Modulators of peroxisome proliferator activated receptors(ppar)

专利摘要:
The present invention provides a compound of formula (I) useful for treating syndrome X, type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagulopathy, hypertension, atherosclerosis and other diseases associated with syndrome X and cardiovascular diseases and pharmaceutically acceptable thereof It relates to salts, solvates, hydrates or stereoisomers.
公开号:KR20040030658A
申请号:KR10-2003-7016048
申请日:2002-05-24
公开日:2004-04-09
发明作者:린 스타시 고세트；조나단 에드워드 그린；제임스 로버트 헨리；윈톤 데니스 주니어 존스；도날드 폴 매튜；쾅 롱 센；다릴 린 스미스；제니퍼 앤 반체；알랜 엠. 와샤우스키；마리아로사리오 곤잘레즈-가르시아
申请人:일라이 릴리 앤드 캄파니；
IPC主号:

专利说明:

MODULATORS OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS (PPAR)}
[2] Peroxysome proliferative activating receptors (PPARs) are members of the nuclear receptor gene family that is activated by fatty acids and fatty acid metabolites. PPARs belong to a subset of nuclear receptors that function as heterodimers with the 9-cis retinic acid receptor (RXR). Three subtypes, designated PPARα, PPARγ and PPARδ, are found in Xenopus, a species that spans humans.
[3] PPARα is a major subtype in the liver and has facilitated the analysis of the mechanism by which peroxysomal proliferatives exert pleiotropic effects. PPARα is activated by a variety of mediators and long chain fatty acids and is associated with stimulating beta oxidation of fatty acids. PPARα is also associated with the activity of fibrates and fatty acids in rodents and humans. Fibric acid derivatives, such as clofibrate, fenofibrate, bezafibrate, cipropibrate, beclofibrate, etofibrate and gemfibrozil, have been shown to reduce plasma triglycerides with moderate reduction of low density lipoprotein (LDL) cholesterol. Produces a substantial reduction and is particularly used for the treatment of hypertriglyceridemia.
[4] PPARγ is a major subtype in adipose tissue and is involved in activating the program of adipocyte differentiation. PPARγ is not associated with stimulating peroxysome proliferation in the liver. There are two isomers of PPARγ, PPARγ1 and PPARγ2: they differ only in that PPARγ2 further contains 28 amino acids at the amino terminus. DNA sequences for PPARγ receptors are described in Elbrecht et al. BBRC 224; 431-437 (1996). Although peroxysomal proliferation agents, including fibrates and fatty acids, activate the transcriptional activity of PPARs, only prostaglandin J ₂ derivatives have been identified as natural ligands for PPARγ and also have a high affinity with the antidiabetic thiazolidinedione. To combine. The physiological functions of PPARα and PPARγ in lipid and carbohydrate metabolism have been elucidated as the respective receptors for fibrate and glitazone drugs have been approved.
[5] PPARα and PPARγ receptors are associated with diabetes, cardiovascular disease, obesity, and diseases associated with gastrointestinal diseases such as inflammatory bowel disease and other inflammations. Diseases associated with such inflammation include, but are not limited to, Alzheimer's disease, Crohn's disease, rheumatoid arthritis, psoriasis, and ischemic reprofusion damage.
[6] In contrast, PPARδ (also referred to as PPARβ and NUC1) is not recorded as a receptor of any known medical molecule class, and its role in mammalian physiology remains undefined. Human nuclear receptor gene PPARδ (hPPARδ) has been cloned from human osteosarcoma cell cDNA library and described in A. Schmidt et al., Molecular Endocrinology, 6: 1634-1641 (1992).
[7] Diabetes is a disease in which the mammal's ability to control glucose levels in the blood is compromised because the mammal's ability to convert glucose to glycogen for storage in muscle and liver cells is reduced. In type I diabetes, the decrease in the ability to store glucose is due to reduced insulin production. "Type II diabetes" or "non-insulin dependent diabetes mellitus" (NIDDM) is a form of diabetes due to severe resistance to insulin stimulation or regulatory effects on glucose and lipid metabolism in major insulin sensitive tissues, muscle, liver and adipose tissue. to be. Resistance to these insulin responses leads to insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin inhibition of lipolysis in adipose tissue and glucose production and secretion in the liver. When these cells are less sensitive to insulin, the body tries to make up by producing an abnormally high amount of insulin, resulting in hyperinsulinemia. Hyperinsulinemia is associated with hypertension and weight gain. Since insulin is associated with promoting the uptake of glucose, amino acids and triglycerides from the blood by insulin sensitive cells, the amount of triglycerides and LDL (known as "bad" cholesterol), which are risk factors for cardiovascular disease due to insensitivity to insulin, May cause an increase. The collection of symptoms including hypertension, weight gain, elevated triglycerides and hyperinsulinemia combined with elevated LDL is known as syndrome X.
[8] Hyperlipidemia is a condition characterized by an abnormal increase in serum lipids such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma but are bound to proteins and transported as macromolecular complexes called lipoproteins. One form of hyperlipidemia is hypercholesterolemia, characterized by the presence of elevated amounts of LDL cholesterol. The first treatment of hypercholesterolemia is often eating less fat and cholesterol with proper physical exercise. Drug intervention is initiated when the LDL-reducing goal is not met by meals and exercise alone. It is desirable to reduce the elevated amount of LDL cholesterol and increase the amount of HDL cholesterol. In general, an increase in the amount of HDL is known to be associated with a reduced risk of coronary heart disease (CHD). Gordon, et al., Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. Engl and J. Med., 325, 373-381 (1991); And Kannel, et al., Ann. Internal Med., 90, 85-91 (1979). An example of an HDL enhancer is nicotinic acid, but the amount needed to achieve HDL elevation is associated with undesirable effects such as flushing.
[9] There are several treatments now available for treating diabetes, but these treatments are still unsatisfactory and limited. Physical exercise and a reduction in dietary intake of calories may improve diabetes symptoms, while it may be difficult to follow this method because of a sedentary lifestyle and excessive food consumption, especially high fat-containing foods. Thus, treatment of hypoglycemia, such as sulfonylureas (e.g. chlorpropamide, tolbutamide, tolazamide and acetohexamide) and biguanides (e.g. phenformin and metformin), are involved in the progression of the disease. Is often needed. As the disease progresses, sulfonylureas stimulate β cells in the pancreas to secrete more insulin. However, the β cell response eventually fails and requires insulin infusion treatment. In addition, sulfonylurea treatment and insulin infusion have the side effects of life-threatening hypoglycemic coma, so patients using these treatments must be carefully adjusted to dosages.
[10] It is well established that improved glycemic control in patients with diabetes (Type I and Type II) involves microvascular reduction complications (DCCT and UKPDS). Because of the difficulty in maintaining adequate glycemic control over time in patients with type II diabetes, the use of insulin sensitizers is increasing in the treatment of type II diabetes. In addition, there is increasing evidence that PPARγ agonists, insulin sensitizers, may have benefits in the treatment of type II diabetes beyond the effects of improving blood sugar control.
[11] In recent decades, a class of compounds known as thiazolidinediones (e.g. US Pat. Nos. 5,089,514; 4,342,771; 4,367,234; 4,340,605; and 5,306,726) have increased insulin sensitivity in insulin sensitive tissues such as skeletal muscle, liver and adipose tissue. It has been shown to be an effective diabetic that seems to cause. Increasing insulin sensitivity rather than increasing the amount of insulin in the blood reduces the likelihood of hypoglycemic coma. Although thiazolidinedione has been shown to increase insulin sensitivity by binding to PPARγ receptors, this treatment also results in unwanted side effects such as weight gain and hepatotoxicity for troglitazone.
[12] In view of the above, there is a need for new pharmaceutical formulations that modulate these receptors to ameliorate the side effects of current treatments while suppressing, treating and / or alleviating the disease or condition.
[1] The present invention relates to compounds of PPAR agonists useful for the treatment and / or prevention of diseases regulated by peroxysome proliferative activator receptors (PPARs).
[13] Summary of the Invention
[14] The present invention relates to compounds of the novel peroxysomal proliferator activated receptor agonists of formula (I) and pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof.
[15]
[16] Where
[17] n ¹ is 2, 3, 4 or 5;
[18] V is a bond or O;
[19] X is CH ₂ or O;
[20] p is 0 or 1;
[21] m is 1 to 4;
[22] Y ¹ is ego;
[23] Is aryl or heteroaryl;
[24] Said aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, haloalkyl and haloalkyloxy;
[25] Y ^1a is hydrogen, (C ₀ -C ₃ ) alkyl-aryl, C (O) -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, NR ⁵ (CH ₂ ) _m OR ⁵ , aryl-Z- Aryl, aryl-Z-heteroaryl, aryl-Z-cycloalkyl, aryl-Z-heterocycloalkyl, heteroaryl-Z-aryl, heteroaryl-Z-heterocycloalkyl or heterocycloalkyl-Z-aryl,
[26] Said aryl, cycloalkyl, aryloxy, heteroaryl and heterocycloalkyl are C ₁ -C ₆ alkoxy optionally substituted with halo, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, N (R ⁵ ) ₂ , Haloalkyl, N (R ⁵ ) ₂ , N [C (O) R ⁵ ] ₂ , N [S (O) ₂ R ⁵ ] ₂ , NR ⁵ S (O) ₂ R ⁵ , NR ⁵ C (O) R Optionally with one or more substituents independently selected from the group consisting of ⁵ , NR ⁵ C (O) OR ⁵ , C (O) N (R ⁵ ) ₂ , C (O) OR ⁵ and C (O) R ⁵ Substituted;
[27] Z is a bond, -O-, -C (O) NR ^5- , -NR ⁵ C (O)-, -NR ⁵ C (O) 0-, -C (O)-, -NR ⁵ -,-[ O] _p (CH ₂ ) _m -,-(CH ₂ ) _m [O] _p- , -NR ⁵ (CH ₂ ) _m -or-(CH ₂ ) _m NR ^5- ;
[28] Y ² and Y ³ are each independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
[29] Y ⁴ is (C ₁ -C ₃ ) alkyl-NR ⁵ C (O)-(C ₀ -C ₅ ) alkyl-Y ⁷ ,
[30] (C ₁ -C ₃₎ alkyl, ^{-NR 5 C (O) - (} C 2 -C 5) alkenyl, -Y ^7,
[31] (C ₁ -C ₃ ) alkyl-NR ⁵ C (O)-(C ₂ -C ₅ ) alkynyl-Y ⁷ ;
[32] (C ₁ -C ₃ ) alkyl-NR ⁵ C (O) O— (C ₀ -C ₅ ) alkyl-Y ⁷ ,
[33] (C ₁ -C ₃₎ alkyl, ^{-NR 5 C (O) NR 5} - (C 0 -C 5) alkyl, -Y ^7,
[34] (C ₁ -C ₃₎ alkyl, ^{-NR 5 C (S) NR 5} - (C 0 -C 5) alkyl, -Y ^7,
[35] (C ₀ -C ₃ ) alkyl-C (O) NR ^5- (C ₀ -C ₅ ) alkyl-Y ⁷ ,
[36] (C ₁ -C ₃₎ alkyl, ^{-OC (O) NY 10 Y 11} ,
[37] (C ₁ -C ₃ ) alkyl-NY ¹⁰ Y ¹¹ ,
[38] (C ₁ -C ₃ ) alkyl-O- (C ₀ -C ₅ ) alkyl-Y ⁷ ,
[39] (C ₁ -C ₃ ) alkyl-S- (C ₀ -C ₅ ) alkyl-Y ⁷ or
[40] CN;
[41] Y ⁷ is hydrogen, aryl, heteroaryl, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, cycloalkyl, heterocycloalkyl, aryloxy, C (O) -heteroaryl or SR ⁶ ,
[42] Said alkyl, aryl, aryloxy, alkoxy, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from R ⁷ ;
[43] Y ¹⁰ and Y ¹¹ are each independently hydrogen, aryl, heteroaryl, C ₁ -C ₁₀ alkyl, cycloalkyl, SO ₂ (R ⁶ ); or
[44] Y ¹⁰ and Y ¹¹ together form a heterocycloalkyl ring conjugated with a 5-10 membered heterocycloalkyl ring or aryl, said heterocycloalkyl ring optionally comprising one or more heteroatoms selected from N, O or S and; Said aryl, heteroaryl, heterocycloalkyl and alkyl are optionally substituted with one or more substituents independently selected from R ⁷ ;
[45] R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
[46] R ⁶ is hydrogen, C ₁ -C ₁₀ alkyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from R ⁷ ;
[47] R ⁷ is halo, nitro, oxo, cyano, hydroxyl, benzyl, phenyl, phenoxy, heteroaryl, C (O) R ⁶ , C ₁ -C ₁₀ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyloxy, O (CH ₂ ) _m -phenyl, (CH ₂ ) _m OC (O) -aryl, C (O) OR ⁵ , S (O) ₂ R ⁵ , S (O) ₂ N (R ⁵ ) ₂ , SR ⁵ or N (R ⁵ ) ₂ ;
[48] The phenyl and phenoxy are optionally substituted with one or more groups independently selected from halo or trifluoromethyl.
[49] Compounds of the invention include hyperglycemia, dyslipidemia, type II diabetes, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, obesity, anorexia nervosa, It is useful for the treatment or prevention of diseases or conditions associated with anorexia nervosa, cardiovascular disease and other diseases in which insulin resistance is a factor.
[50] In one embodiment the invention also relates to a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate and pharmaceutically acceptable carrier thereof. Also included within the scope of the present invention are pharmaceutical compositions comprising an additional therapeutic agent together with one or more compounds of the present invention or pharmaceutically acceptable salts, solvates, hydrates and pharmaceutically acceptable carriers thereof.
[51] In another embodiment, the present invention relates to a method of modulating a peroxysomal proliferator activating receptor to contact a receptor with at least one compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof.
[52] Detailed Description of the Invention
[53] Compounds of the present invention are directed to peroxysomal proliferator activated receptor (PPAR) agonists useful for the treatment and / or prevention of diseases controlled by PPAR.
[54] One embodiment of the invention is a compound of Formula I and pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof:
[55] <Formula I>
[56]
[57] Where
[58] n ¹ is 2, 3, 4 or 5;
[59] V is a bond or O;
[60] X is CH ₂ or O;
[61] p is 0 or 1;
[62] m is 1 to 4;
[63] Y ¹ is ego,
[64] remind Is aryl or heteroaryl,
[65] Said aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, haloalkyl and haloalkyloxy;
[66] Y ^1a is hydrogen, (C ₀ -C ₃ ) alkyl-aryl, C (O) -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, NR ⁵ (CH ₂ ) _m OR ⁵ , aryl-Z- Aryl, aryl-Z-heteroaryl, aryl-Z-cycloalkyl, aryl-Z-heterocycloalkyl, heteroaryl-Z-aryl, heteroaryl-Z-heterocycloalkyl or heterocycloalkyl-Z-aryl,
[67] Said aryl, cycloalkyl, aryloxy, heteroaryl and heterocycloalkyl are C ₁ -C ₆ alkoxy optionally substituted with halo, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, N (R ⁵ ) ₂ , Haloalkyl, N (R ⁵ ) ₂ , N [C (O) R ⁵ ] ₂ , N [S (O) ₂ R ⁵ ] ₂ , NR ⁵ S (O) ₂ R ⁵ , NR ⁵ C (O) R Optionally with one or more substituents independently selected from the group consisting of ⁵ , NR ⁵ C (O) OR ⁵ , C (O) N (R ⁵ ) ₂ , C (O) OR ⁵ and C (O) R ⁵ Substituted;
[68] Z is a bond, -O-, -C (O) NR ^5- , -NR ⁵ C (O)-, -NR ⁵ C (O) O-, -C (O)-, -NR ⁵ -,-[ O] _p (CH ₂ ) _m -,-(CH ₂ ) _m [O] _p- , -NR ⁵ (CH ₂ ) _m -or-(CH ₂ ) _m NR ^5- ;
[69] Y ² and Y ³ are each independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
[70] Y ⁴ is (C ₁ -C ₃ ) alkyl-NR ⁵ C (O)-(C ₀ -C ₅ ) alkyl-Y ⁷ ,
[71] (C ₁ -C ₃₎ alkyl, ^{-NR 5 C (O) - (} C 2 -C 5) alkenyl, -Y ^7,
[72] (C ₁ -C ₃ ) alkyl-NR ⁵ C (O)-(C ₂ -C ₅ ) alkynyl-Y ⁷ ;
[73] (C ₁ -C ₃ ) alkyl-NR ⁵ C (O) O— (C ₀ -C ₅ ) alkyl-Y ⁷ ,
[74] (C ₁ -C ₃₎ alkyl, ^{-NR 5 C (O) NR 5} - (C 0 -C 5) alkyl, -Y ^7,
[75] (C ₁ -C ₃₎ alkyl, ^{-NR 5 C (S) NR 5} - (C 0 -C 5) alkyl, -Y ^7,
[76] (C ₀ -C ₃ ) alkyl-C (O) NR ^5- (C ₀ -C ₅ ) alkyl-Y ⁷ ,
[77] (C ₁ -C ₃₎ alkyl, ^{-OC (O) NY 10 Y 11} ,
[78] (C ₁ -C ₃ ) alkyl-NY ¹⁰ Y ¹¹ ,
[79] (C ₁ -C ₃ ) alkyl-O- (C ₀ -C ₅ ) alkyl-Y ⁷ ,
[80] (C ₁ -C ₃ ) alkyl-S- (C ₀ -C ₅ ) alkyl-Y ⁷ or
[81] CN;
[82] Y ⁷ is hydrogen, aryl, heteroaryl, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, cycloalkyl, heterocycloalkyl, aryloxy, C (O) -heteroaryl or SR ⁶ ,
[83] The alkyl, aryl, aryloxy, alkoxy, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from R ⁷ ;
[84] Y ¹⁰ and Y ¹¹ are each independently hydrogen, aryl, heteroaryl, C ₁ -C ₁₀ alkyl, cycloalkyl, SO ₂ (R ⁶ ); or
[85] Y ¹⁰ and Y ¹¹ together form a heterocycloalkyl ring conjugated with a 5-10 membered heterocycloalkyl ring or aryl, said heterocycloalkyl ring optionally comprising one or more heteroatoms selected from N, O or S and; Said aryl, heteroaryl, heterocycloalkyl and alkyl are optionally substituted with one or more substituents independently selected from R ⁷ ;
[86] R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
[87] R ⁶ is hydrogen, C ₁ -C ₁₀ alkyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from R ⁷ ;
[88] R ⁷ is halo, nitro, oxo, cyano, hydroxyl, benzyl, phenyl, phenoxy, heteroaryl, C (O) R ⁶ , C ₁ -C ₁₀ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyloxy, O (CH ₂ ) _m phenyl, (CH ₂ ) _m OC (O) -aryl, C (O) OR ⁵ , S (O) ₂ R ⁵ , S ( O) ₂ N (R ⁵ ) ₂ , SR ⁵ or N (R ⁵ ) ₂ ;
[89] The phenyl and phenoxy are optionally substituted with one or more groups independently selected from halo or trifluoromethyl.
[90] Embodiments of the present invention include a compound of formula la or a pharmaceutically acceptable salt, hydrate or solvate thereof:
[91] <Formula Ia>
[92]
[93] Y ¹ consists of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-C ₁ -C ₄ alkyl, heteroaryl-C ₁ -C ₄ alkyl, cycloalkyl-C ₁ -C ₄ alkyl and t-butyl An unsubstituted or substituted group selected from the group;
[94] Y ² is selected from the group consisting of H, C ₁ -C ₁₀ alkyl, cycloalkyl, (C ₁ -C ₁₀ alkyl) -Y ⁵ , OY ⁶ ;
[95] Y ⁵ is selected from the group consisting of aryl, substituted aryl group, -COR ⁴ , -COOR ⁴ , -CONR ⁶ R ⁷ , -CSR ⁴ and -C (S) NR ⁶ R ⁷ ;
[96] Y ⁶ is selected from the group consisting of aliphatic groups, substituted aliphatic groups, aryl, substituted aryl groups, -COR ⁴ , -COOR ⁴ , -CONR ⁶ R ⁷ , -CSR ⁴ and -C (S) NR ⁶ R ⁷ Selected;
[97] R ⁴ , R ⁶ and R ⁷ are each independently selected from the group consisting of H, aliphatic group, substituted aliphatic group, aryl group and substituted aryl group;
[98] Y ³ is selected from the group consisting of H, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and (C ₁ -C ₁₀ alkyl) -R ⁸ ; R ⁸ is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
[99] R ⁵ is selected from the group consisting of H, aliphatic group, substituted aliphatic group, heteroaryl, substituted heteroaryl, aryl, substituted aryl and (C ₁ -C ₁₀ alkyl) -R ⁹ ;
[100] R ⁹ is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl, aminoalkyl and cycloalkyl;
[101] V is a bond or O;
[102] X is CH ₂ or O;
[103] Y ⁴ is — (C ₁ -C ₃ ) alkyl-OWY ⁷ , -C (O) NY ⁸ Y ⁹ ,-(C ₁ -C ₃ ) alkyl-NY ¹⁰ Y ¹¹ and-(C ₁ -C ₃ ) alkyl N (Y ¹³ ) W- (C ₀ -C ₅ ) alkyl-Y ¹⁴ ;
[104] W is from the group consisting of a bond, -CONY ¹² , -C (O)-, -OCH _2- , C ₁ -C ₆ alkyl, -CO _2- , -CHOY ^15- , -CSNY ¹⁶ and -SO _2- Selected;
[105] Y ⁷ is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic, branched aliphatic and substituted (C ₁ -C ₁₀ ) alkyl;
[106] Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ are each independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic, branched aliphatic and Selected from the group consisting of substituted (C ₁ -C ₁₀ ) alkyl;
[107] n ¹ is 2, 3, 4 or 5.
[108] Substituent Y ¹ of the compound of formula (la) is ^Comprising , Y ^1a and Are as defined above in formula (I) and the group being substituted is as defined in the embodiments and includes the substituents mentioned above.
[109] Y ^1a of the compound of the present invention as described above is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy,
[110]
[111] It is selected from the group consisting of.
[112] Preferred embodiments of the invention are compounds of the formula:
[113]
[114] Wherein E is O or S.
[115] Another preferred embodiment of the invention is a compound of the formula:
[116]
[117] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[118] Another preferred embodiment of the invention is a compound of the formula:
[119]
[120] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[121] Another preferred embodiment of the invention is a compound of the formula:
[122]
[123] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[124] Another preferred embodiment of the invention is a compound of the formula:
[125]
[126] Wherein q is 0 or 1; Each R ⁵ is independently hydrogen or methyl.
[127] Another preferred embodiment of the invention is a compound of the formula:
[128]
[129] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[130] Another preferred embodiment of the invention is a compound of the formula:
[131]
[132] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[133] Another preferred embodiment of the invention is a compound of the formula:
[134]
[135] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[136] Another preferred embodiment of the invention is a compound of the formula:
[137]
[138] Wherein q is 1 or 2; Each R ⁵ , Y ² and Y ³ is independently hydrogen or methyl.
[139] Another preferred embodiment of the invention is a compound of the formula:
[140]
[141] Wherein Y ^1a is optionally substituted phenyl, naphthyl,
[142] ego,
[143] Z is a bond, oxygen, -NH-, -N (CH ₃ )-, -NHC (O)-, or -C (O) NH-.
[144] Another preferred embodiment of the invention is a compound of the formula:
[145]
[146] Wherein Y ^1a is optionally substituted phenyl, naphthyl or ego,
[147] Z is a bond, oxygen, -NH-, -N (CH ₃ )-, -NHC (O)-, or -C (O) NH-.
[148] Another preferred embodiment of the invention is a compound of the formula:
[149]
[150] Wherein Y ^1a is optionally substituted aryl, heteroaryl, heterocycloalkyl, heteroaryl-Z-heterocycloalkyl or heteroaryl-Z-aryl.
[151] Another preferred embodiment of the invention is a compound of the formula:
[152]
[153] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[154] Another preferred embodiment of the invention is a compound of the formula:
[155]
[156] Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[157] Another preferred embodiment of the invention is a compound of the formula:
[158]
[159] Wherein Y ^1a is hydrogen, aryl, heteroaryl or aryloxy; q is 1 or 2; n ¹ is 2, 3 or 4.
[160] Another preferred embodiment of the invention is a compound of the formula:
[161]
[162] Wherein Y ^1a is hydrogen, aryl, heteroaryl or aryloxy; q is 1 or 2; n ¹ is 2, 3 or 4.
[163] Preferred compounds are those of the formula:
[164]
[165] Preferred compounds are those of the formula:
[166]
[167] More preferred compounds of the invention are listed in the table below:
[168] compound designation One 3- {2- (diphenylacetyl-aminomethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 2 3- (2-{(2-cyclopropylacetylamino) methyl] -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[169] number compound designation 3 3- {2-[(3-methoxybenzoylamino) methyl] -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 4 3- {2-{[biphenyl-2-carbonyl) amino] methyl} -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 5 3- (4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-{(2,5-dichlorothiophen-3-carbonyl) amino ] Methyl} phenyl) propionic acid 6 3- {2-Isopropoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 7 3- {2- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] Phenyl} propionic acid 8 3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-[(3-phenylureido) methyl] phenyl} propionic acid
[170] number compound designation 9 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid 10 3- {2- (Isopropoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid 11 3- {2- (benzoylaminomethyl) -4- [3- (biphenyl-4-yloxy) propoxy] phenyl} propionic acid 12 3- (4- [3- (biphenyl-4-yloxy) propoxy] -2-{[yridine-2-carbonyl) amino] methyl} phenyl) propionic acid 13 3- (2-benzylcarbamoyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 14 3- {2-benzylcarbamoyl-4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] phenyl} propionic acid 15 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-cyanophenyl} propionic acid
[171] number compound designation 16 3- [4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2- (1,3-dioxo-1,3-dihydroisoindole -2-ylmethyl) phenyl] propionic acid 17 3- {2- (2-Isopropoxycarbonyl-aminoethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 18 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 19 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (3-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 20 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (6-phenylpyridin-3-yl) thiazol-4-yl] ethoxy} phenyl) Propionic acid
[172] number compound designation 21 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (2-isopropoxycarbonylaminoethyl) phenyl] propionic acid 22 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (isobutoxycarbonylaminomethyl) phenyl] propionic acid 23 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (cyclopentyloxycarbonyl-aminomethyl) phenyl] propionic acid 24 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [2- (4-isopropoxyphenyl) -5-methyloxazol-4-yl] ethoxy} phenyl) propionic acid 25 3- (2-benzylcarbamoyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[173] number compound designation 26 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl Propionic acid 27 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-piperidin-1-ylphenyl) oxazol-4-yl] ethoxy} Phenyl) propionic acid 28 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-pyrimidin-2-ylphenyl) oxazol-4-yl] ethoxy} phenyl Propionic acid 29 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-pyrazin-2-ylphenyl) oxazol-4-yl] ethoxy} phenyl) Propionic acid 30 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (6-phenoxypyridin-3-yl) thiazol-4-yl] ethoxy} phenyl Propionic acid 31 3- {2-cyclohexylcarbamoyl-oxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[174] number compound designation 32 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-phenylaminophenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 33 3- (4- {2- [5-methyl-2- (6-phenylpyridin-3-yl) thiazol-4-yl] ethoxy} -2-{[(pyridine-2-carbonyl) amino] Methyl} phenyl) propionic acid HCl salt 34 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-[(3-methylbutyrylamino) methyl] phenyl} propionic acid 35 3- {2- (Isopropoxycarbonyl-aminomethyl) -4- [2- (5-methoxy-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 36 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (6-phenoxypyridin-3-yl) oxazol-4-yl] ethoxy} phenyl Propionic acid 37 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-cyclohexylcarbamoyloxy-methylphenyl} propionic acid
[175] number compound designation 38 3- {2-cyclohexylcarbamoyl-oxymethyl-4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid 39 3- (2-cyclohexylcarbamoyl-oxymethyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 40 3- (2-cyclohexylcarbamoyl-oxymethyl-4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 41 3- [2- (isopropoxycarbonyl-aminomethyl) -4- (2- {5-methyl-2- [3- (tetrahydropyran-4-yloxy) phenyl] oxazol-4-yl} Ethoxy) phenyl] propionic acid 42 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (cyclopropylmethoxycarbonylaminomethyl) phenyl] propionic acid 43 3- {2- (Cyclopropylmethoxy-carbonylaminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid HCl salt
[176] number compound designation 44 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (cyclobutoxycarbonyl-aminomethyl) phenyl] propionic acid HCl salt 45 3- {2- (Cyclobutoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid HCl salt 46 3- [4- {2- [2- (4-butyrylaminophenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid 47 3- {2- (isopropoxycarbonyl-amino-methyl) -4- [2- (5-methyl-2- {4- [yridine-2-carbonyl) -amino] -phenyl} oxazole-4 -Yl) -ethoxy] -phenyl} propionic acid 48 3- [4- {2- [2-biphenyl-4-yl-5-methyloxazol-4-yl] ethoxy] -2-{[yrazine-2-carbonyl) amino] methyl} phenyl] propionic acid 49 3- [4- {2- [2- (3-cyclohexylcarbamoylphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[177] number compound designation 50 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (2-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 51 3- (2-Cyano-4- {2- [5-methyl-2- (4-phenoxy-phenyl) -oxazol-4-yl] -ethoxy} -phenyl) propionic acid 52 3- [2- (isopropoxycarbonyl-aminomethyl) -4- (2- {5-methyl-2- [4- (pyridin-2-yloxy) phenyl] oxazol-4-yl} ethoxy ) Phenyl] propionic acid 53 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid 54 3- (2- (isobutoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid 55 3- [2- (isopropoxycarbonyl-aminomethyl) -4- (2- {5-methyl-2- [4- (pyrimidin-2-yloxy) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid 56 3- [4- [2- (2-biphenyl-4-yl-5-methoxyoxazol-4-yl) ethoxy] -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[178] number compound designation 57 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-{[(pyridine-2-carbonyl) -amino] -methyl} -phenyl) Propionic acid 58 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(2,4,5-trifluoro-benzoylamino) -methyl]- Phenyl} -propionic acid 59 3- {2-[(2,4-Difluoro-benzoylamino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} Propionic acid 60 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy-2-{[(thiophen-2-carbonyl) -amino] -methyl} -phenyl) Propionic acid 61 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-{[(thiophen-2-carbonyl) -amino] -methyl} -phenyl ) -Propionic acid 62 3- {2- (Butyrylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 63 3- {2-[(Cyclobutanecarbonyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[179] number compound designation 64 3- {2- (Benzyloxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 65 3- (2- (tert-Butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid 66 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(2-phenoxy-acetylamino) -methyl] -phenyl} -propionic acid 67 3- {2-[(Cyclopentanecarbonyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[180] The invention also encompasses pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof.
[181] The invention also relates to (1) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof of claim 1; (2) insulin sensitizers, sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, insulin secretagogues, insulin, antihyperlipidemic agents, plasma HDL synergists, HMG-CoA reductase inhibitors, statins Acrylic CoA: cholesterol acyltransferase inhibitors, appetite suppressant compounds, anti-cholesterol agents, fibrate, vitamins and aspirin; And (3) a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
[182] The invention also includes a method of modulating a peroxysomal proliferator activated receptor (PPAR) comprising contacting a receptor with at least one compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof. . Peroxysome proliferator activating receptors are alpha-receptors or gamma-receptors.
[183] The invention also includes a method of treating or preventing a peroxisomal proliferator active receptor-gamma mediated disease or condition comprising administering a compound of Formula (I) or Formula (Ia).
[184] The present invention also includes a method of lowering blood-glucose comprising administering an effective amount of a compound of Formula (I) or Formula (Ia).
[185] The invention also includes administering an effective amount of a compound of Formula (I) or Formula (Ia), hyperglycemia, dyslipidemia, type II diabetes, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetes disorders A method of treating or preventing a disease or condition selected from the group consisting of hemostasis, hyperlipidemia, hypercholesterolemia, hypertension, obesity, anorexia nervosa, anorexia nervosa, cardiovascular disease and other diseases in which insulin resistance is one factor It includes.
[186] The invention also includes a method of treating or preventing diabetes in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or Formula Ia.
[187] The invention also includes a method of treating or preventing a cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound of formula (I) or formula (Ia).
[188] The invention also provides for treating Syndrome X in a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound of Formula I or Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. Or how to prevent it.
[189] The invention also provides an effective amount of a compound of formula (I) or formula (I ') and elevated insulin sensitizers, sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, insulin secretagogues, insulin, antihyperlipidemic agents, plasma HDL elevations Administering an effective amount of a second therapeutic agent selected from the group consisting of an HMG-CoA reductase inhibitor, a statin, an acrylic CoA: cholesterol acyltransferase inhibitor, an appetite suppressant compound, an anti-cholesterol drug, fibrate, vitamins and aspirin Including hyperglycemia, dyslipidemia, type II diabetes, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetes dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, obesity, anorexia nervosa, anorexia nervosa A disease selected from the group consisting of sluggishness, cardiovascular disease and other diseases in which insulin resistance is one factor or It includes a method of treating or preventing a condition.
[190] The present invention also includes the use of a compound of formula (I) or formula (Ia) and pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof for the manufacture of a medicament for treating a condition controlled by PPAR.
[191] Embodiments of the present invention also include compounds of Formulas II to IX. These compounds are included within the scope of compounds of Formula Ia. Substituent Y ¹ of these compounds is ^Comprising , Y ^1a and Is as defined in formula (I) and the substituted groups include the aforementioned substituents as defined in the embodiments herein.
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199] Wherein Y ¹⁸ is a (C ₁ -C ₆ ) straight or branched alkyl group
[200]
[201] Wherein Y ¹⁸ is a (C ₁ -C ₆ ) straight or branched alkyl group
[202] The terms used to describe the present invention have the following meanings.
[203] As used herein, the term "aliphatic" or "aliphatic group" is non-aromatic, consists only of carbon and hydrogen and optionally comprises one or more unsaturated units, such as double and / or triple bonds (here also "alkenyl" and Referred to as "alkynyl"). Aliphatic and aliphatic groups may be straight chain, branched chain (referred to herein as "alkyl") or cyclic (also referred to herein as "cycloalkyl"). Straight or branched aliphatic groups generally comprise from about 1 to about 10 carbon atoms, more generally from about 1 to about 6 carbon atoms. When cyclic, aliphatic groups generally contain about 3 to about 10 carbon atoms, more generally about 3 to about 7 carbon atoms. Aliphatic is preferably a C ₁ -C ₁₀ straight or branched alkyl group (ie a fully saturated aliphatic group), more preferably a C ₁ -C ₆ straight or branched alkyl group. Examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl. Further examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexylyl, and the like.
[204] The term "alkyl", unless stated otherwise, refers to an alkyl group of a specified number of carbon atoms in straight or branched, saturated form. Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, isopentyl and the like. Alkyl as defined above may be optionally substituted with a specified number of substituents as set forth in the above-mentioned embodiments.
[205] The term "alkenyl" means a hydrocarbon chain of a certain number of carbon atoms in the form of a straight or branched chain having one or more carbon-carbon double bonds that can occur at any point in the chain, for example ethenyl, pro Phenyl, butenyl, pentenyl, vinyl, alkyl, 2-butenyl and the like. The alkenyl may be optionally substituted with a specified number of substituents as set forth in the above embodiments.
[206] The term "alkynyl" refers to a hydrocarbon chain of a certain number of carbon atoms in straight or branched chain form having one or more carbon-carbon triple bonds that can occur at any point in the chain. Examples of alkynyl include acetylene. The alkynyl described above may be optionally substituted with a specified number of substituents as set forth in the above embodiments.
[207] The term "cycloalkyl" refers to a saturated or partially saturated carbocycle comprising one or more rings of 3 to 12 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyls as described above also include tricycles, such as adamantyl. Said cycloalkyl may be optionally substituted with a specified number of substituents as set forth in the above-mentioned embodiments.
[208] The term "halo" refers to fluoro, chloro, bromo and iodo.
[209] The term "haloalkyl" is a C ₁ -C ₆ alkyl group substituted with one or more halo atoms selected from F, Br, Cl and I. An example of a haloalkyl group is trifluoromethyl.
[210] The term "alkoxy" refers to alkyl groups of the specified number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy and the like. Say. The alkoxy mentioned above may be optionally substituted with a specified number of substituents as shown in the above-mentioned embodiments.
[211] "Haloalkyloxy" refers to a C ₁ -C ₆ haloalkyl group, eg OCF ₃ , attached through an oxygen bridge. “Haloalkyloxy” as described above may be optionally substituted with a specified number of substituents as set forth in the above-mentioned embodiments.
[212] The term "aryl" refers to a carbocyclic aromatic ring system (eg phenyl), a conjugated polycyclic aromatic ring system (eg naphthyl and anthracenyl) and an aromatic ring conjugated with a carbocyclic non-aromatic ring system Systems (eg, 1,2,3,4-tetrahydronaphthyl). "Aryl" as described above may be optionally substituted with a specified number of substituents as set forth in the above-mentioned embodiments.
[213] The term "heteroaryl" group, as used herein, is an aromatic ring system having one or more heteroatoms, such as nitrogen, sulfur or oxygen, and includes 5 to 5 heteroatoms comprising one or more heteroatoms selected from O, N or S. Monocyclic, bicyclic or tricyclic aromatic rings of 14 carbon atoms. "Heteroaryl" as defined above may be optionally substituted with a specified number of substituents as set forth in the above-mentioned embodiments. Examples of heteroaryls are furanyl, thienyl (also referred to herein as "thiophenyl") thiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrazoyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, Pyrimidinyl and furinyl, cynolinyl, benzofuranyl, benzothienyl, benzotriazolyl, benzooxazolyl, quinoline, isoxoxazolyl, isoquinoline, and the like.
[214] The term “heterocycloalkyl” is a monocyclic, bicyclic or tricyclic of 5 to 14 carbon atoms comprising at least one oxygen, nitrogen or sulfur and comprising at least one hetero atom selected from O, N or S And click non-aromatic rings. "Heterocycloalkyl" as defined above may be optionally substituted with a specified number of substituents as set forth in the above-mentioned embodiments. Examples of heterocycloalkyl include, but are not limited to, morpholine, piperidine, piperazine, pyrrolidine and thiomorpholine. Preferred heterocycloalkyl groups are morpholines.
[215] As used herein, an aryl-C ₁ -C ₄ -alkyl group is an aryl substituent linked to a compound by an alkyl group having 1 to 4 carbon atoms.
[216] As used herein, a heteroaryl-C ₁ -C ₄ -alkyl group is a heteroaryl substituent linked to a compound by an alkyl group having 1 to 4 carbon atoms.
[217] As used herein, a cycloalkyl-C ₁ -C ₄ -alkyl group is a cycloalkyl substituent linked to a compound by an alkyl group having 1 to 4 carbon atoms.
[218] Aminoalkyl groups are alkyl groups having 1 to 6 carbon atoms substituted with one or more amines represented by NR ¹² R ¹² , wherein each R ¹² is independently C ₁ -C ₆ alkyl or both R ¹² are attached to them Together with the nitrogen atom to form a 5 or 6 membered heterocycloalkyl.
[219] Unless otherwise indicated, substituents for alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are halo, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ haloalkoxy, nitro, cyano, CHO, hydroxyl, C ₁ -C ₆ alkanoic acid and —C (O) NR ¹³ R ¹³ , each R ¹³ is independently hydrogen or C ₁ -C ₆ alkyl.
[220] Substituents for thiophene-2,5-diyl and phenylene include H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ haloalkoxy.
[221] The term "active ingredient" means a compound generally described by formula (I) and salts, solvates and prodrugs of that compound.
[222] The term "pharmaceutically acceptable" means that the carriers, diluents, excipients and salts must be compatible with the other ingredients of the composition and not deleterious to their receptors. Pharmaceutical compositions of the present invention are prepared by methods known in the art using known and readily available ingredients.
[223] "Prevention" refers to reducing the likelihood of causing or likely developing any pathological condition described herein in a receptor.
[224] "Treatment" refers to mediating a disease or condition, preventing or alleviating further progression, or alleviating a syndrome associated with the disease or condition.
[225] "Pharmaceutically effective amount" means an amount such that a compound of the present invention or a salt, solvate, hydrate or prodrug thereof may elicit a biological or medical response in a tissue, system or mammal. Such amounts can be administered prophylactically to patients deemed to be prone to develop a disease or condition. In addition, when administered prophylactically to a patient, this amount can be effective to prevent or reduce the extent of the mediated condition. Such amount is intended to include an amount sufficient to modulate a PPAR receptor, eg, a PPARα or PPARγ receptor, that mediates a disease or condition. Conditions mediated by PPARα or PPARγ receptors include, for example, diabetes, cardiovascular disease, syndrome X, obesity and gastrointestinal diseases. Additional conditions associated with the regulation of PPAR receptors include, for example, IBD (inflammatory growth disease), rheumatoid arthritis, psoriasis, Alzheimer's disease, Crohn's disease, and ischemic reperfusion injury (stroke and myocardial infarction).
[226] A "mammal" is an individual animal that is a member of the mammalian portal classification. Mammal portals include humans, monkeys, chimpanzees, gorillas, cattle, pigs, horses, sheep, dogs, cats, mice, rats, and the like.
[227] Most preferred is human administration. Humans to whom the compounds and compositions of the present invention are administered are those whose disease or condition is present, although the regulated blood glucose levels are not adequately regulated without medical intervention. Non-insulin dependent diabetes mellitus (NIDDM) is a chronic disease or condition characterized by the presence of insulin in the blood, even at levels above the norm, that are not resistant or lack of sensitization to insulin action in tissues.
[228] Those skilled in the art will recognize that the stereocenter is present in the compounds of Formulas (I) and (Ia). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of Formula (I), including racemic compounds and optically activated isomers.
[229] Compounds of formula (I) or formula (Ia) comprise one or more chiral centers and exist in other optically active forms. When the compound of formula (I) comprises one chiral center, the compound is present in two enantiomeric forms, and the present invention provides a mixture of both enantiomers and enantiomers, eg racemic mixtures. Include. Separation of the final product, intermediate or starting material can be accomplished by the formation of diastereomeric salts which can be separated by any suitable method known in the art, for example by crystallization; Crystallization and formation of diastereomeric derivatives or complexes that can be separated by gas-liquid or liquid chromatography; Selective reaction of one enantiomer with enantiomer-specific reagents such as enzyme esterification; And by gas-liquid or liquid chromatography on a chiral environment, eg, a chiral support, for example silica having chiral ligands with or associated with a chiral solvent. See Strochemistry of Carbon Compounds by E.L.Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S.H.Wilen. When converting the desired enantiomer to another chemical entity by one of the above separation methods, an additional step is required to have the desired enantiomeric form. Alternatively, certain enantiomers can be synthesized by anisotropic synthesis using optically active reagents, substrates, catalysts or solvents or by converting one enantiomer to another by anisotropic modification. In a more preferred embodiment, the compound of the invention is an S-enantiomer.
[230] When the compound of formula (I) or formula (Ia) has one or more chiral substituents, it may exist in diastereomeric form. Diastereomeric pairs can be separated by methods known in the art, such as chromatography or crystallization, and the individual enantiomers in each pair can be separated as described above. The present invention includes each diastereomer of the compound of formula (I) and mixtures thereof.
[231] Certain compounds of formula (I) or formula (I ') may exist in different stable conformation forms that are separable. Limited rotation around asymmetric single bonds, for example torsional asymmetry due to steric hindrance or ring strain, can allow separation of different configurations. The present invention includes each stereoisomeric isomer of the compounds of Formulas (I) and (Ia) and mixtures thereof.
[232] Certain compounds of formula (I) or formula (I ') may exist in the form of zwitter ions, and the present invention includes each zwitter ion form of a compound of formula (I) or formula (I') and mixtures thereof.
[233] Certain compounds of formula (I) or formula (I ') and salts thereof may exist in one or more crystalline forms. Polymorphs of the compounds of formula (I) form part of the present invention and may be used under different conditions by crystallization of compounds of formula (I) or formula (I '), for example using different solvents or different solvent mixtures for recrystallization; Crystallization at different temperatures; It can be prepared by various methods of cooling very quickly to very slowly during crystallization. Polymorphs can also be obtained by heating or melting a compound of Formula (I) or Formula (Ia) and then cooling it gradually or rapidly. The presence of polymorphs can be measured by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other available technique.
[234] Certain compounds of formula (I) or formula (I ') and salts thereof may exist in one or more crystalline forms, and the present invention includes each crystal form and mixtures thereof.
[235] Certain compounds of formula (I) or formula (I ') and salts thereof may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
[236] "Pharmaceutically acceptable salt" refers to salts of compounds of Formula (I) or Formula (Ia) that are substantially nontoxic to mammals. Typical pharmaceutically acceptable salts include mineral organic acids: salts prepared by reacting a compound of the invention with an organic base or an inorganic base. These salts are known as base addition salts, respectively. Certain counterions that form part of any salt of the present invention are not critical unless all of the salts are pharmaceutically acceptable and the counterions provide the entire salt with undesirable properties.
[237] By acidic moieties, compounds of formula (I) or formula (I ') form salts of pharmaceutically acceptable bases. Examples of some of the base addition salts include metal salts such as aluminum; Alkali metal salts such as lithium, sodium or potassium; And alkaline earth metal salts, such as calcium, magnesium, ammonium or substituted ammonium salts. Examples of substituted ammonium salts include lower alkyl amines such as trimethylamine and triethylamine; Hydroxyalkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine; Cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine, N-benzyl-β-phenethylamine, dihydroabiethylamine, N, N'-bisdehydro-biethylamine, glucamine , N-piperazine methylglucamine; Bases of the pyridine type, for example pyridine, collidine, quinine or quinoline; And salts of basic amino acids such as salts with lysine and arginine.
[238] Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. It is not limited to this.
[239] Compounds of formula (I) or formula (I ') substituted with basic groups may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts are hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate [e.g. (+)-tartrate, (-)-tartrate Or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids, such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.
[240] Certain compounds of formula (I) or formula (I ') and salts thereof may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
[241] Compounds of the invention that bind and activate PPARs lower one or more of glucose, insulin, triglycerides, fatty acids and / or cholesterol and, thus, hyperlipidemia, dyslipidemia and especially type II diabetes and syndrome X, type I diabetes, high It is useful for the treatment and / or prevention of triglycerides, insulin resistance, diabetic dyslipidemia, hypercholesterolemia, heart failure, coagulopathy, hypertension and other diseases including cardiovascular diseases, in particular atherosclerosis. These compounds are also known to be useful for the regulation of appetite and food intake in subjects suffering from diseases such as obesity, anorexia nervosa and anorexia nervosa.
[242] The compounds and compositions of the present invention are also useful for treating acute or transient diseases in insulin sensitivity that can often involve surgery, trauma, myocardial infarction, and the like. Compounds and compositions of the present invention are also useful for lowering serum triglyceride levels. Elevated triglyceride levels caused by genetic predisposition or high fatty eating habits are risk factors for the development of heart disease, stroke and circulatory diseases and disorders. One of ordinary skill in the art would know how to distinguish patients from which administration of the compounds and compositions of the present invention may be desirable.
[243] The present invention further provides an effective and non-toxic amount of a compound of formula (I) or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof in a hyperlipidemic patient or human being in need thereof. Provided are methods for the treatment and / or prophylaxis of hyperlipidemia in humans or non-human mammals, comprising administering to other mammals.
[244] The compounds of the present invention are useful as therapeutic substances for preventing or treating syndrome X, diabetes and related endocrine and cardiovascular disorders and diseases in humans or non-human animals.
[245] The invention also relates to the use of a compound of formula (I) as described above for the manufacture of a medicament for the treatment of each or a combination of PPARα or PPARγ mediated conditions.
[246] Therapeutically effective amounts of the compounds of formula (I) for the treatment of, prevention or reduction of the risk of developing atherosclerosis, for the treatment of syndrome X, for the treatment of diabetes, for the treatment of obesity, for the reduction of triglyceride levels, for the rise of plasma levels of dense lipoprotein , In particular for the manufacture of a medicament useful for the prevention or reduction of the risk of first or subsequent atherosclerotic disease in humans. In general, a therapeutically effective amount of a compound of formula (I) of the present invention reduces a patient's serum glucose level, more specifically HbA1c, typically about 0.7%; Reducing the serum triglyceride amount of the patient typically by at least about 20%; Increase the patient's serum HDL level. Preferably, the HDL level may be increased by at least about 30%.
[247] In addition, an effective amount of a compound of formula (I) and a therapeutically effective amount of one or more active agents selected from the treatment of hyperlipidemia, plasma HDL-boosting agents, antihypercholesterolemic agents, fibrate, vitamins, aspirin, insulin secretagogues, insulin, and the like It can be used together for the manufacture of a medicament useful for.
[248] Preferably, a composition comprising a compound of formula (I) or a salt thereof may be provided in dosage unit form, preferably in each dosage unit comprising about 1 to about 500 mg. The amount of a compound of formula (I) or compound that can be administered is determined by the physician taking into account all relevant circumstances.
[249] Syndrome X includes pre-diabetic insulin resistance syndrome and its complications, insulin resistance, non-insulin dependent diabetes mellitus, dyslipidemia, hyperglycemia obesity, coagulation, hypertension and other complications associated with diabetes. The methods and treatments referred to herein include those described above and include pre-diabetic insulin resistance syndrome, complications thereof, insulin resistance, type II or non-insulin dependent diabetes mellitus, dyslipidemia, hyperglycemia, obesity and cardiovascular disease , In particular, the treatment and / or prevention of one or a combination of diseases of the complications associated with diabetes, including atherosclerosis.
[250] The composition is formulated and administered in the same general manner as detailed herein above. The compounds of the present invention can be used either effectively alone or in combination with one or more additional active agents, depending on the desired treatment desired. Combination therapies include the administration of a single dose pharmaceutical composition comprising a compound of formula (I) and one or more additional active agents and the administration of the compound of formula (I) and each active agent in each separate dose pharmaceutical composition. For example, a single oral composition of a compound of formula (I) and an insulin secretagogue, for example biguanide, thiazolidinedione, sulfonylurea, insulin or α-glucoside inhibitor, eg, tablet or capsule Together with the patient or each agent may be administered as a separate oral dosage composition. When used as separate dosage compositions, the compounds of formula (I) and their additional active agents can be administered at the same time, ie at the same time, or at separate intervals, ie, continuously; Combination therapy is understood to include all these regimens.
[251] Examples of combined treatment or prevention of atherosclerosis include administering a compound of Formula (I) or a salt thereof in combination with one or more of the following second active therapeutic agents: antihyperlipidemic agents; Plasma HDL-raising agents; Antihypercholesterolemic drugs, fibrate, vitamins, aspirin, etc. As mentioned above, the compounds of formula (I) may be administered with one or more additional active agents.
[252] Another example of a combination therapy is that the compounds of formula (I) and salts thereof treat, for example, sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, other insulin secretagogues, insulin and atherosclerosis It can be found in the treatment of diabetes and related disorders that can be effectively used in conjunction with the active agents described above.
[253] Examples of second therapeutic agents include insulin sensitizers, PPARγ agonists, glitazones, troglitazones, pioglitazones, englitazones, MCC-555, BRL 49653, biguanides, metformin, phenformin, insulin, insulin analogues, sulfonyls Urea, tolbutamide, glipizide, alpha-glucosidase inhibitors, acarbose, cholesterol lowering agents, HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, other statins, Sequestrates, cholestyramine, cholestipol, dialkylaminoalkyl derivatives of crosslinked dextran, nicotin alcohols, nicotinic acid: nicotinic acid salts, PPARα agonists, fenofibric acid derivatives, gemfibrozil, clofibrate, fenofibrate , Benzafibrate, Cholesterol Absorption Inhibitor, Beta-Sitosterol, Acrylic CoA: Cholesterol Acyltransferase Inhibitor, Melinamid, Pro Cole, a PPARδ agonist, an anti-obesity compound, penpeulruramin, penpeulruramin index, pen tyramine, alcohol bit suramin, orlistat, neuropeptide Y5 inhibitors, β ₃ sympathetic receptor agonist, and ileum bile acid transporter inhibitors.
[254] The compounds of the present invention and their pharmaceutically acceptable salts, solvates and hydrates have useful pharmacological properties and include at least one pharmaceutical agent and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester or prodrug thereof. It can be used as a pharmaceutical composition comprising a pharmaceutically acceptable excipient together. Excipients are inert materials such as, but not limited to, carriers, diluents, fillers, flavors, sweeteners, lubricants, solubilizers, suspending agents, wetting agents, binders, disintegrants, encapsulants, and other conventional auxiliaries. Proper composition depends on the route of administration chosen. Pharmaceutical compositions typically comprise from about 1 to about 99 weight percent of the active ingredient, which is a compound of the present invention.
[255] Preferably, the pharmaceutical composition is in unit dosage form. "Unit dosage form" refers to physically discrete units comprising unit doses suitable for administration to a human subject or other mammal. For example, the unit dosage form may be a capsule or tablet or a plurality of capsules or tablets. "Unit dosage" is a predetermined amount of the active compound of the invention calculated to provide the desired therapeutic effect in association with one or more pharmaceutically acceptable excipients. The amount of active compound in unit dose may vary or may be adjusted to between about 0.1 and about 1000 milligrams or more depending on the particular treatment involved.
[256] Dosage regimens using the compounds of the present invention may be controlled by various factors including, but not limited to, the type of receptor, age, weight, sex, medical condition, degree of treatment, route of administration, level of metabolic and excretory function of the receptor, dosage form employed And the specific compound employed, salts thereof, and the like, and are selected by one of ordinary skill in the medical or veterinary arts.
[257] Preferably, the compounds of the invention may be administered in a single dose or the total daily dose may be administered in two, three or more separate doses per day. If the delivery is in transdermal form, administration is continuous.
[258] Suitable routes of administration of the pharmaceutical compositions of the invention include, for example, oral, ocular drop, rectal, mucosal transit, topical or intestinal administration; Parenteral delivery (bolus or infusion), including intramuscular, subcutaneous, intramedullary injections and intradural, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections. The compounds of the invention can also be administered in a desired drug delivery system, such as liposomes coated with endothelial cell specific antibodies.
[259] For oral administration, the compounds of the present invention can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers may be used as tablets, pills, powders, sakes, granules, dragees, capsules, liquids, elixirs, tinctures, gels, emulsions, syrups, slurries, suspensions, or the like, orally digested by a patient treated with a compound of the present invention. It can be formulated as. Pharmaceutical formulations for oral use may combine the active compounds with solid excipients, optionally grind the resulting mixture, and if necessary add an appropriate adjuvant and then process the granule mixture to obtain a tablet or dragee core.
[260] For oral administration in the form of tablets or capsules, the active ingredient may be an oral nontoxic pharmaceutically acceptable carrier, such as, but not limited to, lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate Can be combined with calcium phosphate, calcium sulfate, sodium carbonate, mannitol, sorbitol, and the like; Optionally, disintegrants, such as, but not limited to, crosslinked polyvinyl pyrrolidone, maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid: or salts thereof, for example Sodium alginate and the like; And optionally binders such as, but not limited to, gelatin, acacia, natural sugars, venta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethyl-cellulose, Polyethylene glycol, wax, and the like; And optionally, lubricants such as, but not limited to, magnesium stearate, sodium stearate, stearic acid: sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc and the like. If the dosage unit form is a capsule, it may comprise a liquid carrier, for example a fatty acid, together with a substance of this kind.
[261] Solid form preparations include powders, tablets, and capsules. The solid carrier can be one or more materials that can also act as flavoring agents, lubricants, solubilizers, suspending agents, binders, tablet disintegrants, and encapsulating materials.
[262] As a powder is a finely dispersed solid in which the carrier is mixed with the finely dispersed active ingredient. As tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable fractions and compacted in the shape and size desired.
[263] Various other materials may be present as a coating or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propylparabens as preservatives, dyes and flavorings such as cherry or orange flavor.
[264] Sterile liquid compositions include suspensions, emulsions, syrups and elixirs. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent or a mixture of sterile water and sterile organic solvent.
[265] The active ingredient can be dissolved in a suitable organic solvent such as aqueous propylene glycol. Other compositions can be prepared by dispersing the finely dispersed active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
[266] Dragee cores are provided with suitable coatings. Concentrated sugar solutions can be used for this purpose, which will include gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Can be. Dyestuffs or pigments may be added to tablets or dragee coatings for characterization or to characterize different combinations of active compound doses.
[267] Pharmaceutical compositions that can be used orally include the form of push-fit capsules of gelatin and soft sealing capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. have. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty acids, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added.
[268] All compositions for oral administration should be in dosages suitable for such administration. In particular, suitable compositions for oral administration are in unit dosage forms such as tablets and capsules.
[269] For parenteral administration, the compounds of the present invention or salts thereof can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Injectable compositions may be present in unit dosage form, eg, with preservatives added in ampoules or in multi-dose containers. The composition may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may comprise a formulation agent, for example suspending, stabilizing and / or dispersing agents. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the instant preparation of sterile injectable solutions or dispersions. In all cases, the formulations must be sterile and must be fluid to the extent that each is injectable. It must be stabilized under the conditions of manufacture and storage and must be preserved against any contamination. The carrier is, for example, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol) in water, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. ), Propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the development of microorganisms.
[270] Injectable solutions prepared in this way can be administered intravenously, intraperitoneally, subcutaneously or intramuscularly and using intramuscular administration desired for humans.
[271] Penetrating agents suitable for the barrier to penetrate for mucosal administration are used in the formulation. Such penetrants are generally known. The active compound may also be administered intranasally, for example by liquid drop or spray.
[272] For buccal administration, the compositions may be in the form of tablets or lozenges formulated in a conventional manner.
