Functionalized long-chain hydrocarbon monocarboxylic acids and dicarboxylic acids and their derivatives, and their use for the prevention or treatment of diseases.

Abstract

The present invention provides methods for treating or preventing renal diseases and fibrosis, such as chronic kidney disease (CKD), renal fibrosis, cardiac fibrosis, uterine fibrosis, and cystic fibrosis, using compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), and (IIIB), their pharma- ceutically acceptable salts and solvates, and compositions thereof.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 141,269, filed on January 25, 2021, and U.S. Provisional Application No. 63 / 285,890, filed on December 3, 2021, the disclosures of each of which are incorporated herein by reference in their entirety.

[0002] The present invention provides a method for treating or preventing renal diseases and fibrosis such as chronic kidney disease (CKD), renal fibrosis, cardiac fibrosis, uterine fibrosis, and cystic fibrosis using compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), and (IIIB), their pharmaceutically acceptable salts and solvates, and compositions thereof.

Background Art

[0003] Kidney disorders are becoming more frequent worldwide due to Western diets and are inadequately treated. Among kidney disorders, the most common are kidney diseases or nephropathies characterized by kidney damage. Kidney problems include acute kidney injury, kidney cysts, kidney stones, and kidney infections, which can result in some degree of loss of kidney function and ultimately complete loss of kidney function, leading to kidney failure. Treatments for kidney failure include kidney transplantation or dialysis, but therapies are still needed for other kidney conditions.

[0004] If kidney dysfunction or structural damage persists for more than three weeks, the condition can become life-threatening. Chronic kidney disease (CKD) is diagnosed when evidence of kidney damage (reduced glomerular filtration rate (GFR) or proteinuria) is present for more than three months. CKD affects 13% of the adult population worldwide. CKD is categorized according to GFR and urinary albumin:creatinine ratio (UACR). The condition is associated with multiple adverse outcomes, including an increased risk of cardiovascular events, acute kidney injury (AKI), and progression to end-stage kidney disease (ESKD).

[0005] Epidemiologists have linked cases to genetic and epigenetic causes, including kidney disease, being African American, Hispanic, Native American, or Asian, socioeconomic factors, and having a family history of drug or other health conditions. Among patients at higher risk for kidney disease are those with diabetes, hypertension, heart disease, or age (being over 60 years old).

[0006] Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies. Patients with chronic liver diseases such as cirrhosis and fibrosis are at increased risk of developing HCC. Therefore, patients with chronic liver diseases need to be closely monitored for the development of HCC. Risk factors for HCC include cirrhosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic alcohol consumption, hepatitis B and C, type IIb hyperlipidemia, mixed dyslipidemia, obesity, and type 2 diabetes.

[0007] Patients with type IIb hyperlipidemia are at high risk of developing NAFLD and non-alcoholic steatohepatitis (NASH), which can develop due to the overproduction and accumulation of hepatic triglycerides. Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides are associated with mixed dyslipidemia, including type IIb hyperlipidemia, which is characterized by elevated levels of apolipoprotein B, very low-density lipoprotein cholesterol (VLDL-C), medium-density lipoprotein cholesterol (IDL), and low-density low-density lipoprotein (LDL), in addition to elevated LDL-C and triglyceride levels.

[0008] The treatment options currently available for type IIb hyperlipidemia are limited. While statins may be effective in lowering LDL-C and reducing inflammation, they are generally not very effective in lowering triglyceride levels. Furthermore, high-dose statin therapy is often poorly tolerated, potentially causing muscle pain (myalgia) and increasing the risk of serious myotoxicity, such as rhabdomyolysis, in patients. Commonly used triglyceride-lowering agents administered in combination with statins are also often poorly tolerated. When administered with statins, fibrates are known to have drug-drug interactions, resulting in elevated blood drug levels of statins, increased risk of myalgia and myotoxicity, and increased safety risks. In fact, the interaction between the statin Baycol (cerivastatin) and the fibrate gemfibrozil resulted in severe myotoxicity and death, raising safety concerns and leading to Baycol's removal from the US market. Fish oil, used to lower triglyceride levels, needs to be taken multiple times a day and can cause a fishy aftertaste, belching, or reflux. Niacin can cause flushing, especially when administered in combination with statins.

[0009] Gastrointestinal (digestive) cancers can affect the gastrointestinal tract and other organs within the digestive system, such as the liver. The origin of digestive cancers has been strongly associated with chronic inflammation of the organ, developing through a series of histopathological stages dependent on the affected organ. In cases of gastrointestinal tract or gastrointestinal stromal tumor (GIST) cancer, surgery is likely to be recommended to remove the tumor and / or help maintain normal function. Other treatment options include radiation therapy, chemotherapy, hormone therapy, or targeted therapy.

[0010] Fibrosis can be triggered by the pathological accumulation of extracellular matrix (ECM) proteins, resulting in scarring and thickening of the affected tissue, much like an excessive wound healing response that interferes with normal organ function. Fibrosis can typically occur in many tissues in the body as a result of inflammation or injury, such as the lungs, liver, brain, heart, kidneys, and uterus.

[0011] There is a need for safe and effective therapies for the treatment or prevention of renal impairment and chronic kidney disease, cancer (e.g., gastrointestinal cancer, hepatocellular carcinoma, or cholangiocarcinoma), malignant or benign tumors of the lungs, liver, gallbladder, bile ducts, or gastrointestinal tract, liver disease or abnormal liver conditions, intrahepatic or extrahepatic bile duct disease, lipoprotein disorders, lipid and metabolic disorders, cirrhosis, fibrosis, glucose metabolism disorders, cardiovascular or related vascular disorders, fatty degeneration, diseases resulting from fibrosis or cirrhosis, diseases associated with increased inflammation (e.g., inflammation of the liver, kidneys, or lungs), hepatocyte ballooning, peroxisome proliferator-activated receptor-associated disorders, ATP citrate lyase disorders, acetylcoenzyme A carboxylase disorders, obesity, pancreatitis, or renal disease. [Overview of the Initiative]

[0012] The present invention relates to a method for treating or preventing a disease, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the disease is chronic kidney disease (CKD), renal fibrosis, autosomal polycystic kidney disease, contrast-induced nephropathy, cardiac Fibrosis, uterine fibrosis, cystic fibrosis, fibrothorax, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, glial scarring, arterial stiffness, arthral fibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive mass fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, end-stage renal failure, clear cell sarcoma, de novo thrombotic microangiopathy after kidney transplant, HNF1B-related autosomal dominant tubulointerstitial kidney disease, IgG 4-related kidney disease, MUC1-related autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-related medullary cystic kidney disease, medullary cavernous kidney, polycystic dysplastic kidney, multilocular cysts, polydactyly, neonatal diabetes mellitus - congenital hypothyroidism - congenital glaucoma - hepatic fibrosis - polycystic kidney syndrome, REN-related autosomal dominant tubulointerstitial kidney disease, rare diseases potentially suitable for kidney transplantation, renal cell carcinoma, renal dysplasia and unilateral or bilateral renal dysplasia The present invention provides a method for treating conditions such as renal or urinary tract malformations, sex-reversed kidney, adrenal and pulmonary dysplasia syndrome (SERKAL syndrome), serpentinofibula-polycystic kidney syndrome, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney), unilateral polycystic dysplastic kidney, ventricular enlargement-cystic kidney disease, Birt-Hogg-Dube syndrome (BHD), or Peutz-Jeghers syndrome (PJS), or complications of coal miner's pneumoconiosis.

[0013] Each of the above methods is a "method of the present invention."

[0014] Each compound described herein and useful in the methods of the present invention is a "compound of the present invention."

[0015] Each composition described herein and useful in the method of the present invention is a "composition of the present invention".

Brief Description of the Drawings

[0016] [Figure 1] Shows a schematic diagram of the ADP-Glo assay. [Figure 2A] Shows the IC50 data for ACC1 inhibition by compound I-32. [Figure 2B] Shows the IC50 data for ACC1 inhibition by compound I-32-CoA. [Figure 2C] Shows the IC50 data for ACC1 inhibition by compound I-1-CoA. [Figure 2D] Shows the IC50 data for ACC1 inhibition by reference compound CP640186. [Figure 3A] Shows the IC50 data for ACC2 inhibition by compound I-32-CoA. [Figure 3B] Shows the IC50 data for ACC2 inhibition by compound I-1-CoA. [Figure 3C] Shows the IC50 data for ACC2 inhibition by reference compound CP640186. [Figure 4A] Shows the IC50 data for ACLY inhibition by compound I-32-CoA. [Figure 4B] Shows the IC50 data for ACLY inhibition by compound I-1-CoA. [Figure 4C] Shows the IC50 data for ACLY inhibition by reference compound BMS-303141. [Figure 4D] Shows the results for compounds I-1, I-1-CoA, I-32, and I-32-CoA in the ACLY inhibition assay. [Figure 5A] Shows the following measurements in mice treated with vehicle or compound I-32 or I-1: steatosis (Figure 5A). [Figure 5B] Shows the following measurements in mice treated with vehicle or compound I-32 or I-1: inflammation (Figure 5B). [Figure 5C] The following measurements are shown in mice treated with the vehicle or compound I-32 or I-1: fibrosis (Figure 5C). [Figure 5D] The following measurements are shown in mice treated with the vehicle or compound I-32 or I-1: NAFLD score (Figure 5D). [Figure 6A] Representative H&E staining (at ×1.25 magnification) at the end of the treatment period is shown for mice carrying the vehicle or compound I-32 or compound I-1. [Figure 6B] Typical H&E staining (at 10x magnification) is shown. [Figure 7A] This shows representative Sirius Red staining (at a magnification of ×1.25) at the end of the treatment period in mice carrying the vehicle or compound I-32 or compound I-1. [Figure 7B] A typical Sirius Red stain (10x magnification) is shown. The arrows indicate perisinusoidal fibrosis and portal vein fibrosis. [Figure 8] The percentage of Sirius Red relative to total liver area in mice treated with the vehicle or compound I-32 or compound I-1 is presented. [Figure 9A] The following liver inflammation gene expression was observed in mice treated with the vehicle or compound I-32 or compound I-1: IL-1β (Figure 9A). [Figure 9B] The following liver inflammation gene expression was observed in mice treated with the vehicle or compound I-32 or compound I-1: MCP-1 (Figure 9B). [Figure 9C] The following liver inflammation gene expression was observed in mice treated with the vehicle or compound I-32 or compound I-1: IL-6 (Figure 9C). [Figure 9D] The following liver inflammation gene expression was observed in mice treated with the vehicle or compound I-32 or compound I-1: NF-κβ (Figure 9D). [Figure 9E]The following liver inflammation gene expression was observed in mice treated with the vehicle or compound I-32 or compound I-1: TLR-4 (Figure 9E). [Figure 9F] The following liver inflammation gene expression was observed in mice treated with the vehicle or compound I-32 or compound I-1: TNF-α (Figure 9F). [Figure 10] A and B show the expression of liver fibrosis genes in mice treated with the vehicle or compound I-32 or compound I-1: TGF-β (Figure 10A) and col1a1 (Figure 10B). [Figure 11] Representative α-SMA immunostaining (at 20x magnification) at the end of treatment in mice carrying the vehicle or compound I-32 or compound I-1 is shown. Arrows indicate α-SMA immunostaining. [Figure 12] This shows the α-SMA% of total liver area in mice treated with the vehicle or compound I-32 or compound I-1. [Figure 13A] This paper describes the construction and timeline of a unilateral ureteral obstruction (UUO) model for renal fibrosis studies in mice treated daily with compound I-1 ("UB") or compound I-32 ("UA"). [Figure 13B] Representative images and quantifications of renal fibrosis evaluated using trichrome staining (Figures 13B and 13C), picosirius Red (PSR) staining (Figures 13D and 13E), and α-SMA staining (Figures 13F and 13G) are shown. (*, **, ***, ****p<0.05). Group sham-V = sham surgical control group created by surgical exposure of the left ureter and lower pole of the kidney followed by closure of the incision, Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13C]Representative images and quantifications of renal fibrosis evaluated using trichrome staining (Figures 13B and 13C), picosirius Red (PSR) staining (Figures 13D and 13E), and α-SMA staining (Figures 13F and 13G) are shown. (*, **, ***, ****p<0.05). Group sham-V = sham surgical control group created by surgical exposure of the left ureter and lower pole of the kidney followed by closure of the incision, Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13D] Representative images and quantifications of renal fibrosis evaluated using trichrome staining (Figures 13B and 13C), picosirius Red (PSR) staining (Figures 13D and 13E), and α-SMA staining (Figures 13F and 13G) are shown. (*, **, ***, ****p<0.05). Group sham-V = sham surgical control group created by surgical exposure of the left ureter and lower pole of the kidney followed by closure of the incision, Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13E] Representative images and quantifications of renal fibrosis evaluated using trichrome staining (Figures 13B and 13C), picosirius Red (PSR) staining (Figures 13D and 13E), and α-SMA staining (Figures 13F and 13G) are shown. (*, **, ***, ****p<0.05). Group sham-V = sham surgical control group created by surgical exposure of the left ureter and lower pole of the kidney followed by closure of the incision, Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13F]Representative images and quantifications of renal fibrosis evaluated using trichrome staining (Figures 13B and 13C), picosirius Red (PSR) staining (Figures 13D and 13E), and α-SMA staining (Figures 13F and 13G) are shown. (*, **, ***, ****p<0.05). Group sham-V = sham surgical control group created by surgical exposure of the left ureter and lower pole of the kidney followed by closure of the incision, Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13G] Representative images and quantifications of renal fibrosis evaluated using trichrome staining (Figures 13B and 13C), picosirius Red (PSR) staining (Figures 13D and 13E), and α-SMA staining (Figures 13F and 13G) are shown. (*, **, ***, ****p<0.05). Group sham-V = sham surgical control group created by surgical exposure of the left ureter and lower pole of the kidney followed by closure of the incision, Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13H] Representative images and quantifications of macrophage infiltration in UUO kidneys using F4 / 80 staining are shown. Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13I] Representative images and quantifications of macrophage infiltration in UUO kidneys using F4 / 80 staining are shown. Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13J] Representative images and quantifications of T lymphocyte infiltration in UUO kidneys using CD3 staining are shown. Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13K] Representative images and quantifications of T lymphocyte infiltration in UUO kidneys using CD3 staining are shown. Group UV = vehicle, Group UA = compound I-32, Group UB = compound I-1. [Figure 13L] This shows the body weight of mice in the UUO mouse group. Group UV = Vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13M] This shows the systolic blood pressure in UUO mice. Inhibitor A = compound I-32, Inhibitor B = compound I-1. [Figure 14] This study demonstrates the suppression of LPS-induced glycolysis by treatment of myeloid-derived macrophages (BMDMs) with compound I-1. Differentiated myeloid-derived macrophages were serum-deprived for 2 hours and then treated for 4 hours with a vehicle (control), LPS (10 ng / mL), or LPS + ACLYi (I-1). Glycolysis rates were evaluated using a Seahorse bioanalyzer. [Figure 15A] RT-qPCR showed that compound I-1 suppressed Il-6 mRNA, a marker of inflammation. [Figure 15B] This shows the suppression of Il-1b mRNA, an inflammation marker, by compound I-1, as evaluated by RT-qPCR. [Figure 16] A and B show the plasma levels of alanine aminotransferase (ALT) (Figure 16A) and aspartate aminotransferase (AST) (Figure 16B) mediated by compound I-1 or compound I-32. [Figure 17A] The liver weight (Figure 17A) is shown for compound I-1 or compound I-32. [Figure 17B] Relative liver weight (Figure 17B) is shown for compound I-1 or compound I-32. [Figure 17C] Liver free fatty acids (Figure 17C) are shown, mediated by compound I-1 or compound I-32. [Figure 17D] The triglycerides (Figure 17D) formed by compound I-1 or compound I-32 are shown. [Figure 17E] Cholesterol (Figure 17E) is shown with compound I-1 or compound I-32. [Figure 18] A and B show the liver expression of the β-catenin gene (Figure 18A) and the HIF-1α gene (Figure 18B). [Figure 19]Figures A-D show the expression of hepatic cancer genes: VEGFR1-3 (Figure 19A), FGFR-1 (Figure 19B), p38 MAP kinase (Figure 19C), and RIPK4 (Figure 19D). [Figure 20A] The following shows plasma markers: cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E). [Figure 20B] The following shows plasma markers: cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E). [Figure 20C] The following shows plasma markers: cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E). [Figure 20D] The following shows plasma markers: cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E). [Figure 20E] The following shows plasma markers: cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E). [Figure 21] A and B represent the plasma marker C-reactive protein CRP (Figure 21A) and serum amyloid A protein SAA (Figure 21B). [Figure 22] The experimental protocol for the in vivo NAHS-HCC Hepa1-6 hepatic orthotopic tumor model is presented (Example 11). [Figure 23] This shows novel lipid formation in the liver of mice treated with compound I-1 or compound I-32 for 7 days. Glucose-derived 14C-labeled lipids in liver tissue after 7 days of treatment with either compound I-1 or compound I-32 at 10, 30, or 60 mg / kg. Each bar represents the mean ± SEM, n=6-10. * indicates a statistically different vehicle group with a p-value < 0.05. [Figure 24] A study design for pharmacokinetic experiments is shown (Example 13). [Figure 25A]This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25B] This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25C]This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25D] This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25E]This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25F] This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25G]This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25H] This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25I]This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 25J] This study demonstrates that compounds I-32(A) and I-1(B) do not significantly affect platelet production. Compounds I-32(A) and I-1(B) were added to enlarged HSPCs on day 0 (Figures 25A-25E) and cultured into megakaryocytes for 8 days, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet level (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell count (Figure 25F), CD41aCd42b+ cell count (Figure 25G), platelet level (Figure 25H), CD41a MFI (Figure 25I), and CD41a FSC cell size (Figure 25J) were analyzed on day 6. [Figure 26] This shows the mean (+SEM) concentration (ng / mL) of compound I-32 in male mouse plasma after single or repeated oral forced administration. QD×1 = once daily, single dose; QD×4 = once daily for 4 consecutive days. [Figure 27] The mean (+SEM) concentration (ng / g) of compound I-32 in the liver of male mice after single or repeated oral forced administration is shown. QD×1 = once daily, single dose; QD×4 = once daily for 4 consecutive days. [Figure 28]This shows the mean (+SEM) concentration (ng / g) of compound I-32 in the brain of male mice after single or repeated oral forced administration. QD×1 = once daily, single dose; QD×4 = once daily for 4 consecutive days. [Figure 29] This shows the mean (+SEM) concentration (ng / mL) of compound I-1 in male mouse plasma after single or repeated oral forced administration. QD×1 = once daily, single dose; QD×4 = once daily for 4 consecutive days. [Figure 30] This shows the mean (+SEM) concentration (ng / g) of compound I-1 in the liver of male mice after single or repeated oral forced administration. QD×1 = once daily, single dose; QD×4 = once daily for 4 consecutive days. [Figure 31] This shows the mean (+SEM) concentration (ng / g) of compound I-1 in the brain of male mice after single or repeated oral forced administration. QD×1 = once daily, single dose; QD×4 = once daily for 4 consecutive days. [Figure 32] Figures A and B show the effects of compounds I-1 and I-32 on the respiratory exchange ratio (RER) in C57Bl / 6 mice fed a high-fructose diet. Figure 32A shows the results as a percentage change in RER compared to the vehicle control at 0 hours. Figure 32B shows the percentage change in RER in each group compared to the respective 0-hour time point. * indicates a statistically significant difference from the vehicle control, where p<0.05. [Figure 33] Figures A and B show the effects of compounds I-1 and I-32 on thermogenesis in high-fructose C57BL / 6 mice up to 24 hours after treatment with compound I-1 or compound I-32. Figure 33A shows the total thermogenesis (day and night), and Figure 33B shows the daytime thermogenesis compared to nighttime. [Figure 34] Figures A and B show the effects of compounds I-1 and I-32 on walking activity in fructose-fed C57BL / 6 mice, calculated as the total number of beam sections in each cage over a 24-hour period. Figure 34A shows the total values, and Figure 34B shows the daytime values ​​compared to nighttime values ​​over a maximum of 24 hours (day + night). * indicates a significant difference from the vehicle control, with p<0.05. [Figure 35]Figures A and B show the effects of compounds I-1 and I-32 on food intake. Figure 35A shows total food intake (day and night), and Figure 35B shows daytime food intake compared to nighttime food intake. [Modes for carrying out the invention]

[0017] definition

[0018] The term "approximately" preceding a number means up to ±20% of the number. For example, "approximately" number means up to ±20% of the number, and in some embodiments, it means up to ±19%, up to ±18%, up to ±17%, up to ±16%, up to ±15%, up to ±14%, up to ±13%, up to ±12%, up to ±11%, up to ±10%, up to ±9%, up to ±8%, up to ±7%, up to ±6%, up to ±5%, up to ±4%, up to ±3%, up to ±2%, up to ±1%, up to ±1%, or any other number or range of numbers.

[0019] Throughout this specification, numerical ranges are provided for specific quantities. These ranges include all subranges within them. Thus, the range "50-80" includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range may be upper and lower limits of the range in which they are contained (e.g., the range 50-80 includes ranges with upper and lower limits such as 55-80, 50-75, etc.).

[0020] The term "pharmaceutically acceptable salt" includes both addition salts of acids and bases.

[0021] pharmaceutically acceptable salts can be obtained by reacting a basic compound of the present invention, for example having an amino group, with an inorganic or organic acid to form salts such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonate. pharmaceutically acceptable salts can also be obtained by reacting an acidic compound of the present invention, for example having a carboxyl group, with an inorganic or organic base to form salts such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, and trimethylamine. In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, ammonium salt, or magnesium salt. In some embodiments, the pharmaceutically acceptable salt is a zinc salt. pharmaceutically acceptable salts can also be obtained by reacting the compounds of the present invention having an acidic, for example, carboxyl group, with a basic amino acid, including, but not limited to, D,L-amino acids, L-amino acids, and D-amino acids. Basic amino acids useful for preparing pharmaceutically acceptable salts may be natural or synthetic amino acids. In some embodiments, basic amino acids include, but are not limited to, histidine (H), arginine (R), lysine (K), glutamine (Q), 2,3-diaminopropionic acid (Dpr), ornithine (Orn), homoarginine (hArg), 2,4-diaminobutyric acid (Dbu), 2,3-diaminobutyric acid (Dab), or p-aminophenylalanine (Phe(p-NH2)). In some embodiments, pharmaceutically acceptable salts are meglumine (N-methyl-D-glucamine) salt, eglumine (N-ethyl-D-glucamine) salt, D-glucamine salt, glucosamine salt, choline salt, lysine salt, arginine salt, histidine salt, or glutamine salt. In some embodiments, pharmaceutically acceptable salts are L-lysine salt, L-arginine salt, L-histidine salt, or L-glutamine salt.Those skilled in the art will further recognize that pharmaceutically acceptable salts can be prepared by reacting the compounds of the present invention with a suitable inorganic or organic acid or base via one of a number of known methods.

[0022] The term "solvate" refers to a solvated complex. Solvates can be formed by solvation (combination of a solvent molecule with a molecule or ion of the compound of the present invention), or they can be aggregates containing solute ions or molecules or solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and hexahydrates. Solvates can be formed via hydration, including the absorption of water. A pharmaceutically acceptable salt may also be a solvate. If the solvate is obtained by crystallization from a solvent, the solvent may be an alcohol such as methanol or ethanol, an aldehyde, a ketone such as acetone, or an ester such as ethyl acetate.

[0023] The compounds of the present invention may have one or more chiral centers and therefore may be enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of the present invention include all such possible isomers (including geometric isomers), whether or not they are specifically shown herein, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and resolution crystallization. Conventional techniques for the preparation or isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates using, for example, chiral high-pressure liquid chromatography (HPLC). Unless otherwise specified, the compounds of the present invention include both E and Z geometric isomers, where the compounds of the present invention contain an olefinic double bond or another geometric chiral center. Similarly, the compounds of the present invention include all tautomer forms.

[0024] "Effective dose" means the amount of a compound, pharmaceutically acceptable salt, or solvate of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, that is effective in the method of the present invention, either alone or in combination with another pharmaceutically active agent, when administered to a subject.

[0025] "Effective amount" means the amount of other pharmaceutically active agents that are effective in the composition or method of the present invention, either alone or in combination with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, when used in conjunction with another pharmaceutically active agent.

[0026] The "subject" is a human or a non-human mammal, such as a cattle, horse, cat, dog, rodent, or non-human primate. A human can be male or female, a child, adolescent, or adult. A female can be pre-menstrual or post-menstrual.

