), dried over sodium sulfate, filtered and evaporated to give the desired (R)-acid as a beige solid.

Step B:

The (R)-acid (15.6 g) from Step A above was dissolved in 150 mL of ethanol, to which was then added 19 mL of trimethylsilyl chloride. The above mixture was stirred overnight at room temperature, then evaporated and mixed with ethyl acetate (100 mL). The resulting organic phase was washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate and purified on FC (silica gel, 5% ethyl acetate/hexanes) to give the desired (R)-ester as a colorless oil.

Step C:

To cooled (-78°C) ethyl [(lR)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetate (7.45 g, 30 mmol ) in 50 mL of anhydrous THF solution was added dropwise with sodium bis(trimethylsilyl)amide solution (1.0 M, 36 mL, 36 mmol). The above reaction mixture was stirred at -78°C for 30 minutes. Neat trimethylsilyl chloride (4.22 mL, 33 mmol) was added dropwise. The above reaction was stirred for an additional 10 minutes, and solid NBS (5.87 g, 33 mmol) was added in one portion. The reaction was warmed to room temperature over one hour, quenched with water and extracted with ethyl acetate. The resulting organic phase was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give a crude oil which was used in the next step without further purification.

Step D:

The crude product from Step C above was treated with thiourea (2.28 g, 30 mmol) and sodium acetate (2.46 g, 30 mmol) in 50 mL of ethanol. The above mixture was refluxed for 13 hours and allowed to cool to room temperature. After adding 20 mL of diethyl ether and 20 mL of hexane, the resulting solid was collected by filtration and washed with hexane. The desired product was obtained as an off-white solid. LC _- MS: _Calcd . _{for C14H16N2O2S} : 276; found: 277 (M+H).

Step E

The product from Step D was mixed with 50 mL of 4N aqueous HCl and 50 mL of ethanol. The above mixture was refluxed overnight (monitored by LC-MS until complete conversion was observed). Ethanol was removed under vacuum and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated and dried in vacuo to give a yellow solid. LC-MS: _Calcd . _{for C14H15NO3S} : 277. Found: 278 (M+H).

Step F

To a stirred cooled (-78° C.) solution of the product from Step E above (4.02 g, 14.5 mmol) in 50 mL of dichloromethane was added boron tribromide in dichloromethane (1.0 M, 30 mL, 30 mmol). Then, the above reaction was warmed to room temperature for 30 minutes, and then quenched with ice water. The resulting product was extracted twice with ethyl acetate. The organic phase obtained was washed twice with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was dried under high vacuum to give a beige solid which was used in the next step without further purification. LC-MS: _Calcd . _{for C13H13NO3S} : 264 Found: 265 (M+H).

Intermediate 4

Step A

To a solution of 6-hydroxy-2,3-dihydrobenzofuran-3-one (30 g, 200 mmol) in DMF (600 mL) was added K ₂ CO ₃ (220 mmol, 30.4 g), followed by BnBr (200 mmol, 24mL). After it was stirred at room temperature for 3 hours, the reaction mixture was partitioned between methyl tert-butyl ether (MTBE, 500 mL) and water (1 L). The aqueous layer was separated and further extracted with MTBE (2 x 500 mL). The organic layers were combined, washed with water (500 mL) and brine (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to afford 6 as a yellow solid. LC _- MS: Calcd. for _C15H13O3 [M+H ⁺ ]: 241.1, found _241.1 .

Step B

To a suspension of NaH (60% in mineral oil, 381 mmol, 15.2 g) in dry THF (900 mL) was added triethyl phosphoacetate (381 mmol, 76 mL) dropwise in an ice bath. After the addition, the reaction was stirred at room temperature for 20 minutes until a clear solution was obtained. Then, a solution of the ketone from Step A (45.7 g, 190 mmol) in THF (100 mL) was added to the above reaction. The reaction was stirred overnight at room temperature, then quenched with 0.1N HCl (1 L). The aqueous layer was separated and extracted with EtOAc (2 x 500 mL). The organic layers were combined, washed with water (500 mL) and then brine (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (10%-30% EtOAc/hexanes) to afford 7 as a yellow solid. LC-MS: Calcd. for _C19H20O4 [M+H ⁺ ]: 311.1 _, found _311.3 .

Step C

To a solution of the unsaturated ester from Step B (6.6 g, 21.3 mmol) in ethanol (75 mL) and EtOAc (75 mL) was added 10% Pd/C (2 g). The above mixture was hydrogenated in a Parr shaker at 50 psi for 2 hours. Then, the resulting mixture was filtered through celite. The filtrate was concentrated in vacuo to afford 8 as a red oil. LC _- MS: Calcd. for _C12H15O4 [M+H ⁺ ]: 223.2 _, found 223.2.

Step D

To a solution of the acid from Step C (2 g, 9 mmol) in DMF (15 mL) and acetone (60 mL) was added _K2CO3 (11 _mmol , 1.5 g), followed by BnBr (11 mmol, 1.3 mL). The reaction was stirred overnight at room temperature, then concentrated in vacuo.

The resulting residue was partitioned between EtOAc (100 mL) and water (200 mL). The aqueous layer was separated and further extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with water (100 mL) and then brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0%-15% EtOAc/hexanes) to afford 9 as an oil. ¹ H NMR (500MHz, CDCl ₃ ) δ7.50-7.30 (m, 5H), 7.06 (d, J=8.0Hz51H), 6.52 (d, J=8.2Hz, 1H), 6.50 (bs, 1H), 5.0 (s, 2H), 4.8(t, J=8.9Hz, 1H), 4.30(dd, J=6.1, 8.9Hz, 1H), 4.2(q, J=7.1Hz, 2H), 4.85(m, 1H) , 2.75 (dd, J=5.5, 16.5 Hz, 1H), 2.58 (dd, J=9.1, 16.2 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H). LC _- MS: Calcd. for _C19H21O4 [M+H ⁺ ]: 313.4 _, found 313.2.

Step E

Anhydrous THF (30 mL) was added to the flame-dried flask, followed by NaHMDS (7.5 mmol, 7.5 mL of 1M in THF). After cooling to -78 °C, a solution of the ester from Step D (2.0 g, 6.3 mmol) in THF (10 mL) was slowly added to the reaction. After the addition, the reaction was stirred at -78°C for 15 minutes before TMSCl (7.2 mL of 1M in THF, 7.2 mmol) was added. After stirring again at -78°C for 30 minutes, NBS (6.9 mmol, 1.2 g) was added in one portion. The reaction was allowed to warm to 0 °C over 2 hours, then quenched with 0.1 N HCl (200 mL). The aqueous layer was separated and further extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with water (100 mL) and then brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0%-18% EtOAc/Hexanes) to afford 2.3 g of an oil. Then, the above oil was dissolved in ethanol (40 mL), and thiourea (7.0 mmol, 0.54 g) and NaOAc (12 mmol, 0.96 g) were added thereto. The above reaction was refluxed for 24 hours, then it was cooled to room temperature. Then, the resulting suspension was filtered. The resulting solid was further washed with cold EtOH (4 mL) and dried in air to afford compound 10 as a white solid. LC-MS _{: Calcd} . for _C18H17N2O3S [M+H ⁺ ]: 341.1, found _341.1 .

Step F

A suspension of the cyclic product from step E (1.5 g, 4.4 mmol) in EtOH (20 mL) and 6N HCl (4 mL) was refluxed overnight. Then, the reaction was concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (0%-50% EtOAc/Hexanes) to afford the desired TZD as a mixture of diastereoisomers. LC _- MS: _Calcd . for _C18H16NO4S [M+H ⁺ ]: 342.1, found 342.1.

Step G

To a suspension of methoxy TZD from step F (300 mg, 0.88 mmol) in EtOH (20 mL) was added 4N HCl in dioxane (500 uL) and 10% Pc/C (500 mg). The above reaction was hydrogenated at 1 atm for 2 hours to complete the reaction. Then, the resulting mixture was filtered through celite. The filtrate was concentrated in vacuo to afford Intermediate 4 as a yellow solid. LC _- MS: _Calcd . for _C11H10NO4S [M+H ⁺ ]: 252.0, found 252.1.

Intermediate 5

Step A

To cooled (-78°C) ethyl [(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]acetate (2.34 g, 10mmol) in 20mL of anhydrous THF solution was added dropwise with sodium bis(trimethylsilyl)amide solution (1.0M, 12mL, 12mmol). The above mixture was stirred at -78°C for 30 minutes, then a solution of neat trimethylsilyl chloride (1.4 mL, 11 mmol) was added dropwise. The above reaction was stirred for an additional 30 minutes before the reaction vessel was gradually warmed to room temperature. The solvent was removed in vacuo (rotary evaporation) and about 75 mL of pentane was added to the resulting residue. Rapid filtration was performed and the solvent was removed in vacuo to yield crude alkyltrimethylketene acetal.

Step B

A precooled (ice-methanol) stirred solution of 2.35 g of MCPBA (77% purity, 10 mmol) in 100 mL of dry hexane was treated with 10 mmol of the above acetal in 100 mL of dry hexane under a nitrogen atmosphere. After the addition was complete (approximately 5 minutes), the resulting slurry was stirred at room temperature for 30 minutes. The reaction mixture was then treated with 1.2 g (10 mmol) of triethylammonium fluoride while stirring and stirring was continued for 30 minutes after the addition was complete. Then, the above mixture was filtered and the filtrate was diluted with 100 mL of ethyl acetate. Then, the above solution was washed sequentially with 200 mL of 5% aqueous hydrochloric acid and 2×200 mL of 5% aqueous sodium carbonate. Subsequently, the obtained organic layer was dried with anhydrous sodium sulfate. Filtration and removal of solvent in vacuo gave the crude hydroxy ester. Subsequently, pure compound was obtained on Combi-Flash (5-10% ethyl acetate/hexane). LC-MS: C ₁₄ H ₁₈ O ₄ [M+H ⁺ ]: calcd. 250, found 251. ¹ H NMR (400 MHz, CDCl ₃ ) (major isomer) δ 7.2 (d, 1H), 6.72 (s, 1H), 6.05(d, 1H), 4.28(d, 1H), 4.18(m, 2H), 3.68(s, 1H), 3.52(m, 1H), 2.90(m, 1H), 2.72( m, 1H), 2.10(m, 2H), 1.22(t, 3H).

Step C

The hydroxy ester from step B was mixed with 4N ammonia-methanol (50 mL) overnight, evaporated and the resulting residue mixed with 5 mL ethyl acetate and 20 mL hexanes. The resulting white powder was filtered, washed with hexanes and dried under high vacuum to give the pure product as a single isomer. LC-MS: C ₁₂ H ₁₅ NO ₃ [M+H ⁺ ]: calcd. 221, found 222. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (d, J = 8.1 Hz, 1 H), 6.77 ( m, 2H), 6.55(bs, 1H), 5.53(bs, 1H), 4.54(s, 1H), 3.76(s, 3H), 2.82(m, 2H), 2.12(m, 1H), 2.00(m , 1H), 1.98 (m, 1H).

Step D

Hydroxyamide (280 mg, 1.267 mmol) and diethyl carbonate (747 mg, 6.335 mmol) were mixed with sodium methoxide (345 mg, 6.335 mmol) and ethanol (10 mL). The above mixture was refluxed for 1.5 hours and then evaporated. The resulting residue was acidified with 3N aqueous HCl, extracted with ethyl acetate, dried over sodium sulfate, evaporated and purified on Comb-Flash (5-30% ethyl acetate/hexanes) to give product. LC-MS calcd _{for C13H13NO4} : 247; found: ₂₄₈ (M+H). ¹ H NMR (400MHz, CDCl ₃ ) (main isomer) δ7.17(d, J=8.0Hz, 1H), 6.75(m, 2H), 5.10(s, 1H), 3.75(s, 3H), 3.00(m, 1H), 2.84(m, 1H), 2.22(m, 2H), 2.04(m, 1H). Primary/secondary ~ 6:1.