[273] For inhalation administration the compounds for use according to the invention are suitable propellants in the form of dry powder inhalants, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other It is conveniently delivered in the form of an aerosol spray from a pressurized pack or sprayer using a suitable gas. In the case of a pressurized aerosol, the dosage unit can be measured by providing a valve to deliver a measured amount. Capsules and cartridges of gelatin for use in an inhaler or injector may be formulated including a powder mix of the compound and a suitable powder base, such as lactose or starch.
[274] The pharmaceutical compositions of the present invention may be prepared by known methods, for example by conventional mixing, dissolving, granulating, dragee-making, powdering, emulsifying, encapsulating, trapping or lyophilizing processes.
[275] In the preparation of the compositions of the present invention, the active component can usually be mixed with the carrier or diluted in the carrier or sealed in a carrier which can be in the form of a capsule, sake, paper or other container. When the carrier is used as a diluent, it may be a solid, lyophilized solid or paste, semi-solid or liquid substance which can act as a vehicle, or may contain, for example, tablets, pills, powders, lozenges containing up to 10% by weight of the active compound. Fats, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium) or ointments.
[276] The following pharmaceutical compositions 1-8 are illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient" refers to a compound of the invention and / or a salt thereof according to formula (I) and / or (la).
[277] Formulation 1
[278] Cured gelatin capsules are prepared using the following ingredients:
[279] Amount (mg / capsule) Active ingredient 250 Starch, dried 200 Magnesium stearate 10 all 460 mg
[280] Formulation 2
[281] Tablets are made using the following ingredients:
[282] Amount (mg / tablet) Active ingredient 250 Cellulose, microhard 400 Silicon dioxide, fume 10 Stearic acid 5 all 665 mg
[283] The ingredients are mixed and compressed to form tablets with a weight of 665 mg each.
[284] Formulation 3
[285] Aerosol solutions are prepared comprising the following components:
[286] weight Active ingredient 0.25 ethanol 25.75 Accelerator 22 (Chlorodifluoromethane) 74.00 all 100.00
[287] The active ingredient was mixed using ethanol and the mixture was added as part of promoter 22, cooled to 30 ° C. and transferred to a peeling device. The required amount was then injected into a stainless steel container and diluted with the residue of the promoter. The valve unit was then mounted in the container.
[288] Formulation 4
[289] Active ingredient 60mg Starch 45mg Microhard cellulose 35mg Polyvinylpyrrolidone (as a 10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg all 150 mg
[290] The active ingredient, starch and cellulose were prepared using No. 45 mesh U.S. Pass the sieve and mix thoroughly. An aqueous solution comprising polyvinylpyrrolidone was mixed using the resulting powder and then the mixture was passed through No. 14 mesh U.S. sieve. The particles so produced were dried at 50 ° C. and passed through No. 18 mesh U.S. sieve. Sodium Carboxymethyl Starch, Magnesium Stearate and Talc were prepared from No. 60 Mesh U.S. The sieve was passed through in advance, added into granules, mixed and compressed onto tablets to give tablets weighing 150 mg each.
[291] Formulation 5
[292] Capsules each containing 80 mg of the active ingredient are prepared as follows:
[293] Active ingredient 80 mg Starch 59mg Microhard cellulose 59mg Magnesium stearate 2mg all 200 mg
[294] The active ingredient, cellulose, starch and magnesium stearate were mixed to prepare No. 45 U.S. Pass through the mesh sieve and place into hard gelatin capsules in 200 mg amount.
[295] Formulation 6
[296] Suppositories each containing 225 mg of the active ingredient are prepared as follows:
[297] Active ingredient 225 mg Saturated Fatty Acid Glyceride 2000 mg all 2225 mg
[298] The active ingredient is 60 mesh U.S. The sieve was passed through and suspended in saturated fatty acid glycerides previously dissolved with the minimum heat required. The mixture was then poured into a standard 2 g suppository template and cooled.
[299] Formulation 7
[300] Suspensions each containing 50 mg of active ingredient per 5 ml dose were prepared as follows:
[301] Active ingredient 50 mg Sodium Carboxymethyl Cellulose 50 mg syrup 1.25ml Benzoic acid solution 0.10ml Flavor A reasonable amount coloring agent A reasonable amount Purified water 5ml
[302] Active ingredient No. 45 mesh U.S. Passed through a sieve and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and colorant are diluted in a small amount of water and added with stirring. Sufficient water was then added to provide the required volume.
[303] Tablets 8
[304] Intravenous formulations can be prepared as follows:
[305] Active ingredient 100mg Isotonic saline 1000 ml
[306] A solution of this substance was administered intravenously, usually in a subject at 1 ml per minute.
[307] In another embodiment of the invention the compound is labeled or tritium labeled with a radiolabel, eg, carbon-14. The radiolabeled or tritiated hydrogenated compounds are useful as standard data for in vitro assays identifying novel PPARα and PPARγ agonists.
[308] Combined and Courtesy Study
[309] The in vitro efficacy of the compounds in modulating PPARγ, PPARα and PPARδ receptors was measured by the procedure detailed below. DNA-dependent binding (ABCD binding) was performed using the flash proximity assay (SPA) technique with the PPAR receptor. Tritium-labeled PPARα and PPARγ agonists were used to generate displacement curves and IC ₅₀ values with the compounds of the present invention. Coatfection assays were performed in CV-1 cells. Reporter plasmids included the TK promoter upstream of acylCoA oxidase (AOX) PPRE and luciferase reporter cDNA. Plasmids containing the CMV promoter were used to structurally express suitable PPARs and RXRα. For PPARα and PPARβ / δ, interference with endogenous PPARγ in CV-1 cells is a problem, so to eliminate such interference, a GAL4 chimeric system was used in which the DNA binding region of the transfected PPAR was replaced with that of GAL4, GAL4 response element was used in place of AOX PPRE. Cortification efficacy was measured in comparison to the PPARα agonist and PPARγ agonist reference compounds. Efficacy was measured by computer fitting the concentration-response curve or in some cases at a single high concentration of agent (10 μM). Typical concentration measurement ranges for IC ₅₀ range from 1 nM to 10 μM. In binding or transfection studies using receptors other than PPAR, similar assays were performed using suitable ligands, receptors, and reporter constructs for that particular receptor.
[310] These studies were performed to estimate the ability of compounds of the invention to bind (bind) and activate various nuclear transcription factors, in particular huPPARα (“hu” represents human), huPPARγ and huPPARδ. These studies provided in vitro data on the efficacy and selectivity of the compounds of the invention. Moreover, the binding and coverage data for the compounds of the invention were compared with the corresponding data for commercial compounds acting on huPPARα or huPPARγ. Representative ranges of concentrations for binding are 1 nM to 10 μM. The concentrations of test compounds required to perform 50% maximal activation on PPARα (IC ₅₀ α) and PPARγ (IC ₅₀ γ) were determined.
[311] Estimation of Triglycerides and Cholesterol Levels in HuapoAI Transgenic Mice
[312] Male mice 5 to 6 weeks old (10 "x 20" x 8 with poplar chips) were used to transform human apoAI [C57Bl / 6-tgn (apoa1) 1rub, Jackson Laboratory, Bar Harbor, ME]. Five were fed per day with always available food (Purina 5001) and water. After a 2-week acclimation period, animals were individually labeled with ear notches, weighed and based on weight Groups were started starting the next morning and administered to mice by oral gavage using a 20 gauge 1½ "curved disposable infusion needle daily for 7 days. Formulations were either test compound (30 mg / kg), positive control (fenofibrate, 100 mg / kg) or excipient [1% carboxymethylcellulose (w / v) /0.25% Tween 80 (w / v); 0.2 ml / rat]. Prior to termination on day 7, rats were weighed and administered. Three hours after administration, animals were anesthetized by inhaling isoflurane (2-4%) and blood was obtained through cardiac puncture (0.7-1.0 ml). Whole blood was transferred to serum separation tubes (Vacutainer SST), cooled on ice and allowed to coagulate. Serum was obtained after centrifugation at 4 ° C. and frozen until analyzed for triglycerides, total cholesterol, compound amounts and serum lipoproteins distributed by rapid protein liquid chromatography (FPLC) connected to a serial detection system. The neck was displaced and killed, then the liver, heart and epididymal fat pads were incised and weighed.
[313] Animals receiving excipients had an average triglyceride level of about 60-80 mg / dl, which was reduced by the positive fenofibrate control (33-58 mg / dl with an average reduction of 37%). Animals receiving excipients had an average total serum cholesterol level of about 140-180 mg / dl, which was increased by fenofibrate (about 190-280 mg / dl with an average rate of 41% rise). For FPLC analysis, serum collected from excipient treated human apoAI transgenic mice has a high density lipoprotein cholesterol (HDLc) peak area in the range of 47v-sec to 62v-sec. Fenofibrate increased the amount of HDLc (68-96 v-sec with an average percent increase of 48%). Test compounds were estimated at the rate of area increase under the curve. Representative compounds of the invention were tested using the above or substantially similar methods.
[314] Estimation of Glucose Level in db / db Rats
[315] Either male diabetic (db / db) rats [C57BlKs / jm + / + Lepr (db), Jackson Laboratory, Bar Harbor, ME], or 5 weeks old rats (db +), were used in the US (10 with poplar chips). Five animals per "x20" x8 ") were fed with always available food (Purina 5015) and water. After a two week acclimation period, animals were individually labeled with ear notches, weighed, Blood was then bleeded through the tail vein to determine the amount of glucose initially, starving each rat with a towel, cutting the tail end with a scalpel, and squeezing blood from the tail into a tailored heparinized capillary tube weighed at the edge of the bench. Blood was collected from animals that did not (100 μl) Samples were placed in a heparinized microcontainer with gel separator (VWR) on ice, plasma was obtained after centrifugation at 4 ° C. and glucose was measured immediately. Remain until the end Frozen plasma and assayed glucose and triglycerides in all samples. Animals were grouped based on initial glucose amount and body weight. Starting with the following morning, using a 20 gauge 1½ "curved disposable infusion needle daily for 7 days The mice were administered by oral gavage. Formulations include test compound (30 mg / kg), positive control agent (30 mg / kg) or excipient [1% carboxymethylcellulose (w / v) /0.25% Tween 80 (w / v); 0.3 ml / rat]. On day 7, rats were weighed and bled for 3 hours after dosing (tail vein). Twenty four hours after the seventh dose (ie on day 8) the animals were bled again (tail vein). Samples obtained on days 0, 7 and 8 from conscious animals were assayed for glucose. After bleeding for 24 hours, the animals were weighed and administered last. Animals were anesthetized by inhaling isoflurane at 3 hours after dosing on day 8, and blood was obtained through cardiac puncture (0.5-0.7 ml). Whole blood was transferred to serum separation tubes and allowed to cool and coagulate on ice. Serum was obtained after centrifugation at 4 ° C. and frozen until the amount of compound was analyzed. The neck was displaced and killed, then the liver, heart and epididymal fat pads were incised and weighed.
[316] Animals receiving excipients had an average triglyceride level of about 170-230 mg / dl, which was reduced by the positive PPARγ control (about 70-120 mg / dl with an average reduction of 50%). Male db / db mice had hyperglycemia (mean glucose level of about 680-730 mg / dl on day 7 of treatment), while lean animals had an average glucose level of about 190-230 mg / dl. Treatment with the positive control agent significantly reduced glucose (approximately 350-550 mg / dl of average reduction rate normalized to 56%).
[317] Glucose was measured colorimetrically using commercially available drug (Sigma # 315-500). Depending on the manufacturer, published publications are published in McGowan et al. Clin Chem, 20: 470-5 (1974) and Keston, A. Specific colorimetric enzymatic analytical reagents for glucose. Abstract of papers 129th Meeting ACS, 31C (1956)], which refines the analysis associated with the color reaction (Trinder, P. Ann Clin Biochem, 6:24 (1969)) first described by Tinder. It depends on the release of hydrogen peroxide for each mole of water. The absorbance of the resulting dye is linearly related to the analyte in the sample. This assay was also modified for use in a 96 well format. Standard (sigma # 339-11, sigma # 16-11, and sigma # CC0534), qualitative control plasma (Sigma # A2034) and samples for each of glucose, triglycerides, and total cholesterol using 200 μl of reagent (2 or 5 μl / well) was measured twice. An additional aliquot of sample pipetted into the third well and diluted in 200 μl water provided a blank for each test piece. Incubate the plates in a plate shaker at room temperature (18, 15 and 10 minutes respectively for glucose, triglycerides and total cholesterol) and at 500 nm (glucose and total cholesterol) or 540 nm (triglycerides) on a plate reader The absorbance was read. Standard curves (100-800, 10-500 and 100-400 mg / dl respectively for glucose, triglyceride and total cholesterol) were compared with sample absorbance. The values for the qualitative control samples were consistently within the expected range and the coefficient of dispersion for the samples was less than 10%. All samples in the experiment were tested simultaneously to minimize variability between assays.
[318] Serum lipoproteins were isolated and cholesterol was quantified with a serial detection system. Samples were placed in a Superose® 6HR 10/30 size exclusion column (Amersham Pharmacia Biotech) and eluted with phosphate buffered saline-EDTA at 0.5 ml / min. It was. Cholesterol reagent (Roche Diagnostics Chol / HP 704036) was mixed with the column eluate via T-linking at 0.16 ml / min, and the mixture was immersed in a 15 m x 0.5 mm inner diameter in a 37 ° C. water bath. knitted) was passed through a tubing reactor. The colored product produced in the presence of cholesterol was monitored at flow rate flow at 505 nm and the analog voltage of the monitor was converted into a digital signal for collection and analysis. The change in voltage corresponding to the change in cholesterol was plotted against time and the area under the curve corresponding to the elution of VLDL, LDL and HDL was calculated (Perkin Elmer Turbochorome software).
[319] Compounds of the invention can be prepared according to the methods of the following schemes and examples and can be further exemplified in detail for the preparation of compounds of the invention. The compounds exemplified in the schemes and examples should not be construed as limited to the kind contemplated as the invention.
[320] General scheme:
[321] Compounds of the invention can generally be prepared according to the following schemes. In describing various aspects of the compounds, the terms "tail" and "head" are used as their concepts illustrate below:
[322]
[323] Scheme 1:
[324]
[325] Z ₁ = leaving machine
[326] Head '= deformation headpiece indicating OH substitution
[327] As shown in Scheme 1, the compounds of the present invention can generally be divided into tail and head portions, where the nucleophilic headpiece is coupled with the electrophilic tailpiece. These moieties may be further modified as shown in the scheme below.
[328] Scheme 2: oxazole tailpiece
[329]
[330] R 1 is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, haloalkyl or haloalkoxy.
[331] R 2 is Y ^1a .
[332] R 3 is alkyl (methyl) or tolyl.
[333] As shown in Scheme 2, the intermediate oxazole tailpiece is obtained by condensation of dionemonooxy (1) with aldehyde (2), for example bromobenzaldehyde, in the presence of an acid, for example hydrochloric acid or acetic acid. It can be prepared to obtain an oxazole n-oxide compound (3). Oxazole n-oxide is then treated with phosphorus oxychloride in organic solvent to form chloromethyl substituted oxazole (4). Compound (4) is further treated with cyanide to form cyanomethyl oxazole compound (5). The cyano group of compound (5) is converted to a carboxylic acid group by treatment with an alkali metal hydroxide such as NaOH to form a carboxymethyl substituted oxazole (6), which is a carboxylic acid reducing agent such as borane or Further treatment with lithium aluminum hydride (LAH) forms compound (7). Compound (7) is prepared by treating sulfonyl halide or sulfonyl anhydride (R ₃ SO ₂ Cl or (R ₃ SO ₂ ) ₂ O) with, for example, tosyl anhydride, mesyl anhydride, tosyl chloride or mesyl chloride In the presence may be converted to oxazolyl sulfonyl ester (8).
[334] Scheme 3: Oxazole Tailpiece
[335]
[336] Alternatively, intermediates of oxazole tailpieces can be prepared as shown in Scheme 3. Acid chloride (9) is reacted with L-aspartic acid dimethyl ester (10) to obtain an amide compound (11), which is treated with a dehydrating agent such as P ₂ O ₅ to cyclize to an oxazole ring (12). ). The ester compound (12) is treated with LAH to reduce to give an alcohol (13), which is then converted to oxazolyl sulfonyl ester (8a) as described above in Scheme 2.
[337] Scheme 4: Oxazole Tailpiece:
[338]
[339] Another route to the intermediate of the oxazole tailpiece is shown in Scheme 4. Acid chloride (9) and L-aspartic acid monomethyl ester (10) are reacted to obtain an amide compound (11), which is further reacted to obtain a ketone (14). The ketone compound is cyclized in the presence of a dehydrating agent such as POCl ₃ or H ₂ SO ₄ / acetic anhydride to form the oxazole ring 15. Compound (15) is reduced to afford alcohol (16), which is then converted to oxazolyl sulfonyl ester (8) as described above in Scheme 2.
[340] Scheme 5: oxazole tailpiece
[341]
[342] X = OTf, l, Br, Cl
[343] R = H or alkyl
[344] Pg = protecting group, for example benzyl
[345] Y ₂ = bond, N or O
[346] ArY ₂ -Ar- = Y ^1a
[347] Another route to the intermediate of the oxazole tailpiece is shown in Scheme 5. The oxazole compound (17) was subjected to a coupling reaction with aryl boronic acid, aryl alcohol or aryl amine in the presence of a palladium catalyst, and then deprotected to obtain the corresponding compound (18). Compound (18) is converted to oxazolyl sulfonyl ester (19) as described above in Scheme 2.
[348] Scheme 6: thiazole tailpiece
[349]
[350] As shown in Scheme 6, the intermediate thiazole tailpiece condenses compound (20) with bromo alkyl ester (21) in the presence of 1,4-dioxane and then cyclizes to form thiazole compound (22). It can manufacture by obtaining. The thiazole 22 is then ester reduced to give the alcohol 13 which is further converted to thiazole sulfonyl ester 8 as described above in Scheme 2.
[351] Scheme 7: Pyrazole Tailpiece
[352]
[353] As shown in Scheme 7, intermediate pyrazole tailpieces are condensed with arylaldehyde 25 and compound 26 in the presence of a base to cyclize to yield pyrazole compound 27. Compound (27) was treated with ethylene carbonate in the presence of a base such as NaH to obtain alkylated compound (28), which was then converted to pyrazole sulfonyl ester (29) as described in Scheme 2 above. Let's do it.
[354] Scheme 8: Preparation of arylether bromide
[355]
[356] Scheme 8 shows the preparation of arylether bromide by nucleophilic substitution of dibromide and aryl alcohol in the presence of a base.
[357] Scheme 9: Preparation of aminomethyldihydrocinnamate
[358]
[359] Z ₂ = COR, CONHR, CSNHR, COOR, SO ₂ R;
[360] Where R is selected from Y ₇ .
[361] Scheme 9 shows a synthetic route to prepare aminomethyldihydrocinamate headpieces. 3-hydroxybenzaldehyde (29) is reacted with bromine to give 2-bromo-5-hydroxybenzaldehyde (30), which is then coupled with t-butylacrylate to give compound (31). Compound (31) is treated with NH ₂ OH to give oxime (32) which is hydrogenated to give aminomethyldihydrocinnamate (33). Various functional groups (Z ₂ ) were introduced into the aminomethyl portion of compound (33) to give compound (34).
[362] Scheme 10: N-alkyl headpiece
[363]
[364] As shown in Scheme 10, the aminomethyl portion of the headpiece compound 34 can be further modified. Phenol 34 is protected with a protecting group, such as benzyl, to give compound 35. Compound 35 is subjected to nucleophilic substituent reaction with alkyl halide (RX) under basic conditions, followed by deprotection to yield phenolic compound (36).
[365] Scheme 11: transesterification
[366]
[367] Scheme 11 illustrates the transesterification of a compound as described above. The tert-butyl ester can be cleaved under acidic conditions, for example TFA. The corresponding carboxylic acid group can be esterified again in the presence of an acid such as H ₂ SO _{4 with} a suitable alcohol such as methanol.
[368] Scheme 12 tail-head coupling reaction with aminomethyldihydrocinnamate
[369]
[370] As shown in Scheme 12, the headpiece and tailpiece can be modified to introduce various functional groups. In pathway A, a protecting group (TBS) is first attached to the phenol of compound 37, followed by radical bromination, followed by alkylation with potassium phthalimide to afford compound 38. Compound (38) was subjected to a Heck coupling reaction with tert-butyl acrylate in the presence of a palladium catalyst, followed by deprotection and hydrogenation of the silyl group to give compound (39). Compound (39) was coupled with the tailpiece and phthaloyl group was removed to give compound (40). After neutralization, the amino functionality of (40) can be modified to afford (41). (42) was obtained by ester hydrolysis under acidic conditions. Alternatively, as seen in the B route, compound 42 may be obtained by coupling headpiece 43 with tailpiece to obtain compound 41 and ester hydrolysis.
[371] Scheme 13: Synthesis of meta-aminomethyldihydrocinnamate
[372]
[373] Scheme 13 shows the synthesis for meta-substituted aminomethyldihydrocinnamate. A protecting group such as a benzyl group is attached with the phenol of the compound (44) to obtain the protective compound (45). Compound (45) is subjected to glycol formation followed by cleavage and oxygenation to obtain a carboxylic acid compound (46), which is then converted to an amide compound (47). Compound (47) is rearranged, followed by amine protection with Boc anhydride, followed by deprotection with benzyl ether to give phenol (48). Compound 48 is coupled with the tailpiece and deprotected to obtain an intermediate, which is then further modified and hydrolyzed to the aminomethyl portion of the compound to yield compound 49.
[374] Scheme 14 Synthesis of Aminoethyldihydrocinnamate
[375]
[376] Scheme 14 shows the synthetic route to making the aminoethyldihydrocinnamate headpiece. A protecting group, such as benzyl, is attached with the aryl alcohol of compound 50 to obtain protected compound 51, which is then converted to nitro-olefin compound 52. Compound (52) is treated with LAH to reduce to nitro-olefin, followed by introduction of an amine protecting group such as Boc to give compound (53). Compound (53) is subjected to a coupling reaction with methyl acrylate in the presence of a palladium catalyst and then deprotected to a phenol group to give phenol compound (54). Compound 54 is then coupled with the tail portion, followed by deprotection of the Boc group to give an intermediate compound, which is then further modified in the aminoethyl portion of the compound to hydrolyze to yield compound 55. Alternatively, compound 57 is deprotected and then modified in the aminoethyl portion of the compound to yield compound 56. Compound (56) can be coupled to the tailpiece and then ester hydrolyzed to yield compound (55).
[377] Scheme 15: Synthesis of aminomethylfibrate
[378]
[379] Scheme 15 shows a synthetic route to prepare aminomethylfibrate compounds. The reaction is carried out along a substantially similar synthetic route as described in Scheme 13.
[380] Scheme 16: Synthesis of carboxamidodihydrocinamate
[381]
[382] Scheme 16 shows the synthetic route to carboxamidodihydrocinamate by route A or route B. In route A, a protecting group, for example benzyl, is attached with the phenol of compound 58 to obtain protected compound 59. Compound (59) is oxidized to give carboxylic acid compound (60), which is then esterified, followed by deprotection with phenol to give compound (61). Compound (61) is coupled with the tailpiece and then deprotected with a carboxylic acid group to give compound (62), followed by amide formation and ester hydrolysis to give compound (63). Alternatively, as shown in route B, compound (64) is amide formed and then reduced and deprotected to a phenol group to yield compound (65). Compound 65 is then coupled with the tailpiece and then ester hydrolyzed to yield compound 63.
[383] Scheme 17: Synthesis of cyanodihydrocinnamate
[384]
[385] Cyanodihydrocinnamate can be prepared as shown in Scheme 17. Compound 66 is brominated with a brominating agent such as NBS to give compound 67 which is then heck coupled to ethyl acrylate in the presence of a palladium catalyst and subsequently hydrogenated to give compound 68. Compound (68) was coupled with the tailpiece and then ester hydrolyzed to give the carboxylic acid compound (69).
[386] Scheme 18: Synthesis of alkoxydihydrocinnamate
[387]
[388] Alkoxyhydrocinamate can be prepared as shown in Scheme 18. In route (a), compound (31) is coupled with the tailpiece to give compound (70), followed by the double bond and subsequent reduction of aldehyde to give alcohol compound (71). Compound (71) is condensed with isocyanate or thioisocyanate, alkyl halide or acryl halide and then ester hydrolyzed to give compound (72). Alternatively, compound (71) is carbon tetrahalid and triphenylphosphate. The pin may be used to switch to the corresponding Halide 73. Nucleophile substitution reaction followed by ester hydrolysis reaction yields compound (74).
[389] In route (b), a protecting group, for example TBDPSi, is attached with an aryl alcohol of compound (75) to give compound (76), which is then followed by a similar reaction sequence as described in route (a). 77). Alternatively, compound (76) can be condensed with Z ₃ -X and then deprotected to yield phenol (78). The phenolic compounds (77) and (78) can be reacted with the tailpiece and then acid hydrolyzed to obtain the final compound separately.
[390] Scheme 19: Synthesis of alkoxyalkyl fibrate
[391]
[392] Scheme 19 illustrates a synthetic route to prepare an alkoxyalkylfibrate compound. Compound (79) is reacted with ethyl 2-bromoisobutyrate in the presence of a base to give compound (80). The phenol of compound (80) is deprotected and then aldehyde reduction in the presence of a reducing agent such as NaBH ₄ to give compound (81). The phenol (81) is then reacted with Z ₃ -X and hydrolyzed to give an alkoxyalkyl fibrate compound (82). Alternatively, the phenolic compound 81 can be converted to the corresponding halide 83 using carbon tetrahalides and triphenylphosphine. Compound (83) is treated with ArZ ₄ H and ester hydrolysis to give compound (84).
[393] Scheme 20: change of tail section
[394]
[395] Scheme 20 illustrates a synthetic route to a compound with altered tailpieces. The oxazole compound (85) is subjected to a coupling reaction with an arylboronic, aryl alcohol, aryl amine or secondary amine in the presence of a palladium catalyst to obtain the modified tailpiece compound (86). Alternatively, compound (85) was reacted with pinacol diborane in the presence of a palladium catalyst to give compound (87), followed by coupling with arylhalide to give a biaryl compound (88). Alternatively, compound 87 is oxidized to yield phenol 89, which is then coupled with arylhalide in the presence of a palladium catalyst to yield aryl-aryloxy compound 90 as shown in route (a). Alternatively, compound (89) is nucleophilized with alkyl halide or alcohol as shown in route (b) to form ether compound (91).
[396] Scheme 21: change the tailpiece
[397]
[398] Ar-C (O) NRR '= Y ^1a
[399] Substituents as defined in NRR '= Y ^1a
[400] Scheme 21 shows a synthetic route to alter the tailpiece of the compound. In route (a), oxazole tailpiece compound 92 is carbonylated to provide carboxylic acid compound 93 which is converted to acid chloride and reacted with amine to form amide compound 94. Similar to route (b), the modified compound 94 forms an intermediate hydroxypyridine ester by palladium catalyzed carbonylation and then reacts with an amine to form an amide compound.
[401] Scheme 22: changing the tailpiece
[402]
[403] Substituents as defined in NH-Z ² = Y ^1a
[404] Scheme 22 shows a synthetic route to alter the tailpiece of the compound. Compound oxazolyl sulfonyl ester (95) is nitrified to give compound (96), followed by coupling reaction with the headpiece to give compound (97). The nitro group of the phenyl ring is reduced to give an aniline compound which is then modified to yield compound (99).
[405] Scheme 23: change of head
[406]
[407] Scheme 23 shows a synthetic route to alter the headpiece of the compound. The headpiece compound 100 may be modified by coupling with an aryl halide (Ar-X) in the presence of a palladium catalyst and hydrolyzing to obtain the compound (101). Alternatively, compound 100 is reacted with Z ₂ -X in the presence of a base to yield modified aminomethyl compound 102. In route (a), compound 102 is nucleophilic substituted in amine and ester hydrolyzed to give acid compound 105. Alternatively, alkylation is carried out under basic conditions by route (b) with Z ₂ as a trifluoro acetyl group and aqueous base hydrolysis to afford secondary amine compound 104. The amine and Z ₂ -X are then functionalized and acid hydrolyzed to give compound 105.
[408] Scheme 24: oxazole tailpiece
[409]
[410] R2 = Y ^1a , for example aryl, aryl-Z-aryl or heteroaryl-Z-aryl, or alkyl
[411] R = alkyl
[412] Scheme 24 shows an alternative synthetic route to obtaining the oxazole tailpiece. The carboxylic acid 106 is condensed with 2-bromo-3-oxopentanoate (preferably methyl ester) 107 to obtain the ketoester 108. The latter is converted to intermediate enamine 109 by treatment with anhydrous ammonium acetate. Subsequently, compound (109) is cyclized in acetic acid in the presence of anhydrous ammonium acetate to obtain compound (110). Anhydrous ammonium acetate obtained by azeotroping with ethanol is used to remove the water in the reaction, which is then decarboxylated. In addition, some of the water liberated during the reaction is removed in the enamine stage. Following a simplified separation process these modifications provide higher yields of oxazole 110.
[413] In the schemes, the following preparations and examples, various reagent symbols and abbreviations have the following meanings:
[414] BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl
[415] Boct-butoxycarbonyl
[416] CBZ Benzyloxycarbonyl
[417] DCM dichloromethane
[418] DEAD diethyl azodicarboxylate
[419] DI deionization
[420] DIAD diisopropyl azodicarboxylate
[421] DIPEAdiisopropylethylamine
[422] DMAP4-dimethylamino pyridine
[423] DMFN, N-dimethylformamide
[424] DMSO dimethyl sulfoxide
[425] eq.equivalent
[426] EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl
[427] ESI-MS Electron Spray Ion Mass Spectrometer
[428] Et ethyl
[429] EtOAc ethyl acetate
[430] FMOC 9-Flulorenylmethyl Carbamate
[431] HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium
[432] HOAc hexafluorophosphate acetic acid
[433] HOAT 1-hydroxy-7-azabenzotriazole
[434] HOBT1-hydroxybenzotriazole hydrate
[435] HPLC High Performance Liquid Chromatography
[436] HRMS High Resolution Mass Spectrometer
[437] h hours
[438] LRMS low resolution mass spectrometer
[439] LAH lithium aluminum hydride
[440] Me methyl
[441] Ms methanesulfonyl
[442] NBSN-bromosuccinimide
[443] Pd ₂ (dba) ₃ Tris (dibenzylideneacetone) dipaladium (0)
[444] Phphenyl
[445] Phephenylalanine
[446] Pr profile
[447] r.t.room temperature
[448] TBAF Tetrabutylammonium Fluoride
[449] TBS tert-butyldimethylsilyl
[450] TFAtrifluoroacetic acid
[451] TEAtriethylamine
[452] THF tetrahydrofuran
[453] TLC thin layer chromatography
[454] Standard way
[455] The following standard methods (A) to (E) are used to prepare the compounds of the present invention as illustrated in the examples below.
[456] Standard Method (A): Mitsunobu Coupling of Aryl Alcohol Headpiece and Alcohol Tailpiece
[457] 2- (5-methyl-2-naphthalen-2-yl-oxazol-4-yl) -ethanol (112 mg, 0.442 mmol, 1 equiv) in 10 ml toluene, 3- [4-hydroxy-2- (iso A mixture of propoxycarbonylamino-methyl) -phenyl] propionic acid tert-butyl ester (150 mg, 0.445 mmol, 1.00 equiv) and triphenylphosphine (116 mg, 0.442 mmol, 1.00 equiv) was added at room temperature for about 3 minutes. Treated with diisopropyl azodicarboxylate (90 μL, 92 mg, 0.46 mmol, 1.0 equiv). The mixture was stirred for about 23 hours and concentrated. The crude material was purified by silica gel chromatography.
[458] Standard Method (B): Hydrolysis of Ester Under Acidic Conditions
[459] A solution of tert-butyl ester-containing compound (0.5 mmol) in CH ₂ Cl ₂ (6 ml) was treated with 90% trifluoroacetic acid / water (3 ml), stirred at ambient temperature for about 3 hours and then concentrated To obtain the corresponding carboxylic acid compound. The crude material was purified by silica gel chromatography if necessary.
[460] Standard Method (C): Hydrolysis of Ester Under Acidic Conditions
[461] A mixture of tert-butyl ester-containing compound (0.2 mmol) in 4M HCl in 1,4-dioxane (5 ml) was stirred at ambient temperature for about 16 hours and concentrated to give the corresponding carboxylic acid compound. The crude material was purified by silica gel chromatography if necessary.
[462] Standard Method (D): Hydrolysis of Ester Under Basic Conditions
[463] A solution of ester (0.25 mmol) in MeOH (3 ml) and THF (1.5 ml) was treated with 2N NaOH (1 ml) and heated at 55 ° C. for about 2 hours. The mixture was cooled and concentrated. The residue was partitioned between CH ₂ Cl ₂ (10 ml), brine (15 ml) and 5N HCl (1 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel chromatography if necessary.
[464] Preparation Example of Intermediate
[465] Tailpiece Production Example-Oxazole
[466] Preparation Example 1
[467] Toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) ethyl ester
[468]
[469] Step A : 4,5-dimethyl-2- (4-bromophenyl) -oxazole oxide
[470] A solution of 2,3-butanedione monooxime (50 g, 0.49 mmol) and 4-bromo-benzaldehyde (101 g, 0.54 mol) in acetic acid (500 ml) was cooled to 0 ° C. and the reaction was then stirred in an iced water bath with gas. HCl in state was passed through the solution into the bubble for 35 minutes. Diethyl ether (500 ml) was added to the reaction to precipitate the product, and the resulting slurry was stirred at 0 ° C. for 45 minutes and then filtered. The solid was rinsed with Et ₂ O (50 ml), poured into water (1 L) and concentrated NH ₄ OH (60 ml) was added to the slurry. The mixture was extracted with CHCl ₃ . The organic layer was dried (MgSO ₄ ) and concentrated to give 97.4 g (74%) of 4,5-dimethyl-2- (4-bromophenyl) -oxazole oxide as a white solid. The compound should be used directly for 24 to 48 hours.
[471]
[472] HRMS (TOF) m / z C ₁₁ H ₁₁ ⁷⁹ BrNO ₂ : calcd 267.997, found: 267.9951
[473] Step B : 2- (4-Bromophenyl-4- (chloromethyl) -5-methyloxazole
[474] A solution of 4,5-dimethyl-2- (4-bromophenyl) -oxazole oxide (96.6 g, 0.36 mol) in CHCl ₃ (0.90 L) was added dropwise to phosphorus oxychloride (61.1 g, 0.40 mol). The treatment was exothermic and then stirred at reflux for 30 minutes. The reaction was cooled to rt and washed with water (2 × 1 L). The organic layer was dried (MgSO ₄ ) and concentrated to afford the crude product which was recrystallized from hot hexane (300 ml) and the hot supernatant was decanted from the dark oily material. The remaining thick oil was stirred in additional hot hexane (200 ml) and the combined supernatants were cooled to 0 ° C. The product, lime green powder, was isolated by filtration (74.2 g, 72%). Rf = 0.39 (in 20% ethyl acetate / hexanes)
[475]
[476] HRMS (FAB) m / z calc'd for C ₁₁ H ₁₀ ⁷⁹ BrClNO: 285.9634, found 285.9641;
[477] Calcd for C ₁₁ H ₉ ClBrNO: C, 46.11; H, 3.17; N, 4.89; Cl; 12.37; Br, 27.88.
[478] Found C, 46 28; H 3.07; N, 4.81; Cl, 12.36; Br, 27.88
[479] Step C : 2- (4-Bromophenyl) -5-methyl-4-oxazoleacetic acid
[480] Powdered potassium cyanide (22.1 g, 0.34 mol) and potassium iodine with a solution of 2- (4-bromophenyl-4- (chloromethyl) -5-methyloxazole (64.8 g, 0.23 mol) in DMF (400 ml) Died (28.6 g, 0.17 mol) was added and the resulting mixture was heated for 3.5 h to 85 ° C. The reaction mixture was cooled to room temperature Potassium carbonate (5 g) was dissolved in water (800 mg) and the reaction Was added dropwise to precipitate 2- (4-brorophenyl-4- (cyanomethyl) -5-methyloxazole (stirring vigorously for 15 minutes after addition), which was then separated by filtration and with water (2x400ml) The crude 2- (4-bromophenyl-4- (cyanomethyl) -5-methyloxazole was used without purification in the next step.
[481]
[482] Crude 2- (4-bromophenyl-4- (cyanomethyl) -5-methyloxazole (about 0.22 mmol) was combined with 2-methoxyethanol (630 ml) to yield 85% solid KOH in water (360 ml) ( 74.6 g, 1.33 mol) was added to the reaction The mixture was heated to reflux for 3 hours, quenched with 2M HCl (500 ml) and extracted with CH ₂ Cl _{2 The} organic layer was dried (MgSO ₄ ) and concentrated The remaining 2-methoxyethanol was removed by azeotropic distillation using toluene The crude product (57.3 g) was recrystallized from toluene (450 ml) to give an off-white powder of 2- (4-bromophenyl) -5-methyl-4 -Oxazole acetic acid 39.89 (60%) was obtained: Rf = 0.23 (in 10% MeOH / CH ₂ Cl ₂ );
[483]
[484] UV (EtOH) _{up to} 288 nm (19626)
[485] Step D : 2- (4-Bromophenyl) -5-methyl-4-oxazolethanol
[486]
[487] A solution of 2- (4-bromophenyl) -5-methyl-4-oxazoleacetic acid (39.1 g, 0.13 mol) in anhydrous THF (175 ml) was added to the borane / THF complex (in THF over 2 hours at about 35 ° C). 227 ml of 1.0 M solution, 1.3 mol) was added dropwise. After stirring for 2 hours at room temperature under N ₂ , the reaction was quenched by the slow addition of methanol (60 ml) and stirred at room temperature overnight. The reaction was diluted with 1N NaOH (50 ml) and extracted with CH ₂ Cl ₂ ( ₂ × ₂₀₀ ml). The organic layer was washed with H ₂ O (3 × 100 ml), dried (MgSO ₄ ) and concentrated. The crude product (38.7 g) was recrystallized from toluene (200 ml, solid washed with cold hexane) to give 26.9 g (72%) of 2- (4-bromophenyl) -5-methyl-4-oxazoleethanol as a white powder Got. Rf = 0.37 (in 10% MeOH / CH ₂ Cl ₂ ).
[488]
[489] Calcd for C ₁₂ H ₁₂ BrNO ₂ : C, 51.09; H, 4. 29; N, 4.96; Br, 28.32.
[490] Found: C, 51.31; H, 4.06; N, 4.90; Br, 28.19.
[491] Step E: 2- (biphenyl-4-yl-5-methyl-oxazol-4-yl) ethanol
[492]
[493] 2- (4-bromophenyl) -5-methyl-4-oxazolethanol (10.0 g, 35.0 mmol) and phenylboronic acid (4.5 g, 38.0 mmol) were dissolved in n-propanol (120 ml), followed by Phenylphosphine (165.2 mg, 0.63 mmol), palladium acetate (46 mg, 2.1 mmol) and Na ₂ CO ₃ (4.5 g, 42 mmol in 30 ml distilled water) were added. The solution was heated at reflux and stirred for 1.5 h. After cooling to room temperature, the mixture was concentrated and then partitioned between CH ₂ Cl ₂ (100 ml) and 1N NaOH (100 ml). The aqueous phase was extracted with CH ₂ Cl ₂ ( ₂ × 50 ml). The combined organic phases were dried (MgSO ₄ ) and concentrated under reduced pressure to afford 2- (4-biphenyl) -5-methyl-4-oxazolethanol (9.5 g, 97% yield) as a white solid, directly without further purification. Used.
[494]
[495] Step F : Toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) ethyl ester
[496] Pyridine (14.7 g, at room temperature under N _{2 with} a solution of 2- (biphenyl-4-yl-5-methyl-oxazol-4-yl) ethanol (15.8 g, 56.6 mmol) in CH ₂ Cl ₂ (250 ml) 185 mmol, 15.0 ml), DMAP (2.03 g, 16.6 mmol) and tosyl anhydride (24.57 g, 75.2 mmol) were added in portions. The reaction was exothermic to 32 ° C., stirred for 30 minutes, and then additional tosyl anhydride (2.3 g) was added. The mixture was diluted with CH ₂ Cl ₂ (100 ml) and stirred vigorously with 1N HCl (150 ml) for 15 minutes. The organic phase was dried (MgSO ₄ ) and filtered through a pad of silica gel (100 ml, packed with CH ₂ Cl ₂ ). The silica gel was eluted with ethyl acetate (100 ml), and the solution was concentrated to give white solid toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) ethyl ester Was obtained (23.3 g, 95%). Rf = 0.51 (in 60% ethyl acetate / hexanes)
[497]
[498] Preparation Example 2
[499] Toluene-4-sulfonic acid 2- (4-bromophenyl-5-methyl-oxazol-4-yl) ethyl ester
[500]
[501] The title compound was prepared according to Method 1, step F from 2- (4-bromophenyl) -5-methyl-4-oxazolethanol: MS (ESI) m / z 436.0 (M + H) ⁺ .
[502] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparations 1 and 2.
[503] 2- (3-Bromophenyl) -5-methyl-4-oxazolethanol :
[504]
[505]
[506] Toluene-4-sulfonic acid 2- (3-bromophenyl-5-methyl-oxazol-4-yl) ethyl ester
[507]
[508]
[509] Toluene-4-sulfonic acid 2- (2-biphenyl-3-yl-5-methyl-oxazol-4-yl) ethyl ester
[510]
[511]
[512] 2- (5-methyl-2-thiophen-2-yl-4-oxazolethanol
[513]
[514]
[515] Toluene-4-sulfonic acid-2- (5-methyl-2-thiophen-2-yloxazol-4-yl) ethyl ester
[516]
[517]
[518] 2- [2- (4-benzyloxy-phenyl) -5-methyl-oxazol-4-yl] -ethanol
[519]
[520]
[521] MS (ES ⁺ ) Analyzes of C ₁₉ H ₂₀ NO ₃ Calculated: found m / e 310 (MH, 100%)
[522] Toluene-4-sulfonic acid 2- [2- (4-benzyloxy-phenyl) -5-methyl-oxazol-4-yl] -ethyl ester
[523]
[524]
[525] HRMS (ES ⁺ ) calc'd for C ₂₆ H ₂₆ NO ₅ S: 464.1532, found: 464.1531;
[526] Chemical analysis of C ₂₆ H ₂₅ NO ₅ S: calc .: C, 67.37; H, 5. 44; N, 3.02
[527] Found: C, 66.59; H, 5. 33; N, 3.06
[528] Preparation Example 3
[529] Toluene-4-sulfonic acid 2- (5-methyl-2-phenethyl-oxazol-4-yl) -ethyl ester
[530]
[531] Step A: 2- (3-phenyl-propionylamino) -succinic acid 4-methyl ester
[532]
[533] The solution was cooled to 5 ° C. by combining methyl L-aspartate (15.0 g, 0.082 mol), DI water (245 ml), acetone (20 ml) and Na ₂ CO ₃ (30.8 g, 0.286 mol). Compound 3-phenyl-propionyl chloride (13.3 ml, 0.089 mol) was added dropwise via addition funnel over 10 minutes. The reaction was allowed to warm to room temperature and stirred for 2 hours. Concentrated HCl (50 ml) was added to the thick slurry until the pH was below 4.0. The reaction mixture was extracted with CH ₂ Cl ₂ (3 × 100 ml). The combined organic layers were washed with water, dried (MgSO ₄ ), filtered and concentrated. Clear and colorless oils were used without further purification.
[534]
[535] Step B: 4-oxo-3- (3-phenyl-propionylamino) -pentanoic acid methyl ester
[536]
[537] 2- (3-phenyl-propionylamino) -succinic acid 4-methyl ester (10 g, 36 mmol), pyridine (50 mL) and acetic anhydride (45 mL) were combined in 500 ml flask. The reaction mixture was heated at 90 ° C. for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, then DI water was added (100 ml). The reaction mixture was partitioned between water and CH ₂ Cl ₂ (200 ml). The organic phase was washed with 1N HCl (50 ml), dried (MgSO ₄ ), filtered and concentrated. The material was used without further purification.
[538]
[539] Step C: (5-Methyl-2-phenethyl-oxazol-4-yl) -acetic acid methyl ester
[540]
[541] 4-oxo-3- (3-phenyl-propionylamino) -pentanoic acid methyl ester (10 g, 36 mmol) and acetic anhydride (28 ml) were combined in a 100 ml flask. After addition of concentrated H ₂ SO ₄ (1 ml), the solution was heated to 90 ° C. for 30 minutes and cooled to room temperature. The reaction was slowly diluted with DI water (30 ml, latent exotherm). The reaction mixture was partitioned between CH ₂ Cl ₂ (150 ml) and water (150 ml). The organic phase was washed with DI water, 10% NaHCO ₃ (aq), brine (150 ml) and concentrated to brown oil. The residue was purified by column chromatography (600ml SiO ₂ , 35% EtOAc / hexanes) to give the desired product (3.25 g) as a pale yellow oil.
[542]
[543] Step D: (5-Methyl-2-phenethyl-oxazol-4-yl) -acetic acid
[544]
[545] (5-Methyl-2-phenethyl-oxazol-4-yl) -acetic acid methyl ester (8.75 g, 33.8 mmol) in MeOH (120 mL) was treated with 5N NaOH (40 mL), and then the solution was brought to 40 ° C. Warmed. After 40 minutes, the reaction mixture was concentrated. The residue was suspended in water (75 ml) and acidified to pH = 1 with 5N HCl. The mixture was extracted with EtOAc (2 ×), dried (MgSO ₄ ) and concentrated to give 5.25 g (63%) of an off-white solid product.
[546]
[547] Step E: 2- (5-Methyl-2-phenethyl-oxazol-4-yl) -ethanol
[548]
[549] BH ₃ -THF complex (49 ml of 1.0 M solution in THF) over 50 minutes (5-methyl-2-phenethyl-oxazol-4-yl) -acetic acid (5.05 g) in THF (35 ml) via funnel , 20.6 mmol) in a dropwise solution. The reaction mixture was stirred at room temperature for 3 hours and then quenched with MeOH (12 ml). After heating to 50 ° C. for 2 hours, the reaction mixture was cooled to room temperature and then partitioned between CH ₂ Cl ₂ and 1N NaOH. The organic phase was washed with brine (1 × 50 ml), dried over MgSO ₄ and concentrated to give a residue, which was purified by column chromatography (500 ml SiO ₂ , 35% EtOAc / hexanes) to give a clear, colorless oil. 3.99 g (84%) was obtained.
[550]
[551] Step F: Toluene-4-sulfonic acid 2- (5-methyl-2-phenethyl-oxazol-4-yl) -ethyl ester
[552] A solution of 2- (5-methyl-2-phenethyl-oxazol-4-yl) -ethanol (1.2 g, 5.19 mmol) in CH ₂ Cl ₂ at 0 ° C. was pyridine (1.64 g, 20.7 mmol, 1.68 ml). , DMAP (190 mg, 1.56 mmol) and tosyl anhydride (2.2 g, 6.75 mmol). The reaction was allowed to warm to room temperature and after 90 minutes the solution was passed through a pad of silica gel (rinsed with CH ₂ Cl ₂ ). The product was used without further purification.
[553]
[554] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparation Example 3.
[555] 2- (2-Cyclohexyl-5-methyl-oxazol-4-yl) -ethanol:
[556]
[557] Toluene-4-sulfonic acid 2- (2-cyclohexyl-5-methyl-oxazol-4-yl) -ethyl ester
[558]
[559] 2- [5-methyl-2- (1-methylcyclohexyl) oxazol-4-yllethanol
[560]
[561] Toluene-4-sulfonic acid 2- [5-methyl-2- (1-methylcyclohexyl) oxazol] -4-yl] ethyl ester
[562]
[563] 2- [5-Methyl-2- (tetrahydro-pyran-4-yl) -oxazol-4-yl] -ethanol
[564]
[565] Toluene-4-sulfonic acid 2- [5-methyl-2- (tetrahydro-pyran-4-yl) -oxazol-4-yl] -ethylester
[566]
[567] 2- (2-benzyl-5-methyl-oxazol-4-yl) -ethanol
[568]
[569] Toluene-4-sulfoic acid 2- (2-benzyl-5-methyl-oxazol-4-yl) -ethyl ester
[570]
[571] 2- (2-Benzo [b] thiophen-2-yl-5-methyl-oxazol-4-yl) -ethanol
[572]
[573] Toluene-4-sulfonic acid 2- (2-benzo [b] thiophen-2-yl-5-methyl-oxazol-4-yl) -ethyl ester
[574]
[575] 2- (5-Methyl-2-naphthalen-2-yl-oxazol-4-yl) -ethanol
[576]
[577] HRMS calcd for C ₁₆ H ₁₆ NO ₂ : m / z 254.1181 Found: 254.1167
[578] 2- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl] -ethanol
[579]
[580] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl] -ethyl ester
[581]
[582] 2- [2- (4-Butoxy-phenyl) -5-methyl-oxazol-4-yl] -ethanol
[583]
[584] Toluene-4-sulfonic acid 2- [2- (4-butoxy-phenyl) -5-methyl-oxazol-4-yl] -ethyl ester
[585]
[586] 2- (2-Bromophenyl-5-methyl-oxazol-4-yl) -ethanol
[587]
[588] Toluene-4-sulfonic acid 2- (2-bromophenyl-5-methyl-oxazol-4-yl) ethyl ester
[589]
[590] Preparation Example 4
[591] Toluene-4-sulfonic acid 2- [2- (6-chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] -ethyl ester
[592]
[593] Step A : 3- [2- (6-Chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] -acetic acid methyl ester
[594]
[595] According to Preparation Example 3, steps A to C, 6-chloronicotinic acid was converted to the title compound. MS (ESI) m / z 267 (M + H) ⁺ .
[596] Step B : 3- [2- (6-Chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] -ethanol
[597]
[598] A solution of 3- [2- (6-chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] -acetic acid methyl ester (500 mg, 1.88 mmol) in THF (20 ml) at 0 ° C. Treatment with LAH (90 mg, 2.3 mmol). The reaction mixture was stirred for 1 hour and quenched with water (0.1 ml), 15% NaOH (0.1 ml) and water (0.3 ml). The mixture was filtered through celite and concentrated to afford the title alcohol used in the next step without further purification. MS (ESI) m / z 239 (M + H) ⁺
[599] Step C : Toluene-4-sulfonic acid 2- [2- (6-chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] -ethyl ester
[600] A solution of crude 3- [2- (6-chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] ethanol in CH ₂ Cl ₂ (10 ml) was dissolved in para-toluenesulfonyl chloride (0.4 g). , 2.3 mmol), DMAP (40 mg) and triethylamine (0.4 ml, 2.82 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH ₂ Cl ₂ (20 ml). The mixture was washed with water and the organic layer was dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica gel chromatography (hexane / EtOAc 10/1 to 2/1) to give the title compound (295 mg, 40% over two steps). MS (ESI) m / z 393 (M + H) ⁺
[601] Preparation Example 5
[602] Toluene-4-sulfonic acid 2- {5-methyl-2- [4- (methyl-phenyl-amino) -phenyl] -oxazol-4-yl} ethyl ester
[603]
[604] Step A : 4- (2-benzyloxy-ethyl) -2- (4-bromo-phenyl) -5-methyl-oxazole
[605]
[606] A solution of 2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] -ethanol (3.17 g, 11.2 mmol) in DMF (25 ml) was washed with NaH (0.67 g, 60% oil dispersion) and stirred for 5 minutes. Benzyl bromide (2.90 g, 16.9 mmol) was added and the resulting mixture was stirred at rt for 3 h. The reaction was quenched with water and the mixture was extracted with EtOAc (2 × 150 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography column (10% EtOAc / hexanes) to afford the title compound as an oil (2.50 g, 60%).
[607] Step B : {4- [4- (2-Benzyloxy-ethyl) -5-methyl-oxazol-2-yl] -phenyl} -methyl-phenyl-amine
[608]
[609] Nitrogen gas flow in a closed tube with a solution of 4- (2-benzyloxy-ethyl) -2- (4-bromo-phenyl) -5-methyl-oxazole (200 mg, 0.538 mmol) in toluene (5.0 ml) Pd (OAc) ₂ (50 mg), 2- (di-t-butylphosphino) biphenyl (20 mg), N-methyl aniline (115 mg, 1.08 mmol) and sodium t-butoxide (104 mg, 1.08) mmol). The tube was sealed and heated at 105 ° C. for 14 hours. The mixture was cooled and purified directly by silica gel column chromatography (30-50% EtOAc / hexanes) to give the title compound (195 mg, 91%). MS (ESI) m / z 399.3 (M + H) ⁺ .
[610] Step C : 2- {5-Methyl-2- [4- (methyl-phenyl-amino) -phenyl] -oxazol-4-yl} -ethanol
[611]
[612] {4- [4- (2-benzyloxy-ethyl) -5-methyl-oxazol-2-yl] -phenyl} -methyl-phenyl-amine (195 mg, in THF (2 mL) and EtOH (10 ml) 0.490 mmol) was treated with a slurry of Pd / C (200 mg) in EtOH (2 ml). The resulting mixture was treated with hydrogen under balun pressure for 14 hours and the celite pad was filtered off. The filtrate was concentrated and the crude product was purified by silica gel chromatography column (50% EtOAc / hexanes) to give the title compound (91 mg, 60%).
[613] Step D : Toluene-4-sulfonic acid 2- {5-methyl-2- [4- (methyl-phenyl-amino) -phenyl] -oxazol-4-yl} -ethyl ester
[614] Solution of 2- {5-methyl-2- [4- (methyl-phenyl-amino) -phenyl] -oxazol-4-yl} -ethanol (91 mg, 0.30 mmol) in CH ₂ Cl ₂ (4.0 mL) Was treated with a small amount of crystals of para-toluenesulfonyl chloride (68 mg, 0.36 mmol), triethyl amine (0.20 mL) and DMAP. The resulting mixture was stirred at rt for 14 h and quenched with water (0.2 ml). The mixture was purified directly by silica gel column chromatography (40% EtOAc / hexanes) to give the title compound (120 mg, 83%). MS (ESI) m / z 463.1 (M + H) ⁺ .
[615] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparation 5.
[616] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-phenylamino-phenyl) -oxazol-4-yl] -ethyl ester
[617]
[618] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-morpholin-4-yl-phenyl) -oxazol-4-yl] -ethyl ester
[619]
[620] Preparation Example 6
[621] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-phenoxy-phenyl) -oxazol-4-yl] -ethyl ester
[622]
[623] Step A: 4- (2-benzyloxy-ethyl) -5-methyl-2- (4-phenoxy-phenyl) -oxazole
[624]
[625] 4- (2-benzyloxy-ethyl) -2- (4-bromo-phenyl) -5-methyl-oxazole (0.025 mol, 9.2 g) in toluene (350 ml), phenol (0.03 mol, 2.8 g), A mixture of K ₃ PO ₄ (0.05 mol, 10.6 g), 2- (di-tert-butylphosphino) biphenyl (1.8 mmol, 0.54 g) and Pd (OAc) ₂ (1.2 mmol, 0.28 g) in nitrogen Degassing and heated at 100 ° C. for 18 h. Additional Pd (OAc) ₂ (0.5 g) and phosphine ligand (1.0 g) were added and the mixture was heated at 100 ° C. for 5 hours. The reaction was concentrated and purified directly by silica chromatography (4/1 hexanes / ethyl acetate) to give the title compound (7.6 g).
[626] Step B : Toluene-4-sulfonic acid 2- [5-methyl-2- (4-phenoxy-phenyl) -oxazol-4-yl] -ethyl ester
[627] According to Preparation Example 5, steps C to D, 4- (2-benzyloxy-ethyl) -5-methyl-2- (4-phenoxy-phenyl) -oxazole was converted to the title compound.
[628]
[629] Preparation Example 7
[630] 4-Methyl-3-nitro-benzenesulfonic acid 2- [5-methyl-2- (4-nitro-phenyl) -oxazol-4-yl] -ethyl ester
[631]
[632] A mixture of potassium nitrate (3.0 g, 30 mmol, 2.7 equiv) and sulfuric acid (10 ml, 18 g, 94 mmol, 17 equiv) was cooled to 0 ° C. Toluene-4-sulfonic acid 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethyl ester (4.00 g, 11.2 mmol, 1 equiv) was added and the cold water bath was removed. The reaction mixture was heated using a heat gun until the tosylate was dissolved. After 30 minutes, the solution was poured into H ₂ O (100 ml) and extracted with EtOAc (100 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to orange oil (4.41 g) (75 ° C.). The crude product was purified by silica gel chromatography (30-50% EtOAc / hexanes) to give the title compound as a yellow solid (3.64 g, 73%). MS (ESI) m / z 447 (M + H) ⁺ .
[633] Preparation Example 8
[634] Toluene-4-sulfonic acid 2- (5-methoxy-2-phenyl-oxazol-4-yl) -ethyl ester
[635]
[636] Step A : 2-benzoylamino-succinic acid dimethyl ester
[637]
[638] A mixture of benzoyl chloride (3.20 mL, 27.7 mmol), L-aspartic acid dimethyl ester (5.0 g, 25.2 mmol) and triethyl amine (5.3 mL, 38 mmol) in CH ₂ Cl ₂ (50 ml) at room temperature for 2 hours. Stir and dilute with water. The organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 1/1) to give a white solid (5.3 g, 79%). MS (ESI) m / z 266 (M + H) ⁺ .
[639] Step B : 3- (5-methoxy-2-phenyl-oxazol-4-yl) -acetic acid methyl ester
[640]
[641] A mixture of 2-benzoylamino-succinic acid dimethyl ester (5.3 g, 20 mmol) in 1,2-dichloroethane (15 mL) was treated with P ₂ O ₅ (5.3 g, 30 mmol) and celite (3.2 g), Heated at 85 ° C. for 2 hours. The solvent was decanted and concentrated. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ . The organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 10/1 to 3/1) to give the title compound (2.9 g, 59%). MS (ESI) m / z 247 (M + H) ⁺ .
[642] Step C : 3- (5-methoxy-2-phenyl-oxazol-4-yl) -ethanol
[643]
[644] Suspension of LAH (0.56 g, 14.1 mmol) in THF (100 mL) was added 3- (5-methoxy-2-phenyl-oxazol-4-yl) -acetic acid methyl ester (2.9 g, 11.7 mmol) in THF (100 mL). Was added dropwise to the solution. After the addition was complete, the reaction mixture was allowed to warm to room temperature, cooled to -20 ° C and quenched with H ₂ O (0.8 ml), 15% NaOH (0.8 ml) and H ₂ O (2.4 ml). The mixture was filtered through celite and concentrated to give the title compound as an oil. MS (ESI) m / z 220.3 (M + H) ⁺ .
[645] Step D : Toluene-4-sulfonic acid 2- (5-methoxy-2-phenyl-oxazol-4-yl) -ethyl ester
[646] A solution of crude 3- (5-methoxy-2-phenyl-oxazol-4-yl) -ethanol (1.7 mmol max.) In CH ₂ Cl ₂ (100 ml) was dissolved in para-toluenesulfonyl chloride (2.7 g, 14.0 mmol), DMAP (100 mg) and triethylamine (2.5 mL, 17.6 mmol). The reaction mixture was stirred for 16 h at room temperature and washed with water. The organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc, 10/1 to 1/1) to afford the title compound (2.0 g, 46% over two steps). MS (ESI) m / z 374 (M + H) ⁺ .
[647] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparation Example 8.
[648] 2- (2-Biphenyl-4-yl-5-methoxy-oxazol-4-yl) -ethanol
[649]
[650] Toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methoxy-oxazol-4-yl) -ethyl ester
[651]
[652] Preparation Example 9
[653] Toluene-4-sulfonic acid 2- [5-methyl-2- (6-phenyl-pyridin-3-yl) thiazol-4-yl] ethyl ester
[654]
[655] Step A: 2-phenyl-5-cyanopyridine
[656]
[657] 5-cyano-2-chloropyridine (5.0 g, 36.1 mmol), phenylboronic acid (6.6 g, 54 mmol) in toluene (100 ml), tetrakis (triphenylphosphine) palladium (0) (0.5 g) and Aqueous Na ₂ CO ₃ (7.6 g) was heated at 90 ° C. for 16 h. The mixture was diluted with EtOAc and washed with H ₂ O. The organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 2/1) to give the title compound (6.1 g, 94%). MS (ESI) m / z 181 (M + H) ⁺ .
[658] Step B:
[659]
[660] A mixture of 2-phenyl-5-cyanopyridine (6.0 g, 33 mmol) and thioacetamide (4.0 g, 53 mmol) in 4N HCl in 1,4-dioxane (50 ml) was heated at 98 ° C. for 20 hours. The reaction mixture was cooled down and poured into aqueous saturated NaHCO ₃ . The precipitate was collected, washed with water and dried under vacuum (60 ° C.) to afford the title compound as a yellow solid (7.0 g, 99%).
[661] Step C: [5-Methyl-2- (6-phenyl-pyridin-3-yl) -thiazol-4-yl] -acetic acid methyl ester
[662]
[663] A mixture of 6-phenyl-thionicotinamide (7.0 g) and 4-bromo-3-oxopentanoic acid methyl ester (9.15 g, 35 mmol) in 1,4-dioxane (30 ml) was heated to reflux for 4 hours. It was. The reaction mixture was cooled down, poured into aqueous saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified using silica gel chromatography (hexane / EtOAc) to give the title compound (6.0 g, 56%). MS (ESI) m / z 325 (M + H) ⁺ .
[664] Step D : [5-Methyl-2- (6-phenyl-pyridin-3-yl) -thiazol-4-yl] -ethanol
[665]
[666] A solution of [5-methyl-2- (6-phenyl-pyridin-3-yl) -thiazol-4-yl] -acetic acid methyl ester (6.0 g, 18.5 mmol) in THF (500 ml) was THF at -78 ° C. (300 ml) was added dropwise with a suspension of LAH (0.90 g, 22.2 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and cooled to _{-20 ℃, H 2 O (1.1ml} ), was subsequently quenched with a 15% NaOH (1.1ml) and H ₂ O (3.3ml). The mixture was filtered through celite and the filtrate was concentrated to give the title compound as an oil which was used directly in the next step.
[667] Step E: Toluene-4-sulfonic acid 2- [5-methyl-2- (6-phenyl-pyridin-3-yl) thiazol-4-yl] ethyl ester
[668] [5-methyl-2- (6-phenyl-pyridin-3-yl) -thiazol-4-yl] -ethanol (18.5 mmol max) in CH ₂ Cl ₂ (300 ml), para-toluenesulfonyl chloride (3.89 g, 20.5 mmol), DMAP (500 mg) and triethylamine (4.0 mL, 28.0 mmol) were stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and the organic layer was separated, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc, 10/1 to 1/1) to give the title compound as a solid (2.0 g, 46% over two steps). MS (ESI) m / z 451 (M + H) ⁺ .
[669] The following intermediate compounds were prepared in a substantially similar manner as described in Preparation 9.
[670] 2- [5-methyl-2- (5-phenyl-pyridin-3-yl) -thiazol-4-yl] -ethanol
[671]
[672] Toluene-4-sulfonic acid 2- [5-methyl-2- (5-phenyl-pyridin-3-yl) thiazol-4-yl] ethyl ester
[673]
[674] Toluene-4-sulfonic acid 2- [5-methyl-2- (6-phenoxy-pyridin-3-yl) -thiazol-4-yl] -ethyl ester
[675]
[676] Toluene-4-sulfonic acid 2- [5-methyl-2- (6-morpholin-4-yl-pyridin-3-yl) -thiazol-4-yl] ethyl ester
[677]
[678] 4- {5-Methyl-4- [2- (toluene-4-sulfonyloxy) -ethyl] -thiazol-2-yl} piperazin-1-carboxylic acid tert-butyl ester
[679]
[680] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-methyl-piperazin-1-yl) -thiazol-4-yll-ethyl ester
[681]
[682] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-phenyl-piperazin-1-yl) -thiazol-4-yl] -ethyl ester
[683]
[684] 2- (5-Methyl-2-phenyl-thiazol-4-yl) -ethanol
[685]
[686] Toluene-4-sulfonic acid 2- (5-methyl-2-phenyl-thiazol-4-yl) -ethyl ester:
[687]
[688] 2- (2-Biphenyl-4-yl-5-methyl-thiazol-4-yl) -ethanol
[689]
[690] Toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyl-thiazol-4-yl) -ethyl ester
[691]
[692] Toluene-4-sulfonic acid 2- (5-methyl-2-pyridin-2-ylthiazol-4-yl) ethyl ester
[693]
[694] Toluene-4-sulfonic acid 2- (5-methyl-2-pyridin-3-ylthiazol-4-yl) ethyl ester
[695]
[696] Toluene-4-sulfonic acid 2- (5-methyl-2-pyridin-4-ylthiazol-4-yl) ethyl ester
[697]
[698] Toluene-4-sulfonic acid 2- [2- (2-methoxyethylamino) -5-methylthiazol-4-yl] ethyl ester
[699]
[700] Pyrazole
[701] Preparation Example 10
[702] Toluene-4-sulfonic acid 2- (5-methyl-3-phenyl-pyrazol-1-yl) -ethyl ester
[703]
[704] Step A: 5-methyl-3-phenyl-1H-pyrazole
[705]
[706] Hydrazine hydrate (9.0 ml, 99 mmol, 35 wt% in H ₂ O; 0.64 equiv) was added as a solution of benzoylacetone (25.00 g, 154.1 mmol, 1 equiv) in ethanol (250 ml). After stirring for 14 hours, additional hydrazine hydrate (8.0 ml, 88 mmol, 0.57 equiv) was added. After 2 hours, the reaction solution was concentrated (95 ° C.) to give the title compound as a white solid (24.31 g, 99.7%). HRMS calcd for C ₁₀ H ₁₁ N ₂ : m / z 159.0922. Found: 159.0917
[707] Step B : 2- (5-Methyl-3-phenyl-pyrazol-1-yl) -ethanol
[708]
[709] 5-methyl-3-phenyl-1H-pyrazole (9.00 g, 56.9 mmol, 1 in DMF (90 ml) cooled sodium hydrate (2.5 g, 1.5 g NaH, 62 mmol, 1.1 equiv) in a cold water bath at 0 ° C. Equivalents) over 3 minutes. After stirring for 15 minutes, ethylene carbonate (7.6 ml, 10 g, 110 mmol, 2.0 equiv) was added. The water bath was removed and the reaction mixture was stirred for 15 hours. The mixture was treated with 4M aqueous K ₂ CO ₃ (90 ml), heated to reflux for 5 hours, and diluted with H ₂ O (200 ml). After the hot mixture was cooled for 15 minutes, additional H ₂ O (100 ml) was added followed by hexane (100 ml). The mixture was stirred vigorously and then allowed to separate. Crystals formed and were present in the upper organic layer. The aqueous layer was separated and the crystals were collected by vacuum filtration and washed with hexane (2x50 ml). The crystals were dissolved in Et ₂ O / EtOAc (1: 1; 200 ml), the solution was dried (Na ₂ SO ₄ ), filtered and concentrated (75 ° C.) to give the title compound as an off-white crystalline solid (6.86 g). , 59.6%). HRMS calcd for C ₁₂ H ₁₅ N ₂ O: m / z 203.1184. Found: 203.1168
[710] Step C : Toluene-4-sulfonic acid 2- (5-methyl-3-phenyl-pyrazol-1-yl) -ethyl ester
[711] Following Preparation Example 9, Step E, 2- (5-methyl-3-phenyl-pyrazol-1-yl) ethanol was converted to the title compound. MS (ESI) m / z 357 (M + H) ⁺ .
[712] Preparation Example 11
[713] 2- (3-Biphenyl-4-yl-5-methyl-pyrazol-1-yl) -ethanol
[714]
[715] Step A : 5-biphenyl-4-yl-3-methyl-1H-pyrazole
[716]
[717] To a stirred mixture of NaH (1.98 g, 0.049 mol, 60% oil dispersion) in dry THF (30 ml) to diethoxyphosphorylacetone tosyl hydrazone (8.98 g, 0.024) in a mixture of THF (35 ml) and DMF (5.0 ml) mol; N Almirante Syn. Lett. 1999, 302.) was added dropwise over 15 minutes. The yellow suspension was stirred at 0-5 ° C. for 30 minutes and treated with 4-biphenyl carboxaldehyde (3.10 g, 0.0169 mol) in dry THF (30 ml) at 0-5 ° C. over 15 minutes. The orange solution was heated, stirred at reflux for 4 h and stirred overnight at room temperature. The mixture was poured into 5% aqueous NaH ₂ PO ₄ (350 ml) and extracted with EtOAc (2 × 200 ml). The organic layers were combined, washed with brine, dried (MgSO ₄ ), filtered and concentrated to a yellow semisolid. The material was triturated with hot EtOAc (2 × 10 ml) and filtered. The solid was washed with EtOAc (2 × 10 ml) and dried under hot vacuum to give the title compound (2.61 g, 47%):
