Deuterated Compounds

Abstract

Disclosed herein are compounds according to formula (I), pharmaceutical compositions containing same, and uses thereof.

Description

[Technical field]

[0001] The present disclosure relates generally to the field of medicine and methods of treating disorders. More specifically, provided herein are novel compounds that are dual agonists of PPARα and PPARγ and are useful for treating and / or preventing diseases, such as diabetes, dyslipidemia, or diabetic nephropathy. [Background technology]

[0002] Diabetes is a disease in which a patient's ability to control glucose levels in the blood is impaired due to a partial loss of the ability to respond appropriately to the action of insulin. In type II diabetes (T2D), often referred to as non-insulin-dependent diabetes mellitus (NIDDM), which afflicts 80-90% of all diabetic patients in developed countries, the islets of Langerhans in the pancreas still produce insulin. However, the target organs, mainly muscle, liver and adipose tissue, exhibit profound resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. However, in the later stages of the disease, insulin secretion declines due to pancreatic fatigue. Moreover, T2D is a metabolic cardiovascular disease syndrome. Comorbidities associated with T2D include insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

[0003] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-activated transcription factors that control gene expression. Various subtypes have been identified and cloned. These include PPARα, PPARβ (also known as PPARδ), and PPARγ. There are at least two major isoforms of PPARγ. PPARγ1 is ubiquitously expressed in most tissues, whereas the longer isoform, PPARγ2, is found almost exclusively in adipocytes. In contrast, PPARα is expressed primarily in the liver, kidney, and heart. PPARs control a variety of bodily responses, including glucose and lipid homeostasis, cell differentiation, inflammatory responses, and cardiovascular events. For clinical drug development, it is crucial to develop specific PPAR-α / γ dual agonists that combine the lipid metabolism-regulating activity of PPARα with the insulin sensitivity-regulating activity of PPARγ to control blood glucose and improve cardiovascular symptoms.

[0004] As a PPAR-α / γ dual agonist, aleglitazar has relatively balanced PPAR-α / γ activity. Aleglitazar can effectively improve fasting and postprandial blood glucose levels, insulin sensitivity and blood lipid parameters. However, the results of phase 3 clinical trials of aleglitazar showed that although aleglitazar can effectively reduce blood glucose and blood lipid levels, it also brings about a certain degree of heart failure risk, so it does not produce corresponding cardiovascular benefits. At the same time, side effects, such as bone fracture risk, were also seen in clinical trials, and these side effects are known to be caused by the activation of PPARγ (Lincoff AM, et al. JAMA. 2014; 311 (15): 1515-1525). Therefore, it is necessary to develop suitable selective PPAR-α / γ dual agonists to improve safety and benefits to patients.

[0005] The present disclosure provides a series of novel dual agonists of PPARα and PPARγ by deuteriumizing aleglitazar. These compounds have PPAR-α / γ selectivity, unlike aleglitazar. Some of these compounds can have stronger PPARα activity, and therefore can show better PPARα activity in in vitro transcription and in vivo lipid lowering, while maintaining a certain degree of PPARγ activity. Thus, they can also have good therapeutic effects in controlling blood lipid and blood glucose levels, while reducing the risk of side effects caused by PPARγ activity, such as weight gain and heart failure. Compared with aleglitazar, these compounds can have a more reasonable risk-benefit ratio for patients suffering from metabolic syndrome, and can have good clinical application potential. Summary of the Invention

[0006] The present disclosure provides deuterated aleglitazar, pharmaceutical compositions containing same, and uses thereof.

[0007] In one embodiment, the disclosure provides a compound of formula (I), or a pharma- ceutically acceptable salt thereof:

[0008] [ka]

[0009] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18, R 19 , R 20 , R 21 , R 22 and R 23 are independently H or D, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 of the following are D's:

[0010] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23Of these, 1 or less, 2 or less, 3 or less, 4 or less, 5 or less, 6 or less, 7 or less, 8 or less, 9 or less, 10 or less, 11 or less, 12 or less, 13 or less, 14 or less, 15 or less, 16 or less, 17 or less, 18 or less, 19 or less, 20 or less, 21 or less, 22 or less, or 23 or less are D.

[0011] In one embodiment, R 6 , R 7 , R 8 and R 9 At least one, two, three or four of the following are D:

[0012] In one embodiment, R 6 , R 7 , R 8 and R 9 Of these, no more than one, no more than two, no more than three, or no more than four are D.

[0013] In one embodiment, R 6 or R 7 One or two of the nuclei are D.

[0014] In one embodiment, R 8 or R 9 One or two of the nuclei are D.

[0015] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0016] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0017] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0018] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least 1, 2, 3, 4, or 5 of

[0019] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5Of these, no more than one, no more than two, no more than three, no more than four, or no more than five are D.

[0020] In one embodiment, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0021] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 All of the are D and R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0022] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9At least 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the

[0023] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 Of these, 1 or less, 2 or less, 3 or less, 4 or less, 5 or less, 6 or less, 7 or less, 8 or less, or 9 or less are D.

[0024] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least one, two, three, four or five of the following are D: 6 , R 7 , R 8 and R 9 At least one, two, three or four of the following are D:

[0025] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least one, two, three, four or five of the following are D: 8 and R 9 At least one or two of the following are D:

[0026] In one embodiment, R 1 and R 5 At least one or two of the groups are D, and R 8 and R 9 At least one or two of the following are D:

[0027] In one embodiment, R 10 , R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0028] In one embodiment, R 12 , R 13 and R 14 At least one, two or three of the following are D:

[0029] In one embodiment, R 12 , R 13 and R 14 Of these, no more than one, no more than two, or no more than three are D.

[0030] In one embodiment, R 12 and R 13 At least one or two of the groups are D, and R 14 is D.

[0031] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0032] In one embodiment, R 16 , R 17 and R 18 At least one, two or three of the following are D:

[0033] In one embodiment, R 16 , R 17 and R 18 Of these, no more than one, no more than two, or no more than three are D.

[0034] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0035] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 16 , R 17 and R 18 At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of the

[0036] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 16 , R 17 and R 18Of these, 1 or less, 2 or less, 3 or less, 4 or less, 5 or less, 6 or less, 7 or less, 8 or less, 9 or less, 10 or less, 11 or less, or 12 or less are D.

[0037] In one embodiment, R 8 and R 9 At least one or two of the groups are D, and R 16 , R 17 and R 18 At least one, two or three of the following are D:

[0038] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least one, two, three, four or five of the following are D: 16 , R 17 and R 18 At least one, two or three of the following are D:

[0039] In one embodiment, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0040] In another aspect, the disclosure provides a compound of formula (Ia), or a pharma- ceutically acceptable salt thereof.

[0041] [ka]

[0042] (In the formula, R 6’ , R 7’ , R 8’ and R 9’ are independently H or D, and R6’ , R 7’ , R 8’ and R 9’ At least one, two, three or four of the are D.)

[0043] In one embodiment, R 6’ , R 7’ , R 8’ and R 9’ Of these, no more than one, no more than two, no more than three, or no more than four are D.

[0044] In one embodiment, R 8’ and R 9’ At least one or two of the following are D:

[0045] In one embodiment, R 6’ and R 7’ At least one or two of the following are D:

[0046] In one embodiment, R 8’ and R 9’ If at least one or two of 6’ and R 7’ Both are H.

[0047] In one embodiment, R 8’ and R 9’ If both are D, then R 6’ and R 7’ Both are H.

[0048] In one embodiment, R 6’ and R 7’ If at least one or two of 8’ and R 9’ Both are H.

[0049] In another aspect, the disclosure provides a compound selected from the following, or a pharma- ceutically acceptable salt thereof:

[0050] [ka]

[0051] In certain embodiments, the deuterium enrichment is 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0052] In certain embodiments, the deuterium enrichment is 99.9% or less, 99% or less, 98% or less, 97% or less, 96% or less, 95% or less, or 90% or less.

[0053] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier and / or adjuvant.

[0054] In another aspect, the present disclosure provides a dual PPARα and PPARγ agonist for use in a method for the treatment and / or prevention of a disease modulated by a PPARα and / or PPARγ agonist, wherein the dual PPARα and PPARγ agonist is deuterated.

[0055] In another aspect, the present disclosure provides a method for the treatment and / or prevention of a disease regulated by a PPARα and / or PPARγ agonist in a subject, comprising administering a PPARα and PPARγ dual agonist to the subject, wherein the PPARα and PPARγ dual agonist is deuterated.

[0056] In another aspect, the present disclosure provides the use of a dual PPARα and PPARγ agonist in the manufacture of a medicament for the treatment and / or prevention of a disease modulated by a PPARα and / or PPARγ agonist, wherein the dual PPARα and PPARγ agonist is deuterated.

[0057] In certain embodiments, the disease is diabetes, non-insulin dependent diabetes mellitus, hypertension, dyslipidemia, atherosclerosis, metabolic syndrome, or diabetic nephropathy.

[0058] In certain embodiments, the disease is renal injury.

[0059] In some embodiments, the kidney damage is caused by a ureteral obstruction.

[0060] In one embodiment, the renal injury is caused by unilateral ureteral obstruction.

[0061] In one embodiment, the dual PPARα and PPARγ agonist is deuterated aleglitazar or a pharma- ceutically acceptable salt thereof.

[0062] In certain embodiments, the dual PPARα and PPARγ agonist is a compound provided herein or a pharma- ceutically acceptable salt thereof.

[0063] In another aspect, the disclosure provides a method of modulating the specific PPARα or PPARγ agonist activity of a dual PPARα and PPARγ agonist, comprising deuterizing the agonist.

[0064] In another aspect, the disclosure provides a method of improving the specific PPARα or PPARγ agonist activity of a dual PPARα and PPARγ agonist, comprising deuterizing the agonist.

[0065] In certain embodiments, the PPARα specific agonist activity of the agonist is improved.

[0066] In certain embodiments, the specific PPARγ agonist activity of the agonist is improved.

[0067] In certain embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of the H of the agonist are deuterated.

[0068] In certain embodiments, no more than 1, no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10 H of the agonist are deuterated.

[0069] In certain embodiments, the dual PPARα and PPARγ agonist is aleglitazar or a pharma- ceutically acceptable salt thereof.

[0070] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Brief description of the drawings]

[0071] [Figure 1] Figure 1A shows the changes in serum TG in each group. Data are presented as mean ± SD; One way ANOVA with Prism GraphPad; n = 6. ****P<0.0001, ***P<0.001, **P<0.001, *P<0.05 vs. vehicle. Figure 1B shows the changes in serum NEFA in each group. Data are presented as mean ± SD; One way ANOVA with Prism GraphPad; n = 6. ****P<0.0001 vs. vehicle. [Diagram 2] Figure 2A shows the change in weight gain of animals in each group compared to day 0. Figure 2B shows the change in the difference in weight gain between animals in each group and the vehicle group. (*: weight gain of treated groups minus the average weight gain of the vehicle group.) [Diagram 3] Figure 3 shows the effect of compounds on the change in body weight of db / db animals. Data are presented as mean ± SEM; Two-way ANOVA by Prism GraphPad followed by Dunnett's test; n = 6-9. [Figure 4] Figure 4A shows the effect of compounds on serum TG levels in db / db animals on day 6. Data presented as mean ± SEM; One way ANOVA with Prism GraphPad followed by Dunnett's test; n=6-9. **P<0.01, ***P<0.001, ****P<0.0001 versus model. Figure 4B shows the effect of compounds on serum TG levels in db / db animals on day 12. Data presented as mean ± SEM; One way ANOVA with Prism GraphPad followed by Dunnett's test; n=6-9. ****P<0.0001 versus model. [Diagram 5] Figure 5 shows the effect of compounds on random blood glucose in db / db animals. Data are shown as mean ± SEM, n = 6-9. [Figure 6] Figure 6A shows the effect of compounds on oral glucose tolerance in db / db animals. Data are presented as mean ± SEM; n = 6-9. Figure 6B shows the effect of compounds on oral glucose tolerance in db / db animals. Data are presented as mean ± SEM; One way ANOVA by Prism GraphPad followed by Dunnett's test; n = 6-9. **P<0.01, ***P<0.001, ****P<0.0001 vs. model group. [Figure 7] FIG. 7 shows the effect of Compound 2 on urinary albumin excretion. [Figure 8] 8A-8D show the effect of Compound 2 on glomerular and tubular injury. [Figure 9] FIG. 9 shows the effect of Compound 2 on ameliorating renal injury in a rat model of unilateral ureteral obstruction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] The following description of the present disclosure is not intended to merely illustrate various embodiments of the present disclosure. Therefore, the specific improvements discussed are not to be construed as limiting the scope of the present disclosure. It is clear to those skilled in the art that various equivalents, changes and improvements can be made without departing from the scope of the present disclosure, and it is understood that such equivalent embodiments are included herein. All references cited herein, including publications, patents and patent applications, are incorporated herein by reference in their entirety.

[0073] definition As used herein, the singular forms "a," "an," and "the" may refer to plural unless specifically stated otherwise.

[0074] As used herein, the term "about" or "approximately" should be considered to disclose a range defined by the absolute values ​​of the two endpoints. The term "about" or "approximately" also refers to an acceptable error for a particular value, which depends in part on how the value is measured or determined. In some embodiments, "about" can refer to one or more standard deviations. For example, the phrase "about 2 to about 4" also discloses a range of "2 to 4". When used to modify a single number, the term "about" can refer to plus or minus 10% of the indicated number, including the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can indicate a range of 0.9 to 1.1.

[0075] therapeutic compounds The present disclosure provides a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0076] [ka]

[0077] (In the formula, R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are independently H or D, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 of the following are D's:

[0078] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 between 1 and 23, between 1 and 22, between 1 and 21, between 1 and 20, between 1 and 19, between 1 and 18, between 1 and 17, between 1 and 16, between 1 and 15, between 1 and 14, between 1 and 13, between 1 and 12, between 1 and 11, between 1 and 10, between 1 and 9, between 1 and 8, between 1 and 7, between 1 and 6, between 1 and 5, between 1 and 4, between 1 and 3, or between 1 and 2 of these are D.

[0079] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 The range between 1 and 6 of these is D.

[0080] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 The range between 1 and 4 of these is D.

[0081] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 One or two of the nuclei are D.

[0082] In one embodiment, R 6 , R 7 , R 8 and R 9 At least one, two, three or four of the following are D:

[0083] In one embodiment, R 6 , R 7 , R 8 and R 9 Between 1 and 4, between 1 and 3, or between 1 and 2 of these are D.

[0084] In one embodiment, R 6 , R7 , R 8 and R 9 Four of them are D.

[0085] In one embodiment, R 6 , R 7 , R 8 and R 9 Two of them are D.

[0086] In one embodiment, R 6 or R 7 One or two of the nuclei are D.

[0087] In one embodiment, R 6 or R 7 One of them is D.

[0088] In one embodiment, R 6 or R 7 are both D.

[0089] In one embodiment, R 8 or R 9 One or two of the nuclei are D.

[0090] In one embodiment, R 8 or R 9 One of them is D.

[0091] In one embodiment, R 8 or R 9 are both D.

[0092] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19, R 20 , R 21 , R 22 and R 23 All of them are H.

[0093] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0094] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0095] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least 1, 2, 3, 4, or 5 of

[0096] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 between 1 and 5, between 1 and 4, between 1 and 3, or between 1 and 2 of these are D.

[0097] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 are all D.

[0098] In one embodiment, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0099] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 All of the are D and R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R23 All of them are H.

[0100] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 At least 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the

[0101] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 of which the range is D, between 1 and 9, between 1 and 8, between 1 and 7, between 1 and 6, between 1 and 5, between 1 and 4, between 1 and 3, or between 1 and 2.

[0102] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least one, two, three, four or five of the following are D: 6 , R 7 , R 8 and R 9 At least one, two, three or four of the following are D:

[0103] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least one, two, three, four or five of the following are D: 8 and R 9 At least one or two of the following are D:

[0104] In one embodiment, R 1 and R 5 At least one or two of the groups are D, and R 8 and R 9 At least one or two of the following are D:

[0105] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all D.

[0106] In one embodiment, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0107] In one embodiment, R 12 , R 13 and R 14 At least one, two or three of the following are D:

[0108] In one embodiment, R 12 , R 13 and R 14 Between 1 and 3 or between 1 and 2 of the above are D.

[0109] In one embodiment, R 12 , R 13 and R 14 One of them is D.

[0110] In one embodiment, R 12and R 13 At least one or two of the groups are D, and R 14 is D.

[0111] In one embodiment, R 12 and R 14 are both D. In one embodiment, R 13 and R 14 are both D. In one embodiment, R 12 , R 13 and R 14 are all D.

[0112] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0113] In one embodiment, R 16 , R 17 and R 18 At least one, two or three of the following are D:

[0114] In one embodiment, R 16 , R 17 and R 18 Between 1 and 3 or between 1 and 2 of the above are D.

[0115] In one embodiment, R 16 , R 17 and R 18 One of them is D.

[0116] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0117] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 16 , R 17 and R 18 At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of the

[0118] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 16 , R 17 and R 18 of which the range is D, between 1 and 12, between 1 and 11, between 1 and 10, between 1 and 9, between 1 and 8, between 1 and 7, between 1 and 6, between 1 and 5, between 1 and 4, between 1 and 3, or between 1 and 2.

[0119] In one embodiment, R 8 and R 9 At least one or two of the groups are D, and R 16 , R 17 and R 18 At least one, two or three of the following are D:

[0120] In one embodiment, R 1 , R 2 , R 3 , R 4 and R 5 At least one, two, three, four or five of the following are D: 16 , R 17 and R 18 At least one, two or three of the following are D:

[0121] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 16 , R 17 and R 18 are all D.

[0122] In one embodiment, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 19 , R 20 , R 21 , R 22 and R 23 All of them are H.

[0123] In another embodiment, the present invention provides a compound of formula (Ia), or a pharma- ceutically acceptable salt thereof:

[0124] [ka]

[0125] (In the formula, R 6’ , R 7’ , R 8’ and R 9’ are independently H or D, and R 6’ , R 7’ , R 8’ and R 9’ At least one, two, three or four of the are D.)

[0126] In one embodiment, R 6’ , R 7’ , R 8’ and R 9’ Of these, no more than one, no more than two, no more than three, or no more than four are D.