[0027] "Mammals" include humans, domesticated animals such as laboratory animals (e.g., mice, rats, rabbits, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domesticated wild animals.

[0028] All weight percentages referenced herein (i.e., "weight %", "wt.%", and "w / w"), unless otherwise indicated, refer to the total weight of the mixture or composition.

[0029] As used herein, the following terms have the meanings set forth below unless otherwise indicated.

[0030] "Halo," "Hal," or "halogen" refers to Br, Cl, F, or I.

[0031] "Alkyl" refers to a linear or branched hydrocarbon chain having 1 to 12 carbon atoms, with atoms bonded by single bonds and completely saturated. This includes alkyls with 1 to 12 carbon atoms. Alkyls with 1 to 12 carbon atoms are C1-C 12 Alkyl alkyl groups, which have 1 to 10 carbon atoms, are C1-C 10 Alkyl groups having 1 to 6 carbon atoms are C1-C6 alkyl groups, and alkyl groups having 1 to 5 carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl groups, C4 alkyl groups, C3 alkyl groups, C2 alkyl groups, and C1 alkyl groups (i.e., methyl groups). C1-C6 alkyl groups include all the parts described above for C1-C5 alkyl groups, but also include C6 alkyl groups. 10Alkyl includes all the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 alkyl. Similarly, C1-C 12 alkyl includes all the moieties described above, but also includes C 11 and C 12 alkyl. Non-limiting examples of C1-C 12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise stated, an alkyl group can be unsubstituted or substituted with substituents disclosed herein.

[0032] "Alkylene" refers to a fully saturated, straight-chain or branched-chain divalent hydrocarbon having 1 to 12 carbon atoms. Non-limiting examples of C1-C 12 alkylene include methylene, ethylene, propylene, n-butylene, etc. The ends of each alkylene are bonded to atoms by single bonds. The bonding points of the alkylene chain can be one or two atoms. Unless otherwise stated, the alkylene chain can be unsubstituted or substituted with substituents disclosed herein.

[0033] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is bonded to an atom by a single bond. An alkenyl group having a number of 2 to 12 carbon atoms is included. An alkenyl group having 2 to 12 carbon atoms is C2-C 12 alkenyl, and an alkenyl group having 2 to 10 carbon atoms is C2-C 10Alkenyl groups having 2 to 6 carbon atoms are C2-C6 alkenyls, and alkenyl groups having 2 to 5 carbon atoms are C2-C5 alkenyls. C2-C5 alkenyls include C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. C2-C6 alkenyls include all the parts described above for C2-C5 alkenyls, but also include C6 alkenyls. 10 Alkenyls include all the parts described above for C2-C5 alkenyls and C2-C6 alkenyls, but also C7, C8, C9 and C 10 This also includes alkenyls. Similarly, C2-C 12 Alkenil includes all the parts mentioned above, but C 11 and C 12 Includes alkenyls. C2-C 12Non-limiting examples of alkenyls include ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl Examples include 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specified, alkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0034] "Alkenylene" refers to a linear or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. C2-C 12 Non-limiting examples of alkenylenes include etenylene, propenylene, and butenylene. Each end of an alkenylene chain is bonded to an atom by a single bond. The bonding sites of an alkenylene chain can be mediated by one or two atoms. Unless otherwise specified, alkenylene chains may be unsubstituted or substituted with substituents disclosed herein.

[0035] "Alkynyl" refers to a linear or branched hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is bonded to an atom by a single bond. Alkynyl groups with 2 to 12 carbon atoms are C2-C 12 Alkynnyl groups, which have 2 to 10 carbon atoms, are C2-C 10 Alkynyl groups with 2 to 6 carbon atoms are C2-C6 alkynyls, and alkynyl groups with 2 to 5 carbon atoms are C2-C5 alkynyls. C2-C5 alkynyls include C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. C2-C6 alkynyls include all the parts described above for C2-C5 alkynyls, but also include C6 alkynyls. 10 Alkynnyl includes all the parts described above for C2-C5 alkynyls and C2-C6 alkynyls, but also C7, C8, C9 and C 10 This also includes alkynyl. Similarly, C2-C 12 Alkinyl includes all of the above parts, but C 11 and C 12 Includes alkynyl. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, and pentynyl. Unless otherwise specified, alkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0036] "Alkynylene" refers to a linear or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. C2-C 12 Non-limiting examples of alkylylenes include ethynylene, propynylene, and butynylene. Each end of an alkylylene chain is bonded to an atom via a single bond. The bonding sites of an alkylylene chain may be mediated by one or two atoms. Unless otherwise specified, alkylylene chains may be unsubstituted or substituted with substituents disclosed herein.

[0037] "alkoxy" is the formula -OR a It refers to the radical of, in the formula, R a This refers to an alkyl, alkenyl, or alkynyl radical as defined herein. Unless otherwise specified, the alkoxy group may be unsubstituted or substituted with substituents disclosed herein.

[0038] "Aryl" refers to a hydrocarbon ring radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include condensed or crosslinked ring systems. Examples of aryl radicals, but not limited to, include aceantrilenyl, acenaphtylenyl, acephenantrilenyl, anthracenyl, azlenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenantrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless otherwise specified, aryls may be unsubstituted or substituted with substituents disclosed herein.

[0039] "Arylene" refers to a divalent aryl group, where aryl is as defined herein. Unless otherwise specified, arylene groups may be unsubstituted or substituted with substituents disclosed herein.

[0040] "Arylalkyl" is defined by formula -R b -R c It refers to the radical of, in the formula, R b R is an alkylene group as defined herein, c is an aryl radical as defined herein, such as benzyl, diphenylmethyl, etc. Unless otherwise specified, arylalkyl groups may be unsubstituted or substituted with substituents disclosed herein. "Arylalkenyl" is defined as formula -R b -R c It refers to the radical of, in the formula, Rb R is an alkenylene group as defined herein, c is an aryl radical as defined herein. Unless otherwise specified, the arylalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0041] "Arylalkynyl" is represented by formula -R b -R c It refers to the radical of, in the formula, R b R is an alkynylene group as defined herein, c is an aryl radical as defined herein. Unless otherwise specified, the arylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0042] "Cycloalkyl" refers to a non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and may include condensed or cross-linked ring systems, bonded to atoms by single bonds. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified, cycloalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0043] "Aryloxy" refers to a radical of the formula -O(aryl), where the aryl radical is as defined herein. Examples of aryloxy include, but are not limited to, phenoxy(-O(phenyl)). Unless otherwise specified, the aryloxy group may be unsubstituted or substituted with substituents disclosed herein.

[0044] A "cycloalkenyl" refers to a non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting of carbon and hydrogen atoms and having one or more carbon-carbon double bonds. Cycloalkenyls may have 3 to 20 carbon atoms, and in some embodiments, 3 to 10 carbon atoms, including condensed or bridging ring systems. The cycloalkenyl group is bonded to atoms by single bonds. Examples of monocyclic cycloalkenyl radicals include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic cycloalkenyl radicals include bicyclo[2.2.1]hepta-2-enyl. Unless otherwise specified, the cycloalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0045] "Cycloalkynyl" refers to a non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and may include a condensed or bridging ring system having 5 to 20 carbon atoms, and in some embodiments, 5 to 10 carbon atoms, which are bonded to the rest of the molecule by single bonds. Examples of monocyclic cycloalkynyl radicals include cycloheptynyl and cyclooctinyl. Unless otherwise specified, the cycloalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0046] "Cycloalkylalkyl" is defined by formula -R b -R d It refers to the radical of, in the formula, R b R is an alkylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, cycloalkylalkyls may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkylalkenyl" is a radical of formula -R b -R d It refers to the radical of, in the formula, R b R is an alkenylene group as defined herein, dis a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkylalkenyl group may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkylalkynyl" is defined as formula -R b -R d It refers to the radical of, in the formula, R b R is an alkynylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0047] "Cycloalkenylalkyl" is a compound of the formula -R b -R d It refers to the radical of, in the formula, R b R is an alkylene group as defined herein, d is a cycloalkenyl radical as defined herein. Unless otherwise specified, cycloalkenylalkyl groups may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkenylalkenyl" is defined as formula -R b -R d It refers to the radical of, in the formula, R b R is an alkenylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkenylalkenyl group may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkenylalkynyl" is defined as formula -R b -R d It refers to the radical of, in the formula, R b R is an alkynylene group as defined herein, d This is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkenylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0048] "Cycloalkylylalkyl" is a compound of the formula -R b-R d It refers to the radical of, in the formula, R b R is an alkylene group as defined herein, d is a cycloalkynyl radical as defined herein. Unless otherwise specified, cycloalkynyl alkyl groups may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkynyl alkenyl" is defined as formula -R b -R d It refers to the radical of, in the formula, R b R is an alkenylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkynylalkenyl group may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkynylalkenyl" is defined as formula -R b -R d It refers to the radical of, in the formula, R b R is an alkynylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkynylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0049] "Carbocyclyl," "carbocyclyl ring," or "carbocyclic ring" refers to a cyclic structure in which each atom forming the ring is carbon. Carbocyclyls, carbocyclyl rings, or carbocyclic rings can contain 3 to 20 carbon atoms within the ring. Examples of carbocyclyls, carbocyclyl rings, or carbocyclic rings as defined herein include aryl, cycloalkyl, cycloalkenyl, and cycloalkynyl rings. Carbocyclyls, carbocyclyl rings, or carbocyclic rings can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and can include condensed, bridged, and helical ring systems. Unless otherwise specified, carbocyclyl groups, carbocyclyl rings, or carbocyclic rings may be unsubstituted or substituted with substituents disclosed herein.

[0050] "Haloalkyl" means an alkyl radical as defined herein that is substituted with one or more halo radicals as defined herein, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. Unless otherwise specified, haloalkyls may be unsubstituted or substituted with substituents disclosed herein.

[0051] "Haloalkenyl" refers to an alkenyl radical as defined herein that is substituted with one or more halo radicals as defined herein, such as 1-fluoropropenyl and 1,1-difluorobutenyl. Unless otherwise specified, the haloalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0052] "Haloalkynyl" refers to an alkynyl radical as defined herein that is substituted with one or more halo radicals as defined herein, such as 1-fluoropropynyl and 1-fluorobutynyl. Unless otherwise specified, the haloalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0053] "Heterocyclyl" refers to a 3-20 membered non-aromatic, partially unsaturated, or aromatic cyclic radical comprising 2-12 carbon atoms and 1-6 nitrogen, oxygen, or sulfur heteroatoms. Heterocyclyls include heteroaryls as defined herein. Unless otherwise stated, heterocyclyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include condensed, bridging, and helical ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atoms may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonyl, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxothiomorpholinil, and 1,1-dioxothiomorpholinil. Unless otherwise specified, the heterocyclyl group may be unsubstituted or substituted with substituents disclosed herein.

[0054] "Heterocyclylalkyl" is a compound of formulas -R b -R e It refers to the radical of, in the formula, R b R is an alkylene group as defined herein, e is a heterocyclyl radical as defined herein. Unless otherwise specified, heterocyclylalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0055] "Heterocyclylalkenyl" is represented by formula -R b -R e It refers to the radical of, in the formula, Rb R is an alkenylene group as defined herein, e is a heterocyclyl radical as defined herein. Unless otherwise specified, the heterocyclyl alkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0056] "Heterocyclylalkynyl" is derived from formula -R b -R e It refers to the radical of, in the formula, R b R is an alkynylene group as defined herein, e is a heterocyclyl radical as defined herein. Unless otherwise specified, the heterocyclylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0057] "N-heterocyclyl" means a heterocyclyl radical as defined herein, comprising at least one nitrogen atom, wherein the bonding site of the heterocyclyl radical of the atoms of the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or their pharmaceutically acceptable salts or solvates, is via the nitrogen atom in the heterocyclyl radical. Unless otherwise stated, the N-heterocyclyl group may be unsubstituted or substituted with substituents disclosed herein.

[0058] A "heteroaryl" refers to a 5-20 membered cyclic radical containing a hydrogen atom, 1-13 carbon atoms, 1-6 nitrogen, oxygen, or sulfur heteroatoms, and at least one aromatic ring. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which may include condensed or bridging cyclic systems. The nitrogen, carbon, or sulfur atoms in the heteroaryl radical can optionally be oxidized, and the nitrogen atom can optionally be quaternized. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzofuranonil, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophene, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, and indo Examples include lyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. Unless otherwise specified, heteroaryl groups are either unsubstituted or substituted.

[0059] "N-Heteroaryl" refers to a heteroaryl radical as defined herein having at least one nitrogen atom, and for a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, the point of attachment of the heteroaryl radical to an atom is via a nitrogen atom in the heteroaryl radical. Unless otherwise stated, an N-heteroaryl group can be unsubstituted or substituted with substituents disclosed herein.

[0060] "Heteroarylalkyl" refers to a radical of the formula -R b -R f wherein R b is an alkylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless otherwise stated, a heteroarylalkyl group can be unsubstituted or substituted with substituents disclosed herein.

[0061] "Heteroarylalkenyl" refers to a radical of the formula -R b -R f wherein R b is an alkenylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless otherwise stated, a heteroarylalkenyl group can be unsubstituted or substituted with substituents disclosed herein.

[0062] "Heteroarylalkynyl" refers to a radical of the formula -R b -R f wherein R b is an alkynylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless otherwise stated, a heteroarylalkynyl group can be unsubstituted or substituted with substituents disclosed herein.

[0063] A “ring” refers to a cyclic group that can be saturated or that may contain one or more double or triple bonds. A ring may be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a ring may be unsubstituted or substituted with substituents disclosed herein.

[0064] "Thioalkyl" is represented by formula -SR a It refers to the radical of, in the formula, R a is an alkyl, alkenyl, or alkynyl radical as defined herein. Unless otherwise specified, thioalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0065] "Ms" refers to the mesyl (methanesulfonyl) group.

[0066] "Ts" refers to the tosyl (4-toluenesulfonyl) group.

[0067] The groups or radicals disclosed herein may be substituted with one or more substituents from the following: halogen atoms such as F, Cl, Br, and I; hydroxyl, alkoxy or ester; thiol, thioalkyl, sulfone, sulfonyl or sulfoxide; amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide and enamine; trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl; and other groups, optionally comprising one or more heteroatoms.

[0068] In some embodiments, the groups or radicals disclosed herein are substituted, or additionally, with one or more of the following substituents: oxo, carbonyl, carboxyl, or ester groups, or imines, oximes, hydrazones, and nitriles.

[0069] In some embodiments, the groups or radicals disclosed herein are substituted, or additionally, with one or more of the following substituents: amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NR g R h , -OR g , -SR g -SOR g , -SO2R g , -OSO2R g , -SO2OR g ,=NSO2R g -SO2NR g R h -C(=O)R g , -C(=O)OR g -C(=O)NR g R h -CH2SO2R g , and -CH2SO2NR g R h And in the formula, R g and R hThese substituents are identical or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, or heteroarylalkyl, where each of the aforementioned substituents is either unsubstituted or substituted with one or more substituents disclosed herein.

[0070] As used herein, “isolated and purified” means isolated and purified in vivo or in vitro from a chemically synthesized reaction mixture, from an organism that is or was an organism, or from a cell (e.g., biosynthesis). In some embodiments, the isolated and purified compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or its pharmaceutically acceptable salt or solvate, is at least 90% pure. “At least x% pure” means that the compound, pharmaceutically acceptable salt, or solvate contains one or more other compounds in (100-x)% or less. In some embodiments, the isolated and purified compound, its salt or solvate is at least 95% pure. In some embodiments, the isolated and purified compound, its salt or solvate is at least 96%, at least 97%, at least 98%, or at least 99% pure.

[0071] Where used herein, the symbol [ka] A "bond point" indicates a bond between two chemical substances, where one substance is depicted as bonding to the bond point, and the other is not. For example, [ka] This indicates that the chemical substance "XY" binds to another chemical substance via a bonding point.

[0072] Coenzyme A (CoA) has the following structure: [ka]

[0073] The CoA radicals referred to as "-CoA" in this specification have the following structure: [ka]

[0074] Compounds useful in the method of the present invention

[0075] The present invention provides compounds useful in the methods of the present invention described herein (each compound, pharmaceutically acceptable salt, and solvate is a "compound of the present invention").

[0076] Compound of formula (I)

[0077] In some embodiments, the compound of the present invention has the structure of formula (I): [ka]

[0078] or having a pharmaceutically acceptable salt or solvate thereof, in the formula,

[0079] Each p is independently 1, 2, 3, 4, 5, 6, or 7.

[0080] each Z 1 and Z 2 However, independently, -C(R 1 )(R 2 )-(CH2) c -X, or -W-(CH2) c -C(R3 )(R 4 )-Y,

[0081] Each c is independently 0, 1, 2, or 3.

[0082] Each R 1 and R 2 However, each carbon atom is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group,

[0083] Each R 3 and R 4 However, each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group,

[0084] Q independently comprises -OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, and -SR. 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A , either heteroaryl, heterocyclyl, or -V-OH, or two Qs independently, together with each carbon atom to which they are bonded, form a heterocyclyl group or a carbocykyl group.

[0085] V is (CH2) t or allerene,

[0086] Each R 1A and R 2AHowever, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl.

[0087] t is 0, 1, 2, 3, or 4,

[0088] Each X and Y independently becomes -OH, -COOH, -COOR 5 -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] And,

[0089] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0090] Each R 7 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0091] Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-.

[0092] Each R 5 However, these are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0093] In some embodiments, the compound of formula (I) has the structure of formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0094] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), Z 1 and Z 2 One or both of these are -C(R 1 )(R 2 )-(CH2) c -CO-CoA, or Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 It is )-CO-CoA.

[0095] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), Z 1 and Z 2 One or both of these are -C(R 1 )(R 2 )-(CH2) c -CO-CoA is one of the embodiments. 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Co-CoA.

[0096] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), Z 1 -C(R 1 )(R 2 )-(CH2) c -CO-CoA, Z 2 -C(R 1 )(R 2 )-(CH2) c -COOH, or -C(R 1 )(R2 )-(CH2) c -COOR 5 That is the case.

[0097] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), each R 1 and R 2 R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, each R 1 and R 2 R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, R 1 and R 2 It is methyl.

[0098] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), Z 1 -C(R 1 )(R 2 )-(CH2) c -CO-CoA, Z 2 -C(R 1 )(R 2 )-(CH2) c -X, where X is -CO-CoA, -COOH, or -COOR. 5 And R 1 and R 2 It is methyl.

[0099] In some embodiments of the compounds of formula (I), (IA), (IB), or (IC), c is 0 or 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3.

[0100] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), each carbon atom is independently bonded to a carbon atom R 1 and R 2Together, they form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a cyclopropyl ring.

[0101] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a -C3-C7 cycloalkyl group. In some embodiments, at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring.

[0102] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0103] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), Y is -COOH or -COOR. 5 That is the case.

[0104] In some embodiments of compounds of formula (I), (IA), (IB), or (IC), R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0105] In some embodiments of the compounds of formula (I), (IA), (IB), or (IC), p is 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7. In some embodiments of compounds of formula (I), (IA), (IB), or (IC), Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -CO-CoA, -COOH, or -COOR 5 In some embodiments, Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -CO-CoA, -COOH, or -COOR 5 And R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -CO-CoA, -COOH, or -COOR 5 And R 5These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0106] In some embodiments of the compounds of formula (I), (IA), (IB), or (IC), Q is independently methyl, methoxy, or -OH. In some embodiments, Q is methyl or -OH.

[0107] In some embodiments of the compounds of formula (I), (IA), (IB), or (IC), t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0108] In some embodiments, pharmaceutically acceptable salts of the compounds of formula (I), (IA), (IB), or (IC) are amino acid salts, meglumine salts, eglumine salts, D-glucamine salts, glucosamine salts, or choline salts. In some embodiments, pharmaceutically acceptable salts are salts of basic amino acids. In some embodiments, pharmaceutically acceptable salts of the compounds of formula (I), (IA), (IB), or (IC) are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0109] In some embodiments, the compound of formula (I) or (IA) has one of the structures shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof.

[0110] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0111] In some embodiments, the compound of formula (I) or (IB) has one of the structures shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof.

[0112] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12]

[0113] In some embodiments, the compound of formula (I) or (IC) has one of the structures shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof.

[0114] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13]

[0115] In some embodiments, the compound of formula (I) or (IA) is shown in Table A-4, and C 1 and C 2 It has one of the structures defined by, or a pharmaceutically acceptable salt or solvate thereof.

[0116] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16]

[0117] In some embodiments, the compound of formula (I) or (IB) is shown in Table A-5, and C 1 and C 2 It has one of the structures defined by, or a pharmaceutically acceptable salt or solvate thereof.

[0118] [Table 5-1] Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 5-12 Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23 Table 5-24 Table 5-25 Table 5-26 Table 5-27 Table 5-28 [Table 5-29] [Table 5-30] [Table 5-31] [Table 5-32] [Table 5-33] [Table 5-34] [Table 5-35] [Table 5-36]

[0119] In some embodiments, the compound of formula (I) or (IC) is shown in Table A-6, and C 1 and C 2 It has one of the structures defined by, or a pharmaceutically acceptable salt or solvate thereof.

[0120] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] Table 6-5 Table 6-6 Table 6-7 Table 6-8 Table 6-9 Table 6-10 Table 6-11 Table 6-12 Table 6-13 Table 6-14 Table 6-15 Table 6-16 Table 6-17 Table 6-18 Table 6-19 Table 6-20 Table 6-21 Table 6-22 Table 6-23 Table 6-24 Table 6-25 Table 6-26 Table 6-27 Table 6-28 Table 6-29 Table 6-30 Table 6-31 Table 6-32 Table 6-33 Table 6-34 Table 6-35 Table 6-36 Table 6-37 Table 6-38 Table 6-39 Table 6-40 Table 6-41 Table 6-42 Table 6-43 Table 6-44 Table 6-45 Table 6-46 Table 6-47 Table 6-48 Table 6-49 Table 6-50 Table 6-51 Table 6-52 Table 6-53 Table 6-54 Table 6-55 Table 6-56 Table 6-57 Table 6-58 Table 6-59 [Table 6-60] [Table 6-61] [Table 6-62] [Table 6-63] [Table 6-64]

[0121] In some embodiments, the compounds of formula (I) are shown in Tables A-1, A-2, A-3, and A-4, and C 1 and C 2 Defined by, or A-5, C 1 and C 2 Defined by, or A-6, C 1 and C 2 A structure defined by having one of the structures, or a pharmaceutically acceptable salt or solvate thereof, in which the phenyl ring of the compound is monosubstituted or disubstituted with -OH or -CH3. In some embodiments, these are shown in Tables A-1, A-2, A-3, A-4, and C 1 and C 2 Defined by, or A-5, C 1 and C 2 Defined by, or A-6, C 1 and C 2 pharmaceutically acceptable salts of compounds having any one of the structures defined by are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0122] In some embodiments, the compound of formula (I), (IA), (IB), or (IC) is a coenzyme A mono(thioester) or di(thioester) of a compound having any one of the structures shown in Table A-7, Table A-8, Table A-9, Table A-10, Table A-11, or Table A-12, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutically acceptable salt of a compound having any one of the structures shown in Table A-7, Table A-8, Table A-9, Table A-10, Table A-11, or Table A-12 is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0123] In some embodiments, a pharmaceutically acceptable salt of a compound having any one of the structures shown in Tables A-7, A-8, A-9, A-10, A-11, or A-12 is a zinc salt. For example, the zinc salt of compound I-61 in Table A-9 has the structure described below: [ka]

[0124] [Table 7-1] [Table 7-2]

[0125] [Table 8-1] [Table 8-2] Table 8-3

[0126] Table 9-1 Table 9-2 Table 9-3 Table 9-4 Table 9-5

[0127] Table 10-1 Table 10-2 Table 10-3 Table 10-4 Table 10-5 Table 10-6

[0128] Table 11-1 Table 11-2 Table 11-3 Table 11-4 Table 11-5 Table 11-6 Table 11-7 Table 11-8 Table 11-9 Table 11-10 Table 11-11 Table 11-12 Table 11-13 Table 11-14 Table 11-15 Table 11-16

[0129] Table 12-1 Table 12-2 Table 12-3 Table 12-4 Table 12-5 Table 12-6 Table 12-7 Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12 Table 12-13 Table 12-14 Table 12-15 Table 12-16 Table 12-17 Table 12-18 Table 12-19 Table 12-20 Table 12-21 Table 12-22 Table 12-23 Table 12-24 Table 12-25 Table 12-26 Table 12-27 Table 12-28 Table 12-29 Table 12-30 Table 12-31 Table 12-32 Table 12-33 Table 12-34 Table 12-35 Table 12-36 Table 12-37 Table 12-38 Table 12-39 [Table 12-40] [Table 12-41]

[0130] In some embodiments, compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or their pharmaceutically acceptable salts or solvates, are isolated and purified. In some embodiments, compounds of formula (I), (IA), (IB), or (IC), or their pharmaceutically acceptable salts or solvates, are isolated and purified. In some embodiments, compounds of formula (I), (IA), (IB), or (IC), or their pharmaceutically acceptable salts or solvates, are ex vivo.