[718] HRMS calcd for C ₁₆ H ₁₅ N ₂ : m / z 235.1235. Found: 235.1230.
[719] Step B : 2- (3-Biphenyl-4-yl-5-methyl-pyrazol-1-yl) -ethanol
[720] The title compound was prepared from 5-biphenyl-4-yl-3-methyl-1H pyrazole following Preparation Example 10, step B. HRMS calcd for C ₁₈ H ₁₉ N ₂ O: m / z 279.1497. Found: 279.1496.
[721] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparations 10 and 11.
[722] 2- [3- (4-Bromo-phenyl) -5-methyl-pyrazol-1-yl] -ethanol
[723]
[724] HRMS calcd for C ₁₂ H ₁₄ BrN ₂ O: m / z 281.0289. Found: 281.0288.
[725] 3-methyl-5-naphthalen-2-yl-1H-pyrazole
[726]
[727] HRMS calcd for C ₁₄ H ₁₂ N ₂ : m / z 208.1001. Found: 208.0981.
[728] 2- (5-Methyl-3-naphthalen-2-yl-pyrazol-1-yl) -ethanol
[729]
[730] HRMS calcd for C ₁₆ H ₁₇ N ₂ O: m / z 253.1341. Found: 253.1339.
[731] 3-methyl-5-naphthalene-I-yl-1 H-pyrazole
[732]
[733] Calc'd for C ₁₄ H ₁₂ N ₂ : C, 80.74; H, 5.81; N, 13.45. Found: C, 80.93; H, 5.70; N, 13.42; mp 115-117 ° C.
[734] 2- (5-Methyl-3-naphthalen-1-yl-pyrazol-1-yl) -ethanol
[735]
[736] Aryl ether bromide production example
[737] Preparation Example 12
[738] 2- (2-bromo-ethoxy) -6-methoxynaphthalene
[739]
[740] To a solution of 6-methoxynaphthalen-2-ol (1.07 g, 6.14 mmol) in DMF (4 ml) was added cesium carbonate (3.11 g, 9.55 mmol) and dibromoethane (2.5 ml, 29 mmol). The mixture was stirred and heated at 55 ° C. for 48 h. The reaction mixture was cooled down, filtered, diluted with EtOAc and washed with brine (2 × 30 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified using radial chromatography (2:98 to 25:75 EtOAc: hexane) to give the title compound as a white solid (0.52 g, 30%).
[741]
[742] The following intermediate compounds are prepared in a manner substantially similar to that described in Preparation 12.
[743] 6- (2-bromoethoxy) -3-phenylbenzofuran
[744]
[745] The compound is referred to as 3-phenylbenzofuran-6-ol (see Bull. Soc. Chim. Fr., 942 (1962)). ¹ H NMR (400 MHz, CDC13) δ 3.60 (t, J = 6.4 Hz, 2H), 4.28 (t, J = 6.4 Hz, 2H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 7.26-7.30 (m, 1H), 7.36-7.44 (m, 2H), 7.52-7.56 (m, 2H), 7.63 (d, J = 9.8 Hz, 2H).
[746]
[747] 4- (2-bromoethoxy) -1-phenoxybenzene
[748]
[749] 4- (3-Bromoethoxy) biphenyl : MS (ESI) m / z 295 (M + NH ₃ ) ⁺ .
[750] 3- (2-bromoethoxy) biphenyl:
[751]
[752] 6- (4-bromopropoxy) -3-phenylbenzofuran:
[753]
[754] 2- (4-bromopropoxy) -6-methoxynaphthalene:
[755]
[756] 3- (4-bromopropoxy) biphenyl:
[757]
[758] 4- (3-Bromopropoxy) -biphenyl:
[759]
[760] 4- (3-bromoproxy) -1-phenoxybenzene:
[761]
[762] 2- (4-bromobutoxy) -6-methoxynaphthalene:
[763]
[764] 6- (4-bromobutoxy) -3-phenylbenzofuran:
[765]
[766] 4- (4-bromobutoxy) biphenyl
[767]
[768] 3- (4-bromobutoxy) biphenyl
[769]
[770] 4- (4-bromobutoxy) -1-phenoxybenzene
[771]
[772] Headpiece Manufacturing Example
[773] Preparation Example 13
[774] 3- (2-Aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester
[775]
[776] Step A : 2-Bromo-5-hydroxybenzaldehyde
[777]
[778] A solution of bromine (1.3 kg, 8.2 mol) in CH ₂ Cl ₂ (620 ml) was added over 1 hour with a suspension of 3-hydroxybenzaldehyde (1 kg, 8.2 mol) in CH ₂ Cl ₂ (10 L). After stirring for about 22 hours, the solid was separated by filtration, washed with CH ₂ Cl ₂ (4 L) and dried under vacuum to give 2-bromo-5-hydroxybenzaldehyde as a dark brown solid (1.05 kg, 63%).
[779] Step B : 3- (2-formyl-4-hydroxy-phenyl) -acrylic acid tert-butyl ester
[780]
[781] Tri-o-tolyl phosphine (75.4 g, 0.25 mol) and diisopropylethylamine under N _{2 with} a solution of 2-bromo-5-hydroxybenzaldehyde (200 g, 1.0 mol) in propionitrile (6 L) (350 ml, 260 g, 2.0 mol) was added. The solution was degassed and purged three times with N ₂ . To this solution tert-butylacrylate (440 ml, 385 g, 3.0 mol) and palladium acetate trimer (27.8 g, 0.12 mol) were added. The mixture was degassed three times and heated to 80 ° C. over 30 minutes. After 30 minutes, the reaction was cooled to room temperature and filtered. The solid was washed with acetonitrile. The filtrate was transferred to a separating funnel with acetonitrile (4 L total) and extracted with hexane (4 × 5 L). Propionitrile / acetonitrile layer was concentrated by rotary evaporator. The residue was dissolved in 4L of toluene and washed successively with 1N HCl (1N), water (1L) and brine (1L). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give crude product as a wet brown solid (293 g). The crude product was dissolved in CH ₂ Cl ₂ (600 ml) with stirring. Hexane (1.8 L) was added to this solution over 2 hours, and the resulting slurry was stirred at room temperature for 1 hour. The slurry was cooled in an ice water bath and stirred for 11 hours. The product was isolated by filtration, washed with hexanes and dried under vacuum to give the product as a dark brown solid (199.5 g, 80.6%).
[782] Step C: 3- [4-hydroxy-2- (hydroxyimino-methyl) -phenyl] acrylic acid tert-butyl ester
[783]
[784] A slurry of hydroxylamine hydrochloride (8.33 g, 0.12 mol), pyridine (9.49 g, 0.12 mol) and ethanol (100 ml) was stirred at room temperature for 30 minutes. 3- (2-formyl-4-hydroxy-phenyl) -acrylic acid tert-butyl ester (14.90 g, 0.06 mol) was added and then rinsed with ethanol (49 ml). The resulting brown solution was stirred for 16 h at room temperature and concentrated. The residue was suspended in water (150 ml) and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were washed with saturated NaCl solution (2 × 100 ml), dried (Na ₂ SO ₄ ) and filtered through a plug of silica gel to remove trace polar impurities. The filtrate was concentrated to give crude product (16.04 g). A 13.56 g sample of crude material was crystallized from heptane (70 ml) and ethyl acetate (80 ml) with the title compound (7.41 g, 55%). mp 146-149 ° C.
[785]
[786] Anal. Calcd. For C ₁₄ H ₁₇ NO ₄ : C: 63.8658; H: 6.5081; N: 5.3198
[787] Anal: C: 63.71; H: 6.38; N: 5.51
[788] Step D: 3- (2-Aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester
[789] A solution of 3- [4-hydroxy-2- (hydroxyimino-methyl) -phenyl] -acrylic acid tert-butyl ester (0.50 g, 1.9 mmol) in ethanol (50 ml) was added with 10% palladium on carbon (0.25 g). It was processed using. The resulting suspension was treated with hydrogen for 16 hours at room temperature and 50 psi using a Parr shaker machine. The reaction mixture was filtered through celite, rinsed with ethanol (20 ml) and concentrated. The residue was dissolved in ethyl acetate (50 ml) and washed with 10% K ₂ CO ₃ solution ( ₂ × ₂₅ ml) and 1N NaOH ( ₂ × ₂₅ ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was crystallized from isopropyl acetate to give the title compound (0.14 g, 40%), mp 154-157 ° C.
[790]
[791] Anal Calcd for C ₁₄ H ₂₁ NO ₃ : C: 66.9069; H: 8.4222; N: 5.5731
[792] Anal: C: 66.57; H: 8.29; N: 5.60
[793] Preparation Example 14
[794] 3- (2-Aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester ethanedioate (2: 1)
[795]
[796] Alternative to crystallization of 3- (2-aminomethyl-4-hydroxy-phenyl) propionic acid tert-butyl ester from isopropyl acetate. Crude tert-butyl-3- [2- (aminomethyl) -4-hydroxyphenyl] propanoate (0.50 g, 0.002 mol) was dissolved in refluxing ethyl acetate (10 ml). Precipitation immediately occurred upon addition of a solution of oxalic acid (0.18 g, 0.002 mol) dissolved in ethyl acetate (5 ml). The resulting slurry was cooled to 0 ° C. and filtered. The separated product was slurried in ethanol (5 ml), cooled to 0 ° C. and filtered to give 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl esterethanedioate (2: 1) (0.41 g, 69%) was obtained. mp 188-190 ° C.
[797]
[798] Analysis of C ₃₀ H ₄₀ N ₂ O ₁₀ . Calculated: C: 100.80; H: 7.48; N: 4.73
[799] Found: C: 60.79; H: 7.51; N: 4.81
[800] Preparation Example 15
[801] 3- [2- (tert-butoxycarbonylamino-methyl) -4-hydroxy-phenyl] -propionic acid methyl ester
[802]
[803] A solution of 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid tert butyl ester (1.00 g, 3.98 mmol) in CH ₂ Cl ₂ (10 ml) was treated with water (12 drops), followed by TFA ( 10 ml). The solution was stirred at room temperature for 6.5 hours and concentrated. The residue was diluted with 2,2-dimethoxypropane (40 ml), concentrated HCl (4 ml) and then MeOH (10 ml). The solution was stirred for 18 h and concentrated to afford 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid: HCl salt as a dark brown solid. MS (ES ⁻ ) m / z 208 [M-1].
[804] The solid was diluted with THF (20 ml) and saturated aqueous NaHCO ₃ solution (12 ml) and treated with di-tert-butyl dicarbonate (1.09 g, 5.00 mmol). The mixture was stirred for 3 h, concentrated and the residue was partitioned between EtOAc (75 ml) and 1N HCl (30 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (1.16 g, 94%). ^{MS (ES -) m / z} 308 [M-1]
[805] Preparation Example 16
[806] 3- [4-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester
[807]
[808] A slurry of 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester (75.4 g, 0.3 mol) in CH ₂ Cl ₂ (900 ml) was triethylamine (60.7 g, 0.6 at 1 ° C. mol). Isopropyl chloroformate (300 ml, 0.3 mol, 1 M in toluene) was added while maintaining the temperature below 12 ° C. The resulting solution was stirred at room temperature for 16 hours. After 16 hours, additional isopropyl chloroformate (15 ml, 0.015 mol, 1.0 M in toluene) was added and the reaction stirred for 1 hour. The reaction mixture was washed with 1N HCl (2 × 200 ml) and saturated NaHCO ₃ solution (2 × 200 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by filtration through Merck silica gel (750 grams, CH ₂ Cl ₂ / MeOH 100/0 to 96/4) to afford the title compound (95.48 g, 94.3%).
[809]
[810] The following intermediate compound was prepared in a manner substantially similar to that described in Preparation 16.
[811] 3- [4-hydroxy-2- (isobutoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester
[812]
[813] 3- [2- (Cyclopropylmethoxycarbonylamino-methyl) -4-hydroxy-phenyl] -propionic acid tert-butylester
[814]
[815] HRMS calcd for C ₁₉ H ₂₆ NO ₅ : m / z 348.1811. Found: 348.1817.
[816] 3- [2- (cyclobutoxycarbonylamino-methyl) -4-hydroxy-phenyl] -propionic acid tert butyl ester
[817]
[818] HRMS calcd for C ₁₉ H ₂₆ NO ₅ : m / z 348.1811. Found: 348.1817.
[819] 3- [2- (Cyclopentyloxycarbonylamino-methyl) -4-hydroxy-phenyl-propionic acid tert-butyl ester
[820]
[821] Preparation Example 17
[822] 3- [4-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid methyl ester
[823]
[824] A solution of 3- [4-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] propionic acid tert-butyl ester (3.0 mmol, 1.0 g) in CH ₂ Cl ₂ (10 mL) at 90 ° C. Treated with% CF ₃ CO ₂ H / H ₂ O (20 ml). The mixture was stirred for 3 hours and concentrated. The residue was dissolved in MeOH (20 mL), treated with concentrated H ₂ SO ₄ (1 mL) and heated to reflux for 14 h. The mixture was cooled down and concentrated. The residue was dissolved in water / ethyl acetate and neutralized with K ₂ CO ₃ . The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.76 g, 86%). HRMS calcd for C ₁₅ H ₂₂ NO ₅ : m / z 296.1498. Found: 296.1504.
[825] Preparation Example 18
[826] 3- [4-hydroxy-2- (3-isopropyl-ureidomethyl) -phenyl] -propionic acid tert-butyl ester
[827]
[828] Treatment of a slurry of 3- (2-aminoethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester (2.24 g, 8.91 mmol) in CH ₂ Cl ₂ (30 ml) with isopropyl isocyanate (1.1 ml, 11 mmol) It was. The reaction mixture was diluted with water, CH ₂ Cl ₂ was removed under reduced pressure and the aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO ₄ ) and concentrated to the title compound as a white solid (2.6 g, 87%). MS (ES ⁺ ) m / z 337 [M + H] ⁺ .
[829] Preparation Example 19
[830] 3- (2-{[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -methyl} -4-hydroxy-phenyl) propionic acid tert-butyl ester
[831]
[832] Step A: 2,5-dichloro-thiophene-3-carboxylic acid
[833]
[834] A mixture of 1- (2,5-dichloro-thiophen-3-yl) -ethanone (10 g, 51.26 mmol) and 9.5% NaOCl (150 mL, 230 mmol, 4.5 equiv., Commercial bleach) was prepared. Treated with 5N NaOH (1 ml, 5 mmol, 0.1 equiv). The mixture was stirred vigorously and heated to 55 ° C. Close monitoring of the intermediate temperature to remove heat to control the exotherm. After 6 hours at 61 ° C. the starting material was consumed completely. The mixture was cooled to 0 ° C. and carefully quenched with 20% aqueous NaHCO ₃ solution (20 ml). The pH was adjusted to 1.5 by addition of 6M HCl (12 ml) at 0 ° C. The combined organic layers were washed with brine (200 ml), dried (Na ₂ SO ₄ ) and concentrated to give a white solid (8.8 g).
[835] Step B : 3- (2-{[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -methyl} -4-hydroxy-phenyl) -propionic acid tert-butyl ester
[836] A solution of 2,5-dichloro-thiophene-3-carboxylic acid (12.9 g, 65.5 mmol) and 4-methylmorpholine (7.17 mL, 65.2 mmol) in anhydrous THF (400 mL) was cooled to -15 ° C. Isobutyl chloroformate (8.46 ml, 65.2 mmol) was added. The mixture was stirred for 3 minutes and triethylamine (9.1 ml, 65 mmol) was added. A solution of 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester (16.4 g, 65.3 mmol) in DMF (130 ml) precooled to -15 [deg.] C. via cannula over 15 minutes Added. After stirring for 1 hour, TLC showed complete reaction. The reaction mixture was allowed to warm to room temperature. The solid was removed by filtration and washed with THF (100 ml). The filtrate was diluted with Et ₂ O (500 ml), washed with water (250 ml) and then with brine (150 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude brown oil was purified by silica gel chromatography (hexane / EtOAc 2/1) and recrystallized (toluene) to give the title compound as a white crystalline solid (22.3 g, 79.6%). MS (ES +) m / z 430.1 [M + H] ⁺ .
[837] Preparation Example 20
[838] 3- (4-hydroxy-2-{[(pyrazine-2-carbonyl) -amino] -methyl} -phenyl) -propionic acid tert-butyl ester
[839]
[840] To a solution of pyrazine-2-carboxylic acid (0.570 g, 4.60 mmol) in CH ₂ Cl ₂ (50 ml) was added EDC (0.960 g, 5.01 mmol) and HOBt (0.620 g, 4.60 mmol) at room temperature. The mixture was stirred for 10 minutes and 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester (1.05 g, 4.18 mmol) was added. The reaction mixture was stirred for 18 h at rt, treated with water (50 ml) and extracted with CH ₂ Cl ₂ ( ₂ × 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography (EtOAc / hexanes 1: 1 to 1: 0) to afford the title compound (1.05 g, 70%).
[841]
[842] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparation 20.
[843] 3- (4-hydroxy-2-{[(pyridine-2-carbonyl) -amino] -methyl} -phenyl) -propionic acid tert butyl ester
[844]
[845] Preparation Example 21
[846] 3- [2- (benzoylamino-methyl) -4-hydroxy-phenyl] propionic acid tert-butyl ester
[847]
[848] A slurry of 3- (2-aminomethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester (0.36 g, 1.43 mmol) in CH ₂ Cl ₂ (10 ml) was cooled in an ice water bath and triethyl amine (0.40 ml, 0.28 mmol), followed by dropwise treatment with benzoyl chloride (0.18 ml, 1.55 mmol). The resulting solution was stirred for 30 minutes and the cold water bath was removed. After 30 minutes, the solution was concentrated and the residue was partitioned between EtOAc (50 ml) and 1N HCl (10 ml). The organic layer was washed with brine (10 ml), dried (Na ₂ SO ₄ ) and concentrated to a solid. The crude mixture was purified by radical chromatography (hexane: EtOAc 3: 1 to 2: 1) to give the title compound as a white solid (325 mg, 64%).
[849]
[850] The following intermediate compounds were prepared in a manner substantially similar to that described in Preparation 21.
[851] 3- {2-[(Cyclobutanecarbonyl-amino) -methyl] -4-hydroxy-phenyl} -propionic acid tert-butyl ester
[852]
[853] Preparation Example 22
[854] 3- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -4-hydroxy-phenyl] -propionic acid tert butyl ester
[855]
[856] Step A: (4-Bromo-3-methyl-phenoxy) -tert-butyl-dimethyl-silane
[857]
[858] A 12 L flask was charged with 4-bromo-3-methyl phenol (428 g, 2.29 mol), CH ₂ Cl ₂ (7.5 L), triethylamine (480 mL, 3.45 mol) and tert-butyldimethylsilyl chloride (324 g , 2.15 mol). 4-dimethylaminopyridine (15.0 g, 0.123 mol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was washed with saturated ammonium chloride (2.2 L) and then DI water (0.9 L). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to crude product (699 g). This material was purified by silica gel chromatography (heptane) to give the title compound (637 g, 98.5%).
[859] Step B : (4-Bromo-3-bromomethyl-phenoxy) -tert-butyl-dimethyl-silane
[860]
[861] (4-Bromo-3-methyl-phenoxy) -tert-butyl-dimethyl-silane (255 g, 0.846 mol), dichloroethane (2.5 L), N-bromosuccinimide (165 g, 0.927 mol) And 2,2'-azobisisobutyronitrile (19.0 g, 0.116 mol) were combined in a 5 liter flask. The mixture was degassed by vacuuming and purging with N ₂ (5 ×). The reaction mixture was heated to 47 ° C. and the heating was stopped. Exotherm occurred at 76 ° C. GC analysis showed 6.5% unreacted starting material. Heated again and the reaction was left at reflux (83 ° C.) for 15 minutes. After cooling to 8 ° C., heptane (1.0 L) was added. The resulting slurry was stirred at 4 ° C. for 30 minutes and filtered. The filtrate was evaporated to dryness. The residue was treated with heptane (1 L), stored in the freezer overnight and filtered. The filtrate was concentrated to the title compound (326 g, 101%).
[862] Step C : 2- [2-Bromo-5- (tert-butyl-dimethyl-silanyloxy) -benzyl] -isoindole-1, 3-dione
[863]
[864] (4-Bromo-3-bromomethyl-phenoxy) -tert-butyl-dimethyl-silane (568 g, 1.49 mol), exotherm to 34 ° C. The 12 L flask was filled with DMF (3.1 L) and potassium phthalimide (316 g, 1.71 mol). After 40 minutes, the reaction mixture was cooled to 18 ° C. Ether (6.2 L) and DI water (4.9 L) were added and the layers separated. The organic layer was washed with saturated NaCl solution (2 L), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was recrystallized from heptane (1.5 L) to give the title compound (454 g, 68%).
[865] Step D: 3- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -4-hydroxy-phenyl] -acrylic acid tert-butyl ester
[866]
[867] The 12 L flask was charged with 2- [2-bromo-5- (tert-butyl-dimethyl-silanyl oxy) -benzyl] -isoindole-1,3-dione (461 g, 1.03 mol), propionitrile (7 L), Filled with tri-ortho-tolyl phosphine (76.0 g, 0.250 mol) and diisopropyl ethyl amine (365 ml, 2.10 mol). The reaction mixture was degassed, purged with N ₂ (3 ×) and tert-butyl acrylate (465 ml, 3.17 mol) was added. After one degassing / purging, palladium (II) acetate (28.0 g, 0.125 mol) was added. The stirred mixture was degassed / purged three times with N ₂ and heated to 95 ° C. for 20 hours. The mixture was filtered through a hyflo cake, washed with acetonitrile and concentrated to brown oil (841 g). The residue was dissolved in THF (3.5 ml) and tetrabutylammonium fluoride (TBAF, 650 ml, 0.65 mol, 1 M in THF) was added. After 1 hour, additional TBAF (95 ml) was added. The mixture was spun on a rotary evaporator for 10 minutes and concentrated to crude product (987 g). This material was purified by silica gel chromatography (toluene / ethyl acetate, 100/0 to 75/25) to give the title compound (340 g, 86.8%).
[868] Step E : 3- [2- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -4-hydroxy-phenyl] -propionic acid tert-butyl ester
[869] 3- [2- (1,3-dioxo-1, 3-dihydro-isoindol-2-ylmethyl) -4-hydroxy-phenyl] -acrylic acid tert-butyl ester (196 g, 0.517 mol), One gallon autoclave was charged with ethyl acetate (2.6 L) and palladium on 5% carbon (75 g). The autoclave was stored for 21 hours at 25 ° C. under 60 psi of hydrogen. The reaction temperature was increased to 40 ° C. and the pressure was increased to 75 psi for 5 hours. The mixture was filtered through a hyflo pad and concentrated to the title compound (186 g, 94.4%): MS (ESI) m / z 380.2 (M ⁻ H) ⁻ .
[870] Preparation Example 23
[871] 3- {4-hydroxy-2-[(isopropoxycarbonyl-methyl-amino) -methyl] -phenyl} -propionic acid tert-butyl ester
[872]
[873] Step A: 3- [5-benzyloxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester
[874]
[875] Cs ₂ CO ₃ (29.6 mmol) with a solution of 3- [5-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (14.8 mmol) in DMF (100 ml) and Benzyl bromide (16.3 mmol) was added. The reaction mixture was stirred at room temperature overnight and diluted with EtOAc (200 ml). The mixture was washed with brine (100 ml) and water (100 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to yellow oil (6.8 g). MS [ES] m / z 428 (M + H) ⁺ .
[876] Step B : 3- {5-hydroxy-2-[(isopropoxycarbonyl-methyl-amino) -methyl] -phenyl} -propionic acid tert-butyl ester
[877] NaH (29.4 mmol, 3-solution of 3- [5-benzyloxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (6.3 g, 0.015 mol) in DMF (100 ml) 60% oil dispersion) was added. The reaction mixture was stirred for 15 min at 0 ° C., treated with methyl iodide (4.18 g, 29.4 mmol) and stirred under N ₂ at room temperature. The mixture was concentrated and triturated with hexane (200 ml). The residue was diluted with EtOAc (200 ml) and the solution was washed with water (200 ml) and brine (200 ml), dried (Na ₂ SO ₄ ) and concentrated to a yellow oil (5.2 g). The material was dissolved in EtOAc (100 ml) and 5% Pd / C (0.725 g) was added. The reaction mixture was shaken overnight at 40 ° C. in a 60 psi Parr apparatus under a hydrogen atmosphere. The mixture was filtered and concentrated to give the title compound (2.1 g). MS [ES] m / z 352 (M + H) ⁺ .
[878] The following intermediate compounds were prepared in a substantially similar manner as described in Preparation 23.
[879] 3- (5-hydroxy-2-{[methyl- (pyridine-2-carbonyl) -amino] -methyl} -phenyl) -propionic acid tert-butyl ester
[880]
[881] The compounds of the invention listed below were prepared using the following general methods.
[882] Common methods I and II
[883] General method I
[884] General method for the parallel synthesis of carboxamides from carboxylic acids
[885]
[886] 3- (2-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester: acetic acid salt (704 mg, 1.4 mmol ) Was dissolved in CH ₂ Cl ₂ (25 ml) and washed with saturated NaHCO ₃ solution (15 ml) The organic layer was dried (NaSO ₄ ), filtered and 3- {2-aminomethyl-4- [2- ( 5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester (636 mg, 1.4 mmol) in amine (0.1 mmol, CH ₂ Cl ₂₎ . 0.1 M) was added as carboxylic acid (1.4 equiv) in 1 dram vial N-hydroxybenzotriazole hydrate (1.4 equiv, 0.17 M in CH ₂ Cl ₂ / DMF 10/1, HOBt) and EDC (1.4 equiv) , 0.18 M CH ₂ Cl ₂ ) was added and the vial was capped and shaken for 18 h DMF (0.5 ml) and triethylamine (0.5 ml) were added and the vial was stirred for 72 h. 1 ml) was added and the mixture was transferred to ChemElute cart. Jiro was transferred and eluted using CH ₂ Cl _2. The solvent was removed under a N ₂ stream. The residue was treated with a mixture of CH ₂ Cl ₂ / TFA / water 60/35/5 (1ml) and shaken briefly After standing at room temperature for 2 hours The solvent was removed under a stream of N _2. The residue was treated with 10% CCl ₄ / CH ₂ Cl ₂ (1 ml) and concentrated under a stream of N ₂ ( ₂ ×). The crude product was dried under vacuum and purified by HPLC connected to mass spectrometer.
[887] General method II
[888] General Method of Parallel Synthesis to Obtain Carboxamide, Carbamate, Sulfonamide, Urea and Thiourea from Carboxylic Acid Chloride, Chloroformate, Sulfonyl Chloride, Isocyanate and Isothiocyanate
[889]
[890] 3- (2-Aminomethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester: acetic acid salt (720 mg, 1.4 mmol) was dissolved in CH ₂ Cl ₂ (25 ml) and washed with saturated NaHCO ₃ solution (15 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and 3- {2-aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} Concentrated with propionic acid tert-butyl ester (586 mg, 92%). This amine (0.1 mmol, 0.1 M in CH ₂ Cl ₂ ) and carboxylic acid chloride, chloroformate, sulfonyl chloride, isocyanate or thioisocyanate (1 equiv) and triethylamine (0.2 ml) were placed in 1 dram vial. The vial was capped and shaken for 18 hours. DMF (0.5 ml) was added to the incomplete reaction mixture and the vial was shaken for 2 hours. Brine (1 ml) was added and the mixture was transferred to chemelite carridge and eluted with CH ₂ Cl ₂ . The solvent was removed under a stream of N ₂ . The residue was treated with a mixture of CH ₂ Cl ₂ / TFA / water 60/35/5 (1 ml), briefly shaken and left at room temperature for 2 hours. The solvent was removed under a stream of N ₂ . The residue was treated with 10% CCl ₄ / CH ₂ Cl ₂ (1 ml) and concentrated under N ₂ ( ₂ ×) stream. The crude product was dried under vacuum and purified by mass-directed HPLC.
[891] Example 1
[892]
[893] Step A: 3- {2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -4- [2- (5-methyl-2-phenyloxazole-4- Yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester
[894]
[895] 3- [2- (1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl) -4-hydroxy-phenyl] -propionic acid tert-butyl ester (67.9 g, 0.178 mol), A 2 L three-necked flask was charged with toluene-4-sulfonic acid 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethyl ester (76.6 g, 0.214 mol) and DMF (680 mL). Cesium carbonate (75.4 g, 0.231 mol) was added and the reaction mixture was heated to 55 ° C for 18 h. After cooling, ethyl acetate (890 ml) and DI water (1200 ml) were added, the mixture was shaken and the layers separated. The aqueous layer was back extracted with ethyl acetate (740 ml). The organic layers were combined and washed with 1N NaOH (375 ml) and then saturated NaCl solution (2 × 375 ml). The organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated to an oil (107 g). The crude oil was dissolved in toluene (50 ml) and heptane (˜100 ml) was added until shaking left cloudy. The mixture was warmed to 50 ° C. on a rotary evaporator to give a solution. Seed crystals were added and rotation continued overnight at room temperature. The product slurry was left overnight in the freezer and filtered. The title compound was dried in a vacuum oven at 35 ° C. (71.4 g, 70.8%).
[896] Step B: 3- {2-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl}-propionic acid tert-butyl ester: acetic acid salt
[897]
[898] 3- {2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) A 3 L three-necked flask was charged with -ethoxy] -phenyl} -propionic acid tert-butyl ester (71. 0 g, 0.125 mol) and isopropanol (IPA, 1.35 L). The solution was still not obtained after warming to 40 ° C. and adding IPA (250 ml). After cooling to below 30 ° C., sodium borohydride (25.6 g, 0.677 mol) was carefully added in portions. Tap water was added to the reactor and the reaction was stirred overnight. The spatula was used to break the solid in the sticky slurry and IPA (200 ml) was added. Glacial acetic acid (130 ml, 2.27 mol) was added dropwise over 2 hours. The reaction mixture was heated to reflux for 10 hours, cooled over the weekend and concentrated to crude product (237 g). CH ₂ Cl ₂ (100 ml) was added to give a sticky gel, which was poured into a column of silica gel equilibrated with CH ₂ Cl ₂ 60. Methanol was used to help dissolve the crude material. Elution with CH ₂ Cl ₂ / MeOH (1/1) gave the resulting mixture (182 g). Ethyl acetate (200 ml) was added and a precipitate formed. The mixture was heated to 40 ° C and the solution was cooled to 0 ° C. The pure product was filtered off, washed with heptane / EtOAc (1: 1, 2 × 100 ml) and dried to give a white floppy solid (35.4 g, 57%). The filtrate was concentrated (116 g) and purified again by silica gel chromatography (CH ₂ Cl ₂ / MeOH 100/0 to 80/20) to give an additional product (13.9 g, 22%) as amber oil.
[899] Example 2-230
[900] Example 2-230 was prepared in a manner substantially similar to that described in Example 1 and General Methods I and II.
[901]
[902]
[903]
[904]
[905]
[906]
[907]
[908]
[909]
[910]
[911]
[912]
[913]
[914]
[915]
[916]
[917]
[918]
[919]
[920]
[921]
[922]
[923]
[924]
[925]
[926]
[927]
[928]
[929]
[930]
[931]
[932]
[933]
[934]
[935]
[936]
[937]
[938]
[939]
[940] Example 231
[941] 3- (4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-{[(2,5-dichloro-thiophen-3- Carbonyl) -amino] -methyl} -phenyl) -propionic acid
[942]
[943] Step A: 3- (4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-{[(2,5-dichlorothiophene- 3-carbonyl) -amino] -methyl} -phenyl) -propionic acid tert-butyl ester
[944]
[945] 3- (2-{[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -methyl} -4-hydroxy-phenyl) -propionic acid tert-butyl ester (280 mg, 0.651 mmol) and Radial by reacting a mixture of toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethyl ester (498 mg, 1.15 mmol) according to standard method A After chromatography (hexane / EtOAc 98: 2 to 90:10) the title compound was obtained as a white solid (367 mg, 82%).
[946]
[947] Step B: 3- (4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-{[(2,5-dichloro-thiophene -3-carbonyl) -amino] -methyl} -phenyl) -propionic acid
[948] 3- (4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-{[(2,5 in CH ₂ Cl ₂ (20 ml) A solution of dichloro-thiophene-3-carbonyl) -amino] -methyl} -phenyl) -propionic acid tert-butyl ester (367 mg, 0.531 mmol) with anisole (2.0 ml) followed by TFA (6.0 ml). Treatment was used. The mixture was stirred at rt for 2 h and concentrated. The residue was co-evaporated three times with CCl ₄ , dried under vacuum, triturated with ether and filtered to give the title compound (301 mg, 73%) as a white solid.
[949]
[950] Example 232-318
[951] Examples 232-318 were prepared following methods and standard coupling method A and standard hydrolysis methods C to E substantially similar to those described in Example 231.
[952]
[953]
[954]
[955]
[956]
[957]
[958]
[959]
[960]
[961]
[962]
[963]
[964]
[965]
[966]
[967] ¹ H NMR data for Example 318:
[968]
[969] Example 319
[970] {4- [2- (5-Methyl-2- (4-phenyl) phenyl-oxazol-4-yl) -ethoxy] -2- (isopropylcarbamate) methyl} -propionic acid
[971]
[972] Step A: {4- [2- (5-Methyl-2- (4-phenyl) phenyl-oxazol-4-yl) -ethoxy] -2- (isopropylcarbamate) methyl} -propionic acid tert- Butyl ester
[973]
[974] 3- [4-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (258 mg, 0.763 mmol) and toluene-4-sulfonic acid 2- (2-biphenyl- 4-yl-5-methyl-oxazol-4-yl) -ethyl ester (654 mg, 1.51 mmol) was reacted according to standard procedure A. Purification by radial chromatography (CH ₂ Cl ₂ / EtOAc 98/2 to 90/10) afforded the title compound in quantitative yield.
[975] ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.14 (d, 6H, J = 5.9 Hz), 1.31 (s, 9H), 2.30 (s, 3H), 2.39 (t, 2H, J = 7.6 Hz), 2.89 (t, 2H, J = 6.6 Hz), 4.14 (t, 2H, J = 6.6 Hz), 4.25 (d, 2H, J = 5.4 Hz), 4.85 (seven line, 1H, J = 5.8 Hz), 6.67 (dd, 1H, J = 8.3 Hz, J = 2.4 Hz), 6.75 (d, 1H, J = 2.4 Hz), 6.99 (d, 1H, J = 8.3 Hz), 7.26-7.30 (m, 1H), 7.37 (t, 2H, J = 7.6 Hz), 7.53-7.58 (m, 4H), 7.95 (d, 2H, J = 8.3 Hz). MS (ES) m / e 599.4 [M + l].
[976] Step B: {4- [2- (5-Methyl-2- (4-phenyl) phenyl-oxazol-4-yl) -ethoxy] -2- (isopropylcarbamate) methyl} -propionic acid
[977] {4- [2- (5-methyl-2- (4-phenyl) phenyl-oxazol-4-yl) -ethoxy] -2- (isopropylcarbamate) methyl in CH ₂ Cl ₂ (10 mL) } -Propionic acid (414 mg, 0.763 mmol) solution was treated with anisole (1.0 mL), followed by trifluoroacetic acid (TFA, 3.0 mL). The solution was concentrated by stirring at room temperature for 2 hours. The residue was co-evaporated twice with CCl ₄ , dried in vacuo, triturated with ether and filtered to give the title compound (287 mg, 69%) as a white solid.
[978] ¹ H NMR (400 MHz, CDC ₁₃ ) δ 1.11 (d, 6H, J = 5.9 Hz), 2.28 (s, 3H), 2.46 (t, 2H, J = 7.6 Hz), 2.79 (t, 2H, J = 7. 6 Hz), 2.86 (t, 2H, J = 6.6 Hz), 4.11 (t, 2H, J = 6.8 Hz), 4.24 (d, 2H, J = 5. 4 Hz), 4.82 (midline, 1H, J = 6.1 Hz), 5.05 (bs, 1H), 6.66 (dd, 1H, J = 2.4, 8.3 Hz), 6.73 (d, 1H, J = 2.4 Hz), 6.99 (d, 1H, J = 8.3 Hz), 7.24-7.28 (m, 1H), 7.35 (t, 2H, J = 7.6 Hz), 7.51-7.56 (m, 4H), 7.98 (d, 2H, J = 8.3 Hz). MS (ES) m / e 543.1 [M + l].
[979] Example 320
[980] 3- {2- (Isopropoxycarbonylaminomethyl) -4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl) ethoxy] -phenyl} propionic acid
[981]
[982] Step A: 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl) -ethoxy]- Phenyl} -propionic acid tert-butyl ester
[983]
[984] 3- [4-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (272 mg, 0.806 mmol) and toluene-4-sulfonic acid 2- (5-methyl-2 -Morpholin-4-yl-thiazol-4-yl) -ethyl ester (522 mg, 1.36 mmol) was reacted according to standard procedure A. Purification by radial chromatography (CH ₂ Cl ₂ / EtOAc 98: 2 to 75:25) afforded the title compound as a white solid in quantitative yield (387 mg, 98%).
[985] ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.14 (d, 6H, J = 5.9 Hz), 1.32 (s, 9H), 2.16 (s, 3H), 2.39 (t, 2H, J = 7.6 Hz), 2.77 (t, 2H, J = 7.6 Hz), 2.84 (t, 2H, J = 7.1 Hz), 3.28 (t, 4H, J = 4.9 Hz), 3.70 (t, 4H, J = 4.9 Hz), 4.08 (t , 2H, J = 7.1 Hz), 4.25 (d, 2H, J = 5.4 Hz), 4.83 (seven line, 1H, J = 4.9 Hz), 6.66 (dd, 1H, J = 2.4, 8.3 Hz), 6.72 ( d, 1H, J = 2.4 Hz), 6.98 (d, 1H, J = 8.3 Hz). MS (ES) m / e 548.3 [M + l].
[986] Step B: 3- {2- (Isopropoxycarbonylaminomethyl) -4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl) ethoxy] -phenyl} Propionic acid
[987] 3- {2- (isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl in CH ₂ Cl ₂ (10 mL) ) -Ethoxy] -phenyl} -propionic acid tert-butyl ester (387 mg, 0.706 mmol) was treated with anisole (1 mL) followed by TFA (3 mL). The solution was stirred at rt for 2 h and concentrated. The residue was co-evaporated twice with CCl ₄ , dried in vacuo, triturated with ether and filtered to separate the title compound (236 mg, 60%) as a white solid as a trifluoroacetic acid salt.
[988] ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.12 (d, 6H, J = 6.4 Hz), 2.16 (s, 3H), 2.47 (t, 2H, J = 7.6 Hz), 2.79 (t, 2H, J = 7.6 Hz), 2.87 (t, 2H, J = 6.4 Hz), 3.35 (t, 4H, J = 4.9 H), 3.70 (t, 4H, J = 4.9 Hz), 4.07 (t, 2H, J = 6.6 Hz ), 4.23 (d, 2H, J = 5.4 Hz), 4.82 (seven line, 1H, J = 6.1 Hz), 5.07 (bs, 1H), 6.63 (dd, 1H, J = 2.7, 8.6 Hz), 6.69 ( d, 1H, J = 2.9 Hz), 6.98 (d, 1H, J = 8.3 Hz). MS (ES) m / e 492.1 [M + l].
[989] Example 321
[990] 3- (2- (2-isopropoxycarbonyl-ethyl) -4- {2- [5-methyl-2- (6-phenoxy-pyridin-3-yl) -oxazol-4-yl] Methoxy} -phenyl) -propionic acid
[991]
[992] Step A: 3- (2- (2-isopropoxycarbonyl-ethyl) -4- {2- [5-methyl-2- (6-chloro-pyridin-3-yl) oxazol-4-yl] Ethoxy} -phenyl) -propionic acid t-butyl ester
[993]
[994] Toluene-4-sulfonic acid 2- [2- (6-chloro-pyridin-3-yl) -5-methyl-oxazol-4-yl] -ethyl ester tosylate (290 mg, 0.74 mmol) and 3- [4 -Hydroxy-2- (2-isopropoxycarbonyl-ethyl) -phenyl] -propionic acid t-butyl ester (274 mg, 0.81 mmol) was converted to the title compound (183 mg, 44%) according to standard procedure A. I was. MS (ESI) m / z 559 (M + H) ⁺ .
[995] Step B: 3- (2- (2-Isopropoxycarbonyl-ethyl) -4- {2- [5-methyl-2- (6-phenoxy-pyridin-3-yl) -oxazole-4- I] ethoxy} -phenyl) -propionic acid
[996] Phenol (45 mg, 0.48 mmol) was added to a suspension of NaH (20 mg, 0.48 mmol) in DMF (10 mL) at ambient temperature. The mixture is stirred at 60 ° C. for 20 minutes and 3- (2- (2-isopropoxycarbonyl-ethyl) -4- {2- [5-methyl-2- (6-chloro-pyridin-3-yl ) Oxazol-4-yl] ethoxy} -phenyl) -propionic acid t-butyl ester (180 mg, 0.32 mmol) was added. The resulting mixture was stirred at 60 ° C. overnight, cooled, diluted with EtOAc and washed with water / brine (4 ×). The organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 3/1 to 1/1) to give the intermediate ester as an oil (60 mg, 30%). The title compound was produced using standard hydrolysis procedure C.
[997]
[998] Example 322
[999] 3- [4- [2- (3-biphenyl-4-yl-5-methyl-pyrazol-1-yl) -ethoxy] -2- (isopropoxycarbonyl-amino-methyl) -phenyl] Propionic acid
[1000]
[1001] 3- [4-hydroxy-2- (isopropoxycarbonyl-amino-methyl) -phenyl] -propionic acid tert-butyl ester (Preparation 16) and 2- (3-biphenyl-4-yl-5- The title compound was prepared from methyl-pyrazol-1-yl) -ethanol (Preparation 11) using standard coupling procedure B followed by standard hydrolysis procedure C. MS [ES] m / e 542 (M + l) ⁺ .
[1002] Examples 323 to 333 below were prepared following procedures substantially similar to those described in Example 322.
[1003] Example 323
[1004] 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-3-phenyl-pyrazol-1-yl) -ethoxy] phenyl} -propionic acid
[1005]
[1006] HRMS calcd for C ₂₆ H ₃₂ N ₃ O ₅ : m / z 466.2342. Found: 466.2331.
[1007] Example 324
[1008] 3- (4- [2- (3-biphenyl-4-yl-5-methyl-pyrazol-1-yl) -ethoxy] -2-{[(pyridine-2-carbonyl) amino] -methyl } -Phenyl) -propionic acid trifluoroacetate
[1009]
[1010] HRMS calcd for C ₂₈ H ₃₀ N ₄ 0 ₄ : m / z 486.2267. Found: 486.2233.
[1011] Example 325
[1012] 3- [4- [2- (5-Biphenyl-4-yl-3-methyl-pyrazol-1-yl) -ethoxy] -2- (isopropoxycarbonylaminomethyl) -phenyl] -propionic acid
[1013]
[1014] HRMS calcd for C ₃₂ H ₃₆ N ₃ O ₅ : m / z 542.2655. Found: 542.2678
[1015] Example 326
[1016] 3- [4- {2- [3- (4-Bromo-phenyl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid tert-butyl ester
[1017]
[1018] HRMS calcd for C ₃₀ H ₃₉ BrN ₃ O ₅ : m / z 600.2073. Found: 600.2064;
[1019] Example 327
[1020] 3- [4- {2- [3- (4-Bromo-phenyl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid
[1021]
[1022] HRMS calcd for C ₂₆ H ₃₁ BrN ₃ O ₅ : m / z 544.1447. Found: 544.1456.
[1023] Example 328
[1024] 3- (4- [2- (5-methyl-3-naphthalen-2-yl-pyrazol-1-yl) -ethoxy] -2-{[(pyridine-2-carbonyl) -amino] -methyl } -Phenyl) -propionic acid hydrochloride
[1025]
[1026] The compound was prepared using standard hydrolysis procedure D.
[1027] HRMS calcd for C ₃₂ H ₃₁ N ₄ 0 ₄ : m / z 535.2345. Found: 535.2343
[1028] Example 329
[1029] 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-3-naphthalen-2-yl-pyrazol-1-yl) -ethoxy] -phenyl} -propionic acid
[1030]
[1031] HRMS calcd for C ₃₀ H ₃₄ N ₃ O ₅ : m / z 516.2498. Found: 516.2485.
[1032] Example 330
[1033] 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-3-naphthalen-1-yl-pyrazol-1-yl) -ethoxy] -phenyl} -propionic acid
[1034]
[1035] C ₃₀ H ₃₄ N ₃ O ₅ : m / z 516.2498. Found: 516.2529.
[1036] Example 331
[1037] 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-2-naphthalen-2-yl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1038]
[1039] HRMS calcd for C ₃₀ H ₃₃ N ₂ O ₆ : m / z 517.2339. Found: 517.2328.
[1040] Example 332
[1041] 3- {4- [2- (3-Biphenyl-4-yl-5-methyl-pyrazol-1-yl) -ethoxy] -2-[(isopropoxy-carbonyl-methyl-amino)- Methyl] -phenyl} -propionic acid
[1042]
[1043] HRMS calcd for C ₃₃ H ₃₈ N ₃ O ₅ : m / z 556.2811. Found: 556.2819
[1044] Example 333
[1045] 3- {4- {2- [3- (4-Bromo-phenyl) -5-methyl-pyrazol-1-yl] -ethoxy} -2-[(isopropoxy-carbonyl-methyl-amino ) -Methyl] -phenyl} -propionic acid
[1046]
[1047] HRMS calcd for C ₂₇ H ₃₃ BrN ₃ O ₅ : m / z 558.1604. Found: 558.1608
[1048] Example 334
[1049] 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (1-methyl-4-phenyl-1-H-imidazol-2-yl) -ethoxy] -phenyl} -propionic acid
[1050]
[1051] 3- [4-hydroxy-2- (isopropoxycarbonyl-amino-methyl) -phenyl] -propionic acid tert-butyl ester (Preparation 16) and 2- (1-methyl-4-phenyl-1H-imi Dazol-2-yl) -ethanol (J. Med. Chem. 1998,4125), 5037-5054) was used to prepare the title compound as an off-white, microcrystalline solid using standard coupling procedure B followed by standard hydrolysis procedure D. Prepared. HRMS calcd for C ₂₆ H ₃₁ N ₃ O ₅ :
[1052] m / z 466.2342. Found: 466.2355.
[1053] Tail Piece Aryl Ring Change
[1054] Example 335
[1055] 3- [4- {2- [2- (4-Bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonyl-amino-methyl)- Phenyl] -propionic acid tert-butyl ester
[1056]
[1057] Toluene-4-sulfonic acid 2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] -ethyl ester (5.06 g, 11.6 mmol) and 3- [4-hydroxy-2 -(Isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (3.01 g, 8.92 mmol) was coupled using standard procedure A to afford the title compound (3.41 g, 64%) as a white solid. Got it.
[1058] MS [ES] m / z 601,603 (M + H).
[1059] Examples 336-337 below were prepared following procedures substantially similar to those described in Example 335.
[1060] Example 336
[1061] 3- [4- {2- [2- (3-Bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxy-carbonylamino-methyl)- Phenyl] -propionic acid tert-butyl ester
[1062]
[1063] Example 337
[1064] 3- [4- {2- [2- (2-Bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid tert-butyl ester.
[1065]
[1066] Example 338
[1067] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-pyridin-3-yl-phenyl) oxazol-4-yl] -ethoxy} -Phenyl) -propionic acid
[1068]
[1069] Suzuki Coupling With Aryl Boronic Acid:
[1070] 3- [4- {2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycar in n-propanol (15 mL) Bonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (450 mg, 0.75 mmol), 3-pyridineboronic acid (120 mg, 0.97 mmol), triphenylphosphine (6 mg, 0.024 mmol), 2M aqueous carbonate Nitrogen was blown into the mixture of sodium (3 mL) for 5 minutes. Palladium acetate (2 mg, 0.008 mmol) was added and the reaction was heated to reflux for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated and then partitioned between water / EtOAc. The organic layer was dried (MgSO ₄ ) and concentrated to give crude product (290 mg). The material was purified by silica gel column chromatography to obtain 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-pyridin-3-yl-phenyl) -Oxazol-4-yl] -ethoxy} -phenyl) -propionic acid tert-butyl ester was obtained as a white solid (230 mg, 51%).
[1071]
[1072] The ester (225 mg, 0.375 mmol) was dissolved in THF (15 mL) and treated with 1N HCl (1 mL). The mixture was heated to reflux for 7 hours, cooled and concentrated. The residue was azeotroduced twice with acetonitrile and dried in a vacuum oven to afford the title compound isolated as HCl salt (140 mg, 64%).
[1073] ¹ H NMR (DMSO-d ₆ ) δ 1.15 (d, 6H), 2.41 (s, 3H), 2.45 (t, 2H), 2.76 (t, 2H), 2.95 (t, 2H), 4.17 (duplicated t And d, 4H), 4.75 (q, 1H), 6.77 (m, 2H), 7.07 (dd, 1H), 7.55 (t, 1H), 8.02 (m, 4H), 8.73 (d, 1H), 8.85 ( d, 1 H), 9.25 (s, 1 H). MS [EI +] m / z 544 (M + H).
[1074] Examples 339 to 367 below were prepared following procedures substantially similar to those described in Example 338.
[1075] Example 339
[1076] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4-pyridin-3-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1077]
[1078] Example 340
[1079] 3- {2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4-pyridin-4-yl-phenyl) oxazol-4-yl] ethoxy} phenyl) Propionic acid
[1080]
[1081] Example 341
[1082] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (3-pyridin-3-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1083]
[1084] Example 342
[1085] 3- (2- (isopropoxycarbonylaminemethyl) -4- {2- [5-methyl-2- (3-pyridin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1086]
[1087] Example 343
[1088] 3- [4- {2- [2- (4'-fluorobiphenyl-4-yl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl Propionic acid
[1089]
[1090] Example 344
[1091] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4'-trifluoromethylbiphenyl-4-yl) oxazol-4-yl] Methoxy} phenyl) propionic acid
[1092]
[1093] Example 345
[1094] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (2'-trifluoromethylbiphenyl-4-yl) oxazol-4-yl] Methoxy} phenyl) propionic acid
[1095]
[1096] Example 346
[1097] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (4'-methoxybiphenyl-4-yl) -5-methyloxazol-4-yl] ethoxy} phenyl Propionic acid
[1098]
[1099] Example 347
[1100] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (3'-methoxybiphenyl-4-yl) -5-methyloxazol-4-yl] ethoxy} phenyl Propionic acid
[1101]
[1102] Example 348
[1103] 3- [4- {2- [2- (4'-fluorobiphenyl-3-yl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl Propionic acid
[1104]
[1105] Example 349
[1106] 3- [4- {2- [2- (3'-fluorobiphenyl-3-yl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl Propionic acid
[1107]
[1108] Example 350
[1109] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4'-trifluoromethylbiphenyl-3-yl) oxazol-4-yl] Methoxy} phenyl) propionic acid
[1110]
[1111] Example 351
[1112] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (3'-trifluoromethylbiphenyl-3-yl) oxazol-4-yl] Methoxy} phenyl) propionic acid
[1113]
[1114] Example 352
[1115] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (2'-trifluoromethylbiphenyl-3-yl) oxazol-4-yl] Methoxy} phenyl) propionic acid
[1116]
[1117] Example 353
[1118] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (3'-methoxybiphenyl-3-yl) -5methyloxazol-4-yl] ethoxy} phenyl) Propionic acid
[1119]
[1120] Example 354
[1121] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (2'-methoxybiphenyl-3-yl) -5 methyloxazol-4-yl] ethoxy} phenyl) Propionic acid
[1122]
[1123] Example 355
[1124] 3- [4- {2- [2- (3'-fluorobiphenyl-4-yl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl Propionic acid
[1125]
[1126] Example 356
[1127] 3- [4- {2- [2- (2'-Fluoro-biphenyl-4-yl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonyl Aminomethyl) -phenyl] -propionic acid
[1128]
[1129] Example 357
[1130] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (3'-trifluoromethylbiphenyl-4-yl) oxazol-4-yl] Methoxy} phenyl) propionic acid
[1131]
[1132] Example 358
[1133] 3- [4- [2- (2-biphenyl-2-yl-5-methyl-oxazol-4-yl) -ethoxy] -2- (isopropoxycarbonylamino-methyl) -phenyl]- Propionic acid
[1134]
[1135] Example 359
[1136] 4 '-(4- {2- [4- (2-carboxy-ethyl) -3- (isopropoxycarbonylamino-methyl) -phenoxy] -ethyl} -5-methyl-oxazol-2-yl ) -Biphenyl-3-carboxylic acid
[1137]
[1138] The compound was prepared after an additional hydrolysis step using standard procedure E. MS (ES) m / z 587.3 (M + l) ⁺ .
[1139] Example 360
[1140] 4 '-(4- {2- [4- (2-carboxy-ethyl) -3- (isopropoxycarbonylamino-methyl) -phenoxy] -ethyl} -5-methyl-oxazol-2-yl ) -Biphenyl-4-carboxylic acid
[1141]
[1142] The compound was prepared after an additional hydrolysis step using standard procedure E. MS (ES) m / z 587.2 (M + l) ⁺ .
[1143] Example 361
[1144] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-3- (4-pyridin-4-yl-phenyl) -pyrazol-1-yl] -ethoxy } -Phenyl) -propionic acid hydrochloride
[1145]
[1146] HRMS calcd for C ₃₁ H ₃₅ N ₄ O ₅ : m / z 543.2607. Found: 543.2614.
[1147] Example 362
[1148] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-3- (4-pyridin-3-yl-phenyl) -pyrazol-1-yl] -ethoxy Phenyl) -propionic acid hydrochloride
[1149]
[1150] HRMS calcd for C ₃₁ H ₃₅ N ₄ O ₅ : m / z 543.2607. Found: 543.2612.
[1151] Example 363
[1152] 3- [4- {2- [3- (4'-Fluoro-biphenyl-4-yl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1153]
[1154] HRMS calcd for C ₂₈ H ₃₅ FN ₃ O ₅ : m / z 560.2561. Found: 560.2575.
[1155] Example 364
[1156] 3- [4- {2- [3- (4'-methoxy-biphenyl-4-yl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1157]
[1158] HRMS calcd for C ₃₃ H ₃₈ N ₃ 0 ₆ : m / z 572.2761. Found: 572.2752.
[1159] Example 365
[1160] 3- [4- {2- [3- (3'-methoxy-biphenyl-4-yl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1161]
[1162] HRMS calcd for C ₃₃ H ₃₈ N ₃ 0 ₆ : m / z 572.2761. Found: 572.2776.
[1163] Example 366
[1164] 3- [4- {2- [3- (2'-Fluoro-biphenyl-4-yl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1165]
[1166] HRMS calcd for C ₃₂ H ₃₅ FN ₄ O ₅ : m / z 560.2561. Found: 560.2540.
[1167] Example 367
[1168] 3- [4- {2- [3- (2'-Methyl-biphenyl-4-yl) -5-methyl-pyrazol-1-yl] -ethoxy} -2- (isopropoxycarbonylamino -Methyl) -phenyl] -propionic acid
[1169]
[1170] C ₃₃ H ₃₈ N ₃ 0 ₅ : m / z 556.2811. Found: 556.2802.
[1171] Example 368
[1172] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-pyrazin-2-yl-phenyl) oxazol-4-yl] -ethoxy} -Phenyl) -propionic acid
[1173]
[1174] Step A: 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -phenyl] -oxazol-4-yl} -ethoxy) -phenyl] -propionic acid
[1175]
[1176] 3- [4- {2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonyl in DMSO (50 mL) Amino-methyl) -phenyl] -propionic acid tert-butyl ester (4.00 g, 6.65 mmol) was treated with bis (pinacolalate) diborane (2.20 g, 8.64 mmol) and potassium acetate (1.96 g, 19.95 mmol). Nitrogen was blown into the solution for 10 minutes, Pd (dppf) Cl ₂ (980 mg, 1.20 mmol; 1: 1 complex with CH ₂ Cl ₂ ) was added and the reaction mixture was heated at 80 ° C. for 4 hours. The mixture was partitioned between water and ethyl acetate and the organic phase was dried (MgSO ₄ ), filtered and concentrated. Purification by silica gel chromatography (9: 1 hexanes: ethyl acetate) gave the title compound as a yellow oil (2.81 g).
[1177]
[1178] Step B:
[1179] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-pyrazin-2-yl-phenyl) -oxazol-4-yl] -ethoxy } -Phenyl) -propionic acid
[1180] Suzuki coupling with haloaryl compound: 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (4,4,5,5-tetra Methyl- [1,3,2] -dioxaborolan-2-yl) -phenyl] -oxazol-4-yl} -ethoxy) -phenyl] -propionic acid (500 g, 0.771 mmol), CsF (258 g, 1.69 mmol), PdCl ₂ (dppf) (0.057 g, 0.07 mmol), and 2-chloropyrazine (.0971 g, 0.85 mmol) were added to a 3-neck flask and dissolved in anhydrous dioxane (25 mL). . The reaction mixture was stirred at 100 ° C. under a stream of N ₂ for about 12 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated NaCl (100 mL) and water (100 mL). The organic phase was filtered through celite, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product (1.2 g) was purified by radial chromatography (10-70% EtOAc / hexanes) to give intermediate ester (0.312 g): MS (ES) m / z 601 (M + H) ⁺ . The ester was dissolved in 4M HCl / dioxane (10 mL). The mixture was stirred under N _{2 for} 16 h and concentrated to give the title compound (305 mg, 72%): MS (ES) m / z 545 (M + H) ⁺ . Analytical Calcd: C 66.16%, H 5.92%, N 10.29%. Found: C 65.97%, H 6.07%, N 10.45%.
[1181] Examples 369-382 below were prepared following procedures substantially similar to those described in Example 368.
[1182] Example 369
[1183] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4-pyridin-2-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1184]
[1185] Example 370
[1186] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (5-methylpyridin-2 yl) phenyl] oxazol-4-yl} ethoxy ) Phenyl] propionic acid
[1187]
[1188] Example 371
[1189] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (3-methylpyridin-2-yl) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid
[1190]
[1191] Example 372
[1192] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (6-methylpyridin-2-yl) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid
[1193]
[1194] Example 373
[1195] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (4-methylpyridin-2 yl) phenyl] oxazol-4-yl} ethoxy ) Phenyl] propionic acid
[1196]
[1197] Example 374
[1198] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (4-trifluoromethylpyridin-2-yl) phenyl] oxazole-4- Ethoxy) phenyl] propionic acid
[1199]
[1200] Example 375
[1201] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (5-trifluoromethylpyridin-2-yl) phenyl] oxazole-4- Ethoxy) phenyl] propionic acid
[1202]
[1203] Example 376
[1204] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {2- [4- (6-methoxypyridin-3-yl) phenyl] -5-methyloxazol-4-yl} Ethoxy) phenyl] propionic acid
[1205]
[1206] Example 377
[1207] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {2- [4- (6-methoxypyridin-2-yl) phenyl] -5-methyloxazol-4-yl} Ethoxy) phenyl] propionic acid
[1208]
[1209] Example 378
[1210] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4-quinolin-4-ylphenyl) oxazol 4-yl] ethoxy} phenyl) propionic acid
[1211]
[1212] Example 379
[1213] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4-pyrazin-2-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1214]
[1215] Example 380
[1216] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {2- [4- (4-methoxypyridin-2-yl) phenyl] -5-methyloxazol-4-yl} Ethoxy) phenyl] propionic acid
[1217]
[1218] Example 381
[1219] 3- [4- (2- {2- [4- (5-cyanopyridin-2-yl) phenyl] -5-methyloxazol-4-yl} ethoxy) -2- (isopropoxycarbonyl Aminomethyl) phenyl] propionic acid
[1220]
[1221] Example 382
[1222] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-pyrimidin-2-yl-phenyl) oxazol-4-yl] -ethoxy } -Phenyl) -propionic acid:
[1223]
[1224] Example 383
[1225] 3 [4- (2- {2- [4- (4-Fluoro-phenylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1226]
[1227] 3- [4- {2- [2- (4-bromo-phenyl) -5-methoxy-oxazol-4-yl] -ethoxy} -2- (isopropoxy-carr in sealed tube apparatus Bonylamino-methyl) -propionic acid tert-butyl ester (0.10 g, 0.17 mmol) was dissolved in DME (5 mL). N ₂ was bubbled through the solution, 4-fluoroaniline (24 mg, 0.20 mmol), 2- (di-t-butylphosphino) -biphenyl (20 mg), Pd ₂ (dba) ₃ ( 10 mg), and K ₃ PO ₄ (50 mg, 0.24 mmol) were added. The tube was sealed and heated at 100 ° C. for 16 hours. The reaction mixture was cooled down, diluted with EtOAc and washed with water. The organic phase was dried (MgSO ₄ ), filtered and concentrated. The residue was purified using silica gel chromatography (hexane / EtOAc 2/1 to 1/1). Using standard hydrolysis procedure C, the material was converted to the title compound in oil form: MS (ESI) m / z 594 (M + H) ⁺ .
[1228] Examples 384-387 below were prepared following procedures substantially similar to those described in Example 383.
[1229] Example 384
[1230] 3- [4- (2- {2- [4- (4-cyano-phenylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycar Bonylamino-methyl) -phenyl] -propionic acid
[1231]
[1232] Example 385
[1233] 3- [4- (2- {2- [4- (3,5-Difluoro-phenylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (iso Propoxycarbonylamino-methyl) -phenyl] -propionic acid
[1234]
[1235] Example 386
[1236] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-p-tolylamino-phenyl) -oxazol-4-yl] -ethoxy} -Phenyl) -propionic acid
[1237]
[1238] Example 387
[1239] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {2- [4- (4-methoxy-phenylamino) -phenyl] -5-methyl-oxazol-4-yl } -Ethoxy) -phenyl] -propionic acid
[1240]
[1241] Example 390
[1242] 3 [4- (2- {2- [3-Benzylamino-phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycarbonylamino-methyl) -phenyl] Propionic acid
[1243]
[1244] 3- [4- {2- [2- (3-bromo-phenyl) -5-methoxy-oxazol-4-yl] -ethoxy} -2- (isopropoxy-carr in sealed tube apparatus Bonylamino-methyl) -propionic acid tert-butyl ester (0.10 g, 0.17 mmol) was dissolved in toluene (5 mL). N ₂ was bubbled through the solution, benzylamine (46 μl, 0.42 mmol), 2- (dicyclohexylphosphino) -biphenyl (12 mg), Pd ₂ (dba) ₃ (16 mg) and t -BuONa (23 mg, 0.24 mmol) was added. The tube was sealed and heated at 100 ° C. for 16 hours. The reaction mixture was cooled down, dissolved in EtOAc and washed with water. The organic phase was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 2/1 to 1/1). Using the standard hydrolysis procedure C, the material was converted to the corresponding carboxylic acid; The title compound was isolated as HCl salt by treatment with 1M HCl in ether (15 mg). MS (ES) m / z 572 (M + H) ⁺ .
[1245] Example 391
[1246] 3- [4- {2- [2- (4-Diethylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl)- Phenyl] -propionic acid
[1247]
[1248] The compound was prepared following a procedure substantially similar to that described in Example 390 except that the reaction was performed at 80 ° C. in DME.
[1249] MS (ES) m / z 538.2 (M + H) ⁺ .
[1250] Example 392
[1251] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) -oxazol-4-yl] -ethoxy } -Phenyl) -propionic acid
[1252]
[1253] 3- [4- {2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} in toluene (3.0 mL) under N ₂ airflow in a sealed tube apparatus. A solution of 2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (60 mg, 0.100 mmol) was added to Pd (OAc) ₂ (5 mg), 2- (di-t-butyl Phosphino) biphenyl (10 mg), morpholine (17 mg, 0.20 mmol), and sodium t-butoxide (19 mg, 0.200 mmol). The tube was sealed and heated at 105 ° C. for 14 hours. The mixture was cooled and purified directly using silica gel chromatography (30-50% EtOAc / hexanes) to afford intermediate esters. A solution of ester in TFA (1.0 ml) / CH ₂ Cl ₂ (1.5 ml) / H ₂ O (0.1 mL) was stirred for 14 hours and concentrated. The residue was purified using silica gel chromatography (hexane / EtOAc / HOAc, 5/5 / 0.02) to give the title compound (36 mg, 65%): MS (ESI) m / z 552.3 (M + H) ⁺ .
[1254] Examples 393-395 below were prepared following procedures substantially similar to those described in Example 392.
[1255] Example 393
[1256] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-morpholin-4-yl-phenyl) oxazol-4-yl] -ethoxy } -Phenyl) -propionic acid
[1257]
[1258] Example 394
[1259] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-piperidin-1-yl-phenyl) -oxazol-4-yl]- Ethoxy} -phenyl) -propionic acid
[1260]
[1261] Example 395
[1262] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-piperidin-1-yl-phenyl) oxazol-4-yl]- Methoxy} -phenyl) -propionic acid
[1263]
[1264] Example 396
[1265] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (morpholin-4-ylamino) phenyl] -oxazol-4-yl} -Ethoxy) -phenyl] -propionic acid
[1266]
[1267] 3- [4- {2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2 in toluene (2.0 mL) under nitrogen stream in a sealed tube A solution of-(isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester (120 mg, 0.200 mmol) was added to Pd ₂ (dba) ₃ (10 mg), 2- (di-t-butylforce). Pino) biphenyl (10 mg), N-aminomorpholine (29 mg, 0.28 mmol), and sodium t-butoxide (38 mg, 0.40 mmol). The tube was sealed and heated at 100 ° C. for 60 minutes. The mixture was cooled and silica gel chromatography (5-10% MeOH / EtOAc) gave the title compound directly (22 mg, 21%): MS (ESI) m / z 567.3 (M + H) ⁺ .
[1268] Example 397
[1269] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-phenoxy-phenyl) -oxazol-4-yl] -ethoxy} -phenyl ) -Propionic acid
[1270]
[1271] 3- [4- {2- [2- (4-bromo-phenyl) -5-methyl-oxazol-4-yl] ethoxy} -2- (isopropoxycarbonylamino in toluene (7 mL) -Methyl) -phenyl] -propionic acid tert-butyl ester (0.44 mmol, 0.24 g), phenol (0.53 mmol, 0.050 g), K ₃ PO ₄ (0.88 mmol, 0.19 g), 2- (di-t-butylforce) Pino) removed gas under vacuum from a mixture of biphenyl (0.066 mmol, 0.020 g), and Pd (OAc) ₂ (0.044 mmol, 0.010 g), again charged with nitrogen (3 ×) and 18 h at 110 ° C. Heated. Additional Pd (OAc) ₂ (10 mg) and 2- (di-t-butylphosphino) biphenyl (20 mg) were added to ensure complete reaction and the mixture was heated for 5 hours. After cooling, the mixture was placed directly on a silica gel column and eluted with 30% -50% EtOAc / hexanes to afford 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl -(4-phenoxy-phenyl) -oxazol-4-yl] -ethoxy} -phenyl) -propionic acid tert-butyl ester (0.11 g) was obtained.
[1272] tert-butyl ester (0.18 mmol, 0.11 g) was dissolved in CH ₂ Cl ₂ (3 mL) and 90% TFA / water (5 mL) was added. The mixture was stirred for 3 hours and concentrated. The residue was purified by silica gel chromatography (50% ethyl acetate / hexanes) to give an oil. Trituration with Et ₂ O gave the title compound (90 mg, 90%) as a white solid: ¹ H NMR (250 MHz, CDCl ₃ ) δ 8.11 (d, 2H, J = 8.8 Hz), 7.56 (t, 2H, J = 7.9 Hz), 7.37-7.20 (m, 6H), 7.0-6.93 (m, 2H), 5.11 (seven line, 1H, J = 6.3 Hz), 4.53 (d, 2H, J = 5.1 Hz), 4.38 (t, 2H, J = 6.7 Hz), 3.12 (q, 4H, J = 7.3 Hz), 2.80 (t, 2H, J = 7.6 Hz), 2.54 (s, 3H), 1.41 (d, 6H, J = 6.3 Hz).
[1273] Examples 398-4O5, below, were prepared following procedures substantially similar to those described in Examples 396 and 397.
[1274] Example 398
[1275] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-phenoxy-phenyl) -oxazol 4-yl] -ethoxy} -phenyl) Propionic acid
[1276]
[1277] Example 399
[1278] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (2-phenoxy-phenyl) oxazol-4-yl] -ethoxy} -phenyl) Propionic acid
[1279]
[1280] MS (ESI) 559 (M + H) ⁺ . Analytical calcd. For C ₃₂ H ₃₄ N ₂ O ₇ : C, 68.8; H, 6.1; N, 5.0. Found: C, 67.9; H, 6.2; N, 5.3.
[1281] Example 400
[1282] 3- [4- (2- {2- [4- (4-cyano-phenoxy) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycar Bonylamino-methyl) -phenyl] -propionic acid
[1283]
[1284] Example 401
[1285] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (4-trifluoromethylphenoxy) -phenyl] -oxazole-4- I} -ethoxy) -phenyl] -propionic acid
[1286]
[1287] Example 402
[1288] 3- [4- (2- {2- [4- (4-Fluoro-phenoxy) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycar Bonylamino-methyl) -phenyl] -propionic acid
[1289]
[1290] Example 403
[1291] 3- [4- (2- {2- [4- (3,4-Difluoro-phenoxy) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (iso Propoxycarbonylamino-methyl) -phenyl] -propionic acid
[1292]
[1293] Example 404
[1294] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-m-tolyloxy-phenyl) oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1295]
[1296] Example 405
[1297] 3- [4- (2- {2- [4- (4-acetyl-phenoxy) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1298]
[1299] Example 406
[1300] 3- [4- {2- [2- (4-hydroxy-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid tert-butyl ester
[1301]
[1302] Organic Synthesis, vol. V, p. 918], 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (4,4,5,5- in THF (8 mL) Tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -oxazol-4-yl} -ethoxy) -phenyl] -propionic acid tert-butyl ester (1.4 g, 2.16 mmol, The solution of Example 368, step A) was treated with glacial acetic acid (194 mg, 3.24 mmol) at 0 ° C. Was diluted with 30% H ₂ 0 ₂ aqueous solution (4.75mL) in H ₂ O (1mL) was added to the reaction mixture. The mixture was warmed to rt and treated with 1 M aqueous Na ₂ S ₂ 0 ₃ solution (50 mL). THF was removed in vacuo and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with 1M Na ₂ S ₂ O ₃ (2 × 50 mL), dried (MgSO ₄ ), filtered and concentrated to an oil content (1.21 g). Purification by silica gel chromatography (1: 1 hexanes: ethyl acetate) gave the title compound (1.10 g, 95%) as a white solid.
[1303]
[1304] Example 407
[1305] 3- [4- {2- [2- (3-hydroxy-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid tert-butyl ester:
[1306]
[1307] The compound was prepared following a procedure substantially similar to that described in Example 406. MS [El +] m / z 539 (M + H).
[1308] Examples 408-409 below were prepared following procedures substantially similar to those described in Example 406, and the corresponding carboxylic acid was obtained from standard hydrolysis procedure C:
[1309] Example 408
[1310] 3- [4- {2- [2- (4-hydroxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1311]
[1312] Example 409
[1313] 3- [4- {2- [2- (3-hydroxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid:
[1314]
[1315] Example 410
[1316] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1317]
[1318] 3- [4- {2- [2- (4-hydroxy-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino in ethanol (20 mL) Treat a solution of -methyl) -phenyl] -propionic acid tert-butyl ester (300 mg, 0.557 mmol, Example 406) with 2-iodopropane (473 mg, 2.78 mmol) and K ₂ CO ₃ (231 mg, 1.67 mmol) And stirred overnight at reflux. The reaction mixture was cooled down and concentrated. The residue was diluted with H ₂ 0 and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated to give an oil. 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [2- (4-isopropoxy-phenyl)-using silica gel chromatography (3: 1 hexanes: ethyl acetate) 5-Methyl-oxazol-4-yl] -ethoxy} -phenyl) -propionic acid tert-butyl ester was obtained as a yellow oil (210 mg).
[1319]
[1320] The ester was converted to the title compound as a white solid according to standard procedure C (134 mg).
[1321]
[1322] Examples 411 to 422 below were prepared following procedures substantially similar to those described in Example 410.
[1323] Example 411
[1324] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (4-propoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1325]
[1326] Example 412
[1327] 3- [4- {2- [2- (4-ethoxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1328]
[1329] Example 413
[1330] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (4-methoxyphenyl) -5-methyloxazol-4-yl] ethoxy} phenyl) propionic acid
[1331] MS (ES) m / z 497 (M + l).
[1332] Example 414
[1333] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (3-methoxyphenyl) -5-methyloxazol-4-yl] ethoxy} phenyl) propionic acid
[1334] MS (ES) m / z 497 (M + 1)
[1335] Example 415
[1336] 3- [4- {2- [2- (3-ethoxyphenyl) -5-methyloxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1337]
[1338] Example 416