[0127] In one embodiment, R 6’ , R 7’ , R 8’ and R 9’ Between 1 and 4, between 1 and 3, or between 1 and 2 of the following are D:

[0128] In one embodiment, R 8’ and R 9’ At least one or two of the following are D:

[0129] In one embodiment, R 8’ and R 9’ are both D.

[0130] In one embodiment, R 6’ and R 7’ At least one or two of the following are D:

[0131] In one embodiment, R 8’ and R 9’ If at least one or two of 6’ and R 7’ Both are H.

[0132] In one embodiment, R 8’ and R9’ If both are D, then R 6’ and R 7’ Both are H.

[0133] In one embodiment, R 6’ and R 7’ are both H and R 8’ and R 9’ Both are D.

[0134] In one embodiment, R 6’ and R 7’ If at least one or two of 8’ and R 9’ Both are H.

[0135] In one embodiment, R 8’ and R 9’ are both H and R 6’ and R 7’ Both are D.

[0136] In another aspect, the present invention provides a compound selected from the following, or a pharma- ceutically acceptable salt thereof:

[0137] [ka]

[0138] In certain embodiments, the compound is: or a pharma- ceutically acceptable salt thereof.

[0139] [ka]

[0140] The term "compound", when referring to a compound of the present invention, refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations among the constituent atoms of the molecule. Thus, it will be apparent to one skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains lesser amounts of isotopic species having hydrogen atoms at one or more of the designated deuterium positions of the structure. The relative amounts of such isotopic species in the compounds of the present invention will depend on a number of factors, including the isotopic purity of the deuteration reagent used to make the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0141] The term "is deuterium / D," when used to describe a given location in a drawing of a molecule or molecular structure, means that the specified location is deuterium or that the specified location is enriched in deuterium over the naturally occurring distribution of deuterium.

[0142] deuterium( 2 H or D) is the most common isotope of hydrogen, protium ( 1 It is a stable, non-radioactive isotope of hydrogen with approximately twice the mass of hydrogen (H).

[0143] In the compounds of the present invention, any atom that is not specifically designated as a particular isotope is intended to represent any stable isotope of that atom.Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its naturally occurring isotopic composition.Also, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", that position is understood to have deuterium in an abundance that is at least 3340 times greater than the natural abundance of deuterium of 0.015% (i.e., at least 50.1% deuterium incorporation).

[0144] In certain embodiments, the deuterium enrichment of the compounds provided herein is 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0145] In certain embodiments, the compounds provided herein are no more than 99.9%, no more than 99%, no more than 98%, no more than 97%, no more than 96%, no more than 95%, or no more than 90% deuterium enriched.

[0146] In certain embodiments, the deuterium enrichment of the compounds provided herein is, for example, between 50% and 99.9%, between 50% and 99%, between 50% and 98%, between 50% and 97%, between 50% and 96%, between 50% and 95%, between 50% and 90%, between 60% and 99.9%, between 60% and 99%, between 60% and 98%, between 60% and 97%, between 60% and 96%, between 60% and 95%, between 60% and 90%, between 70% and 99.9%, between 70% and 99%, between 70% and 98%, between 70% and 97%, between 70% and 96%, between 70% and 95%, between 70% and 90%, between 80% and 99.9%, between 80% and 9 ... between 8%, between 80% and 97%, between 80% and 96%, between 80% and 95%, between 80% and 90%, between 90% and 99.9%, between 90% and 99%, between 90% and 98%, between 90% and 97%, between 90% and 96%, between 90% and 95%, between 95% and 99.9%, between 95% and 99%, between 95% and 98%, between 95% and 97%, between 95% and 96%, between 96% and 99.9%, between 96% and 99%, between 96% and 98%, between 96% and 97%, between 97% and 99.9%, between 97% and 99%, between 97% and 98%, between 98% and 99.9%, between 98% and 99% or between 99% and 99.9%.

[0147] In certain embodiments, the deuterium enrichment of the compounds provided herein is between 90% and 99.9%, preferably between 95% and 99.9%, preferably between 97% and 99%, preferably between 98% and 99%, particularly 98.5%. The overall deuterium enrichment of the compounds of the present disclosure can be determined using mass spectrometry according to methods known in the art.

[0148] As used herein, the term "deuterium enrichment" refers to the percentage of deuterium incorporation at a given position in hydrogen sites.For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position.Since the distribution of naturally occurring deuterium is about 0.0156%, the deuterium enrichment at any position of a compound synthesized using non-enriched starting material is about 0.0156%.Deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[0149] The present invention also provides pharma- ceutically acceptable salts of the compounds of the present invention.

[0150] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0151] As used herein, the term "pharmaceutical acceptable salts" includes salts that retain the biological effectiveness of the free acids and bases of a particular compound, and are not biologically or otherwise undesirable, unless otherwise specified. Possible pharmaceutical acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, etc. Pharmaceutically acceptable salts are those that are non-toxic in the amounts and concentrations at which they are administered. Preparing such salts can facilitate pharmacological use by altering the physical properties of a compound without preventing it from exerting its physiological effects. Beneficial changes in physical properties include lowering the melting point to facilitate transmucosal administration, and increasing solubility to facilitate administration of higher concentrations of the drug.

[0152] Pharmaceutically acceptable salts include those containing acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid.

[0153] Pharmaceutically acceptable salts also include base addition salts when an acidic functional group, such as a carboxylic acid or a phenol, is present, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, e.g., Remington's Pharmaceutical Sciences, 1999. th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0154] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent, such as an aqueous or water-alcoholic solution containing a suitable acid, and then isolated by evaporating the solution. Thus, when a particular compound is a base, the desired pharma-ceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, etc.

[0155] Similarly, if a particular compound is an acid, the desired pharma- ceutically acceptable salt can be prepared in any suitable manner, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Helpful examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine and L-arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0156] It is also understood that the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0157] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by combining one or more water molecules with one molecule of a substance in which water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0158] As used herein, the terms "crystal form", "crystalline form", "polymorphic form" and "polymorph" can be used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can result in one crystal form dominating. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0159] Those skilled in the art will understand that the compounds of the present disclosure can exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted by a low energy barrier. The presence and concentration of isomers can vary depending on the environment in which the compound is found, for example, depending on whether the compound is a solid or in an organic or aqueous solution. By way of example, proton tautomers (also known as prototropic tautomers) include interconversions by migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and ring formations in which a proton can occupy more than one position in a heterocyclic ring system. Valence tautomers include interconversions by rearrangement of some of the bond electrons. Tautomers can be in equilibrium or sterically fixed in one form by appropriate substitution. Compounds of the disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0160] The synthesis of the compounds provided herein, including their pharma- ceutically acceptable salts, is illustrated in the synthetic schemes of the Examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes, and therefore these schemes are merely an aid to understanding and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. Furthermore, the steps in the schemes are for better illustration and can be changed as necessary. The compound embodiments of the Examples were synthesized for research and possible submission to regulatory agencies.

[0161] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0162] Preparation of the compounds of the present disclosure may involve protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter GMWuts, Greene's Protective Groups in Organic Synthesis, 5th Ed., 1999, pp. 1171-1175 ... pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175, 2003, pp. 1171-1175 th Edition, Wiley, 2014, all of which are incorporated herein by reference in their entireties.

[0163] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic techniques such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0164] The structures of the compounds of the examples were characterized by nuclear magnetic resonance (NMR). The NMR spectra were: 1 The measurements were obtained on Bruker AVANCE III HD 400 and Bruker AVANCE NEO 300 nuclear magnetic resonance spectrometers operating at 400 MHz and 300 MHz for H, respectively. 1 H NMR spectra were recorded at 400 MHz and 300 MHz in CHCl3-d and (CH3)2SO-d6 with residual amounts of CHCl3 (7.26 ppm) and DMSO (2.50 ppm) as internal standards.

[0165] LCMS was performed on an Agilent Technology 1260-6125 (ESI).

[0166] HPLC spectra were performed on an Agilent Technology 1260 instrument equipped with a DAD detector and a 1290 instrument equipped with a DAD detector.

[0167] Known starting materials of the present disclosure can be synthesized using or according to methods known in the art or can be purchased from commercial sources. Analytical grade solvents and commercially available reagents were used without further purification unless otherwise stated.

[0168] Unless otherwise specified, reactions in this disclosure were all carried out in dry tubes under a positive pressure of nitrogen or argon or in anhydrous solvents, and reaction flasks were typically fitted with rubber septa for introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried.

[0169] For illustrative purposes, the Examples section below shows synthetic routes and key intermediates for preparing the compounds of the present disclosure. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are shown, they can be easily substituted with other starting materials and reagents to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0170] composition The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I and / or Formula Ia (e.g., including any of the formulas herein), or a pharma- ceutically acceptable salt of the compound, and a pharma- ceutically acceptable carrier and / or adjuvant.

[0171] As used herein, the term "pharmaceutical composition" refers to a composition containing a molecule or compound of the present disclosure in a form suitable for administration to a subject.

[0172] As used herein, the term "pharmaceutical acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject being treated therewith.

[0173] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0174] The pharmaceutical compositions provided herein can be in any form that allows the composition to be administered to a subject, including, but not limited to, a human, and can be formulated to be compatible with the intended route of administration.

[0175] Various routes are contemplated for the pharmaceutical compositions provided herein, and therefore, the pharmaceutical compositions provided herein may be provided in bulk or in unit dosage form depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable liquid dosage forms, and suitable powders for reconstitution with a suitable solution may be acceptable solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams, and sprays can be acceptable dosage forms.

[0176] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a dosage form for oral administration.

[0177] In an embodiment, the pharmaceutical composition of the present disclosure may be in the form of a tablet. Suitable pharma- ceutically acceptable excipients for tablets include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid, binders such as starch, lubricants such as magnesium stearate, stearic acid or talc, preservatives such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate, and antioxidants such as ascorbic acid. Tablets may be uncoated or may be coated, either to improve their disintegration and subsequent absorption of active ingredients in the gastrointestinal tract, or to improve their stability and / or appearance, in each case using conventional coating agents and procedures well known in the art.

[0178] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.

[0179] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which typically contains the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, a dispersing agent or wetting agent, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecaethyleneoxyethanol, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl p-hydroxybenzoate, an antioxidant (for example, ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (for example, sucrose, saccharin or aspartame).

[0180] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oil suspensions, which generally include the active ingredient suspended in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (e.g., liquid paraffin). Oil suspensions may also contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those mentioned above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0181] In some embodiments, the pharmaceutical composition of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or any mixture thereof. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phospholipids, such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners, flavoring agents and preservatives.

[0182] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs which may contain sweetening agents, for example, glycerol, propylene glycol, sorbitol, aspartame or sucrose, analgesics, preservatives, flavoring and / or coloring agents.

[0183] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for injectable administration.

[0184] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be prepared as a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be used as a solvent or suspending agent. For this purpose, any sterile fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, can also be used in the preparation of injectables.

[0185] In some embodiments, pharmaceutical compositions of the present disclosure may be in the form of a formulation for administration by inhalation.

[0186] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous or non-aqueous aerosol (e.g., in a fluorocarbon propellant) containing any suitable solvent and optionally other compounds, such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the requirements of the particular compound, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffer substances, salts, sugars, or sugar alcohols.

[0187] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a topical or transdermal formulation.

[0188] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may typically be obtained by formulating the active ingredients with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0189] In certain embodiments, the pharmaceutical compositions provided herein can be formulated in the form of transdermal skin patches, which are well known to those of ordinary skill in the art.

[0190] In addition to those representative dosage forms described above, pharma- ceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in “Remington’s Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), in “Remington: The Science and Practice of Pharmacy”, Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005), which are incorporated herein by reference.

[0191] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending on the subject being treated and the particular mode of administration.

[0192] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical compositions of the present disclosure can also be formulated for controlled release or sustained release.

[0193] In another embodiment, the composition of the invention further comprises a second therapeutic agent, which can be selected from any compound or therapeutic agent known or demonstrating beneficial properties when administered together with a compound having the same mechanism of action as the compound of the invention.

[0194] In another embodiment, the present invention provides one or more separate dosage forms of any of the compounds of the present invention and a second therapeutic agent, where the compound and the second therapeutic agent are associated with each other. As used herein, the term "associated with each other" means that the separate dosage forms are packaged together or otherwise connected to each other such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of each other, either consecutively or simultaneously).

[0195] In some embodiments, the second therapeutic agent can include (1) cholesterol absorption inhibitors, (2) HMG-CoA reductase inhibitors, (3) bile acid sequestrants, (4) nicotinyl alcohol, nicotinic acid or salts thereof, (5) phenolic antioxidants, (6) ACAT inhibitors, and (7) CTEP inhibitors.

[0196] In the pharmaceutical compositions of the present invention, the compounds of the present invention are present in an effective amount. As used herein, the term "effective amount" refers to an amount sufficient to treat the target disorder when administered in a proper dosing regimen.

[0197] The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50:219. Body surface area can be roughly determined from the subject's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537.

[0198] In some embodiments, the effective amount of the compound of the invention may range from about 0.5 μg per day to about 90 mg per day, from about 1 μg per day to about 50 mg per day, from 2 μg per day to about 10 mg per day, from 3 μg per day to about 1 mg per day, from 5 μg per day to about 800 μg per day, from 5 μg per day to about 600 μg per day, from 5 μg per day to about 500 μg per day, from 10 μg per day to about 500 μg per day, from 12 μg per day to about 500 μg per day, from 15 μg per day to about 500 μg per day, from 20 μg per day to about 500 μg per day, from 25 μg per day to about 500 μg per day. In some embodiments, the effective amount of the compound of the invention may range from about 25 μg per day to about 300 μg per day. In some embodiments, an effective amount of a compound of the present invention may range from about 50 μg per day to about 150 μg per day.

[0199] Effective amounts will also vary, as recognized by those skilled in the art, depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, the use of excipients, the possibility of co-administration with other therapeutic treatments, e.g., the use of other substances, and the judgment of the treating physician. For example, advice for selecting an effective amount can be determined by reference to the prescribing information for aleglitazar.

[0200] For pharmaceutical compositions that include a second therapeutic agent, the effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally used in a monotherapy regimen using only that agent. Preferably, the effective amount is between about 70% and 100% of the normal monotherapy dosage. The normal monotherapy dosages of these second therapeutic agents are well known to those skilled in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which is incorporated herein by reference in its entirety.

[0201] Some of the second therapeutic agents are expected to act synergistically with the compounds of the present invention.When this occurs, it is possible to use less effective amounts of the second therapeutic agent and / or the compounds of the present invention than is required for monotherapy.This has the advantage of minimizing the toxic side effects of either the second therapeutic agent or the compounds of the present invention, synergistically improving efficacy, improving ease of administration or use, and / or reducing the overall cost of preparing or formulating the compound.

[0202] Treatment In another aspect, the present disclosure provides a dual PPARα and PPARγ agonist for use in a method for the treatment and / or prevention of a disease modulated by a PPARα and / or PPARγ agonist, wherein the dual PPARα and PPARγ agonist is deuterated.

[0203] In another aspect, the present disclosure provides a method for the treatment and / or prevention of a disease regulated by a PPARα and / or PPARγ agonist in a subject, comprising administering a PPARα and PPARγ dual agonist to the subject, wherein the PPARα and PPARγ dual agonist is deuterated.

[0204] In another aspect, the present disclosure provides the use of a dual PPARα and PPARγ agonist in the manufacture of a medicament for the treatment and / or prevention of a disease modulated by a PPARα and / or PPARγ agonist, wherein the dual PPARα and PPARγ agonist is deuterated.

[0205] The term "subject" refers to animals, including, but not limited to, primates (e.g., humans, monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, etc.), lagomorphs, porcines (e.g., pigs, minipigs), equines, canines, felines, etc. The terms "subject" and "patient" are used interchangeably herein, e.g., with reference to a mammalian subject, e.g., a human patient.

[0206] The terms "treat", "treating" and "treatment" are intended to include ameliorating, preventing, alleviating or reversing a disorder, or alleviating, preventing or reversing one or more of the symptoms associated with a disorder, and / or preventing, alleviating or eradicating the cause of the disorder itself, i.e., preventing significant progression of clinical symptoms in a mammal susceptible to the disease but not yet feeling or showing symptoms of the disease. This may include improving a subject's ability to perform activities of daily living, perform household tasks, manage finances, and / or perform a job, or reducing the level of care required for the subject. Treating, treating or treatment may include at least 20%, 30%, 50%, 80%, 90%, or 100% improvement in symptoms. Symptoms associated with a particular disorder will depend on the particular disorder at hand.

[0207] The term "administering" means either directly administering a compound or composition of the invention, or administering a prodrug, derivative, or analog that forms an equivalent amount of the active compound or substance in the body.

[0208] The term "disease" means any condition or disorder that impairs or interferes with the normal function of a cell, tissue, or organ.

[0209] In certain embodiments, the disease is diabetes, non-insulin dependent diabetes mellitus, hypertension, dyslipidemia, atherosclerosis, metabolic syndrome, or diabetic nephropathy.

[0210] In certain embodiments, the disease is non-insulin dependent diabetes mellitus or diabetic nephropathy.

[0211] In certain embodiments, the disease is diabetic nephropathy.

[0212] As used herein, the term "diabetes" refers to a disease in which a patient's ability to control glucose levels in the blood is impaired, partially due to a loss of ability to respond appropriately to the action of insulin.

[0213] As used herein, the term "non-insulin-dependent diabetes mellitus", also referred to as type II diabetes (T2D), afflicts 80-90% of all diabetic patients in developed countries, in which the pancreatic islets of Langerhans still produce insulin. However, the target organs, primarily muscle, liver and adipose tissue, exhibit profound resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. However, in the later stages of the disease, insulin secretion declines due to pancreatic fatigue.

[0214] As used herein, the term "atherosclerosis," also known as arteriosclerotic vascular disease or ASVD, is a specific form of arteriosclerosis in which the arterial wall thickens as a result of infiltration and accumulation of white blood cells (foam cells) and proliferation of intimal smooth muscle cells resulting in atheromatous (fibrofatty) plaques.

[0215] As used herein, the term "metabolic syndrome" refers to a group of conditions that occur together to increase the risk of heart disease, stroke, and type 2 diabetes. These conditions include high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.