[0131] Compound of formula (ID)

[0132] In some embodiments, the compound of the present invention has the structure of formula (ID): [ka]

[0133] or having a pharmaceutically acceptable salt or solvate thereof, in the formula,

[0134] Each p is independently 1, 2, 3, 4, 5, 6, or 7.

[0135] each Z 1 and Z 2 However, independently, -C(R 1 )(R 2 )-(CH2) c -X, or -W-(CH2) c -C(R 3 )(R 4 )-Y,

[0136] Each c is independently 0, 1, 2, or 3.

[0137] Each R 1 and R 2 However, each carbon atom is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group,

[0138] Each R 3 and R 4 However, each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group,

[0139] Q 1 However, it is F, Cl, Br, -CF3, or -O(C1-C4 alkyl),

[0140] Each Q 2 However, independently, -OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A , either heteroaryl, heterocyclyl, or -V-OH, or two Qs independently, together with each carbon atom to which they are bonded, form a heterocyclyl group or a carbocykyl group.

[0141] V is (CH2) t or allerene,

[0142] Each R 1A and R2A However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl.

[0143] t is 0, 1, 2, or 3,

[0144] Each X and Y independently becomes -OH, -COOH, -COOR 5 -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] And,

[0145] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is either unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0146] Each R 7 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0147] Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-.

[0148] Each R 5 However, these are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0149] In some embodiments, the compound of formula (ID) has the structure of formula (IE), formula (IF), or formula (IG), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0150] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), Z 1 and Z 2 Each of these is independent of -C(R 1 )(R 2 )-(CH2) c -X. In some embodiments, Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y.

[0151] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), X is -COOH, -CO-CoA, or -COOR 5 That is the case.

[0152] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), Z 1 -C(R 1 )(R 2 )-(CH2) c -CO-CoA, Z 2 -C(R 1 )(R 2 )-(CH2) c -COOH, or -C(R 1 )(R 2 )-(CH2) c -COOR 5 In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), Z 2 -C(R 1 )(R 2 )-(CH2) c -CO-CoA, Z 1-C(R 1 )(R 2 )-(CH2) c -COOH, or -C(R 1 )(R 2 )-(CH2) c -COOR 5 That is the case.

[0153] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), Z 1 and Z 2 One or both of these are -C(R 1 )(R 2 )-(CH2) c -CO-CoA is one of the embodiments. 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Co-CoA.

[0154] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), each R 1 and R 2 R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, each R 1 and R 2 R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, R 1 and R 2 It is methyl.

[0155] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), Z 1 -C(R 1 )(R 2 )-(CH2) c -CO-CoA, Z 2 -C(R 1 )(R 2 )-(CH2) c -X, where X is -CO-CoA, -COOH, or -COOR.5 And R 1 and R 2 It is methyl.

[0156] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), c is 0 or 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3.

[0157] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a cyclopropyl ring.

[0158] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a -C3-C7 cycloalkyl group. In some embodiments, at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring.

[0159] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0160] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), Y is -COOH or -COOR. 5 That is the case.

[0161] In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0162] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), p is 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7. In some embodiments of compounds of formula (ID), (IE), (IF), or (IG), Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -CO-CoA, -COOH, or -COOR 5 In some embodiments, Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4)-Y, where Y is -CO-CoA, -COOH, or -COOR 5 And R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -CO-CoA, -COOH, or -COOR 5 And R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0163] In some embodiments of the compounds of formula (ID), (IE), (IF), or (IG), t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0164] In some embodiments, pharmaceutically acceptable salts of the compound of formula (ID), (IE), (IF), or (IG) are amino acid salts, meglumine salts, eglumine salts, D-glucamine salts, glucosamine salts, or choline salts. In some embodiments, pharmaceutically acceptable salts are salts of basic amino acids. In some embodiments, pharmaceutically acceptable salts of the compound of formula (ID), (IE), (IF), or (IG) are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0165] In some embodiments, the pharmaceutically acceptable salts of the compounds of formula (ID), (IE), (IF), or (IG) are zinc salts.

[0166] In some embodiments, the pharmaceutically acceptable salts of the compound of formula (IF) or (IG) are zinc salts, where p is 3 or 4 and each X and Y is -COOH.

[0167] In some embodiments, compounds of formula (ID), (IE), (IF), or (IG) are shown in Table A-13, C 1 and C 2 Defined by, if present, R, R 1 and R 2 It has one of the structures defined by, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R of the compounds in Table A-13 is CH3. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-13 are CH3. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-13 are F. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-13 are Cl. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-13 are Br. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-13 are CF3.

[0168] In some embodiments, as shown in Table A-13, C 1 and C 2 A pharmaceutically acceptable salt of a compound having any one of the structures defined by, and if present, R, R1, and R2, is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0169] Table 13-1 Table 13-2 Table 13-3 Table 13-4 Table 13-5 Table 13-6 Table 13-7 Table 13-8 Table 13-9 Table 13-10 Table 13-11 Table 13-12 Table 13-13 Table 13-14 Table 13-15 Table 13-16 Table 13-17 Table 13-18 Table 13-19 Table 13-20 Table 13-21 Table 13-22 Table 13-23 Table 13-24 Table 13-25 Table 13-26 Table 13-27 Table 13-28 Table 13-29 Table 13-30 Table 13-31 Table 13-32 Table 13-33 Table 13-34 Table 13-35 Table 13-36 Table 13-37 Table 13-38 Table 13-39 Table 13-40

[0170] In some embodiments, compounds of formula (ID), (IE), (IF), or (IG) are shown in Table A-14, C 1 and C 2 Defined by, if present, R, R 1 and R 2 It has one of the structures defined by, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R of the compounds in Table A-14 is CH3. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-14 are CH3. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-14 are F. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-14 are Cl. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-14 are Br. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-14 are CF3.

[0171] In some embodiments, as shown in Table A-14, C 1 and C 2 A pharmaceutically acceptable salt of a compound having any one of the structures defined by, and if present, R, R1, and R2, is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0172] [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] Table 14-5 Table 14-6 Table 14-7 Table 14-8 Table 14-9 Table 14-10 Table 14-11 Table 14-12 Table 14-13 Table 14-14 Table 14-15 Table 14-16 Table 14-17 Table 14-18 Table 14-19 Table 14-20 Table 14-21 Table 14-22 Table 14-23 Table 14-24 Table 14-25 Table 14-26 Table 14-27 Table 14-28 Table 14-29 Table 14-30 Table 14-31 Table 14-32 Table 14-33 Table 14-34 Table 14-35 Table 14-36 Table 14-37 Table 14-38 Table 14-39 Table 14-40 Table 14-41 Table 14-42 Table 14-43 Table 14-44 Table 14-45 Table 14-46 Table 14-47 Table 14-48 Table 14-49 Table 14-50 Table 14-51 Table 14-52 Table 14-53 Table 14-54 Table 14-55 Table 14-56 Table 14-57 Table 14-58 Table 14-59 Table 14-60 Table 14-61 Table 14-62 Table 14-63 Table 14-64 Table 14-65 Table 14-66 Table 14-67 Table 14-68 Table 14-69 Table 14-70 Table 14-71 Table 14-72 [Table 14-73] [Table 14-74] [Table 14-75] [Table 14-76] [Table 14-77] [Table 14-78] [Table 14-79] [Table 14-80] [Table 14-81]

[0173] In some embodiments, compounds of formula (ID), (IE), (IF), or (IG) are shown in Table A-15, C 1 and C 2It is defined by and, if present, has one of the structures defined by R, R1 and R2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R of the compounds in Table A-15 is CH3. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-15 is CH3. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-15 is F. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-15 is Cl. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-15 is Br. In some embodiments, one or more of R, R1 and R2 of the compounds in Table A-15 is CF3.

[0174] In some embodiments, as shown in Table A-15, C 1 and C 2 A pharmaceutically acceptable salt of a compound having any one of the structures defined by, and if present, R, R1, and R2, is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0175] [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] Table 15-6 Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16 Table 15-17 Table 15-18 Table 15-19 Table 15-20 Table 15-21 Table 15-22 Table 15-23 Table 15-24 Table 15-25 Table 15-26 Table 15-27 Table 15-28 Table 15-29 Table 15-30 Table 15-31 Table 15-32 Table 15-33 Table 15-34 Table 15-35 Table 15-36 Table 15-37 Table 15-38 Table 15-39 Table 15-40 Table 15-41 Table 15-42 Table 15-43 Table 15-44 Table 15-45 Table 15-46 Table 15-47 Table 15-48 Table 15-49 Table 15-50 Table 15-51 Table 15-52 Table 15-53 Table 15-54 Table 15-55 Table 15-56 Table 15-57 Table 15-58 Table 15-59 Table 15-60 Table 15-61 Table 15-62 Table 15-63 Table 15-64 Table 15-65 Table 15-66 Table 15-67 Table 15-68 Table 15-69 Table 15-70 Table 15-71 Table 15-72 Table 15-73 Table 15-74 Table 15-75 Table 15-76 Table 15-77 Table 15-78 Table 15-79 Table 15-80 Table 15-81 Table 15-82 Table 15-83 Table 15-84 Table 15-85 Table 15-86 Table 15-87 Table 15-88 Table 15-89 Table 15-90 Table 15-91 Table 15-92 Table 15-93 Table 15-94 Table 15-95 Table 15-96 Table 15-97 Table 15-98 Table 15-99 Table 15-100 Table 15-101 Table 15-102 Table 15-103 Table 15-104 Table 15-105 Table 15-106 Table 15-107 Table 15-108 Table 15-109

Table 15-110

Table 15-120

[0176] Compounds of formula (IH)

[0177] In some embodiments, the compound has the structure of formula (IH): [ka]

[0178] or having a pharmaceutically acceptable salt or solvate thereof, in the formula,

[0179] Z 1 However, -C(R 1 )(R 2 )-(CH2) c -X, or -W-(CH2) c -C(R 3 )(R 4 )-Y,

[0180] c is 0, 1, 2, or 3,

[0181] Each R 1 and R 2 However, each carbon atom is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group,

[0182] Each R 3 and R 4 However, each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4Together, they form a -C3-C7 cycloalkyl group,

[0183] Q independently comprises -OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, and -SR. 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A , either heteroaryl, heterocyclyl, or -V-OH, or two Qs independently, together with each carbon atom to which they are bonded, form a heterocyclyl group or a carbocykyl group.

[0184] V is (CH2) t or allerene,

[0185] Each R 1A and R 2A However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl.

[0186] t is 0, 1, 2, 3, or 4,

[0187] Each X and Y independently becomes -OH, -COOH, -COOR 5 -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] And,

[0188] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is either unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0189] Each R 7 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0190] Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-.

[0191] Each R 5 However, independently, they are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is unsubstituted or contains one or more halogens, -OH, -O (C1-C6 alkyl) or substituted with a phenyl group.

[0192] In some embodiments of the compound of formula (IH), Z 1 -C(R 1 )(R 2 )-(CH2) c -X. In some embodiments, Z 1 -C(R 1 )(R 2 )-(CH2) c -X, where X is -COOH, -COOR 5 , or -CO-CoA. In some embodiments, Z 1 -C(R 1 )(R 2 )-(CH2) c -X, where X is -COOH. In some embodiments, c is 0.

[0193] In some embodiments of the compound of formula (IH), each R 1 and R 2 Independently, R is a C1-C6 alkyl group. In some embodiments, R 1 and R 2 It is methyl.

[0194] In some embodiments of the compound of formula (IH), each carbon atom is independently bonded to a carbon atom R1 and R 2 Together, they form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a cyclopropyl ring.

[0195] In some embodiments of the compound of formula (IH), t is 0.

[0196] In some embodiments, the compound of formula (IH) has one of the structures shown in Table A-16, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutically acceptable salt of the compound having one of the structures shown in Table A-16 is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt. In some embodiments, a pharmaceutically acceptable salt of the compound having one of the structures shown in Table A-16 is a zinc salt.

[0197] [Table 16]

[0198] Compound of formula (IJ)

[0199] In some embodiments, the compound has the structure of formula (IJ): [ka]

[0200] or having a pharmaceutically acceptable salt or solvate thereof, in the formula,

[0201] Each p is independently either 1 or 2.

[0202] Z1 However, -C(R 1 )(R 2 )-(CH2) c -X, or -W-(CH2) c -C(R 3 )(R 4 )-Y,

[0203] c is 0, 1, 2, or 3,

[0204] Each R 1 and R 2 However, each carbon atom is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group,

[0205] Each R 3 and R 4 However, each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group,

[0206] Q independently comprises -OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, and -SR. 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A , either heteroaryl, heterocyclyl, or -V-OH, or two Qs independently, together with each carbon atom to which they are bonded, form a heterocyclyl group or a carbocykyl group.

[0207] V is (CH2) t or allerene,

[0208] Each R 1A and R 2A However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl.

[0209] t is 0, 1, 2, 3, or 4,

[0210] Each X and Y independently becomes -OH, -COOH, -COOR 5 -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] And,

[0211] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is either unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0212] Each R 7 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0213] Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-.

[0214] Each R 5 However, independently, they are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is unsubstituted or contains one or more halogens, -OH, -O (C1-C6 alkyl) or substituted with a phenyl group.

[0215] In some embodiments of the compound of formula (IJ), Z 1 -C(R 1 )(R 2 )-(CH2) c -X. In some embodiments, Z 1 -C(R 1 )(R 2 )-(CH2) c -X, where X is -COOH, -COOR 5 , or -CO-CoA. In some embodiments, Z 1 -C(R 1 )(R 2 )-(CH2) c -X, where X is -COOH. In some embodiments, c is 0.

[0216] In some embodiments of the compound of formula (IJ), each R 1 and R 2 Independently, R is a C1-C6 alkyl group. In some embodiments, R 1 and R 2 It is methyl.

[0217] In some embodiments of the compound of formula (IJ), each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a cyclopropyl ring.

[0218] In some embodiments of the compound of formula (IJ), t is 0.

[0219] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (IJ) is a zinc salt.

[0220] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (IJ) is a zinc salt, where X and Y are -COOH.

[0221] In some embodiments, the compound of formula (IJ) has one of the structures shown in Table A-17, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutically acceptable salt of the compound having one of the structures shown in Table A-17 is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt. In some embodiments, a pharmaceutically acceptable salt of the compound having one of the structures shown in Table A-17 is a zinc salt.

[0222] [Table 17]

[0223] Compounds in Table A-18

[0224] In some embodiments, the compounds of the present invention are compounds having any one of the structures shown in Table A-18, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of formula (I) or (IC) have any one of the structures shown in Table A-18, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, pharmaceutically acceptable salts of the compounds in Table A-18 are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt. In some embodiments, the pharmaceutically acceptable salt of the compounds having any one of the structures shown in Table A-18 is a zinc salt.

[0225] [Table 18-1] [Table 18-2]

[0226] Compounds in Table A-19

[0227] In some embodiments, the compounds of the present invention are shown in Table A-19, C 1 , C 2 A compound having any one of the structures defined by , and R, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (I) or (IC) has any one of the structures shown in Table A-19, or a pharmaceutically acceptable salt or solvate thereof, and C 1 or C 2 At least one of them is CO-CoA. In some embodiments, the compound of formula (I), (ID), or (IG) has one of the structures shown in Table A-19, or a pharmaceutically acceptable salt or solvate thereof, and at least one R is F, Cl, Br, -CF3, or -O(C1-C4 alkyl). In some embodiments, R of the compound is CH3. In some embodiments, at least one R of the compounds in Table A-19 is CH3. In some embodiments, at least one R of the compounds in Table A-19 is F. In some embodiments, at least one R of the compounds in Table A-19 is Cl. In some embodiments, at least one R of the compounds in Table A-19 is Br. In some embodiments, at least one R of the compounds in Table A-19 is CF3.

[0228] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0229] Compound of formula (II)

[0230] In some embodiments, the compounds of the present invention have the structure of formula (II): [ka]

[0231] or having a pharmaceutically acceptable salt or solvate thereof, in the formula,

[0232] Each R 1 and R 2 However, each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group,

[0233] Each n is independently 0, 1, 2, or 3.

[0234] Each m is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0235] X is -C(=O)-, -CHR 3 -, -CH-CH2(OR 3 )-, -O-, -S-, -S(=O)-, -S(O)2-, -NR 3 -, -N(OH)-, -N(→O)-, or -Se-

[0236] R 3The group is H, -OH, -O(C1-C6 alkyl), -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl, or benzyl, where each of the -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl, and benzyl is either unsubstituted or substituted with one or more halogens, -CN, -NO2, or -CF3 groups.

[0237] Each Y is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-.

[0238] Each Z independently corresponds to -OH, -COOH, and -COOR. 5 -CO-CoA, -CONH2, -CON editing 5 , -CONHMs, -CONHTs, -SO3H, -SO3R 5 , [ka] And,

[0239] Each R 5 However, independently, these are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0240] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is either unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0241] Each R 7 However, these are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0242] In some embodiments of the compound of formula (II), one or both Z groups are -CO-CoA.

[0243] In some embodiments of the compound of formula (II), X is -C(=O)-, -CHR 3 X is -, -O-, -S-, -S(=O)-, or Se. In some embodiments, X is -C(=O)-, -CH(OH)-, -O-, -S-, -S(=O)-, or Se.

[0244] In some embodiments of the compound of formula (II), R 3 The group is H, -OH, -O(C1-C3 alkyl), or -C1-C3 alkyl.

[0245] In some embodiments of the compound of formula (II), each Y is independently -O- or -S-.

[0246] In some embodiments of the compound of formula (II), each R 1 and R 2 R is independently H, -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, each R 1 and R 2 It is independently either H or methyl.

[0247] In some embodiments of the compound of formula (II), each Z is independently -COOH or -COOR 5 In some embodiments, each Z is -COOH.

[0248] In some embodiments of the compound of formula (II), each R 5 These are independently -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0249] In some embodiments of the compound of formula (II), each n is independently 0, 1, or 2. In some embodiments, n is 1.

[0250] In some embodiments of the compound of formula (II), each m is independently 3, 4, 5, or 6. In some embodiments, each m is independently 4 or 5.

[0251] In some embodiments, pharmaceutically acceptable salts of the compound of formula (II) are amino acid salts, meglumine salts, eglumine salts, D-glucamine salts, glucosamine salts, or choline salts. In some embodiments, pharmaceutically acceptable salts of the compound of formula (II) are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0252] In some embodiments, the compound of formula (II) is shown in Table B1, and C 1 and C 2 It has one of the structures defined by, or a pharmaceutically acceptable salt or solvate thereof.

[0253] In some embodiments, the compound of formula (II) is a compound having any one of the structures shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof, a coenzyme A mono(thioester) or di(thioester).

[0254] In some embodiments, C 1 and C 2pharmaceutically acceptable salts of compounds having any one of the structures shown in Table B1 or Table B2, as defined by [the relevant definition], are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0255] [Table 20-1] [Table 20-2] [Table 20-3]

[0256] [Table 21-1] [Table 21-2] [Table 21-3]

[0257] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is isolated and purified. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is ex vivo.

[0258] Compounds of formulas (III), (IIIA), and (IIIB)

[0259] In some embodiments, the compound of the present invention has the structure of formula (III): [ka]

[0260] or having a pharmaceutically acceptable salt or solvate thereof, in the formula,

[0261] R 1 and R 2 However, independently, they are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 However, together with the carbon atoms to which they are bonded, they form a -C3-C7 cycloalkyl group.

[0262] Each m is independently 3, 4, 5, 6, or 7.

[0263] Each n is independently 0, 1, 2, 3, 4, or 5.

[0264] Each q is 0, 1, 2, 3, or 4.

[0265] X is -O-, -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-,

[0266] Z1 and Z2 independently have -C1-C6 alkyl, -OH, -COOH, and -COOR 5 -CO-CoA, -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, -SO3R 5 , [ka] And,

[0267] Each R 5However, independently, these are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0268] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0269] Each R 7 However, these are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0270] In some embodiments, the compound has the structure of formula (IIIA): [ka]

[0271] or having a pharmaceutically acceptable salt or solvate thereof,

[0272] R 1 and R 2 However, independently, they are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 However, together with the carbon atoms to which they are bonded, they form a -C3-C7 cycloalkyl group.

[0273] Each m is independently 2, 3, 4, 5, 6, or 7.

[0274] Each n is independently 0, 1, 2, 3, 4, or 5.

[0275] Each q is 0, 1, 2, 3, or 4.

[0276] X is -O-, -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-,

[0277] Z1 and Z2 are -C1-C6 alkyl, -COOH, -COOR 5 -CO-CoA, -CONH2, -CONHR 5 -CONHMs, -CONHTs, -SO3R 5 , [ka] In the formula, Z1 and Z2 are the same,

[0278] Each R 5 However, independently, these are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0279] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is either unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0280] Each R 7 However, these are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0281] In some embodiments, the compound has the structure of formula (IIIB): [ka]

[0282] or having a pharmaceutically acceptable salt or solvate thereof,

[0283] R 1 and R 2 However, independently, they are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 However, together with the carbon atoms to which they are bonded, they form a -C3-C7 cycloalkyl group.

[0284] Each m is independently 2, 3, 4, 5, 6, or 7.

[0285] Each n is independently 0, 1, 2, 3, 4, or 5.

[0286] Each q is 0, 1, 2, 3, or 4.

[0287] X is -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-.

[0288] Z1 and Z2 independently have -C1-C6 alkyl, -OH, -COOH, and -COOR 5 -CO-CoA, -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, -SO3R 5 , [ka] And,

[0289] Each R 5However, independently, these are -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0290] Each R 6 However, independently, these are H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0291] Each R 7 However, these are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0292] In some embodiments of the compounds of formulas (III), (IIIA), and (IIIB), one or both of Z1 and Z2 are -CO-CoA.

[0293] In some embodiments of the compounds of formulas (III) and (IIIB), Z 1 is -CO-CoA, and Z 2 These are -OH, -COOH, -CO-CoA, or -COOR 5 In some embodiments, Z 2 is -CO-CoA, and Z 1 These are -OH, -COOH, -CO-CoA, or -COOR 5 That is the case.

[0294] In some embodiments of the compounds of formula (III), (IIIA), and (IIIB), Z 1 and Z 2 Each of these is -CO-CoA.

[0295] In some embodiments of the compound of formula (III), X is -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-.

[0296] In some embodiments of the compounds of formula (III) and (IIIA), X is O. In some embodiments of the compounds of formula (III), when X is O, m is 2, 3, 5, 6, or 7.

[0297] In some embodiments of the compounds of formulas (III), (IIIA), and (IIIB), each n is independently 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0298] In some embodiments of the compounds of formulas (III), (IIIA), and (IIIB), each m is independently 4, 5, or 6. In some embodiments, m is 5 or 6. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 2 or 3.

[0299] In some embodiments of the compounds of formula (III), (IIIA), and (IIIB), R 1 and R 2 These, together with the carbon atoms to which they are bonded, form a -C3-C7 cycloalkyl group.

[0300] In some embodiments, pharmaceutically acceptable salts of the compounds of formulas (III), (IIIA), and (IIIB) are amino acid salts, meglumine salts, eglumine salts, D-glucamine salts, glucosamine salts, or choline salts. In some embodiments, pharmaceutically acceptable salts are salts of basic amino acids. In some embodiments, pharmaceutically acceptable salts of the compounds of formulas (III), (IIIA), and (IIIB) are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0301] In some embodiments, the compound of formula (III) or (IIIA) has one of the structures shown in Table B3, or a pharmaceutically acceptable salt or solvate thereof.

[0302] In some embodiments, the compound of formula (III) or (IIIA) has one of the structures shown in Table B4, or a pharmaceutically acceptable salt or solvate thereof.

[0303] In some embodiments, the compound of formula (III) or (IIIA) is a compound having any one of the structures shown in Table B4, or a pharmaceutically acceptable salt or solvate thereof, a coenzyme A mono(thioester) or di(thioester).