Step E

To a stirred cooled (-78° C.) solution of the product from Step D above (100 mg, 0.4 mmol) in 5 mL of dichloromethane was added boron tribromide in dichloromethane (1.0 M, 1.0 mL, 1.0 mmol) . Then, the above reaction was warmed to room temperature for 50 minutes, and then the reaction was quenched with ice water. The resulting product was extracted twice with ethyl acetate. The organic phase obtained was washed twice with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was dried under high vacuum to give a beige solid which was used in the next step without further purification. LC-MS _: Calcd _{for C12H11NO4} : 233 Found: 234 (M+H).

Intermediate 6

Step A

Ethyl (6-methoxy-1-benzothiophen-3-yl)acetate (2.50 g, 10 mmol) was refluxed overnight with triethylsilane (5 mL) and trifluoroacetic acid (10 mL). TFA was removed in vacuo and the resulting residue was diluted with ethyl acetate, washed with water and saturated aqueous sodium carbonate, then dried over sodium sulfate, filtered, evaporated and purified by FC (silica gel, 10% ethyl acetate/hexanes). It is purified to obtain the product.

Step B

Replace [(1S)-5-methoxy-2,3-dihydro-1H-indene with ethyl (6-methoxy-2,3-dihydro-1-benzothiophen-3-yl)acetate -1-yl]ethyl acetate, the compound was prepared according to the same method as Intermediate 1. LC _- MS calcd _{for C11H9NO3S2} : 267; found _: 268 (M+H).

Intermediate 7

step a.

To a dry 3-neck 2L round bottom flask was added freshly azeotropic 7-(benzyloxy)chroman-4-one (287 g, 1.13 mol, synthesized according to J. Med. Chem. 1998, 41, 1172-1184) and 2L dry THF (without inhibitors). Then, zinc (124.9 g, 1.92 mol) and CuI (10.7 g, 56.5 mmol) were quickly added to the reaction solution. After refluxing for 30 minutes under _N2 atmosphere, 81 mL of ethyl bromoacetate (1/2 of all required, FW167.01, d 1.506, 0.7 mol) was added dropwise to the refluxing mixture. Then, the heat was turned off and the reaction was stirred at ambient temperature for 4-5 hours. Then, another 81 ml of ethyl bromoacetate (FW167.01, d 1.506, 0.7 mol) was added dropwise and the reaction was stirred without heating until the reaction temperature returned to ambient temperature. The solids were removed by vacuum filtration through celite, the resulting filtrate was concentrated by rotary evaporation to ~800 mL, poured into 1 L of 1N HCl(aq) and 1000 g of ice and stirred vigorously for 30 minutes. The above mixture was extracted with EtOAc (1 x 2 L, 2 x 1 L). The combined organic layers were washed with H ₂ O (1×3 L) and brine (1×2 L), dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting crude compound was used without further purification.

Step B

To a solution of the crude product from step A (-356 g, 1.1 mol) in THF/MeOH/ _H2O (2:2:1, 2.5 L) was added LiOH- _H2O (92.4 g, MW 41.96, 2.2mol). The above reaction was stirred overnight at ambient temperature. The organic solvent was removed in vacuo and the resulting residue was diluted with water to a volume of 3 L. The aqueous solution was washed with diethyl ether (2 x 500 mL), then the aqueous layer was acidified to pH=1 with 10N HCl(aq). The solid was isolated by vacuum filtration, washed with EtOAc and dried under vacuum. The filtrate was extracted with EtOAc (2 x 500 mL). The combined organics were washed with brine (400 mL) and concentrated in vacuo. All solids were combined, triturated with a little EtOAc and dried under high vacuum to give a mixture of two isomers.

Step C

A solution of the product from Step B (20 g, 67.6 mmol) in anhydrous methanol (800 mL) was degassed by bubbling _N2 for 1 h. Then, (R)-BINAP _RuCl (1.11 g, FW794.65, 1.4 mmol) and 950 μL of freshly degassed triethylamine (FW101.19, d 0.72, 6.76 mmol) were quickly added thereto under _N2 atmosphere . The above mixture was hydrogenated under _H2 (50 psi) atmosphere for 4 days. Then, the above reaction mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by column chromatography to give the desired product (70% ee) and recovered starting material. The resulting product was dissolved in a small amount of EtOAc (-20 mL) and petroleum ether (-20 mL) and allowed to recrystallize to give the chiral acid (-95% ee).

Step D

A solution of the chiral acid from Step C (6.5 g, 21.8 mmol) in 100 mL of 6N HCl/EtOH was stirred at room temperature for 5 hours. The reaction was then concentrated in vacuo to afford the desired chiral ester. ¹ H NMR (400MHz, CDC ₁₃ ) δ7.5-7.25(m, 5H), 7.0(d, J=10Hz, 1H), 6.55(m, 1H), 6.44(s, 1H), 5.01(s, 2H ), 4.20-4.12(m, 4H), 3.34-3.28(m, 1H), 2.78-2.73(m, 1H), 2.51-2.45(m, 1H), 2.18-2.10(m, 1H), 1.85-1.78 (m, 1H), 1.30-1.24 (m, 3H).

Step E

To a solution of the chiral ester from Step D (7.3 g, 22.4 mmol) in anhydrous THF (100 mL) was added NaHMDS (2.0 M in THF, 14.6 mL, 29.2 mmol) at -78 °C. After the addition, the reaction was stirred at -78 °C for 30 min, then TMSCl (2M in THF, 13.5 mL, 26.9 mmol) was added. After adding TMSCl, the reaction was stirred for an additional 30 minutes and NBS (4.4 g, 24.7 mmol) was added in one portion. The above reaction was allowed to warm to 0°C over a period of 2-3 hours. The above reaction was partitioned between 0.1 N aqueous HCl (200 mL) and ethyl acetate (200 mL). The resulting organic layer was washed with 0.1 N aqueous HCl (1 x 200 mL). The aqueous layers were combined and further back extracted with EtOAc (1 x 100 mL). The organic layers were combined and washed with brine (2 x 100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give the desired product. The resulting crude product was used without further purification.

Step F

To a solution of the crude material from step E (-20 mmol) in 100 mL EtOH was added thiourea (MW 76.12, 1.979 g, 26 mmol) and sodium acetate (MW 82.03, 3.281 g, 40 mmol). The above reaction was refluxed overnight. The organic solvent was removed in vacuo and the residue was partitioned between 50 mL 6N HCl(aq) and 50 mL EtOAc. The resulting organic layer was further extracted with 6N HCl(aq) (2 x 25 mL). The aqueous layers were combined and further washed with EtOAc (1 x 10 mL). The aqueous layer was separated and EtOH (50 mL) was added to the aqueous solution. The above solution was refluxed for 24 hours, then it was cooled to room temperature. The above reaction was diluted with water (400 mL) and extracted with EtOAc (1 x 400 mL, 2 x 200 mL). The organic layers were combined and washed with brine (1×100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue _was purified by column chromatography (silica, 0-20% EtOAc/ _CH2Cl2 ) to afford the desired intermediate 7. LC _- MS negative [MH]: Calcd _{for C12H10NO4S} : 264 Found: 264.

Intermediate 7 can also be prepared by the following method:

Synthesis of 7-Benzyloxychroman-4-one

Resorcinol (50 g) was slurried in trifluoroacetic acid (200 ml) at 20°C.

3-Chloropropionyl chloride (45.8 ml) was added in one portion. The above mixture was stirred at 20°C (slightly exothermic) for 1 hour to give a black solution. Trifluoromethanesulfonic acid (56.3ml) was heated to 67°C, and a solution of resorcinol/3-chloropropionyl chloride/trifluoroacetic acid was added thereto over a period of 1 hour, maintaining the temperature at 67-69°C. The resulting black solution was further stirred at 68°C for 30 minutes. HPLC indicated complete reaction.

The mixture was cooled to 10°C and water (500ml) was added at below 21°C over a period of 30 minutes. The resulting mixture was extracted with 2:1 toluene:MTBE (2 x 150 mL). The combined organic extracts were washed with 10% brine solution (3 x 150ml) and evaporated to about 100ml. The above solution was applied to a silica gel adsorption tower (250 g), and the non-cyclized product was eluted with 15% MTBE in toluene (about 900 ml). Fractions (HPLC) containing product were combined and evaporated to give a dark red solution (350ml) which crystallized on standing.

The resulting slurry was diluted with water (125ml) and 5N NaOH (150ml) was added over 20 minutes below 25°C. The above biphasic mixture was stirred at 20°C for 1 hour. HPLC indicated complete cyclization. The phases were separated and the organic phase was washed with water (50ml). The aqueous layers were combined and acidified to pH 3 by the slow addition of 2N HCl (200 ml) below 21 °C. 7-Hydroxychromanone first precipitated as an oil, but at pH 7 and with addition of seed crystals, the oil slowly Slow crystallization. The above aqueous slurry was stirred at 20°C for 2 hours and filtered. The resulting solid was washed with water (2 x 100ml), collected and dried under vacuum at 40°C overnight. 7-Hydroxychromanone was isolated as a reddish solid.

7-Hydroxychromanone was converted into benzyloxy derivatives by dissolving 49.2 g (0.3 mol) of 7-Hydroxychromanone in DMF, then adding 66.7 g of benzyl bromide to it, and then at room temperature , 72 ml of potassium carbonate solution (0.76 g/ml, 0.42 mol) was added dropwise to the above well-stirred solution within 30 minutes. The temperature was raised from 24°C to 37°C. After one hour a thick slurry had formed. HPLC showed no residual hydroxychromanone. The above mixture was stirred for 3.5 hours, and then 250 ml of water were gradually added thereto. The slurry was stirred for an additional hour before being filtered. The resulting filter cake was washed with 2 x 50ml 1:1 DMF/water and 3 x 50ml water. After air drying to constant weight, crude benzyl ether (purity 69 wt%) was obtained. Its purity was increased to 97.5 wt% by recrystallization in iPAC/heptane.

Synthesis of vinyl ester intermediates

Under nitrogen, lithium hexamethyldisilylamide (LiHMDS, 130 ml of a 1.OM solution) was cooled to -70°C. Ethyl acetate (11.7 g) was added over 5 minutes with stirring and cooling, and the solution was stirred at -70°C for about 65 minutes. 7-Benzyloxychroman-4-one (30.0 g) was dissolved in 150 ml THF and added dropwise to the reaction at -70°C over a period of 40 minutes. The reaction temperature was maintained at -70°C for about 50 minutes, then allowed to warm to 0°C. LC assay showed 99% conversion. The above reaction was cooled to -20°C. Methanesulfonic acid (MsOH, 8.5 mL) was added dropwise while keeping the temperature below -15°C. Then, the temperature of the above reaction was raised to 0°C. Additional MsOH (16.0 mL) was added dropwise while maintaining the temperature below 10 °C. Ethanol (5.89 g) was added in one portion, causing the temperature to rise from 6°C to 13°C. The above reaction was allowed to warm to ambient temperature. HPLC assay indicated complete elimination. Then, water (150ml) was added thereto. The layers were separated. The resulting organic layer was washed with saturated aqueous NaHCO ₃ (60 mL), then brine (60 mL). The above product was concentrated to a solid on a rotary evaporator.

The resulting solid crude product was added to a round bottom flask. THF (41.5 mL) was added thereto, and the mixture was heated to 50°C. The solids did not all dissolve. Additional THF (7.0ml) was added to give a slightly cloudy solution. The above solution was cooled to 45°C, and the seed crystals from the previous batch were added to it. The above solution was cooled slowly to form a slurry. When the temperature reached 28°C, 260 mL of methanol was added dropwise thereto. After standing overnight, the slurry was cooled to 1 °C and filtered. The resulting solid cake was washed with methanol (2 x 70 mL) and dried under vacuum/ _N2 to give a light yellow solid.