[0216] As used herein, the term "diabetic nephropathy" refers to kidney disease resulting from diabetes, which is the primary cause of kidney failure. Nearly one-third of people with diabetes develop diabetic nephropathy. Early diabetic nephropathy often has no symptoms. As kidney function deteriorates, symptoms may include swelling of the hands, feet, and face, sleep problems and inability to concentrate, loss of appetite, nausea, weakness, itching (end-stage renal failure) and excessive dry skin, drowsiness (end-stage renal failure), abnormalities in the normal rhythm of the heartbeat due to elevated blood potassium, and muscle spasms.

[0217] In some embodiments, the disease is kidney damage. In some embodiments, the kidney damage is caused by ureteral obstruction. In some embodiments, the kidney damage is caused by unilateral ureteral obstruction.

[0218] In one embodiment, the dual PPARα and PPARγ agonist is deuterated aleglitazar or a pharma- ceutically acceptable salt thereof.

[0219] As used herein, the term "aleglitazar", also known as RG-1439 or RO-0728804, is a dual agonist of peroxisome proliferator-activated receptor α / γ (PPARα / γ) with insulin-sensitizing and glucose-lowering effects and favorable effects on lipid profile. It is being studied for use in patients with type II diabetes to reduce their risk of cardiovascular mortality and morbidity. "Aleglitazar" has the following structure:

[0220] [ka]

[0221] As used herein, the term "PPARα / γ dual agonist" refers to a compound that exhibits both significant PPARα and PPARγ agonism. In some embodiments, a PPARα / γ dual agonist exhibits significant PPARα and / or PPARγ agonism, where the half-maximal concentration efficacy (EC ) for activation of hPPARγ is greater than or equal to 1000 mAs. 50 ) and EC for activation of hPPARα 50 differ by less than 30-fold, 25-fold, 20-fold, 15-fold, 10-fold, 5-fold, or 3-fold. In some embodiments, the PPARα / γ dual agonist exhibits significant PPARα agonism and / or PPARγ agonism, where the half-maximal concentration efficacy (EC 50 ) and EC for activation of hPPARα 50 is greater than 30-fold, 25-fold, 20-fold, 15-fold, 10-fold, 5-fold, or 3-fold difference.

[0222] In certain embodiments, the dual PPARα and PPARγ agonist is a compound provided herein or a pharma- ceutically acceptable salt thereof.

[0223] In another aspect, the disclosure provides a method of modulating the specific PPARα or PPARγ agonist activity of a dual PPARα and PPARγ agonist, comprising deuterizing the agonist.

[0224] In another aspect, the disclosure provides a method of improving the PPARα or PPARγ specific agonist activity of a dual PPARα and PPARγ agonist, comprising deuterizing the agonist.

[0225] In certain embodiments, the PPARα specific agonist activity of the agonist is improved.

[0226] In certain embodiments, the specific PPARγ agonist activity of the agonist is improved.

[0227] In certain embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of the H of the agonist are deuterated.

[0228] In certain embodiments, no more than 1, no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10 H of the agonist are deuterated.

[0229] In certain embodiments, the dual PPARα and PPARγ agonist is aleglitazar or a pharma- ceutically acceptable salt thereof.

[0230] It is understood that both the general description above and the detailed description below are merely exemplary and explanatory and are not intended to limit the claimed invention. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of the term "comprising" as well as other forms such as "comprises" and "includes" is not limiting. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical values, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0231] The following examples are provided to better illustrate the claimed invention and are not to be construed as limiting the scope of the invention. All specific compositions, materials, and methods described below are entirely or to some extent within the scope of the invention. These specific compositions, materials, and methods are not intended to limit the invention, but merely illustrate specific embodiments within the scope of the invention. Those skilled in the art can produce equivalent compositions, materials, and methods without using inventive ability and without departing from the scope of the invention. It is understood that many variations can be made in the procedures described herein and still be within the scope of the invention. It is the inventor's intention that such variations are included within the scope of the invention. EXAMPLES

[0232] [Example 1] Synthesis of Compound 1 Reaction scheme

[0233] [ka]

[0234] Process Description A 300 mL hydrogenation reactor was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (2.3 g, 5.3 mmol), (S)-phenylethylamine (230 mg, 1.9 mmol), CD3OD (24 mL), THF (16 mL) and Ru-cat (CAS: 261948-85-0, 46 mg). The reaction mixture was stirred at 70 °C under 30 bar D2 for 1 day. After opening the autoclave, the yellow solution was rotary evaporated to dryness (45 °C). The crude product was dissolved in EtOAc (200 mL) and washed with 1 N HCl (60 mL x 2). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product was dissolved in refluxing isopropyl acetate and cooled to 0 °C, whereby crystallization started. The formed crystals were collected by filtration, washed with isopropyl acetate (50 mL) and dried to give a pale yellow solid (940 mg, ca. 60% ee), which was separated by chiral HPLC (OJ-H(OJH0CD-WB010)) eluting with 0.1% HCOOH in MeOH and further purified by preparative HPLC (CHCN and water, 0.1% FA) to give compound 1 (610 mg, 26.2% yield) as a white solid.

[0235] 1 H NMR (400 MHz, CDCl3) δ: 7.97 (dd, J = 6.4, 2.4 Hz, 2H), 7.48 (d, J = 5.5 Hz, 1H), 7.43-7.41 (m, 3H), 7.32 (d, J = 5.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.35 (t, J = 6.5 Hz, 2H), 3.34 (s, 3H), 3.19 (s, 1H), 3.06 (t, J = 6.5 Hz, 2H), 2.40 (s, 3H).

[0236] LC-MS (ESI + ): m / z = 440.2 ([M+H] + ).

[0237] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.99% ee.

[0238] [Example 2] Synthesis of Compound 2

[0239] [ka]

[0240] To a suspension of LiAlD4 (1.9 g, 45.4 mmol) in THF (40 mL) was added methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (7.0 g, 30.3 mmol) in THF (60 mL) at 0° C. under N2. The reaction was stirred for 2 h at 0° C. and then quenched with water (3 mL). The resulting solid was collected by filtration. The filter cake was washed with EtOAc (500 mL), DCM / MeOH (10 / 1, 500 mL). The filtrate was concentrated under vacuum to give 2-(5-methyl-2-phenyloxazol-4-yl)ethan-1,1-d2-1-ol (5.0 g, 80.6% yield) as a yellow solid.

[0241] 1 H NMR (400 MHz, CDCl3) δ: 8.05-7.87 (m, 1H), 7.50-7.33 (m, 2H), 2.71 (s, 2H), 2.34 (s, 3H).

[0242] LC-MS (ESI + ): m / z = 206.2 ([M+H] + ).

[0243] To a solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethan-1,1-d2-1-ol (5.0 g, 24.4 mmol) in DCM (100 mL) was added Et3N (5.4 g, 53.7 mmol). The reaction mixture was cooled to 0 °C and MsCl (5.6 g, 48.8 mmol) was added under N2. The reaction was stirred at 0 °C for 2 h and then poured into water. 1N HCl (40 mL) was added and the mixture was extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: EtOAc = 20: 1 to 10: 1) to give 2-(5-methyl-2-phenyloxazol-4-yl) ethyl-1,1-d2 methanesulfonate (5.0 g, 72.5% yield) as a white solid.

[0244] 1 H NMR (400 MHz, CDCl3) δ: 7.97 (dd, J = 7.4, 2.2 Hz, 2H), 7.53-7.34 (m, 3H), 3.04-2.90 (m, 5H), 2.36 (s, 3H).

[0245] LC-MS (ESI + ): m / z = 284.0 ([M+H] + ).

[0246] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (3.2 g, 17.7 mmol) in DMF (30 mL) was added K2CO3 (2.9 g, 21.2 mmol). The reaction mixture was heated to 85° C. under N2. 2-(5-methyl-2-phenyloxazol-4-yl)ethyl-1,1-d2 methanesulfonate (5.0 g, 17.7 mmol) in DMF (15 mL) was added dropwise at this temperature. The reaction was stirred at 85° C. for 5 h, then cooled to room temperature, poured into water and extracted with EtOAc (300 mL×2). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with petroleum ether / EtOAc=5 / 1 to give 4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (5.7 g, 88.2% yield) as a brown solid.

[0247] 1 H NMR (300 MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 8.00-7.86 (m, 2H), 7.82 (d, J = 5.5 Hz, 1H), 7.62-7.38 (m, 4H), 7.23 (d, J = 8.1 Hz, 1H), 3.06 (s, 2H), 2.40 (s, 3H).

[0248] LC-MS (ESI + ): m / z = 366.0 ([M+H] + ).

[0249] To a solution of methyl 2-methoxyacetate (5.9 g, 57.2 mmol) in THF (40 mL) was added TiCl4 (10.8 g, 57.2 mmol) at 0 °C under argon. The yellow solution was stirred for 15 min at 0 °C and DIEA (7.9 g, 61.6 mmol) was added. The black solution was stirred for an additional 15 min and 4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (4.0 g, 11.0 mmol) in DCM (60 mL) was added dropwise. The reaction was stirred for 1 h at 0 °C and allowed to warm to room temperature overnight. It was then cooled to 0 °C, quenched with water and extracted with DCM (200 mL x 2). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give crude methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (7.7 g), which was used directly in the next step without further purification.

[0250] LC-MS (ESI + ): m / z = 470.2 ([M+H] + ).

[0251] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (7.7 g, crude) in DMF (40 mL) was added concentrated H2SO4 (10 mL) dropwise at ambient temperature. The reaction was stirred overnight at 100°C, then diluted with EtOH (40 mL) and stirred for 1 h at 0°C. The solid was filtered and washed with EtOH (10 mL) and water (50 mL). The wet cake was dried to give methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (2.3 g, 46.4% yield for two steps) as a yellow solid.

[0252] 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 7.6, 1.8 Hz, 2H), 7.53-7.37 (m, 4H), 7.34 (d, J = 5.5 Hz, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.08 (s, 2H), 2.40 (s, 3H).

[0253] LC-MS (ESI + ): m / z = 452.2 ([M+H] + ).

[0254] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (2.3 g, 5.1 mmol) in MeOH (50 mL) was added KOH (1.7 g, 30.6 mmol) in HO (5 mL) at room temperature. The reaction was stirred for 2 h at 80 °C. The reaction mixture was cooled to room temperature, diluted with HO (50 mL) and adjusted to pH = 3 with 6N HCl. The mixture was cooled to 0 °C and the solid was filtered. The filter cake was suspended in EtOH (40 mL) at 80 °C for 1 h, cooled to 0 °C and stirred for 1 h. The solid was filtered and dried to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (1.5 g, 68.2% yield) as a brown solid.

[0255] 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 7.6, 1.9 Hz, 2H), 7.49 (d, J = 5.5 Hz, 1H), 7.48-7.39 (m, 3H), 7.35 (t, J = 2.7 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 3.10 (s, 2H), 2.41 (s, 3H).

[0256] LC-MS (ESI + ): m / z = 438.2 ([M+H] + ).

[0257] A 300 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (1.5 g, 3.4 mmol), (S)-phenylethylamine (82 mg, 0.68 mmol), MeOH (18 mL), THF (12 mL) and Ir-cat([(S)-DTBSIPHOX)Ir(COD)]BArF, 9.3 mg, 0.001 equiv). The autoclave was sealed and hydrogenation was carried out for 16 h at 70° C. under 30 bar of hydrogen. LCMS showed approximately half of the starting material remained, Ir-cat (10.3 mg) was added and the reaction was stirred for an additional day. After opening the autoclave, the yellow solution was rotary evaporated to dryness (45° C.). The crude product was dissolved in EtOAc (150 mL) and washed with 1N HCl (40 mL×2). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product was dissolved in refluxing isopropyl acetate and cooled to 0° C., whereby crystallization was initiated. The formed crystals were collected by filtration, washed with isopropyl acetate (50 mL) and dried to give a pale yellow solid (920 mg), which was further purified by preparative HPLC (CH3CN and water, 0.1% FA) to give compound 2 (518 mg, 34.5% yield) as a white solid.

[0258] 1H NMR (400 MHz, CDCl3) δ: 7.99 (dd, J = 6.4, 2.4 Hz, 2H), 7.48 (d, J = 5.6 Hz, 1H), 7.43 - 7.41 (m, 3H), 7.32 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.20 (dd, J = 7.9, 4.7 Hz, 1H), 3.39-3.28 (m, 4H), 3.23-3.18 (m, 1H), 3.05 (s, 2H), 2.40 (s, 3H).

[0259] LC-MS (ESI + ): m / z = 440.2 ([M+H] + ).

[0260] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% ヘキサン / 9.99%EtOH / 0.01%TFA, 210nm): 99.57%ee.

[0261] [Example 3] Synthesis of Compound 3

[0262]

change

[0263] Description of プロセス To a solution of 2-(2-phenyloxazol-4-yl)ethan-1-ol (22.7 g, 120.0 mmol, 1.0 equiv) in DMF (230 mL) was added imidazole (24.5 g, 360.0 mmol, 3.0 equiv) and t-butyldimethylsilyl chloride (27.1 g, 180.0 mmol, 1.5 equiv) in small portions. The mixture was stirred for 1 h at room temperature. After completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (100 mL x 2) and brine (100 mL x 2). The organic phase was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc = 30:1) to give 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-phenyloxazole (30.0 g, 82.3% yield) as a colorless oil.

[0264] 1 HNMR (400 MHz, CDCl3) δ: 8.03-8.01 (m, 2H), 7.50 (s, 1H), 7.47-7.42 (m, 3H), 3.92 (t, J = 6.8 Hz, 2H), 2.83-2.80 (m, 2H), 0.88 (s, 9H), 0.03 (s, 6H).

[0265] LC-MS (ESI + ):304.1 ([M+H] + ).

[0266] A solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-phenyloxazole (30.0 g, 99.0 mmol, 1.0 equiv) in THF (300 mL) under argon was cooled to -78 °C, then t-BuLi (1 M, 114 mL, 148.0 mmol, 1.5 equiv) was added dropwise. The mixture was warmed to -40 °C and stirred for 1 h. The mixture was cooled again to -78 °C, after which CD3I (28.7 g, 198.0 mmol, 2.0 equiv) was added dropwise. The reaction mixture was stirred for 1 h at this temperature, then warmed to -40 °C and stirred for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (300 mL x 2). The organic phase was dried over Na2SO4, filtered and concentrated to give a crude residue, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=50:1) to give 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(methyl-d3)-2-phenyloxazole (11.0 g, 35.6% yield) as a yellow oil.

[0267] 1 HNMR (400 MHz, CDCl3) δ: 7.98 (dd, J = 7.6, 1.6 Hz, 2H), 7.44-7.39 (m, 3H), 3.89 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H), 0.87 (s, 9H), 0.00 (s, 6H).

[0268] LC-MS (ESI + ): 321.2 ([M+H] + ).

[0269] To a solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(methyl-d3)-2-phenyloxazole (10.0 g, 31.1 mmol, 1.0 equiv.) in THF (100 mL) under argon was added TBAF (1 M in THF, 62.2 mL, 62.2 mmol, 2.0 equiv.) dropwise at 0° C., and the resulting mixture was then stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NH4Cl (100 mL×2) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=2:1) ​​to give 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethan-1-ol (5.7 g, 88.7% yield) as a colorless oil.

[0270] 1 HNMR (400 MHz, CDCl3) δ: 8.00-7.97 (m, 2H), 7.46-7.41 (m, 3H), 3.93 (t, J = 6.0 Hz, 2H), 2.90 (brs, 1H), 2.73 (t, J = 6.0 Hz, 2H).

[0271] LC-MS (ESI + ): 207.1 ([M+H] + ).

[0272] To a solution of 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethan-1-ol (3.5 g, 16.9 mmol, 1.0 equiv) in dichloromethane (32.5 mL) was added triethylamine (3.8 g, 37.2 mmol, 2.2 equiv) at room temperature. The mixture was cooled to 0° C. and methanesulfonyl chloride (3.9 g, 33.8 mmol, 2.0 equiv) was added dropwise over 10 min. The reaction was stirred for 2 h at 5° C. The reaction mixture was quenched with 1N HCl (10 mL) and extracted with dichloromethane (20 mL×2). The combined organic layers were washed with aqueous NaHCO3 (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to give 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethyl methanesulfonate (4.5 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0273] 1 HNMR (400 MHz, CDCl3) δ: 7.99 (dd, J = 7.6, 2.7 Hz, 2H), 7.46-7.44 (m, 3H), 4.54 (t, J = 6.8 Hz, 2H), 2.99-2.96 (m, 5H).

[0274] LC-MS (ESI + ): 285.2 ([M+H] + ).

[0275] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (2.8 g, 15.7 mmol, 1.0 equiv.) in N,N-dimethylformamide (35 mL) under argon was added K2CO3 (2.6 g, 18.8 mmol, 1.2 equiv.) at room temperature. The reaction mixture was heated to 85° C., and then a solution of 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethyl methanesulfonate (4.5 g, 15.7 mmol, 1.0 equiv.) in DMF (20 mL) was added. The reaction mixture was stirred for 5 h. The reaction mixture was then poured into water (150 mL) and extracted with EtOAc (150 mL×2). The organic layer was washed with water (100 mL×2), brine (100 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was washed with EtOAc to give 4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (4.1 g, 71.1% yield) as a white solid. The crude product was used directly in the next step without further purification.

[0276] 1 HNMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 8.00-7.97 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.56 (s, 2H), 7.46-7.40 (m, 3H), 6.95 (d, J = 8.0 Hz, 1H), 4.53 (t, J = 6.4 Hz, 2H), 3.13 (t, J = 6.4 Hz, 2H).

[0277] LC-MS (ESI + ): 367.0 ([M+H] + ).

[0278] To a solution of methyl 2-methoxyacetate (5.9 g, 57.0 mmol, 5.2 equiv) in THF (65 mL) under argon was added TiCl4 (10.7 g, 57.0 mmol, 5.2 equiv) dropwise at 0 °C. The yellow solution was stirred for 15 min, then DIEA (7.86 g, 61 mmol, 5.6 equiv) was added. The solution was stirred for 15 min, and a solution of 4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (4.1 g, 11 mmol, 1.0 equiv) in dichloromethane (65 mL) was added dropwise. After stirring for 60 min, the reaction mixture was allowed to warm to 20 °C and stirred overnight. The reaction mixture was cooled to 0 °C and quenched with cold water (150 mL). The organic layer was separated and the aqueous layer was extracted with DCM (50 mL×2). The combined organic layers were washed with water (50 mL×2), dried over Na2SO4, filtered and evaporated to dryness to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (crude, 6.2 g) as an orange oil, which was used directly in the next step without further purification.