[1339] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [2- (3-isopropoxyphenyl) -5-methyloxazol-4-yl] ethoxy} phenyl) propionic acid
[1340]
[1341] Example 417
[1342] 3- (2- (isopropoxycarbonylaminomethyl) -4- {2- [5-methyl-2- (3-propoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1343]
[1344] Example 418
[1345] 3- [4- {2- [2- (3-butoxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1346]
[1347] Example 419
[1348] 3- [4- {2- [2- (3-cyclopentyloxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1349]
[1350] Example 420
[1351] 3- [4- {2- [2- (3-cyclohexyloxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) -phenyl] propionic acid
[1352]
[1353] Example 421
[1354] 3- [4- {2- [2- (4-cyclopentyloxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1355]
[1356] Example 422
[1357] 3- [4- {2- [2- (4-cyclohexyloxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid
[1358]
[1359] Example 423
[1360] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (tetrahydro-pyran-4-yloxy) -phenyl] -oxazole-4 -Yl} -ethoxy) -phenyl] -propionic acid
[1361]
[1362] 3- [4- {2- [2- (4-hydroxy-phenyl) -5-methyl-oxazol-4-yl] ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl] Propionic acid tert-butyl ester (120 mg, 0.223 mmol, Example 406), tetrahydro-pyran-4-ol (22.7 mg, 0.223 mmol), triphenylphosphine (58.4 mg, 0.223 mmol) and toluene (10 mL To the mixture was added dropwise DIAD (45 mg, 0.223 mmol). The mixture was stirred at ambient temperature under N ₂ for 16 h and concentrated. The crude product was purified by radial chromatography (10-70% EtOAc / hexanes) to give 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- ( Tetrahydro-pyran-4-yloxy) -phenyl] -oxazol-4-yl} -ethoxy) phenyl] -propionic acid tert-butyl ester was obtained. The ester product was dissolved in 4M HCl / dioxane (5 mL), stirred for 16 h and concentrated to give the title compound: MS [ES] m / z 525 (M + H).
[1363] Examples 424-431 below were prepared following procedures substantially similar to those described in Example 423.
[1364] Example 424
[1365] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (l-methylpiperidin-4-yloxy) phenyl] oxazole-4- Ethoxy) phenyl] propionic acid
[1366]
[1367] Example 425
[1368] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [3- (tetrahydropyran-4-yloxy) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid
[1369]
[1370] Example 426
[1371] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [3- (1-methylpiperidin-4-yloxy) phenyl] oxazole-4- Ethoxy) phenyl] propionic acid
[1372]
[1373] Example 427
[1374] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [3- (piperidin-4-yloxy) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid
[1375]
[1376] Example 428
[1377] 3- [4- (2- {2- [3- (3-dimethylaminopropoxy) phenyl] -5-methyloxazol-4-yl} ethoxy) -2- (isopropoxycarbonylaminomethyl) Phenyl] propionic acid
[1378]
[1379] Example 429
[1380] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (piperidin-4-yloxy) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid
[1381]
[1382] Example 430
[1383] 3- [4- (2- {2- [4- (2-dimethylaminoethoxy) phenyl] -5-methyloxazol-4-yl} ethoxy) -2- (isopropoxycarbonylaminomethyl) Phenyl] propionic acid
[1384]
[1385] Example 431
[1386] 3- [4- (2- {2- [4- (3-dimethylaminopropoxy) phenyl] -5-methyloxazol-4-yl} ethoxy) -2 (isopropoxycarbonylaminomethyl) phenyl Propionic acid
[1387]
[1388] Example 432
[1389] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (pyridin-2-yloxy) phenyl] oxazol-4-yl} ethoxy) Phenyl] propionic acid
[1390]
[1391] 3- {2- [2- (4-hydroxy-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxy-carbonylamino-methyl) -phenyl]- Propionic acid tert-butyl ester (Example 406) was reacted with 2-bromopyridine by the procedure of Example 397 to afford the title compound.
[1392] MS (ES) m / z 560 (M + l).
[1393] Examples 433-435, below, were prepared following procedures substantially similar to those described in Example 432.
[1394] Example 433
[1395] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (pyridin-4-yloxy) phenyl] oxazol-4-yl} ethoxy) Phenyl] propionic acid
[1396]
[1397] Example 434
[1398] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (pyridin-3-yloxy) phenyl] oxazol-4-yl} ethoxy) Phenyl] propionic acid
[1399]
[1400] Example 435
[1401] 3- [2- (isopropoxycarbonylaminomethyl) -4- (2- {5-methyl-2- [4- (pyrimidin-2-yloxy) phenyl] oxazol-4-yl} ethoxy ) Phenyl] propionic acid
[1402]
[1403] Example 436
[1404] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-carbamoyl-phenyl) -oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1405]
[1406] Step A: 4- (4- {2- [4- (2-tert-butoxycarbonyl-ethyl) -3- (isopropoxycarbonylamino-methyl) phenoxy] -ethyl} -5-methyl- Oxazol-2-yl) -benzoic acid methyl ester
[1407]
[1408] 3- [4- {2- [2- (4-bromo-phenyl) -5-methoxy-oxazol-4-yl] -ethoxy} -2- (isopropoxy) in acetonitrile (2 mL) -Carbonylamino-methyl-phenyl) -propionic acid tert-butyl ester (0.25 g, 0.42 mmol), 1,1'-bis (diphenylphosphino) -ferrocene palladium (II) chloride (50 mg), MeOH (0.1 mL) and triethylamine (0.12 mL, 0.66 mmol) were stirred at 70 ° C. under CO gas (balloon) for 16 h and heated. The reaction mixture was cooled down and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc, 5/1 to 1/1) to give the title compound (0.12 g, 50%) as a white solid:
[1409]
[1410] 4- (4- {2- [4- (2-tert-butoxycarbonyl-ethyl) -3- (isopropoxycarbonyl-amino-methyl) -phenoxy] -ethyl} in methanol (2 mL) A -5-methyl-oxazol-2-yl) -benzoic acid methyl ester (100 mg, 0.17 mmol) solution was treated with 1.5 N aqueous LiOH (1.0 mL) and stirred at ambient temperature for 3 hours. The reaction mixture was acidified with 1N HCl and extracted with CH ₂ Cl ₂ . The organic phase was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (hexane / EtOAc, 1/1 to 0/1) to afford the title compound (55 mg, 57%). MS (ESI) m / z 567 (M + H) ⁺ .
[1411] Step C: 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-carbamoylphenyl) -oxazol-4-yl] -ethoxy } -Phenyl) -propionic acid
[1412] 4- (4- {2- [4- (2-tert-butoxycarbonyl-ethyl)-(isopropoxycarbonyl-amino-methyl) -phenoxy] -ethyl in CH ₂ Cl ₂ (2 mL) } -5-Methyl-oxazol-2-yl) -benzoic acid (40 mg, 0.07 mmol) was treated with oxalyl chloride (1.0 μl, 0.12 mmol) and 1 drop of DMF. The reaction mixture was stirred at ambient temperature for 30 minutes, concentrated and coevaporated with toluene. The residue was dissolved in CH ₂ Cl ₂ (2 mL) and added to a flask containing 2.0 M methylamine (2M, 0.04 mL) and triethylamine (20 μl, 0.12 mmol) in THF. The mixture was stirred at ambient temperature for 16 hours, diluted with CH ₂ Cl ₂ (10 mL) and washed with H ₂ O. The organic layer was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (hexane / EtOAc, 3: 1 to 0: 1) to give tert-butyl ester. The ester was converted to the acid by standard procedure C and purified by HPLC linked by mass spectrometry to afford the title compound. MS (ESI) m / z 524 (M + H) ⁺ .
[1413] Examples 437-448 below were prepared following procedures substantially similar to those described in Example 436.
[1414] Example 437
[1415] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-methylcarbamoyl-phenyl) oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1416]
[1417] Example 438
[1418] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-propylcarbamoyl-phenyl) oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1419]
[1420] Example 439
[1421] 3- [4- {2- [2- (3-cyclobutylcarbamoyl-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl ) -Phenyl] -propionic acid
[1422]
[1423] Example 440
[1424] 3- [4- {2- [2- (3-isobutylcarbamoyl-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl ) -Phenyl] -propionic acid
[1425]
[1426] Example 441
[1427] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-phenylcarbamoyl-phenyl) oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1428]
[1429] Example 442
[1430] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [3- (morpholin-4-carbonyl) phenyl] -oxazol-4-yl} -Ethoxy) -phenyl] -propionic acid
[1431]
[1432] Example 443
[1433] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-propylcarbamoyl-phenyl) oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1434]
[1435] Example 444
[1436] 3- [4- {2- [2- (4-cyclobutylcarbamoyl-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl ) -Phenyl] -propionic acid
[1437]
[1438] Example 445
[1439] 3- [4- {2- [2- (4-cyclohexylcarbamoyl-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2 (isopropoxycarbonylamino-methyl) -Phenyl] -propionic acid
[1440]
[1441] Example 446
[1442] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-phenylcarbamoyl-phenyl) oxazol-4-yl] -ethoxy}- Phenyl) -propionic acid
[1443]
[1444] Example 447
[1445] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (pyridin-3-ylcarbamoyl) -phenyl] -oxazole-4- I} -ethoxy) -phenyl] -propionic acid
[1446]
[1447] Example 448
[1448] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {5-methyl-2- [4- (pyrrolidine-1-carbonyl) -phenyl] -oxazole-4- I} -ethoxy) -phenyl] -propionic acid
[1449]
[1450] Example 449
[1451] 4- (4- {2- [4- (2-carboxy-ethyl) -3- (isopropoxycarbonylamino-methyl) -phenoxy] -ethyl} -5-methyl-oxazol-2-yl) -Benzoic acid
[1452]
[1453] 4- (4- {2- [4- (2-tert-butoxycarbonyl-ethyl) -3- (isopropoxycarbonylamino-methyl) -phenoxy] -ethyl} -5-methyl-oxazole -2-yl) -benzoic acid (50 mg, 0.09 mmol, Example 436, step B) was converted to the title compound according to standard procedure C (40 mg, 95%): MS (ESI) m / z 525 (M + H) ⁺ .
[1454] Example 450
[1455] 3- (4- {2- [4- (2-carboxy-ethyl) -3- (isopropoxycarbonylamino-methyl) -phenoxy] -ethyl} -5-methyl-oxazol-2-yl) Benzoic acid:
[1456]
[1457] The compound was prepared following a procedure substantially similar to that described in Example 449. MS (ESI) m / z 525 (M + H) &lt; + &gt;.
[1458] Example 451
[1459] 3- [4- {2- [2- (3-cyclohexylcarbamoyl-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl ) -Phenyl] -propionic acid
[1460]
[1461] 3- [4- {2- [2- (4-bromo-phenyl) -5-methoxy-oxazol-4-yl] -ethoxy} in acetonitrile (20 ml) in a dried 3-neck flask. A solution of 2- (isopropoxy-carbonylamino-methyl) -propionic acid tert-butyl ester (230 mg, 0.38 mmol) was prepared with 2-hydroxypyridine (44 mg, 0.46 mmol) and 1,1'-bis (di Treated with phenylphosphino) -ferrocene palladium (II) chloride (47 mg, 0.057 mmol). The mixture was stirred under N _{2 for} about 5 minutes and triethylamine (58 mg, 0.57 mmol) was added dropwise. CO gas was bubbled through the mixture and the reaction heated at 70 ° C. for 4 h. CO bubbling was replaced with a balloon filled with CO and the reaction stirred for a further 16 h. The mixture was cooled and equally dispensed in two flasks. One portion was treated with cyclohexylamine (46 mg, 0.46 mmol) and triethylamine (58 mg, 0.57 mmol). The mixture was stirred at 70 ° C. for 16 h, cooled, filtered through celite and concentrated to a brown solid (196 mg). The solid was purified by radial chromatography (10-70% EtOAc / hexanes) to give fenultimate tert-butyl ester (78 mg; MS (ESI) m / z 648.6 (M + H) ⁺ ). The ester was converted to the title compound by standard procedure D (72 mg, 64%). MS (ESI) m / z 592.0 (M + H) ⁺ .
[1462] Example 452
[1463] 3- [4- (2- {2- [4- (3-Fluoro-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycar Bonylamino-methyl) -phenyl] -propionic acid
[1464]
[1465] Step A:
[1466] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-nitro-phenyl) -oxazol-4-yl] -ethoxy} -phenyl) Propionic acid tert-butyl ester
[1467]
[1468] 4-Methyl-3-nitro-benzenesulfonic acid 2- [5-methyl-2- (4-nitro-phenyl) oxazol-4-yl] -ethyl ester (Preparation 7) and 3- [4-hydroxy- 2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid tert-butyl ester was coupled according to standard procedure A to afford the title compound.
[1469] Step B: 3- [4- {2- [2- (4-Amino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -Phenyl] -propionic acid tert-butyl ester
[1470]
[1471] 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (4-nitro-phenyl) -oxazol-4-yl]-in EtOAc (20 mL)- Ethoxy} -phenyl) -propionic acid tert-butyl ester (207 mg, 0.365 mmol) and 10% Pd-C (27 mg) were stirred under H ₂ (1 atm) for 18 hours. The reaction mixture was filtered through celite and concentrated (75 ° C.) to give the title compound as a colorless oil (196 mg, 100%): MS (ESI) m / z 538 (M + H) ⁺ .
[1472] Step C: 3- [4- (2- {2- [4- (3-Fluoro-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (iso Propoxycarbonylamino-methyl) -phenyl] -propionic acid
[1473] 3- [4- {2- [2- (4-amino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxy) in CH ₂ Cl ₂ (5 mL) Carbonyl-amino-methyl) -phenyl] -propionic acid tert-butyl ester. To a solution of (58 mg, 0.11 mmol, 1 equiv) and triethylamine (30 μl, 22 mg, 0.22 mmol, 2.0 equiv) was added 3-fluorobenzoyl chloride (31 mg, 0.20 mmol, 1.8 equiv). After 16 h, the reaction solution was washed with 1 M aqueous HCl (5 mL) and saturated aq. Wash with NaHC0 ₃ (5 mL). The organic layer was dried (MgSO ₄ ) and concentrated (75 ° C.) to yield the intermediate ester as a pale yellow oil. The oil was diluted with 4 M HCl in 1,4-dioxane (5 mL), stirred for 64 h and concentrated to give the title compound (73 mg, 110%). HRMS calcd for C ₃₃ H ₃₅ FN ₃ O ₇ : m / z 604.2459. Found: 604.2453.
[1474] Examples 453 to 475 below were prepared following procedures substantially similar to those described in Examples 451 and 452.
[1475] Example 453
[1476] 3- [4- (2- {2- [4- (4-Fluoro-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycar Bonylamino-methyl) -phenyl] -propionic acid
[1477]
[1478] HRMS calcd for C ₃₃ H ₃₅ FN ₃ O ₇ : m / z 604.2459. Found: 604.2454.
[1479] Example 454
[1480] 3- [4- (2- {2- [4- (3,5-Difluoro-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (iso Propoxycarbonylamino-methyl) -phenyl] -propionic acid
[1481]
[1482] HRMS calcd for C ₃₃ H ₃₄ F ₂ N ₃ O ₇ : m / z 622.2365. Found: 622.2352.
[1483] Example 455
[1484] 3- [4- (2- {2- [4- (3,4-Difluoro-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (iso Propoxycarbonylamino-methyl) -phenyl] -propionic acid
[1485]
[1486] HRMS calcd for C ₃₃ H ₃₄ F ₂ N ₃ 0 ₇ : m / z 622.2365. Found: 622.2382.
[1487] Example 456
[1488] 3- (4- {2- [2- (4-acetylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2-{[(pyridine-2-carbonyl) -amino ] -Methyl} -phenyl) -propionic acid
[1489]
[1490] Example 457
[1491] 3- (4- {2- [2- (4-amino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2-{[(pyridine-2-carbonyl) amino]- Methyl} -phenyl) -propionic acid
[1492]
[1493] Example 458
[1494] 3- (4- {2- [2- (4-isobutoxycarbonylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2-{[(pyridine-2-carbonyl ) -Amino] -methyl} -phenyl) -propionic acid
[1495]
[1496] Example 459
[1497] 3- [4- {2- [2- (4-Amino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl] Propionic acid
[1498]
[1499] Example 460
[1500] 3- [4- {2- [2- (4-benzoylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid
[1501]
[1502] Example 461
[1503] 3- (4- {2- [2- (4-benzoylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2-{[(pyridine-2-carbonyl) -amino ] -Methyl} -phenyl) -propionic acid
[1504]
[1505] Example 462
[1506] 3- (4- (2- {2- [4- (4-methoxy-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2-{[(pyridine- 2-carbonyl) -amino] -methyl} -phenyl) -propionic acid
[1507]
[1508] Example 463
[1509] 3- (4- [2- (5-methyl-2- {4-[(pyridine-3-carbonyl) -amino] -phenyl} -oxazol-4-yl) -ethoxy] -2-{[ (Pyridine-2-carbonyl) -amino] -methyl} -phenyl) -propionic acid
[1510]
[1511] Example 464
[1512] 3- (4- [2- (2- {4-[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -phenyl} -5-methyl-oxazol-4-yl)- Methoxy] -2-{[(pyridine-2-carbonyl) -amino] -methyl} -phenyl) -propionic acid
[1513]
[1514] Example 465
[1515] 3- (4- (2- {2- [4- (N, N-di- (butane-1-sulfonyl) amino) -phenyl] -5-methyl-oxazol-4-yl} ethoxy)- 2-{[(Pyridine-2-carbonyl) -amino] -methyl} -phenyl) -propionic acid
[1516]
[1517] Example 466
[1518] 3- (4- (2- {2- [4- (butane-1-sulfonylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2-{[(pyridine- 2-carbonyl) -amino] -methyl} -phenyl) -propionic acid
[1519]
[1520] Example 467
[1521] 3- [4- {2- [2- (4-acetylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl) -phenyl ] -Propionic acid
[1522]
[1523] Example 468
[1524] 3- [4- {2- [2- (4-butyrylamino-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2- (isopropoxycarbonylamino-methyl)- Phenyl] -propionic acid
[1525]
[1526] Example 469
[1527] 3- [4- (2- {2- [4- (cyclobutanecarbonyl-amino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopropoxycarbonyl Amino-methyl) -phenyl] -propionic acid
[1528]
[1529] Example 470
[1530] 3- [2- (isopropoxycarbonylamino-methyl) -4- (2- {2- [4- (4-methoxy-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl } -Ethoxy) -phenyl] -propionic acid
[1531]
[1532] Example 471
[1533] 3- [4- (2- {2- [4- (3,5-Dimethoxy-benzoylamino) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -2- (isopro Poxycarbonylamino-methyl) -phenyl] -propionic acid
[1534]
[1535] Example 472
[1536] 3- {2- (isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-2- {4-[(pyridine-3-carbonyl) amino] -phenyl} -oxazole-4 -Yl) -ethoxy] -phenyl} -propionic acid
[1537]
[1538] Example 473
[1539] 3- [4- [2- (2- {4-[(2,5-dichloro-thiophene-3-carbonyl) -amino] -phenyl} -5-methyl-oxazol-4-yl)- Methoxy] -2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid
[1540]
[1541] Example 474
[1542] 3- {2- (Isopropoxycarbonylamino-methyl) -4- [2- (5-methyl-2- {4-[(pyridine-2-carbonyl) amino] -phenyl} -oxazole-4 -Yl) -ethoxy] -phenyl} -propionic acid
[1543]
[1544] MS (ES) m / z 587 (M + l).
[1545] Example 475
[1546] 3- [4- [2- (2- {4-[(furan-2-carbonyl) -amino] -phenyl} -5-methyl-oxazol-4-yl) -ethoxy] -2- (iso Propoxycarbonylamino-methyl) -phenyl] -propionic acid
[1547]
[1548] Example 476
[1549] 3- [4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (pyrimidin-2-ylaminomethyl) -phenyl] -propionic acid
[1550]
[1551] 3- {2-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester in DMF (2 mL): acetic acid Salt (0.40 mmol, 0.20 g, Example 1 Step B) was treated with K ₂ CO ₃ (1.0 mmol, 0.14 g) and 2-chloropyrimidine (1.2 mmol, 0.14 g). The mixture was heated at 60 ° C. for 18 h, cooled, diluted with water (50 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography to give tert-butyl ester intermediate. The material was converted to the title compound (80 mg) using standard procedure C. MS (ESI) m / z 459.2 (M + H) ⁺ .
[1552] Example 477
[1553] 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(2-methylsulfanyl-pyrimidin-4-ylamino) -methyl] -Phenyl} -propionic acid
[1554]
[1555] The compound was prepared following a procedure substantially similar to that described in Example 476. MS (ESI) m / z 505.1 (M + H) ⁺ .
[1556] Example 478
[1557] 3- {2- (Benzothiazol-2-ylaminomethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1558]
[1559] 3- {2-aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester acetic acid salt in toluene (5 mL) (150 mg, 0.302 mmol; Example 1 Step B) and a solution of 2-chloro-benzothiazole (154 mg, 0.907 mmol) were treated with K ₂ CO ₃ (42 mg). The suspension was heated at 110 ° C. for 48 hours and concentrated. The residue was purified by silica gel chromatography (25-50% EtOAc / hexanes) to give tert-butyl ester intermediate (15 mg). The material was converted to the title compound (80 mg) using standard procedure C. The intermediate was treated with TFA (0.25 ml) / CH ₂ Cl ₂ (1.0 ml) / H ₂ 0 (0.1 mL), stirred for 3 hours, and concentrated. The residue was dissolved in CH ₂ Cl ₂ (10 ml), washed with aqueous buffer (pH = 7), dried (Na ₂ SO ₄ ) and concentrated to give the title compound (12 mg, 8%). MS (ESI) m / z 514.3 (M + H) ⁺ .
[1560] Example 479
[1561] 3- {2-[(2-Benzoyl-phenylamino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1562]
[1563] 3- {2-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester acetic acid in anisole (20 mL) Salt (290 mg, 0.665 mmol, Example 1, Step B) and 2-benzoyl-cyclohexanone (161 mg, 0.797 mmol) were treated with a slurry of Pd / C (60 mg) in anisole (2 mL). . The mixture was refluxed at 200 ° C. for 2 hours with azeotropic removal of water and cooled to room temperature. The catalyst was filtered off and a fresh slurry of Pd / C (60 mg) was added in anisole. The mixture was heated at 110 ° C. for 72 h and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography (25% EtOAc / hexanes) to give a mixture of starting material and the desired tert butyl ester intermediate. The mixture was treated with TFA (1.0 ml) / CH ₂ Cl ₂ (1.0 ml) / H ₂ O (0.1 mL), stirred for 3 h, and concentrated. The residue was purified by silica gel chromatography (MeOH / EtOAc 1/9) to give the title compound (38 mg, 10%). MS (ESI) m / z 561.3 (M + H) ⁺ .
[1564] Example 480
[1565] 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(4-trifluoromethyl-phenylamino) -methyl] -phenyl}- Propionic acid
[1566]
[1567] 3- {2-aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} in toluene (5.0 mL) under nitrogen in a sealed tube apparatus. Pd (OAc) ₂ (15 mg), 2- (di-t-butylphosphino) biphenyl (10 mg) in a solution of propionic acid tert-butyl ester (174 mg, 0.40 mmol, Example 1 and Procedure I), Sodium t-butoxide (54 mg, 0.56 mmol) and 4-trifluoromethylchlorobenzene (29 mg, 0.16 mmol) were added. The tube was sealed and heated at 110 ° C. for 14 hours. The reaction mixture was cooled down, quenched with water (1.0 mL) and extracted with EtOAc (2 × 15 mL). The combined organic phases were concentrated and purified using silica gel chromatography column (10-50% EtOAc / hexanes) to give tert-butyl ester intermediate (80 mg). The material was converted to the title compound (40 mg, 48%) using standard procedure C. MS (ESI) m / z 525.4 (M + H) ⁺ .
[1568] Examples 481-484 below were prepared following procedures substantially similar to those described in Examples 478-480.
[1569] Example 481
[1570] 3- {2-[(4-Methanesulfonyl-phenylamino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1571]
[1572] Example 482
[1573] 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(4-propionyl-phenylamino) -methyl] -phenyl} -propionic acid
[1574]
[1575] Example 483
[1576] 3- {2-{[bis- (4-methoxy-phenyl) -amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -phenyl } -Propionic acid
[1577]
[1578] Example 484
[1579] 3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (pyridin-2-ylaminomethyl) -phenyl] propionic acid
[1580]
[1581] Example 485
[1582] 3- {2-{[(2,5-Dichloro-thiophene-3-carbonyl) -methyl-amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazole-4- Yl) -ethoxy] -phenyl} -propionic acid
[1583]
[1584] Step A: 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(2,2,2-trifluoroacetylamino) -methyl ] -Phenyl} -propionic acid tert-butyl ester
[1585]
[1586] 3- {2-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid tert-butyl ester: acetic acid salt (894 mg, 1.80 mmol ) Was dissolved in CH ₂ Cl ₂ (25 mL) and washed with saturated NaHCO ₃ solution (15 mL). The organic phase was dried (NaSO ₄ ), filtered and concentrated to yellow oil (681 mg). The crude amine was dissolved in CH ₂ Cl ₂ (25 mL) and treated with anhydrous trifluoroacetic acid (0.66 mL, 4.7 mmol) followed by pyridine (0.37 mL, 4.6 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and concentrated. The residue was partitioned between EtOAc and 1N HCl and the organic layer was washed with saturated NaHCO ₃ solution followed by brine. The organic phase was dried (Na ₂ SO ₄ ) and concentrated to give a pale yellow solid (839 mg, 88%).
[1587] Step B: 3- (4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-{[methyl- (2,2,2-trifluoroacetyl) -Amino] -methyl} -phenyl) -propionic acid tert-butyl ester
[1588]
[1589] 3- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(2,2,2 + trifluoro-) in anhydrous DMF (10 mL) A solution of acetylamino) -methyl] -phenyl} -propionic acid tert-butyl ester (151 mg, 0.28 mmol) was cooled in an ice bath and treated with NaH (22 mg, 0.55 mmol, 60% oil dispersion). After the reaction mixture was stirred for 25 minutes, iodomethane (0.15 mL, 3.0 mmol) was added and the reaction was slowly warmed to ambient temperature. After 4 hours, additional iodomethane (0.10 mL, 2 mmol) was added. The mixture was stirred overnight and partitioned between EtOAc and aqueous LiCl solution. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel radial chromatography (CH ₂ Cl ₂ / EtOAc 100/0 to 95/5) to give the title compound (111 mg, 73%).
[1590] Step C: 3- {2-Methylaminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert-butyl ester
[1591]
[1592] 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-{[methyl- (2,2,) in methanol (5 mL) and THF (5 mL) 2,2-trifluoro-acetyl) -amino] -methyl} -phenyl) -propionic acid tert-butyl ester (111 mg, 0.20 mmol) solution was treated with 2N NaOH (1.0 mL, 2.0 mmol) and 1 at 55 ° C. Heated for hours. The reaction mixture was cooled down, concentrated, neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with saturated NaHCO ₃ solution and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel radial chromatography (CH ₂ Cl ₂ / methanol 95/5 to 90/10) to give the title compound (37 mg, 42%). MS (ES) m / z 451.3 [M + l].
[1593] Step D: 3- {2-{[(2,5-Dichloro-thiophene-3-carbonyl) -methyl-amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid tert butyl ester
[1594]
[1595] 3- {2-methylaminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert- in CH ₂ Cl ₂ (5 mL). Butyl ester (37 mg, 0.083 mmol) was treated with triethylamine (0.035 mL, 0.25 mmol) followed by 2,5-dichloro-thiophene-3-carbonyl chloride (0.054 mL, 0.25 mmol) and ambient temperature Stir overnight at. The mixture was diluted with EtOAc (25 mL) and washed with brine (3 x 10 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (50 mg, 96%). MS (ES) m / z 629, 631 [M + l].
[1596] Step E: 3- {2-{[(2,5-Dichloro-thiophene-3-carbonyl) -methyl-amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid
[1597] 3- {2-{[(2,5-Dichloro-thiophene-3-carbonyl) -methyl-amino] methyl} -4- [2- (5-methyl-2) in CH ₂ Cl ₂ (2 mL) A solution of -phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid tert butyl ester (50 mg, 0.079 mmol) was treated with anisole (1.0 mL) followed by TFA (0.6 mL). The solution was stirred at ambient temperature for 2 hours and additional TFA (1.0 mL) was added. After 15 minutes, the reaction was concentrated and coevaporated with CCl ₄ (3 ×). The residue was triturated with hexanes to give a foam (43 mg, 95%).
[1598]
[1599] Examples 486-488 below were prepared following procedures substantially similar to those described in Example 485.
[1600] Example 486
[1601] 3- {2-[(Butyryl-methyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid
[1602]
[1603] Example 487
[1604] 3- {2-[(Cyclobutanecarbonyl-methyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1605]
[1606] Example 488
[1607] 3- {2-[(Benzyloxycarbonyl-methyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4 yl) -ethoxy] -phenyl} -propionic acid
[1608]
[1609] Example 489
[1610] 3- {4- [2- (2-Biphenyl-3-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-[(isopropoxycarbonyl-methyl-amino) -methyl ] -Phenyl} -propionic acid
[1611]
[1612] 3- {4-hydroxy-2-[(isopropoxycarbonyl-methyl-amino) -methyl] -phenyl} -propionic acid tert-butyl ester (500 mg, 1.4 mmol; Preparation Example 22 using standard procedure A) ) And toluene-4-sulfonic acid-2- (2-biphenyl-3-yl-5-methyl-oxazol-4-yl) ethyl ester (617 mg, 1.4 mmol; Preparation 1/2) Phenultimate tert-butyl ester was obtained. The ester was converted to the title compound using standard procedure D (326 mg): MS (ESI) m / z 557 (M + H) ⁺ .
[1613] Examples 490 to 501 below were prepared following procedures substantially similar to those described in Example 489.
[1614] Example 490
[1615] 3- {4- {2- [2- (3-bromophenyl) -5-methyloxazol-4-yl] ethoxy} -2-[(isopropoxy-carbonylmethylamino) methyl] phenyl} Propionic acid
[1616]
[1617] Example 491
[1618] 3- {4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2-[(isopropoxy-carbonylmethylamino) methyl] phenyl} propionic acid
[1619]
[1620] Example 492
[1621] 3- {4- [2- (2-cyclohexyl-5-methyloxazol-4-yl) ethoxy] -2-[(isopropoxycarbonylmethylamino) methyl] phenyl} propionic acid
[1622]
[1623] Example 493
[1624] 3- {2-[(isopropoxycarbonylmethylamino) methyl] -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid
[1625]
[1626] Example 494
[1627] 3- {4- {2- [2- (4-bromophenyl) -5-methyloxazol-4-yl] ethoxy} -2-[(isopropoxy-carbonylmethylamino) methyl] phenyl} Propionic acid
[1628]
[1629] Example 495
[1630] 3- {2-[(isopropoxycarbonylmethylamino) methyl] -4- [2- (5-methyl-2-phenylthiazol-4-yl) ethoxy] phenyl} propionic acid
[1631]
[1632] Example 496
[1633] 3- {4- [2- (2-biphenyl-4-yl-5-methylthiazol-4-yl) ethoxy] -2-[(isopropoxycarbonylmethylamino) methyl] phenyl} propionic acid
[1634]
[1635] Example 497
[1636] 3- (2-[(isopropoxycarbonylmethylamino) methyl] -4- {2- [5-methyl-2- (1-methyl-cyclohexyl) oxazol-4-yl] ethoxy} phenyl) Propionic acid
[1637]
[1638] Example 498
[1639] 3- {2-[(isopropoxycarbonylmethylamino) methyl] -4- [2- (5-methyl-2-phenethyl-oxazol-4-yl) ethoxy] phenyl} propionic acid
[1640]
[1641] Example 499
[1642] 3- {2-[(isopropoxycarbonylmethylamino) methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4 yl) ethoxy) phenyl} propionic acid
[1643]
[1644] Example 500
[1645] 3- (4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2-{[methyl (pyridine-2-carbonyl) amino] methyl} phenyl Propionic acid
[1646]
[1647] Example 501
[1648] 3- [4- {2- [2- (2-bromophenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxy-carbonylaminomethyl) phenyl] propionic acid
[1649]
[1650] Example 502
[1651] 3- {4- [2- (2-Biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-[(ethyl-isopropoxycarbonylamino) -methyl] -Phenyl} -propionic acid
[1652]
[1653] Step A: 3- [4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2- (isopropoxycarbonylamino-methyl)- Phenyl] -propionic acid methyl ester
[1654]
[1655] 3- [4-hydroxy-2- (isopropoxycarbonylamino-methyl) -phenyl] -propionic acid methyl ester (preparation 17) and toluene-4-sulfonic acid 2- (2-biphenyl-4-yl- 5-Methyl-oxazol-4-yl) ethyl ester (Preparation 1) was mixed according to standard procedure A to afford the title compound.
[1656] Step B: 3- {4- [2- (2-Biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-[(ethyl-isopropoxycarbonyl-amino ) -Methyl] -phenyl} -propionic acid
[1657] 3- [4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2- (isopropoxycarbonylamino- in DMF (15 mL) Methyl) -phenyl] -propionic acid methyl ester (200 mg, 0.36 mmol) was treated with sodium bis (trimethylsilyl) amide (132 mg, 0.719 mmol). Ethyl iodide (112 mg, 0.719 mmol) was added and the reaction mixture was stirred at rt overnight under N ₂ . The mixture was diluted with EtOAc (100 mL), brine (100 mL) and then washed with water (100 mL). The organic phase was dried (MgSO ₄ ) and concentrated to give fenultimate ester as a white solid (179 mg). The material was dissolved in EtOH (20 mL), treated with 5N NaOH (20 mL) and stirred at rt overnight. The mixture was acidified with 1N HCl (10 mL) and extracted with EtOAc (50 mL). The organic phase was dried (MgSO ₄ ) and concentrated to give a white solid (201 mg). MS [EI +] m / z 571 (M + H) ⁺ . Analytical Calcd for C ₃₄ H ₃₈ N ₂ 0 ₆ : C, 71.6; H, 6.7; N, 4.9. Found: C, 70.8; H, 6.8; N, 5.0.
[1658] Examples 503 to 504 below were prepared following procedures substantially similar to those described in Example 502.
[1659] Example 503
[1660] 3- {4- [2- (2-Biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2-[(isopropoxycarbonyl-methyl-amino) -methyl ] -Phenyl} -propionic acid
[1661]
[1662] MS [EI +] m / z 557 (M + H) ⁺ . Analytical Calcd for C ₃₃ H ₃₆ N ₂ 0 ₆ : C, 71.2; H, 6.5; N, 5.0. Found: C, 70.6; H, 6.6; N, 5.1.
[1663] Example 504
[1664] 3- {2-[(isopropoxycarbonyl-methyl-amino) -methyl] -4- [2- (5-methyl-3-phenyl-pyrazol-1-yl) -ethoxy] -phenyl}- Propionic acid
[1665]
[1666] Example 505
[1667] 3- (2-[(isopropoxycarbonyl-methyl-amino) -methyl) -4- {2- [5-methyl-2- (3-pyridin-3-yl-phenyl) -oxazole-4- Ill] -ethoxy} -phenyl) -propionic acid
[1668]
[1669] N-methylation of carbamate: 3- (2- (isopropoxycarbonylamino-methyl) -4- {2- [5-methyl-2- (3-pyridin-3-yl-) in a small screw cap vial Phenyl) -oxazol-4-yl] -ethoxy} -phenyl) -propionic acid tert-butyl ester (0.5 mmol) was introduced. A 1: 1 mixture of CHCl ₃ / TFA (1.6 mL) was added followed by 37% HCHO (50 μl). The reaction mixture was shaken for 0.5 h at ambient temperature and triethylsilane (110 μl, 0.7 mmol) was added. The mixture was further shaken for 0.5 h and concentrated. The resulting mixture was purified by massguided reversed phase HPLC to afford the title compound (85%). MS [EI +] m / z 571 (M + H) ⁺ .
[1670] Examples 506 to 509 below were prepared following procedures substantially similar to those described in Example 505.
[1671] Example 506
[1672] 3- (2-[(isopropoxycarbonyl-methyl-amino) -methyl] -4- {2- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl ] -Ethoxy} -phenyl) -propionic acid
[1673]
[1674] Example 507
[1675] 3- {4- {2- [2- (4-Butoxy-phenyl) -5-methyl-oxazol-4-yl] -ethoxy} -2-[(isopropoxycarbonyl methyl-amino)- Methyl] -phenyl} -propionic acid
[1676]
[1677] Example 508
[1678] 3- (2-[(isopropoxycarbonyl-methyl-amino) -methyl] -4- {2- [5-methyl-2- (3-pyridin-3-yl-phenyl) -oxazole-4- Ill] -ethoxy} -phenyl) -propionic acid
[1679]
[1680] Example 509
[1681] 3- {2-[(isopropoxycarbonyl-methyl-amino) -methyl] -4- [2- (5-methyl-2-pyridin-4-yl-thiazol-4-yl) -ethoxy] -Phenyl} -propionic acid
[1682]
[1683] Example 510
[1684] 3- {3-{[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -Ethoxy] -phenyl} -propionic acid
[1685]
[1686] Step A: 3- (3-allyl-4-benzyloxy-phenyl) -propionic acid methyl ester
[1687]
[1688] 3- (3-allyl-4-hydroxy-phenyl) -propionic acid methyl ester in DMF (50 mL) (20.5 g, 93.0 mmol; brown GR, et al. Bioorg. And Med. Chem. Lett. 1997, 7, 597) was treated with Cs ₂ CO ₃ (32.6 g, 100 mmol) followed by benzyl bromide (12.8 mL, 108 mmol) and heated at 55 ° C. for 16 h. Cs ₂ CO ₃ (16.3 g, 50 mmol) and benzyl bromide (6.4 mL, 54 mmol) were added. The mixture was stirred at 55 ° C. for 23 h, cooled and partitioned between EtOAc (250 mL) and water (100 mL). The organic layer was washed with brine (75 mL). The aqueous layers were combined and back extracted with EtOAc (100 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / hexane 1/1 to 100/0) to give the title compound (27.0 g, 93%).
[1689] Step B: 3- (4-benzyloxy-3-carboxymethyl-phenyl) -propionic acid methyl ester
[1690]
[1691] A solution of 3- (3-allyl-4-benzyloxy-phenyl) -propionic acid methyl ester (25.0 g, 80.5 mmol) in acetone (300 mL) and water (30 mL) was dissolved in 4-methylmorpholine 4-oxide (12.96 g, 95.8 mmol), followed by osmium (IV) oxide (5 chips). The flask was covered with foil and stirred for 20 hours. The solution was diluted with EtOAc (1 L) and washed with 1N Na ₂ S ₂ O ₃ (2 × 150 mL) and brine (125 mL). The organic layer was concentrated to give a yellow oil (28.9 g). The oil was dissolved in THF (190 mL) and water (125 mL) and sodium periodate (49.0 g, 229 mmol) was added. THF (190 mL) and water (125 mL) were added. The thick white slurry was stirred for 2 hours and filtered. The filtrate was extracted with EtOAc (1 L). The organic layer was washed with brine, 1N Na ₂ S ₂ 0 ₃ , and brine (150 mL each) and concentrated to give an orange oil (25.3 g). The oil was diluted with tert-butanol (400 mL) and 2-methyl-2-butene (100 mL) and cooled in an ice bath. The mixture was treated with sodium chlorite (68 g, 0.76 mol) and added with NaH ₂ PO ₄ (68 g, 0.49 mol) in water (250 mL) for 5 minutes. After 15 minutes, the ice bath was removed. The mixture was stirred for 2 hours and partitioned between EtOAc (1 L) and water (125 mL). The organic phase was washed with 1N Na ₂ S ₂ 0 ₃ (125 mL) and brine (125 mL), dried (NaSO ₄ ) and concentrated to concentrate the title compound as a tan solid (31.4 g, 119%). The material was used for the subsequent reaction without further purification.
[1692]
[1693] 3- (4-benzyloxy-3-carboxymethyl-phenyl) -propionic acid methyl ester (80.5 mmol), ammonium chloride (7.75 g, 145 mmol), EDC (27.7 g, 144 mmol), and N-hydroxybenzotriazole hydroxide Rate (19.6 g, 145 mmol) was mixed in the flask and diluted with DMF (320 mL). Ethyl-diisopropyl-amine (51 mL, 293 mmol) was added. The solution was stirred for 20 h and partitioned between EtOAc (1.2 L) and 1N HCl (250 mL). The organic phase was washed with saturated NaHCO ₃ (200 mL) and brine (200 mL), dried (NaSO ₄ ) and concentrated. The crude product was slurried with ethyl ether and filtered to give the title compound (15.9 g, 60%).
[1694] Step C: 3- [4-benzyloxy-3- (tert-butoxycarbonylamino-methyl) -phenyl] -propionic acid methyl ester
[1695]
[1696] 3- (4-benzyloxy-3-carbamoylmethyl-phenyl) -propionic acid methyl ester (15.9 g, 48.6 mmol) was dissolved in warming with CH ₃ CN (850 mL) and DMF (8 mL). Water was added, the solution was cooled to ambient temperature and [bis (trifluoroacetoxy) iodo] benzene (31.32 g, 72.8 mmol) was added. After 30 minutes, pyridine (8.2 mL) was added and the solution stirred for 17 hours. Triethylamine (28 mL, 200 mmol) and di-tert-butyl dicarbonate (16.0 g, 73.3 mmol) were added. The mixture was stirred for 2.5 hours and concentrated. The residue was partitioned between EtOAc (1 L) and brine (150 mL). The organic phase is washed with ice cold 1N HC1 (150 mL), saturated NaHCO ₃ solution (150 mL) and brine (100 mL); Dried (NaSO ₄ ); Concentrated. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / EtOAc 100/0 to 95/5) to give a yellow oil (11.0 g, 57%).
[1697] Step D: 3- [3- (tert-Butoxycarbonylamino-methyl) -4-hydroxy-phenyl] -propionic acid methyl ester
[1698]
[1699] A solution of 3- [4-benzyloxy-3- (tert-butoxycarbonylamino-methyl) -phenyl] -propionic acid methyl ester (8.50 g, 21.3 mmol) in THF (100 mL) was dissolved in Pd on 5% carbon ( 1.1 g) and shake for 6 hours at ambient temperature under hydrogen atmosphere (60 psi). The mixture was filtered through celite and concentrated to give a pale yellow solid (5.63 g, 85%).
[1700] Step E: 3- {3- (tert-Butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid Methyl ester
[1701]
[1702] 3- [3- (tert-butoxycarbonylamino-methyl) -4-hydroxy-phenyl] -propionic acid methyl ester (5.50 g, 17.8 mmol), toluene-4-sulfonic acid 2- (5-methyl-2- Phenyl-oxazol-4-yl) -ethyl ester (7.93 g, 22.2 mmol) and Cs ₂ CO ₃ (7.23 g, 22.2 mmol) were suspended in DMF (40 mL) and stirred at 55 ° C for 18 h. Additional toluene-4-sulfonic acid 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethyl ester (3.00 g, 8.39 mmol) and Cs ₂ CO ₃ (2.73 g, 8.39 mmol) were added, Stirring was continued for 22 hours. The reaction mixture was cooled down and partitioned between EtOAc (125 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried (NaSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / EtOAc 97/3 to 80/20) to give pure product (3.33 g, 38%) and slightly impure product (7.08 g).
[1703] Step F: 3- {3-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} propionic acid methyl ester: trifluoroacetic acid salt
[1704]
[1705] 3- {3- (tert-butoxycarbonylamino-methyl) -4- [2- (5-methyl-phenyl-oxazol-4-yl) -ethoxy]-in CH ₂ Cl ₂ (24 mL) A solution of phenyl} -propionic acid methyl ester (3.33 g, 6.73 mmol) was treated with TFA (10 mL) at ambient temperature and stirred for 3 hours. The solution was concentrated and co-evaporated with CCl ₄ (3 ×) to give the title compound as a foam (4.13 g, quant.)
[1706] Step G: 3- {3-{[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazole-4 -Yl) -ethoxy] -phenyl} -propionic acid
[1707] General parallel synthetic procedure: 3- {3-aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid methyl ester:
[1708] Trifluoroacetic acid salt (565 mg, 1.1 mmol) was dissolved in CH ₂ Cl ₂ (25 mL) and washed with saturated NaHCO ₃ solution (15 mL). The organic phase is dried (NaSO ₄ ), filtered and concentrated to 3- {3-aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} Propionic acid methyl ester (368 mg, 0.93 mmol, 84%) was obtained. A portion of the free base (26 mg, 0.071 mmol) in CH ₂ Cl ₂ (0.5 mL) was added triethylamine (0.075 mL, 0.54 mmol), followed by 2,5-dichloro-thiophene-3-carbonyl chloride ( 0.049 mL, 0.22 mmol). The reaction mixture was shaken overnight and dimethylethylenediamine (0.15 mL, 1.4 mmol) was added. The reaction mixture was shaken for 2 hours and added to an SCX column (1 g, 2 mL MeOH, then equilibrated with 2 mL MeOH / CH ₂ Cl ₂ 1/1). The methyl ester-amide product was eluted with MeOH / CH ₂ Cl ₂ (1: 1, 10 mL) and concentrated. The residue was dissolved in THF (2 mL) and MeOH (2 mL) and treated with 5N NaOH (1 mL). The solution was heated at 55 ° C. for 2.5 h, cooled and acidified with 5N HC1 (1.5 mL). The mixture was transferred to a ChemElute cartridge and eluted with CH ₂ Cl ₂ . The solution was removed under an N ₂ stream. The crude product was dried under vacuum and purified by mass spectrometry with HPLC to give the title compound (9.9 mg, 26%) as foam. MS (ESI) m / z 559.1 (M + H) ⁺ .
[1709] Example 511-543
[1710] Examples 511-543 were prepared following procedures substantially similar to those described in Example 510.
[1711]
[1712]
[1713]
[1714]
[1715]
[1716] Example 544
[1717] 3- {2- (2-Isopropoxycarbonylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1718]
[1719] Step A: 5-benzyloxy-2-bromo- (2-nitrovinyl) benzene
[1720]
[1721] A solution of 2-bromo-5-hydroxy-benzaldehyde (5.99 g, 29.8 mmol, Preparative Example 13 Step A) in DMF (50 mL) was added to benzyl bromide (7.65 g, 44.7 mmol) and Cs ₂ CO ₃ (15.1 g). , 44.7 mmol). The resulting mixture was heated at 80 ° C. for 60 minutes and quenched with water (200 mL). The mixture was extracted with EtOAc (2 × 100 mL), dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc 9/1) to 5-benzyloxy-2. Bromo-benzaldehyde was obtained in quantitative yield as a white solid.
[1722] A solution of nitromethane (2.02 mL, 37.3 mmol) in ethanol (10 mL) was treated with 10 N NaOH (3.0 mL) at ambient temperature. A white solid immediately precipitated and a solution of 5-benzyloxy-2-bromo-benzaldehyde (8.67 g, 29.8 mmol) in CH ₂ Cl ₂ (50 mL) was added. The reaction mixture was stirred for 18 hours and quenched with water (100 mL). The mixture was extracted with CH ₂ Cl ₂ (2 × 50 mL), dried (Na ₂ SO ₄ ), concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc 8/2) to give 1- ( 5-benzyloxy-2-bromo-phenyl) -2-nitroethanol was obtained as a yellow oil.
[1723] The intermediate was dissolved in CH ₂ Cl ₂ (150 mL) and cooled to 0 ° C. Methanesulfonyl chloride (2.55 mL, 60.0 mmol) was added and the mixture was stirred for 15 minutes. Triethylamine (8.41 mL) was added and the mixture was stirred for 60 minutes. The reaction was quenched with water (200 mL) and extracted with CH ₂ Cl ₂ (150 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 8/2) to afford the title compound (8.60 g, 86%).
[1724]
[1725] Step B: 2- (5-benzyloxy-2-bromo-phenyl) -ethylamine
[1726]
[1727] To a solution of 5-benzyloxy-2-bromo- (2-nitrovinyl) benzene (8.60 g, 25.6 mmol) in THF (100 mL) at −78 ° C. add LAH (4.1 g, 102 mmol) for 30 minutes. Partially added. The reaction mixture was slowly warmed up to ambient temperature. After 18 hours, the mixture was quenched carefully using water (4 mL), 2N NaOH (4 mL), and water (12 mL) in turn. The slurry was filtered and the precipitate was washed with CH ₂ Cl ₂ (3 × 150 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (EtOAc, then CH ₂ Cl ₂ / MeOH / NH ₄ 0H 10/1 / 0.01) to afford the title compound as an oil (3.36 g, 43%).
[1728]
[1729] Step C: 2- (5-Benzyloxy-2-bromo-phenyl) -ethyl] -carbamic acid tert-butyl ester
[1730]
[1731] A solution of 2- (5-benzyloxy-2-bromo-phenyl) -ethylamine (3.36 g, 10.97 mmol) in CH ₂ Cl ₂ (50 mL) at 0 ° C. was diluted with Et ₃ N (3.08 mL, 21.9 mmol) and di treated with -tertbutyl dicarbonate (2.87 g, 13.2 mmol). The mixture was stirred for 2 h while slowly warming to ambient temperature and concentrated. The residue was purified by silica gel chromatography (EtOAc / hexanes, 65: 35) to give the title compound (4.45 g, 100%) as an oil.
[1732]
[1733] Step D: 3- [4-benzyloxy-2- (2-tert-butoxycarbonylamino-ethyl) -phenyl] -acrylic acid methyl ester
[1734]
[1735] A solution of 2- (5-benzyloxy-2-bromo-phenyl) -ethyl] -carbamic acid tertbutyl ester (4.40 g, 10.8 mmol) in propionitrile (100 mL) was degassed (vacuum / Ar purge, 3x). Tri-ortho-tolylphosphine (0.660 g, 2.17 mmol), methyl acrylate (2.93 mL, 32.5 mmol), and diisopropylethyl amine (3.76 mL, 21.6 mmol) were added. The mixture was degassed (vacuum / Ar purge, 3 ×). Pd (OAc) ₂ (242 mg, 1.08 mmol) was added and the reaction mixture was degassed again. The mixture was stirred at 95 ° C for 18 h, concentrated to give a residue, which was purified by silica gel chromatography (EtOAc / hexanes, 7/3) to give the title compound (4.15 g, 93%).
[1736] ¹ H NMR (400 MHz, CDCl ₃ ) (major isomers): δ 1.43 (s, 9H), 2.94 (t, 2H, J = 6.8 Hz), 3.33 (dt, 2H, J = 6.3 Hz, 6.8 Hz), 3.79 (s, 3H), 5.08 (s, 2H), 6.28 (d, 1H, J = 15.6 Hz), 6.84 (br s, 1H), 6.86 (d, 1H, J = 8.3 Hz), 7.34- 7.43 (m, 5H), 7.55 (d, 1H, J = 8.3 Hz), 7.91 (d, 1H, J = 15.6 Hz).
[1737] Step E: 3- [2- (2-tert-butoxycarbonylamino-ethyl) -4-hydroxy-phenyl] -propionic acid methyl ester
[1738]
[1739] THF (10 mL) in a solution of 3- [4-benzyloxy-2- (2-tert-butoxycarbonylamino-ethyl) phenyl] -acrylic acid methyl ester (4.15 g, 10.1 mmol) in THF (100 mL) 5% Pd-C (200 mg) was added. The resulting suspension was treated with hydrogen for 18 hours under balloon pressure. The mixture was filtered through a pad of celite and concentrated. The residue was purified by silica gel chromatography (EtOAc / hexanes, 6/4) to afford the title compound (1.20 g, 34%).
[1740]
[1741] Step F: 3- {2- (2-tert-Butoxycarbonylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} Propionic acid methyl ester
[1742]
[1743] 3- [2- (2-tert-butoxycarbonylamino-ethyl) -4-hydroxy-phenyl] -propionic acid methyl ester (0.807 g, 2.50 mmol) and toluene-4-sulfonic acid 2 in DMF (5 mL) To a solution of-(5-methyl-2-phenyl-oxazol-4-yl) -ethyl ester (1.34 g, 3.74 mmol) was added Cs ₂ CO ₃ (1.22 g, 3.74 mmol). The suspension was stirred at 65 ° C. for 48 h, quenched with H ₂ O (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified on silica gel chromatography (hexane / EtOAc 9/1 to 8/2 to 6/4) to give the title compound as a colorless oil (0.90). g, 71%) were obtained.
[1744]
[1745] Step G: 3- {2- (2-Amino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid methyl ester
[1746]
[1747] 3- {2- (2-tert-butoxycarbonylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl in CH ₂ Cl ₂ (10 mL) at 0 ° C. A solution of) -ethoxy] -phenyl} -propionic acid methyl ester (0.90 g, 1.77 mmol) was treated with TFA (5.0 mL) and water (0.2 mL). The resulting solution was slowly warmed up to ambient temperature. After 18 hours, the mixture was concentrated. The residue was partitioned between CH ₂ Cl ₂ (30 mL) and 5N NaOH (2 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic layers were dried (K ₂ CO ₃ ) and concentrated to give a residue, which was purified by silica gel chromatography (CH ₂ Cl ₂ / MeOH / NH40H, 8/2 / 0.05) to give the title compound as a colorless oil (0.42 g). , 58%)
[1748]
[1749] Step H: 3- {2- (2-Isopropoxycarbonylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-ylethoxy] -phenyl} -propionic acid
[1750]
[1751] 3- {2- (2-amino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-ylethoxy] -phenyl in CH ₂ Cl ₂ (2 mL) at 0 ° C. } -Propionic acid methyl ester (26 mg, 0.064 mmol) solution was treated with TEA (0.2 mL) and isopropyl chloroformate (0.13 mL, 1.0 M in ether) The resulting mixture was allowed to slowly warm up to ambient temperature. After time, the mixture was concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc 7/3) to give isopropyl carbamate as a colorless oil.
[1752]
[1753] The compound was dissolved in THF (1.0 mL) and MeOH (0.5 mL). The solution was treated with 2N NaOH (0.32 mL) and heated at 60 ° C. for 60 minutes. The reaction mixture was concentrated, neutralized with 2N HCl (0.40 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc 9/1, then EtOAc / MeOH 95/5) to give the title compound as a white solid ( 12 mg, 32% over 2 steps).
[1754]
[1755] Examples 545 to 552 below were prepared following procedures substantially similar to those described in Example 544.
[1756] Example 545
[1757] 3- {2- [2- (butane-1-sulfonylamino) -ethyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl}- Propionic acid
[1758]
[1759] Example 546
[1760] 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- {2-[(pyridine-2-carbonyl) -amino] -ethyl}- Phenyl) -propionic acid
[1761]
[1762] Example 547
[1763] 3- {2- {2-[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -ethyl} -4- [2- (5-methyl-2-phenyl-oxazole-4- Yl) -ethoxy] -phenyl} -propionic acid
[1764]
[1765] Example 548
[1766] 3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (2-phenylacetylamino-ethyl) -phenyl] propionic acid
[1767]
[1768] Example 549
[1769] 3- {2- [2- (Cyclobutanecarbonyl-amino) -ethyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1770]
[1771] Example 550
[1772] 3- {2- (2-Benzoylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} propionic acid
[1773]
[1774] Example 551
[1775] 3- {2- (2-Isobutoxycarbonylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid
[1776]
[1777] Example 552
[1778] 3- {2- (2-Benzyloxycarbonylamino-ethyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid
[1779]
[1780] Example 553
[1781] 3- (2- (2-isopropoxycarbonylamino-ethyl) -4- {2- [5-methyl-2- (4-morpholin-4-yl-phenyl) -oxazol-4-yl] -Ethoxy} -phenyl) -propionic acid
[1782]
[1783] Step A: 3- [4-hydroxy-2- (2-isopropoxycarbonylamino-ethyl) -phenyl] -propionic acid methyl ester
[1784]
[1785] 3- [2- (2-tert-butoxycarbonylamino-ethyl) -4-hydroxy-phenyl] -propionic acid methyl ester in CH ₂ Cl ₂ (10 mL) (282 mg, 0.876 mmol; Example 544, The solution of step E) was treated with TFA (5.0 mL) at ambient temperature, stirred for 60 minutes and concentrated. The residue in CH ₂ Cl ₂ (10 mL) was treated with triethyl amine (2.0 mL) and iso-propyl chloroformate (0.97 mL, 1.0 M in toluene). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated. The crude material was purified by silica gel chromatography (50% EtOAc / hexanes) to afford the title compound (180 mg, 67%).
[1786] Step B: 3- (2- (2-Isopropoxycarbonylamino-ethyl) -4- {2- [5-methyl-2- (4-morpholin-4-yl-phenyl) -oxazole-4 -Yl] -ethoxy} -phenyl) -propionic acid
[1787] Toluene-4-sulfonic acid 2- [5-methyl-2- (4-morpholin-4-ylphenyl) -oxazol-4-yl] -ethyl ester (44 mg, 0.10 mmol; prepared in DMF (1.0 mL); Example 5) and a solution of 3- [4-hydroxy-2- (2-isopropoxycarbonylamino-ethyl) -phenyl] -propionic acid methyl ester (31 mg, 0.1 mmol) was added to K ₂ CO ₃ ( 30 mg). The resulting suspension was stirred at 65 ° C. for 16 h and diluted with water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography (50% EtOAc / hexanes) to give 3- (2- (2-isopropoxycarbonylamino-ethyl) -4- { 2- [5-Methyl-2- (4-morpholin-4-yl-phenyl) -oxazol-4-yl] -ethoxy} -phenyl) -propionic acid methyl ester was obtained.
[1788] The ester intermediate was dissolved in THF (0.6 mL) and MeOH (0.4 mL) and treated with aqueous 2M LiOH (1.0 mL, 2.0 mmol). The mixture was stirred for 16 h at ambient temperature, neutralized with HCl (1.0 mL, 2.0 M) and concentrated. The residue was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography column (hexane / EtOAc / HOAc, 5/5 / 0.02) to afford the title compound (10 mg, 18%). MS (ES +) m / z 566.2 (M + H) ⁺ .
[1789] Examples 554 to 560 below were prepared following procedures substantially similar to those described in Example 553.
[1790] Example 554
[1791] 3- [4- [2- (2-biphenyl-3-yl-5-methyl-oxazol-4-yl) -ethoxy] -2- (2-isopropoxycarbonyl-aminoethyl) -phenyl ] -Propionic acid
[1792]
[1793] Example 555
[1794] 3- [4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -2- (2-isopropoxycarbonyl-aminoethyl) -phenyl ] -Propionic acid
[1795]
[1796] Example 556
[1797] 3- {2- (2-Isopropoxycarbonyl-amino-ethyl) -4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl) ethoxy] -phenyl } -Propionic acid
[1798]
[1799] Example 557
[1800] 3- {2- (2-Isopropoxycarbonylamino-ethyl) -4- [2- (5-methyl-2-pyridin-2-yl-thiazol-4-yl) ethoxy] -phenyl}- Propionic acid
[1801]
[1802] Example 558
[1803] 3- {2- (2-Isopropoxycarbonylamino-ethyl) -4- [2- (5-methyl-3-phenyl-pyrazol-1-yl) -ethoxy] phenyl} -propionic acid
[1804]
[1805] Example 559
[1806] 3- (2- (2-isopropoxycarbonylamino-ethyl) -4- {2- [5-methyl-2- (4-phenylamino-phenyl) -oxazol-4-yl] -ethoxy} -Phenyl) -propionic acid
[1807]
[1808] Example 560
[1809] 3- [2- (2-isopropoxycarbonylamino-ethyl) -4- (2- {5-methyl-2- [4- (methyl-phenyl-amino) phenyl] -oxazol-4-yl} -Ethoxy) -phenyl] -propionic acid
[1810]
[1811] Example 561
[1812] 2- {2- (tert-Butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenoxy} -2-methyl- Propionic acid
[1813]
[1814] Step A: 2- (2-allyl-4-benzyloxy-phenoxy) -2-methyl-propionic acid ethyl ester
[1815]
[1816] Cool all 2-allyl-4-benzyloxy-phenol (WO 9728137 Al 19970807, Adams etal.) (6.04 g, 25.1 mmol) in anhydrous DMF (75 mL) in an ice bath, NaH (1.78 g, 44.5 mmol, 60 % Oil dispersion). After 30 minutes, the red reaction mixture was treated with ethyl bromoisobutyrate (7.4 mL, 50 mmol) over 5 minutes. After 5 minutes the cooling bath was removed and the reaction stirred for 20 minutes and placed in an oil bath (T = 85 ° C.). After 18 hours, the mixture was cooled and partitioned between brine (75 mL) and ether (200 mL). The organic phase was washed with brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated to give a brown oil (12 g). The crude product was purified by flash chromatography (hexane: ethyl acetate, 100: 0 to 5: 1) to afford the desired product (8.47 g, 95%).
[1817] Step B: 2- (4-Benzyloxy-2-carboxymethyl-phenoxy) -2-methyl-propionic acid ethyl ester
[1818]
[1819] A solution of 2- (2-allyl-4-benzyloxy-phenoxy) -2-methyl-propionic acid ethyl ester (8.07 g, 22.8 mmol) in acetone (85 mL) and water (8.5 mL) Treated with Pauline 4-oxide (3.68 g, 27.2 mmol) followed by osmium (IV) oxide (2 chips). The flask was covered with foil and stirred for 5 hours. The solution was diluted with EtOAc (600 mL) and washed with 1N Na ₂ S ₂ 0 ₃ (2 × 75 mL) and brine (75 mL).
[1820] The organic phase was concentrated to give a tan oil (8.74 g). The oil was dissolved in THF (54 mL) and water (36 mL), and sodium periodate (15.4 g, 72.0 mmol) was added. THF (54 mL) and water (36 mL) were added. The thick white slurry was stirred for 3 hours and filtered. The filtrate was extracted with EtOAc (500 mL). The organic phase was washed sequentially with brine, 1NNa ₂ S ₂ 0 ₃ , and brine (75 mL each) and concentrated to give an orange oil (7.65 g). The oil was diluted with tert-butanol (180 mL) and 2-methyl-2-butene (60 mL) and cooled in an ice bath. The mixture was treated with sodium chlorite (19 g, 0.21 mol) and a solution of NaH ₂ PO ₄ (19 g, 0.14 mol) in water (120 mL) was added over 5 minutes. After 15 minutes, the ice bath was removed. The mixture was stirred for 2 hours and partitioned between EtOAc (500 mL) and water (50 mL). The organic layer was washed with 1N Na ₂ S ₂ 0 ₃ (75 mL), brine (75 mL), dried (NaSO ₄ ) and concentrated to give the title compound as a pale yellow solid (6.52 g, 77%). The material was used for the subsequent reaction without further purification.
[1821] Step C: 2- (4-Benzyloxy-2-carbamoylmethyl-phenoxy) -2-methyl-propionic acid ethyl ester
[1822]
[1823] 2- (4-benzyloxy-2-carboxymethyl-phenoxy) -2-methyl-propionic acid ethyl ester (500 mg, 1.34 mmol), ammonium chloride (108 mg, 2.02 mmol), EDC (3.86 mg, 2.01 mmol) , And N-hydroxybenzotriazole hydrate (272 mg, 2.01 mmol) were mixed in the flask and diluted with DMF (5 mL). Ethyl diisopropyl amine (0.70 mL, 4.0 mmol) was added. The solution was stirred for 18 h and partitioned between EtOAc (25 mL) and 1N HCl (10 mL). The organic phase was washed with saturated NaHCO ₃ solution (10 mL) then brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by radial chromatography (hexane / EtOAc 1/2 to 1/4) to give the title compound (430 mg, 86%).
[1824] Step D: 2- [4-benzyloxy-2- (tert-butoxycarbonylamino-methyl) -phenoxy]-2-methyl-propionic acid ethyl ester
[1825]
[1826] 2- (4-benzyloxy-2-carbamoylmethyl-phenoxy) -2-methyl-propionic acid ethyl-ester (430 mg, 1.16 mmol) was dissolved in CH ₃ CN (4.5 mL) and water (4.5 mL). [Bis (trifluoroacetoxy) iodo] benzene (745 mg, 1.73 mmol) was added. After 10 minutes, pyridine (0.19 mL, 2.3 mmol) was added and the solution stirred for 17 hours. Triethylamine (0.60 mL, 4.3 mmol) and di-tert-butyl dicarbonate (506 mg, 2.32 mmol) were added. The mixture was stirred for 1 hour and concentrated. The residue was partitioned between ether (50 mL) and brine (15 mL). The organic layer was washed with ice cold 1N HCl, saturated NaHCO ₃ solution, and brine (15 mL each); Dried (NaSO ₄ ); Concentrated. The residue was purified by silica gel column chromatography (hexane / EtOAc 4/1 to 3/2) to give a yellow oil (345 g, 67%).
[1827] Step E: 2- [2- (tert-Butoxycarbonylamino-methyl) -4-hydroxy-phenoxy] -2-methyl-propionic acid ethyl ester
[1828]
[1829] A solution of 2- [4-benzyloxy-2- (tert-butoxycarbonylamino-methyl) -phenoxy] -2-methyl-propionic acid ethyl ester (0.38 g, 0.86 mmol) in THF (15 mL) was added 5 Treated with% Pd on carbon (47 mg) and shaken for 18 hours at ambient temperature under hydrogen atmosphere (60 psi). The mixture was filtered through celite and concentrated. The crude product was purified by radial chromatography (hexane / EtOAc 2.5 / 1) to give the title compound (208 mg g, 69%).
[1830] Step F: 2- {2- (tert-Butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy}- 2-Methyl-propionic acid
[1831] 2- [2- (tert-butoxycarbonylamino-methyl) -4-hydroxy-phenoxy] -2-methyl-propionic acid ethyl ester (200 mg, 0.566 mmol), toluene-4-sulfonic acid 2- (5 -Methyl-2-phenyl-oxazol-4-yl) -ethyl ester (245 mg, 686 mmol) and Cs ₂ CO ₃ (185 mg, 0.567 mmol) are suspended in DMF (5 mL) and at 55 ° C. Stir for 39 hours. The reaction mixture was cooled and partitioned between Et ₂ O (50 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried (NaSO ₄ ) and concentrated. The residue was purified by radial chromatography (hexane / EtOAc 4/1) to give an oil (280 mg). The solution of the product in MeOH (6 mL) and THF (3 mL) was treated with 2.5N aqueous NaOH solution (2 mL) and heated at 55 ° C. for 2 h. The mixture was cooled and concentrated. Ice cubes (˜5) were added and the mixture was acidified with 5N aqueous HCL solution (2 mL). The reaction mixture was partitioned between EtOAc (30 mL) and brine (15 mL). The organic phase was washed with brine (2 x 10 mL), dried (NaSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (hexane / EtOAc / HOAc 3/2/0 to 3/2 / 0.05) to give the title compound as a white foam (156 mg, 54%). MS (ES−) m / z 509.1 [M ⁻ H] ⁻ . Analytical Calcd for C ₂₈ H ₃₄ N ₂ 0 ₇ : C: 65.88; H: 6.71; N: 5.49. Found: C: 65.67; H: 6.79; N: 5.52.
[1832] Example 562
[1833] {2- (tert-Butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -acetic acid
[1834]
[1835] The compound was prepared following a procedure substantially similar to that described in Example 322. MS [ES] m / z 483.2 (M + l).
[1836] Example 563
[1837] 2- {2- (Ethoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -2-methyl-propionic acid
[1838]
[1839] Step A: 2- {2-Aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -2-methyl-propionic acid ethyl ester: tri Fluoroacetic acid salts
[1840]
[1841] 2- {2- (tert-butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy in CH ₂ Cl ₂ (10 mL) ] -Phenoxy} -2-methyl-propionic acid ethyl ester (350 mg, 0.650 mmol) was treated with TFA (4 mL) at ambient temperature and stirred for 2.5 h. The solution was concentrated and coevaporated with CCl ₄ (3 ×) to afford the title compound in the form of a foam (381 mg, quant.).
[1842] Step B: 2- {2- (Ethoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -phenoxy} -2-methyl Propionic acid
[1843] General Parallel Synthesis Procedure: 2- {2-Aminomethyl-4- [2- (5-methyl-phenyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -2-methyl-propionic acid Ethyl ester: trifluoroacetic acid salt (381 mg, 0.650 mmol max.) Was dissolved in CH ₂ Cl ₂ (25 mL) and washed with saturated NaHCO ₃ solution (15 mL). The organic phase is dried (NaSO ₄ ), filtered and concentrated to 2- {2-aminomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -phenoxy} 2-Methyl-propionic acid ethyl ester (245 mg, 0.59 mmol, 86%) was obtained. A portion of this free base (13 mg, 0.030 mmol) in CH ₂ Cl ₂ (0.8 mL) was treated with triethylamine (0.050 mL, 0.36 mmol) followed by ethyl chloroformate (0.020 mL, 0.21 mmol). The reaction mixture was shaken overnight and dimethylethylenediamine (0.050 mL, 0.47 mmol) was added. The reaction mixture was shaken for 2 hours, diluted with MeOH (0.5 mL) and passed through an SCX column (1 g, equilibrated with 4 mL MeOH / CH ₂ Cl ₂ 1/1). The methyl ester-amide product was eluted with MeOH / CH ₂ Cl ₂ (1: 1, 8 mL) and concentrated. The residue was dissolved in THF (1 mL) and EtOH (1 mL) and treated with 2N NaOH (0.5 mL). The solution was heated at 45 ° C. for 45 min, cooled, concentrated and acidified with 1N HCl (2.5 mL). The mixture was diluted with CH ₂ Cl ₂ (0.5 mL), transferred to a 3-mL chemyllute cartridge and eluted with CH ₂ Cl ₂ (8 mL). Solvent was removed under N ₂ stream. The crude product was dried under vacuum and purified by mass spectrometry with HPLC to give foam (2.7 mg, 19%). MS (ES +) m / z 483.5 [M + H] ⁺ .
[1844] Examples 564 to 570 below were prepared following procedures substantially similar to those described in Example 563.
[1845] Example 564
[1846] {2- (Benzyloxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -acetic acid
[1847]
[1848] Example 565
[1849] To {2-{[(2,5-dichloro-thiophen-3-carbonyl) -amino] -methyl} -4- [2- (5-methyl-2-phenyl-oxazol-4-yl)- Methoxy] -phenoxy} -acetic acid
[1850]
[1851] Example 566
[1852] {2-[(Cyclobutanecarbonyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -phenoxy} -acetic acid
[1853]
[1854] Example 567
[1855] 2- {2- (Butyrylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -2 methyl-propionic acid
[1856]
[1857] Example 568
[1858] 2- {2-{[(2,5-Dichloro-thiophene-3-carbonyl) -amino] -methyl} -4- [2- (5-methyl-2-phenyloxazol-4-yl)- Ethoxy] -phenoxy} -2-methyl-propionic acid
[1859]
[1860] Example 569
[1861] 2- {2- (Ethoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenoxy} -2-methyl-propionic acid
[1862]
[1863] Example 570
[1864] 2- {2-[(Cyclobutanecarbonyl-amino-methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -phenoxy} -2-methyl- Propionic acid
[1865]
[1866] Example 571
[1867] 3- (2-cyano-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1868]
[1869] Step A: 2-Bromo-5-hydroxy-benzonitrile
[1870]
[1871] To a stirred solution of 3-cyanophenol (2. 00 g, 18.0 mmol) in anhydrous acetonitrile (20 mL) at -30 ° C under nitrogen was added dropwise 54% HBF ₄ .Et ₂ O (2.48 mL, 18.0 mmol). . The temperature was kept below -20 ° C during the addition. NBS (3.27 g, 18.0 mmol) was added in portions to the stirred solution while maintaining the temperature below −10 ° C. After the addition was complete, the solution was warmed up to 19 ° C. The reaction mixture was diluted with 38% NaHSO ₃ (10 mL) and extracted with MTBE (2 × 25 mL). The organic layer was washed with H ₂ 0 (2 × 25 mL) and brine (25 mL), dried (MgSO ₄ ), filtered and concentrated to give a white solid (3.15 g). A portion of the product (1.0 g) was purified by radial chromatography (30% EtOAc / hexanes) to yield 0.51 g of the title compound as a white solid. mp 183-184. Analytical Calcd for C ₇ H ₄ BrNO: C, 42.46; H, 2.04; N, 7.07. Found: C, 42.44; H, 1.93; N, 6.90.
[1872] Step B: 2- (3-ethoxy-buta-1,3-dienyl) -5-hydroxy-benzonitrile
[1873]
[1874] 2-bromo-5-hydroxy-benzonitrile (1.4 g, 7.1 mmol), ethyl acrylate (2.12 g, 21.2 mmol), palladium (II) acetate (0.159 g, 7.0 mmol), diisopropylethylamine Propionitrile (50 mL) was added to a stirred solution of (0.82 g, 14.1 mmol), and tri-ortho-tolylphosphine (0.430 g, 14.1 mmol). The reaction was stirred overnight at 80 ° C. under a nitrogen stream. The mixture was cooled down, filtered and concentrated. The crude material (3.0 g) was purified by radial chromatography (10-70% EtOAc / hexanes) to give the title compound as a white solid (1.1 g). MS [EI] m / z 216 (M + H) ⁺ .