Hydrogenation of vinyl esters

The structure of the (S)-Me-BoPhoz ligand is shown below. It can be purchased from the market.

(S)-Me-BoPhoz (144.5 mg, 0.236 mmol) was mixed with (COD) _2RhBF4 (91.4 mg, 0.225 mmol) in a glass vial in a nitrogen-filled glove box. _CH2Cl2 (0.5 mL, N2 degassed) was added and the resulting slurry was stirred _for 30 minutes. The ligand is rapidly dissolved. The rhodium precursor is dissolved within seconds to 15 minutes.

Vinyl ester (8.0 g crude, 92.2 wt%, 22.7 mmol) was charged to the autoclave reactor in a nitrogen-filled glove box followed by _CH2Cl2 (22 mL) _. Then, the catalyst solution was transferred into the autoclave. The autoclave was assembled into the glove box, which was then removed from the glove box and connected to the gas manifold. The autoclave was heated to 30°C and degassed with _H2 (3 x 85 psig). Then, it was charged with H ₂ to 85 psig, and it was stirred or shaken at 30° C. for 18 hours. The reaction was monitored by IR spectroscopy and was almost complete after about 12 hours. After 18 hours, no starting vinyl ester was observed by HPLC. The above reaction was cooled to ambient temperature and discharged. _The reaction product was removed from the reactor, and an additional volume of _CH2Cl2 was used to rinse the reactor (83% ee by assay).

Hydrolysis and upgrading of chiral acid ee

The crude hydrogenation solution (including the rinse) was converted to a higher ee chiral acid by applying dichloromethane solutions (120 ml of a solution containing 20 g of hydrogenated ester) from different hydrogenation batches as described above On a silica gel drying column (56g). Additional dichloromethane (450ml) was eluted through the column until all the ester was eluted. The dichloromethane solution was evaporated to a volume of 50ml and diluted with methanol (75ml), THF (75ml) and water (75ml) at room temperature. Solid lithium hydroxide hydrate (5.14 g) was added in one portion and the resulting mixture was stirred at 20-23°C for 2.5 hours until hydrolysis was complete as determined by HPLC. The above mixture was evaporated to 80ml under reduced pressure and diluted with water (160ml). The aqueous solution obtained above was washed with MTBE (60ml), acidified to pH 1 with 6N HCl (24ml) below 25°C and extracted with IPAc (200ml). The IPAc solution was azeotropically dried (KF = 150 μg/ml) by adding more IPAc (250 ml) and distilled to a volume of 200 ml at atmospheric pressure. The above solution was diluted with IPAc (200ml). HPLC assay indicated the presence of reduced acid at 81% ee.

The above IPAc solution was heated to reflux temperature (87°C) and S-(-)-α-methylbenzylamine (2.30 g) was added thereto. The above mixture was seeded with the previously obtained product (98% ee) and stirred at reflux temperature for 20 minutes. At this point the product begins to crystallize. The remaining S-(-)-α-methylbenzylamine (3.71 g) was added at reflux temperature over a period of 1 hour, and the mixture was further heated at this temperature for 1 hour. The above mixture was cooled to 20°C over a period of 1 hour and stirred at 20°C for one hour before being filtered. The resulting solid was washed with IPAc (50ml), collected and dried under vacuum at 40°C overnight. The reduced acid α-MBA salt was isolated as a white crystalline solid (97.0%ee, LCWP 99.7%). It was converted to the carboxylic acid by acidification as described below. It should be noted that the methods described below were performed in different batches and at different scales.

Under nitrogen, the chiral amine salt (100 g) was added to the flask, followed by 500 ml of water and 500 ml of MTBE. To this slurry was added 6N HCl (79.5ml). The above mixture was left at ambient temperature for 1 hour until all salts had dissolved. The phases were separated and the resulting organic phase was washed with saturated brine (1 x 250ml). The resulting organic layer was transferred to a 1 L 3-neck flask equipped with a thermocouple, a jacketed short-path distillation head with a thermometer, and a collection flask. The batch was concentrated to ~425ml, then 400ml of MTBE (4 volumes relative to the amine salt) was added during a constant volume (425ml) distillation (performed at ambient pressure using a ~65-70°C oil bath) in. MTBE was then converted to THF by adding 400 ml (4 volumes relative to the amine salt) THF during a constant volume (425 ml) distillation. The Kf at the end of the distillation was ~3 mole% _H2O (relative to free acid) and the MTBE:THF ratio (determined by1H NMR) was 1:5. A solution of the free acid in a 1:5 MTBE:THF mixture was then used in the bromination step.

Conversion of Chiral Acids to Thiazolidinedione Products

bromination reaction

To a 2L 4 neck round bottom flask equipped with overhead stirrer, thermocouple and addition funnel was added 620ml of LiHMDS (1.0M in THF) under nitrogen. The above solution was cooled to -50°C (using an acetone/dry ice bath) and a solution of the free acid in THF:MTBE (above) was added slowly via an addition funnel, keeping the batch temperature <-40°C. After 1 hour at -50°C, TMSCl was added slowly via the addition funnel, keeping the batch temperature <-40°C. After 1 hour at -50°C, the reaction was judged to be complete based on ¹ H NMR spectroscopy (in CD ₂ Cl ₂ ). The reaction mixture was then warmed to -20°C, and solid NBS (1.0 equiv, 42.42 g) was added in quarters (15 min intervals). After 1 hour at -20°C, an additional 0.2 equiv of NBS (8.47 g) was added in one portion. The total amount of NBS was 1.2 equivalents. After an additional 1 hour at -20°C, the reaction was judged to be complete (starting acid levels reached <1% as determined by HPLC). Then, the above reaction mixture was slowly transferred into a cooled (-5 to 0° C.) mixture of 1 N NaHSO ₃ (238 ml), MTBE (356 ml) and a 1:1 mixture of water/85% H ₃ PO ₄ (142 ml) , while keeping the material temperature <10°C. The above solution (pH = 2.84) was warmed to ambient temperature, the layers were separated, and the resulting aqueous layer was additionally back-extracted with MTBE (1 x 140ml). The combined organic layers were used in the cyclization step without isolation/purification. (The next steps described below were performed on different scales based on different experiments, using solutions similar to those obtained above).

Cyclization reaction

Based on the measured amount of bromoacid (6.0 g, 16 mmol) from the previous step, 3 equivalents of thiourea (3.65 g) and n-PrOH (30 mL, 5 ml/g bromoacid) were added to the reaction flask. The resulting slurry was heated to 70-90°C. Then, the organic layer from the previous step was added thereto. The resulting mixture was concentrated by distillation at atmospheric pressure to a reaction mixture with a boiling point of about 97°C (boiling point of n-PrOH) and a volume of about 30ml (about 5ml/g starting bromoacid). More thiourea (3.65 g) was added along with 30 ml 6N HCl. The resulting solution formulation is then refluxed until the reaction is complete (12-24 hours, depending on concentration). The reaction solution was cooled to room temperature, water (60 mL) and MTBE (30 mL) were added thereto, and the phases were separated. Then, the obtained organic layer was washed twice with 60 mL of water. The resulting aqueous layer was back extracted with the same MTBE (15 mL). The combined organic layers were concentrated and the product was crystallized from IPA (4 mL) and toluene (16 mL) by the slow addition of heptane (total 60 mL).

Intermediate 8

Step A

To a cooled (-78°C) solution of [(S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]ethyl acetate (2.48g, 10mmol) in 20mL of anhydrous THF A solution of sodium bis(trimethylsilyl)amide (1.0 M, 12 mL, 12 mmol) was added dropwise. The above mixture was stirred at -78°C for 30 minutes, then a solution of neat trimethylsilyl chloride (1.4 mL, 11 mmol) was added dropwise. The above reaction was stirred for an additional 30 minutes before the reaction vessel was gradually warmed to room temperature. The solvent was removed in vacuo (rotary evaporation) and about 75 mL of pentane was added to the resulting residue. Rapid filtration was performed and the solvent was removed in vacuo to yield crude alkyltrimethylketene acetal.

Step B

A precooled (ice-methanol) stirred solution of 2.35 g of MCPBA (77% purity, 10 mmol) in 100 mL of dry hexane was treated with 10 mmol of the above acetal in 100 mL of dry hexane under a nitrogen atmosphere. After the addition was complete (approximately 5 minutes), the resulting slurry was stirred at room temperature for 30 minutes. The reaction mixture was then treated with 1.2 g (10 mmol) of triethylammonium fluoride while stirring and stirring was continued for 30 minutes after the addition was complete. Then, the above mixture was filtered and the filtrate was diluted with 100 mL of ethyl acetate. Then, the above solution was washed sequentially with 200 mL of 5% aqueous hydrochloric acid and 2×200 mL of 5% aqueous sodium carbonate. Subsequently, the obtained organic layer was dried with anhydrous sodium sulfate. Filtration and removal of solvent in vacuo gave the crude hydroxy ester. Then, pure compound (1.1 g) was obtained on Combi-Flash (5-10% ethyl acetate/hexane). LC-MS: _Calcd . 264, found 265 for _C15H20O4 [M+H ⁺ ] _.

Step C

The hydroxy ester from Step B (1.1 g, 4 mmol) was mixed with 4N ammonia-methanol (50 mL) overnight, evaporated and the resulting residue mixed with 5 mL ethyl acetate and 20 mL hexanes. The resulting white powder was filtered, washed with hexanes and dried under high vacuum to give the pure product as a single isomer (0.54 g). LC _- MS _: Calcd. 235, found 236 for _C13H17NO3 [M+H ⁺ ].

Step D

Hydroxyamide (540 mg, 2.3 mmol) and diethyl carbonate (2.72 g, 23 mmol) were mixed with sodium methoxide in methanol (0.5M, 30 mL). The above mixture was refluxed for 1.5 hours and then evaporated. The resulting residue was acidified with 3N aqueous HCl, extracted with ethyl acetate, dried over sodium sulfate, evaporated and purified on Comb-Flash (5-30% ethyl acetate/hexanes) to give product (470 mg). LC _- MS Calcd. _{for C14H15NO4} : 261; found: 262 (M+H).

Step E

To a stirred cooled (-78° C.) solution of the product from Step D above (470 mg, 1.8 mmol) in 5 mL of dichloromethane was added boron tribromide in dichloromethane (1.0 M, 3.0 mL, 3.0 mmol) . Then, the above reaction was warmed to room temperature for 50 minutes, and then the reaction was quenched with ice water. The resulting product was extracted twice with ethyl acetate. The organic phase obtained was washed twice with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was dried under high vacuum to give a beige solid which was used in the next step without further purification. LC-MS: Calcd _{for C13H13NO4} : 247 Found: 248 ₍ M+H).

Intermediate 9

Step A

To a cooled (-78°C) solution of [(4S)-7-(benzyloxy)-3,4-dihydro-2H-chromen-4-yl]ethyl acetate (1.0 g, 3 mmol) in 10 mL of anhydrous Sodium bis(trimethylsilyl)amide solution (1.0 M, 3.6 mL, 3.6 mmol) was added dropwise to the THF solution. The above mixture was stirred at -78°C for 30 minutes, then a solution of trimethylsilyl chloride in THF (3.3 mL, 3.3 mmol) was added dropwise. The above reaction was stirred for an additional 30 minutes before the reaction vessel was gradually warmed to room temperature. The solvent was removed in vacuo (rotary evaporation) and about 25 mL of pentane was added to the resulting residue. Rapid filtration was performed and the solvent was removed in vacuo to yield crude alkyltrimethylketene acetal.