[0279] LC-MS (ESI + ): 471.2 ([M+H] + ).

[0280] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (crude, 6.2 g) in DMF (100 mL) was added concentrated H2SO4 (25 mL). The resulting dark brown solution was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, poured into cold water (100 mL) and extracted with EtOAc (100 ml x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL x 2). The organic layer was concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (1.5 g, 30.1% yield for two steps) as an oil.

[0281] 1 HNMR (400 MHz, DMSO-d6) δ: 8.03 (d, J = 8.4 Hz, 1H), 7.92-7.89 (m, 2H), 7.70 (d, J = 5.6 Hz, 1H), 7.52-7.46 (m, 3H), 7.43 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 4.43 (t, J = 6.4 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.04 (t, J = 6.4Hz, 2H).

[0282] LC-MS (ESI + ): 453.2 ([M+H] + ).

[0283] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (1.5 g, 3.4 mmol, 1.0 equiv.) in MeOH (30 mL) was added a solution of KOH (1.14 g, 20.2 mmol, 6.0 equiv.) in water (3 mL). The suspension was stirred at 60 °C for 1.5 h. The formed yellow reaction solution was cooled to room temperature, adjusted to pH 3-4 with 1 N HCl, and extracted with EtOAc (30 mL x 2). The organic phase was dried over Na2SO4, filtered and concentrated to give the crude product, which was triturated with EtOAc and filtered to give (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (1.1 g, 73.8% yield) as a white solid.

[0284] 1 HNMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 8.00-7.98 (m, 2H), 7.47 (d, J = 5.6 Hz, 1H), 7.46-7.41 (m, 3H), 7.36-7.34 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.47 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H).

[0285] LC-MS (ESI + ): 439.0 ([M+H] + ).

[0286] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (300.0 mg, 0.68 mmol, 1.0 equiv), (S)-phenylethylamine (16.6 mg, 0.14 mmol, 0.2 equiv), MeOH (3.6 mL), THF (2.4 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 2.4 mg, 0.002 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (20 mL) and washed with 1 N HCl (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give compound 3 (200 mg, 66.1% yield) as a white solid.

[0287] 1 HNMR (400 MHz, CDCl3) δ: 7.97 (dd, J = 8.0, 2.8 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 7.44-7.40 (m, 3H), 7.31 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.34 (t, J = 6.4 Hz, 2H), 4.21-4.18 (m, 1H), 3.36-3.32 (m, 4H), 3.24-3.18 (m, 1H), 3.06 (t, J = 6.4 Hz, 2H).

[0288] LC-MS (ESI + ): 441.1 ([M+H] + ).

[0289] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.0% ee.

[0290] [Example 4] Synthesis of Compound 4

[0291] [ka]

[0292] Process Description To a solution of benzamide-2,3,4,5,6-d5 (9.6 g, 76.2 mmol, 1.0 equiv) in toluene (150 mL) was added methyl 4-bromo-3-oxopentanoate (23.9 g, 114.3 mmol, 1.5 equiv). After stirring for 10 h at 110° C., another batch of methyl 4-bromo-3-oxopentanoate (23.9 g, 114.3 mmol, 1.5 equiv) was added and the mixture was continued to stir for another 20 h at 110° C. The reaction mixture was then concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=15:1) to give methyl 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)acetate (9.8 g, 54.4% yield) as a yellow oil.

[0293] 1 HNMR (400 MHz, CDCl3) δ: 3.73 (s, 3H), 3.57 (s, 2H), 2.36 (s, 3H).

[0294] LC-MS (ESI + ): 237.2 ([M+H] + ).

[0295] To an ice-cooled solution of lithium aluminum hydride (2.4 g, 62.2 mmol, 1.5 equiv) in Et2O (100 mL) was added dropwise a solution of methyl 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)acetate (9.8 g, 41.5 mmol, 1.0 equiv) in Et2O (100 mL). The reaction mixture was then warmed to room temperature and stirred for 15 min. The reaction mixture was quenched with water (2.4 mL) and aqueous NaOH (15%, 2.4 mL) at 0 °C. Water (7.2 mL) was then added to the reaction mixture and stirred at room temperature for 15 min. Na2SO4 (12 g) was added to the mixture. The mixture was filtered and concentrated to give 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethan-1-ol (7.0 g, 81.0% yield) as a white solid.

[0296] 1 HNMR (400 MHz, CDCl3) δ: 3.93 (t, J = 5.6 Hz, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.34 (s, 3H).

[0297] LC-MS (ESI + ): 209.0 ([M+H] + ).

[0298] To a solution of 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethan-1-ol (4.4 g, 21.3 mmol, 1.0 equiv) in dichloromethane (45 mL) was added triethylamine (4.3 g, 42.6 mmol, 2.0 equiv) at room temperature. The mixture was cooled to 0° C. and methanesulfonyl chloride (3.7 g, 32.0 mmol, 1.5 equiv) was added dropwise over 10 min. The reaction was maintained at 5° C. for 2 h, then quenched with 1N HCl (10 mL) and extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL x 2), brine (20 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to give 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethyl methanesulfonate (6.1 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0299] 1 HNMR (400 MHz, CDCl3) δ: 4.52 (t, J = 6.6 Hz, 2H), 2.94 (t, J = 6.6Hz, 5H), 2.36 (s, 3H).

[0300] LC-MS (ESI + ): 287.2 ([M+H] + ).

[0301] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (3.8 g, 21.3 mmol, 1.0 equiv.) in N,N-dimethylformamide (40 mL) under argon was added K2CO3 (3.5 g, 25.6 mmol, 1.2 equiv.) at room temperature. The reaction mixture was heated to 86° C., and then a solution of 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethyl methanesulfonate (6.1 g, 21.3 mmol, 1.0 equiv.) in DMF (20 mL) was added. The reaction mixture was stirred at 86° C. for 3 h, then cooled, poured into water (150 mL), extracted with EtOAc (150 mL×2), washed with water (100 mL×2) and brine (100 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was washed with EtOAc to give 4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (5.3 g, 67.9% yield) as a yellow solid. The crude product was used directly in the next step without further purification.

[0302] 1 HNMR (400 MHz, CDCl3) δ: 10.05 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 (s, 2H), 6.94 (d, J = 8.0 Hz, 1H), 4.53 (t, J = 6.0 Hz, 2H), 3.12 (t, J = 6.6 Hz, 2H), 2.42 (s, 3H).

[0303] LC-MS (ESI + ): 368.9 ([M+H] + ).

[0304] To a solution of methyl 2-methoxyacetate (7.8 g, 74.9 mmol, 5.2 equiv) in tetrahydrofuran (100 mL) under argon was added TiCl4 (14.2 g, 74.9 mmol, 5.2 equiv) dropwise at 0 °C. The yellow solution was stirred for 15 min and diisopropylethylamine (10.4 g, 80.6 mmol, 5.6 equiv) was added. The solution was stirred for 15 min and a solution of 4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (5.3 g, 14.4 mmol, 1.0 equiv) in DCM (100 mL) was added dropwise. After stirring for 60 min, the reaction mixture was allowed to warm to 20 °C and stirred overnight. The reaction mixture was cooled to 0 °C and quenched with cold water (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with water (50 mL×2), dried over Na2SO4, filtered and evaporated to dryness to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (7.0 g, crude) as a red oil, which was used directly in the next step without further purification.

[0305] LC-MS (ESI + ): 472.9([M+H] + ).

[0306] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (crude, 6.5 g) in dimethylformamide (120 mL) was added concentrated H2SO4 (30 mL). The resulting dark brown solution was stirred at 100° C. overnight. The reaction solution was cooled to room temperature and poured into cold water (100 mL). The reaction was extracted with EtOAc (100 ml×2) and the combined organic layers were washed with water (100 mL×2) and brine (100 mL×2). The organic layer was concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (1.9 g, 30.6% yield for two steps) as an oil.

[0307] 1 HNMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.21 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.47 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H).

[0308] LC-MS (ESI + ): 455.1([M+H] + ).

[0309] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (1.75 g, 3.9 mmol, 1.0 equiv.) in methanol (42 mL) and tetrahydrofuran (14 mL) was added a solution of KOH (1.3 g, 23.4 mmol, 6.0 equiv.) in water (4.2 mL). The reaction mixture was stirred for 2 h at 65° C. Then the reaction mixture was diluted with water (50 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with dichloromethane / methanol=10:1 (150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (1.1 g, 72.8% yield) as a white solid.

[0310] 1 HNMR (400 MHz, CDCl3) δ: 8.11 (d, J = 8.4 Hz, 1H), 7.49 (d, J =5.2 Hz, 1H), 7.38-7.34 (m, 2H), 6.88 (d, J =8.4 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 3.79 (s, 3H), 3.12 (t, J =6.6 Hz, 2H), 2.42 (s, 3H).

[0311] LC-MS (ESI + ): 440.9 ([M+H] + ).

[0312] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (350.0 mg, 0.79 mmol, 1.0 equiv), (S)-phenylethylamine (19.3 mg, 0.16 mmol, 0.2 equiv), methanol (3.6 mL), tetrahydrofuran (2.4 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 2.8 mg, 0.002 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (20 mL) and washed with 1 N HCl (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give compound 4 (205 mg, 58.6% yield) as a white solid.

[0313] 1 HNMR (400 MHz, CDCl3) δ: 7.48 (d, J = 5.6 Hz, 1H), 7.32 (d, J =5.6 Hz, 1H), 7.15 (d, J =8.0 Hz, 1H), 3.34 (t, J = 6.4 Hz, 2H), 4.19 (dd, J = 7.6, 4.8 Hz, 1H), 3.36-3.32 (m, 4H), 3.24-3.18 (m, 1H), 3.06 (t, J = 6.4 Hz, 2H), 2.40 (s, 3H).

[0314] LC-MS (ESI + ): 443.1 ([M+H] + ).

[0315] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.3% ee.

[0316] [Example 5] Synthesis of Compound 5

[0317] [ka]

[0318] Process Description To an ice-cooled solution of LiAlD4 (1.0 g, 24.1 mmol, 1.5 equiv) in diethyl ether (25 mL) was added dropwise a solution of methyl 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)acetate (3.8 g, 16.1 mmol, 1.0 equiv) in diethyl ether (15 mL) and stirred at room temperature for 15 min. The reaction mixture was quenched with water (1.0 mL) and aqueous NaOH (15%, 1.0 mL) at 0 °C. Water (3.0 mL) was then added. The mixture was stirred at room temperature for 15 min. Na2SO4 was added and the mixture was filtered and concentrated to give 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethan-1,1-d2-1-ol (2.6 g, 78.2% yield) as a white solid.

[0319] 1 HNMR (400 MHz, CDCl3) δ: 2.71 (s, 2H), 2.33 (s, 3H).

[0320] LC-MS (ESI + ): 211.0 ([M+H] + ).

[0321] To a solution of 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethan-1,1-d2-1-ol (2.5 g, 11.9 mmol, 1.0 equiv) in DCM (45 mL) was added TEA (2.4 g, 23.8 mmol, 2.0 equiv) and MsCl (2.0 g, 17.9 mmol, 1.5 equiv) dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature, then quenched with water (20 mL) and extracted with DCM (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethyl-1,1-d2 methanesulfonate (3.3 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0322] LC-MS (ESI + ):288.9 ([M+H] + ).

[0323] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (1.7 g, 9.5 mmol, 0.9 equiv.) in DMF (30 mL) under argon was added K2CO3 (1.7 g, 12.4 mmol, 1.2 equiv.) at room temperature. The reaction mixture was heated to 86° C., and then a solution of 2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethyl-1,1-d2 methanesulfonate (3.0 g, 10.6 mmol, 1.0 equiv.) in DMF (20 mL) was added. The reaction mixture was stirred for 4 h at 86° C., and then poured into water (150 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were washed with water (100 mL×2) and brine (100 mL×2). The organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated with EtOAc to give 4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (2.2 g, 56.0% yield) as a yellow solid, which was used directly in the next step without further purification.

[0324] 1 HNMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.53 (s, 1H), 6.94 (d, J = 8.0Hz, 1H), 3.11(s, 2H), 2.42 (s, 3H).

[0325] LC-MS (ESI + ): 370.9 ([M+H] + ).

[0326] To a solution of methyl 2-methoxyacetate (3.2 g, 30.9 mmol, 5.2 equiv) in THF (22 mL) was added TiCl4 (5.9 g, 30.9 mmol, 5.2 equiv) dropwise at 0° C., followed by the addition of DIEA (4.3 g, 33.0 mmol, 5.6 equiv). After 15 min, a solution of 4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (2.0 g, 5.9 mmol, 1.0 equiv) in DCM (22 mL) was added. The reaction mixture was stirred for 4 h at 0° C., then quenched with water (40 mL) at 0° C. and extracted with DCM (40 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.7 g, 60.7% yield) as a yellow oil.

[0327] LC-MS (ESI + ): 474.8([M+H] + ).

[0328] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.3 g, 2.7 mmol, 1.0 equiv) in DMF (15 mL) was added concentrated H2SO4 (274 mg, 2.7 mmol, 1.0 equiv) dropwise at room temperature. The reaction mixture was stirred for 5 h at 100 °C, then quenched with cold water (45 mL) and extracted with DCM (60 mL x 2). The organic layer was dried (Na2SO4), filtered and concentrated to give the crude product which was triturated with EtOAc to give methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (680 mg, 47.2% yield) as a yellow solid.

[0329] 1 HNMR (400 MHz, CDCl3) δ: 8.11 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.08 (s, 2H), 2.41 (s, 3H).

[0330] LC-MS (ESI+): 457.0([M+H] + ).

[0331] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (680 mg, 1.5 mmol, 1.0 equiv) in MeOH / THF=3:1 (20 mL) was added a solution of KOH (501 mg, 8.9 mmol, 6.0 equiv) in water (1.2 mL). The reaction mixture was stirred for 1 h at 65° C., then diluted with water (20 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with DCM / MeOH=10:1 (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (600 mg, 91.0% yield) as a yellow solid.

[0332] 1 HNMR (400 MHz, CDCl3) δ: 8.11 (d, J = 8.4 Hz, 1H), 7.49 (d, J =5.2 Hz, 1H), 7.35 (d, J = 6.0 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 3.10 (s, 2H), 2.42 (s, 3H).

[0333] LC-MS (ESI+): 442.7([M+H] + ).

[0334] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (300.0 mg, 0.7 mmol, 1.0 equiv), (S)-phenylethylamine (16.5 mg, 0.14 mmol, 0.2 equiv), MeOH (3.6 mL), THF (2.4 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 4.8 mg, 0.004 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (20 mL) and washed with 1 N HCl (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in refluxing isopropyl acetate and filtered. The filtrate was cooled to room temperature, which initiated crystallization. The formed crystals were filtered and dried to give compound 5 (150 mg, 48.2% yield) as a white solid.

[0335] 1 HNMR (400 MHz, CDCl3) δ: 7.46 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.21-4.17 (m, 1H), 3.36-3.31 (m, 4H), 3.23-3.18 (m, 1H), 3.07 (s, 2H), 2.41 (s, 3H).

[0336] LC-MS (ESI+): 445.1 ([M+H] + ).

[0337] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.46% ee.

[0338] [Example 6] Synthesis of Compound 6

[0339] [ka]

[0340] Process Description To a solution of NaH (60%, 28.8 g, 717.6 mmol, 1.3 equiv) in THF (1.0 L) was added methyl 3-oxobutanoate (64.2 g, 552.0 mmol, 1.0 equiv) under argon at 0° C. and stirred for 10 min. Then n-BuLi (2.4 M, 300 mL, 717.6 mmol, 1.3 equiv) was added dropwise at −20° C. and stirred for 5 min. CD3I (100.0 g, 690.0 mmol, 1.25 equiv) was added dropwise. The reaction mixture was stirred for 4 h at room temperature and then quenched with saturated NH4Cl (500 mL) and extracted with EtOAc (1000 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give methyl 3-oxopentanoate-5,5,5-d3 (80.0 g, crude) as a yellow oil.

[0341] 1 HNMR (400 MHz, CDCl3) δ: 3.72 (s, 3H), 3.45 (s, 2H), 2.54 (s, 2H).

[0342] To a solution of methyl 3-oxopentanoate-5,5,5-d3 (73.5 g, 552.0 mmol, 1.0 equiv) in CHCl3 (500.0 mL) was added a solution of Br2 (101.1 g, 635.0 mmol, 1.15 equiv) in CHCl3 (200 mL) dropwise over 30 min at 0 °C. The reaction mixture was stirred at room temperature for 2 h, then quenched with saturated aqueous NaHCO3 (300 mL) and extracted with DCM (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc = 100:1) to give 4-bromo-3-oxopentanoate-5,5,5-d3 (57.0 g, 48.7% yield) as a yellow oil.

[0343] 1 HNMR (400 MHz, CDCl3) δ: 4.60 (s, 1H), 3.88-3.65 (m, 5H).

[0344] To a solution of benzamide (4.0 g, 32.7 mmol, 1.0 equiv) in toluene (75 mL) was added methyl 4-bromo-3-oxopentanoate-5,5,5-d3 (10.4 g, 49.0 mmol, 1.5 equiv) at room temperature. The mixture was kept stirring at 110° C. for 12 h and then concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=20:1) to give methyl 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)acetate (3.6 g, 30.1% yield) as a yellow oil.

[0345] 1 HNMR (400 MHz, CDCl3) δ: 7.99-7.97 (m, 2H), 7.44-7.40 (m, 3H), 3.73 (s, 3H), 3.58 (s, 2H)

[0346] LC-MS (ESI+): 235.0 ([M+H] + )

[0347] To a solution of methyl 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)acetate (3.6 g, 15.4 mmol, 1.0 equiv) in Et2O (36 mL) was added LiAlD4 (968 mg, 23 mol, 1.5 equiv) in portions at 0° C. The mixture was stirred for 2 h at 5° C. and then diluted with Et2O (50 mL). The mixture was quenched with water (1 mL) and NaOH (0.15 g) in water (1 mL) at 0° C. Then water (3 mL) was added and stirred for 15 min at room temperature. After adding Na2SO4, the mixture was filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethan-1,1-d2-1-ol (2.2 g, 68.6% yield) as a yellow oil.