[1875] Step C: 2- (3-ethoxy-but-3-enyl) -5-hydroxy-benzonitrile
[1876]
[1877] To a solution of 2- (3-ethoxy-buta-1,3-dienyl) -5-hydroxy-benzonitrile (600 mg) in EtOAc (50 mL) was added 5% Pd / C (0.3 g). The reaction was exposed to hydrogen at ambient temperature overnight at 60 psi in the Parr apparatus. The reaction mixture was filtered and concentrated to give the title compound (410 mg). MS [EI] m / z 218 (M + H) ⁺ .
[1878] Step D: 3- (2-Cyano-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[1879] 2- (3-ethoxy-but-3-enyl) -5-hydroxy-benzonitrile (220 mg, 1.00 mmol) in DMF (10 mL), toluene-4-sulfonic acid 2- [5-methyl-2- ( A mixture of 4-phenoxy-phenyl) -oxazol-4-yl] ethyl ester (450 mg, 1.00 mmol; Preparation 6), and CsC0 ₃ (978 mg, 3.00 mmol) was stirred overnight at 60 ° C. under N _2. I was. The mixture was cooled down, diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The mixture of products was purified by radial chromatography (10-70% EtOAc / hexanes) to give 3- (2-cyano-4- {2- [5-methyl-2- (4-phenoxyphenyl) -oxazole- 4-yl] ethoxy} phenyl) propionic acid ethyl ester (201 mg) was obtained. A solution of this ester in EtOH (10 mL) and 5N NaOH (10 mL) was heated at 70 ° C. overnight, concentrated, acidified with 1N HCl and extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (192 mg). MS [ES] m / z 469 (M + l).
[1880] Examples 572-573 and 575-581 below were prepared following procedures substantially similar to those described in Example 571.
[1881] Example 572
[1882] 3- {4- [2- (2-Biphenyl-4-yl-5-methyloxazol-4-yl) -ethoxy] -2-cyanophenyl} propionic acid:
[1883]
[1884] Example 573
[1885] 3- {4- [3- (biphenyl-4-yloxy) propoxy] -2-cyanophenyl} propionic acid
[1886]
[1887] Example 575
[1888] 3- (4- {2- [2- (4-Bromo-phenyl) -5-methyloxazol-4-yl] ethoxy} -2-cyanophenyl) propionic acid
[1889]
[1890] Example 576
[1891] 3- {4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2-cyanophenyl} propionic acid
[1892]
[1893] Example 577
[1894] 3- {2-cyano-4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid
[1895]
[1896] Example 578
[1897] 3- {2-cyano-4- [2- (5-methyl-3-phenylpyrazol-1-yl) ethoxy] phenyl} propionic acid:
[1898]
[1899] Example 579
[1900] 3- (4- {2- [2- (4-butoxyphenyl) -5-methyloxazol-4-yl] ethoxy} -2-cyanophenyl) propionic acid
[1901]
[1902] Example 580
[1903] 3- (2-cyano-4- {2- [5-methyl-2- (6-phenylpyridin-3-yl) thiazol-4-yl] ethoxy} phenyl) propionic acid
[1904]
[1905] Example 581
[1906] 3- {2-cyano-4- [2- (5-methyl-2-phenylthiazol-4-yl) ethoxy] phenyl} propionic acid
[1907]
[1908] Example 582
[1909] 3- {2-benzylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1910]
[1911] Step A: 3- (4-benzyloxy-2-formyl-phenyl) -acrylic acid tert-butyl ester
[1912]
[1913] Benzyl bromide (2.85 mL, 24.0 mmol) and Cs ₂ CO _{3 in a} solution of 3- (2-formyl-4-hydroxy-phenyl) -acrylic acid tert-butyl ester (4.97 g, 20.0 mmol) in DMF (40 mL). (7.82 g, 24.0 mmol) was added. The suspension was stirred at 80 ° C. for 30 minutes and TLC confirmed the reaction was complete. The mixture was quenched with H ₂ 0 (500 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc 9/1) to give the title compound as a yellow solid (6.70 g, 99%).
[1914] Step B: 5-benzyloxy-2- (2-tert-butoxycarbonyl-vinyl) -benzoic acid
[1915]
[1916] A solution of 3- (4-benzyloxy-2-formyl-phenyl) -acrylic acid tert-butyl ester (6.70 g, 19.8 mmol) in tert-butanol (150 mL) with 2-methyl-2-butene (50 mL) Treated and cooled to 0 ° C. A solution of NaClO ₂ (17.0 g, 188 mmol) and NaH ₂ PO ₄ (17.0 g, 142 mmol) in H ₂ O (200 mL) was added and the mixture was stirred at 0 ° C. for 15 minutes. The ice bath was removed and the mixture was stirred at rt for 2 h. The organic phase was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 9/1 to 0/10) to afford the title compound as a white solid (6.78 g, 96%).
[1917]
[1918] Step C: 5-benzyloxy-2- (2-tert-butoxycarbonyl-vinyl) -benzoic acid 2-trimethylsilanylethyl ester
[1919]
[1920] To a solution of 5-benzyloxy-2- (2-tert-butoxycarbonyl-vinyl) -benzoic acid (5.50 g, 15.5 mmol) in CH ₂ Cl ₂ (100 mL) 2-trimethylsilyl-ethanol (3.67 g, 31.0 mmol), EDC (5.36 g, 27.9 mmol), and DMAP (3.67 g, 31.0 mmol) were added. The resulting mixture was stirred at rt for 12 h, washed with aqueous NH ₄ Cl (150 mL) and extracted with CH ₂ Cl ₂ (100 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 9/1) to afford the title compound as an oil (5.90 g, 84%).
[1921]
[1922] Step D: 2- (2-tert-butoxycarbonyl-ethyl) -5-hydroxy-benzoic acid 2-trimethylsilanyl-ethyl ester
[1923]
[1924] 5-benzyloxy-2- (2-tert-butoxycarbonyl-vinyl) -benzoic acid 2-trimethylsilanyl-ethyl ester (6.20 g, 13.6 mmol) in EtOH (95 mL) was diluted with Pd / C (5%, 0.775 g). The resulting suspension was stirred with hydrogen at 60 psi for 6 hours at room temperature. The catalyst was filtered through a pad of celite and the filtrate was concentrated to give an oil (4.30 g, 86%).
[1925]
[1926] Step E: 2- (2-tert-butoxycarbonyl-ethyl) -5- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzoic acid 2-trimethylsilanyl Ethyl ester
[1927]
[1928] 2- (2-tert-butoxycarbonyl-ethyl) -5-hydroxy-benzoic acid 2-trimethylsilanyl-ethyl ester (4.30 g, 11.7 mmol) and toluene-4-sulfonic acid 2- in DMF (30 mL) To a solution of (5-methyl-2-phenyl-oxazol-4-yl) -ethyl ester (4.61 g, 12.9 mmol) was added Cs ₂ CO ₃ (4.59 g, 14.1 mmol). The suspension was stirred at 55 ° C for 12 h. The reaction mixture was quenched with H ₂ 0 (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc 9/1 to 8/2) to give the title compound as a colorless oil (5.04 g, 78 %).
[1929]
[1930] Step F: 2- (2-tert-Butoxycarbonyl-ethyl) -5- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] benzoic acid
[1931]
[1932] 2- (2-tert-butoxycarbonyl-ethyl) -5- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzoic acid 2- in THF (100 mL) A solution of trimethylsilanylethyl ester (5.04 g, 9.13 mmol) was treated with TBAF (20 mL, 1.0 M) for 1 hour at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography (hexane / EtOAc 1/1) to afford the title compound as a colorless oil (4.04 g, 98%).
[1933]
[1934] Step G: 3- {2-Benzylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} propionic acid
[1935] 2- (2-tert-butoxycarbonyl-ethyl) -5- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] -benzoic acid in CH ₂ Cl ₂ (2 mL) To a solution of (93 mg, 0.200 mmol) was added benzylamine (52 mg g, 0.49 mmol), EDC (54 mg, 0.28 mmol), triethylamine (0.057 ml, 0.40 mmol), and DMAP (catalyst). The resulting mixture was stirred at rt for 12 h and washed with aqueous NH ₄ Cl (2 mL). The organic layer was purified using a silica gel column (Sep-Pak column, 10 g; hexanes / EtOAc 1/1) to give tert-butyl ester intermediate. The ester was treated with a mixture of CH ₂ Cl ₂ (1.0 mL), TFA (0.8 mL), and water (0.1 mL) for 2 hours at room temperature. The reaction mixture was concentrated and dried under vacuum to afford the title compound as a white solid (35 mg, 36%).
[1936]
[1937] Example 583
[1938] 3- {2-benzylcarbamoyl-4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -phenyl} propionic acid
[1939]
[1940] Step A: 3- (2-benzylaminocarbonyl-4-benzyloxy-phenyl) -acrylic acid tert-butyl ester
[1941]
[1942] Benzylamine (0.613 g, 5.73 mmol), EDC in a solution of 5-benzyloxy-2- (2-tert-butoxycarbonyl-vinyl) -benzoic acid (1.45 g, 4.09 mmol) in CH ₂ CH ₂ (40 mL) (1.254 g, 6.54 mmol), and DMAP (1.00 g, 8.18 mmol) were added. The resulting mixture was stirred at rt for 12 h, washed with aqueous NH ₄ Cl (50 mL) and extracted with CH ₂ Cl ₂ ( ₂ × 50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was then purified by silica gel chromatography (hexane / EtOAc 8/2) to afford the title compound as an oil (720 mg, 40%).
[1943]
[1944]
[1945] 3- (2-benzylaminocarbonyl-4-benzyloxy-phenyl) -acrylic acid tert-butyl ester (720 mg, 1.625 mmol) in EtOH (15 mL) and THF (5 mL) was charged with Pd / C (5%, 70 mg). The resulting suspension was treated with hydrogen at room temperature for 4 hours using a balloon. The catalyst was filtered through a pad of celite and the filtrate was concentrated to give an oil (450 mg, 78%).
[1946]
[1947] Step C: 3- {2-Benzylcarbamoyl-4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[1948] 3- (2-benzylaminocarbonyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester (50 mg, 0.140 mmol) and toluene-4-sulfonic acid 2- (5-methyl-2) in DMF (1.0 mL) To a solution of-(4-phenylphenyl) -oxazol-4-yl) -ethyl ester (73 mg, 0.168 mmol) was added K ₂ CO ₃ (100 mg, 0.724 mmol). The suspension was stirred at 65 ° C for 12 h. The reaction mixture was quenched with H ₂ 0 (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified using silica gel chromatography (hexane / EtOAc 7/3) to give tert-butyl ester intermediate as an oil. The ester was treated with a mixture of CH ₂ Cl ₂ (1.0 mL), TFA (0.8 mL) and water (0.1 mL) for 2 hours at room temperature. The reaction mixture was concentrated and dried in vacuo to yield the title compound as a white solid (37 mg, 47%).
[1949]
[1950] Example 584-643
[1951] Examples 584-643 were prepared following procedures substantially similar to those described in Examples 582 and 583. Examples 584-628 were prepared following procedures substantially similar to those described in Example 582. Examples 629-643 were prepared following procedures substantially similar to those described in Example 583.
[1952] No. compound Compound name MS (ES +) 584 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-phenyl-carbamoyl-phenyl} -propionic acid 471.2 585 3- {2-benzylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 485.2 586 3- {2- (3,4-Dichloro-benzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid 553 587 3- {2- (4-Methoxy-benzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid 515.2 588 3- {2-[(biphenyl-3-ylmethyl) -carbamoyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl}- Propionic acid 561.2
[1953] No. compound Compound name MS (ES +) 589 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -2-phenethylcarbamoyl-phenyl} -propionic acid 499.3 590 3- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (3-phenylpropylcarbamoyl) -phenyl] -propionic acid 513.3 591 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) ethoxy] -2-[(thiophen-2-ylmethyl) -carbamoyl] phenyl} -propionic acid 491.2 592 3- {2-hexylcarbamoyl-4- [2- (5-methyl-2-phenyl oxazol-4-yl) -ethoxy] phenyl} -propionic acid 479.3 593 3- {2-Methylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 409.1 594 3- {2-Butylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 451.1
[1954] No. compound Compound name MS (ES +) 595 3- {2-Isopropylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 437.2 596 3- {2-Cyclohexylmethyl-carbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 491.2 597 3- {2-t-Butylcarbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 451.2 598 3- {2-Carbamoyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl} -ethoxy] -phenyl-propionic acid 395.1 599 3- {2- (2-Fluorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl} -ethoxy] -phenyl-propionic acid 503.1 600 3- {2- (2-Chloro-benzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 519.1
[1955] No. compound Compound name MS (ES +) 601 3- {2- (2,4-Dichlorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 553 602 3- {2- (2-Methoxybenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 515.1 603 3- {2- (Indan-1-ylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 511.1 604 3- {2- (3-Fluorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl} -ethoxy] -phenyl-propionic acid 503.1 605 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl} ethoxy] -2- (4-trifluoromethyl-benzylcarbamoyl) phenyl] -propionic acid 553 606 3- {2- (3-Methylbenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy-phenyl} -propionic acid 499.1
[1956] No. compound Compound name MS (ES +) 607 3- {2- (4-Fluorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 503.1 608 3- {4- [2- (5-Methyl-2-phenyloxazol-4-yl) -ethoxy] -2- [naphthalen-1-ylmethyl) -carbamoyl] phenyl} -propionic acid 535.1 609 3- {2- (4-Methylsulfonylbenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 563.1 610 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) ethoxy] -2- (2-trifluoromethylbenzylcarbamoyl) -phenyl] propionic acid 553.1 611 3- {2- (4-Nitrobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid 530.1 612 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (4-sulfamoylbenzylcarbamoyl) phenyl} -propionic acid 564.1
[1957] No. compound Compound name MS (ES +) 613 3- {2- (3,5-Dimethylbenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 513.2 614 3- {2-4- (tert-butylcarbamoyl) -4- [2- (5-methyl-2-phenyloxazol-4-ylethoxy] phenyl} -propionic acid 541.2 615 3- {2- (2-Methylbenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 499.2 616 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) ethoxy] -2-[(pyridin-ylmethyl) carbamoyl) -phenyl] propionic acid 486.2 617 3- {2- (3-methoxybenzylcarbamoyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid 515.2 618 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (3-trifluoromethylbenzylcarbamoyl) phenyl} -propionic acid 553.1
[1958] No. compound Compound name MS (ES +) 619 3- {2- (3,5-Bis-trifluoromethylbenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} Propionic acid 621.1 620 3- {2- (3-Chlorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyloxazol-4-ylethoxy] phenyl} -propionic acid 519.1 621 3- {2- (3-Fluoro-5-trifluoromethylbenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl } -Propionic acid 571.1 622 3- {2- (3,5-Difluorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] -phenyl] propionic acid 521.1 623 3- {2- (3,5-Dichlorobenzylcarbamoyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid 553 624 (R) -3- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2- (1-phenylethylcarbamoyl) phenyl} -propionic acid 499.2
[1959] No. compound Compound name MS (ES +) 625 3- {2- (Benzylethylcarbamoyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 513.2 626 {3- {2- (benzylmethyl) carbamoyl] -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid 499.2 627 (S) -3- {2-[(carboxyphenylmethyl) carbamoyl] -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -phenyl} -propionic acid 529.1 628 (S) -3- {4- {2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2- (1-phenylethylcarbamoyl) -phenyl] propionic acid 499.2 629 3- {2-benzylcarbamoyl) -4- [2- (2-biphenyl-3-yl-5-methyl-oxazol-4-yl) ethoxy] phenyl} -propionic acid 561.3 630 3- {2-benzylcarbamoyl-4- [2- (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 561.3
[1960] No. compound Compound name MS (ES +) 631 3- {2-Benzylethylcarbamoyl-4- [2- (2-cyclohexyl-5-methyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 491.3 632 3- {2-benzylcarbamoyl] -4- {2- (5-methyl-2- (1-methylcyclohexyl) oxazol-4-yl) ethoxy] phenyl} -propionic acid 505.4 633 3- {2-benzylcarbamoyl] -4- [2- (5-methyl-2-morpholin-4-yl) thiazol-4-yl) ethoxy] -phenyl} -propionic acid 510.3 634 (R) -3- {4- {2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (1-phenylethylcarbamoyl) -phenyl] Propionic acid 575.3 635 (R) -3- {4- {2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2- (1-phenylethylcarbamoyl) -phenyl] Propionic acid 575.3 636 (R) -3- {4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl) ethoxy] -2- (1-phenylethylcarbamoyl) phenyl} Propionic acid 524.2
[1961] No. compound Compound name MS (ES +) 637 3- {4- [2- (2-Biphenyl-4-yl-5-methyloxazol-4-yl) -ethoxy] -2- (3,5-difluorobenzylcarbamoyl) -phenyl } -Propionic acid 597.3 638 3- {4- [2- (2-Biphenyl-3-ylmethyloxazol-4-yl) -ethoxy] -2- (3,5-difluorobenzylcarbamoyl) -phenyl} -propionic acid 597.3 639 3- {2- (3,5-Difluorobenzylcarbamoyl] -4- [2- (5-methyl-2-morpholin-4-yl) thiazol-4-yl) ethoxy] -phenyl } -Propionic acid 546.1 640 3- {2- (3,5-Difluorobenzylcarbamoyl] -4- [2- (5-methyl-2-phenyl-4-thiazol-4-yl) ethoxy] -phenyl} -propionic acid 537.1 641 3- (2-benzylcarbamoyl-4- {2- {5-methyl-2- [4- {phenoxyphenyloxazol-4-yl] ethoxy} -phenyl] propionic acid 577.3 642 3- (2-benzylcarbamoyl-4- (2- {5-methyl-2- [4- (methylphenylamino) phenyl] oxazol-4-yl} ethoxy) -phenyl] propionic acid 590.2 643 3- (2-benzylcarbamoyl-4- {2- [5-methyl-2- (4-phenylaminophenyl) oxazol-4-yl] ethoxy} -phenyl) propionic acid 576.2
[1962] Example 644
[1963] 3- {2-cyclopentylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[1964]
[1965] Step A: 3- {2-formyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} acrylic acid tert-butyl ester
[1966]
[1967] Toluene-4-sulfonic acid 2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester (3.74 g, 10.5 mmol), 3- (2-formyl-4- in a flame dried 100 mL round bottom flask Hydroxyphenyl) acrylic acid tert-butyl ester (2.0 g, 8.05 mmol), and anhydrous DMF (40 mL) were charged. Cesium carbonate (3.94 g, 12.1 mmol) was added and heated to 55 ° C. for 18 hours under reactant nitrogen atmosphere. The volatiles were removed in vacuo and the crude residue was dissolved in EtOAc (250 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ), and concentrated to give a yellow oil (1.70 g, 49%).
[1968]
[1969] Step B: 3- {2-formyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} acrylic acid tert-butyl ester
[1970]
[1971] 3- {2-formyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] phenyl} acrylic acid tert-butyl ester (1.69 g, 3.90 mmol) in a 100 mL round bottom flask ), THF (40 mL), and then 10% Pd / C catalyst (0.17 g) were charged. The reaction was stirred vigorously for 18 hours at 1 atmosphere under hydrogen atmosphere. The mixture was filtered through celite and concentrated to give a yellow solid (1.70 g, quant.).
[1972]
[1973] Step C: 3- {2-hydroxymethyl-4- [2- (2-phenyl-oxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[1974]
[1975] In a 100 mL round bottom flask, 3- {2-formyl-4- [2- (phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester (1.82 g, 4.18 mmol) and anhydrous ethanol (20 mL )). The solution was cooled in an ice / ethanol bath with stirring and treated with sodium borohydride (0.31 g, 8.36 mmol). The cold bath was removed and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into EtOAc (100 mL) and ice water (100 mL). The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a yellow oil (1.62 g, 88%).
[1976]
[1977] Step D: 3- {2-cyclopentylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid tert-butyl ester
[1978]
[1979] In a 15 mL round bottom flask, 3- {2-hydroxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester (0.10 g, 0.23 mmol), cyclopentyl Isocyanate (0.15 mL, 1.38 mmol), and anhydrous CH ₂ Cl ₂ (0.75 mL) were charged. 1.0 M HCl solution in ether (0.115 mL, 0.115 mmol) was added and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 24 h. The reaction mixture was diluted with CH ₂ Cl ₂ (30 mL), washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give an oil. The crude product was purified using radial chromatography (EtOAc: hexanes 10:90 to 35:65) to give a colorless oil (0.105 g, 83%).
[1980]
[1981] Step E: 3- {2-cyclopentylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid
[1982] 3- {2-cyclopentylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester (0.097 g, 0.18 mmol in a 15 mL round bottom flask ), CH ₂ Cl ₂ (1.2 mL), and then trifluoroacetic acid (1.2 mL). The solution was stirred at ambient temperature under nitrogen atmosphere for 4 hours and concentrated. The residue was purified using radial chromatography (MeOH: CH ₂ Cl ₂ 2:98 to 10:90) to give a white solid (0.085 g, 93%).
[1983]
[1984] Examples 645 to 651 below were prepared following procedures substantially similar to those described in Example 644.
[1985] Example 645
[1986] 3- {2-isopropylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[1987] MS (ES) m / e 523 (M + l).
[1988] Example 646
[1989] 3- {2-isopropylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[1990]
[1991] Example 647
[1992] 3- {2-benzylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[1993] MS (ES) m / e 571 (M + l).
[1994] Example 648
[1995] 3- {2-benzylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[1996]
[1997] Example 649
[1998] Morpholine-4-carboxylic acid 2- (2-carboxyethyl) -5- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] benzyl ester
[1999]
[2000] Example 650
[2001] 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2002] MS (ES) m / e 563 (M + 1)
[2003] Example 651
[2004] 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2005]
[2006] Example 652
[2007] 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2008]
[2009] Step A: 3- [4- (tert-butyldiphenylsilanyloxy) -2-formylphenyl] acrylic acid tert-butyl ester
[2010]
[2011] In a flame dried 200 mL round bottom flask, 3- (2-formyl-4-hydroxyphenyl) acrylic acid tert-butyl ester (10.0 g, 40.3 mmol), tert-butylchlorodiphenylsilane (12.6 mL, 48.3 mmol), And anhydrous CH ₂ Cl ₂ (150 mL). Triethylamine (11.2 mL, 80 mmol) and N, N-dimethylaminopyridine (1.0 g, 1.0 mmol) were added and the mixture was stirred at ambient temperature under nitrogen atmosphere for 16 hours. The reaction mixture was diluted with additional CH ₂ Cl ₂ , washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give an oil. The crude product was purified using Biotage medium pressure chromatography system (EtOAc: hexanes 5:95) to give a pale yellow oil (18.3 g, 93%).
[2012]
[2013] Step B: 3- [4- (tert-Butyldiphenylsilanyloxy) -2-hydroxymethylphenyl] propionic acid tertbutyl ester
[2014]
[2015] In a 500 mL par hydrogenation vessel, 3- [4- (tert-butyldiphenylsilanyloxy) -2-formylphenyl] acrylic acid tert-butyl ester (18.3 g, 37.6 mmol), THF (60 mL), and methanol ( 120 mL) was charged. Triethylamine (2 mL) and then 5% Pd / C (5.9 g) were added. The mixture was shaken with hydrogen for 48 hours under 60 psi pressure. The mixture was filtered through celite and concentrated to an oil. The oil was purified using Biotage medium pressure chromatography (EtOAc: hexane 15:85) to give a pale yellow oil (12.8 g, 69%).
[2016]
[2017] Step C: 3- [4- (tert-Butyldiphenylsilanyloxy) -2-cyclohexylcarbamoyloxymethylphenyl] propionic acid tert-butyl ester
[2018]
[2019] In a 100 mL round bottom flask under nitrogen, 3- [4- (tert-butyldiphenylsilanyloxy) -2-hydroxymethylphenyl] propionic acid tert-butyl ester (3.0 g, 6.11 mmol), cyclohexyl isocyanate (4.7 mL, 36.7 mmol), and anhydrous CH ₂ Cl ₂ (25 mL). 1.0 M HCl solution in ether (3.06 mL, 3.06 mmol) was added and the reaction mixture was stirred for 16 h at ambient temperature under a nitrogen atmosphere. The mixture was diluted with CH ₂ Cl ₂ (100 mL), washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a brown oil. The crude oil was purified using a Biotage medium pressure chromatography system (EtOAc: hexanes 5:95) to give a colorless oil (3.1 g, 82%).
[2020]
[2021] Step D: 3- (2-cyclohexylcarbamoyloxymethyl-4-hydroxyphenyl) propionic acid tert-butyl ester
[2022]
[2023] In a 500 mL round bottom flask, 3- [4- (tert-butyldiphenylsilanyloxy) -2-cyclohexylcarbamoyloxymethylphenyl] propionic acid tert-butyl ester (3.1 g, 5.03 mmol) and anhydrous THF (180 mL) Filled. Tetrabutylammonium fluoride (15.1 mL, 15.1 mmol, 1.OM in THF) was added and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 4 hours. The mixture was concentrated and the residue was diluted with EtOAc (100 mL), washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give an oil. The crude oil was purified using a Biotage medium pressure chromatography system (EtOAc: hexanes 10:90 to 50:50) to give a colorless oil (1.67 g, 88%).
[2024]
[2025] Step E: 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2026]
[2027] Fill a 40 mL Carousel tube with 3- (2-cyclohexylcarbamoyloxymethyl-4-hydroxyphenyl) propionic acid tert-butyl ester (0.10 g, 0.26 mmol) in anhydrous DMF (1.0 mL). I was. Toluene-4-sulfonic acid 2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester (0.104 g, 0.292 mmol) and cesium carbonate (0.13 g, 0.40 mmol) were added. The mixture was heated at 55 ° C. under nitrogen atmosphere for 30 h and concentrated. The residue was diluted with EtOAc (50 mL), washed twice with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated. The crude residue was purified using radial chromatography (EtOAc: CH ₂ Cl ₂ 2:98 to 5:95) to give a white solid (0.085 g, 57%).
[2028]
[2029] Step F: 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxyazol-4-yl) ethoxy] phenyl} propionic acid
[2030] In a 25 mL round bottom flask 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester (0.080 g, 0.14 mmol) and CH ₂ Cl ₂ (2 mL). Trifluoroacetic acid (2 mL) was added and the solution was stirred for 1.5 h at ambient temperature under a nitrogen atmosphere. The solution was concentrated to give a white solid (0.068 g, 94%).
[2031]
[2032] Examples 653-661, below, were prepared following procedures substantially similar to those described in Example 652.
[2033] Example 653
[2034] 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-cyclohexylcarbamoyloxymethylphenyl} propionic acid tert-butyl ester
[2035]
[2036] Example 654
[2037] 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-cyclohexylcarbamoyloxymethylphenyl} propionic acid
[2038]
[2039] Example 655
[2040] 3- {4- [2- (2-biphenyl-3-yl-5-methyloxyazol-4-yl) ethoxy] -2-cyclohexylcarbamoyloxymethylphenyl} propionic acid tert-butyl ester
[2041] MS (ES) m / e 639 (M + 1)
[2042] Example 656
[2043] 3- {4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2-cyclohexylcarbamoyloxymethylphenyl} propionic acid
[2044]
[2045] Example 657
[2046] 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-morpholin-4-ylthiazol-4- yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2047] MS (ES) m / e 588 (M + 1)
[2048] Example 658
[2049] 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-morpholin-4-ylthiazol-4 yl) ethoxy] phenyl} propionic acid
[2050]
[2051] Example 659
[2052] 3- (2-cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4 yl] ethoxy} phenyl) propionic acid tert-butyl ester
[2053] MS (ES) m / e 655 (M + 1)
[2054] Example 660
[2055] 3- (2-cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[2056]
[2057] Example 661
[2058] 3- (4- {2- [2- (4-bromophenyl) -5-methyloxyazol-4-yl] ethoxy} -2-cyclohexylcarbamoyloxymethylphenyl) propionic acid tert-butyl ester
[2059]
[2060] Example 662
[2061] 3- (2-cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[2062]
[2063] Step A: 3- (2-cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl Propionic acid tert-butyl ester
[2064]
[2065] 3- (4- {2- [2- (4-bromophenyl) -5-methyloxazol-4-yl] ethoxy} -2-cyclohexylcarbamoyloxymethylphenyl in 1 mL microvial under nitrogen atmosphere ) -Propionic acid tert-butyl ester (0.30 g, 0.468 mmol; Example 39), toluene anhydrous (0.5 mL), and then morpholine (0.053 mL, 0.61 mmol) were charged. Tris (dibenzylideneacetone) -dipalladium (O) (0.004 g, 0.0044 mmol), 2- (di-tertbutylphosphine) biphenyl (0.006 g, 0.020 mmol), and sodium tert-butoxide (0.063 g , 0.655 mmol) was added sequentially. The mixture was stirred at ambient temperature under nitrogen atmosphere for 5 hours and poured onto EtOAc (50 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give a dark yellow oil. The crude product was purified using radial chromatography (EtOAc: hexanes 15: 5 to 50:50) to give a yellow oil (0.058 g, 19%).
[2066]
[2067] Step B : 3- (2-cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-morpholin-4-phenyl) oxazol-4-yl] ethoxy} phenyl) Propionic acid
[2068] In a 15 mL round bottom flask, 3- (cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl Propionic acid (0.058 g, 0.09 mmol) and CH ₂ Cl ₂ (1 mL) were charged. Trifluoroacetic acid (0.5 mL) was added and the solution stirred for 1.5 h at ambient temperature under a nitrogen atmosphere. The mixture was concentrated to give a yellow solid (0.052 g, 98%).
[2069]
[2070] Examples 663-664 below were prepared following procedures substantially similar to those described in Example 662.
[2071] Example 663
[2072] 3- (2-cyclohexylcarbamoyloxymethyl-4- {2- [5-methyl-2- (4-phenylaminophenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[2073]
[2074] Example 664
[2075] 3- [2-cyclohexylcarbamoyloxymethyl-4- (2- {5methyl-2- [4- (methylphenylamino) phenyl] oxazol-4-yl} ethoxy) phenyl] propionic acid
[2076]
[2077] Example 665
[2078] 3- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2079]
[2080] Step A: 3- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2081]
[2082] In a 15 mL round bottom flask, 3- {2-hydroxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl in anhydrous DMF (1 mL) Ester (0.10 g, 0.23 mmol) and methyl iodide (0.21 mL, 2.3 mmol) were charged under nitrogen atmosphere. The mixture was cooled in an ice bath and treated in one portion with NaH (0.018 g, 0.25 mmol, 60% oil dispersion). The reaction mixture was stirred for 2 hours, concentrated and diluted with EtOAc (40 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified using radial chromatography (EtOAc: hexanes 10:90 to 25:75) to give a yellow oil (0.060 g, 58%). MS (ES) m / e 648 (M + 1)
[2083] Step B: 3- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2084] In a 15 mL round bottom flask, 3- {2-methoxymethyl-4- [2- (methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester (0.060 g, 0.13 mmol), CH ₂ Cl ₂ (1.2 mL), and then trifluoroacetic acid (0.6 mL) was charged. The solution was stirred for 16 h under nitrogen atmosphere at ambient temperature and concentrated. The residue was diluted with CH ₂ Cl ₂ (30 mL) and washed with brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give a white solid (0.046 g, 89%). MS (ES) m / e 648 (M + l).
[2085] Examples 666-673 below were prepared following procedures substantially similar to those described in Example 665.
[2086] Example 666
[2087] 3- {2-benzyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2088] MS (ES) m / e 528 (M + 1)
[2089] Example 667
[2090] 3- {2-benzyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2091]
[2092] Example 668
[2093] 3- {2-ethoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2094] MS (ES) m / e 466 (M + 1)
[2095] Example 669
[2096] 3- {2-ethoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2097]
[2098] Example 670
[2099] 3- {2- (4-tert-Butyl-benzyloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2100] MS (ES) m / e 584 (M + 1)
[2101] Example 671
[2102] 3- {2- (4-tert-Butyl-benzyloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2103]
[2104] Example 672
[2105] 3- {2- (biphenyl-4-ylmethoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2106] MS (ES) m / e 604 (M + 1)
[2107] Example 673
[2108] 3- {2- (biphenyl-4-ylmethoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2109]
[2110] Example 674
[2111] 3- {2-sec-butoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2112]
[2113] Step A: 3- {2-Bromomethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester
[2114]
[2115] 3- {2-hydroxymethyl- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tert-butyl ester (1.0 g, 2.29 mmol) in a 100 mL round bottom flask, Anhydrous THF (25 mL), and then triphenylphosphine (1.20 g, 4.57 mmol) and CBr ₄ (1.52 g, 4.57 mmol) were charged. The yellow mixture was stirred at ambient temperature under nitrogen atmosphere for 1 hour and poured into EtOAc (100 mL). The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified using radial chromatography (EtOAc: hexanes 15:85 to 25:75) to give a colorless oil (0.95 g, 83%). MS (ES) m / e 501 (M + 1).
[2116] Step B: 3- {2-sec-butoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2117] The flame dried 15 mL round bottom flask was charged with 2-butanol (0.92 mL, 1.0 mmol), anhydrous DMF (1 mL), and then NaH (0.013 g, 0.2 mmol, 60% oil dispersion). The reaction mixture was cooled in an ice bath for 15 minutes and 3- {2-bromomethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] in anhydrous DMF (0.5 mL). Phenyl} propionic acid tertbutyl ester ((0.050 g, 0.1 mmol) was added. The reaction mixture was stirred under nitrogen atmosphere for 2 hours. A product mixture of free acid and tert-butyl ester was formed. 40 mL), washed with brine (3 ×), dried (Na ₂ SO ₄ ) and concentrated, then the crude oil was dissolved directly in CH ₂ Cl ₂ (1 mL) and with TFA (1.5 mL). The solution was stirred for 16 h at ambient temperature and concentrated The crude product residue was purified using radial chromatography (EtOAc: hexanes 15:85 to 1: 1) to give a yellow oil (0.012 g, 27%). MS (ES) m / e 438 (M + l).
[2118] Examples 675 to 680 below were prepared following procedures substantially similar to those described in Example 674.
[2119] Example 675
[2120] 3- {2-Isopropoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] -phenyl] propionic acid
[2121]
[2122] Example 676
[2123] 3- {2-cyclohexyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2124]
[2125] Example 677
[2126] 3- {2-isobutoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] phenyl} propionic acid
[2127]
[2128] Example 678
[2129] 3- {2-cyclohexylmethoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2130]
[2131] Example 679
[2132] 3- {2- (biphenyl-4-yloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2133]
[2134] Example 680
[2135] 3- {2- (3-methylbutoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2136]
[2137] Example 681
[2138] 3- [4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid
[2139]
[2140] General procedure for parallel synthesis using the DynaVac Carousel apparatus. 3- {2-bromomethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid tertbutyl ester in 50 mL glass tube with screw cap and nitrogen inlet (0.040 g, 0.080 mmol), 4-trifluoromethylphenol (0.019 g 0.12 mmol), anhydrous DMF (0.5 mL), and then cesium carbonate (0.039 g, 0.12 mmol) were charged. The mixture was stirred at ambient temperature for 16 hours. MS analysis of the reaction showed that the intermediate ester product [MS (ES) m / e 582 (M + 1)] was formed. The reaction mixture was poured into ether (30 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated. The residue was diluted with CH ₂ Cl ₂ (1 mL) and trifluoroacetic acid (0.25 mL) was added. The mixture was stirred at ambient temperature for 1.5 hours and concentrated. The crude product mixture was purified by reverse phase HPLC connected by mass spectrometry to afford the title compound (0.045 g, 64%). MS (ES) m / e 526 (M + l).
[2141] Examples 682 to 691 below were prepared following procedures substantially similar to those described in Example 681.
[2142] Example 682
[2143] 3- {2- (4-fluorophenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2144]
[2145] Example 683
[2146] 3- {2- (3-fluorophenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2147]
[2148] Example 684
[2149] 3- {2- (2-fluorophenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2150]
[2151] Example 685
[2152] 3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-p-tolyloxymethylphenyl} propionic acid
[2153]
[2154] Example 686
[2155] 3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-m-tolyloxymethylphenyl} propionic acid
[2156]
[2157] Example 687
[2158] 3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-o-tolyloxymethylphenyl} propionic acid
[2159]
[2160] Example 688
[2161] 3- {2- (4-methoxyphenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2162]
[2163] Example 689
[2164] 3- {2- (biphenyl-2-yloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2165]
[2166] Example 690
[2167] 3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-phenylsulfanylmethylphenyl} propionic acid
[2168]
[2169] Example 691
[2170] 3- {2-benzenesulfonylmethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2171]
[2172] Example 692
[2173] 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (4-trifluoromethylphenoxy methyl) -phenyl] -propionic acid
[2174]
[2175] Step A: 3- [2-bromomethyl-4- (tert-butyldiphenylsilanyloxy) phenyl] propionic acid tert butyl ester
[2176]
[2177] In a 200 mL round bottom flask, 3- [4- (tert-butyldiphenylsilanyloxy) -2-hydroxymethylphenyl] propionic acid tert-butyl ester (3.03 g, 6.18 mmol), anhydrous THF (75 mL), and then Triphenylphosphine (3.24 g, 12.4 mmol) and CBr ₄ (4.10 g, 12.4 mmol) were charged. The yellow mixture was stirred at ambient temperature under nitrogen atmosphere for 1 hour and concentrated. The residue was diluted with EtOAc (500 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give a solid. The crude product was purified using a Biotage medium pressure chromatography system (EtOAc: hexanes 10:90) to give a yellow oil (2.95 g, 86%). MS (ES) m / e 572 (M + NH ₄ ).
[2178] Step B: 3- [4- (tert-Butyldiphenylsilanyloxy) -2- (4-trifluoromethylphenoxymethyl) phenyl] -propionic acid tert-butyl ester
[2179]
[2180] In a 50 mL round bottom flask, 3- [2-bromomethyl-4- (tert-butyldiphenylsilanyloxy) phenyl] propionic acid tert-butyl ester (1.0 g, 1.81 mmol), anhydrous DMF (10 mL), and then , 4-trifluoromethylphenol (0.44 g, 2.7 mmol) and cesium carbonate (0.88 g, 2.7 mmol) were charged. The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 18 hours and concentrated. The residue was diluted with EtOAc (100 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give a yellow oil. The crude residue was purified using radial (EtOAc: hexanes 15:85 to 50:50) to give a yellow oil (0.66 g, 58%). MS (ES) m / e 635 (M + l).
[2181] Step C: 3- [4-hydroxy-2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid tertbutyl ester
[2182]
[2183] 3- [4- (tertbutyldiphenylsilanyloxy) -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid tert butyl ester (0.65 g, 1.2 mmol) in 100 mL round bottom flask, THF anhydrous (40 mL), followed by tetrabutylammonium fluoride (3.1 mL, 3.1 mmol, 1.0 M in THF). The reaction was stirred under nitrogen atmosphere for 1.5 hours and concentrated. The residue was diluted with EtOAc (100 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give an orange oil. The crude oil was purified using radial chromatography (EtOAc: hexanes 15:85) to give a white solid (0.31 g, 77%). MS (ES) m / e 395 (M-1).
[2184] Step D: 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (4-trifluoromethylphenoxy-methyl)- Phenyl] -propionic acid
[2185] General Procedure for Parallel Synthesis Using a DynaVac Carousel Apparatus: 3- [4-hydroxy-2- (4-trifluoromethylphenoxy) in a 50 mL glass tube with screw cap and nitrogen inlet Methyl) phenyl] propionic acid tert-butyl ester (0.050 g, 0.146 mmol), toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethyl ester (0.078 g, 0.18 mmol), anhydrous DMF (0.5 mL), and then cesium carbonate (0.072 g, 0.22 mmol). The mixture was stirred at ambient temperature for 16 hours. MS analysis of the reaction showed that the intermediate ester product [MS (ES) m / e 658 (M + 1)] was formed. The reaction mixture was poured into ether (30 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated. The residue was diluted with CH ₂ Cl ₂ (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at ambient temperature for 2 hours and concentrated under a stream of nitrogen. The crude product was purified by reverse phase HPLC connected by mass spectrometry to afford the title compound (0.053 g, 71%).
[2186]
[2187] Examples 693-697, below, were prepared following procedures substantially similar to those described in Example 692.
[2188] Example 693
[2189] 3- [4- [2- (2-cyclohexyl-5-methyloxazol-4-yl) ethoxy] -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid
[2190]
[2191] Example 694
[2192] 3- [4- [2- (5-methyl-2-morpholin-4-yl-thiazol-4-yl) ethoxy] -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid
[2193]
[2194] Example 695
[2195] 3- [4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2- (4-trifluoromethyl-phenoxymethyl) phenyl] propionic acid
[2196]
[2197] Example 696
[2198] 3- [4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid
[2199]
[2200] Example 697
[2201] 3- [4- [4-methyl-2- (4-trifluoromethylphenyl) thiazol-5-ylmethoxy] -2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid
[2202] MS (ES) m / e 596 (M + 1)
[2203] Example 698
[2204] 3-2-benzyloxymethyl-4- [2- (2-cyclohexyl-5-methyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[2205]
[2206] Step A: 3- [2-benzyloxymethyl-4- (tert-butyl-diphenyl-silanyloxy) -phenyl] -propionic acid tert-butyl ester
[2207]
[2208] In a 100 mL round bottom flask, 3- [4- (tert-butyldiphenylsilanyloxy) -2-hydroxymethylphenyl] propionic acid tert-butyl ester (1.52 g, 3.10 mmol), anhydrous DMF (15 mL), and then Benzyl bromide (1.84 mL, 15.5 mmol) was charged under nitrogen atmosphere. The solution was cooled to -10 ° C and NaH (0.124 g, 3.10 mmol, 60% oil dispersion) was added. The mixture was stirred for 5 hours and poured onto EtOAc (150 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ), and concentrated to give a brown oil. The crude oil was purified using radial chromatography (EtOAc: hexanes 2:98 to 5:95) to give a pale yellow oil (1.04 g, 58%). MS (ES) m / e 598 (M + NH ₄ ).
[2209] Step B: 3- (2-benzyloxymethyl-4-hydroxy-phenyl) -propionic acid tert-butyl ester
[2210]
[2211] In a 250 mL round bottom flask 3- [2-benzyloxymethyl-4- (tert-butyl-diphenyl-silanyloxy) -phenyl] -propionic acid tert-butyl ester (1.03 g, 1.77 mmol), anhydrous THF (60 mL ), And then tetrabutylammonium fluoride (5.3 mL, 5.3 mmol, 1.0 M in THF). The reaction mixture was concentrated under nitrogen atmosphere for 1 hour and diluted with EtOAc (100 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give an oil. The crude oil was purified using radial chromatography (EtOAc: hexanes 10:90 to 50:50) to give a white solid (0.52 g, 86%). MS (ES) m / e 343 (M-1).
[2212] Step C: 3- {2-benzyloxymethyl-4- [2- (2-cyclohexyl-5-methyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[2213] General Procedure for Synthetic Synthesis Using a DynaVac Carousel Apparatus: 3- (2-benzyloxymethyl-4-hydroxy-phenyl) -propionic acid tert in a 50 mL glass tube with screw cap and nitrogen inlet -Butyl ester (0.050 g, 0.146 mmol), toluene-4-sulfonic acid 2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethyl ester (0.078 g, 0.18 mmol), anhydrous DMF (0.5 mL), followed by cesium carbonate (0.072 g, 0.22 mmol). The mixture was stirred at ambient temperature for 16 hours. MS analysis of the reaction showed that the intermediate ester product [MS (ES) m / e 534 (M + 1)] was formed. The reaction mixture was poured into ether (30 mL), washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude residue was diluted with CH ₂ Cl ₂ (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at ambient temperature for 2 hours and concentrated under a stream of nitrogen. The crude product was purified by reverse phase HPLC connected by mass spectrometry to 0.053 g of 3- {4- [2- (2-cyclohexyl-5-methyloxazol-4-yl) ethoxy] -2-phenoxymethylphenyl} propionic acid ( 71%). MS (ES) m / e 478 (M + l).
[2214] Examples 699 to 704 below were prepared following procedures substantially similar to those described in Example 698.
[2215] Example 699
[2216] 3- {2-benzyloxymethyl-4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid
[2217]
[2218] Example 670
[2219] 3- {2-benzyloxymethyl-4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2220]
[2221] Example 671
[2222] 3- {2-benzyloxymethyl-4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] phenyl} propionic acid
[2223]
[2224] Example 672
[2225] 3- (2-benzyloxymethyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[2226]
[2227] Example 673
[2228] 3- (2-benzyloxymethyl-4- {2- [2- (4-butoxyphenyl) -5-methyloxyazol-4-yl] ethoxy} phenyl) propionic acid
[2229]
[2230] Example 674
[2231] 3- (2-benzyloxymethyl-4- {2- [5-methyl-2- (4-trifluoromethylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
[2232]
[2233] Example 705
[2234] 3- {4- [3- (Biphenyl-4-yloxy) -propoxy] -2-cyclohexylcarbamoyloxymethyl-phenyl} -propionic acid
[2235]
[2236] Step A: 3- {4- [3- (biphenyl-4-yloxy) -propoxy] -2-cyclohexylcarbamoyloxymethyl-phenyl} -propionic acid tert-butyl ester
[2237]
[2238] 3- (2-cyclohexylcarbamoyloxymethyl-4-hydroxy-phenyl) propionic acid tert-butyl ester (50 mg, 0.13 mmol; Example 652 step D), 4- (3 in acetonitrile (6 mL) -Bromo-propoxy) -biphenyl (58 mg, 0.2 mmol; Tetrahedron 1994, 50, 3427, and potassium carbonate (53 mg, 0.39 mmol) were heated overnight at 80 ° C. ethyl acetate (20 mL) and H ₂ 0 (20 mL) was added, the organic layer was separated and the aqueous layer washed with ethyl acetate (3 ×) The combined organic layers were dried (MgSO ₄ ), filtered and concentrated The crude mixture was subjected to silica gel column chromatography. Purification using (hexane / ethyl acetate 4/1) gave the title compound (50 mg, 65%).
[2239]
[2240] Step B : 3- {4- [3- (Biphenyl-4-yloxy) -propoxy] -2-cyclohexylcarbamoyloxymethyl-phenyl} -propionic acid
[2241] At room temperature, trifluoroacetic acid (0.032 mL, 0.42 mmol) was added 3- {4- [3- (biphenyl-4-yloxy) -propoxy] -2-cyclohexyl in CH ₂ Cl ₂ (5 mL). To a solution of carbamoyloxymethyl-phenyl} -propionic acid tert-butyl ester (50 mg, 0.085 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo to afford the title compound (41 mg, 90%).
[2242]
[2243] Example 706
[2244] 3- {4- [3- (4-Benzoyl-phenoxy) -propoxy] -2-cyclohexylcarbamoyloxymethyl-phenyl} propionic acid
[2245]
[2246] Step A: 3- {4- [3- (4-Benzoyl-phenoxy) -propoxy] -2-cyclohexylcarbamoyloxymethyl-phenyl} -propionic acid tert-butyl ester
[2247]
[2248] 3- (2-cyclohexylcarbamoyloxymethyl-4-hydroxy-phenyl) propionic acid tert-butyl ester (50 mg, 0.13 mmol; Example 652 step D) in acetonitrile (6 mL), [4- ( A mixture of 3-bromo-propoxy) -phenyl] -phenyl-methanone (64 mg, 0.2 mmol, Bull. Chem. Soc. Jpn. 1990, 63, 1342) and potassium carbonate (53 mg, 0.39 mmol) Heated at 80 ° C. overnight. Ethyl acetate (20 mL) and H ₂ 0 (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 ×). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated. The crude mixture was purified using silica gel column chromatography (hexane / ethyl acetate 4/1) to give the title compound (50 mg, 62%).
[2249]
[2250] Step B: 3- {4- [3- (4-Benzoyl-phenoxy) -propoxy] -2-cyclohexylcarbamoyloxymethyl-phenyl} -propionic acid
[2251] Trifluoroacetic acid (0.031 mL, 0.4 mmol) was added to 3- {4- [3- (4-benzoyl-phenoxy) -propoxy] -2-cyclohexylcarba in CH ₂ Cl ₂ (5 mL) at room temperature. To a solution of moyloxymethyl-phenyl} -propionic acid tert-butyl ester (50 mg, 0.08 mmol). The reaction mixture was stirred overnight and concentrated in vacuo to afford the title compound. (39 mg, 88%).
[2252]
[2253] Example 708
[2254] 2- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2255]
[2256] Step A: 2- (4-Benzyloxy-2-formyl-phenoxy) -2-methyl-propionic acid ethyl ester
[2257]
[2258] 5-benzyloxy-2-hydroxy-benzaldehyde in anhydrous DMF (600 mL) (Kappe, T .; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (169 g, 741 mmol ), Ethyl bromoisobutyrate (164 mL, 1.11 mol), and cesium carbonate (240 g, 741 mmol) were heated at 80 ° C for 15 h. Additional cesium carbonate (5 g) and ethyl bromoisobutyrate (20 mL) were added and the reaction mixture was heated for 6 hours. The reaction mixture was cooled down, diluted with EtOAc (4 L) and washed with water (3 x 2 L). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give a brown oil. The crude product was recrystallized from EtOAc (150 mL) with hexanes until it became cloudy to afford the title compound as a pale yellow solid (210 g, 83%): mp 65 ° C .;
[2259]
[2260] Step B: 2- (4-hydroxy-2-hydroxymethyl-phenoxy) -2-methyl-propionic acid ethyl ester
[2261]
[2262] 2- (4-benzyloxy-2-formyl-phenoxy) -2-methyl-propionic acid ethyl ester (185 g, 540 mmol) in ethanol (700 mL) was added with 10% Pd / C (205 g) and hydrogen ( 60 psi) and 50 ° C. for 2 hours (2 d). The mixture was filtered through celite, washed with ethanol (1.5 L) and concentrated. The residue was recrystallized from EtOAc / hexanes to give the title compound (116 g).
[2263]
[2264] Step C: 2- {2-hydroxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid ethyl ester
[2265]
[2266] Toluene-4-sulfonic acid 2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester (0.77 g, 2.17 mmol), 2- (4-hydroxy-2- in a 25 mL round bottom flask under nitrogen atmosphere Charged hydroxymethylphenoxy) -2-methylpropionic acid ethyl ester (0.5 g, 1.97 mmol), and anhydrous ethanol (10 mL). Potassium carbonate (0.54 g, 3.94 mmol, 325 mesh) was added and the reaction heated to 80 ° C for 12 h. The mixture was concentrated and the crude residue was diluted with EtOAc (75 mL). The organic layer was washed with brine (2 ×), dried (Na ₂ SO ₄ ) and concentrated to give an oil. The crude product was purified using radial chromatography (EtOAc: Hex 5:95 to 35:65) to give a colorless oil (0.17 g, 20%). MS (ES) m / e 452 (M + l).
[2267] Step D: 2- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid ethyl ester
[2268]
[2269] To a 15 mL round bottom flask under nitrogen atmosphere, 2- {2-hydroxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionate ethyl Filled with ester (0.075 g, 0.17 mmol), anhydrous DMF (1 mL), and then methyl iodide (0.16 mL, 1.7 mmol). The solution was cooled in an ice bath and treated with NaH (0.014 g, 0.34 mmol, 60% oil dispersion). The mixture was stirred for 2 h, poured onto EtOAc (6 mL) and brine (10 mL) and acidified with dilute sulfuric acid. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated to give an oil. The crude product was purified using radial chromatography (EtOAc: Hex 15:85) to give a colorless oil (0.039 g, 51%). MS (ES) m / e 454 (M + l).
[2270] Step E: 2- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2271] In a 25 mL round bottom flask 2- {2-methoxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid ethyl ester (0.039 g , 0.087 mmol), ethanol (2 mL), and then aqueous 2N NaOH (0.22 mL, 0.44 mmol). The solution was heated at 55 ° C for 1 h. The mixture was concentrated, acidified with 5% H ₂ SO ₄ (1.5 mL) and partitioned between CH ₂ Cl ₂ (15 mL) and brine (15 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give a white solid (0.024 g, 66%). MS (ES) m / e 426 (M + l).
[2272] Example 709
[2273] 2- {2-benzyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] phenoxy} -2-methylpropionic acid
[2274]
[2275] The compound was prepared by substantially the same procedure as described in Example 708. MS (ES) m / e 502 (M + 1).
[2276] Example 710
[2277] 2- {2-Cyclohexylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -2-methyl-propionic acid
[2278]
[2279] Step A : 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid ethyl ester
[2280]
[2281] In a 15 mL round bottom flask under nitrogen, 2- {2-hydroxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid ethyl ester ( 0.075 g, 0.17 mmol), cyclohexyl isocyanate (0.13 mL, 1.0 mmol), anhydrous CH ₂ Cl ₂ (0.5 mL), and then 1.0 N HCl in ether (0.086 mL, 0.086 mmol) were sequentially charged. The reaction mixture was stirred at ambient temperature for 18 hours and diluted with CH ₂ Cl ₂ (10 mL). The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 0.10 g of crude oil which was used directly in the next step. MS (ES) m / e 564 (M + l).
[2282] Step B: 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} -propionic acid
[2283] 3- {2-cyclohexylcarbamoyloxymethyl-4- [2- (2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid ethyl ester (0.10 g, 0.17 mmol) in a 15 mL round bottom flask, Ethanol (2 mL), and then 2N NaOH (0.48 mL, 0.96 mmol) was charged. The solution was heated at 55 ° C for 2 h. The mixture was concentrated, acidified with 5% H ₂ SO ₄ (1.5 mL) and partitioned between CH ₂ Cl ₂ (15 mL) and brine (15 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was HPLC purified by mass spectrometry to give a white solid (0.058 g, 63%). MS (ES) m / e 537 (M + l).
[2284] Examples 711 to 713 below were prepared following procedures substantially similar to those described in Example 710.
[2285] Example 711
[2286] 2- [2-isopropylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxyazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2287]
[2288] Example 712
[2289] 2- {2-benzylcarbamoyloxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2290]
[2291] Example 713
[2292] 2- {2- (4-fluorobenzylcarbamoyloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2293]
[2294] Example 714
[2295] 2-Methyl-2- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-m-tolyloxymethyl-phenoxy} -propionic acid
[2296]
[2297] Step A: 2- {2-Bromomethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenoxy} -2-methyl-propionic acid ethyl ester
[2298]
[2299] A 2- {2-hydroxymethyl-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy]-dissolved in anhydrous THF (75 mL) in a 100 mL round bottom flask. Phenoxy} -2-methyl-propionic acid ethyl ester (1.0 g, 2.25 mmol), followed by triphenylphosphine (1.18 g, 4.50 mmol) and CBr ₄ (1.49 g, 4.50 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 hour and poured into EtOAc (135 mL). The organic layer was washed with brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified using radial chromatography (EtOAc: hexanes 15:85) to give the title compound as a colorless oil (0.95 g, 76%).
[2300] Step B: 2-Methyl-2- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-m-tolyloxymethylphenoxy} -propionic acid
[2301] General Procedure for Parallel Synthesis Using a DynaVac Carousel Apparatus: 2- {2-bromomethyl-4- [2- (5-methyl-) in a 50 mL glass tube with screw cap and nitrogen inlet 2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid ethyl ester (0.040 g, 0.080 mmol), m-cresol (0.012 mL, 0.12 mmol), ethanol anhydride (1 mL), and Then potassium carbonate (0.022 g, 0.16 mmol; 325 mesh) was charged. The mixture was heated at 80 ° C for 4 h. MS analysis of the reaction showed 2-methyl-2- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-m-tolyloxymethylphenoxy} -ethyl propionate It was confirmed that an ester (MS (ES) m / e 530 (M + 1)) was formed. The reaction mixture was treated with 2N NaOH (0.4 mL), heated at 55 ° C. for 3 h, cooled and concentrated. The residue was treated with 5N HCl (0.75 mL) and CH ₂ Cl ₂ (1 mL) and poured onto a 3-mL chemyllute cartridge to remove the aqueous layer. The cartridge was washed with CH ₂ Cl ₂ and the solution was removed under reduced pressure. The crude residue was purified by reverse phase HPLC connected by mass spectrometry to afford the title compound (0.032 g, 38%). MS (ES) m / e 502 (M + l).
[2302] Examples 715 to 723 below were prepared following procedures substantially similar to those described in Example 714.
[2303] Example 715
[2304] 2- {2- (4-fluorophenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2305]
[2306] Example 716
[2307] 2- {2- (3-fluorophenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2308]
[2309] Example 717
[2310] 2- {2- (2-fluorophenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2311]
[2312] Example 718
[2313] 2-Methyl-2- {4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] -2-p-tolyloxymethylphenoxy} propionic acid
[2314]
[2315] Example 719
[2316] 2-methyl-2- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-o-tolyloxymethylphenoxy} propionic acid
[2317]
[2318] Example 720
[2319] 2- {2- (4-methoxyphenoxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} 2-methylpropionic acid
[2320]
[2321] Example 721
[2322] 2-methyl-2- [4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2- (4-trifluoromethylphenoxymethyl) phenoxy] propionic acid
[2323]
[2324] Example 722
[2325] 2- {2- (biphenyl-2-yloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2326]
[2327] Example 723
[2328] 2- {2- (biphenyl-4-yloxymethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenoxy} -2-methylpropionic acid
[2329]
[2330] Example 724
[2331] 3- {2- (benzoylaminomethyl) -4- [3- (biphenyl-4-yloxy) propoxy] phenyl} propionic acid
[2332]
[2333] 4- (3-Bromo-propoxy) -biphenyl (291 mg, 1.00 mmol; Preparation 12) and 3- [2- (benzoylamino-methyl) -4-hydroxy-phenyl in DMF (5 mL) A solution of] -propionic acid tert butyl ester (320 mg, 0.90 mmol; Preparation 21) was treated with K ₂ CO ₃ (100 mg) and heated at 60 ° C. for 48 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified using silica gel chromatography (10-30% EtOAc / hexanes) to 3- {2- (benzoylaminomethyl) -4- [3- ( Biphenyl-4-yloxy) propoxy] phenyl} propionic acid tert-butyl ester (450 mg) was obtained. The material was treated with a mixture of CH ₂ Cl ₂ (1.0 mL) / TFA (0.8 mL) / water (0.1 mL) at ambient temperature for 2 hours. The reaction mixture was concentrated and dried under vacuum to afford the title compound as a white solid (380 mg, 75%). MS (ES) m / e 510.1 (M + l).
[2334] Examples 725-757 below were prepared following procedures substantially similar to those described in Example 724.
[2335] Example 725
[2336] 3- {2- (benzoylaminomethyl) -4- [2- (4-phenoxy-phenoxy) ethoxy] phenyl} propionic acid
[2337]
[2338] Example 726
[2339] 3- {2- (benzoylaminomethyl) -4- [2- (3-phenylbenzofuran-6-yloxy) ethoxy] -phenyl} -propionic acid
[2340]
[2341] Example 727
[2342] 3- {2- (benzoylaminomethyl) -4- [2- (6-methoxynaphthalen-2-yloxy) ethoxy] -phenyl} propionic acid
[2343]
[2344] Example 728
[2345] 3- {2-[(cyclobutanecarbonylamino) methyl] -4- [2- (4-phenoxyphenoxy) -ethoxy] phenyl} propionic acid
[2346]
[2347] Example 729
[2348] 3- [4- [2- (biphenyl-4-yloxy) ethoxy] -2- (isopropoxycarbonylaminomethyl) -phenyl] propionic acid
[2349]
[2350] Example 730
[2351] 3- (4- [2- (biphenyl-4-yloxy) ethoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} -phenyl) propionic acid
[2352]
[2353] Example 731
[2354] 3- (4- [2- (biphenyl-3-yloxy) ethoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} phenyl) propionic acid
[2355]
[2356] Example 732
[2357] 3- (4- [2- (4-phenoxy-phenoxy) ethoxy] -2-{[(pyridine-2-carbonyl) amino] -methyl} phenyl) propionic acid
[2358]
[2359] Example 733
[2360] 3- (4- [2- (3-phenylbenzofuran-6-yloxy) ethoxy] -2-{[(pyridine-2-carbonyl) -amino] methyl} phenyl) propionic acid
[2361]
[2362] Example 734
[2363] 3- (4- [2- (6-methoxynaphthalen-2-yloxy) ethoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} phenyl) propionic acid
[2364]
[2365] Example 735
[2366] 3- {2- (benzoylaminomethyl) -4- [4- (biphenyl-4-yloxy) butoxy] phenyl} propionic acid:
[2367]
[2368] Example 736
[2369] 3- {2- (benzoylaminomethyl) -4- [4- (biphenyl-3-yloxy) butoxy] phenyl} propionic acid:
[2370]
[2371] Example 737
[2372] 3- {2- (benzoylaminomethyl) -4- [4- (4-phenoxyphenoxy) butoxy] phenyl} propionic acid:
[2373]
[2374] Example 738
[2375] 3- {2- (benzoylaminomethyl) -4- [4- (3-phenylbenzofuran-6-yloxy) butoxy] phenyl} propionic acid
[2376]
[2377] Example 739
[2378] 3- {2- (isopropoxycarbonylaminomethyl) -4- [4- (4-phenoxyphenoxy) butoxy] phenyl} propionic acid
[2379]
[2380] Example 740
[2381] 3- {2- (isopropoxycarbonylaminomethyl) -4- [4- (3-phenylbenzofuran-6-yloxy) butoxy] phenyl} propionic acid
[2382]
[2383] Example 741
[2384] 3- (4- [4- (biphenyl-3-yloxy) butoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} -phenyl) propionic acid
[2385]
[2386] Example 742
[2387] 3- (4- [4- (4-phenoxyphenoxy) butoxy] -2-{[(pyridine-2-carbonyl) amino] -methyl} phenyl) propionic acid
[2388]
[2389] Example 743
[2390] 3- (4- [4- (3-phenylbenzofuran-6-yloxy) butoxy] -2-{[(pyridine-2-carbonyl) -amino] methyl} phenyl) propionic acid
[2391]
[2392] Example 744
[2393] 3- (4- [4- (6-methoxynaphthalen-2-yloxy) butoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} phenyl) propionic acid
[2394]
[2395] Example 745
[2396] 3- (4- [4- (biphenyl-3-yloxy) butyloxy] -2-{[(2,5-dichlorothiophen-3-carbonyl) amino] methyl} phenyl) propionic acid
[2397]
[2398] Example 746
[2399] 3- {2- (benzoylaminomethyl) -4- [3- (biphenyl-3-yloxy) propoxy] phenyl} propionic acid:
[2400]
[2401] Example 747
[2402] 3- [4- [3- (biphenyl-3-yloxy) propoxy] -2- (isopropoxycarbonylaminomethyl) -phenyl] propionic acid
[2403]
[2404] Example 748
[2405] 3- (4- [3- (biphenyl-4-yloxy) propoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} -phenyl) propionic acid
[2406]
[2407] Example 749
[2408] 3- (4- [3- (biphenyl-3-yloxy) propoxy] -2-{[(pyridine-2-carbonyl) amino] methyl} phenyl) propionic acid
[2409]
[2410] Example 750
[2411] 3- (4- [3- (6-methoxynaphthalen-2-yloxy) propoxy] -2-{[(pyridine-2-carbonyl) -amino] methyl} phenyl) propionic acid
[2412]
[2413] Example 751
[2414] 3- (4- [3- (biphenyl-4-yloxy) propoxy] -2-{[(2,5-dichlorothiophen-3-carbonyl) -amino] methyl} phenyl) propionic acid
[2415]
[2416] Example 752
[2417] 3- {2-{[(2,5-Dichlorothiophene-3-carbonyl) amino] methyl} -4- [3- (3-phenyl-benzofuran-6-yloxy) propoxy] phenyl} propionic acid
[2418]
[2419] Example 753
[2420] 3- [4- [3- (biphenyl-4-yloxy) propoxy] -2- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) phenyl] propionic acid
[2421]
[2422] Example 754
[2423] 3- [4- (3- (biphenyl-4-yloxy) propoxy] -2- (isopropoxycarbonylaminomethyl) -phenyl] propionic acid
[2424]
[2425] Example 755
[2426] 3- {2- (benzoylaminomethyl) -4- [3- (4-phenoxyphenoxy) propoxy] phenyl} propionic acid
[2427]
[2428] Example 756
[2429] 3- {2- (isopropoxycarbonylaminomethyl) -4- [3- (4-phenoxyphenoxy) propoxy] -phenyl} propionic acid
[2430]
[2431] Example 757
[2432] 3- (4- [3- (4-phenoxyphenoxy) propoxy] -2-{[(pyridine-2-carbonyl) amino] -methyl} phenyl) propionic acid
[2433]
[2434] Example 758
[2435] (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -acetic acid methyl ester
[2436]
[2437] Step 1: 4-bromo-3-oxo-pentanoic acid methyl ester
[2438]
[2439] A solution of bromine (28.3 g, 0.177 mol) in chloroform (30 mL) was added dropwise to a solution of methyl propionyl acetate (23.5 g, 0.177 mol) in chloroform (155 mL) at 0-5 ° C. The mixture was stirred for 30 minutes and the cold bath was removed. The mixture was stirred for 18 hours and ice water (200 mL) was added. The organic layers were combined and washed with cold water (2 x 200 mL), 10% aqueous sodium thiosulfate (2 x 200 mL) and brine (200 mL). The filtered solution was dried (Na ₂ SO ₄ ) and concentrated to give 36.5 g of the title compound as a clear liquid.
[2440] Step 2: Biphenyl-4-carboxylic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester
[2441]
[2442] To the mixture of biphenyl-4-carboxylic acid (800 g, 4.03 mol) in acetone (4.6 L) was added dropwise triethylamine (0.6 L, 4.3 mol, 1.07eq) for 13 minutes while maintaining the temperature at 15-30 ° C. Treated. 4-Bromo-3-oxo-pentanoic acid methyl ester (880 g, 4.21 mol, 1.04 eq) was added dropwise at 15-30 ° C for 21 minutes. The mixture was stirred overnight at room temperature. Water (9.6 L) was added dropwise over 85 minutes at 15-30 ° C. The mixture was stirred for 2 hours. The precipitated product was collected by filtration and washed twice with water (1 L). The product was dried under vacuum at 50 ° C. to give 1291 g (98% yield, 96% HPLC purity) of the title compound.
[2443] Step 3: Biphenyl-4-carboxylic acid 2-amino-3-methoxycarbonyl-l-methyl-allyl ester
[2444]
[2445] Of biphenyl-4-carboxylic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (1275 g, 3.9 mol, 1 eq) and ammonium acetate (640 g, 8.3 mol) in ethanol (10 L) The mixture was heated at 70-75 ° C. with stirring until the keto ester compound was consumed completely (1-2 h). The mixture was then maintained at 0-5 ° C. for 1.5 h. The precipitated solid was collected by filtration and washed with hexane (2.5 L). The product was dried at 50 ° C. under vacuum overnight to give 1244 g (90% yield, 98% HPLC purity) of the title compound.
[2446] Step 4: (2-biphenyl-4-yl-5-methyl-oxazol-4-yl) -acetic acid methyl ester
[2447] Of biphenyl-4-carboxylic acid 2-amino-3-methoxycarbonyl-1-methyl-allyl ester (566 g, 1.74 mol, 1 eq) and ammonium acetate (283 g, 3.67 mol) in glacial acetic acid (11.3 L) The mixture was heated at reflux for 2 hours, cooled and concentrated. The residue was coevaporated with toluene (2 x 2.5 L) and EtOAc (2.5 L). The mixture was diluted with EtOAc (6.6 L) and transferred into a separate flask with inlet at the bottom using EtOAc (2.2 L). The mixture was washed twice with water (2.2 L), saturated aqueous NaHCO ₃ (1.1 L), and brine (2 × 2.2 L). The organic phase was dried (Na ₂ SO ₄ , 550 g), filtered with the help of EtOAc (1.1 L) and concentrated. The residue was dissolved in isopropanol (2 L) at 50 ° C. and cooled overnight at room temperature. The mixture was kept at 0 ° C. to 5 ° C. for time. The precipitated solid was broken up and collected by filtration. The solid was washed with cold isopropanol (4 × 0.55 L) and dried overnight in a vacuum oven at 50 ° C. to give 428 g of the title compound (72% from step 2).