Step B

A precooled (ice-methanol) stirred solution of 740 mg MCPBA (77% purity, 3.3 mmol) in 25 mL of dry hexane was treated with 3 mmol of the above acetal in 25 mL of dry hexane under a nitrogen atmosphere. After the addition was complete (approximately 5 minutes), the resulting slurry was stirred at room temperature for 30 minutes. Then, the above mixture was filtered and the filtrate was diluted with 100 mL of ethyl acetate. Then, the above solution was washed sequentially with 200 mL of 5% aqueous hydrochloric acid and 2×200 mL of 5% aqueous sodium carbonate. Subsequently, the obtained organic layer was dried with anhydrous sodium sulfate. Filtration and removal of solvent in vacuo gave the crude hydroxy ester. The pure compound (300 mg) was then obtained on Combi-Flash (5-10% ethyl acetate/hexane). LC-MS _: Calcd. 342, found 343 for _C20H22O5 [M+H ⁺ ] _.

Step C

The hydroxy ester from step B was mixed with 4N ammonia-methanol (50 mL) in a sealed tube and heated at 60 °C for 3 days, evaporated and the resulting residue was mixed with 5 mL ethyl acetate and 20 mL hexane . The resulting white powder was filtered, washed with hexanes and dried under high vacuum to give the pure product as a single isomer. LC _- MS: Calcd. ₃₁₃ , found 314 for _C18H19NO4 [M+H ⁺ ].

Step D

Hydroxyamide (280 mg, 0.9 mmol) and diethyl carbonate (1 mL) were mixed with sodium methoxide in methanol (15 mL, 7.5 mmol). The above mixture was refluxed for 1.5 hours and then evaporated. The resulting residue was acidified with 3N aqueous HCl, extracted with ethyl acetate, dried over sodium sulfate, evaporated and purified on Comb-Flash (5-30% ethyl acetate/hexanes) to give product. LC _{-MSC calcd. for 19H17NO5 : 339} ; found: 340 (M+H).

Step E

The product from Step D above (210 mg) was mixed with 20 mL of methanol and 20 mg of Pd/C (10%) and hydrogenated on a Parr shaker under 20 lbs of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated and dried under high vacuum to give a white gum (110 mg). LC-MS _: Calcd. _{for C12H11NO5} : 249 Found: 250 (M+H).

Example 1

In 10 mL of N,N-dimethylacetamide, intermediate 1 (500 mg, 2 mmol) was mixed with commercially available 3-chloro-4-fluorobenzotrifluoride (440 mg, 2.2 mmol) and Cs ₂ CO ₃ (2.0 g, 6mmol) mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. ¹ H NMR (400MHz, CDCl ₃ ) δ8.37, 8.31 (bs, bs, ratio = 1:3, 1H), 7.69 (d, J = 2.2Hz, 1H), 7.41 (d, J = 9.6Hz, 1H ), 7.11 (d, J=9.5, 1H), 6.98-6.70 (m, 3H), 4.90, 4.60 (dd, J=3.8, 4.60Hz, ratio=1:3, 1H), 4.02-4.20 (m , 1H), 2.80-3.05 (m, 2H), 2.50, 2.30, 1.98 (mmm, 2H), LC-MS Calcd for C ₁₉ H ₁₃ ClF ₃ NO ₃ S: 427; Found: 428 (M+H ).

Example 2

In 5 mL of N,N-dimethylacetamide, intermediate 1 (250 mg, 1.0 mmol) was mixed with 3-bromo-4-fluorobenzotrifluoride (255 mg, 1.05 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol )mix. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC-MSC Calcd. _{for 19 H13BrF3NO3S :} 470; found: 471 (M+H).

Example 3

In 5 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.5 mmol) was mixed with 3-trifluoromethyl-4-fluorobenzotrifluoride (140 mg, 0.6 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. _{for C20H13F6NO3S} : 461; found: 462 ₍ M+H).

Example 4

In 5 mL of N,N-dimethylacetamide, intermediate 1 (755 mg, 0.3 mmol) was mixed with 2-trifluoromethyl-4-fluorobenzonitrile (72 mg, 0.3 mmol) and Cs ₂ CO ₃ (1.0 g , 3mmol) mixed. The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 20H13F3N2O3S : 418 ;} found: 419 ₍ M+H).

Example 5

In 5 mL of N,N-dimethylacetamide, intermediate 1 (200 mg, 0.80 mmol) was mixed with 3-methyl-4-bromobenzonitrile (160 mg, 0.55 mmol) and Cs ₂ CO ₃ (1.65 g, 5 mmol )mix. The above reaction mixture was stirred at 150°C for 5 hours, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{- MSC} Calcd. _{for 20H16N2O3S} : 364; found: 365 (M+H).

Example 6

In 5 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.50 mmol) was mixed with 3-chloro-4-fluorobenzonitrile (102 mg, 0.6 mmol) and Cs ₂ CO ₃ (1.65 g, 5 mmol) mix. The above reaction mixture was stirred at 130°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. _{for C19H13ClN2O3S :} 384; found: 385 (M+H).

Example 7

In 5 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.50 mmol) was mixed with 3-bromo-4-fluorobenzonitrile (100 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.65 g, 5 mmol) mix. The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C19H13BrN2O3S} : 427; found: 428 (M+H).

Example 9

In 5 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.50 mmol) was mixed with 2,6-dimethyl-4-fluorobenzonitrile (75 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 150°C for 1 hour, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 21H18N2O3S : 378 ;} found: 379 (M+H).

Example 10

In 5 mL of N,N-dimethylacetamide, Intermediate 1 (125 mg, 0.50 mmol) was mixed with 4-fluoronaphthonitrile (76 mg, 0.5 mmol) and _Cs2CO3 (1.0 _g , 3 mmol). The above reaction mixture was stirred at 150°C for 1 hour, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C23H16N2O3S} : 400; found: 401 (M+H).

Example 1l

In 2 mL of N,N-dimethylacetamide, Intermediate 1 (50 mg, 0.20 mmol) was mixed with 4-fluorobenzonitrile (24 mg, 0.2 mmol) and Cs ₂ CO ₃ (650, 2 mmol). The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{- MS Calcd} . for _C19H14N2O3S : 350; found: 351 (M+H).

Example 12

In 2 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.50 mmol) was mixed with 3-methyl-4-fluoronitrobenzene (79 mg, 0.2 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 19H16N2O5S : 384 ;} found: 385 (M+H).

Example 13

In 2 mL of N,N-dimethylacetamide, Intermediate 1 (125 mg, 0.50 mmol) was mixed with 3,4-dichloro-nitrobenzene (100 mg, 0.2 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol )mix. The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C18H13ClN2O5S} : 404; found: 405 (M+H).

Example 14

In 5 mL of N,N-dimethylacetamide, Intermediate 1 (125 mg, 0.50 mmol) was mixed with 4-fluoronitronaphthalene (95 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol). The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C22H16N2O5S} : 420; found: 421 (M+H).

Example 15

Intermediate 1 (250 mg, 1.0 mmol) was mixed with 2,3-dichloro-4-trifluoromethylpyridine (216 mg, 1.0 mmol) and Cs ₂ CO ₃ ( 1.4g, 4mmol 1) mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C18H12ClF3N2O3S :} 428; found: 429 ₍ M+H) _.

Example 16

In 5 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.5 mmol) was mixed with 2-chloro-4-trifluoromethyl-6-methylpyridine (110 mg, 0.6 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol) were mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . for _{C19H15F3N2O3S :} 408; found: 409 (M+H) _.

Example 17

In 5 mL of N,N-dimethylacetamide, intermediate 1 (125 mg, 0.5 mmol) was mixed with 2-chloro-3-trifluoromethylpyridine (110 mg, 0.6 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmo1) mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 18H13F3N2O3S : 394 ; found} : 395 (M+H).

Example 18

In 5 mL of N,N-dimethylacetamide, Intermediate 1 (125 mg, 0.5 mmol) was mixed with 1-chloro-isoquinoline (100 mg, 0.6 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol). The above reaction mixture was stirred at 125°C for 1.5 hours, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . for _C21H16N2O3S : 376; found: ₃₇₇ (M+H).

Example 19

In 5 mL of N,N-dimethylacetamide, Intermediate 2 (263 mg, 1.0 mmol) was mixed with 1-chloro-isoquinoline (180 mg, 1.1 mmol) and _Cs2CO3 ( _1.0 g, 3 mmol). The above reaction mixture was stirred at 125°C for 1.5 hours, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C22H18N2O3S} : 390; found: 391 (M+H).

Example 20

In 5 mL of N,N-dimethylacetamide, intermediate 2 (263 mg, 1.0 mmol) was mixed with 2-chloro-3-trifluoromethylpyridine (200 mg, 1.1 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 19H15F3N2O3S : 408 ; found} : 409 (M+H).

Example 21

In 5 mL of N,N-dimethylacetamide, intermediate 2 (263 mg, 1.0 mmol) was mixed with 2-chloro-4-trifluoromethyl-6-methylpyridine (210 mg, 1.1 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol) were mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C20H17F3N2O3S :} 422; found: 423 ( _M +H) _.

Example 22

Intermediate 2 (263 mg, 1.0 mmol) was mixed with 2,3-dichloro-4-trifluoromethylpyridine (238 mg, 1.1 mmol) and Cs ₂ CO ₃ ( 1.0 g, 3 mmol) were mixed. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C19H14ClF3N2O3S :} 442; found: 443 ( _M +H) _.

Example 23

In 5 mL of N,N-dimethylacetamide, intermediate 2 (263 mg, 1.0 mmol) was mixed with 3-chloro-4-fluorobenzotrifluoride (220 mg, 1.1 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol )mix. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 20H15ClF3NO3S : 441 ;} found: 442 (M+H).

Example 24

In 5 mL of N,N-dimethylacetamide, intermediate 2 (132 mg, 0.5 mmol) was mixed with 3-trifluoromethyl-4-fluorobenzotrifluoride (140 mg, 0.6 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. _{for C21H15F6NO3S} : 475; found: 476 ₍ M+H).

Example 25

In 5 mL of N,N-dimethylacetamide, intermediate 2 (132 mg, 0.5 mmol) was mixed with 2-trifluoromethyl-4-fluorobenzotrifluoride (103 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C21H15F3N2O3S :} 432; found: 433 ( _M +H) _.

Example 26

In 5 mL of N,N-dimethylacetamide, intermediate 2 (132 mg, 0.50 mmol) was mixed with 3-methyl-4-bromobenzonitrile (100 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.65 g, 5 mmol )mix. The above reaction mixture was stirred at 150°C for 5 hours, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 21H18N2O3S : 378 ;} found: 379 (M+H).

Example 27

Intermediate 2 (263 mg, 1.0 mmol) was mixed with 3-chloro-4-fluorobenzonitrile (178 mg, 1.1 mmol) and Cs ₂ CO ₃ (3.26 g, 10 mmol) in 10 mL of N,N-dimethylacetamide mix. The above reaction mixture was stirred at 130°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . for _{C20H15ClN2O3S :} 398; found: 399 (M+H).

Example 28

In 5 mL of N,N-dimethylacetamide, intermediate 2 (132 mg, 0.50 mmol) was mixed with 3-bromo-4-fluorobenzonitrile (100 mg, 0.50 mmol) and Cs ₂ CO ₃ (1.65 g, 5 mmol) mix. The above reaction mixture was stirred at 90°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C20H15BrN2O3S} : 442; found: 443 (M+H).

Example 29

In 5 mL of N,N-dimethylacetamide, intermediate 2 (132 mg, 0.50 mmol) was mixed with 2,6-dimethyl-4-fluorobenzonitrile (75 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 150°C for 1 hour, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 22H20N2O3S : 392 ;} found: 393 (M+H).