[0304] In some embodiments, the compound of formula (III) or (IIIA) has one of the structures shown in Table B5, or a pharmaceutically acceptable salt or solvate thereof.

[0305] In some embodiments, the compound of formula (III) or (IIIA) is a compound having any one of the structures shown in Table B5, or a pharmaceutically acceptable salt or solvate thereof, a coenzyme A mono(thioester) or di(thioester).

[0306] In some embodiments, C 1 and C 2 pharmaceutically acceptable salts of compounds having any one of the structures shown in Table B3, Table B4, or Table B5, as defined by [the relevant definition], are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0307] [Table 22-1] [Table 22-2]

[0308] [Table 23-1] [Table 23-2]

[0309] [Table 24-1] [Table 24-2]

[0310] In some embodiments, the compound of formula (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, is isolated and purified. In some embodiments, the compound of formula (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, is ex vivo.

[0311] Compositions useful for the method of the present invention

[0312] The present invention provides compositions useful for the methods of the present invention described herein (each composition is referred to as "the Composition of the Invention").

[0313] In some embodiments, the composition of the present invention comprises (i) an effective amount of the compound of the present invention, and (ii) a pharmaceutically acceptable carrier or vehicle.

[0314] In some embodiments, the compositions of the present invention include an effective amount of a compound having the structure described in Table A-1, A-2, A-3, A-4, A-5, A-6, A-13, A-14, A-15, A-16, A-17, A-18, or A-19, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, pharmaceutically acceptable salts of compounds having the structure described in Table A-1, A-2, A-3, A-4, A-5, A-6, A-13, A-14, A-15, A-16, A-17, A-18, or A-19 are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt. In some embodiments, the composition of the present invention comprises an effective amount of a coenzyme A ester of an acid having the structure described in Tables A-7, A-8, A-9, A-10, A-11, or A-12, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention comprises an effective amount of a compound having the structure described in Table B1. In some embodiments, the composition of the present invention comprises an effective amount of a monocoenzyme A ester or dicoenzyme A ester of an acid having the structure described in Table B2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention comprises an effective amount of a compound having the structure described in Table B3. In some embodiments, the composition of the present invention comprises an effective amount of a monocoenzyme A ester or dicoenzyme A ester of an acid having the structure described in Table B4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention comprises an effective amount of a monocoenzyme A ester or dicoenzyme A ester of an acid having the structure described in Table B5, or a pharmaceutically acceptable salt or solvate thereof.

[0315] In some embodiments, the compositions of the present invention comprise (i) pharmaceutically acceptable amino acids, meglumine, eglumine, D-glucamine, glucosamine, or choline salts of the compounds of formula (I), (IA), (IB), (IC), (II), (III), (IIIA), (IIIB), Tables A-7, A-8, A-9, A-10, A-11, A-12, Table B1, B2, B3, B4, and B5, and (ii) a pharmaceutically acceptable carrier or vehicle.

[0316] In some embodiments, the composition of the present invention further comprises another pharmaceutically active agent. In some embodiments, the composition is a fixed-dose composition.

[0317] In some embodiments, the composition of the present invention is further combined with another composition containing another pharmaceutically active agent. In some embodiments, the composition of the present invention and the composition containing another pharmaceutically active agent are formulated separately. In some embodiments, the composition of the present invention and the composition containing another pharmaceutically active agent are formulated separately but administered together. In some embodiments, the composition of the present invention and the composition containing another pharmaceutically active agent are formulated and administered separately. In some embodiments, the composition of the present invention and the composition containing another pharmaceutically active agent are useful in adjuvant therapy.

[0318] In some embodiments, other pharmaceutically active agents include statins, thiazolidinedions or fibrates, bile acid binding resins, niacin, anti-obesity drugs, hormones, thyrophostine, sulfonylurea-based drugs, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type-5 inhibitors, cardiovascular drugs, HDL-enhancing agents, HDL enhancers, apolipoprotein AI gene or protein agonists, apolipoprotein A-IV gene or protein agonists, apolipoprotein gene agonists, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, or acetyl-CoA carboxylase allosteric inhibitors. In some embodiments, other pharmaceutically active agents include statins, thiazolidinedions or fibrates, bile acid binding resins, niacin, anti-obesity drugs, hormones, thyrophostine, sulfonylurea-based drugs, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type-5 inhibitors, cardiovascular drugs, HDL-enhancing drugs, HDL enhancers, apolipoprotein AI gene or protein agonists, and apolipoprotein A-I These include agonists of the V gene or protein, agonists of apolipoprotein genes, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, acetyl-CoA carboxylase allosteric inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP1R) agonists, rapamycin's mammalian target (mTOR) inhibitors, or transforming growth factor beta (TGFβ) inhibitors.

[0319] In some embodiments, the other pharmaceutically active agent is an antagonist or inhibitor of a pro-inflammatory gene or protein, or an agonist of an anti-inflammatory gene or protein. In some embodiments, the other pharmaceutically active agent inhibits or reduces the pro-inflammatory function of IL-6, CRP, TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB, or TGF-β1, or increases its anti-inflammatory function.

[0320] In some embodiments, other pharmaceutically active agents affect the expression or function of fibrosis genes or proteins, or mitotic genes or proteins. In some embodiments, other pharmaceutically active agents modulate the expression or function of FGF-21, MMP-2, TIMP-1, ASK1, or type 3 collagen.

[0321] In some embodiments, other pharmaceutically active agents are regulators of lipid metabolism-related or transport-related genes, regulators of PPAR-α target genes such as HD(ECHS1), PDK4, and Cyp7A1, and regulators of SGLT1, SGL2, ApoC-III, Sulf-2, ANGPTL3, ANGPTL4, and LPL genes.

[0322] In some embodiments, the other pharmaceutically active agent is a statin. In some embodiments, the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the statin is lovastatin. In some embodiments, the statin is atorvastatin or lovastatin.

[0323] In some embodiments, the other pharmaceutically active agent is a fibrate. In some embodiments, the fibrate is fenofibrate, gemfibrozil, or fenofibric acid.

[0324] In some embodiments, the other pharmaceutically active agent is sorafenib. In some embodiments, sorafenib is a pharmaceutically acceptable salt. In some embodiments, sorafenib is sorafenib tosylate. In some embodiments, sorafenib is a free base. In some other embodiments, the other pharmaceutically active agent is paclitaxel. In some embodiments, paclitaxel is a pharmaceutically acceptable salt. In some embodiments, paclitaxel is a free base. In some other embodiments, the other pharmaceutically active agent is carotuximab. In some other embodiments, the other pharmaceutically active agent is pembrolizumab. In some other embodiments, the other pharmaceutically active agent is lenvatinib. In some embodiments, lenvatinib is a pharmaceutically acceptable salt. In some embodiments, lenvatinib is lenvatinib mesylate. In some embodiments, lenvatinib is a free base. In some other embodiments, the other pharmaceutically active agent is avelumab. In some embodiments, the other pharmaceutically active agent is durvalumab. In some other embodiments, the other pharmaceutically active agent is tremelimumab. In some other embodiments, the other pharmaceutically active agent is nivolumab. In some other embodiments, the other pharmaceutically active agent is regorafenib. In some embodiments, regorafenib is a pharmaceutically acceptable salt or solvate. In some embodiments, regorafenib is a hydrate. In some embodiments, regorafenib is a monohydrate. In some embodiments, regorafenib is a free base. In some other embodiments, other pharmaceutically active agents include T-cell receptor (TCR) immunotherapy agents such as tazemetostat, semiprimab, ABX196, and LioCyx; TBI-302, namodenoson, MM-310; tumor injection oncolytic viruses or recombinant oncolytic viruses, such as, but not limited to, telomericin and imurizic; or immunomodulatory genetherapy agents such as MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3.

[0325] In several other embodiments, other pharmaceutically active agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexo, tropifexol, EDP-305, INT-767, and galactoarabino-rhamno Galacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201 / BMS-986263, vorixibat, anlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipercast, oltipraz, MSDC-0602K, ASP9831, roflumilast, ellafibranol, pioglitazone, rosiglitazone, fenofibrate, saroglitazal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, or narumafen. In some embodiments, other pharmaceutically active agents include pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, sarogritazal magnesium, vorixibat, filsocostat, silofexol, ellafibrano, nalmefene, solithromycin, 99m technetium-mebrophenine, and tropifexol. S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpal, physogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424,Brivanib, Tepotinib, Temsirolimus, Epacadostat, RO7119929, Guadecitabine, Linrhodostat, Copanlisib, MIV-818, Bororanib, RO7070179, Axitinib, Sunitinib, Zotiliklib citrate, Scintilimab, Camrelizumab, Spartalizumab, Tripalimab, Bispecific antibody XmAb20717, Mapatumumab, Tremelimumab, Carotuximab, Tocilizumab, Ipil Mumab, atezolizumab, bevacizumab, ramucirumab, IBI305, askrinbakumab, citravatinib, cytokine-based biologics IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, glypican 3-specific chimeric antigen receptor expressing T cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR T cells, novel antigen-reactive T cells, pexastimogene devacirepvec, talimogene laherparepvec, GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, IMA970A, or anti-SARS-CoV-2 vaccine, novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG) DNA, paclitaxel, olaxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, BLU-554 (FGFR4 inhibitor), or CMP-001, or pharmaceutically acceptable salts thereof. In some embodiments, other pharmaceutically active agents include pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazal magnesium, vorixibat, filsocostat, silofexol, ellafibrano, nalmefene, solithromycin, 99m technetium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seradelpal, physogatinib, doxorubicin,Cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, zotilib citrate, cintilimab, camrelizma Spartalizumab, Tripalimab, Bispecific antibody XmAb20717, Mapatumumab, Tremelimumab, Carotuximab, Tocilizumab, Ipilimumab, Atezolizumab, Bevacizumab, Ramucirumab, IBI305, Askrinbakumab, Citravatinib, Cytokine-based biological agent IRX-2, Bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, Glypican 3-specific chimeric antigen receptor expressing T cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR T cells, novel antigen-reactive T cells, pexastimogene devacirepvec, talimogene laherparepvec, GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, IMA970A, or anti-SARS-CoV-2 vaccine, novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG) DNA, paclitaxel, olaxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, BLU-554 (FGFR4 inhibitor), CMP-001, salsalate, or tolvaptan, or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the anti-SARS-CoV-2 vaccine is BNT162b2 (Pfizer / BioNTech), mRNA-1273 (Moderna), JNJ-78436735 (Janssen), ADZ1222 (Oxford / AstraZeneca), NVX-CoV2373 (Novavax), BBIBP-CorV (Vero cells) (Sinopharm), BBV152 (Bharat Biotech), or inactivated SARS-CoV-2 virus (CZ02 strain) (Sinovac).

[0327] In some embodiments, other pharmaceutically active agents are anticancer agents. In some embodiments, anticancer agents include sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, and NGM. 282, Pegberfermin, PF-05231023, Obeticholic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Vorixibat, Anlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogrit Zaal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, sarogritazal magnesium, vorixibat, ellafibranolic acid, nalmefen, solithromycin, 99m Technetium-mebrophenine, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpal, physogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat,RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, or zotiraklib citrate, or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the composition of the present invention further comprises an anticancer agent. In some embodiments, the composition of the present invention further comprises an anti-NASH agent or an anticancer agent.

[0329] In some embodiments, anticancer drugs include sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, These include meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, or zoctiliclib citrate, or a pharmaceutically acceptable salt thereof. In some embodiments, the anticancer agent is salsalate or tolvaptan.

[0330] In some embodiments, the anti-NASH agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, and vildagliptin. NGM282, Pegberfermin, PF-05231023, Obeticholic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Vorixibat, Anlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602 K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Saroglitazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, VK2809, MGL-3196, Narumafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ur These include sodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazal magnesium, vorixibat, ellafibranol, nalmefene, solithromycin, 99m-technetium-mebrophenine, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpal, physogatinib, or doxorubicin, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-NASH agent is salsalate or tolvaptan.

[0331] In some embodiments, other pharmaceutically active agents are immunotherapeutic agents. In some embodiments, immunotherapeutic agents include pembrolizumab, avelumab, durvalumab, nivolumab, semiprimab, ABX196, cintilimab, camrelizumab, spartalizumab, tripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, askrinbakumab, and TCR. These include T cell therapy agents, citravatinib, cytokine-based biological agents IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, glypican 3-specific chimeric antigen receptor expressing T cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR-T cells, or novel antigen-reactive T cells.

[0332] In some embodiments, the composition of the present invention further comprises an immunotherapy agent.

[0333] In some embodiments, the other pharmaceutically active agent is an oncovirus. In some embodiments, the oncovirus is pexastimogene devacirepvec or talimogene laherparepvec. In some embodiments, the composition of the present invention further comprises an oncovirus.

[0334] In some embodiments, the other pharmaceutically active agent is a vaccine. In some embodiments, the vaccine is GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, IMA970A, or an anti-SARS-CoV-2 vaccine. In some embodiments, the anti-SARS-CoV-2 vaccine is BNT162b2 (Pfizer / BioNTech), mRNA-1273 (Moderna), JNJ-78436735 (Janssen), ADZ1222 (Oxford / AstraZeneca), NVX-CoV2373 (Novavax), BBIBP-CorV (Vero cells) (Sinopharm), BBV152 (Bharat Biotech), or an inactivated SARS-CoV-2 virus (CZ02 strain) (Sinovac). In some embodiments, the composition of the present invention further comprises a vaccine.

[0335] In some embodiments, other pharmaceutically active agents include novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG)DNA, paclitaxel, olaxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.

[0336] In some embodiments, the composition of the present invention further comprises two or more other pharmaceutically active agents. In some embodiments, the two or more other pharmaceutically active agents are, but are not limited to, oncolytic agents such as nanatinostat and valganciclovir.

[0337] In some embodiments, the composition of the present invention includes sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, and Guberfermin, PF-05231023, obeticholic acid, silofexol, tropifexol, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, anlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipercast, ortipraz, MSDC-0602K, ASP9831, roflumilast, ellafibranol, pioglitazone, rosiglitazone, fenofibrate, saroglitazal, ranifibranol Lu, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Vorixibat, Elafibranol, Nalmefene, Solithromycin, 99m Technetium-Mebrophenine, S-Adenoid Silmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpal, Physogatinib, Doxorubicin, Cabozantinib, Deferoxamine, Itacitinib, Thiauranib, SF1126, Anlotinib, P1101, Vallitinib, SHR-1210, SHR6390, Capmatinib, Dabrafenib, Trametinib, Sapanicertib, Meclizine, Enzalutamide, H3B-6527, OBI-3424, Brivanib, Tepotinib, Temsirolimus, Epacadostat, RO7119929, Guadecitabine, Linrhodostat,The present invention further comprises a pharmaceutically active agent which is copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, or zoctilaclib citrate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition of the present invention is sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Obeticholic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Vorixibat, Anlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, E Rafibranol, pioglitazone, rosiglitazone, fenofibrate, saroglitazal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, narumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L -Alanine, Sarogritazal Magnesium, Vorixibat, Elafibranol, Nalmefene, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpal, Physogatinib, Doxorubicin, Cabozantinib, Deferoxamine, Itacitinib, Thiauranib, SF1126, Anlotinib, P1101, Vallitinib, SHR-1210, SHR6390, Capmatinib, Dabrafenib,The following are further pharmaceutically active agents, including trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, zoctilakrib citrate, salsarate, or tolvaptan, or pharmaceutically acceptable salts thereof.

[0338] In some embodiments, the compositions of the present invention include (a) an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertib, LY2109761, LDE225, Filsocostat, Aparalenone, Metformin, Leucine-Metformin-Sildenafil combination, Vitamin E, Cysteamine, Seroncertib, Losartan, RO5093151, Prazigastat, Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Oveticolic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Vorixibat, Anlexanox, PF-068 35919, leptin, metreleptin, simtuzumab, tipercast, oltipraz, MSDC-0602K, ASP9831, roflumilast, ellafibranol, pioglitazone, rosiglitazone, fenofibrate, saroglitazal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, narumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin Myricolinant, Ursodeoxycholic acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal magnesium, Vorixibat, Elafibranol, Nalmefene, Solithromycin, 99m-Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpal, Fisogatinib, Doxorubicin, Cabozantinib, Deferoxamine, Itacitinib, Thiauranib, SF1126, Anlotinib, P1101, Vallitinib, SHR-1210, SHR6390,This includes pharmaceutically active agents such as capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, or zoctilaclib citrate.

[0339] In some embodiments, the composition of the present invention comprises an effective amount of (a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically active agent, such as sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, regorafenib, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, an oncolytic virus for tumor injection, or a recombinant oncolytic virus, or an immunomodulatory gene therapy agent.

[0340] In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically active agent, such as sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, regorafenib, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, an oncolytic virus for tumor injection, or a recombinant oncolytic virus, or an immunomodulatory gene therapy agent.

[0341] In some embodiments, the composition of the present invention comprises an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, and sorafenib or lenvatinib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-1 or compound I-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-32 or compound I-32-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition comprises (a) an effective amount of compound I-32 or compound I-32-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-32 or compound I-32-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) lenvatinib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-61 or compound I-61-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-61 or compound I-61-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-61 or compound I-61-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) lenvatinib.In some embodiments, the composition of the present invention comprises (a) an effective amount of compound III-1 or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib.

[0342] In some embodiments, the composition of the present invention comprises an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, and regorafenib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) regorafenib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-1 or compound I-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) regorafenib. In some embodiments, the composition comprises (a) an effective amount of compound I-32 or compound I-32-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) regorafenib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound I-61 or compound I-61-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) regorafenib. In some embodiments, the composition of the present invention comprises (a) an effective amount of compound III-1 or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) regorafenib.

[0343] In some embodiments, formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), and (IIIB), or compounds of Table A-18, or their pharmaceutically acceptable salts or solvates, as well as other pharmaceutically active agents, are synergistic in the compositions or methods of the present invention. In some embodiments, the pharmaceutically acceptable salts are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0344] In some embodiments, pharmaceutically acceptable amino acids, meglumine, eglumine, D-glucamine, glucosamine, or choline salts of compounds of formula (I), (IA), (IB), and (IC), or Table A-7, A-8, A-9, A-10, A-11, or A12, as well as other pharmaceutically active agents, are synergistic in the compositions or methods of the present invention. In some embodiments, pharmaceutically acceptable meglumine, lysine, or arginine salts of compounds of formula (I), (IA), (IB), and (IC), or Table A-7, A-8, A-9, A-10, A-11, or A12, as well as other pharmaceutically active agents, are synergistic in the compositions or methods of the present invention. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0345] Table D shows exemplary compositions A1-A4, B1-B4, C1-C4, D1-D4, E1-E4, F1-F4, G1-G4, H1-H4, I1-I4, J1-J4, K1-K4, L1-L4, M1-M4, N1-N4, O1-O4, P1-P4, Q1-Q4, R1-R4, S1-S4, and T1-T4. Each composition in Table D contains (a) an effective amount of the compound of the present invention and (b) another pharmaceutically active agent. For example, composition A1 comprises (a) an effective amount of compound I-1 (or a pharmaceutically acceptable salt, solvate, or CoA mono(thioester) or di(thioester) thereof) and (b) sorafenib, and composition A2 comprises (a) an effective amount of compound I-32 (or a pharmaceutically acceptable salt, solvate, or CoA mono(thioester) or di(thioester) thereof) and (b) sorafenib, etc.

[0346] [Table 25-1] [Table 25-2]

[0347] In some embodiments, pharmaceutically acceptable carriers or vehicles include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow promoters, colorants, pigment transfer inhibitors, sweeteners, or flavoring agents.

[0348] The binder or granulator imparts cohesiveness to the tablets so that they remain intact after compression. Suitable binders or granulators include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH1500), sugars such as gelatin, sucrose, glucose, dextrose, molasses, and lactose, acacia, alginic acid, alginates, Irish moss extract, Panwar gum, Guttia gum, mucilage of Isabugol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), bee gum, larch arabogalactan, powdered tragacanth, and guar gum, celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC), AVISEL-PH-101, AVISEL-PH-103, AVISEL Examples include microcrystalline cellulose such as RC-581 and AVICEL-PH-105 (FMC Corp., Marcus Hook, PA), as well as mixtures thereof.

[0349] Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder is hydroxypropyl cellulose.

[0350] The binder or filler may be present in about 2% to about 49% by weight of the composition of the present invention provided herein, or in any range within these values. In some embodiments, the binder or filler may be present in about 5% to about 15% by weight of the composition of the present invention. In some embodiments, the binder or filler may be present in about 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 8% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, or 15% by weight of the composition of the present invention, or in any range within any of these values.

[0351] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantities, can impart certain properties to some compressible tablets, allowing them to disintegrate in the mouth by chewing. Such compressible tablets can be used as chewable tablets. In some embodiments, the diluent is lactose monohydrate. In some embodiments, the diluent is Fast-Flo 316 NF lactose monohydrate.

[0352] The compositions of the present invention may include a diluent, for example, a diluent in an amount of about 5% to about 49% by weight of the composition, or any range between any of these values. In some embodiments, the diluent is present in the composition of the present invention in an amount of about 15% to about 30% by weight. In some embodiments, the diluent is present in the composition of the present invention in an amount of about 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 18% by weight, 20% by weight, 21% by weight, 22% by weight, 23% by weight, 24% by weight, 25% by weight, 26% by weight, 27% by weight, 28% by weight, 29% by weight, or 30% by weight, or any range between any of these values.

[0353] Suitable disintegrants include, but are not limited to, cellulose such as agar, bentonite, methylcellulose and carboxymethylcellulose, wood products, natural sponges, cation exchange resins, gums such as alginic acid, guar gum and bee gum HV, citrus fruit pulp, cross-linked cellulose such as croscarmellose, cross-linked polymers such as crospovidone, cross-linked starch, microcrystalline cellulose such as calcium carbonate and sodium starch glycolate, starches such as potassium polaritrin, corn starch, potato starch, tapioca starch and pregelatinized starch, clay, algin (align), and mixtures thereof. The amount of disintegrant in the composition of the present invention may vary. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is croscarmellose sodium NF (Ac-Di-Sol).

[0354] The compositions of the present invention may contain a disintegrant, for example, about 0.5% to about 15% by weight or about 1% to about 10% by weight. In some embodiments, the compositions of the present invention contain a disintegrant in an amount of about 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 8% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, or 15% by weight of the composition, or in any range within any of these values.

[0355] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycerol behenate and glycols such as polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil, zinc stearate, ethyl oleate, ethyl laureate, agar, starch, lycopodium, silica or silica gel, such as AEROSIL® 200 (WRGrace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA), and mixtures thereof. In some embodiments, the lubricant is magnesium stearate.

[0356] The compositions of the present invention may contain a lubricant, for example, in about 0.1 to about 5% by weight. In some embodiments, the compositions of the present invention contain a lubricant in an amount of about 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 0.8% by weight, 1.0% by weight, 1.1% by weight, 1.2% by weight, 1.3% by weight, 1.4% by weight, 1.5% by weight, 1.6% by weight, 1.7% by weight, 1.8% by weight, 1.9% by weight, 2.0% by weight, 2.1% by weight, 2.2% by weight, 2.3% by weight, 2.4% by weight, 2.5% by weight, 2.6% by weight, 2.7% by weight, 2.8% by weight, 2.9% by weight, or 3.0% by weight of the composition, or any range within any of these values.

[0357] Suitable flow promoters include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and talc (such as asbestos-free talc).

[0358] Colorants may include approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes and lake pigments suspended on alumina hydrate, or mixtures thereof.

[0359] Flavoring agents include natural fragrances extracted from plants such as fruits, as well as synthetic blends of compounds that provide pleasant tastes, such as peppermint and methyl salicylate.

[0360] Examples of sweeteners include sucrose, lactose, mannitol, syrup, glycerin, sucralose, and artificial sweeteners such as saccharin and aspartame.

[0361] Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, bee gum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include glycerin, methyl and propylparabens, benzoic acid additives, sodium benzoate, and alcohol. Suitable humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0362] Examples of solvents include glycerin, sorbitol, ethyl alcohol, and syrup.

[0363] Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of organic acids include citric acid and tartaric acid. Examples of carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0364] The compositions of the present invention can be formulated in formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles for administration by various means, including orally, parenterally, by inhalation spray, topically, or rectally. As used herein, the term “parenterally” includes injection into the subcutaneous, intravenous, intramuscular, and intra-arterial regions by various infusion techniques. As used herein, intra-arterial and intravenous infusions include administration via a catheter.