[0348] 1 HNMR (400 MHz, CDCl3) δ: 7.99-7.97 (m, 2H), 7.46-7.41 (m, 3H), 2.72 (s, 2H).

[0349] LC-MS (ESI+): 209.0 ([M+H] + ).

[0350] To a solution of 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethan-1,1-d2-1-ol (2.2 g, 10.6 mmol, 1.0 equiv) in DCM (35 mL) was added TEA (2.1 g, 21.1 mmol, 2.0 equiv). The mixture was cooled to 0° C. and methanesulfonyl chloride (1.82 g, 15.8 mmol, 1.5 equiv) was added dropwise. The reaction was stirred for 1 h at 5° C. The resulting reaction was adjusted to pH=7 with 1N HCl and extracted with DCM (50 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to give 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethyl-1,1-d2 methanesulfonate (3.0 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0351] 1 HNMR (400 MHz, CDCl3) δ: 7.98-7.95 (m, 2H), 7.46-7.41 (m, 3H), 3.13 (s, 3H), 2.94 (d, J = 6.4 Hz, 2H).

[0352] LC-MS (ESI+): 287.0 ([M+H] + ).

[0353] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (1.7 g, 9.6 mmol, 0.9 equiv.) in DMF (20 mL) was added K2CO3 (1.76 g, 12.7 mmol, 1.2 equiv.). The reaction mixture was heated to 86° C. under argon atmosphere and a solution of 2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethyl-1,1-d2 methanesulfonate (3.0 g, crude, 10.6 mmol, 1.0 equiv.) in DMF (10 mL) was added. The reaction mixture was stirred at 86° C. for 4 h, then poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL×2) and brine (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was triturated with EtOAc and filtered to give 4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (2.4 g, 61.4% yield for two steps) as a yellow solid.

[0354] 1 HNMR (400 MHz, CDCl3) δ: 10.06 (d, J = 2.4 Hz, 1H), 7.99-7.97 (m, 2H), 7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.53 (d, J = 2.4, 2H), 7.43-7.39 (m, 3H), 6.94 (dd, J = 8.0, 2.4 Hz, 1H) ), 3.11 (s, 2H).

[0355] LC-MS (ESI+): 369.2 ([M+H] + ).

[0356] To a solution of methyl 2-methoxyacetate (3.5 g, 33.9 mmol, 5.2 equiv) in THF (24 mL) was added dropwise at 0° C. under argon TiCl4 (6.4 g, 33.9 mmol, 5.2 equiv). After stirring the yellow solution for 15 min, DIEA (4.7 g, 36.5 mmol, 5.6 equiv) was added. The solution was stirred for 15 min. A solution of 4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (2.4 g, 6.5 mmol, 1.0 equiv) in DCM (24 mL) was added dropwise. The reaction mixture was allowed to warm to 20° C. and stirred overnight. The reaction mixture was cooled to 0° C. and quenched with cold water (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (50 mL x 2). The combined organic layers were washed with water (50 mL x 3), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified on a silica gel column (eluted with petroleum ether / EtOAc = 3:1) to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.9 g, 61.9% yield) as a yellow solid.

[0357] LC-MS (ESI+): 473.2 ([M+H] + ).

[0358] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.7 g, 3.6 mmol, 1.0 equiv) in DMF (20 mL) was added concentrated H2SO4 (540 mg, 7.2 mmol, 2.0 equiv) dropwise at room temperature. The reaction mixture was stirred for 16 h at 100 °C, then quenched with cold water (100 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was triturated with EtOAc and filtered to give methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (1.0 g, 61.1% yield) as an off-white solid.

[0359] 1 HNMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 8.00-7.98 (m, 2H), 7.48 (d, J = 5.6 Hz, 1H), 7.44-7.42 (m, 3H), 7.34 (d, J = 5.2 Hz, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.08 (s, 2H).

[0360] LC-MS (ESI+): 455.2 ([M+H] + ).

[0361] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (1.0 g, 2.4 mmol, 1.0 equiv) in MeOH / THF (3:1, 32 mL) was added a solution of KOH (792 mg, 14.1 mmol, 6.0 equiv) in water (2 mL). The reaction mixture was stirred for 1.5 h at 65° C., then diluted with water (50 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with DCM / MeOH (10:1, 50 mL×2). The organic layer was dried over Na2SO4, filtered, and concentrated to give (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (770 mg, 72.8% yield) as an off-white solid.

[0362] 1 HNMR (400 MHz, DMSO-d6) δ: 8.12 (d, J = 8.4 Hz, 1H), 8.01-7.98 (m, 2H), 7.49 (d, J = 5.6 Hz, 1H), 7.46-7.41 (m, 3H), 7.36-7.34 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 3.10 (s, 2H).

[0363] LC-MS (ESI+): 441.2 ([M+H] + ).

[0364] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (300.0 mg, 0.7 mmol, 1.0 equiv), (S)-phenylethylamine (16.5 mg, 0.14 mmol, 0.2 equiv), MeOH (3.6 mL), THF (2.4 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 4.8 mg, 0.004 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (20 mL) and washed with 1 N HCl (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in refluxing isopropyl acetate and filtered. The filtrate was cooled to room temperature, which initiated crystallization. The formed crystals were filtered and dried to give compound 6 (134 mg, 44.5% yield) as a white solid.

[0365] 1 HNMR (400 MHz, CDCl3) δ: 7.97 (dd, J = 8.0, 2.8 Hz, 1H), 7.48-7.40 (m, 4H), 7.31 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.21-4.18 (m, 1H), 3.33-3.31 (m, 4H), 3.24-3.18 (m, 1H), 3.05 (s, 2H).

[0366] LC-MS (ESI+): 443.2 ([M+H] + ).

[0367] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.51% ee.

[0368] [Example 7] Synthesis of Compound 7

[0369] [ka]

[0370] Process Description To a solution of ((4-bromo-3-oxopentanoyl-5,5,5-d3)oxy)methylium (9.0 g, 70.8 mmol, 1.0 equiv.) in toluene (90.0 mL) was added benzamide-2,3,4,5,6-d5 (44.8 g, 212.3 mmol, 3.0 equiv.) in two batches over 10 h. The mixture was kept stirring at 110° C. for 20 h. The reaction mixture was then concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=15:1) to give methyl 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)acetate (7.3 g, 43.2% yield) as a yellow oil.

[0371] 1 HNMR (400 MHz, CDCl3) δ: 3.72 (s, 3H), 3.58 (s, 2H).

[0372] LC-MS (ESI+): 240.2 ([M+H] + ).

[0373] To an ice-cooled solution of LAH (832.8 mg, 21.9 mmol, 1.5 equiv) in diethyl ether (25 mL) was added dropwise a solution of methyl 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)acetate (3.5 g, 14.6 mmol, 1.0 equiv) in diethyl ether (25 mL) and stirred at room temperature for 15 min. The reaction mixture was quenched with water (1.0 mL) and aqueous NaOH (15%, 1.0 mL) at 0 °C. Water (3.0 mL) was added and stirred at room temperature for 15 min. After addition of Na2SO4, the mixture was filtered and concentrated to give 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethan-1-ol (2.8 g, 87.7% yield) as a white solid.

[0374] 1 HNMR (400 MHz, CDCl3) δ: 3.91 (t, J = 6.0 Hz, 2H), 2.71 (t, J = 6.0 Hz, 2H), 3.35 (brs, 1H).

[0375] LC-MS (ESI+): 212.1 ([M+H] + ).

[0376] To a solution of 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethan-1-ol (2.8 g, 13.4 mmol, 1.0 equiv) in DCM (45 mL) was added TEA (2.7 g, 26.7 mmol, 2.0 equiv) and methanesulfonyl chloride (2.3 g, 20.0 mmol, 1.5 equiv) dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature, then quenched with water (20 mL) and extracted with DCM (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethyl methanesulfonate (3.8 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0377] LC-MS (ESI+): 290.1 ​​([M+H] + ).

[0378] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (2.1 g, 13.1 mmol, 0.9 equiv.) in DMF (30 mL) under argon was added K2CO3 (2.17 g, 15.7 mmol, 1.2 equiv.) at room temperature. The reaction mixture was heated to 85° C., and then a solution of 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethyl methanesulfonate (3.8 g, 13.1 mmol, 1.0 equiv.) in DMF (20 mL) was added. The reaction mixture was stirred at 85° C. for 4 h, and then poured into water (150 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were washed with water (100 mL×2) and brine (100 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was triturated with EtOAc to give 4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (2.7 g, 55.5% yield) as an off-white solid.

[0379] 1 HNMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.53 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 6.4 Hz, 2H).

[0380] LC-MS (ESI+): 372.1 ([M+H] + ).

[0381] To a solution of methyl 2-methoxyacetate (3.9 g, 37.8 mmol, 5.2 equiv) in THF (30 mL) was added TiCl4 (7.2 g, 37.8 mmol, 5.2 equiv) and DIEA (5.3 g, 40.7 mmol, 5.6 equiv) dropwise at 0 °C. After 15 min, a solution of 4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (2.7 g, 7.3 mmol, 1.0 equiv) in DCM (30 mL) was added. The reaction mixture was stirred for 4 h at 0 °C, then quenched with water (40 mL) at 0 °C and extracted with DCM (40 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (1.7 g, 49.2% yield) as a yellow oil.

[0382] LC-MS (ESI+): 476.1 ([M+H] + ).

[0383] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (1.7 g, 3.6 mmol, 1.0 equiv) in DMF (15 mL) was added concentrated H2SO4 (536 mg, 5.4 mmol, 1.5 equiv) dropwise at room temperature. The reaction mixture was stirred for 5 h at 100 °C, then quenched with cold water (45 mL) and extracted with DCM (60 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude residue which was triturated with EtOAc to give methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (840 mg, 51.4% yield) as a yellow solid.

[0384] 1 HNMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.21 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.46 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H).

[0385] LC-MS (ESI+): 458.0 ([M+H] + ).

[0386] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (840.0 mg, 1.8 mmol, 1.0 equiv) in MeOH / THF (3:1, 32 mL) was added a solution of KOH (618.0 mg, 11.0 mmol, 6.0 equiv) in water (2.0 mL). The reaction mixture was stirred for 1 h at 65° C., then diluted with water (20 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with DCM / MeOH (10:1, 50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (700 mg, 85.7% yield) as an off-white solid.

[0387] 1 HNMR (400 MHz, CDCl3) δ: 8.11 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 5.2 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 4.46 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H).

[0388] LC-MS (ESI+): 444.1([M+H] + ).

[0389] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (300.0 mg, 0.7 mmol, 1.0 equiv), (S)-phenylethylamine (16.5 mg, 0.14 mmol, 0.2 equiv), MeOH (3.6 mL), THF (2.4 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 4.8 mg, 0.004 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (20 mL) and washed with 1 N HCl (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in refluxing isopropyl acetate and filtered. The filtrate was cooled to room temperature, which initiated crystallization. The formed crystals were filtered and dried to give compound 7 (130 mg, 41.7% yield) as a white solid.

[0390] 1 HNMR (400 MHz, CDCl3) δ: 7.46 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.34 (t, J = 6.4 Hz, 2H), 4.21-4.18 (m, 1H), 3.36-3.31 (m, 4H), 3.24-3.18 (m, 1H), 3.08 (t, J = 6.4 Hz, 2H).

[0391] LC-MS (ESI+): 446.1 ([M+H] + ).

[0392] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 98.68% ee.

[0393] [Example 8] Synthesis of Compound 8

[0394] [ka]

[0395] Process Description To a solution of methyl 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)acetate (3.8 g, 15.9 mmol, 1.0 equiv) in Et2O (70 mL) was added LiAlD4 (976 mg, 23.8 mol, 1.5 equiv) portionwise at 0 °C. The mixture was stirred for 2 h at 5 °C and then diluted with Et2O (50 mL). The reaction was quenched with water (1 mL) and a solution of NaOH (0.15 g) in water (1 mL) at 0 °C. Water (3 mL) was added and the mixture was stirred for 15 min. After adding Na2SO4, the mixture was filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethan-1,1-d2-1-ol (2.9 g, 83.1% yield) as a yellow oil.

[0396] 1 HNMR (400 MHz, CDCl3) δ: 3.19 (brs, 1H), 2.73 (s, 2H).

[0397] LC-MS (ESI+): 214.0 ([M+H] + ).

[0398] To a solution of 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethan-1,1-d2-1-ol (2.9 g, 13.22 mmol, 1.0 equiv) in DCM (45 mL) was added TEA (2.7 g, 26.5 mmol, 2.0 equiv). The mixture was cooled to 0° C. and methanesulfonyl chloride (2.3 g, 19.8 mmol, 1.5 equiv) was added dropwise. The reaction mixture was stirred for 1 h at room temperature, then quenched with water (20 mL) and extracted with DCM (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethyl-1,1-d2 methanesulfonate (4.0 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0399] LC-MS (ESI+): 292.2 ([M+H] + ).

[0400] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (2.12 g, 11.9 mmol, 0.9 equiv.) in DMF (30 mL) was added K2CO3 (2.19 g, 15.86 mmol, 1.2 equiv.). The reaction mixture was heated to 85° C. under argon atmosphere and a solution of 2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethyl-1,1-d2 methanesulfonate (3.85 g, crude, 13.22 mmol, 1.0 equiv.) in DMF (10 mL) was added. The reaction mixture was stirred at 85° C. for 4 h, then poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL×2) and brine (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was triturated with EtOAc to give 4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (2.4 g, 50.2% yield for two steps) as an off-white solid.

[0401] 1HNMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.81 (d, J = 8 Hz, 1H), 7.53 (s, 2H), 6.94 (d, J = 8 Hz, 1H) ), 3.11 (s, 2H).

[0402] LC-MS (ESI+): 374.2 ([M+H] + ).

[0403] To a solution of methyl 2-methoxyacetate (3.48 g, 33.4 mmol, 5.2 equiv) in THF (24 mL) was added TiCl4 (6.34 g, 33.4 mmol, 5.2 equiv) dropwise at 0° C. under argon. The yellow solution was stirred for 15 min before adding DIEA (4.65 g, 36 mmol, 5.6 equiv). The solution was stirred for 15 min. A solution of 4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (2.4 g, 6.4 mmol, 1.0 equiv) in DCM (24 mL) was added dropwise and stirred for 60 min. The reaction mixture was allowed to warm to 20° C. and stirred overnight. The reaction was then cooled to 0° C. and quenched with cold water (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (50 mL x 2). The combined organic layers were washed with water (50 mL x 3), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified on a silica gel column (eluted with petroleum ether / EtOAc = 3:1) to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.85 g, 60.9% yield) as a yellow solid.

[0404] LC-MS (ESI+): 478.2 ([M+H] + ).

[0405] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.85 g, 3.9 mmol, 1.0 equiv) in DMF (20 mL) was added concentrated H2SO4 (582 mg, 5.8 mmol, 1.5 equiv) dropwise at room temperature. The reaction mixture was stirred for 16 h at 100 °C, then quenched with cold water (100 mL) and extracted with DCM (50 mL x 3). The organic layer was dried (Na2SO4) and concentrated to give a crude residue which was triturated with EtOAc and filtered to give methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (1.4 g, 78.2% yield) as a yellow solid.

[0406] 1 HNMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.08 (s, 2H).

[0407] LC-MS (ESI+): 460.2 ([M+H] + ).

[0408] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (1.4 g, 3.05 mmol, 1.0 equiv) in MeOH / THF (3:1, 44 mL) was added a solution of KOH (1.03 g, 18.3 mmol, 6.0 equiv) in water (2 mL). The reaction mixture was stirred for 1.5 h at 65° C., then diluted with water (50 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with DCM / MeOH (10:1, 50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (1.1 g, 81.0% yield) as a yellow solid.

[0409] 1 HNMR (400 MHz, DMSO-d6) δ: 8.15 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.39-7.36 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.13 (s, 2H).

[0410] LC-MS (ESI+): 446.0 ([M+H] + ).

[0411] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-(methyl-d3)-2-(phenyl-d5)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (300.0 mg, 0.7 mmol, 1.0 equiv), (S)-phenylethylamine (16.5 mg, 0.14 mmol, 0.2 equiv), MeOH (3.6 mL), THF (2.4 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 4.8 mg, 0.004 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (20 mL) and washed with 1N HCl (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in refluxing isopropyl acetate and filtered. The filtrate was cooled to room temperature, which initiated crystallization. The formed crystals were filtered and dried to give compound 8 (145 mg, 54.1% yield) as a white solid.

[0412] 1 HNMR (400 MHz, CDCl3) δ: 7.45 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.21-4.18 (m, 1H), 3.35-3.31 (m, 4H), 3.23-3.20 (m, 1H), 3.07 (s, 2H).

[0413] LC-MS (ESI+): 448.2 ([M+H] + ).

[0414] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.79% ee.

[0415] [Example 9] Synthesis of Compound 9

[0416] [ka]

[0417] Process Description To a solution of quinolin-8-amine (30.0 g, 208.1 mmol, 1.0 equiv) in DCM (300 mL) was added TEA (25.3 g, 249.7 mmol, 1.2 equiv) at room temperature under argon. Benzoyl chloride (35.1 g, 249.7 mmol, 1.2 equiv) was added dropwise at 0° C. The reaction mixture was stirred for 14 h at room temperature, then quenched with saturated NaHCO3 and extracted with DCM (300 mL×2). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=15:1) to give N-(quinolin-8-yl)benzamide (45.0 g, 87.1% yield) as a yellow solid.

[0418] 1 HNMR (400 MHz, CDCl3) δ: 10.76 (s, 1H), 8.95 (dd, J = 7.5 Hz, 1H), 8.86 (dd, J = 4.2 Hz, 1H), 8.20 (dd, J = 8.3 Hz, 1H), 8.11 - 8.08 (m, 2H), 7.63 - 7.53 (m, 5H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H).

[0419] LC-MS (ESI+): 280.1 ([M+Na] + ).

[0420] A 300 mL stainless steel autoclave was charged with N-(quinolin-8-yl)benzamide (5.0 g, 20.1 mmol, 1.0 equiv), Pd(OAc)2 (904 mg, 4.1 mmol, 0.2 equiv) and DO (100 mL). The autoclave was sealed and stirred at 140° C. for 36 h. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=10:1) to give N-(quinolin-8-yl)benzamide-2,6-d2 (2.5 g, 49.6% yield) as a white solid.