Example 30

In 5 mL of N,N-dimethylacetamide, _Intermediate 2 (132 mg, 0.50 mmol) was mixed with 4-fluoronaphthonitrile (76 mg, 0.5 mmol) and _Cs2CO3 (1.0 g, 3 mmol). The above reaction mixture was stirred at 150°C for 1 hour, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C24H18N2O3S} : 414; found: 415 (M+H).

Example 31

In 5 mL of N,N-dimethylacetamide, Intermediate 2 (132 mg, 0.20 mmol) was mixed with 4-fluorobenzonitrile (62 mg, 0.20 mmol) and Cs ₂ CO ₃ (1.0 g, 5 mmol). The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C20H14N2O3S} : 350; found: 351 (M+H).

Example 32

In 2 mL of N,N-dimethylacetamide, intermediate 2 (132 mg, 0.50 mmol) was mixed with 3-methyl 4-fluoronitrobenzene (78 mg, 0.2 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol )mix. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C20H18N2O5S :} 398; found: ₃₉₉ (M+H).

Example 33

In 5 mL of N,N-dimethylacetamide, intermediate 2 (263 mg, 1.0 mmol) was mixed with 3,4-dichloro-nitrobenzene (200 mg, 1.05 mmol) and Cs ₂ CO ₃ (1.6 g, 3 mmol )mix. The above reaction mixture was stirred at 100°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C19H15ClN2O5S} : 418; found: 419 (M+H).

Example 34

In 5 mL of N,N-dimethylacetamide, Intermediate 2 (132 mg, 0.50 mmol) was mixed with 4-fluoronitrobenzene (79 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol). The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. _{for C19H16N2O5S} : 384; found: ₃₈₅ (M+H).

Example 35

In 5 mL of N,N-dimethylacetamide, Intermediate 3 (263 mg, 1.0 mmol) was mixed with 1-chloro-isoquinoline (180 mg, 1.1 mmol) and _Cs2CO3 (1.0 _g , 3 mmol). The above reaction mixture was stirred at 125°C for 1.5 hours, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS _Calcd . _{for C22H18N2O3S} : 390; found: 391 (M+H).

Example 36

In 5 mL of N,N-dimethylacetamide, intermediate 3 (263 mg, 1.0 mmol) was mixed with 2-chloro-3-trifluoromethylpyridine (200 mg, 1.1 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 19H15F3N2O3S : 408 ;} Found: 409 (M+H ₎

Example 36a

In 5 mL of N,N-dimethylacetamide, intermediate 3 (263 mg, 1.0 mmol) was mixed with 2-chloro-4-trifluoromethyl-6-methylpyridine (210 mg, 1.1 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol) were mixed. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C20H17F3N2O3S :} 422; found: 423 ( _M +H) _.

Example 37

Intermediate 3 (263 mg, 1.0 mmol) was mixed with 2,3-dichloro-4-trifluoromethylpyridine (240 mg, 1.1 mmol) and Cs ₂ CO ₃ ( 1.0 g, 3 mmol) were mixed. The above reaction mixture was stirred at 125°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. for _{C19H14ClF3N2O3S :} 442; found: 443 ( _M +H) _.

Example 38

Step A

In 50 mL of N,N-dimethylacetamide, 2,4-dichlorophenol (2.45 g, 15 mmol), 5-fluoroindanone (2.0 g, 13.3 mmol) and potassium carbonate (2.76 g, 20 mmol) The mixture was stirred overnight at 150°C, cooled to room temperature, diluted with water and extracted with diethyl ether. The resulting black ether layer was washed with 10% aqueous NaOH and brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the product. LC _{-MSC calcd. for 15H10Cl2O2 : 292} ; found: ₂₉₃ (M+H).

Step B

In a small flask, the ketone from Example 38, Step A (0.865 g, 2.95 mmol) was mixed with 2,4-thiazolidinedione (433 mg, 3.7 mmol) and sodium acetate (600 mg, 7.3 mmol), and It was heated at 145° C. overnight under nitrogen flow. The reaction was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified on Combi-Flash (5-20% ethyl acetate/hexanes) to give the product as a yellow solid. LC _- MS Calcd. _{for C18H11Cl2NO3S :} 390; found: 391 (M+H).

Step C

The condensation product from Example 38, Step B (280 mg, 0.716 mmol) was mixed with pyridine (0.61 mL) and THF (0.61 mL) and cooled at 0°C. To the above mixture was added lithium borohydride in THF (2.0 M, 1.0 mL, 2.0 mmol). The mixture was stirred at room temperature for 10 minutes, then it was refluxed for 3 hours, quenched with 3N aqueous HCl (pH<2), extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified on Combi-Flash (5-20% ethyl acetate/hexanes) to give the product as a mixture of 2 diastereoisomers. LC _- MS Calcd. _{for C18H13Cl2NO3S} : 393 _; found: 394 (M+H).

Example 39

According to the same method as in Example 38, substituting 3,5-xylenol for dichlorophenol, this compound was prepared as a racemic mixture of diastereoisomers. LC _{-MSC calcd. for 20H19NO3S : 353} ; found: 354 (M+H).

Example 40

According to the same method as in Example 38, substituting 3-trifluoromethoxyphenol for dichlorophenol, this compound was prepared as a racemic mixture of diastereoisomers. LC _{-MSC Calcd. for 19H14F3NO4S : 409 ;} found: 410 (M+H).

Example 41

To intermediate 1 (50mg, 0.2mmol), iodobenzene (44.9mg, 0.22mmol), cesium carbonate (195.5mg, 0.6mmol), ketone iodide (I) (3.8mg, 0.02mmol) and N, N- To a mixture of dimethylglycine (8.4 mg, 0.06 mmol) was added 1,4-dioxane (1 mL) and dimethylformamide (1 mL). The above reaction was sealed, degassed, backfilled twice with _N2 and heated at 110 °C overnight. The completed reaction above was poured into 0.1 N aqueous hydrochloric acid (6 mL) and extracted with ethyl acetate (3 x 6 mL). The combined organic fractions were concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (YMC-Pack Pro C18 5 micron, 40%-100% _CH3CN / _H2O /0.1% TFA). The combined pure fractions were lyophilized overnight to give a white solid as an approximately 7:3 mixture of diastereoisomers R,S- and R,R-, respectively. LC _- MS: _Calcd . for _C18H16NO3S [M+H ⁺ ]: 326.1, found 326.2.

According to the same method as described in the preparation of Example 41, further examples were prepared. These compounds are shown in Table 1.

Table 1

compound R1 R2 R3 R4 molecular formula Calculated [M+H ⁺ ] Measured [M+H ⁺ ] Example 42 h h h h C ₁₈ H ₁₅ NO ₃ S 326.1 326.2 Example 43 h Et h h C ₂₀ H ₁₉ NO ₃ S 354.1 354.3 Example 44 Cl h F h C ₁₈ H ₁₃ ClFNO ₃ S 378.0 Nonionic Example 45 h Me F h C ₁₉ H ₁₆ FNO ₃ S 358.1 Nonionic Example 46 Me h F h C ₁₉ H ₁₆ FNO ₃ S 358.1 359.2 Example 47 Et h CN h C ₂₁ H ₁₈ N ₂ O ₃ S 379.1 379.2 Example 48 Me h CF3 h C ₂₀ H ₁₆ F ₃ NO ₃ S 408.1 408.2

Examples 49-51

The examples in Table 2 below were prepared according to the same procedure as described in the preparation of Example 1, by substituting Intermediate 1 for Intermediate 4.

Table 2

compound R1 R2 R3 R4 R5 molecular formula Calculated [M+H ⁺ ] Measured [M+H ⁺ ] Example 49 Me h CN h h C ₁₉ H ₁₅ N ₂ O ₄ S 367.1 367.0 Example 50 Cl h CF ₃ h h C ₁₈ H ₁₂ ClF ₃ NO ₄ S 430.0 430.0 Example 51 F h CN h h C ₁₈ H ₁₂ FN ₂ O ₄ S 371.0 371.0

Example 52

Step A

In 50 mL of N,N-dimethylacetamide, 5-hydroxyindanone (2.96 g, 20 mmol), 2-chloro-4-fluorobenzotrifluoride (4.30 g, 22 mmol) and cesium carbonate (13 g, 40 mmol ), which was stirred overnight at 150° C., cooled to room temperature, diluted with water and extracted with diethyl ether. The resulting black ether layer was washed with 10% aqueous NaOH and brine, dried over anhydrous sodium sulfate, filtered, evaporated and purified by FC (silica gel, 10% ethyl acetate) to give the product. _{LC -} MS calcd _{for C16H10ClF3O2} : 326; found: 327 (M+H).

Step B

In a flask containing 50 mL of ethanol, the ketone from Example 52, Step A (3.27 g, 10 mmol) was mixed with hydroxylamine hydrochloride (770 mg, 11 mmol) and sodium acetate (900 mg, 11 mmol). The above mixture was refluxed overnight under nitrogen flow. The reaction was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated. The residue was purified by FC (silica gel, 20% ethyl acetate/hexanes) to give the product as a yellow solid. LC _- MS Calcd. _{for C16H11ClF3NO2} : 341; found _: 342 (M+H).

Step C

The oxime from Example 52, Step B (1.5 g, 4.4 mmol) was mixed with sodium cyanoborohydride (380 mg, 6 mmol) in 20 mL of methanol. 4N HCl in dioxane was slowly added to the above stirred mixture until the pH was 4. The resulting mixture was stirred at room temperature for one hour, quenched with saturated aqueous sodium carbonate, extracted with ethyl acetate, backwashed with water, dried over sodium sulfate, filtered and evaporated, and purified on a Comb-Flash (ethyl acetate). It was purified to give the product as a colorless solid. _{LC -} MS calcd for _{C16H13ClF3NO2} : 343; found _: 344 (M+H).

Step D

To a stirred solution of hydroxylamine from Example 52, Step C (1.02 g, 3 mmol) in 15 mL of a mixture of anhydrous dioxane and 15 mL of anhydrous THF was added dropwise a solution of neat trimethylsilyl isocyanate (0.61 mL, 4.5 mmol). The above mixture was stirred for one hour, mixed with water and extracted with ethyl acetate, dried over sodium sulfate, evaporated and purified in Combi-Flash (80-100% ethyl acetate/hexanes) to give solid product. LC _- MS calcd. _{for C17H14ClF3N2O3 :} 386; found: 387 ₍ M+H).

Step E

To a stirred solution of hydroxyurea from Example 52, Step D (460 g, 1.2 mmol) in 20 mL of anhydrous THF was added sodium hydride (60% in oil, 68 mg, 1.7 mmol).

The resulting mixture was stirred for one hour, treated with methyl chloroformate (189 mg, 2.0 mmol), stirred for another hour, poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give an oily residue things. The resulting residue was dried under high vacuum, dissolved in 10 mL of anhydrous DMF and treated with sodium hydride (60% oil, 68 mg, 1.7 mmol). After stirring for one hour, the reaction mixture was mixed with water, extracted with ethyl acetate and purified on Combi-Flash (ethyl acetate) to give the product. LC _- MS Calcd. _{for C18H12ClF3N2O4} : 412; _found : no molecular ion (M+H ₎ .

Example 53

Step A

In a pressure flask, the oxime from Example 52, Step B (3.42 g, 10 mmol) was mixed with Ra-Ni (1.0 g) and 7N ammonia-methanol (50 mL). Hydrogenation was performed overnight on a Parr shaker under 50 psi hydrogen. The catalyst was removed by filtration through celite. The filtrate was evaporated and the residue dried under high vacuum to give a white solid which was used in the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ7.82(s, 1H), 7.51(m, 1H), 7.40(m, 1H), 7.02(m, 3H), 3.80(bs, 1H), 3.10-2.60( m, 4H), 1.90 (bs, 2H). LC _{-MSC calcd. for 16H13ClF3NO : 377} ; found: 311 (M- _NH2 ).