[0365] The compositions of the present invention can be formulated according to routine procedures that are suitable for the desired administration route. Therefore, the compositions of the present invention can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The compositions of the present invention can be formulated as preparations suitable for transplantation or injection. Therefore, for example, the compositions of the present invention can be formulated with suitable polymer or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or slightly soluble derivatives (e.g., as slightly soluble salts). The compositions of the present invention may also be in powder form for preparation with a suitable vehicle, such as sterile pyrogen-free water, before use. Suitable formulations for each of these administration methods can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0366] In some embodiments, the compositions of the present invention are suitable for oral administration. These compositions may include solid, semi-solid, gel matrix, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, tongue, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pastilles, cachets, pellets, medicinal chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some embodiments, the compositions of the present invention suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compositions of the present invention are in the form of tablets. In some embodiments, the compositions of the present invention are in the form of capsules. In some embodiments, the compounds of the present invention are contained in capsules.

[0367] In some embodiments, the capsule is an immediate-release capsule. A non-limiting example of the capsule is the coni-snap® rigid gelatin capsule.

[0368] The compositions of the present invention may be in the form of compressed tablets, powder tablets, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to the action of stomach acid while dissolving or disintegrating in the intestines, thus protecting the active ingredient from the acidic environment of the stomach. Examples of enteric coatings, but not limited to, include fatty acids, fats, phenyl salicylates, waxes, shellac, ammonium shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in masking undesirable tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Examples of film coatings, but not limited to, include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general properties as sugar coatings. Multiple compression tablets are compression tablets manufactured through multiple compression cycles, including layered tablets and tablets that are press-coated or dry-coated.

[0369] In some embodiments, the coating is a film coating. In some embodiments, the film coating comprises Opadry White and 30% Simethicone Emulsion USP. In some other embodiments, the film coating comprises Opadry Yellow.

[0370] In some embodiments, compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or pharmaceutically acceptable salts or solvates thereof, are contained in the tablets. In some embodiments, the tablets are compressed tablets. In some embodiments, the tablets are film-coated compressed tablets.

[0371] In some embodiments, the compositions of the present invention are prepared by fluid-bed granulation of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, using one or more pharmaceutically acceptable carriers, vehicles, or excipients. In some embodiments, the compositions of the present invention prepared by the fluid-bed granulation process can provide tablet formulations with good flowability, good compressibility, rapid solubility, good stability, and / or minimal to no cracking. In some embodiments, the fluidized bed granulation process enables the preparation of formulations with high drug loads, such as more than 70% or more than 75% of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof.

[0372] The compositions of the present invention may be in the form of soft or hard capsules made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), may contain two sections, one of which slips into the other, thereby completely encapsulating the active ingredient. Flexible elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, that are plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are as described herein and include methyl and propylparabens, as well as sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oil, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patents No. 4,328,245, No. 4,409,239, and No. 4,410,545. Capsules may also be coated with coatings known to those skilled in the art to adjust or maintain the solubility of the active ingredient.

[0373] The compositions of the present invention may be in liquid or semi-solid dosage forms, such as emulsions, solutions, suspensions, elixirs, and syrups. An emulsion may be a two-phase system in which one liquid is dispersed in the form of spheres throughout another liquid, and it may be oil-in-water or water-in-oil. An emulsion may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. A suspension may contain a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcohol solutions may contain pharmaceutically acceptable acetals, such as di-(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal (the term "lower" means alkyl having 1 to 6 carbon atoms), as well as water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs may be clear, sweet, and hydro-alcoholic solutions. A syrup may be a concentrated aqueous solution of sugar, such as sucrose, and may also contain a preservative. In the case of liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, thereby facilitating measurement during administration.

[0374] The compositions of the present invention, suitable for oral administration, can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle formulations can be prepared as described in U.S. Patent No. 6,350,458.

[0375] The compositions of the present invention can be provided as non-foaming or foaming granules and powders that can be reconstituted into liquid dosage forms. pharmaceutically acceptable carriers and excipients used in non-foaming granules or powders may include diluents, sweeteners, and wetting agents. pharmaceutically acceptable carriers and excipients used in foaming granules or powders may include organic acids and carbon dioxide sources.

[0376] Colorants and flavorings can be used in all of the above dosage forms. Flavorings and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0377] The compositions of the present invention can be formulated as immediate or modified-release dosage forms, including delayed, sustained, pulsed, controlled, targeted, and programmed-release forms.

[0378] In some embodiments, the composition of the present invention includes a film coating.

[0379] The compositions of the present invention may contain other active ingredients that do not impair the therapeutic or preventive effects of the composition, or may contain substances that enhance or complement the effectiveness of the composition.

[0380] The tablet dosage form may be in powder, crystalline, or granular form and may contain a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, and may further contain a carrier or vehicle as described herein, which includes a binder, disintegrant, controlled-release polymer, lubricant, diluent, or colorant.

[0381] In some embodiments, the compositions of the present invention may further include excipients such as diluents, disintegrants, wetting agents, binders, flow enhancers, lubricants, or any combination thereof. In some embodiments, the tablets include a binder. In some embodiments, the binder includes microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyridone, hydroxypropyl cellulose, hydroxymethyl cellulose, or any combination thereof. In other embodiments, the tablets include a disintegrant. In other embodiments, the disintegrant includes croscarmellose sodium, starch glycolate sodium, or any combination thereof. In other embodiments, the tablets include a lubricant. In some embodiments, the lubricant includes magnesium stearate (stearic acid), hydrogenated oil, stearyl fumarate sodium, or any combination thereof.

[0382] In some embodiments, the composition of the present invention is in the form of a tablet comprising a binder, for example, any of the binders described herein.

[0383] In some embodiments, the composition of the present invention is in the form of a tablet comprising a disintegrant, for example, any of the disintegrants described herein.

[0384] In some embodiments, the composition of the present invention is in the form of a tablet containing a lubricant, for example, any of the lubricants described herein.

[0385] In some embodiments, the compositions of the present invention may be in modified-release or controlled-release dosage forms. In some embodiments, the compositions of the present invention may include particles exhibiting a specific release profile. For example, the compositions of the present invention may include a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB) in immediate-release form, or a pharmaceutically acceptable salt or solvate thereof, and simultaneously include a statin or a pharmaceutically acceptable salt thereof in modified-release form, both of which are compressed into a single tablet. Other combinations and modifications of release profiles can be carried out as understood by those skilled in the art. Examples of modified release formulations suitable for the pharmaceutical compositions of the present invention are not limited to, but include U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, and 5,739,108. These are listed in documents No. 5,891,474, No. 5,922,356, No. 5,972,891, No. 5,980,945, No. 5,993,855, No. 6,045,830, No. 6,087,324, No. 6,113,943, No. 6,197,350, No. 6,248,363, No. 6,264,970, No. 6,267,981, No. 6,376,461, No. 6,419,961, No. 6,589,548, No. 6,613,358, and No. 6,699,500.

[0386] In some embodiments, the compositions of the present invention are matrix-controlled release formulations. For example, the compositions of the present invention may include about 300 mg to about 600 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, provided as a matrix-controlled release form. In some embodiments, the matrix-controlled release form may further include another pharmaceutically active agent. In some embodiments, the release profiles of the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, and the other pharmaceutically active agent may be identical or different. Suitable matrix-controlled release formulations are described, for example, in Takada et al., “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999.

[0387] In some embodiments, the composition of the present invention comprises about 10 mg to about 400 mg of another pharmaceutically active agent and about 300 mg to about 600 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention comprises about 10 mg to about 400 mg of an anticancer agent and about 300 mg to about 600 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is in a matrix-controlled modified release formulation.

[0388] In some embodiments, the composition of the present invention comprises about 10 mg to about 40 mg of a statin and about 300 mg to about 600 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, wherein the composition is in a matrix-controlled modified release form.

[0389] In some embodiments, the matrix-controlled release form includes an erosive matrix containing water-swellable, erosive, or soluble polymers, including synthetic polymers, as well as naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0390] In some embodiments, the erosive matrix in a matrix-controlled release form is chitin, chitosan, dextran or pullulan; gum agar, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gatti gum, guar gum, xanthan gum or scleroglucan; starch, e.g., dextrin or maltodextrin; hydrophilic colloid, e.g., pectin; phosphatide, e.g., lecithin; alginate; propylene glycol alginate; gelatin; collagen; cellulose compounds, e.g., ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), carboxymethylethylcellulose (CMEC), hydroxyethylcellulose (HEC), hydroxyethylcellulose (HEC), hydroxyethylcellulose, Hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) or ethyl hydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerin fatty acid ester; polyacrylamide; polyacrylic acid; copolymer of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactic acid; copolymers of L-glutamic acid and ethyl-L-glutamate; biodegradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyrate; or other acrylic acid derivatives, e.g., copolymers of homopolymers and butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate or chloride (trimethylaminoethyl) methacrylate; or any combination thereof.

[0391] In other embodiments, the compositions of the present invention are matrix-controlled modified release forms comprising a non-erosive matrix. In some embodiments, statins, compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or pharmaceutically acceptable salts or solvates thereof, are dissolved or dispersed in an inert matrix and, upon administration, are released primarily by diffusion through the inert matrix. In some embodiments, the non-erosive matrix in a matrix-controlled release form is an insoluble polymer, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride-vinyl acetate copolymer, vinylidene chloride, ethylene or propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydride This includes rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer, ethylene / vinyl oxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, or hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone, or crosslinked partially hydrolyzed polyvinyl acetate, aliphatic compounds (e.g., carnauba wax, microcrystalline wax, or triglycerides), or any combination thereof.

[0392] The compositions of the present invention, which are modified release formulations, can be prepared by methods known to those skilled in the art, such as direct compression, drying or wet granulation, subsequent compression, melt granulation, and subsequent compression.

[0393] In some embodiments, the compositions of the present invention include an in-capsule tablet system, which may be a multifunctional and multi-unit system comprising a versatile minitablet in a rigid gelatin capsule. The minitablet may be an immediate-release, sustained-release, pulsed-release, delayed-sustained-release minitablet, or any combination thereof. In some embodiments, a combination of minitablets, or a combination of minitablets and minibeads containing multiple active agents, may each have a specific lag time for a multiple pulsed-release drug delivery system (DDS), site-directed DDS, delayed-rapid DDS, rapid / delayed DDS, and zero-order DDS.

[0394] In some embodiments, the composition of the present invention is in an osmotically controlled release form.

[0395] In some embodiments, the osmotic pressure-controlled release device includes a one-chamber system, a two-chamber system, asymmetric membrane technology (AMT), an extrusion core system (ECS), or any combination thereof. In some embodiments, such a device comprises at least two components, namely (a) a core containing an active drug(s), and (b) a semipermeable membrane enclosing the core and having at least one delivery port. The semipermeable membrane controls the inflow of water from the aqueous environment to the core during use, so as to cause drug release by extrusion through the delivery port(s).

[0396] In some embodiments, the core of the osmotic device optionally contains an osmotic agent that generates a driving force for the transport of water from the device's operating environment to the core. One class of penetrating agents useful in the compositions of the present invention includes, but is not limited to, water-swellable hydrophilic polymers also called "osmopolymers" or "hydrogels," hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic acid) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers having hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

[0397] Another class of penetrants useful in the compositions of the present invention includes osmogens that can absorb water to influence the osmotic pressure gradient across the entire barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts (e.g., magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium), sugars (e.g., dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol), organic acids (e.g., ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid), urea and mixtures thereof.

[0398] By using penetrating agents with different dissolution rates, the degree of rapid dissolution after administration of compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or their pharmaceutically acceptable salts or solvates, can be influenced. For example, by incorporating amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, DE), faster delivery can be provided during the first few hours (e.g., about 1 to 5 hours) to rapidly produce prophylactic or therapeutic efficacy, and then the remaining amount can be released gradually and continuously to maintain the desired level of therapeutic or prophylactic effect over a longer period. In some embodiments, compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or pharmaceutically acceptable salts or solvates thereof, are released from the composition of the present invention at a rate that replaces the amount of compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or pharmaceutically acceptable salts or solvates thereof that are metabolized or excreted by the subject.

[0399] The core can also contain a wide variety of other excipients and carriers described herein to improve the performance of the dosage form or to improve its stability or processability.

[0400] Materials useful for forming semipermeable films include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives, which are either permeable and water-insoluble at physiologically appropriate pH, or readily become water-insoluble through chemical changes such as crosslinking. Examples of suitable polymers useful for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, nitrocellulose, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA Examples include p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halide, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0401] Semipermeable membranes can be hydrophobic microporous membranes, as disclosed in U.S. Patent No. 5,798,119, in which the pores are substantially filled with gas and not wetted by an aqueous medium, but are permeable to water vapor. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyhalogenated vinyl, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0402] Delivery ports(s) on a semipermeable film can be formed by post-coating by mechanical or laser drilling. Delivery ports(s) can also be formed in situ by erosion of a water-soluble material plug or by rupture of a thinner portion of the film over a recess in the core. In addition, delivery ports can be formed during the coating process, as in the case of asymmetric film coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0403] The total amount and release rate of compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or their pharmaceutically acceptable salts or solvates, can be substantially controlled through the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0404] In some embodiments, the compositions of the present invention, which are osmotically controlled release formulations, may further contain additional conventional excipients described herein to enhance the performance or processability of the formulations.

[0405] Osmotically controlled release formulations can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy (above), Santus and Baker, J. Controlled Release 1995, 35, 1-21, Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708, Verma et al., J. Controlled Release 2002, 79, 7-27).

[0406] In some embodiments, the compositions of the present invention are formulated as asymmetric membrane technology (AMT) controlled-release formulations comprising an asymmetric permeability membrane coating a core containing an active ingredient(s) and other pharmaceutically acceptable excipients. See U.S. Patent No. 5,612,059 and WO2002 / 17918. AMT controlled-release formulations can be prepared according to conventional methods and techniques known to those skilled in the art, such as direct compression, dry granulation, wet granulation, and dip coating.

[0407] In some embodiments, the compositions of the present invention are formulated as ESC-controlled release formulations comprising a permeable membrane coating a core containing a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, hydroxyethylcellulose, and other pharmaceutically acceptable excipients.

[0408] In some embodiments, the compositions of the present invention are modified release formulations manufactured as multi-particle controlled release formulations, comprising a plurality of particles, granules, or pellets, fine particles, beads, microcapsules, and microtablets ranging in diameter from approximately 10 μm to approximately 3 mm, approximately 50 μm to approximately 2.5 mm, or approximately 100 μm to approximately 1 mm.

[0409] Multi-particle controlled-release formulations can provide long-release formulations with improved bioavailability. Suitable carriers for maintaining the release rate of compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or their pharmaceutically acceptable salts or solvates, include, but are not limited to, ethylcellulose, HPMC, HPMC-phthalate, colloidal silicon dioxide, and Eudragit-RSPM.

[0410] The pelletized composition of the present invention may contain 50-80% (w / w) of a drug and 20-50% (w / w) of microcrystalline cellulose or other polymers. Suitable polymers include, but are not limited to, microcrystalline waxes, pregelatinized starch, and maltose dextrin.

[0411] The beads can be prepared in capsule and tablet dosage forms. Beads in tablet dosage forms may exhibit a slower dissolution profile than microparticles in capsule form. Suitable microparticle fillers for the compositions and therapeutic or preventive methods of the present invention include, but are not limited to, sorbitan monooleate (Span 80), HPMC, or any combination thereof. Suitable dispersions for controlled-release latex include, for example, ethyl acrylate and methyl acrylate.

[0412] In some embodiments, the compositions of the present invention are in the form of microcapsules and / or microtablets. In some embodiments, the microcapsules include sustained-release polymer microcapsules containing a statin and compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB) having various solubility properties, or pharmaceutically acceptable salts or solvates thereof. The sustained-release polymer microcapsules can be prepared by colloidal polymer dispersions in an aqueous environment. In other embodiments, microcapsules suitable for the compositions and methods provided herein can be prepared using conventional microencapsulation techniques (Bodmeier & Wang, 1993).

[0413] Such multiparticulates can be produced by processes known to those skilled in the art, such as wet and dry granulation, extrusion / spheroidization, roller compression, melt-solidification, and spray coating of seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994 and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989. Excipients for such technologies are commercially available and listed in the United States Pharmacopeia.

[0414] Other excipients described herein can be blended with the compositions of the present invention to assist in the processing and formation of multiplicative materials. The resulting particles can constitute multiplicative dosage forms themselves or can be coated with various film-forming materials such as enteric polymers, water-swellable polymers, or water-soluble polymers. The multiplicative materials can further be processed into capsules or tablets.

[0415] In other embodiments, the composition of the present invention is a dosage form comprising an immediate-release component and at least one delayed-release component, which can discontinuously release the compound in the form of at least two consecutive pulses with a time difference of about 0.1 hours to about 24 hours.

[0416] In some embodiments, the compositions of the present invention contain about 1 mg to about 1000 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, or any amount within this range. In some embodiments, the compositions of the present invention contain about 1 mg to about 500 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, or any amount within this range. In some embodiments, the compositions of the present invention contain about 1 mg to about 400 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, or any amount within this range. In some embodiments, the compositions of the present invention contain about 200 mg to about 600 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, or any amount within this range. In some embodiments, the compositions of the present invention include about 1 mg to about 200 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, or any amount in the range between these values.

[0417] In other embodiments, the composition of the present invention comprises about 1 mg to about 1000 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, in an amount that is any amount of molar equivalent between these values. In other embodiments, the composition of the present invention comprises about 1 mg to about 500 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, in an amount that is any molar equivalent between these values. In other embodiments, the composition of the present invention comprises about 1 mg to about 400 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, in an amount that is any molar equivalent between these values.In other embodiments, the composition of the present invention comprises about 200 mg to about 600 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, or any molar equivalent within the range between these values. In other embodiments, the composition of the present invention comprises about 1 mg to about 200 mg of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or solvate thereof, in an amount that is any amount of molar equivalent between these values.

[0418] In some embodiments, the compositions of the present invention contain, in an amount of about 10% to about 99% by weight of the total weight of the compositions of the present invention, compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), or (IIIB), or pharmaceutically acceptable salts or solvates thereof.

[0419] Method of the present invention

[0420] The present invention further provides a method for treating or preventing a disease in a subject in need of treatment or prevention of the disease, comprising administering an effective amount of the compound or composition of the present invention to the subject in need, wherein the disease is chronic kidney disease (CKD), renal fibrosis, cardiac fibrosis, uterine fibrosis, cystic fibrosis, or end-stage renal failure.

[0421] The present invention provides a method for slowing, inhibiting, or delaying the progression of a disease in a subject who needs to slow the progression of a disease or delay its onset, comprising administering an effective amount of a compound or composition of the present invention to the subject who needs to slow the progression of a disease, wherein the disease is chronic kidney disease (CKD), autosomal polycystic kidney disease, contrast-induced nephropathy, renal fibrosis, cardiac fibrosis, uterine fibrosis, cystic fibrosis, or end-stage renal failure. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, CKD is Alport syndrome.

[0422] The present invention further provides a method for treating or preventing a disease in a subject in need of treatment or prevention of the disease, comprising administering an effective amount of the compound or composition of the present invention to the subject in need, wherein the disease is chronic kidney disease (CKD), renal fibrosis, autosomal polycystic kidney disease, contrast-induced nephropathy, cardiac fibrosis, uterine fibrosis, cystic fibrosis, fibrothorax, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, glial scarring, arterial stiffness, articular fibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive nodular fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or complications of miners' pneumoconiosis. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, CKD is Alport syndrome.

[0423] The present invention relates to a method for treating or preventing a disease in a subject in need of treatment or prevention of the disease, comprising administering an effective amount of the compound or composition of the present invention to the subject in need, wherein the disease is renal cell carcinoma, autosomal dominant polycystic kidney disease, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis, autosomal dominant tubulointerstitial kidney disease, bilateral polycystic dysplastic kidney, clear cell sarcoma, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-related autosomal dominant tubulointerstitial kidney disease, IgG4-related kidney disease, MUC1-related autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-related medullary cystic kidney disease, medullary cavernous kidney, polycystic dysplastic kidney, multilocular cysts, and polynodular thyroid gland. The method further provides for polydactyly cystic kidney syndrome, neonatal diabetes mellitus-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidney syndrome, REN-related autosomal dominant tubulointerstitial kidney disease, rare diseases potentially suitable for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract malformations, sex reversal-kidney, adrenal and pulmonary dysplasia syndrome (SERKAL syndrome), serpentinofibula-polycystic kidney syndrome, uromodulin-related kidney disease, medullary cystic kidney disease type 2 (UMOD-related autosomal dominant tubulointerstitial kidney), unilateral polycystic dysplastic kidney, ventricular enlargement-cystic kidney disease, Birt-Hogg-Dube syndrome (BHD), or Peutz-Jeghers syndrome (PJS).In some embodiments, the disease is autosomal dominant polycystic kidney disease, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis, autosomal dominant tubulointerstitial kidney disease, bilateral polycystic dysplastic kidney, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-related autosomal dominant tubulointerstitial kidney disease, IgG4-related kidney disease, MUC1-related autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-related medullary cystic kidney disease, cavernous kidney, polycystic dysplastic kidney, polylocular cysts, polydactyly, neonatal diabetes mellitus - congenital hypothyroidism - congenital glaucoma - hepatic fibrosis -Polycystic kidney syndrome, REN-associated autosomal dominant tubulointerstitial kidney disease, rare diseases potentially suitable for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract malformations, sex-reverse kidney, adrenal and pulmonary dysplasia syndrome (SERKAL syndrome), serpentinofibula-polycystic kidney syndrome, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney), unilateral polycystic dysplastic kidney, ventricular enlargement-cystic kidney disease, Birt-Hogg-Dube syndrome (BHD), or Peutz-Jeghers syndrome (PJS). In some embodiments, the disease is Birt-Hogg-Dube syndrome (BHD) or Peutz-Jeghers syndrome (PJS).

[0424] The present invention provides a method for slowing, inhibiting, or delaying the onset of a disease in a subject who needs to slow the progression of a disease, comprising administering an effective amount of a compound or composition of the present invention to the subject who needs to slow the progression of a disease, wherein the disease is chronic kidney disease (CKD), renal fibrosis, autosomal polycystic kidney disease, contrast-induced nephropathy, cardiac fibrosis, uterine fibrosis, cystic fibrosis, fibrothorax, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, glial scarring, arterial stiffness, arthral fibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive nodular fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or complications of miners' pneumoconiosis. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, CKD is Alport syndrome.

[0425] The present invention further provides a method for slowing, inhibiting, or delaying the onset of fibrosis in a subject, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof, wherein the fibrosis is a complication of chronic kidney disease (CKD), renal fibrosis, autosomal polycystic kidney disease, contrast-induced nephropathy, cardiac fibrosis, uterine fibrosis, cystic fibrosis, fibrothorax, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, glial scarring, arterial stiffness, articular fibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive nodular fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or a complication of coal miner's pneumoconiosis. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, CKD is Alport syndrome.

[0426] The present invention further provides methods for inhibiting, reducing, or delaying the development of complications of the target chronic kidney disease (CKD), autosomal polycystic kidney disease, contrast-induced nephropathy, renal fibrosis, cardiac fibrosis, uterine fibrosis, cystic fibrosis, fibrothorax, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, glial scarring, arterial stiffness, articular fibrosis, Dupuytren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive nodular fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or coal miner's pneumoconiosis.

[0427] In some embodiments, the subject has a stage 1 CDK. Stage 1 is 90 ml / min / 1.73 m 2 The above glomerular filtration rate (GFR) is characterized. In some embodiments, the subject has a stage 2 CDK. Stage 2 is 60-89 ml / min / 1.73m 2It is characterized by a GFR. In some embodiments, the subject has a CDK of stage 3A. Stage 3A is 45-59 ml / min / 1.73m 2 It is characterized by a GFR. In some embodiments, the subject has a CDK of stage 3B. Stage 3B is 30-44 ml / min / 1.73m 2 It is characterized by a GFR. In some embodiments, the subject has a stage 4 CDK. Stage 4 is 15-29 ml / min / 1.73m 2 It is characterized by a GFR. In some embodiments, the subject has a CDK of stage 5. Stage 5 is 15 ml / min / 1.73 m 2 Characterized by a GFR of less than a certain level, or chronic dialysis.

[0428] In some embodiments, treating CDK means preventing the development of CDK to the next stage or reversing one or more stages of CDK development. In some embodiments, delaying or postponing CDK development means delaying or postponing the development of CDK to the next stage or reversing one or more stages of CDK development.