[0421] 1 HNMR (400 MHz, CDCl3) δ: 10.75 (s, 1H), 8.95 (dd, J = 7.5 Hz, 1H), 8.86 (dd, J = 4.2 Hz, 1H), 8.19 (dd, J = 8.3 1H), 7.63 - 7.54 (m, 5H), 7.48 (dd, J = 8.3 Hz, 1H).

[0422] LC-MS (ESI+): 250.1 ([M+H] + ).

[0423] A mixture of N-(quinolin-8-yl)benzamide-2,6-d2 (4.0 g, 16.0 mmol, 1.0 equiv) and H2SO4 water (40%, 100 mL) was stirred for 14 h at 120° C. The reaction mixture was then poured into water (150 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give benzoic-2,6-d2 acid (1.8 g, 92.3% yield) as a white solid, which was used directly in the next step without further purification (>98% D based on HNMR).

[0424] 1 HNMR (400 MHz, CDCl3) δ:7.63 (t, J = 7.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H).

[0425] LC-MS (ESI+): 122.8 ([MH] - ).

[0426] To a solution of benzoic-2,6-d2 acid (1.5 g, 12.1 mmol, 1.0 equiv) in DCM (15 mL) was added oxalyl chloride (2.3 g, 18.1 mmol, 1.5 equiv) and DMF (few drops). The reaction mixture was stirred at room temperature for 1 h, then concentrated and redissolved in THF (15 mL). NH3.H2O (25%, 15 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 15 min, then extracted with DCM / MeOH=10:1 (200 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give benzamide-2,6-d2 (1.2 g, 76.9% yield) as a white solid.

[0427] 1 HNMR (400 MHz, DMSO-d6) δ: 7.93 (brs, 1H), 7.50-7.46 (m, 1H), 7.41 (d, J = 6.9 Hz, 2H), 7.31 (brs, 1H).

[0428] LC-MS (ESI+): 124.2 ([M+H] + ).

[0429] To a solution of benzamide-2,6-d2 (1.2 g, 9.7 mmol, 1.0 equiv) in toluene (30 mL) was added methyl 4-bromo-3-oxopentanoate (3.05 g, 14.7 mmol, 1.5 equiv). After 10 h, another batch of methyl 4-bromo-3-oxopentanoate (3.05 g, 14.7 mmol, 1.5 equiv) was added. The mixture was stirred for 20 h at 110° C. and then concentrated to give a residue. The crude product was purified on a silica gel column (eluted with petroleum ether / EtOAc=15:1) to give methyl 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)acetate (1.3 g, 57.5% yield) as a yellow oil.

[0430] 1 HNMR (400 MHz, CDCl3) δ: 7.41 (t, J = 7.6 Hz, 3H), 3.73 (s, 1H), 3.58 (s, 2H), 2.36 (s, 3H).

[0431] LC-MS (ESI+): 233.9 ([M+H] + ).

[0432] To an ice-cooled solution of LiAH4 (313.0 mg, 8.3 mmol, 1.5 equiv) in diethyl ether (10 mL) was added dropwise a solution of methyl 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)acetate (1.3 g, 5.5 mmol, 1.0 equiv) in diethyl ether (10 mL). The reaction mixture was stirred at room temperature for 15 min and then quenched with water (0.3 mL) and aqueous NaOH (15%, 0.3 mL) at 0 °C. Water (1.0 mL) was added and stirred at room temperature for 15 min. After addition of Na2SO4, the mixture was filtered and concentrated to give 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethan-1-ol (1.0 g, 88.5% yield) as a white solid.

[0433] 1 HNMR (400 MHz, CDCl3) δ: 7.43 (t, J = 8.4 Hz, 3H), 3.93 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H).

[0434] LC-MS (ESI+): 206.2 ([M+H] + ).

[0435] To a solution of 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethan-1-ol (1.0 g, 4.9 mmol, 1.0 equiv) in DCM (15 mL) was added TEA (986.0 mg, 9.7 mmol, 2.0 equiv) and methanesulfonyl chloride (837 mg, 7.31 mmol, 1.5 equiv) dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature, then quenched with water (20 mL) and extracted with DCM (50 mL). The organic layer was dried (Na2SO4) and concentrated to give 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethyl methanesulfonate (1.2 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0436] LC-MS (ESI+): 284.1 ([M+H] + ).

[0437] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (679.0 mg, 3.8 mmol, 0.9 equiv) in DMF (10 mL) under argon was added K2CO3 (697.0 mg, 5.0 mmol, 1.2 equiv) at room temperature. The reaction mixture was heated to 86° C., and then a solution of 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethyl methanesulfonate (1.2 g, 4.2 mmol, 1.0 equiv) in DMF (10 mL) was added. The reaction mixture was stirred for 5 h at 86° C., and then poured into water (100 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were washed with water (100 mL×2) and brine (100 mL×2). The organic layers were dried over Na2SO4, filtered and concentrated. The crude product was triturated with EtOAc to give 4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (960 mg, 62.7% yield) as a yellow solid, which was used directly in the next step without further purification.

[0438] 1HNMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.53 (s, 2H), 7.43 (q, J = 3.7 Hz, 3H), 6.95 (d, J = 8.1 Hz, 1H), 4.54 (t, J = 6.6 Hz, 2H), 3.13 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H).

[0439] LC-MS (ESI+): 365.9 ([M+H] + ).

[0440] To a solution of methyl 2-methoxyacetate (1.4 g, 13.7 mmol, 5.2 equiv.) in THF (10 mL) was added TiCl4 (2.6 g, 13.7 mmol, 5.2 equiv.) and DIEA (1.9 g, 14.7 mmol, 5.6 equiv.) was added dropwise at 0° C. After 15 min, a solution of 4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophene-7-carbaldehyde (960.0 mg, 2.63 mmol, 1.0 equiv.) in DCM (10 mL) was added. The reaction mixture was stirred for 4 h at 0° C., then quenched with water (40 mL) at 0° C. and extracted with DCM (40 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (740.0 mg, 60.0% yield) as a yellow oil.

[0441] LC-MS (ESI+): 470.1 ([M+H] + ).

[0442] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)propanoate (740 mg, 1.6 mmol, 1.0 equiv) in DMF (10 mL) was added concentrated H2SO4 (235.0 mg, 2.3 mmol, 1.5 equiv) dropwise at room temperature. The reaction mixture was stirred for 14 h at 100° C., then quenched with cold water (30 mL) and extracted with DCM (60 mL×2). The organic layer was dried (Na2SO4) and concentrated to give the crude product, which was triturated with EtOAc to give methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (340.0 mg, 47.2% yield) as a yellow solid.

[0443] 1 HNMR (300 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.43-7.40 (m, 3H), 7.34 (d, J = 5.5 Hz, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.45 (t, J = 8.8 Hz, 2H) 3.88 (s, 3H), 3.77 (s, 3H), 3.09 (t, J = 8.8 Hz, 2H), 2.41 (s, 3H).

[0444] LC-MS (ESI+): 452.2([M+H] + ).

[0445] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylate (340.0 mg, 0.8 mmol, 1.0 equiv) in MeOH / THF=3:1 (16 mL) was added a solution of KOH (254.0 mg, 4.5 mmol, 6.0 equiv) in water (1.1 mL). The reaction mixture was stirred for 1 h at 65° C., then diluted with water (20 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with DCM / MeOH=10:1 (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was triturated with EtOAc to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (200.0 mg, 61.0% yield) as a yellow solid.

[0446] 1 HNMR (400 MHz, CDCl3) δ: 8.11 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.43 (q, J = 4.1 Hz, 3H), 7.35 (d, J = 5.6 Hz, 2H), 6.88 (d, J = 8.5 Hz, 1H), 4.48 (t, J = 6.5 Hz, 2H), 3.79 (s, 3H), 3.12 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H).

[0447] LC-MS (ESI+): 438.0 ([M+H] + ).

[0448] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy)benzo[b]thiophen-7-yl)acrylic acid (350.0 mg, 0.8 mmol, 1.0 equiv), (S)-phenylethylamine (19.4 mg, 0.16 mmol, 0.2 equiv), MeOH (4.2 mL), THF (2.8 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 7.0 mg, 0.004 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (40 mL) and washed with 1N HCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in refluxing isopropyl acetate and filtered. The filtrate was cooled to room temperature, which initiated crystallization. The formed crystals were collected by filtration to give compound 9 (142.7 mg, 40.6% yield) as a white solid.

[0449] 1 HNMR (400 MHz, CDCl3) δ: 7.49-4.47 (m, 1H), 7.43-7.41 (m, 3H), 7.32 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.34 (t, J = 6.4 Hz, 2H), 4.20-4.18 (m, 1H), 3.37-3.32 (m, 4H), 3.24-3.18 (m, 1H), 3.06 (t, J = 6.4 Hz, 2H), 2.40 (s, 3H).

[0450] LC-MS (ESI+): 440.1 ([M+H] + ).

[0451] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.37% ee.

[0452] [Example 10] Synthesis of Compound 10

[0453] [ka]

[0454] Process Description To an ice-cooled solution of LiAlD4 (530.0 mg, 14.0 mmol, 1.5 equiv) in diethyl ether (25 mL) was added dropwise a solution of methyl 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)acetate (2.2 g, 9.3 mmol, 1.0 equiv) in diethyl ether (15 mL) and stirred at room temperature for 15 min. The reaction mixture was quenched with water (0.5 mL) and aqueous NaOH (15%, 0.5 mL) at 0 °C. Water (1.5 mL) was then added and stirred at room temperature for 15 min. After addition of Na2SO4, the mixture was filtered and concentrated to give 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethan-1,1-d2-1-ol (1.7 g, 88.5% yield) as a white solid.

[0455] 1 HNMR (400 MHz, CDCl3) δ: 7.45-7.41 (m, 3H), 2.71 (s, 2H), 2.34 (s, 3H).

[0456] LC-MS (ESI+): 208.1 ([M+H] + ).

[0457] To a solution of 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethan-1,1-d2-1-ol (1.7 g, 8.2 mmol, 1.0 equiv) in DCM (30.0 mL) was added triethylamine (1.7 g, 16.4 mmol, 2.0 equiv) and methanesulfonyl chloride (1.4 g, 12.4 mmol, 1.5 equiv) dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature, then quenched with water (30 mL) and extracted with DCM (50 mL). The organic layer was dried (Na2SO4) and concentrated to give 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethyl-1,1-d2 methanesulfonate (2.2 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0458] LC-MS (ESI+): 286.0 ([M+H] + ).

[0459] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (1.2 g, 6.9 mmol, 0.9 equiv.) in DMF (20 mL) under argon was added K2CO3 (1.3 g, 9.2 mmol, 1.2 equiv.) at room temperature. The reaction mixture was heated to 86° C., and then a solution of 2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethyl-1,1-d2 methanesulfonate (2.2 g, 7.7 mmol, 1.0 equiv.) in DMF (10 mL) was added. The reaction mixture was stirred for 5 h at 86° C., and then poured into water (150 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were washed with water (100 mL×2), brine (100 mL×2). The organic layers were dried over Na2SO4, filtered and concentrated. The crude product was triturated with EtOAc to give 4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (1.9 g, 66.4% yield) as a yellow solid, which was used directly in the next step without further purification.

[0460] 1HNMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.45-7.41 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 3.11(s, 2H), 2.42 (s, 3H).

[0461] LC-MS (ESI+): 368.0 ([M+H] + ).

[0462] To a solution of methyl 2-methoxyacetate (2.8 g, 26.6 mmol, 5.2 equiv.) in THF (20 mL) was added TiCl4 (5.1 g, 26.6 mmol, 5.2 equiv.) and diisopropylethylamine (3.7 g, 28.7 mmol, 5.6 equiv.) dropwise at 0° C. After 15 min, a solution of 4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (1.9 g, 5.1 mmol, 1.0 equiv.) in DCM (20 mL) was added. The reaction mixture was stirred for 4 h at 0° C., then quenched with water (50 mL) at 0° C. and extracted with DCM (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified on a silica gel column (eluted with petroleum ether / EtOAc=3:1) to give methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.4 g, 58.0% yield) as a yellow oil.

[0463] LC-MS (ESI+): 472.0 ([M+H] + ).

[0464] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (1.4 g, 2.9 mmol, 1.0 equiv) in DMF (15 mL) was added concentrated H2SO4 (440.0 mg, 4.4 mmol, 1.5 equiv) dropwise at room temperature. The reaction mixture was stirred for 14 h at 100 °C, then quenched with cold water (45 mL) and extracted with DCM (60 mL x 2). The organic layer was dried (Na2SO4) and concentrated to give the crude product which was triturated with EtOAc to give methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (600.0 mg, 45.6% yield) as a yellow solid.

[0465] 1 HNMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.43 - 7.40 (m, 3H), 7.34 (d, J = 5.5 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.07 (s, 2H), 2.40 (s, 3H).

[0466] LC-MS (ESI+): 454.0([M+H] + ).

[0467] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (600.0 mg, 1.3 mmol, 1.0 equiv) in MeOH / THF=3:1 (20 mL) was added a solution of KOH (445.0 mg, 7.9 mmol, 6.0 equiv) in water (1.5 mL). The reaction mixture was stirred for 1 h at 65° C., then diluted with water (30 mL), concentrated and adjusted to pH=3 with 1N HCl. The mixture was extracted with DCM / MeOH=10:1 (50 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (550.0 mg, 94.8% yield) as a yellow solid, which was used directly in the next step without further purification.

[0468] 1 HNMR (400 MHz, CDCl3) δ: 8.09 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 5.5 Hz, 1H), 7.44 - 7.41 (m, 3H), 7.34 - 7.32 (m, 2H), 6.85 (d, J = 8.3 Hz, 1H), 3.78 (s, 3H), 3.08 (s, 2H), 2.40 (s, 3H).

[0469] LC-MS (ESI+): 440.0([M+H] + ).

[0470] A 30 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-(phenyl-2,6-d2)oxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (550.0 mg, 1.0 mmol, 1.0 equiv), (S)-phenylethylamine (26.0 mg, 0.2 mmol, 0.2 equiv), MeOH (4.8 mL), THF (3.2 mL) and Ir-cat([((S)-DTBSIPHOX)Ir(COD)]BArF, 8.0 mg, 0.004 equiv). The autoclave was sealed and hydrogenation was carried out for 36 h at 70° C. under 30 bar of hydrogen. The reaction solution was evaporated to dryness. The crude product was dissolved in DCM (40 mL) and washed with 1N HCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in refluxing isopropyl acetate and filtered. The filtrate was cooled to room temperature, which initiated crystallization. The formed crystals were filtered and dried to give compound 10 (250.0 mg, 45.0% yield) as a white solid.

[0471] 1 HNMR (400 MHz, CDCl3) δ: 7.48-4.47 (m, 1H), 7.43-7.42 (m, 3H), 7.31 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.21-4.18 (m, 1H), 3.34-3.33 (m, 4H), 3.24-3.18 (m, 1H), 3.04 (s, 2H), 2.40 (s, 3H).

[0472] LC-MS (ESI+): 442.1 ([M+H] + ).

[0473] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.81% ee.

[0474] [Example 11] Synthesis of Compound 11

[0475] [ka]

[0476] Process Description To a stirred solution of methyl 2,2-dimethoxyacrylate (50 g, 372.77 mmol, 1.00 equiv.) was added PCl5 (77.63 g, 372.77 mmol, 1.00 equiv.) in portions at 0 °C under N2 atmosphere for 30 min. The resulting solution was transferred to a 350 mL sealed tube and stirred at 140 °C for 1.5 h. The mixture was cooled to room temperature. The crude product was purified by distillation under oil pump vacuum (10 Torr) and fractions were collected at 55 °C. This gave methyl 2-chloro-2-methoxyacetate (43.0 g, 83.2%) as a colorless oil.

[0477] 1 H NMR (400 MHz, CDCl3) δ: 5.76 (s, 1H), 3.87 (s, 3H), 3.63 (s, 3H)

[0478] To a stirred solution of methyl 2-chloro-2-methoxyacetate (20.0 g, 144.35 mmol, 1.00 equiv) in dichloromethane (100 mL) was added triphenylphosphine (37.86 g, 144.35 mmol, 1.00 equiv) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred overnight, then concentrated under reduced pressure and washed with Et2O (3 x 100 mL). This gave (1,2-dimethoxy-2-oxoethyl)triphenylphosphonium chloride (45 g, 77.77%) as a pale yellow solid.

[0479] To a stirred solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (4.0 g, 22.44 mmol, 1.00 equiv.) and diisopropylethylamine (11.60 g, 89.78 mmol, 4.00 equiv.) in dichloromethane (40 mL) was added bromo(methoxy)methane (4.21 g, 33.66 mmol, 1.50 equiv.) dropwise at 0° C. under N2 atmosphere. The resulting solution was stirred at room temperature for 2 h, then quenched with H2O (50 mL) at 0° C. and filtered. The filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with aqueous NaCl (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (10:1) to give 4-(methoxymethoxy)benzo[b]thiophene-7-carbaldehyde (1.5 g, 30.07%) as a colorless oil.

[0480] LC-MS (ESI+): 223 ([M+H] + ).

[0481] 1 H NMR (400 MHz, DMSO-d6) δ: 10.10 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 5.5 Hz, 1H), 7.60 (d, J = 5.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 5.53 (s, 2H), 3.47 (s, 3H).

[0482] To a stirred solution of 4-(methoxymethoxy)benzo[b]thiophene-7-carbaldehyde (1.5 g, 6.74 mmol, 1.00 equiv.) and (1,2-dimethoxy-2-oxoethyl)triphenylphosphonium chloride (21.64 g, 53.99 mmol, 8.00 equiv.) in tetrahydrofuran (30 mL) and CHCl3 (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.22 g, 53.99 mmol, 8.00 equiv.) at room temperature under a N2 atmosphere. The resulting solution was stirred at 60 °C for 2 h. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (10:1) to give methyl (E)-2-methoxy-3-(4-(methoxymethoxy)benzo[b]thiophen-7-yl)acrylate (1.43 g, 68.7%) as a colorless oil and methyl (Z)-2-methoxy-3-(4-(methoxymethoxy)benzo[b]thiophen-7-yl)acrylate (0.30 g, 14.4%) as a colorless oil.