Step B

The crude amine from Example 53, Step A (1.0 g, 3 mmol) and potassium carbonate (1.38 g, 10 mmol) were dissolved in 20 mL of N,N-dimethylacetamide. To the above mixture was added ethyl bromoacetate (0.5 mg, 3.1 mmol). Then, the above reaction was stirred at room temperature for 2 hours, and then water was added thereto. The organic layer was separated, washed with water, dried over sodium sulfate, filtered and evaporated, and purified on Combi-Flash (50% ethyl acetate) to give the product. ¹ H NMR (400MHz, CDCl ₃ ) δ7.69(1, 1H), 7.35(dd, J=8.5, 7.9Hz, 2H), 6.90(d, J=8.6Hz, 1H), 6.85(s, 1H) , 6.84(d, J=8.8Hz, 1H), 4.20(m, 3H), 3.40(s, 21H), 3.00(m, 1H), 2.98(m, 1H), 2.38(m, 1H), 2.17( bs, 1H), 1.90 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H). LC _- MS Calcd. _{for C20H19ClF3NO3} : ₄₁₃ ; found: 414 (M+H).

Step C

To a stirred solution of glycinate (380 mg, 0.92 mmol) and diisopropylethylamine (129 mg, 1.0 mmol) from Example 53, step B in 5 mL of anhydrous dichloromethane was added trichloroacetyl isocyanate (188 mg , 1.0 mmol) in 1 mL of dichloromethane solution.

The resulting mixture was evaporated and mixed with potassium carbonate (276 mg, 2 mmol) and ethanol (20 mL). The above mixture was refluxed for 2 hours, acidified with 6N aqueous HCl, stirred for another hour, diluted with water and extracted with ethyl acetate. The crude product was purified on Combi-Flash (50-80% ethyl acetate/hexanes) to give the product as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.21(bs, 1H), 7.71(s, 1H), 7.41(d, J=8.5Hz, 1H), 7.16(d, J=8.9Hz, 1H), 6.96 (d, J=8.5Hz, 1H), 6.88(d, J=8.5Hz, 1H), 6.87(s, 1H), 5.74(t, J=7.4Hz, 1H), 3.73, 3.57(dd, J= 14.6, 17.5Hz, 2H), 2.95(m, 2H), 2.50(m, 1H), 1.99(m, 1H). LC _- MS Calcd. _{for C19H14ClF3N2O3 :} 410; found _: 411 (M+H).

Example 54

In 5 mL of N,N-dimethylacetamide, intermediate 5 (crude product, 100 mg, 0.4 mmol) was mixed with 3-chloro-4-fluorobenzotrifluoride (75 mg, 0.37 mmol) and Cs ₂ CO ₃ (1.0 g, 3mmol) mixed. The above reaction mixture was stirred at 90°C for 60 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 30-50% ethyl acetate/hexanes gradient) afforded the product. LC _- MS Calcd. _{for C19H13ClF3NO4} : 411; found _: 412 (M+H). ¹ H NMR (400MHz, CDCl ₃ ) (main isomer) δ8.18(bs, 1H), 7.89(s, 1H), 7.60(d, J=8.2Hz, 1H), 7.47(d, J=7.8 Hz, 1H), 7.14(d, J=8.6Hz, 1H), 7.04(m, 2H), 5.36(d, J=2.7Hz, 1H), 4.02(m, 1H), 3.22(m, 1H), 3.05(m, 1H), 2.45(m, 2H), 2.24(m, 1H). The two diastereomers of Example 54 were separated as single enantiomers (54a and 54b) on Chiracel AD or OD columns.

Example 55

In 5 mL of N,N-dimethylacetamide, intermediate 6 (134 mg, 0.5 mmol) was mixed with 3-chloro-4-fluorobenzotrifluoride (110 mg, 0.5 mmol) and Cs ₂ CO ₃ (1.0 g, 3 mmol )mix. The above reaction mixture was stirred at 120°C for 30 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 30-50% ethyl acetate/hexanes gradient) afforded the product. LC _{-MSC Calcd. for 18H11ClF3NO3S2 : 444 ; found} : 445 (M+H).

Example 56

To a mixture of Intermediate 7 (97 mg, 0.366 mmol) and Cs ₂ CO ₃ (298 mg, 0.915 mmol) was added DMF (2 mL), followed by the addition of commercially available 3-chloro-4-fluoro-benzotrifluoride (95 mg, 0.48 mmol). The reaction was heated at 110 °C for 2 h, then quenched with 0.1 N HCl (15 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0%-45% EtOAc/hexanes) to give a white solid as a mixture of diastereomers.

Rf = 0.15 (30% EtOAc/ _Hexane ); LC-MS Calcd for _{C19H13ClF3NO4S} : _443.02 Found (ES-) _: 442.0 [MH]; ^1H NMR (500MHz, _CDCl3 ) δ8.60(s, 1H), 8.54(s, 0.4H), 7.75(d, J=1.8Hz, 1.4H), 7.51-7.47(m, 1.4H), 7.10-7.02(m, 2.8H), 6.63-6.60(m, 1H), 6.57-6.54(m, 0.4H), 6.50(d, J=2.6Hz, 1.4H), 5.11(d, J=4.1Hz, IH), 4.60(d, J= 4.6Hz, 0.4H), 4.45-4.41(m, IH), 4.29-4.10(m, 1.8H), 3.98-3.94(m, 1H), 3.84-3.81(m, 0.4H), 2.36-2.30(0.4 H), 2.24-1.90 (m, 2.4H). The reaction was run on _a larger scale as follows: In a 50 L three necked round bottom flask was charged intermediate 7 (3.00 kg), commercially available 3-chloro-4-fluorobenzotrifluoride (2.47 kg), _Cs2CO3 (11.1kg) and DMSO (12L). The above slurry was warmed to 110°C and left until the reaction was complete, after 6-8 hours < 1% (assay %) of Intermediate 7 remained. The above slurry was cooled to ambient temperature, and water (12 L) and EtOAc (20 L) were added. The resulting organic layer was washed with 5N HCl (5 L). The pH of the aqueous layer is 1-2. Then, the organic layer was washed with 5% NaHCO ₃ (10 L). The organic layer was then treated with Darco KB (20 wt%, 800 g), allowed to stand at room temperature for 2 hours, filtered through solka floc and rinsed with EtOAc (8 L).

The resulting product is then epimerized and crystallized at the thiazolidinedione center. Firstly, the obtained filtrate was transferred into NPA (n-propanol), and the amount of NPA was adjusted to 20L. The above solution was warmed to 70° C., water (30 L) was added, and then the seed crystals from the previous batch were added. Additional water (30 L) was added over a period of one hour while maintaining the temperature at 70°C. The above solution was left at 70°C for 2-3 hours and then allowed to cool to room temperature over a period of 2-3 hours. Then, the crystals were filtered, washed with 1:3 NPA/ _H2O (16 L) and dried under _N2 . The resulting crude cake was dissolved in toluene (15 L) at 60°C. Heptane (30 L) was added over 1 hour, then the solution was allowed to cool to room temperature over 1 hour. The resulting crystals were filtered, washed with 1:2 toluene/heptane (11 L) and dried under _N2 .

Examples 57-71

Using the reaction scheme detailed in Example 56, substituting the corresponding aryl fluoride or aryl chloride for 3-chloro-4-fluoro-benzotrifluoride, compounds with variables on the left side of the structure were prepared. All reactants or starting materials are either commercially available or are described in the Intermediates section or can be readily prepared by one skilled in the art of synthetic organic chemistry. These compounds are summarized in the table below.

Example 72

This compound was prepared by coupling intermediate 7 with 4-iodo-3-methylbenzotrifluoride as follows: p-2-Methyl-4-trifluoromethylaniline (9.7 g), 15 % sulfuric acid (80 mL) and ethanol (16 mL) was stirred. Sodium nitrite (4.2 g) was added to the above reaction mixture at 0°C, and the above mixture was stirred at the same temperature for 1 hour. Then, sodium iodide (9.97 g) was added thereto at 0°C, and the above mixture was allowed to warm to room temperature over a period of 1.5 hours. The above reaction mixture was extracted with ethyl acetate (200 mL×3), and the combined organic layers were washed with saturated aqueous sodium sulfite and brine, dried over magnesium sulfate, filtered and concentrated. It was subjected to silica gel column chromatography using ethyl acetate/hexane (10/1) as an eluent to obtain 4-iodo-3-methylbenzotrifluoride.

Intermediate 7 (183 mg, 0.69 mmol), Cs ₂ CO ₃ (730 mg, 2.24 mmol), 4-iodo-3-methyl-benzotrifluoride (0.96 mmol, 274 mg), CuI (0.14 mmol, 26 mg) and N , DMF (2 mL) and dioxane (2 mL) were added to a mixture of N-dimethylglycine HCl salt (0.42 mmol, 60 mg). The reaction was heated at 110 °C for 20 h, then quenched with 0.1 N HCl (60 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The organic layers were combined, washed with brine (1 x 40 mL), dried over _{anhydrous Na2SO4} and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0%-45% EtOAc/hexanes) to give the desired product (mixture of two diastereomers) as a light yellow solid. Ry = 0.14 (30% EtOAc/Hexane ₎ ; LC-MS calc. for _C20H16F3NO4S : 423.08 Found (ES+): 423.91 _[ M+H _] ; major diastereomer ¹ H NMR (500MHz, d6-DMSO) of sodium salt: δ7.66(s, 1H), 7.52(d, J=8.4Hz, 1H), 7.32(d, J=8.4Hz, 1H), 6.94(d , J=8.4Hz, 1H), 6.48(dd, J=2.4, 8.5Hz, 1H), 6.32(d, J=2.5Hz, 1H), 4.82(d, J=3.9Hz, 1H), 4.31-4.27 (m, 1H), 4.03-3.98 (m, 1H), 3.57-3.54 (m, 1H), 2.27 (s, 3H), 1.87-1.83 (m, 1H), 1.64-1.60 (m, 1H).

Example 73

In 5 mL of N,N-dimethylacetamide, intermediate 8 (crude product, 125 mg, 0.5 mmol) was mixed with 3-chloro-4-fluorobenzotrifluoride (170 mg, 0.6 mmol) and Cs ₂ CO ₃ (499 mg , 1.5mmol) mixed. The above reaction mixture was stirred at 90°C for 60 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 30-50% ethyl acetate/hexanes gradient) gave the product as a mixture of two diastereoisomers. LC _- MS Calcd. _{for C20H15ClF3NO4} : 425; found _: 426 (M+H). It was further separated into two single enantiomers (74a and 74b) on Chiracel AD or OD columns.

Examples 74-86

Using the reaction scheme detailed in Example 73, substituting the corresponding aryl fluoride or aryl chloride for 3-chloro-4-fluoro-benzotrifluoride, or using the reaction scheme detailed in Example 41, substituting the corresponding aryl Substituting phenyl bromide or aryl iodide for iodobenzene produced compounds with variables on the left side and core of the structure. All reactants or starting materials are either commercially available or are described in the Intermediates section or can be readily prepared by one skilled in the art of synthetic organic chemistry. Two single isomers were prepared by HPLC on OD or AD columns. These compounds are summarized in the table below.

Example 87

In 2 mL of N,N-dimethylacetamide, intermediate 9 (crude product, 25 mg, 0.1 mmol) was mixed with 3-chloro-4-fluorobenzotrifluoride (20 mg, 0.1 mmol) and Cs ₂ CO ₃ (97.5 mg, 0.3mmol) mixed. The above reaction mixture was stirred at 90°C for 60 minutes, then poured into water and acidified to pH<2 with 2N aqueous HCl. The resulting solid precipitate was extracted with ethyl acetate, washed with water, then brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. Purification by Combi-Flash (silica, 30-50% ethyl acetate/hexanes gradient) afforded the product. LC _- MS calcd _{for C19H13ClF3NO5} : 427; found _: 428 (M+H).