[0429] The present invention provides a method for slowing the progression, inhibiting the progression, or delaying the onset of a disease in a subject who needs to slow the progression, inhibit the progression, or delay the onset of the disease, comprising administering an effective amount of the compound or composition of the present invention to the subject who needs to slow the progression, or delaying the onset of the disease being renal cell carcinoma, autosomal dominant polycystic kidney disease, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis, autosomal dominant tubulointerstitial kidney disease, bilateral polycystic kidney disease, clear cell sarcoma, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-related autosomal dominant tubulointerstitial kidney disease, IgG4-related kidney disease, MUC1-related autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-related medullary cystic kidney disease, cavernous kidney, polycystic kidney disease, and polylocular kidney disease. The method further provides for cysts, polydactyly polynodular thyroid polycystic kidney syndrome, neonatal diabetes mellitus-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidney syndrome, REN-associated autosomal dominant tubulointerstitial kidney disease, rare diseases potentially suitable for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract malformations, sex reversal-kidney, adrenal and pulmonary dysplasia syndrome (SERKAL syndrome), serpentinofibula-polycystic kidney syndrome, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney), unilateral polycystic dysplastic kidney, ventricular enlargement-cystic kidney disease, Birt-Hogg-Dube syndrome (BHD), or Peutz-Jeghers syndrome (PJS).In some embodiments, the disease is autosomal dominant polycystic kidney disease, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis, autosomal dominant tubulointerstitial kidney disease, bilateral polycystic dysplastic kidney, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-related autosomal dominant tubulointerstitial kidney disease, IgG4-related kidney disease, MUC1-related autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-related medullary cystic kidney disease, cavernous kidney, polycystic dysplastic kidney, polylocular cysts, polydactyly, neonatal diabetes mellitus - congenital hypothyroidism - congenital glaucoma - hepatic fibrosis -Polycystic kidney syndrome, REN-associated autosomal dominant tubulointerstitial kidney disease, rare diseases potentially suitable for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract malformations, sex-reverse kidney, adrenal and pulmonary dysplasia syndrome (SERKAL syndrome), serpentinofibula-polycystic kidney syndrome, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney), unilateral polycystic dysplastic kidney, ventricular enlargement-cystic kidney disease, Birt-Hogg-Dube syndrome (BHD), or Peutz-Jeghers syndrome (PJS). In some embodiments, the disease is Birt-Hogg-Dube syndrome (BHD) or Peutz-Jeghers syndrome (PJS). In some embodiments, renal dysplasia is unilateral or bilateral renal dysplasia.

[0430] The present invention further provides a method for reversing the progression of non-alcoholic steatohepatitis (NASH), fibrosis, or hepatocellular carcinoma (HCC), comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0431] In some embodiments, the subject is obese or diabetic. In some embodiments, the subject has diabetes, cirrhosis, hypertension, hypertriglyceridemia, metabolic syndrome, hyperlipidemia, hypercholesterolemia, coronary heart disease (CHD), one or more risk factors for CHD, acute coronary syndrome (ACS) or a history of acute coronary syndrome, non-ST-elevation ACS (unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI)), ST-elevation myocardial infarction (STEMI), abnormal betalipoproteinemia, hypoalphalipoproteinemia, risk of pancreatitis, or sitosterolemia. In some embodiments, hyperlipidemia is primary hyperlipidemia or mixed hyperlipidemia. In some embodiments, hypercholesterolemia is primary hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), or heterozygous familial hypercholesterolemia (HeFH). In some embodiments, abnormal betalipoproteinemia is primary abnormal betalipoproteinemia. In some embodiments, sitosterolemia is homozygous familial sitosterolemia. In some embodiments, the subject has a history of myocardial infarction, a history of stroke, or established peripheral artery disease. In some embodiments, diabetes is type 2 diabetes. In some embodiments, the subject has abnormally high LDL-C. In some embodiments, the subject has type 2 diabetes but does not have CHD.

[0432] In some embodiments, risk factors for CHD include high LDL cholesterol, low HDL cholesterol, high total cholesterol, high triglycerides, hypertension, family history of CHD, diabetes, smoking, age (over 40 for men, over 45 for women), or obesity.

[0433] The present invention further provides a method for reducing lipotoxicity, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0434] In some embodiments, fibrosis is hepatic fibrosis, pulmonary fibrosis, chronic kidney disease (CKD), autosomal polycystic kidney disease, contrast-induced nephropathy, renal fibrosis, cardiac fibrosis, uterine fibrosis, cystic fibrosis, fibrothorax, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, glial scarring, arterial stiffness, articular fibrosis, Dupuytren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive nodular fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or a complication of miners' pneumoconiosis. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, CKD is Alport syndrome.

[0435] The present invention further provides a method for inhibiting, reducing, or delaying novel lipid formation or lipid accumulation, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0436] The present invention further provides a method for slowing down, inhibiting, or delaying the progression of novel lipid formation or lipid accumulation, or delaying the onset of such a condition, comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0437] In some embodiments, the lipid accumulation is ectopic lipid accumulation.

[0438] The present invention further provides a method for preventing or delaying the onset of end-stage renal failure, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0439] This invention relates to Aurora A kinase, Aurora B kinase, Aurora C kinase, Etk / Bmx tyrosine kinase, c-Kit receptor tyrosine kinase, calcium / calmodulin-dependent protein kinase type II gamma chain (CAMK2G), discoidine domain-containing receptor 2 (DDR2), mitogen-activated protein kinase 15 (MAPK15 / ERK7), glycogen synthase kinase 3 beta (GSK3B), LIM domain kinase 1 (LIMK1), MAP kinase-activated protein kinase 2 (MAPKAPK2), and maternal embryonic leucine zipper. The present invention provides a method for modulating, directly inhibiting, or allosterically inhibiting kinases (MELK), myosin light chain kinases (MYLK / MLCK), NIMA-related kinase 2 (NEK2), serine-threonine kinase PIM3, receptor-interacting serine / threonine protein kinase 4 (RIPK4), TRAF2 and NCK-interacting protein kinase (TNIK), or vascular endogenous growth factor receptor 1 (VEGFR1 / FLT1), comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0440] This invention relates to Aurora A kinase, Aurora B kinase, Aurora C kinase, Etk / Bmx tyrosine kinase, c-Kit receptor tyrosine kinase, calcium / calmodulin-dependent protein kinase type II gamma chain (CAMK2G), discoidine domain-containing receptor 2 (DDR2), mitogen-activated protein kinase 15 (MAPK15 / ERK7), glycogen synthase kinase 3 beta (GSK3B), LIM domain kinase 1 (LIMK1), MAP kinase-activated protein kinase 2 (MAPKAPK2), maternal embryonic leucine zipper kinase (MELK), myosin light chain kinase (MYLK / MLCK), and NIMA-related kinase 2 (NEK2). The present invention provides a method for modulating, directly inhibiting, or allosterically inhibiting serine-threonine kinase PIM3, receptor-interacting serine / threonine protein kinase 4 (RIPK4), TRAF2 and NCK-interacting protein kinase (TNIK), or vascular endogenous growth factor receptor 1 (VEGFR1 / FLT1), comprising administering an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, or a composition thereof, to a subject in need thereof. In some embodiments, pharmaceutically acceptable salts of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is an L-arginine salt.

[0441] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting receptor-interacting serine / threonine protein kinase 4 (RIPK4), comprising administering an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, or a composition thereof, to a subject requiring such inhibition. In some embodiments, the pharmaceutically acceptable salt of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA is a sodium salt, potassium salt, magnesium salt, ammonium salt, calcium salt, meglumine salt, lysine salt, or arginine salt. In some embodiments, the lysine salt is an L-lysine salt. In some embodiments, the arginine salt is L-arginine salt.

[0442] The present invention further provides a method for treating or preventing skin cancer, ovarian cancer, cervical cancer, colorectal cancer, or pancreatic cancer, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0443] The present invention further provides a method for slowing, inhibiting the progression of, or delaying the onset of skin cancer, ovarian cancer, cervical cancer, colorectal cancer, or pancreatic cancer, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0444] In some embodiments, the diseases associated with increased inflammation are inflammation of the liver, inflammation of the lungs, inflammation of the heart, inflammation of the uterus, cystic fibrosis, inflammation of the kidneys, fatty liver disease, endometriosis, type 2 diabetes, type 1 diabetes, inflammatory bowel disease, asthma, rheumatoid arthritis, obesity, Alzheimer's disease, Parkinson's disease, or cancer.

[0445] In some embodiments, hepatocellular carcinoma (HCC) is accompanied by or without cirrhosis. In some embodiments, hepatocellular carcinoma (HCC) is accompanied by or without fibrosis.

[0446] In some embodiments of the methods disclosed herein, the disease is a disease resulting from fatty degeneration, fibrosis, and cirrhosis. In some embodiments, the disease resulting from fatty degeneration is inflammation. In some embodiments, the disease resulting from fatty degeneration is NAFLD, NASH, or ASH. In some embodiments, the disease resulting from fibrosis is cirrhosis or liver failure. In some embodiments, the disease resulting from cirrhosis is hepatocellular carcinoma, liver injury, or hepatic encephalopathy.

[0447] The present invention provides a method for treating a disease, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof, wherein the disease is an inflammatory disease, gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmune disease.

[0448] In some embodiments of the methods disclosed herein, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0449] In some embodiments of the methods disclosed herein, the disease is an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus.

[0450] The present invention provides a method for regressing, reducing the rate of progression of, or inhibiting the progression of fibrosis, hepatocyte ballooning, or hepatic inflammation, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0451] The present invention provides a method for inhibiting, reducing, or delaying the development of target lipid synthesis, hepatic steatosis, hepatocyte ballooning or inflammation, hepatic fibrosis, pulmonary fibrosis, or cirrhosis, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0452] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting ATP citrate lyase (ACLY), comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0453] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting acetyl-CoA carboxylase 1 (ACC1) or acetyl-CoA carboxylase 2 (ACC2), comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0454] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered to a subject in need of them in an amount ranging from about 1 mg to about 1000 mg, or any amount within this range. In some embodiments, the compounds of the present invention are administered to a subject in need of them in an amount ranging from about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, or about 1 mg to about 300 mg.

[0455] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered to subjects requiring them in a daily dose ranging from about 1 mg to about 1000 mg, or any amount within this range. In some embodiments, the compounds of the present invention are administered to subjects requiring them in a daily dose of about 1000 mg, about 950 mg, about 900 mg, about 850 mg, about 800 mg, about 750 mg, about 700 mg, about 650 mg, about 600 mg, about 550 mg, about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0456] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered once daily to subjects requiring them in doses ranging from about 1 mg to about 1000 mg, or any amount within this range.

[0457] In some embodiments of the methods disclosed herein, the compounds or compositions of the present invention are administered twice daily to subjects in need, with each dose comprising the compounds of the present invention in amounts ranging from about 1 mg to about 500 mg, or any amount within this range. In some embodiments, the compounds or compositions of the present invention are administered twice daily to subjects in need, with each dose comprising the compounds of the present invention in amounts ranging from about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0458] In some embodiments of the methods disclosed herein, the compounds or compositions of the present invention are administered three times daily to a subject in need, with each dose comprising the compounds of the present invention in amounts ranging from about 1 mg to about 400 mg, or any amount within this range. In some embodiments, the compounds or compositions of the present invention are administered three times daily to a subject in need, with each dose comprising the compounds of the present invention in amounts ranging from about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0459] In some embodiments of the methods disclosed herein, the method further includes administering an effective amount of another pharmaceutically active agent. In some embodiments, the other pharmaceutically active agent is administered simultaneously with or sequentially (before or after) the administration of the compound of the present invention. In some embodiments, the other pharmaceutically active agent is administered as adjuvant therapy.

[0460] In some embodiments of the methods disclosed herein, the subject is treated with another pharmaceutically active agent.

[0461] In some embodiments, other pharmaceutically active agents include statins, thiazolidinedions or fibrates, bile acid binding resins, niacin, anti-obesity drugs, hormones, thyrophostine, sulfonylurea-based drugs, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type-5 inhibitors, cardiovascular drugs, HDL-enhancing drugs, HDL enhancers, apolipoprotein AI gene modulators, apolipoprotein A-IV gene modulators, apolipoprotein gene modulators, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, or acetyl-CoA carboxylase allosteric inhibitors. In some embodiments, other pharmaceutically active agents include statins, thiazolidinediones or fibrates, bile acid binding resins, niacin, anti-obesity drugs, hormones, thyrophostine, sulfonylurea-based drugs, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type-5 inhibitors, cardiovascular drugs, HDL-enhancing agents, HDL enhancers, apolipoprotein AI gene modulators, apolipoprotein A-IV gene modulators, apolipoprotein gene modulators, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, acetyl-CoA carboxylase allosteric inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, GLP1R agonists, mTOR inhibitors, or TGFβ inhibitors. In some embodiments, another pharmaceutically active agent is lovastatin.In some embodiments, other pharmaceutically active agents include sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, regorafenib, ABX196, T-cell receptor (TCR) immunotherapy agents, TBI-302, namodenoson, MM-310, tumor injection oncolytic viruses or recombinant oncolytic viruses, for example, telomerisin and imurizic, but not limited to these, or immunomodulatory genetherapy agents, for example, MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3.

[0462] In some embodiments of the methods disclosed herein, the method further comprises administering two or more other pharmaceutically active agents. In some embodiments, the method of the present invention comprises administering two or more other pharmaceutically active agents in any combination. In some embodiments, the two or more other pharmaceutically active agents are, but are not limited to, oncolytic agents such as nanatinostat and valganciclovir. In other embodiments, the method of the present invention comprises orally administering the compounds of the present invention and compositions of the present invention, further comprising administering tumor injection oncolytic therapy. In some embodiments, this combination is administered orally.

[0463] In some embodiments, other pharmaceutically active agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, and pla Digastat, Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Obeticholic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, ND-L02-s0201 / BMS-986263, Borixibat, Anlexanox, PF-06835919, Leptin, Meth Lereptin, simtuzumab, tipercast, oltipraz, MSDC-0602K, ASP9831, roflumilast, ellafibranol, pioglitazone, rosiglitazone, fenofibrate, saroglitazal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, Na Lumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazal magnesium, vorixibat, solithromycin, 99m technetium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, or ceradelpal.In some embodiments, other pharmaceutically active agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, and prazigasta. , sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol, tropifexol, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201 / BMS-986263, vorixibat, anlexanox, PF-06835919, leptin, metreleptin, s Mutuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narumafen, Pentamidine These are berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazal magnesium, vorixibat, solithromycin, 99m technetium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpal, salsalate, or tolvaptan.

[0464] In some embodiments of the methods disclosed herein, the methods of the present invention involve administering an effective amount of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof. In some embodiments, the pharmaceutically acceptable salts of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the arginine salt is an L-arginine salt.

[0465] In some embodiments of the methods disclosed herein, the methods of the present invention provide to a subject requiring it an effective amount of (a) the compounds of the present invention, and (b) sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, rosal Tan, RO5093151, Prazigastat, Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Oveticolate, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Vorixibat, Anlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibran Pioglitazone, Rosiglitazone, Fenofibrate, Saroglitazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narumafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Saroglitazal Magnesium, Vorixibat, Elafy Branol, nalmefene, solithromycin, 99m technetium-mebrophenine, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpal, physogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib,The method of the present invention involves administering to a subject in need of it an effective amount of (a) a compound of the present invention, and (b) sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, elafibranol, eicosapentaenoic acid, garnicertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol, tropifexol, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, anlexanox, PF-06835919, leptin, metreleptin Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narumafen, Pentamidine, Berberine, L-Cal Nitin, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Vorixibat, Elafibranol, Nalmefene, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpal, Physogatinib, Doxorubicin, Cabozantinib, Deferoxamine, Itacitinib,This includes administering another pharmaceutically active agent, such as thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, zotilaclib citrate, salsarate, or tolvaptan.

[0466] In some embodiments of the methods disclosed herein, the methods of the present invention provide to a subject requiring it an effective amount of (a) Compound I-1, Compound I-1-CoA, Compound I-32, Compound I-32-CoA, Compound I-61, Compound I-61-CoA, Compound III-1, or Compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) Sorafenib, Paclitaxel, Lenvatinib, Tazemetostat, TBI-302, Namodenoson, MM-310, Cenicliviroc, Elafibranol, Eicosapentaenoic acid, Garnicertiveb, LY2109761, LDE225, Filsocostat, Aparalenone, Metformin, Leucine-Metformin-Sildenafil combination, Vitamin E, Cysteamine, Seroncertib, Losartan, RO5093151, Prazigastat, Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Oveticolic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenat D, Borixibat, Anlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narumafen, Pentamidine, Bell Berine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazal magnesium, vorixibat, ellafibranol, nalmefene, solithromycin, 99m technetium-mebrophenine, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpal, physogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101,This includes administering another pharmaceutically active agent, such as vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, regorafenib, or zoctilaclib citrate. In some embodiments, pharmaceutically acceptable salts of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the arginine salt is an L-arginine salt.

[0467] In some embodiments of the methods disclosed herein, the methods of the present invention involve administering to a subject in need of it an effective amount of (a) a compound of the present invention, and (b) another pharmaceutically active agent, which is sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, tumor injection oncolytic virus, recombinant oncolytic virus, or immunomodulatory genetherapy agent. In some embodiments of the methods disclosed herein, the methods of the present invention involve administering to a subject requiring it an effective amount of (a) compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA, or a pharmaceutically acceptable salt or solvate thereof, and (b) another pharmaceutically active agent, such as sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, regorafenib, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, tumor injection oncolytic virus, recombinant oncolytic virus, or immunomodulatory genetherapy agent. In some embodiments, pharmaceutically acceptable salts of compound I-1, compound I-1-CoA, compound I-32, compound I-32-CoA, compound I-61, compound I-61-CoA, compound III-1, or compound III-1-CoA are sodium salts, potassium salts, magnesium salts, ammonium salts, calcium salts, meglumine salts, lysine salts, or arginine salts. In some embodiments, the arginine salt is an L-arginine salt.

[0468] In some embodiments, the method of the present invention involves administering an effective amount of the compound of the present invention and another pharmaceutically active agent described in the embodiments of Table D to a subject requiring it. In some embodiments, the other pharmaceutically active agent is administered simultaneously with, before, or after the administration of the compound of the present invention or the composition of the present invention.

[0469] In some embodiments, the compounds of the present invention and other pharmaceutically active agents are synergistic in the compositions or methods of the present invention.

[0470] In some embodiments of the methods disclosed herein, the methods further include being applied to radiotherapy. In some embodiments, the radiotherapy is gamma-ray radiotherapy or X-ray radiotherapy. In some embodiments, the radiotherapy is applied via a gamma-ray or X-ray radiation device.

[0471] In some embodiments, radiotherapy is administered simultaneously with, before, or after the administration of the compound of the present invention.

[0472] In some other embodiments of the methods disclosed herein, the subject is undergoing surgical or procedural treatment for hepatocellular carcinoma.

[0473] In some embodiments of the methods disclosed herein, the methods further include performing transarterial chemoembolization (TACE).

[0474] In some embodiments of the methods disclosed herein, the methods further include performing excision, transplantation, or percutaneous ablation.

[0475] In some embodiments, the subject is obese or diabetic. In some embodiments, the subject has diabetes, cirrhosis, hypertension, hypertriglyceridemia, metabolic syndrome, hyperlipidemia, hypercholesterolemia, coronary heart disease (CHD), one or more risk factors for CHD, acute coronary syndrome (ACS) or a history of acute coronary syndrome, non-ST-elevation ACS (unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI)), ST-elevation myocardial infarction (STEMI), abnormal betalipoproteinemia, hypoalphalipoproteinemia, risk of pancreatitis, or sitosterolemia. In some embodiments, hyperlipidemia is primary hyperlipidemia or mixed hyperlipidemia. In some embodiments, hypercholesterolemia is primary hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), or heterozygous familial hypercholesterolemia (HeFH). In some embodiments, abnormal betalipoproteinemia is primary abnormal betalipoproteinemia. In some embodiments, sitosterolemia is homozygous familial sitosterolemia. In some embodiments, the subject has a history of myocardial infarction, a history of stroke, or established peripheral artery disease. In some embodiments, diabetes is type 2 diabetes. In some embodiments, the subject has abnormally high LDL-C. In some embodiments, the subject has type 2 diabetes but does not have CHD.

[0476] Example of synthesis

[0477] Synthesis and General Protocols

[0478] The compounds of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), and (IJ) can be prepared via the synthetic methodologies shown in Schemes 1 to 7. Starting materials useful for preparing the compounds of the present invention and their intermediates are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.

[0479] Scheme 1: General composition of equation (I) [ka]

[0480] In Scheme 1, A can be a halogen such as Cl, Br, or I. In some embodiments, A is Br. In Scheme 1, B can be an ester of a carboxylic acid or a carbanion of a malonic acid ester. In Scheme 1, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0481] Scheme 2: General composition of equation (I) [ka]

[0482] In Scheme 2, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It may be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0483] Scheme 3: General composition of equation (I) In the equation, Z is -C(R 1 )(R 2 )-(CH2) c -X is COOR 5 , or COOH, where c is 0. [ka]

[0484] In Scheme 3, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It may be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0485] Scheme 3 is a dicarboxylic acid of formula 7 (wherein R is an integer in the range of 2 to 5) of ortho, meta, or para ω-haloalkyl-substituted arenes of formula 5 (wherein p is an integer in the range of 2 to 5, and Hal is Cl, Br, or I) 1 Furthermore, R 2 This represents a conversion to an alkyl and / or aryl moiety (or linked to a 3- to 7-membered ring). This conversion can be carried out by two different, but related, pathways. According to the first method, formula R 1 R2 CHCO2R 5 Ester of (wherein R 1 Furthermore, R 2 The alkyl and / or aryl moiety, or linked to a 3- to 7-membered ring, 5 The compound (which is typically ethyl or methyl) is deprotonated with a strong base, preferably with butyllithium or lithium diisopropylamide, and then reacted with the dihalide of formula 5 to provide the corresponding diester of formula 6. Generally, the reaction is carried out at a temperature of about -78°C to about 25°C, and the reaction solvent is preferably THF or diethyl ether (for considerations regarding the scope of this method, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd See ed.;Wiley-VCH, New York, 1999, pp 1725-1726. For specific examples of this method, see Dasseux et al., US6, 646, 170 and US6, 410, 802, Oniciu et al. US10, 227, 285, and Ackerley et al., J.Med.Chem. 1995, 38, 1608-1628). In the second step, the diester of formula 6 is saponified (for an overview, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1959-1968, and Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th See John Wiley and Sons, New York, 2001, pp. 469-474, to obtain the diacid of formula 7. Alternatively, this conversion of the dihalide of formula 5 to the diacid of formula 7 is also obtained from formula R 1 R2 CHCO2H (in the formula, R 1 and R 2 The carboxylic acid is alkyl and / or aryl, as described above. 1 R 2 CHCO2R 5 This can also be carried out in one step by deprotonating twice under conditions similar to the alkylation process, followed by reaction with dibromide 5 (for discussion, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd See ed.;Wiley-VCH, New York, 1999, pp 1717-1718). For example, the compound of formula 5 (ortho, p=3, Hal=Br) is reacted with lithioethyl isobutyrate (prepared from ethyl isobutyrate with lithium diisopropylamide) in a solvent mixture of THF and DMPU at a temperature in the range of approximately -78°C to room temperature to obtain the corresponding diester of formula 7 (ortho, p=3). This diester is then hydrolyzed under standard conditions (aqueous ethanol solution, potassium hydroxide, reflux temperature), re-acidified with dilute hydrochloric acid solution, and then the dicarboxylic acid of formula 7 (ortho substitution pattern, R 1 =R 2 =methyl, and p=3) is obtained. Alternatively, as described in Gleiter et al., J. Org. Chem. 1992, 57, 252-258, isobutyric acid is deprotonated twice with n-butyllithium and diisopropylamine in THF solution, first at about -20°C and then at about 50°C. After recooling to about -20°C, the compound of formula 5 (ortho, R) in THF is obtained. 1 =R 2 A solution of (=methyl, p=3, Hal=Br) is added dropwise while maintaining the temperature below 10°C. The mixture is then stirred first at room temperature and then at about 40°C, and post-treatment is carried out in a typical manner to obtain the corresponding diacid 7. Type 5 halogenated derivatives can be obtained by several methods, such as those described, for example, Gleiter et al., J. Org. Chem. 1992, 57, 252-258.