权利要求:
Claims (35)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:
<Formula I>

Where
n ¹ is 2, 3, 4 or 5;
V is a bond or O;
X is CH ₂ or O;
p is 0 or 1;
m is 1 to 4;
Y ¹ is ego;
remind Is aryl or heteroaryl;
Said aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, haloalkyl and haloalkyloxy;
Y ^1a is hydrogen, (C ₀ -C ₃ ) alkyl-aryl, C (O) -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, NR ⁵ (CH ₂ ) _m OR ⁵ , aryl-Z- Aryl, aryl-Z-heteroaryl, aryl-Z-cycloalkyl, aryl-Z-heterocycloalkyl, heteroaryl-Z-aryl, heteroaryl-Z-heterocycloalkyl or heterocycloalkyl-Z-aryl,
Said aryl, cycloalkyl, aryloxy, heteroaryl and heterocycloalkyl are C ₁ -C ₆ alkoxy optionally substituted with halo, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, N (R ⁵ ) ₂ , Haloalkyl, N (R ⁵ ) ₂ , N [C (O) R ⁵ ] ₂ , N [S (O) ₂ R ⁵ ] ₂ , NR ⁵ S (O) ₂ R ⁵ , NR ⁵ C (O) R Optionally with one or more substituents independently selected from the group consisting of ⁵ , NR ⁵ C (O) OR ⁵ , C (O) N (R ⁵ ) ₂ , C (O) OR ⁵ and C (O) R ⁵ Substituted;
Z is a bond, -O-, -C (O) NR ^5- , -NR ⁵ C (O)-, -NR ⁵ C (O) 0-, -C (O)-, -NR ⁵ -,-[ O] _p (CH ₂ ) _m -,-(CH ₂ ) _m [O] _p- , -NR ⁵ (CH ₂ ) _m -or-(CH ₂ ) _m NR ^5- ;
Y ² and Y ³ are each independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
Y ⁴ is (C ₁ -C ₃ ) alkyl-NR ⁵ C (O)-(C ₀ -C ₅ ) alkyl-Y ⁷ ,
(C ₁ -C ₃₎ alkyl, ^{-NR 5 C (O) - (} C 2 -C 5) alkenyl, -Y ^7,
(C ₁ -C ₃ ) alkyl-NR ⁵ C (O)-(C ₂ -C ₅ ) alkynyl-Y ⁷ ;
(C ₁ -C ₃ ) alkyl-NR ⁵ C (O) O— (C ₀ -C ₅ ) alkyl-Y ⁷ ,
(C ₁ -C ₃₎ alkyl, ^{-NR 5 C (O) NR 5} - (C 0 -C 5) alkyl, -Y ^7,
(C ₁ -C ₃₎ alkyl, ^{-NR 5 C (S) NR 5} - (C 0 -C 5) alkyl, -Y ^7,
(C ₀ -C ₃ ) alkyl-C (O) NR ^5- (C ₀ -C ₅ ) alkyl-Y ⁷ ,
(C ₁ -C ₃₎ alkyl, ^{-OC (O) NY 10 Y 11} ,
(C ₁ -C ₃ ) alkyl-NY ¹⁰ Y ¹¹ ,
(C ₁ -C ₃ ) alkyl-O- (C ₀ -C ₅ ) alkyl-Y ⁷ ,
(C ₁ -C ₃ ) alkyl-S- (C ₀ -C ₅ ) alkyl-Y ⁷ or
CN;
Y ⁷ is hydrogen, aryl, heteroaryl, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, cycloalkyl, heterocycloalkyl, aryloxy, C (O) -heteroaryl or SR ⁶ ,
Said alkyl, aryl, aryloxy, alkoxy, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from R ⁷ ;
Y ¹⁰ and Y ¹¹ are each independently hydrogen, aryl, heteroaryl, C ₁ -C ₁₀ alkyl, cycloalkyl, SO ₂ (R ⁶ ); or
Y ¹⁰ and Y ¹¹ together form a heterocycloalkyl ring conjugated with a 5-10 membered heterocycloalkyl ring or aryl, said heterocycloalkyl ring optionally comprising one or more heteroatoms selected from N, O or S and; Said aryl, heteroaryl, heterocycloalkyl and alkyl are optionally substituted with one or more substituents independently selected from R ⁷ ;
R ⁵ is hydrogen or C ₁ -C ₆ alkyl;
R ⁶ is hydrogen, C ₁ -C ₁₀ alkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from R ⁷ ;
R ⁷ is halo, nitro, oxo, cyano, hydroxyl, benzyl, phenyl, phenoxy, heteroaryl, C (O) R ⁶ , C ₁ -C ₁₀ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyloxy, O (CH ₂ ) _m -phenyl, (CH ₂ ) _m OC (O) -aryl, C (O) OR ⁵ , S (O) ₂ R ⁵ , S (O) ₂ N (R ⁵ ) ₂ , SR ⁵ or N (R ⁵ ) ₂ ;
The phenyl and phenoxy are optionally substituted with one or more groups independently selected from halo or trifluoromethyl.
[2" claim-type="Currently amended] A compound of formula la or a pharmaceutically acceptable salt, hydrate or solvate thereof:
<Formula Ia>