Examples 88-93

Using the reaction scheme detailed in Example 87, substituting the corresponding aryl fluoride or aryl chloride for 3-chloro-4-fluoro-benzotrifluoride, or using the reaction scheme detailed in Example 41, substituting the corresponding aryl Substituting phenyl bromide or aryl iodide for iodobenzene produced compounds with variables on the left side and core of the structure. All reactants or starting materials are either commercially available or are described in the Intermediates section or can be readily prepared by one skilled in the art of synthetic organic chemistry. Two single isomers were prepared by HPLC on OD or AD columns. These compounds are summarized in the table below.

Example 94

Intermediate 5 (162mg, 0.69mmol), Cs ₂ CO ₃ (730mg, 2.24mmol), 4-bromo-2,3-dimethyl-trifluorotoluene (0.96mmol, 241mg), CuI (0.14mmol, 26mg ) and N,N-Dimethylglycine HCl salt (0.42mmol, 60mg) were added DMF (2mL) and dioxane (2mL). The reaction was heated at 110 °C for 20 h, then quenched with 0.1 N HCl (60 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The organic layers were combined, washed with brine (1 x 40 mL), dried over _{anhydrous Na2SO4} and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0%-45% EtOAc/hexanes) to give the desired product (mixture of two diastereomers) as a light yellow solid. LC-MSC Calcd _{for 21 H18F3NO4} : 405.12 Found (ES+): 406 [M+H] _.

Examples 95-128

Using the reaction scheme detailed in Example 54, substituting the other corresponding aryl fluoride or aryl chloride for 3-chloro-4-fluoro-benzotrifluoride, or using the reaction scheme detailed in Example 94, substituting the other corresponding Substituting aryl bromide or aryl iodide for 4-bromo-2,3-dimethyl-benzotrifluoride produced compounds with variables on the left and core of the structure. All reactants or starting materials are either commercially available or are described in the Intermediates section or can be readily prepared by one skilled in the art of synthetic organic chemistry. Two single isomers were prepared by HPLC on OD or AD columns. These compounds are summarized in the table below.

Examples 129-182

Compounds with variables on the left or right side of the structure were prepared using one of the following methods:

a) Using the reaction scheme detailed in Example 54, substituting Intermediates 1, 2 or 7 for Intermediate 5 and substituting the other corresponding aryl fluoride or aryl chloride for 3-chloro-4-fluoro-trifluorotoluene ;

b) Using the reaction scheme detailed in Example 94, replacing Intermediate 5 with Intermediate 1, 2 or 7, and replacing 4-bromo-2,3-dimethyl with the other corresponding aryl bromide or aryl iodide - Trifluorotoluene. All reactants or starting materials are either commercially available or are described in the Intermediates section or can be readily prepared by one skilled in the art of synthetic organic chemistry. These compounds are summarized in the table below.

Claims (22)

1. formula I compound or its pharmacy acceptable salt:

Wherein A be selected from-CH-and-N-;

B is selected from-S-,-O-,-NH-,-C (=O)-and-CH ₂-;

D is selected from-C (=O)-,-C (=S)-,-C (=NH)-,-O-and-NH-;

W and Z are independently selected from-CH ₂-,-CF ₂-,-CH ₂CH ₂-and-CH ₂CH ₂CH ₂-, and among W and the Z one randomly can be selected from-O-,-C (=O)-,-NR ⁶-,-S-,-SO-and-SO ₂-;

Y is selected from=CH-and=N-;

Heterocycle is to have the monocyclic heterocycles that 1-3 is independently selected from the saturated or fractional saturation of the heteroatomic 5-6 unit of O, N and S;

Heteroaryl is to have 1-3 the first monocycle hetero-aromatic ring of heteroatomic 5-6 that is independently selected from O, N and S;

R ¹, R ², R ³And R ⁴Be selected from independently of one another H, halogen ,-CN ,-NO ₂,-C ₁-C ₆Alkyl ,-OC ₁-C ₆Alkyl ,-SC ₁-C ₆Alkyl ,-S (O) ₂C ₁-C ₆Alkyl ,-N (R ⁶) (R ⁶) ,-N (R ⁶) C (=O) C ₁-C ₆Alkyl ,-N (R ⁶) S (O) ₂C ₁-C ₆Alkyl ,-C (=O) H ,-C (=O) OH ,-C (=O) OC ₁-C ₆Alkyl ,-C (=O) C ₁-C ₆Alkyl ,-C (=O) N (R ⁶) (R ⁶) ,-C (=O) phenyl ,-C (=O) naphthyl ,-C (=O) heterocycle, heterocycle, heteroaryl, C ₃-C ₇-cycloalkyl, phenyl and naphthyl;

Wherein-C ₁-C ₆Alkyl and-OC ₁-C ₆Alkyl ,-SC ₁-C ₆Alkyl ,-S (O) ₂C ₁-C ₆Alkyl ,-N (R ⁶) C (=O) C ₁-C ₆Alkyl ,-N (R ⁶) S (O) ₂C ₁-C ₆Alkyl ,-C (O) OC ₁-C ₆Alkyl and-C (=O) C ₁-C ₆The alkyl of alkyl randomly replaced by 1-5 halogen and randomly by 1-2 be independently selected from-OH ,-OC ₁-C ₃The group of alkyl replaces, and is described-OC ₁-C ₃Alkyl randomly by 1-5 halogen ,-CF ₃,-S (O) ₂C ₁-C ₃Alkyl ,-C (=O) C ₁-C ₃Alkyl ,-OC (=O) C ₁-C ₆Alkyl ,-NHC (=O) CH ₃,-NHC (=O) OC ₁-C ₆Alkyl ,-NHS (O) ₂CH ₃,-N (R ⁶) (R ⁶), heterocycle, heteroaryl, C ₃-C ₇-cycloalkyl, phenyl and naphthyl substituted;

Wherein-C (=O) phenyl ,-C (=O) naphthyl ,-C (=O) heterocycle, heterocycle, heteroaryl, C ₃-C ₇-cycloalkyl, phenyl and naphthyl are as R ¹, R ², R ³, R ^{4 or}The person is as R ¹, R ², R ³And R ⁴On substituting group, randomly be independently selected from following substituting group and replace by 1-4: halogen ,-CF ₃,-OCF ₃,-CN ,-NO ₂,-OH ,-C ₁-C ₃Alkyl ,-C (=O) C ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl and-OC ₁-C ₃Alkyl, wherein said-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl and-C (=O) C ₁-C ₃Alkyl substituent is randomly replaced by 1-3 halogen; And wherein

Alternatively a pair of (the R that is selected from ¹-R ²), (R ²-R ¹), (R ²-R ³), (R ³-R ²), (R ³-R ⁴) and (R ⁴-R ³) ortho-substituent can link together, thereby form divalence bridge joint group with 3-5 atomic length, wherein said divalence bridge joint group is selected from-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂CH ₂-,-OCH ₂CH ₂-,-OCH ₂CH ₂CH ₂-,-OCH ₂CH ₂CH ₂CH ₂-,-CH ₂OCH ₂-,-CH ₂OCH ₂CH ₂-,-CH ₂OCH ₂CH ₂CH ₂-,-CH ₂CH ₂OCH ₂CH ₂-and-SCH ₂CH ₂-, wherein said bridge joint group randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace; And wherein

Alternatively described that a pair of ortho-substituent R ¹-R ²Can connect by 4-carbochain-CH=CH-CH=CH-, thereby at R ¹And R ²The position forms the condensed benzyl ring, perhaps by be selected from-CH=CH-CH=N-,-N=CH-CH=CH-,-CH=N-CH=CH-,-CH=CH-N=CH-,-CH ₂CH ₂CH ₂C (=O) or-C (=O) CH ₂CH ₂CH ₂-the 4-atomchain connect, thereby at R ¹And R ²The position forms condensed pyridyl ring or condensed pimelinketone ring, wherein said condensed benzyl ring, described condensed pyridine basic ring and described condensed pimelinketone ring randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace; And wherein

Alternatively described that a pair of ortho-substituent R ¹-R ²Can by be selected from-CH=CHO-,-OCH=CH-,-CH=CH-S-,-SCH=CH-,-CH=CHN (R ⁶)-,-N (R ⁶) CH=CH-,-CH ₂CH ₂C (=O)-and-C (=O) CH ₂CH ₂-the 3-atomchain connect, thereby at R ¹And R ²The position forms the five-ring be fused on the benzyl ring, wherein said condensed five-ring randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace; And

R ⁶Be selected from H and-C ₁-C ₆Alkyl.

2. the compound of claim 1 or its pharmacy acceptable salt, wherein R ¹, R ², R ³And R ⁴Be independently selected from (1) H; (2) halogen; (3)-NO ₂(4)-CN; (5)-C _1-6Alkyl, it is randomly replaced by 1-5 halogen, and randomly also by 1-2 be independently selected from-OH ,-CF ₃,-C (=O) C ₁-C ₃Alkyl and randomly by 1-3 halogen replace-OC ₁-C ₃The substituting group of alkyl replaces; (6)-OC _1-6Alkyl, it is randomly replaced by 1-5 halogen, and randomly is independently selected from-CF by 1-2 ₃With-C (=O) C ₁-C ₃The group of alkyl replaces; (7)-C (=O) C ₁-C ₃Alkyl, it is randomly replaced by 1-5 halogen, and randomly is independently selected from-CF by 1-2 ₃Group replace; (8) C ₃-C ₇Cycloalkyl; (9) phenyl; (10) heterocycle, wherein C ₃-C ₇Cycloalkyl, phenyl and heterocycle separately randomly by 1-3 be independently selected from halogen ,-OH ,-OC _1-3Alkyl, CF ₃With-C (=O) C ₁-C ₃The substituting group of alkyl replaces.

3. the compound of claim 1 or its pharmacy acceptable salt, wherein R ¹, R ², R ³And R ⁴Be selected from H, F, Br, Cl, CH independently of one another ₃, CF ₃,-CH ₂OH ,-CH (OH) CH ₃,-C (=O) H ,-C (=O) OH ,-C (=O) CH ₃,-CH ₂CH ₃,-CH ₂CF ₃, cyclopropyl ,-CN ,-OCH ₃,-OCF ₃,-NO ₂, CH (CH ₃) ₂, n-C ₃H ₇, n-C ₅H ₁₁,-C ₂F ₅,-CHFCH ₃,-CHFCF ₃,-CF ₂CH ₃,-CHF ₂,-CH ₂F ,-OCHF ₂,-OCH ₂F ,-OCH ₂Phenyl ,-C (=O) OCH ₃,-S (O) ₂CH ₃,-C (=O) NH ₂,-CH ₂OC (=O) CH ₃,-NH ₂,-CH ₂NH ₂,-CH ₂N (CH ₃) ₂,-CH ₂NHC (=O) OC (CH ₃) ₃,-CH ₂(1-pyrrolidyl) and-C (=O) (3,3-two fluoro-1-azetidinyls).

4. the compound of claim 3 or its pharmacy acceptable salt, wherein R ¹, R ², R ³And R ⁴Be selected from H, F, Br, Cl, CH independently of one another ₃, CF ₃,-CH ₂OH ,-CH (OH) CH ₃,-C (=O) H ,-C (=O) OH ,-C (=O) CH ₃,-CH ₂CH ₃,-CH ₂CF ₃, cyclopropyl ,-CN ,-OCH ₃,-OCF ₃With-NO ₂

5. the compound of claim 1 or its pharmacy acceptable salt, wherein R ¹And R ²Connect by 4-carbochain-CH=CH-CH=CH-, thereby at R ¹And R ²The position forms the condensed phenyl, wherein said condensed phenyl randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace.