[0486] Scheme 4: General synthesis of compound 5-Br (compound 5 where Hal=Br) [ka]

[0487] In Scheme 4, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0488] Scheme 4 shows the synthesis of para, meta, and orthodibromoalkyl-substituted arene compounds 5-Br (wherein (p-1) is an integer in the range of 1 to 2) from the parent dicarboxylic acid 10. Scheme 4 is first described in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1932-1941, and Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 thAn overview of esterifying the compound of formula 10 to the diester of formula 20 (wherein R is an alkyl moiety, such as methyl, ethyl, or isopropyl, but not limited to the formula) using the general procedure referenced in ed.; John Wiley and Sons, New York, 2001, pp. 484–486 is outlined. The diol 30 can be prepared from diester 20 by known synthetic methods (for consideration of preferred reduction methods, see, for example, Hudlicky, M., Reductions in Organic Chemistry, 2001). nd See ed.;ACS Monograph 188, Washington, DC, 1996, pp 212-216). In the next step, the conversion of the alcohol functional group in compound 5-Br in 30 to the bromo moiety is described in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 ndThis can be carried out by various standard methods referenced in ed.;Wiley-VCH, New York, 1999, pp 693-695. For example, the compound of formula 10 having a para substitution pattern and (p-1)=1 (available from Aldrich Chemical Co., Milwaukee, Wisconsin) is treated with excess methanol and concentrated sulfuric acid at reflux temperature to obtain the corresponding dimethyl ester of formula 2. The procedure that can be used for this conversion is referenced, for example, in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494, which is incorporated herein by reference. In addition, as referenced in Reynolds et al., US2,789,970, application No. 397,037 filed December 8, 1953, the compound of formula 20 (para, (p-1)=1) can be converted to the corresponding compound of formula 30 by reaction with a metal hydride complex, preferably but not limited to lithium aluminum hydride, in an aproton organic solvent (e.g., THF or diethyl ether). Furthermore, the diol of formula 30 (para, p=1) can be converted to the bromide of formula 5-Br(para, p=1) by treatment at high temperature with sodium bromide and concentrated sulfuric acid. A useful solvent for this conversion is water, as described in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494.

[0489] Scheme 5: General synthesis of compound 5A-Br [ka]

[0490] In Scheme 5, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1AIt can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0491] Scheme 5 shows the preparation of ortho, meta, and para-substituted arene compounds having two 3-bromopropyl substituents of formula 5A-Br. Specific examples for the synthesis of compounds 5A-Br with meta and para substitutions are described in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494 and Gleiter et al., J. Org. Chem. 1992, 57, 252-258, respectively. For example, the compound of formula 50 is treated with malonic acid and piperidine in a pyridine solution at about 90-110°C to obtain the α,β-unsaturated carboxylic acid of formula 60. The endpoint of this conversion is typically indicated by the cessation of CO2 effervescence. This procedure is known as the Knoevenagel-Doebner reaction, and a useful reaction protocol for this conversion is described in Organikum, Organisch-Chemisches Grundpraktikum, VEB Verlag Deutscher Wissenschaften, Berlin 1984, pp 572-574. The reduction of the compound of formula 60 to the compound of formula 70 is described in Hudlicky, M. Reductions in Organic Chemistry, 2 ndAs discussed in ed.;ACS Monograph 188, Washington, DC, 1996, pp 196-197, this can be carried out by catalytic hydrogenation on colloidal palladium, Raney nickel, or copper chromate. The conversion of the compound of formula 60 to the corresponding compound 70 by meta-substitution by treatment with hydrogen gas in an aqueous sodium hydroxide solution on a palladium / carbon catalyst at a pressure of about 20-60 psi is reported in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494, the entire contents of which are incorporated herein by reference. Subsequently, the further conversion of the compound of formula 70 to the compound of formula 5A-Br can be carried out according to the methodology described in Scheme 4.

[0492] Scheme 6: General synthesis of compound 5-Br by chain elongation [ka]

[0493] In Scheme 6, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0494] Scheme 6 shows a general method for chain extension from a bromide of formula 90 having an alkyl chain of (p-2) methylene groups to a bromide of formula 5-Br having an alkyl chain of p methylene groups. The conversion sequence from alkyl halides (e.g., 90) to carboxylic acids (e.g., 120) is described in Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5. th ed.; John Wiley and Sons, New York, 2001, p 549, and Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 ndAlkylation can be performed via deprotonation with a lithium base, followed by alkylation with a suitable electrophile, according to ed. Wiley-VCH, New York, 1999, p 1765. Generally, monoalkylation of malonic acid esters (where R is typically ethyl or methyl) is performed using a combination of sodium ethoxide base solvents in ethanol, which inhibits the formation of dialkylation byproducts (Organic Reactions, Volume IX, editor-in-chief: R. Adams; Robert E. Krieger Publishing Company, Malabar, Florida, 1957, p 132), to obtain the compound of formula 100. The compound of formula 100 is then saponified to obtain the compound of formula 110, which can be decarboxylated to the compound of formula 120 by heating it to a temperature above its melting point. Next, the conversion of dicarboxylic acid 120 to the chain-extended dibromide 5-Br via diester 20 is carried out according to the methodology described in Scheme 4. Alternatively, the direct decarbalkoxylation of geminal diester 100 to the compound of formula 20 can be carried out by treatment with water and DMSO, with or without the addition of salts. However, the rate of decarbalkoxylation of these substrates can be improved by adding salts such as KCN, NaCl, or LiCl to the water / DMSO solvent (Fakhri, SA; Yousefi, BHTetrahedron 2000, 56, 8301-8308). For example, ethyl malonate is reacted with sodium metal in ethanol and a solution of the compound of formula 90 ((p-2)=2), and ethyl malonate is added to obtain the corresponding compound of formula 100. This tetraester is then saponified, for example, using aqueous ethanol and potassium hydroxide to obtain the corresponding tetraacid of formula 110. The tetraacid is then decarboxylated at a temperature of about 200°C to obtain the diacid of formula 120. After esterification with methanol and concentrated sulfuric acid (see Scheme 4), diester 20 is obtained.A useful method for converting the tetraester (ortho, (p-2)=1, R=ethyl) of formula 100 to the diester of formula 20 is described in Fakhri, SA; Yousefi, BHTetrahedron 2000, 56, 8301-8308, which is incorporated herein by reference in its entirety.

[0495] Scheme 7: General synthesis of the compound of formula 7 [ka]

[0496] In Scheme 7, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0497] Scheme 7 shows the synthesis of ortho, meta, and para-substituted arene compounds of formula 7 by ω-carboxyalkyl substitution, where (p-1) is an integer in the range of 2 to 12, and R 1 and R 2This is either an alkyl moiety and / or an aryl moiety, or two alkyl moieties linked by a 3- to 7-membered ring. The synthesis begins with two deprotonations of ortho-, meta-, or para-xylene 3 with a strong base, not limited to a combination of n-butyllithium and tert-potassium butoxide, in an aprotic solvent such as hexane, and then the dianion of the formed 3 and a suitable electrophile A-(CH2) p-1 -CR 1 R 2 -CH2O-PG(in the formula, (p-1), R 1 and R 2 It is defined as above, and reacts with (where A is Cl, Br, or I). "PG" is a hydroxyl protecting group. Examples of hydroxyl protecting groups are incorporated herein by reference to Greene, TW; Wuts, PGMP (Protective groups in organic synthesis, 3) rd Methylarene is described in ed., John Wiley and Sons, New York, 1999, pp. 17-245. Methylarene is described in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd According to ed.;Wiley-VCH, New York, 1999, p 88, alkylation can be performed via deprotonation with a lithium base followed by alkylation with a suitable electrophile. For example, see Bates et al., J.Am.Chem.Soc.1981, 103, 5052-5058 for an example of xylenedianion preparation. In the next step, the protecting group of 190 is removed to liberate the terminal hydroxylmethyl moiety in 200, which is then oxidized using a suitable oxidizing agent (Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nded.; Wiley-VCH, New York, 1999, pp 1646-1648, and Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th (ed.; John Wiley and Sons, New York, 2001, p 1537), a dicarboxylic acid of formula 7 is obtained. For example, m-xylene (meta-3) is reacted with n-butyllithium and potassium tert-butoxide in hexane, first at room temperature and then at reflux temperature. After cooling to 0°C, the compound of formula 180 (A=Br, (p-1)=3, R 1 =R 2 =methyl, PG=tetrahydropyranil (prepared according to Dasseux et al., US6,646,170 and US6,410,802) are added, and the reaction is continued at reflux temperature. After normal workup and purification by column chromatography, the corresponding compound of formula 190 is obtained. Then, 190~200 (R 1 , R 2 Deprotection of methyl (p=3) is carried out by heating in methanol and concentrated hydrochloric acid aqueous solution (Vogel, A.Vogel's textbook of practical organic chemistry, 5 th (ed., Longman Scientific and Technical, 1989, p. 552). Next, compound 200 was treated with pyridinium dichromate in N,N'-dimethylformamide according to Vedejs, E.; Dent, WH, III; Gapinski, DM; McClure, CKJAm. Chem. Soc. 1987, 109, 5437-5446 to obtain the dicarboxylic acid of formula 7 (meta, p=3, R 1 , R 2 (=methyl).

[0498] Scheme 8 shows exemplary alternative synthesis methods for compounds I-1 and I-32. A commercially available benzene-dicarboxyaldehyde (Sigma-Aldrich, AK Scientific, etc.) is reacted with (5-ethoxy-4,4-dimethyl-5-oxopentyl)triphenylphosphonium bromide (220) (prepared as described in Oniciu, D, C. et al., WO2012 / 054535 and US8, 349, 833B2) in the presence of a base (not limited to sodium or potassium hydroxide, tert-potassium or sodium butoxide, potassium or sodium carbonate, and sodium hydride, etc.) as a mixture of cis and trans isomers by the method described in Le Bigot Y. et al., 1988, Tetrahedron 44(4), pp. 1057-1072. A mixture of cis and trans isomers of formula (230) or (240) can be catalytically reduced by methods for the hydrogenation of olefins known in the art, such as those described in H.-U. Blaser, F. Spindler, M. Thommen, The Handbook of Homogeneous Hydrogenation, JG De Vries, CJ Elsevier, Eds. (Wiley-VCH, 2008), chap. 37, Scharnagl, F. Ket al., Sci. Adv. 2018, 4:eaau1248, 21 September 2018, and the references cited herein. The esters thus obtained are subjected to hydrolysis after the hydrogenation reaction is deemed substantially complete using appropriate analytical methods. Reaction mixtures containing the compounds of formula (250) or (260), respectively, are hydrolyzed in reflux alcohol for 2 to 96 hours in the presence of an alkaline earth metal salt or base, or an oxide, or an alkali metal salt or base. Typical examples include, but are not limited to, the hydrolysis of K2CO3 in a refluxed mixture of DMSO and water.Other preferred procedures are referenced in Houben-Weyl, Methoden der Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol.XII / 2, pp.143-210 and 872-879, or Anderson, NG, Practical Process Research & Development, Academic Press, London, 2000, pp.93-94 and 181-182.

[0499] Scheme 8. Exemplary synthesis of compounds I-1 and I-32. [ka]

[0500] Scheme 9. General synthesis of compounds of formula (III) or (IIIA) (wherein X=O, Z 1 , Z 2 =COOH, q=0, and R 1 and R 2 (They form a cyclopropyl ring together.) [ka]

[0501] Compounds of formula (III) or (IIIA) where X=O can be prepared by Williamson synthesis by reacting an alcohol with a derivative containing a leaving group, such as a halide, tolylsulfonate, or mesylate. See Scheme 9.

[0502] Example 1A: Synthesis of 1,1'-(oxybis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid) (Compound III-17)

[0503] Step 1: 2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (adapted from Kanth et al, Tetrahedron, 58(6), 1069-1074 (2002)) [ka]

[0504] 3,4-Dihydro-2H-pyran (36.9 ml, 404 mmol) was slowly added on an ice bath to a stirred orange solution of 5-bromopentan-1-ol (32.6 ml, 269 mmol) and pTsOH (5.12 g, 26.9 mmol) in dichloromethane (540 ml). After addition, the orange mixture turned green. The reaction mixture was warmed to room temperature and stirred for 2 hours. The dark green reaction mixture was diluted with NaHCO3 and extracted three times with dichloromethane. The mixed organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 78.27 g of a brown solution. The target was purified four times by flash column chromatography and a 220 g silica column with a gradient of siRNA (0-10%) in heptane. The mixed fraction was concentrated to obtain 56 g of a colorless liquid. The target was stripped with ether and concentrated again under reduced pressure until dry to obtain 54.6 g of a colorless liquid with 99% purity (GCMS). 1 H NMR(400MHz,CDCl3 / TMS):δ 4.57(t,J=4.5Hz,1H),3.86(m,1H),3.75(m,1H),3.51(m,1H),3.42(m,2H),3. 40(m,1H),1.87(quin,2H),1.82(m,1H),1.74-1.61(m,3H),1.60-1.51(m,6H). 13 C NMR(100MHz,CDCl3 / TMS):δ 98.9,67.2,62.4,33.8,32.6,30.8,28.9,25.5,25.0,19.7.MS(HRMS):C 10 H 19 O2[M+Na + ] + Calculated value for this: 273.04606, measured value: 273.04611.

[0505] Step 2: tert-butyl 1-(5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)cyclopropane-1-carboxylate (adapted from US2013 / 109699) [ka]

[0506] LDA (47.0 ml, 94 mmol) was cooled to -78°C under an N2 atmosphere. Over approximately 4 hours, a solution of 2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (11.80 g, 47 mmol) and tert-butylcyclopropanecarboxylate (10.02 g, 70.5 mmol) in tetrahydrofuran (dried, 94 ml) was slowly added to the mixture. After the addition, the mixture was slowly warmed to room temperature by removing the dry ice from the isopropanol cold bath. Sample analysis showed 73% conversion to the target and approximately 2% residual starting material. The reaction mixture was poured into a mixture of ice water (20 mL and 60 mL, respectively) and saturated NaHCO3 aqueous solution (40 mL), and the product was then extracted with SiO2 (3 × 50 mL). The organic layers were mixed, washed with a mixture of brine and saturated NaHCO3 aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain an orange liquid (20.74 g). The product was further purified by flash chromatography on two 220 g silica column batches using a gradient of siRNA (0-10%) in heptane. The second eluate was collected and concentrated to obtain 12 g of the product as a colorless oil with 95% purity (GC). Yield 60%. 1 H NMR(400MHz,CDCl3 / TMS):δ 4.57(t,1H),3.86(m,1H),3.73(m,1H),3.49(m,1H),3.38(m,1H),1.82(m,1H),1.70(m,1H),1. 61-1.53(m,6H),1.42(s,9H),1.35(m,2H),1.09(q,J=4Hz,2H),0.57(q,J=4Hz,2H).MS(GCMS):C 14 H 23Calculated value for O4[M-tBu]: 255.16, measured value: 255.1.

[0507] Step 3: tert-butyl 1-(5-hydroxypentyl)cyclopropane-1-carboxylate (adapted from US2013 / 109699) [ka]

[0508] p-toluenesulfonic acid monohydrate (1.681 g, 8.84 mmol) was added at room temperature to a stirred solution of tert-butyl 1-(5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)cyclopropane-1-carboxylate (27.62 g, 88 mmol) in methanol (325 ml). After 6 hours, the sample showed approximately 1% residual starting material and the product at >80% pty. The mixture was stirred overnight at room temperature. Volatile substances were removed under vacuum, water (50 mL) was added, and the product was extracted with siRNA (3 × 50 mL). The mixture was then washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 25 g of a yellow oil. Since the product's stability is compromised at room temperature, the batch was stored at 4°C and purified by chromatography immediately before the next step. Purification by flash chromatography was performed, for example, using 2 g of material in 80 g of silica with a gradient of SiO (0-22%) in heptane. The main component was collected, yielding 1.37 g of the product as a colorless oil. Only the molecular ion [M-OtBu]m / z155, which was not found by LCMS or GCMS techniques, was found at 99% (GCMS). NMR consistent with the structure confirmed 99% purity (90% yield). 1 H NMR (400MHz, CDCl3 / TMS): δ 3.64(t,6.6Hz,2H),1.57(quin,2H),1.46-1.51(m,4H),1.42(s,9H),1.35(m,2H),1.10(q,5.2Hz,2H),0.59(q,5.2Hz,2H). 13C NMR (100MHz, CDCl3 / TMS): δ 174.6,79.9,62.9,34.1,32.7,28.1,27.5,25.9,24.2,15.2.GCMS:99%, Mass: m / z [M-OtBu] + Calculated value: 155.11, measured value: 155.1.

[0509] Step 4: Di-tert-butyl 1,1'-(oxybis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylate) [ka]

[0510] To a solution of tert-butyl 1-(5-hydroxypentyl)cyclopropane-1-carboxylate (7.36 g, 32.2 mmol) in dry toluene (150 ml), triethylamine (3.00 ml, 21.60 mmol) was added, and the mixture was placed under N2 and cooled in a dry ice / acetone bath for 10 minutes until it reached -20°C. Methanesulfonic anhydride (3.66 ml, 19.34 mmol) was added, and the reaction mixture was held at this temperature for 30 minutes. The mixture was then allowed to stand to reach room temperature, and then heated to 30°C. The formation of a methanesulfonic acid intermediate in half the equivalent volume of the starting material was controlled by GC-MS. A new aqueous solution with 61% w / w KOH was prepared by dissolving potassium hydroxide (70.4 g, 1255 mmol) in demineralized water (45 ml) with stirring and cooling using an ice bath. The total volume obtained was approximately 75 mL and was set aside. After a further 1 hour of reaction, an aqueous solution of 55% w / w tetrabutylammonium hydroxide (0.627 ml, 1.289 mmol) was added, followed by the addition of the above KOH (aqueous) solution under vigorous stirring. The mixture was then stirred overnight at 40°C, and the conversion in the final product was controlled by chromatography or NMR techniques. After heating at 40°C for 17 hours, the conversion in the final product exceeded 80%, and the reaction was considered complete, so heating was stopped. Water (50 mL) was added, and the reaction mixture was quenched by stirring. The organic fractions were collected, and the aqueous fraction was washed with toluene. The two organic fractions were mixed, washed with water, sulfuric acid (2N), and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7.72 g of a yellow oily substance, which was further purified by flash column chromatography on 120 g of silica using a gradient elution of 0-25% ethyl acetate in heptane. The product was eluted with 10% ethyl acetate in the heptane fraction. The concentrated fraction yielded 5.5 g of a colorless oily substance. The final compound was found to be incompatible with detection by UV-LC and GC-MS. 1H NMR (400MHz, CDCl3 / TMS): δ 3.38(t,4H),1.56(quin,4H),1.46(d,4H),1.42(s,18H),1.35-1.28(m,6H),1.09(q,4H),0.88(t,2H),0.59(q,4H). 13 C NMR (100MHz, CDCl3 / TMS): δ 174.6,79.8,70.9,34.1,29.7,28.1,27.6,26.4,24.2,15.2.

[0511] Step 5: 1,1'-(oxybis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid) (Compound III-17) [ka]

[0512] Di-tert-butyl 1,1'-(oxybis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylate) (5.6 g, 12.77 mmol) was stirred in dry toluene (42.6 ml), and methanesulfonic acid (2.071 ml, 31.9 mmol) was slowly added at room temperature. Stirring was continued overnight. 2N aqueous sulfuric acid (10 mL) was added, and the mixture was quenched by stirring. After 30 minutes, the original orange mixture became almost colorless. The organic layer was collected, and the aqueous layer was washed with toluene. The mixed organic fraction was treated with 2M aqueous NaOH (50 mL), stirred for 15 minutes, and the aqueous fraction containing the product was collected. The organic layer was washed with an additional 2M NaOH (20 mL). The mixed aqueous fraction was stirred, and 6M HCl (100 mL) was slowly added until the mixture became a cloudy white, and stirring was continued until the pH remained stable. When the mixture began to form an emulsion, 100 mL of diethyl ether was added, and vigorous stirring was continued until both the aqueous and ether phases became translucent. The organic fraction was collected, and the aqueous fraction was washed with 2 × 50 mL of diethyl ether. The mixed organic fraction was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.85 g of an off-white oily substance. The product was allowed to solidify overnight, then ground with diethyl ether, and subjected to rotary evaporation at room temperature for 4 hours to obtain a white crystalline powder (yield 85%). 1 H NMR (400MHz, CDCl3 / TMS): δ 10.83(bs,2H),3.39(t,4H),1.56(t,J=6.8Hz,4H),1.49(m,4H),1.46(m,4H),1.33(q,4H),1.26(dd,J=4Hz,J=3Hz 4H),0.75(dd,J=4Hz,J=3Hz,4H). 13 C NMR(100MHz,CDCl3 / TMS):δ 182.5,70.8,33.5,29.6,27.4,26.3,23.3,16.5.MS(HRMS):C 18 H 30 O5[M+H + ] + Calculated value for this: 327.21660, measured value: 327.21592

[0513] Example 1B: 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (I-32). [ka]

[0514] Step 1: Ethyl 5-bromo-2,2-dimethylpentanoate

[0515] Under an argon atmosphere, ethyl isobutyrate (30 g, 258 mmol) was dissolved in anhydrous THF (250 mL). The flask was cooled in a dry ice / acetone bath, and 2 M lithium diisopropylamide solution (150 mL) was added dropwise over 30-40 minutes. The mixture was stirred for a further 1 hour at -78°C while 1,3-dibromopropane (150 g, 743 mmol, 2.88 equivalents) was added dropwise (rapidly) over 5-10 minutes. The mixture was slowly warmed to room temperature and stirred overnight. After 16 hours at room temperature, the reaction was quenched with saturated ammonium chloride (200 mL), and the product was extracted with ethyl acetate (2 × 500 mL). The mixed ethyl acetate extract was washed with 10% HCl (2 × 200 mL) and brine (200 mL), dried on magnesium sulfate, filtered, and concentrated on rotovap. The remaining yellowish-brown oily substance (200 g) was filtered through silica gel (800 g), eluted with heptane, and then eluted with 2-5% ethyl acetate in heptane. The product containing the fractions was mixed and concentrated on a rotovap. The experiment produced ethyl 5-bromo-2,2-dimethylpentanoate 3 (49.3 g, yield 80.5%) as a colorless oily substance. 1 H NMR(300MHz,CDCl3)δ 4.10(q,1H,J=7.2Hz),3.63(t,2H,J=6.3Hz),1.85-1.70(m,2H),1.70-1.60(m,2H),1.24(t,3H,J=7.2Hz),1.17(s,6H). 13 C NMR(75MHz,CDCl3)δ 177.6,60.5,41.9,39.2,34.0,28.7,25.3,14.4. [ka]

[0516] Step 2: (5-ethoxy-4,4-dimethyl-5-oxopentyl)(triphenyl)phosphanium bromide

[0517] Triphenylphosphine (77.4 g, 0.295 mol) was added to a solution of ethyl 5-bromo-2,2-dimethylpentanoate 3 (70.5 g, 0.295 mol) in toluene (600 mL). The solution was refluxed for 24 hours. The toluene was concentrated to approximately 250 mL on a rotovap. The toluene was decanted and stored. The residue was stirred with heptane (200 mL) under an argon atmosphere at room temperature for 1 hour. The heptane was decanted, and the remaining solid was dried under high vacuum. The procedure produced the first harvest of intermediate 4 (68.4 g, harvest 1). The toluene and heptane washing solution was mixed and concentrated. The remaining residue (75.3 g) was mixed with toluene (200 mL) and refluxed under argon for 24 hours. After 24 hours, the flask was cooled to room temperature and stored in a freezer (-15°C) for 1 hour. Toluene was decanted, and the remaining residue was stirred with heptane (200 mL) under an argon atmosphere for 1 hour. Heptane was decanted, and the solid was dried under high vacuum to prepare a second harvest of intermediate 4 (52.5 g). After mixing the harvests, the experiment produced intermediate 4 as an off-white solid (120.9 g, yield 82%). 1 H NMR(300MHz,CDCl3)δ 7.89-7.70(m,15H),3.97(q,2H,J=7.2Hz),3.82(m,2H),1.92(m,2H),1.60(m,2H),1.11(m,9H). 13 C NMR(75MHz,CDCl3)δ 177.2,135.1,133.6(d,J=9.2Hz),130.4(d,J=12.6Hz),118.1(d,J=84.7Hz),60.3,42.1,40.7(d,J=16Hz),25.0,23.1(d,J=49.3Hz),18.4,14.2. 31 P (292MHz, CDCl3)δ 24.0. [ka]

[0518] Step 3: Ethyl(5E / Z)-6-{3-[(1E / Z)-5,5-dimethyl-6-ethoxy-6-oxohexe-1-en-1-yl]phenyl}2,2-dimethyl-hexe-5-enoate