Y ¹ consists of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-C ₁ -C ₄ alkyl, heteroaryl-C ₁ -C ₄ alkyl, cycloalkyl-C ₁ -C ₄ alkyl and t-butyl An unsubstituted or substituted group selected from the group;
Y ² is selected from the group consisting of H, C ₁ -C ₁₀ alkyl, cycloalkyl, (C ₁ -C ₁₀ alkyl) -Y ⁵ , OY ⁶ ;
Y ⁵ is selected from the group consisting of aryl, substituted aryl groups, -COR ⁴ , -COOR ⁴ , -CONR ⁶ R ⁷ , -CSR ⁴ and -C (S) NR ⁶ R ⁷ ;
Y ⁶ is selected from the group consisting of aliphatic groups, substituted aliphatic groups, aryl, substituted aryl groups, -COR ⁴ , -COOR ⁴ , -CONR ⁶ R ⁷ , -CSR ⁴ and -C (S) NR ⁶ R ⁷ Selected;
R ⁴ , R ⁶ and R ⁷ are each independently selected from the group consisting of H, aliphatic group, substituted aliphatic group, aryl group and substituted aryl group;
Y ³ is selected from the group consisting of H, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and (C ₁ -C ₁₀ alkyl) -R ⁸ ; R ⁸ is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R ⁵ is selected from the group consisting of H, aliphatic group, substituted aliphatic group, heteroaryl, substituted heteroaryl, aryl, substituted aryl and (C ₁ -C ₁₀ alkyl) -R ⁹ ;
R ⁹ is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl, aminoalkyl and cycloalkyl;
V is a bond or O;
X is CH ₂ or O;
Y ⁴ is-(C ₁ -C ₃ ) alkyl-OWY ⁷ , -C (O) NY ⁸ Y ⁹ ,-(C ₁ -C ₃ ) alkyl-NY ¹⁰ Y ¹¹ and- (C ₁ -C ₃ ) alkyl N (Y ¹³ ) W— (C ₀ -C ₅ ) alkyl-Y ¹⁴ ;
W is from the group consisting of a bond, -CONY ¹² , -C (O)-, -OCH _2- , C ₁ -C ₆ alkyl, -CO _2- , -CHOY ^15- , -CSNY ¹⁶ and -SO _2- Selected;
Y ⁷ is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic, branched aliphatic and substituted (C ₁ -C ₁₀ ) alkyl;
Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ are each independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic, branched aliphatic and Selected from the group consisting of substituted (C ₁ -C ₁₀ ) alkyl;
n ¹ is 2, 3, 4 or 5.
[3" claim-type="Currently amended] The method of claim 1,
Y ^1a is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy,