6. the compound of claim 1 or its pharmacy acceptable salt, wherein Z is-CH ₂-and W be selected from-CH ₂-,-CF ₂-,-CH ₂CH ₂-,-O-and-S-.

7. the compound of claim 1 or its pharmacy acceptable salt, wherein A be-CH-or-N-;

B is selected from-S-,-O-,-NH-and-CH ₂-; And

D is-C (=O)-.

8. the compound of claim 1 or its pharmacy acceptable salt, wherein R ¹And R ²By being selected from-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-,-CH ₂CH ₂O-,-OCH ₂CH ₂-,-CH ₂CH ₂S-,-SCH ₂CH ₂-,-CH ₂CH ₂C (=O)-and-C (=O) CH ₂CH ₂Divalence bridge joint group connect, at R ¹And R ²The position forms 5-or 6-unit fused rings, wherein at R ¹And R ²The described fused rings of position randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace.

9. claim 1 compound of formula Ia, perhaps its pharmacy acceptable salt, wherein

R ¹, R ², R ³And R ⁴Be selected from H, F, Br, Cl, CH independently of one another ₃, CF ₃,-CH ₂OH ,-CH (OH) CH ₃,-C (O) H ,-C (=O) OH ,-C (=O) CH ₃,-CH ₂CH ₃,-CH ₂CF ₃, cyclopropyl ,-CN ,-OCH ₃,-OCF ₃,-NO ₂, CH (CH ₃) ₂, n-C ₃H ₇, n-C ₅H ₁₁,-C ₂F ₅,-CHFCH ₃,-CHFCF ₃,-CF ₂CH ₃,-CHF ₂,-CH ₂F ,-OCHF ₂,-OCH ₂F ,-OCH ₂Phenyl ,-C (=O) OCH ₃,-S (O) ₂CH ₃,-C (=O) NH ₂,-CH ₂OC (=O) CH ₃,-NH ₂,-CH ₂NH ₂,-CH ₂N (CH ₃) ₂,-CH ₂NHC (=O) OC (CH ₃) ₃,-CH ₂(l-pyrrolidyl) and-C (=O) (3,3-two fluoro-1-azetidinyls);

Perhaps alternatively, R ¹And R ²By be selected from-CH=CH-CH=CH-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂C (=O) and-C (=O) CH ₂CH ₂-3-or 4-carbochain connect, thereby at R ¹And R ²The position forms condensed phenyl, cyclopentyl or pimelinketone ring, wherein said condensed phenyl, cyclopentyl and cyclopentanone ring randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace;

Y is selected from=CH-and=N-;

W is selected from-CH ₂-,-CF ₂-,-CH ₂CH ₂-,-O-and-S-;

A is-CH-or-N-; With

B is selected from-S-,-O-,-NH-and-CH ₂-.

10. claim 9 compound of formula Ia or its pharmacy acceptable salt, wherein

R ¹Be selected from H, F, Br, Cl, CH ₃, CF ₃With-CH ₂CH ₃

R ²Be selected from H, CH ₃, CF ₃,-CH ₂CH ₃With-OCF ₃

Perhaps R alternatively ¹And R ²Connect by 4-carbochain-CH=CH-CH=CH-, thereby at R ¹And R ²The position forms the fused phenyl ring;

R ³Be selected from H, Cl, CH ₃, CF ₃,-CN and-NO ₂

R ⁴For H or-CH ₃

Y is selected from=CH-and=N-;

W is selected from-CH ₂-,-CH ₂CH ₂-and-S-;

A is-CH-or-N-; And

B is selected from-S-,-O-and-CH ₂-.

11. the claim 1 of formula Ib compound or its pharmacy acceptable salt,

R wherein ¹, R ², R ³, R ⁴, Y, W, Z, A and B as defined in claim 1.

12. the claim 11 of formula Ib compound or its pharmacy acceptable salt, wherein

R ¹, R ², R ³And R ⁴Be selected from H, F, Br, Cl, CH independently of one another ₃, CF ₃,-CH ₂OH ,-CH (OH) CH ₃,-C (=O) H ,-C (=O) OH ,-C (=O) CH ₃,-CH ₂CH ₃,-CH ₂CF ₃, cyclopropyl ,-CN ,-OCH ₃,-OCF ₃,-NO ₂, CH (CH ₃) ₂, n-C ₃H ₇, n-C ₅H ₁₁,-C ₂F ₅,-CHFCH ₃,-CHFCF ₃,-CF ₂CH ₃,-CHF ₂,-CH ₂F ,-OCHF ₂,-OCH ₂F ,-OCH ₂Phenyl ,-C (=O) OCH ₃,-S (O) ₂CH ₃,-C (=O) NH ₂,-CH ₂OC (=O) CH ₃,-NH ₂,-CH ₂NH ₂,-CH ₂N (CH ₃) ₂,-CH ₂NHC (=O) OC (CH ₃) ₃,-CH ₂(1-pyrrolidyl) and-C (=O) (3,3-two fluoro-l-azetidinyls);

Perhaps alternatively, R ¹And R ²By be selected from-CH=CH-CH=CH-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂C (=O) and-C (=O) CH ₂CH ₂-3-or 4-carbochain connect, thereby at R ¹And R ²The position forms condensed phenyl, cyclopentyl or pimelinketone ring, wherein said condensed phenyl, cyclopentyl and cyclopentanone ring randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace;

Y is selected from=CH-and=N-;

W is selected from-CH ₂-,-CF ₂-,-CH ₂CH ₂-,-O-and-S-;

Z is-CH ₂-;

A is-CH-or-N-; And

B is selected from-S-,-O-,-NH-and-CH ₂-.

13. the claim 1 of formula I compound or its pharmacy acceptable salt, wherein

R ¹, R ², R ³And R ⁴Be selected from H, F, Br, Cl, CH independently of one another ₃, CF ₃,-CH ₂OH ,-CH (OH) CH ₃,-C (=O) H ,-C (=O) OH ,-C (=O) CH ₃,-CH ₂CH ₃,-CH ₂CF ₃, cyclopropyl ,-CN ,-OCH ₃,-OCF ₃,-NO ₂, CH (CH ₃) ₂, n-C ₃H ₇, n-C ₅H ₁₁,-C ₂F ₅,-CHFCH ₃,-CHFCF ₃,-CF ₂CH ₃,-CHF ₂,-CH ₂F ,-OCHF ₂,-OCH ₂F ,-OCH ₂Phenyl ,-C (=O) OCH ₃,-S (O) ₂CH ₃,-C (=O) NH ₂,-CH ₂OC (=O) CH ₃,-NH ₂,-CH ₂NH ₂,-CH ₂N (CH ₃) ₂,-CH ₂NHC (=O) OC (CH ₃) ₃,-CH ₂(l-pyrrolidyl) and-C (=O) (3,3-two fluoro-1-azetidinyls);

Perhaps alternatively, R ¹And R ²By be selected from-CH=CH-CH=CH-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂C (=O) and-C (=O) CH ₂CH ₂-3-or 4-carbochain connect, thereby at R ¹And R ²The position forms condensed phenyl, cyclopentyl or pimelinketone ring, wherein said condensed phenyl, cyclopentyl and cyclopentanone ring randomly by 1-3 be independently selected from halogen ,-OH ,-CN ,-NO ₂,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-SC ₁-C ₃Alkyl ,-S (O) ₂C ₁-C ₃Alkyl ,-CF ₃With-OCF ₃Substituting group replace;

Y is selected from=CH-and=N-;

W is selected from-O-,-S-and CH ₂

Z is selected from-CH ₂-and-CH ₂CH ₂-;

A is-CH-or-N-;

B is selected from-S-,-O-and-CH ₂-; And

D is-C (=O).

14. the compound of the claim 13 of formula Ic or its pharmacy acceptable salt, wherein

W is selected from-O-and-S-.

15. the claim 14 of formula Id compound or its pharmacy acceptable salt, wherein

R ¹, R ², R ³And R ⁴Be selected from H, F, Br, Cl, CH independently of one another ₃, CF ₃,-CH ₂OH ,-CH (OH) CH ₃,-C (=O) H ,-C (=O) OH ,-C (=O) CH ₃,-CH ₂CH ₃,-CH ₂CF ₃, cyclopropyl ,-CN ,-OCH ₃,-OCF ₃,-NO ₂, CH (CH ₃) ₂, n-C ₃H ₇, n-C ₅H ₁₁,-C ₂F ₅,-CHFCH ₃,-CHFCF ₃,-CF ₂CH ₃,-CHF ₂,-CH ₂F ,-OCHF ₂,-OCH ₂F ,-OCH ₂Phenyl ,-C (=O) OCH ₃,-S (O) ₂CH ₃,-C (=O) NH ₂,-CH ₂OC (=O) CH ₃,-NH ₂,-CH ₂NH ₂,-CH ₂N (CH ₃) ₂,-CH ₂NHC (=O) OC (CH ₃) ₃,-CH ₂(l-pyrrolidyl) and-C (=O) (3,3-two fluoro-1-azetidinyls);

Perhaps alternatively, R ¹And R ²By be selected from-CH=CH-CH=CH-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂C (=O) and-C (=O) CH ₂CH ₂-3-or 4-carbochain connect, thereby at R ¹And R ²The position forms fused phenyl, cyclopentyl or pimelinketone ring; And

B is selected from-S-and-O-.

16. the compound of claim 13 is selected from following compound or its pharmacy acceptable salt:

17. the compound of claim 13 is selected from following (a) and (b) compound or its pharmacy acceptable salt, wherein

(a) for being selected from the compound that compound number is 42-48 with following formula:

The substituent R of compound 42-48 wherein ¹, R ², R ³And R ⁴For:

R1 R2 R3 R4

42 H H H H

43 H Et H H

44 C1 H F H

45 H Me F H

46 Me H F H

47 Et H CN H

48 Me H CF3 H

And (b) for being selected from the compound with following formula that compound number is 49-51:

The substituent R of compound 49-51 wherein ¹, R ², R ³, R ⁴And R ⁵For:

R1 R2 R3 R4 R5

49 Me H CN H H

50 C1 H CF ₃ H H

51 F H CN H H

。

18. the compound of claim 13 is selected from following compounds or its pharmacy acceptable salt:

19. a pharmaceutical composition comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.

20. the compound of claim 1 or its pharmacy acceptable salt are used to make the purposes of the medicine for the treatment of diabetes B.

21. the method for a treatment diabetes B in the patient of needs treatment comprises formula I compound or its pharmacy acceptable salt to described patient's drug treatment significant quantity.

22. a pharmaceutical composition comprises

(1) compound of claim 1 or its pharmacy acceptable salt;

(2) one or more are selected from following compound:

(a) PPAR gamma agonist and partial agonist;

(b) biguanides;

(c) Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor;

(d) DPP IV (DP-IV) inhibitor;

(e) Regular Insulin or insulin-simulated dose;

(f) sulfonylurea;

(g) alpha-glucosidase inhibitor;

(h) improve the reagent of patient's lipid profile, described reagent is selected from (i) HMG-CoA reductase inhibitor, (ii) bile acid multivalent chelator, (iii) nicotinic alcohol, nicotinic acid or its salt, (iv) PPAR alfa agonists, (v) cholesterol absorption inhibitor, (h) acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, (i) CETP inhibitor and (j) phenol antioxidant;

(i) PPAR α/γ binary agonist,

(j) PPAR delta agonists,

(k) the sick compound of anti-obesity,

(l) ileal bile acid transfer protein inhibitor;

(m) antiphlogistic drug;

(n) glucagon receptor antagonist;

(o)GLP-1；

(p)GIP-1；

(q) GLP-1 analogue; With

(r) HSD-1 inhibitor; And

(3) pharmaceutically acceptable carrier.