[0483] LC-MS (ESI+): 309 ([M+H] + ).

[0484] 1 H NMR (400 MHz, DMSO-d6) δ: 8.04 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 5.5 Hz, 1H), 7.55 (d, J = 5.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 5.42 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.45 (s, 3H).

[0485] To a solution of methyl (E)-2-methoxy-3-(4-(methoxymethoxy)benzo[b]thiophen-7-yl)acrylate (1.4 g, 4.54 mmol, 1.00 equiv) in methanol (140 mL) in a 250 mL pressure reactor under nitrogen atmosphere was added Pd(OH)2 (20 wt% on carbon, 0.14 g). The mixture was hydrogenated at room temperature under 40 atm hydrogen atmosphere for 40 h. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was dissolved in dichloroethane (28 mL) and manganese dioxide (7.89 g, 90.80 mmol, 20 equiv) was added. The mixture was stirred at 80 °C under N2 atmosphere for 6 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (10:1) to give methyl 2-methoxy-3-(4-(methoxymethoxy)benzo[b]thiophen-7-yl)propanoate (750.0 mg, 53.2%) as a colorless oil.

[0486] LC-MS (ESI+): 328 ([M+NH4] + ).

[0487] 1 H NMR (400 MHz, DMSO-d6) δ: 7.69 (d, J = 5.5 Hz, 1H), 7.50 (d, J = 5.5 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 5.34 (s, 2H), 4.21 (dd, J = 7.9, 5.1 Hz, 1H), 3.66 (s, 3H), 3.43 (s, 3H), 3.23 (s, 3H), 3.20 - 3.03 (m, 2H).

[0488] To a stirred solution of methyl 2-methoxy-3-(4-(methoxymethoxy)benzo[b]thiophen-7-yl)propanoate (750 mg, 1 equiv.) in dioxane (7.5 mL) was added HCl in 1,4-dioxane (4 M, 7.5 mL) at room temperature under N2 atmosphere. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This afforded methyl 3-(4-hydroxybenzo[b]thiophen-7-yl)-2-methoxypropanoate (600.0 mg, 93.2%) as a light brown oil.

[0489] LC-MS (ESI+): 289 ([M+Na] + ).

[0490] 1 H NMR (400 MHz, DMSO-d6) δ: 9.29 (s, 1H), 8.03 - 7.99 (m, 1H), 7.97 (d, J = 5.5 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.14 (d, J = 1.4 Hz, 3H), 3.74 (d, J = 1.4 Hz, 3H), 3.61 (qd, J = 14.4, 6.7 Hz, 2H).

[0491] To a stirred solution of methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (500.0 mg, 2.16 mmol, 1.00 equiv) in CD3OD (5 mL, 112.293 mmol, 51.94 equiv) and D2O (5 mL, 274.621 mmol, 127.01 equiv) was added Cs2CO3 (2113.4 mg, 6.48 mmol, 3.00 equiv) at room temperature under N2 atmosphere. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in fresh CD3OD (5 mL) and D2O (5 mL) and stirred at room temperature for 24 h. Stirring for longer did not increase the deuterium value. The resulting mixture was diluted with H2O (50 mL) and extracted with methyl tert-butyl ether (1×30 mL) and the aqueous layers were combined. The combined aqueous layers were acidified with 1N HCl(aq) to pH=3. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with aqueous NaCl (1×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 2-(5-methyl-2-phenyloxazol-4-yl)acetic-2,2-d2 acid (420 mg, 88.60%) as a white solid.

[0492] LC-MS (ESI+): 220 ([M+H] + ).

[0493] D / H ratio by LC-MS (ESI+): 92.46%.

[0494] To a stirred solution of LiAlH4 (58.8 mg, 1.55 mmol, 2.00 equiv) in tetrahydrofuran (8.5 mL) was added dropwise a solution of 2-(5-methyl-2-phenyloxazol-4-yl)acetic-2,2-d2 acid (170.0 mg, 0.77 mmol, 1.00 equiv) in tetrahydrofuran (1.5 mL) at 0 °C under N2 atmosphere. The resulting mixture was stirred at 0 °C for 2 h, then diluted with tetrahydrofuran (20 mL) and quenched with Na2SO4·10H2O at 0 °C. The resulting mixture was filtered and the filter cake was washed with tetrahydrofuran (2 × 20 mL). The filtrate was concentrated under reduced pressure. This gave 2-(5-methyl-2-phenyloxazol-4-yl)ethan-2,2-d2-1-ol (155 mg, 97.39%) as a pale yellow solid.

[0495] LC-MS (ESI+): 206 ([M+H] + ).

[0496] D / H ratio by LC-MS (ESI+): 92.12%.

[0497] To a stirred solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethane-2,2-d2-1-ol (60.0 mg, 0.29 mmol, 1.00 equiv), methyl 3-(4-hydroxybenzo[b]thiophen-7-yl)-2-methoxypropanoate (51.3 mg, 0.19 mmol, 0.66 equiv) and PPh3 (153.3 mg, 0.58 mmol, 2.00 equiv) in tetrahydrofuran (6 mL) was added diethyl azodicarboxylate (101.8 mg, 0.58 mmol, 2.00 equiv) in tetrahydrofuran (0.5 mL) dropwise at 0 °C under N2 atmosphere. The reaction was stirred at room temperature for 2 h and then quenched with H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with aqueous NaCl (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate, 4:1) to give methyl 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-2,2-d2)benzo[b]thiophen-7-yl)propanoate (20.0 mg, 15.0%) as a pale yellow solid.

[0498] LC-MS (ESI+): 454 ([M+H] + ).

[0499] To a stirred solution of methyl 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-2,2-d2)benzo[b]thiophen-7-yl)propanoate (20.0 mg, 0.044 mmol, 1.00 equiv) in tetrahydrofuran (4 mL) and H2O (2 mL) was added LiOH (4.2 mg, 0.17 mmol, 4.00 equiv) at 0 °C under N2 atmosphere. After stirring at room temperature for 1 h, the resulting mixture was diluted with H2O (10 mL) and acidified to pH = 4 with 1N HCl (aq). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with aqueous NaCl (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (18 mg) was purified by preparative chiral HPLC under the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile phase A: HEX:MTBE=1:1 (0.2% FA)-HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 6% B to 6% B in 15.5 min; Wavelength: 220 / 254 nm; RT1 (min): 11.8; RT2 (min): 14.1; Sample solvent: EtOH--HPLC; Injection volume: 0.3 mL; Number of runs: 7) to give an early fraction as a white solid (3.2 mg, 16.5%) and a late fraction as a white solid (3.1 mg, 15.9%).

[0500] LC-MS (ESI+): 440 ([M+H] + ).

[0501] D / H ratio by LC-MS (ESI+): 92.17%.

[0502] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm):>99.99% ee.

[0503] 1H NMR (400 MHz, chloroform-d) δ: 8.38 (d, J = 7.5 Hz, 2H), 7.68 - 7.58 (m, 3H), 7.40 (d, J = 5.5 Hz, 1H), 7.34 (d, J = 5.4 Hz, 1H), 7.23 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 4.58 (s, 2H), 4.18 (dd, J = 8.1, 4.3 Hz, 1H), 3.35 (dd, J = 14.6, 4.2 Hz, 1H), 3.32 (s, 3H), 3.18 (dd, J = 14.7, 8.1 Hz, 1H), 2.53 (s, 3H).

[0504] [Example 12] Synthesis of compound 12

[0505] [ka]

[0506] Process Description To a stirred solution of LiAlD4 (53.9 mg, 1.28 mmol, 2 equiv) in THF (2.5 mL) was added methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate-d2 (150.0 mg, 0.64 mmol, 1.00 equiv) dropwise at 0 °C under N2 atmosphere. The resulting solution was stirred at 0 °C for 1 h, then diluted with THF (20 mL) and quenched with Na2SO4·10H2O at 0 °C. The resulting solution was dried over Na2SO4 and filtered. The filter cake was washed with THF (2 × 20 mL). The filtrate was concentrated under reduced pressure. This gave 2-(5-methyl-2-phenyloxazol-4-yl)ethan-1,1,2,2-d4-1-ol (140 mg, 105.04%, crude) as a pale yellow solid.

[0507] LC-MS (ESI+): 208 ([M+H] + ).

[0508] D / H ratio by LC-MS (ESI+): 95.59%.

[0509] To a stirred solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethane-1,1,2,2-d4-1-ol (60.0 mg, 0.28 mmol, 1.00 equiv.), methyl 3-(4-hydroxybenzo[b]thiophen-7-yl)-2-methoxypropanoate (50.8 mg, 0.19 mmol, 0.66 equiv.) and PPh3 (151.8 mg, 0.57 mmol, 2 equiv.) in THF (3 mL) was added diethyl azodicarboxylate (100.83 mg, 0.578 mmol, 2 equiv.) in THF (0.5 mL) dropwise under N2 atmosphere at 0° C. The resulting solution was stirred at room temperature for 2 h, then quenched with HO (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous NaCl (1×20 mL) and dried over anhydrous Na2SO4. After filtration, the filter cake was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate, 4:1) to give methyl 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1,2,2-d4)benzo[b]thiophen-7-yl)propanoate (28 mg, 21.23%) as a pale yellow solid.

[0510] LC-MS (ESI+): 456 ([M+H] + ).

[0511] D / H ratio by LC-MS (ESI+): 95.41%.

[0512] To a stirred solution of methyl 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1,2,2-d4)benzo[b]thiophen-7-yl)propanoate (28 mg, 0.061 mmol, 1.00 equiv) in tetrahydrofuran (4 mL) and HO (2 mL) was added LiOH (5.8 mg, 0.244 mmol, 4.00 equiv) at 0 °C under N2 atmosphere. After stirring at room temperature for 2 h, the resulting mixture was diluted with HO (10 mL) and acidified to pH 4 with 1N HCl (aq). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with aqueous NaCl (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (22 mg) was purified by preparative chiral HPLC under the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile phase A: HEX:MtBE=1:1 (0.2% FA)-HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 6% B to 6% B in 16 min; Wavelength: 220 / 254 nm; RT1 (min): 11.7; RT2 (min): 14.3; Sample solvent: EtOH--HPLC; Injection volume: 0.3 mL; Number of runs: 7) to give an early fraction as a white solid (8.7 mg, 32.06%) and a late fraction as a white solid (7.3 mg, 26.90%).

[0513] LC-MS (ESI+): 442 ([M+H] + ).

[0514] D / H ratio by LC-MS (ESI+): 95.57%.

[0515] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% Hexane / 9.99% EtOH / 0.01% TFA, 210nm):>99.99% ee.

[0516] 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J = 5.7 Hz, 2H), 7.53 - 7.44 (m, 4H), 7.35 (d, J = 5.5 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.22 (dd, J = 8.0, 4.4 Hz, 1H), 3.43 - 3.35 (m, 1H), 3.36 (s, 3H), 3.22 (dd, J = 14.7, 8.0 Hz, 1H), 2.45 (s, 3H).

[0517] [Example 13] Evaluation of compounds against PPARα / PPARγ activity using a luciferase reporter system HEK293T cells were cultured according to the ATCC guidelines. Experiments were performed when the cells were in the logarithmic phase of growth. A total of 6 × 10 6 The cells were seeded in 60 mm cell culture dishes and incubated overnight at 37° C., 5% CO2. Lipofectamine® 3000 transfection reagent was mixed with the plasmid combinations (mixtures of pGL4.35[luc2P / 9XGAL4 UAS / Hygro], pBIND-RXRα, and pBIND-PPPARα, or mixtures of pGL4.35[luc2P / 9XGAL4 UAS / Hygro], pBIND-RXRα, and pBIND-PPPARγ) and then added to the dishes. After incubation for 5 hours at 37° C., 5% CO2, the cells were trypsinized, seeded in 384-well assay plates, and then incubated with test compounds at a range of concentrations overnight at 37° C., 5% CO2. The following day, the cells were lysed and analyzed by Steady-Glo. TM Luciferase was activated using the Luciferase Assay System. The luminescence signal from the luciferase assay was measured using an Envision HTS / 2105. Since peroxisome proliferator-activated transcription controls the expression of luciferase, the agonist activity of the test compound can be quantified by the luminescence intensity. The EC 50Values ​​were calculated for PPARα / γ agonist potency using Graphpad 8.0 and the results are shown in Table 1. The selectivity of the compounds for PPARα or PPARγ was evaluated by the PPARγ EC 50 / PPARα EC 50 It is expressed as:

[0518] [Table 1]

[0519] Example 14: Effects of compounds provided herein on a rat model of dyslipidemia induced by a high cholesterol diet 14.1 Experimental Materials 42 Sprague-Dawley rats, aged 6-8 weeks; Source: SPF (Beijing) Biotechnology Co., Ltd.; Animal Certificate Number: 110324201104469613.

[0520] 14.2 Experimental Method 14.2.1 An animal model of dyslipidemia was induced in SD rats using a high cholesterol diet (ASHF4).

[0521] 14.2.2 Male SD rats were fed a high-cholesterol diet (ASHF4, Dyet, China) for 14 days. The day before the start of dosing (day 0), animals were divided into seven groups based on body weight and serum indexes and continued to be fed the high-cholesterol diet. Treatment groups were orally administered either compound or vehicle while continuing the high-cholesterol diet for a total of one week. Animals were weighed daily before treatment and given compound between 9:00 and 9:30 in the morning based on their body weight for that day. The specific grouping and dosing schedule are shown in Table 2.

[0522] [Table 2]

[0523] Formulations. Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 5g sodium carboxymethylcellulose was added to 900ml ddH2O, stirred until completely dissolved, then filled up to 1000ml with ddH2O. 2. Working solution for 0.6mg / kg dosing: 0.12mg / ml working solution. 12mg of compound was added to 100ml 0.5% sodium carboxymethylcellulose, then vortexed until well suspended. 3. Working solution for 0.2mg / kg dosing: 0.04mg / ml working solution. 30ml of 0.12mg / ml compound solution was mixed with 60ml 0.5% sodium carboxymethylcellulose, then vortexed until well suspended.

[0524] 14.2.3 The day before treatment and at the end of the final day of the study, blood was collected from the animals and serum was separated for analysis of serum lipid indicators.

[0525] 14.2.4 Serum indices of triglycerides (TG) and non-esterified fatty acids (NEFA) were determined using an automated blood biochemistry analyzer.

[0526] 14.3 Results Serum lipid analysis showed that after 7 days of treatment (day 8), aleglitazar, compound 2, and compound 4 could all significantly reduce serum TG and NEFA levels at both 0.2 mg / kg and 0.6 mg / kg dose levels compared to the vehicle group. The TG and NEFA in the serum of the animals were shown in Figures 1A and 1B, and their values ​​were shown in Tables 3 and 4, respectively. There were no abnormal clinical observations during the experiment. For comparison purposes, T-test statistical analysis was performed on the results of each compound at a dose of 0.2 mg / kg using GraphPad 8.0 software package. At a dose level of 0.2 mg / kg, compound 2 could significantly reduce TG and NEFA (P<0.05), and compound 4 could significantly reduce NEFA (P<0.05) compared to aleglitazar.

[0527] [Table 3]

[0528] [Table 4]

[0529] [Example 15] Effect of oral gavage on body weight of ICR mice for 7 consecutive days 15.1 Experimental Materials Seventy male ICR mice, aged 6–8 weeks; source: Laboratory Animal Business Department, Shanghai Institute of Planned Parenthood Research.

[0530] 15.2 Method After 3 days of acclimation, ICR mice were divided into groups according to body weight. The day of grouping was designated as day 0. After grouping, either vehicle or compound was administered by oral gavage once per day for 7 consecutive days. The dosage and grouping are shown in Table 5. The body weight of animals was measured and recorded every day.

[0531] [Table 5]

[0532] Formulations. Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 2.5 g of sodium carboxymethylcellulose was weighed and mixed with 500 ml of ddH2O and stirred until completely dissolved. 2. Working solution for 1 mg / kg dosing: 0.1 mg / ml working solution. 3 mg of compound was added to 30 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended. 3. Working solution for 0.2 mg / kg dosing: 0.02 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 24 ml of 0.5% sodium carboxymethylcellulose and then stirred until well suspended.

[0533] 15.3 Results The effect of the compounds on the weight change of ICR mice is shown in Table 6 and Figure 2A. During the experiment, the weight of the animals gradually increased over time. The daily average weight gain of the aleglitazar group at the dose of 0.2 mg / kg (days 4 and 5) and 1 mg / kg (day 6) was significantly greater than the vehicle group. Compared to the vehicle group, the daily weight gain of the compound 2 group at the low dose of 0.2 mg / kg was not significantly different throughout the study. The daily average weight gain of the compound 2 group at the high dose of 1 mg / kg (days 4 and 5) was significantly greater than the vehicle group. The weight gain of compounds 4 and 10 at the dose of 1 mg / kg was significantly greater than the vehicle group on days 4 to 7, respectively. The complete data is shown in Table 6. For comparison purposes, the net weight gain of the treatment was calculated by subtracting the average weight gain of the vehicle group from each treatment group and is shown in Figure 2B.

[0534] [Table 6]

[0535] Example 16: Pharmacodynamic study of compounds provided herein in a db / db type II diabetes model 16.1 Experimental Materials

[0536] [Table A]

[0537] 16.2 Experimental Method 16.2.1 Grouping in the experiment: Six wild mice were used as the control group (Group 1). Forty-five Db / db mice were equally divided into five groups based on body weight, serum triglyceride (TG) level, and random blood glucose level before the start of treatment.

[0538] 16.2.2 Formulations. Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 2.5 g of sodium carboxymethylcellulose was weighed and mixed with 500 ml of ddH2O until completely dissolved. 2. Working solution for 1 mg / kg dosing: 0.1 mg / ml working solution. 3 mg of compound was added to 30 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended. 3. Working solution for 0.2 mg / kg dosing: 0.02 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 24 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended. 4. Working solution for 0.05 mg / kg dosing: 0.005 mg / ml working solution. 6 ml of 0.02 mg / ml compound solution was mixed with 18 ml of 0.5% sodium carboxymethylcellulose and then stirred until well suspended.

[0539] 16.2.3 Dosing: Animals were orally dosed according to grouping: vehicle (Group 2), aleglitazar (Group 3) at a dose level of 0.2 mg / kg, and Compound 2 at dose levels of either 0.05 mg / kg (Group 4), 0.2 mg / kg (Group 5) or 1 mg / kg (Group 6). All animals were weighed daily before each dose and were treated daily for 14 consecutive days.