Compound selected from the group consisting of.
[4" claim-type="Currently amended] The compound according to claim 1 or 2, represented by the formula:

Wherein E is O or S.
[5" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ is independently hydrogen or methyl.
[6" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ is independently hydrogen or methyl.
[7" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ is independently hydrogen or methyl.
[8" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 0 or 1;
Each R ⁵ is independently hydrogen or methyl.
[9" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ is independently hydrogen or methyl.
[10" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ is independently hydrogen or methyl.
[11" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ is independently hydrogen or methyl.
[12" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein q is 1 or 2;
Each R ⁵ , Y ² and Y ³ is independently hydrogen or methyl.
[13" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein Y ^1a is optionally substituted phenyl, naphthyl,
ego,
Z is a bond, oxygen, -NH-, -N (CH ₃ )-, -NHC (O)-, or -C (O) NH-.
[14" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein Y ^1a is optionally substituted phenyl, naphthyl or ego,
Z is a bond, oxygen, -NH-, -N (CH ₃ )-, -NHC (O)-, or -C (O) NH-.
[15" claim-type="Currently amended] The compound of claim 4 represented by the formula:

Wherein Y ^1a is optionally substituted aryl, heteroaryl, heterocycloalkyl, heteroaryl-Z-heterocycloalkyl or heteroaryl-Z-aryl.
[16" claim-type="Currently amended] A compound according to claim 1 represented by the formula:

Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[17" claim-type="Currently amended] A compound according to claim 1 represented by the formula:

Wherein q is 1 or 2; Each R ⁵ is independently hydrogen or methyl.
[18" claim-type="Currently amended] A compound according to claim 1 represented by the formula:

Wherein Y ^1a is hydrogen, aryl, heteroaryl or aryloxy; q is 1 or 2; n ¹ is 2, 3 or 4.
[19" claim-type="Currently amended] A compound according to claim 1 represented by the formula:

Wherein Y ^1a is hydrogen, aryl, heteroaryl or aryloxy; q is 1 or 2; n ¹ is 2, 3 or 4.
[20" claim-type="Currently amended] The compound according to claim 1 or 2, represented by the formula:

[21" claim-type="Currently amended] The compound according to claim 1 or 2, represented by the formula:

[22" claim-type="Currently amended] A compound selected from the group consisting of the compounds listed in the following table:
compound designation One 3- {2- (diphenylacetyl-aminomethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 2 3- (2-{(2-cyclopropylacetylamino) methyl] -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 3 3- {2-[(3-methoxybenzoylamino) methyl] -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 4 3- {2-{[biphenyl-2-carbonyl) amino] methyl} -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 5 3- (4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-{(2,5-dichlorothiophen-3-carbonyl) amino ] Methyl} phenyl) propionic acid 6 3- {2-Isopropoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
number compound designation 7 3- {2- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] Phenyl} propionic acid 8 3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -2-[(3-phenylureido) methyl] phenyl} propionic acid 9 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid 10 3- {2- (Isopropoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid 11 3- {2- (benzoylaminomethyl) -4- [3- (biphenyl-4-yloxy) propoxy] phenyl} propionic acid 12 3- (4- [3- (biphenyl-4-yloxy) propoxy] -2-{[pyridine-2-carbonyl) amino] methyl} phenyl) propionic acid
number compound designation 13 3- (2-benzylcarbamoyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 14 -3- {2-benzylcarbamoyl-4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] phenyl} propionic acid 15 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-cyanophenyl} propionic acid 16 3- [4- [2- (2-biphenyl-3-yl-5-methyloxazol-4-yl) ethoxy] -2- (1,3-dioxo-1,3-dihydroisoindole -2-ylmethyl) phenyl] propionic acid 17 3- {2- (2-Isopropoxycarbonyl-aminoethyl) -4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 18 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid
number compound designation 19 -3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (3-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 20 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (6-phenylpyridin-3-yl) thiazol-4-yl] ethoxy} phenyl) Propionic acid 21 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (2-isopropoxycarbonylaminoethyl) phenyl] propionic acid 22 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (isobutoxycarbonylaminomethyl) phenyl] propionic acid 23 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (cyclopentyloxycarbonyl-aminomethyl) phenyl] propionic acid
number compound designation 24 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [2- (4-isopropoxyphenyl) -5-methyloxazol-4-yl] ethoxy} phenyl) propionic acid 25 3- (2-benzylcarbamoyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 26 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl Propionic acid 27 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-piperidin-1-ylphenyl) oxazol-4-yl] ethoxy} Phenyl) propionic acid 28 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-pyrimidin-2-ylphenyl) oxazol-4-yl] ethoxy} phenyl Propionic acid 29 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-pyrazin-2-ylphenyl) oxazol-4-yl] ethoxy} phenyl) Propionic acid
number compound designation 30 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (6-phenoxypyridin-3-yl) thiazol-4-yl] ethoxy} phenyl Propionic acid 31 3- {2-cyclohexylcarbamoyl-oxymethyl-4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid 32 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (4-phenylaminophenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 33 3- (4- {2- [5-methyl-2- (6-phenylpyridin-3-yl) thiazol-4-yl] ethoxy} -2-{[(pyridine-2-carbonyl) amino] Methyl} phenyl) propionic acid HCl salt 34 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-[(3-methylbutyrylamino) methyl] phenyl} propionic acid 35 3- {2- (Isopropoxycarbonyl-aminomethyl) -4- [2- (5-methoxy-2-phenyloxazol-4-yl) ethoxy] phenyl} propionic acid
number compound designation 36 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (6-phenoxypyridin-3-yl) oxazol-4-yl] ethoxy} phenyl Propionic acid 37 3- {4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2-cyclohexylcarbamoyloxy-methylphenyl} propionic acid 38 3- {2-cyclohexylcarbamoyl-oxymethyl-4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid 39 3- (2-cyclohexylcarbamoyl-oxymethyl-4- {2- [5-methyl-2- (4-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 40 3- (2-cyclohexylcarbamoyl-oxymethyl-4- {2- [5-methyl-2- (4-morpholin-4-ylphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 41 3- [2- (isopropoxycarbonyl-aminomethyl) -4- (2- {5-methyl-2- [3- (tetrahydropyran-4-yloxy) phenyl] oxazol-4-yl} Ethoxy) phenyl] propionic acid
number compound designation 42 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (cyclopropylmethoxycarbonylaminomethyl) phenyl] propionic acid 43 3- {2- (Cyclopropylmethoxy-carbonylaminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid HCl salt 44 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy] -2- (cyclobutoxycarbonyl-aminomethyl) phenyl] propionic acid HCl salt 45 3- {2- (Cyclobutoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid HCl salt 46 3- [4- {2- [2- (4-butyrylaminophenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid 47 3- {2- (isopropoxycarbonyl-amino-methyl) -4- [2- (5-methyl-2- {4- [pyridine-2-carbonyl) -amino] -phenyl} oxazole-4 -Yl) -ethoxy] -phenyl} propionic acid
number compound designation 48 3- [4- {2- [2-biphenyl-4-yl-5-methyloxazol-4-yl] ethoxy] -2-{[pyrazine-2-carbonyl) amino] methyl} phenyl] propionic acid 49 3- [4- {2- [2- (3-cyclohexylcarbamoylphenyl) -5-methyloxazol-4-yl] ethoxy} -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid 50 3- (2- (isopropoxycarbonyl-aminomethyl) -4- {2- [5-methyl-2- (2-phenoxyphenyl) oxazol-4-yl] ethoxy} phenyl) propionic acid 51 3- (2-Cyano-4- {2- [5-methyl-2- (4-phenoxy-phenyl) -oxazol-4-yl] -ethoxy} -phenyl) propionic acid 52 3- [2- (isopropoxycarbonyl-aminomethyl) -4- (2- {5-methyl-2- [4- (pyridin-2-yloxy) phenyl] oxazol-4-yl} ethoxy ) Phenyl] propionic acid 53 3- [4- [2- (2-biphenyl-4-yl-5-methyloxazol-4-yl) ethoxy-2- (4-trifluoromethylphenoxymethyl) phenyl] propionic acid
number compound designation 54 3- (2- (isobutoxycarbonyl-aminomethyl) -4- [2- (5-methyl-2-morpholin-4-ylthiazol-4-yl) ethoxy] phenyl} propionic acid 55 3- [2- (isopropoxycarbonyl-aminomethyl) -4- (2- {5-methyl-2- [4- (pyrimidin-2-yloxy) phenyl] oxazol-4-yl} Methoxy) phenyl] propionic acid 56 3- [4- [2- (2-biphenyl-4-yl-5-methoxyoxazol-4-yl) ethoxy] -2- (isopropoxycarbonylaminomethyl) phenyl] propionic acid 57 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-{[(pyridine-2-carbonyl) -amino] -methyl} -phenyl) Propionic acid 58 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2 [-(2,4,5-trifluoro-benzoylamino) -methyl]- Phenyl} -propionic acid 59 3- {2-[(2,4-Difluoro-benzoylamino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} Propionic acid 60 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy-2-{[(thiophen-2-carbonyl) -amino] -methyl} -phenyl) Propionic acid
number compound designation 61 3- (4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-{[(thiophen-2-carbonyl) -amino] -methyl} -phenyl ) -Propionic acid 62 3- {2- (Butyrylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 63 3- {2-[(Cyclobutanecarbonyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 64 3- {2- (Benzyloxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 65 3- (2- (tert-Butoxycarbonylamino-methyl) -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] phenyl} -propionic acid 66 3- {4- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -2-[(2-phenoxy-acetylamino) -methyl] -phenyl} -propionic acid 67 3- {2-[(Cyclopentanecarbonyl-amino) -methyl] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
[23" claim-type="Currently amended] A pharmaceutical composition comprising at least one compound of claims 1 to 22 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable carrier.
[24" claim-type="Currently amended] (1) the compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof; (2) insulin sensitizers, sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, insulin secretagogues, insulin, antihyperlipidemic agents, plasma HDL-uplifters, HMG-CoA reductase inhibitors, Statins, acrylic CoA: cholesterol acyltransferase inhibitors, anti-obesity compounds, antihypercholesterolemic agents, fibrate, vitamins and aspirin; And (3) a pharmaceutically acceptable carrier.
[25" claim-type="Currently amended] A method of modulating a peroxysomal proliferator activated receptor (PPAR) comprising contacting a receptor with at least one compound of claims 1-22 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
[26" claim-type="Currently amended] The method of claim 25, wherein the peroxysomal proliferator activating receptor is an alpha-receptor.
[27" claim-type="Currently amended] The method of claim 25, wherein the peroxysomal proliferator activating receptor is a gamma-receptor.
[28" claim-type="Currently amended] A method of treating or preventing a peroxysomal proliferating agent activating receptor-gamma mediated disease or condition comprising administering an effective amount of at least one compound of claim 1.
[29" claim-type="Currently amended] A method of lowering glucose in the blood comprising administering an effective amount of at least one compound of claim 1.
[30" claim-type="Currently amended] Hyperglycemia, dyslipidemia, type II diabetes, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, dyslipidemia, comprising administering an effective amount of at least one compound of claim 1 or 2, A method of treating or preventing a disease or condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases in which insulin resistance is one factor.
[31" claim-type="Currently amended] A method of treating or preventing diabetes in a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1.
[32" claim-type="Currently amended] A method of treating or preventing a cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. .
[33" claim-type="Currently amended] A method of treating or preventing syndrome X in a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
[34" claim-type="Currently amended] Effective amounts of one or more compounds of claims 1 or 2, and insulin sensitizers, sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, insulin secretagogues, insulins, antihyperlipidemic agents, plasma HDL -An effective amount of a second therapeutic agent selected from the group consisting of a synergist, an HMG-CoA reductase inhibitor, a statin, an acrylic CoA: a cholesterol acyltransferase inhibitor, an antiobesity compound, an antihypercholesterolemic drug, fibrate, vitamins and aspirin Hyperglycemia, dyslipidemia, type II diabetes, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, obesity, anorexia A disease selected from the group consisting of bulimia, anorexia nervosa, cardiovascular disease and other diseases in which insulin resistance is one factor or How to treat or prevent the condition.
[35" claim-type="Currently amended] Use of a compound of claim 1 or 2 and a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof for the manufacture of a medicament for the treatment of a condition mediated by PPAR.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-06-07|Priority to US29670101P

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2001-06-07|Priority to US60/296,701

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2002-05-24|Application filed by 일라이 릴리 앤드 캄파니

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2002-05-24|Priority to PCT/US2002/015143

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2004-04-09|Publication of KR20040030658A

优先权:

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申请号 | 申请日 | 专利标题

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US29670101P| true| 2001-06-07|2001-06-07|

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US60/296,701|2001-06-07|

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PCT/US2002/015143|WO2002100403A1|2001-06-07|2002-05-24|Modulators of peroxisome proliferator activated receptors |