[0540] 16.2.4 Study outcomes will include daily body weights throughout the study; pre-dose serum TG levels on study days 6 and 12; pre-dose random blood glucose levels on study days 7 and 14; and results from an oral glucose tolerance test (OGTT) performed on study day 14.

[0541] 16.3 Data Analysis All data were imported into an Excel file and presented as mean ± SEM. Graphpad Prism 7.0 software was used for statistical analysis of data by One-way or Two-way ANOVA, with P<0.05 as the criterion for significant differences.

[0542] 16.4 Experimental Results Both aleglitazar and all compound 2 groups significantly reduced lipid, free fatty acid and blood glucose levels and significantly increased body weight when compared to the vehicle group.

[0543] 16.4.1 Animal weight The body weight changes of db / db model animals treated with aleglitazar and different doses of compound 2 are shown in Figure 3. As shown in Figure 3, the body weights of animals in the aleglitazar administration group (0.2 mg / kg) and compound 2 administration groups (0.05 mg / kg, 0.2 mg / kg, 1 mg / kg) gradually increased over time during the experiment, and the daily average body weights (days 10 to 15) were all significantly greater than those of the vehicle group.

[0544] 16.4.2 Animal Blood Biochemical Indicators TG, a biochemical indicator of the animals' blood, was measured on days 6 and 12, and the results are shown in Figures 4A and 4B. As shown in Figures 4A and 4B, the serum TG levels of the groups treated with either aleglitazar or compound 2 at different doses were significantly lower than the vehicle group on days 6 and 12, with the greatest effect observed in group 6 (compound 2, 1 mg / kg).

[0545] 16.4.3 Random Blood Glucose The effect of aleglitazar and different doses of compound 2 on random blood glucose of db / db model animals during the experimental period is shown in Figure 5. Compared with the vehicle group, the random blood glucose level of animals treated with either aleglitazar or different doses of compound 2 was reduced on the 7th day. Such reduction reached statistical significance in group 3 (aleglitazar, 0.2 mg / kg) and group 6 (compound 2, 1 mg / kg), but not in groups 4 and 5 (compound 2, 0.05 mg / kg and 0.2 mg / kg). On the 14th day, a more significant effect of blood glucose reduction was observed in group 6 (compound 2, 1 mg / kg) versus group 2 (vehicle) on the 7th day, while groups 3 and 5 (aleglitazar, 0.2 mg / kg, and compound 2, 0.2 mg / kg) showed a similar effect. Meanwhile, such effect in group 3 (compound 2, 0.05 mg / kg) also did not reach statistical significance. Thus, compound 2 had a slightly weaker effect on lowering blood glucose when compared to aleglitazar (Table 7).

[0546] [Table 7]

[0547] 16.4.4 Glucose Tolerance Tests in Animals At the end of the experiment, oral glucose tolerance test was performed on db / db animals treated with different compounds. Within 120 min after the test, blood glucose values ​​at each time point and areas under the blood glucose-time curve were shown in Figures 6A and 6B. Compared with the vehicle group, blood glucose levels of both aleglitazar and different doses of compound 2 were significantly decreased at each time point. Among them, the AUC of test article aleglitazar (0.2 mg / kg, P<0.001) and compound 2 (0.2 mg / kg, P<0.01 and 1 mg / kg, P<0.0001) were significantly decreased. 0-120分 was significantly lower than that of the vehicle group. Furthermore, when compared with aleglitazar, the AUC 0-120分In addition, the results for Group 4 (Compound 2, 0.05 mg / kg) showed a trend towards a decrease, but did not reach statistical significance at all time points when compared to the vehicle group.

[0548] [Table 8]

[0549] 16.5 Discussion In this disclosure, we have obtained a novel compound, namely compound 2, with better α / γ activity.

[0550] In vitro transcriptional activity experiments showed that the EC 50 was at the nanomolar level, indicating that compound 2 had good in vitro bioactivity. Compared with aleglitazar, compound 2 exhibited superior PPARα agonist activity and weaker PPARγ agonist potency.

[0551] Dyslipidemia rat model experiment showed that compound 2 and compound 4 could effectively and significantly reduce blood lipid levels in animals. Moreover, compound 2 and compound 4 at low dose levels had better blood lipid-reducing effect than aleglitazar at corresponding concentrations. Therefore, the results showed that compound 2 and compound 4 had better PPARα activity at low dose levels, resulting in better lipid-reducing effect.

[0552] ICR mouse body weight experiment showed that after treatment with low dose level of compound 2, the body weight of animals was comparable to the control group without significant change. In contrast, aleglitazar at the same dose level caused a significant increase in body weight. Since weight gain is a well-known side effect of PPARγ, this indicated that the PPARγ activity of the compound at low dose level was weaker than aleglitazar.

[0553] The study of db / db mice showed that compound 2 could effectively reduce blood glucose level and triglyceride content in type II diabetic mice. This indicated that compound 2 could exhibit the in vitro biological effect of PPARγ and control blood glucose. Moreover, compound 2 at the same dose level can achieve the same blood glucose lowering effect as aleglitazar. Therefore, the agonistic effect of compound 2 on the PPARγ pathway is sufficient to obtain the control of glucose homeostasis.

[0554] [Example 17] Pharmacodynamic model of diabetic nephropathy 17.1 Experimental Method 17.1.1 Animals: Five-week-old wild-type and db / db:BLKS male mice were purchased from Jiangsu GemPharmatech, Co., Ltd. The animals were housed in an SPF environment with a 12-hour light / dark cycle. The housing temperature was maintained at 22-26°C and humidity at 40%-60%. The mice had free access to food and water. At 6 weeks of age, db / db mice were anesthetized with 2.5% isopentane and subjected to uninephrectomy to remove the right kidney. Buprenorphine was applied postoperatively.

[0555] 17.1.2 Procedure. Two weeks after surgery, db / db mice were randomly assigned to five groups. Wild-type mice served as control animals. A total of five groups of animals were included in the study: Group 1, a control group of six animals receiving vehicle; Group 2, a vehicle group of ten animals receiving vehicle; Group 3, a Compound-Low group of ten animals receiving 0.1 mg / kg Compound 2; Group 4, a Compound-Medium group of ten animals receiving 0.3 mg / kg Compound 2 orally; and Group 5, a Compound-High group of ten animals receiving 1 mg / kg Compound 2 orally. Compounds were administered orally once per day for 10 weeks.

[0556] 17.1.3 Formulations. Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 2.5 g of sodium carboxymethylcellulose was weighed and mixed with 500 ml of ddH2O until completely dissolved. 2. Working solution for 1 mg / kg dosing: 0.2 mg / ml working solution. 6 mg of compound was added to 30 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended. 3. Working solution for 0.3 mg / kg dosing: 0.06 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 14 ml of 0.5% sodium carboxymethylcellulose and then stirred until well suspended. 4. Working solution for 0.1 mg / kg dosing: 0.02 mg / ml working solution. 2 ml of 0.2 mg / ml compound solution was mixed with 18 ml of 0.5% sodium carboxymethylcellulose and then stirred until well suspended.

[0557] At the 5th and 9th week after compound administration, mice were placed in metabolic cages for urine collection. Albumin levels were measured for calculation of 24-hour albumin excretion. At the 10th week after treatment, animals were sacrificed for kidney dissection. Kidneys were fixed in 10% neutral buffered formalin and then paraffin embedded for histopathological analysis. Glomerulosclerosis was determined by evaluating glomerular basement membrane, mesangial expansion, nodular sclerosis and glomerulosclerosis. Severity was graded as follows: 0: normal; 1: thickened glomerular basement membrane: thickening of isolated glomerular basement membrane and mild nonspecific changes by light microscopy; 2: mild (IIa) or severe (IIb) mesangial expansion: glomeruli with mild or severe mesangial expansion but without nodular sclerosis or widespread glomerular sclerosis in >50% of the glomerulus; 3: nodular sclerosis: at least one glomerulus with nodular expansion in the mesangial matrix; 4: advanced diabetic glomerulosclerosis: widespread glomerular sclerosis in >50% with other clinical or histopathological evidence that the sclerosis is attributable to diabetic nephropathy. Tubular damage was scored as follows: 0: no obvious lesion; 1: involvement of up to 25% of the tubules; 2: involvement of 25%–50% of the tubules; 3: 50%–75% tubular involvement and grade 4: >75% tubular involvement.

[0558] 17.1.4 Data are presented as mean ± SEM. Graphpad 8.0 software was used for statistical analysis. Differences between values ​​were analyzed by one-way ANOVA. Differences between histopathological scores were analyzed by Kruskal-Wallis nonparametric test. All values ​​were compared with Group 2.

[0559] 17.2 Results. 1. 24-hour urinary albumin. Vehicle-treated non-unilateral nephrectomized db / db mice had a >10-fold increase in 24-hour urinary albumin compared to controls. Compound 2 significantly reduced 24-hour urinary albumin at weeks 5 and 9 after compound administration. More than 50% reduction in urinary albumin was obtained with compound 2 treatment (Figure 7). 2. Glomerular sclerosis. As shown in Figure 8A, control animals have normal glomerular appearance and glomerular volume. However, mesangial expansion, thickening of the glomerular basement membrane, and nodular sclerosis were observed in vehicle-treated db / db animals. Compound 2 inhibited glomerular injury and improved glomerular hypertrophy. Both histopathological scores and glomerular volumes were statistically significantly reduced after animals were given a high dose of compound 2 (Figures 8B and 8C). 3. Renal tubular injury. Histopathological analysis showed that control animals had normal tubular architecture, whereas vehicle-treated animals developed tubular dilatation, thickened basement membrane / tubular atrophy, and tubular casts. Compound 2 at all dose levels ameliorated tubular damage to some extent (Figure 8D).

[0560] [Example 18] Effect of Compound 2 on improving renal injury in a rat model of unilateral ureteral obstruction 18.1 Experimental Method 18.1.1 Male SD rats weighing 240-260g were housed in a SPF environment with a 12-hour light / dark cycle. The temperature was maintained at 22-26°C and the humidity at 40%-60%. The rats were fed a standard diet and had free access to food and water.

[0561] 18.1.2 Formulations. Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose was prepared as described in 17.1.3. 2. 0.2 mg / ml solutions of either Compound 2 and Aleglitazar. 6 mg of compound was added to 30 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended. 3. 0.02 mg / ml solutions of either Compound 2 and Aleglitazar for dosing at 0.2 mg / kg. 2 ml of the 0.2 mg / ml solution was mixed with 18 ml of 0.5% sodium carboxymethylcellulose and then stirred until well suspended.

[0562] 18.1.3 Procedure. After acclimatization, animals were randomly assigned to the following groups: a control group of 8 rats receiving 10 ml / kg vehicle; a model group of 10 rats receiving 10 ml / kg vehicle, a reference group of 10 animals receiving 0.2 mg / kg aleglitazar; and a compound group of 10 animals receiving 0.2 mg / kg compound 2. Vehicle or compound was administered by oral gavage daily. Unilateral ureteral obstruction was performed on the second day of compound treatment. One hour after compound administration, animals in the model, reference and compound groups underwent urethral ligation under isoflurane anesthesia. A flank incision was made to expose the left ureter, and ureteral obstruction was obtained by two ligations using 4-0 surgical sutures. The ureter was cut between the two ligation points. Animals in the control group were subjected to the same surgical procedure except for ligation and cutting. Following surgery, animals in each group continued to receive vehicle or compound for 12 more days, for a total of 14 treatment days.

[0563] After 14 days of compound treatment, rats were sacrificed. Obstructed kidneys were weighed and collected for histology. Tissue samples were fixed in formalin and then embedded in paraffin. Embedded tissues were sectioned and stained with hematoxylin and eosin and Masson's trichrome to determine renal structure and fibrosis. Focal lesions included fissures, tubular dilatation, tubular obstruction, and necrosis, each given a score between 0 and 4 as a percentage of the lesion area of ​​the biopsy (score 0: No, 1: <25%; 2: 25%-50%, 3: 50%-75%, 4: >75%). The severity of renal injury was assessed by the total lesion score. Renal fibrosis was graded as 0-4 based on the percentage of the area stained with Masson's trichrome (score 0: No, 1: <25%; 2: 25%-50%, 3: 50%-75%, 4: >75%).

[0564] 18.1.4 Data are presented as mean ± SEM. Multiple comparisons were analyzed by the Kruskal-Wallis non-parametric test. Dunnett's test was used to compare differences with the model group. A p-value <0.05 was considered statistically significant.

[0565] 18.1.5 Results. Compared with the vehicle-treated model group, compound 2 at 0.2 mg / kg significantly improved the total score consisting of renal focal lesions, coating cracks, tubular dilatation, tubular obstruction, fibrosis, and necrosis (Figure 9). Meanwhile, the reference compound aleglitazar at the same dose of 0.2 mg / kg did not produce a statistically significant improvement in the total score. Thus, compound 2 is superior to aleglitazar in preventing and reducing renal damage caused by unilateral ureteral obstruction.

[0566] All compositions and methods disclosed and claimed herein can be made and performed without undue experimentation in light of the present disclosure. Although the compositions and methods of the present invention are described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the methods described herein and in the steps or sequence of steps in the methods without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain substances that are both chemically and physiologically related may be substituted for the substances described herein while the same or similar results would be obtained. All such similar substitutes and modifications will be apparent to those skilled in the art and are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ and R ２３ are independently H or D, R ６ , R ７ , R ８ and at least one of R9 is D.

2. R ６ , R ７ , R ８ and R ９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least two of:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least three of R 6 , R 7 , R 8 and R 9 are D.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 and R 9 are all D.

5. R ６ , R ７ , R ８ and R ９ or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein no more than two of R 6 , R 7 , R 8 and R 9 are D.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein no more than three of R 6 , R 7 , R 8 and R 9 are D.

8. R ６ or R ７ or a pharmaceutically acceptable salt thereof.

9. R ８ or R ９ or a pharmaceutically acceptable salt thereof.

10. R １ , R ２ , R ３ , R ４ , R ５ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ and R ２３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein all of are H.

11. R １ , R ２ , R ３ , R ４ , R ５ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ and R ２３ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein all of are H.

12. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ and R ２３ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein all of are H.

13. R １ , R ２ , R ３ , R ４ and R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

14. R １ , R ２ , R ３ , R ４ and R ５ At least one of R is D, ８ and R ９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

15. R １ and R ５ At least one of R is D, ８ and R ９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

16. R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ and R ２３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein all of are H.

17. R １２ , R １３ and R １４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

18. R １２ and R １３ At least one of R is D, １４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

19. R １６ , R １７ and R １８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

20. R ８ and R ９ At least one of R is D, １６ , R １７ and R １８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

21. R １ , R ２ , R ３ , R ４ and R ５ At least one of R is D, １６ , R １７ and R １８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of:

22. R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １９ , R ２０ , R ２１ , R ２２ and R ２３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein all of are H.

23. A compound of formula (Ia), or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 (In the formula, R ６’ , R ７’ , R ８’ and R ９’ are independently H or D, R ６’ , R ７’ , R ８’ and R ９’ At least one of is D.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein at least two of R 6' , R 7' , R 8' and R 9' are D.

25. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein at least three of R 6' , R 7' , R 8' and R 9' are D.

26. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein all of R 6' , R 7' , R 8' and R 9' are D.

27. R ６’ , R ７’ , R ８’ and R ９’ or a pharmaceutically acceptable salt thereof.

28. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein no more than two of R 6' , R 7' , R 8' and R 9' are D.

29. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein no more than three of R 6' , R 7' , R 8' and R 9' are D.

30. R ８’ and R ９’ or a pharmaceutically acceptable salt thereof.

31. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein both R 8′ and R 9′ are D.

32. R ６’ and R ７’ or a pharmaceutically acceptable salt thereof.

33. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein both R 6′ and R 7′ are D.

34. R ８’ and R ９’ When at least one of ６’ and R ７’ and R are H. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein both of R and R are H.

35. R ８’ and R ９’ If both are D, then R ６’ and R ７’ and R are H. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein both of R and R are H.

36. R ６’ and R ７’ When at least one of ８’ and R ９’ and R are H. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein both of R and R are H.

37. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein when both R 6' and R 7' are D, then both R 8' and R 9' are H.

38. A compound selected from the following, or a pharmaceutically acceptable salt thereof: 【Transformation 3】

39. 39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 50% or more.

40. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 60% or more.

41. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 70% or more.

42. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, wherein the deuterium enrichment is 80% or more.

43. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 90% or more.

44. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, having a deuterium enrichment of 95% or more.

45. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, having a deuterium enrichment of 96% or more.

46. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, having a deuterium enrichment of 97% or more.

47. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, having a deuterium enrichment of 98% or more.

48. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 99% or more.

49. 39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 99.9% or less.

50. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 99% or less.

51. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 98% or less.

52. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 97% or less.

53. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 96% or less.

54. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 95% or less.

55. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, having a deuterium enrichment of 90% or less.

56. 56. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant.

57. Use of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 56, in the manufacture of a medicament for the treatment and / or prevention of diseases which are modulated by agonists of PPARα and / or PPARγ.

58. 58. The use of claim 57, wherein the disease is diabetes, hypertension, dyslipidemia, atherosclerosis, metabolic syndrome, or diabetic nephropathy.

59. The use of claim 57, wherein the disease is non-insulin dependent diabetes mellitus.

60. 58. The use of claim 57, wherein the disease is kidney damage.

61. 61. The use of claim 60, wherein the kidney damage is caused by ureteral obstruction.

62. 61. The use of claim 60, wherein the renal damage is caused by unilateral ureteral obstruction.

63. 56. A method for modulating the specific agonist activity of PPARα or PPARγ of a dual agonist of PPARα and PPARγ, comprising deuterizing the agonist, wherein the dual agonist of PPARα and PPARγ is aleglitazar or a pharmaceutically acceptable salt thereof, and the agonist obtained by deuterizing is a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof.

64. 56. A method for improving the specific agonist activity of a PPARα and PPARγ dual agonist, comprising deuterizing the agonist, wherein the PPARα and PPARγ dual agonist is aleglitazar or a pharmaceutically acceptable salt thereof, and the agonist obtained by deuterizing is a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof.

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