[0519] (5-ethoxy-4,4-dimethyl-5-oxopentyl)(triphenyl)phosphanium bromide 4 (56.4 g, 112.9 mmol) and isophthalaldehyde (8.0 g, 59.6 mmol) were dissolved in dichloromethane (170 mL) under an argon atmosphere at room temperature. The flask was cooled in a water bath at room temperature. Sodium hydroxide (32.0 g, 800 mmol) in water (32 g) was added dropwise over 10 minutes. After 30 minutes, an additional intermediate 4 (14.0 g, 28.0 mmol) was added, and the mixture was vigorously stirred at room temperature for 2 hours. Water (DI, 400 mL) was added, and the layers were separated. The aqueous fraction was extracted with dichloromethane (200 mL). The dichloromethane extracts were mixed, dried over magnesium sulfate, filtered, and concentrated. The remaining yellow solid (62.5 g) was dissolved in dichloromethane (200 mL), filtered through a silica gel (400 g) column, and eluted with dichloromethane. The product containing the fractions was mixed and concentrated. The remaining yellow oily substance (17.23 g) was purified by column chromatography on silica gel (350 g) eluted with 4% ethyl acetate in heptane. The procedure produced intermediate 7 (10.65 g, yield 43%, isomer E / Z mixture) as a pale yellow oily substance (retaining some heptane). The second fraction of the monoolefinized intermediate (3.28 g) was also recovered. (Isomer E / Z mixture): 1 H NMR(300MHz,CDCl3)δ 7.28-7.13(m,4H),6.40-6.32(m,2H),6.22-6.12(m,1H),5.65-5.56(m,1H), 4.15-4.04(m,4H),2.30-2.12(m,4H),1.73-1.65(m,4H),1.30-1.17(m,18H). 13C NMR(75MHz,CDCl3)δ 177.6,137.8,137.6,137.4,132.3,130.5,129.9,129.0,128.2,127.9,127.1,126.7,1 26.4,124.5,124.1,123.6,60.3,42.1,41.9,40.7,40.2,28.7,25.2,25.1,24.3,14.2. [ka]

[0520] Step 4: 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoate diethyl ester

[0521] Intermediate 7 (10.5 g, 25.3 mmol) was dissolved in ethanol (120 mL) and added to 5% palladium (2.5 g) on ​​carbon at room temperature under a nitrogen atmosphere. The nitrogen atmosphere was replaced with hydrogen gas (40-45 psi), and the mixture was hydrogenated on a Parr hydrogenator at room temperature for 5 hours. After 5 hours, the hydrogen was replaced with nitrogen, and the mixture was filtered through a Celite pad. The ethanol was concentrated on a rotovap, and the crude was used in the final step without purification. The procedure produced intermediate 8 (8.59 g, 81% yield, pure by NMR) as a very pale yellow oily substance. 1 H NMR(300MHz,CDCl3)δ 7.21(t,1H,J=8.4Hz),7.03-7.01(m,3H),4.15(q,4H,J=6.9Hz),2.62(t,4H,J=7. 5Hz),1.70-1.55(m,8H),1.38-1.30(m,4H),1.27(t,6H,J=6.9Hz),1.21(s,12H). 13 C NMR(75MHz,CDCl3)δ 177.9,142.5,128.5,128.1,125.6,60.1,42.1,40.5,35.8,32.0,25.1,24.7,14.2. [ka]

[0522] Step 5: 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (compound I-32)

[0523] Intermediate 8 (8.50 g, 20.3 mmol) was dissolved in ethanol (65 mL). 60 mL of water containing potassium hydroxide (8.0 g, 143 mmol) was added, and the mixture was refluxed under an argon atmosphere. After 7 hours, heating was stopped, the mixture was cooled to room temperature, and stirred overnight. After 18 hours, the solution was concentrated on a rotovap to remove the ethanol. The remaining aqueous solution was diluted with water (100 mL) and extracted with diethyl ether (100 mL). The aqueous portion was acidified with concentrated hydrochloric acid (to pH=2), and the solid product was extracted with ethyl acetate (2 × 100 mL). The mixed ethyl acetate extract was washed with brine (100 mL), dried on magnesium sulfate, filtered, and concentrated on a rotovap. The remaining white solid (7.0 g) was mixed with heptane (50 mL) and stirred overnight at room temperature under an argon atmosphere. After 20 hours, the solid was filtered and dried at 35°C under high vacuum. The procedure involved preparing 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-32 (6.47 g, 88% yield, 99.4% by HPLC, producing a white solid at NMR (mp=99~101°C). 1 H(300MHz,CDCl3),δ 7.18(t,1H,J=7.2Hz),7.00-6.90(m,3H),2.58(t,4H,J=6.9Hz),1.66-1.54(m,8H),1.32-1.22(m,4H),1.18(s,12H). 13 C(75MHz,CDCl3),δ 185.3;142.4;128.5;128.2;127.8;42.1;40.5;35.7;31.6;25.0;24.5.

[0524] Example 1C: 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (compound I-1) [ka]

[0525] Step 1: Ethyl(5E / Z)-6-{4-[(1E / Z)-5,5-dimethyl-6-ethoxy-6-oxohexe-1-en-1-yl]phenyl}2,2-dimethyl-hexe-5-enoate

[0526] (5-ethoxy-4,4-dimethyl-5-oxopentyl)(triphenyl)phosphanium bromide 4 (60.0 g, 120.1 mmol) and terephthalaldehyde 5 (8.0 g, 59.6 mmol), prepared as described in Step 2 of Example 1B, were dissolved in dichloromethane (180 mL) under an argon atmosphere at room temperature. The flask was cooled in a water bath at room temperature. Sodium hydroxide (32.0 g, 800 mmol) in water (38 g) was added dropwise over 10-15 minutes. After 30 minutes, an additional intermediate 4 (14.47 g, 28.97 mmol) was added, and the mixture was vigorously stirred at room temperature for 2 hours. Water (DI, 200 mL) was added, and the layers were separated. The aqueous fraction was extracted with dichloromethane (200 mL). The dichloromethane extracts were mixed, dried over magnesium sulfate, filtered, and concentrated. The remaining yellow solid (64.2 g) was dissolved in dichloromethane (100 mL), filtered through a silica gel (400 g) column, and eluted with dichloromethane. The product containing the fractions was mixed and concentrated. The remaining yellow oily substance (18.0 g) was purified by column chromatography on silica gel (360 g) eluted with 5% ethyl acetate in heptane. The procedure produced intermediate 9 (9.5 g, yield 38.5%, isomer E / Z mixture) as a yellow oily substance (retaining trace amounts of heptane). The second fraction of the monoolefinized intermediate (3.62 g) was also recovered. (Isomer E / Z mixture): 1 H NMR(300MHz,CDCl3)δ 7.29-7.16(m,4H),6.40-6.30(m,2H),6.22-6.12(m,1H),5.70-5.50(m,1H), 4.15-4.05(m,4H),2.30-2.10(m,4H),1.74-1.65(m,4H),1.28-1.17(m,18H). 13C NMR(75MHz,CDCl3)δ 177.6,136.3,136.1,1375.9,135.8,132.2,131.9,130.2,129.9,129.6,128. 8,128.4,125.9,125.6,60.2,42.0,41.9,40.6,40.2,25.1,25.0,24.4,14.2. [ka]

[0527] Step 2: 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoate diethyl ester

[0528] Intermediate 9 (11.0 g, 26.5 mmol) was dissolved in ethanol (200 mL) and added to 5% palladium (3.0 g) on ​​carbon at room temperature under a nitrogen atmosphere. The nitrogen atmosphere was replaced with hydrogen gas (40-45 psi), and the mixture was hydrogenated at room temperature for 5 hours on a Parr hydrogenator. After 5 hours, the hydrogen was replaced with nitrogen, and the mixture was filtered through a Celite pad. The ethanol was concentrated on a rotovap, and the crude was used in the final step without purification. The procedure produced intermediate 10 (10.24 g, 92% yield, pure by NMR) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.06(s,4H),4.09(q,4H,J=7.2Hz),2.56(t,4H,J=7.5Hz),1.62-1.50(m,8H),1.32-1.22(m,4H),1.22(t,6H,J=7.2Hz),1.10(s,12H). 13 C NMR(75MHz,CDCl3)δ 177.9,139.8,128.2,60.1,42.1,40.5,35.3,31.9,25.1,24.6,14.2. [ka]

[0529] Step 3: 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (compound I-1)

[0530] Intermediate 10 (10.2 g, 24.4 mmol) was dissolved in ethanol (85 mL). 80 mL of water containing potassium hydroxide (9.57 g, 170.5 mmol) was added, and the mixture was refluxed under an argon atmosphere. After 7 hours, heating was stopped, the mixture was cooled to room temperature, and stirred overnight. After 18 hours, the solution was concentrated on a rotovap to remove the ethanol. The remaining mixture was diluted with water (250 mL) and acidified with concentrated hydrochloric acid (to pH=2). After mixing for 1 hour, the solid product was extracted with ethyl acetate (2 × 150 mL). The mixed ethyl acetate extract was washed with brine (100 mL), dried on magnesium sulfate, filtered, and concentrated on a rotovap. The remaining white solid (8.5 g) was mixed with heptane (40 mL) and stirred overnight at room temperature under an argon atmosphere. After 20 hours, the solid was filtered and dried at 45°C under high vacuum. The procedure involved preparing 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-1 (7.82 g, yield 88.5%, 99.6% by HPLC, producing a white solid (mp=126~127°C). NMR 1 H(300MHz,CDCl3)δ 7.03(s,4H),2.62(m,4H),1.67-1.54(m,4H),1.53-1.44(m,4H),1.15(s,12H),1.07-0.96(m,4H). 13 C(75MHz,CDCl3):δ 185.3,138.7,128.5,42.4,41.5,34.5;30.6;24.9;23.3.

[0531] Example 1D: Synthesis of 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoic acid) (compound I-62) [ka]

[0532] Step 1: Ethyl 6-iodo-2,2-dimethylhexanoate.

[0533] Commercially available ethyl 6-iodo-2,2-dimethylhexanoate (1 g, 3.98 mmol) and acetone (6 ml) were added to a 20 mL round-bottom flask. Sodium iodide (1.194 g, 7.96 mmol) was added, and the flask was covered with aluminum foil. The reaction mixture was stirred at room temperature for 48 to 72 hours. The solid was filtered off and rinsed with dichloromethane. The filtrate was concentrated under vacuum to obtain a solid slurry. Dichloromethane was added, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain ethyl 6-iodo-2,2-dimethylhexanoate (1.125 g, 3.77 mmol, yield 95%). 1 H NMR(400MHz,DMSO / TMS):δ 4.05(q,J=7.1Hz,2H),3.26(t,J=6.8Hz,2H),1.71(p,J=7.0Hz,2H),1.52-1.43(m,2H) ,1.33-1.23(m,2H),1.18(t,J=7.1Hz,3H),1.10(s,6H).GCMS:>95%, Mass: m / z[M-C2H5O] - 253.1.

[0534] Step 2: (6-ethoxy-5,5-dimethyl-6-oxohexyl)zinc iodide(II).

[0535] A 50 ml oven-dried three-necked round-bottom glass flask (vacuum outlet, inlet to argon-filled balloon, stopper) equipped with a Teflon stirrer was filled with anhydrous lithium chloride (239 mg, 5.63 mmol) and zinc (dust (<10 μM), 368 mg, 5.63 mmol) and heated under vacuum (standard laboratory vacuum pump) using a heat gun for approximately 5 minutes. The mixture was cooled to room temperature. The mixture was suspended in dry THF (10 ml). Zinc was activated by adding 1,2-dibromoethane (0.024 ml, 0.282 mmol), heated for a few seconds using a heat gun, and stirred at room temperature for 5 minutes. Trimethylsilyl chloride (0.024 ml, 0.188 mmol) was added, the mixture was heated for a few seconds using a heat gun, and stirred at room temperature for 5 minutes. Iodine (19.07 mg, 0.075 mmol) was added as a solid. A yellow suspension formed in approximately 1 minute, and the mixture was stirred at room temperature for 10 minutes. A solution of ethyl 6-iodo-2,2-dimethylhexanoate (1120 mg, 3.76 mmol) in dry THF (5.00 ml) was added dropwise within 1-2 minutes at room temperature. The reaction mixture was stirred under argon at 45°C (oil bath) for 1 hour, then cooled to room temperature and allowed to stand for 1 hour before being used in the next step.

[0536] Step 3: Diethyl 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoate).

[0537] A 40 ml screw-cap vial was placed under argon and packed with 1,2-dibromobenzene (0.112 ml, 0.933 mmol) and dry THF (10 ml), followed by the addition of S-phos (38.3 mg, 0.093 mmol) and palladium(II) acetate (10.47 mg, 0.047 mmol). (6-ethoxy-5,5-dimethyl-6-oxohexyl)zinc(II) iodide (1017 mg, 2.80 mmol) from the THF was filtered and added dropwise at room temperature (1-2 minutes). The reaction mixture was stirred overnight at 40°C. The reaction was stopped and EtOH (5 mL) was added. Hydromatrix was added and the solvent was evaporated. The crude product was purified by direct-phase chromatography using heptane / diisopropyl ether 0->20%. The fractions containing the product were mixed and concentrated under reduced pressure to obtain diethyl 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoate) (210 mg). The product was used without further characterization. LC-MS: 72% m / z [M+NH4] + 436.3.

[0538] Step 4: 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoic acid).

[0539] Crude diethyl 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoate) (210 mg) was dissolved in ethanol (1 ml), and 6 M KOH aqueous solution (1.254 ml, 7.52 mmol) was added. A precipitate formed, and the reaction mixture was stirred overnight at 60°C. The mixture was cooled to room temperature and acidified to a pH of approximately 8. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The residue was dissolved in H2O / acetonitrile / THF and subjected to basic pretreatment for purification. The product fraction was concentrated in genevac, reformatted, and lyophilized to obtain 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoic acid) (95.4 mg, 0.263 mmol, 28% yield over two steps). 1H NMR (400MHz, [MeOD] / TMS): δ7.11-7.02(m,4H),2.63-2.56(m,4H),1.60-1.48(m,8H),1.41-1.29(m,4H),1.14(s,12H). 13 C NMR(100MHz,[MeOD] / TMS):δ183.02,141.37,130.27,126.84,43.34,42.05,33.64,33.30,26.37,25.98.LCMS:>95%, Mass: m / z[MH] - 361.3.

[0540] Example 1E: Synthesis of 7,7'-(1,4-phenylene)bis(3,3-dimethylheptanoic acid) (compound I-84) [ka]

[0541] Step 1: Dimethyl 7,7'-(1,4-phenylene)(5E,5'E)-bis(3,3-dimethylhepta-5-enoate).

[0542] The reaction was carried out in a 500 ml round-bottom flask under an argon atmosphere. (1,4-phenylenebis(ethane-2,1-diyl))bis(triphenyl-phosphonium) bromide (3.18 g, 3.58 mmol, prepared as described in U.S. Patent No. 4,689,344) was co-evaporated with dry tetrahydrofuran (THF, 150 mL) to remove the solvent residue. To a stirred suspension of (1,4-phenylenebis(ethane-2,1-diyl))bis(triphenyl-phosphonium) bromide (3.18 g, 3.58 mmol) in dry THF (150 mL), n-butyllithium (13.44 mL, 21.50 mmol) was added at room temperature. A dark orange / brown solution was obtained. After 10 minutes, a freshly prepared solution of methyl 3,3-dimethyl-5-oxopentanoate (2.324 g, 14.69 mmol) in dry THF (25 mL) was added dropwise over 2 minutes. A pale amber solution was obtained. The mixture was stirred at room temperature for 30 minutes for complete conversion. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and separated into Et2O (250 mL) and ELISA (250 mL). The phases were separated, and the organic phase was washed with saturated NaCl aqueous solution (4 × 500 mL), followed by washing with brine (250 mL). The aqueous phase was then back-extracted with a single portion of Et2O (500 mL). This Et2O phase was then washed with brine (250 mL). The mixed organic phase was dried over Na2SO4 and allowed to stand overnight. Na2SO4 was filtered off, and the filtrate was concentrated under reduced pressure to obtain 4.09 g of crude product. The crude product was dissolved in dichloromethane, coated onto a hydromatrix, and purified by flash column chromatography (80 g silica, gradient, heptane / siRNA, 1:0-9:1, collection by ELSD, 50 ml fraction). Fractions 28-33 were mixed, and the solvent was removed under reduced pressure to obtain 466 mg of the product as a clear, colorless oil (LCMS, 415[M+H]+ m / z). 1H NMR(400MHz,CDCl3 / TMS):δ 7.10(s,4H),5.68(m,J=12.6,7.3Hz,2H),5.61-5.46(m,2H),3.65(s,6H),3.64(s,1H),3.37(d,J=7.2Hz,4H) ,3.33(d,J=6.1Hz,1H),2.25(s,4H),2.19(d,J=7.7Hz,5H),2.03(d,J=6.7Hz,1H),1.04(s,12H),0.99(s,2H).

[0543] Step 2: Dimethyl 7,7'-(1,4-phenylene)bis(3,3-dimethylheptanoate).

[0544] Dimethyl 7,7'-(1,4-phenylene)(5E,5'E)-bis(3,3-dimethylhepta-5-enoate) (466 mg, 1.124 mmol) was dissolved in ethanol (Abs) (14.410 mL) in a 20 ml Biotage microwave vial, and the solution was purged with nitrogen. Pd-C (59.8 mg, 0.056 mmol) was added to activated carbon, wetted with 10 wt% Pd and 50 wt% water, and unreduced, and the vial was capped. The reaction mixture was flushed with hydrogen and then stirred at room temperature for 1 hour under a hydrogen atmosphere (balloon). The reaction mixture was filtered through three high-capacity nylon microfilters. Each filter was rinsed with EtOH (20 mL). The mixed filtrate was concentrated under reduced pressure to obtain 472 mg of crude product. The product was coated onto a hydromatrix using dichloromethane and purified using flash column chromatography (24 g silica, gradient 5 / 20 / 5 min, heptane / siRNA, 1:0~9:1, 32 mL / min, collection 220 nm / ELSD, all fractions collected, 25 ml fraction). The selected fractions were mixed and concentrated under reduced pressure to obtain 441 mg (94%) of the product as a clear, colorless oil, LCMS m / z 441.4[M+Na] + We obtained a result that matches the structure. 1 H-NMR. 1H NMR(400MHz,CDCl3 / TMS):δ 7.08(s,4H),3.64(s,6H),2.63-2.53(m,4H),2.19(s,4H),1.64-1.50(m,8H)(water signal),1.32(m,J=3.7Hz,8H),0.97(s,12H).

[0545] Step 3: 7,7'-(1,4-phenylene)bis(3,3-dimethylheptanoic acid).

[0546] A 1M potassium hydroxide aqueous solution (16.86 mL, 16.86 mmol) was added to a solution of dimethyl 7,7'-(1,4-phenylene)bis(3,3-dimethyl-heptanoate) (441 mg, 1.053 mmol) in ethanol (Abs) (8.042 mL). The reaction mixture was stirred overnight at 70°C. A clear, colorless solution was formed (LC-MS showed a complete and clean conversion; m / z 389.2 [MH]). - and 194.2[M-2H] 2- (Observed at 2 / 2). The mixture was cooled to room temperature. The reaction mixture was diluted with desalted water (75 mL) and extracted with dichloromethane (2 × 75 mL). Complete phase separation was not possible because the deprotonation product behaved very soapy in the aqueous phase. The organic phase was discarded. The aqueous phase was acidified with 1 M KHSO4 aqueous solution (50 mL), and dichloromethane (50 mL) was added to separate the phases. The pH of the aqueous phase was measured at 1. The phases were separated, and the aqueous phase was extracted with dichloromethane (4 × 50 mL). The mixed organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 403.1 mg (98%) of the product as a white solid. The product was placed under reduced pressure to obtain 398 mg of the product as a white solid (LCMS m / z 389.2 [MH]). - . 1 H NMR (400MHz, CDCl3 / TMS): δ 7.07(s,4H),2.64-2.51(m,4H),2.21(s,4H),1.58(p,J=7.3Hz,4H),1.46-1.20(m,8H),1.01(s,12H).

[0547] Example 1F: Synthesis of 7,7'-(1,3-phenylene)bis(3,3-dimethylheptanoic acid) (compound I-85) [ka]

[0548] Step 1: Dimethyl 7,7'-(1,3-phenylene)(5E,5'E)-bis(3,3-dimethylhepta-5-enoate).

[0549] (1,4-phenylenebis(ethane-2,1-diyl))bis(triphenyl-phosphonium) bromide (4.1 g, 3.56 mmol, prepared as described in U.S. Patent No. 4,689,344) was co-evaporated with dry tetrahydrofuran (THF) (150 ml) to remove solvent residue. In a round-bottom flask dried under 250 ml of argon, n-butyllithium (13.37 ml, 21.39 mmol) was added at room temperature to a stirred suspension of 1,3-bis(2-(bromotriphenyl-15-phosphineyl)ethyl)benzene (4.1 g, 3.56 mmol) in dry tetrahydrofuran (150 ml). A dark orange solution was obtained, but still contained some small white lumps. After 10 minutes, methyl 3,3-dimethyl-5-oxopentanoate (2.312 g, 14.62 mmol) diluted in dry THF (25 ml) was added dropwise over 2 minutes. A yellow solution was obtained. The mixture was stirred for 30 minutes. TLC (heptane / ethyl, 9 / 1) was taken and showed one new main signal. The mixture was quenched with water (1 ml) and concentrated to a small volume (40 ml) under vacuum. Water (100 ml) was added and the mixture was extracted with ethyl (2 × 100 ml). The organic layer was mixed, washed with brine (50 ml), dried over Na₂SO₄, and concentrated under vacuum. The residue was dissolved in dichloromethane, coated onto a hydromatrix, and purified by flash column chromatography (80 g silica gel, heptane, ethyl 0-10%). After a second column chromatography (40 g silica gel), 650 mg of the desired compound was obtained. 1H NMR(400MHz,CDCl3 / TMS):δ 7.23-7.16(m,1H),7.00-70.2(m,3H),5.71-5.51(m,4H),3.64(s,6H), 3.42-3.35(m,4H),2.25(s,4H),2.22-2.16(m,4H),1.12-0.94(m,12H).

[0550] Step 2: Dimethyl 7,7'-(1,3-phenylene)bis(3,3-dimethylheptanoate).

[0551] Dimethyl 7,7'-(1,3-phenylene)(5E,5'E)-bis(3,3-dimethylhepta-5-enoate) (650 mg, 1.568 mmol) was diluted in anhydrous ethanol (20 ml), and the solution was purged with nitrogen for 5 minutes. Non-reducing Pd / C (10% on activated carbon, 50% wetted with water) (167 mg, 0.078 mmol) was added under a nitrogen atmosphere. A hydrogen balloon was applied and the mixture was purged with hydrogen for 5 minutes. The round-bottom flask was sealed under a hydrogen atmosphere and stirred for 1 hour. TLC (heptane / siRNA, 9 / 1) was collected and showed spot-to-spot conversion. The mixture was filtered on a Celite pad. The residue was rinsed with EtOH (10 ml). The filtrate was concentrated under vacuum. The resulting colorless oil was dissolved in dichloromethane, coated onto a hydromatrix, and purified by flash column chromatography (24 g, heptane, siRNA 0-10%) to obtain 590 mg of the desired compound. 1 H NMR(400MHz,CDCl3 / TMS):δ 7.22-7.13(m,1H),6.99(d,J=6.1Hz,3H),3.64(s,6H),2.58(t,J=9.0,6.7 Hz,4H),2.19(s,4H),1.64-1.51(m,4H),1.33-1.31(m,8H),0.98(s,12H).

[0552] Step 3: 7,7'-(1,4-phenylene)bis(3,3-dimethylheptanoic acid).

[0553] Dimethyl 7,7'-(1,3-phenylene)bis(3,3-dimethylheptanoate) (550 mg, 1.314 mmol) was dissolved in anhydrous ethanol (10 ml). KOH (1 M in water) (21.02 ml, 21.02 mmol) was added, and the mixture was stirred at 70°C for 5 hours and then at 60°C overnight. Complete conversion of the starting material was observed according to LC-MS analysis. The mixture was cooled to room temperature, and 75 ml of water was added. The mixture was extracted with dichloromethane (2 × 75 ml), and the organic layer was discarded. The aqueous layer was acidified with 1 M HCl (30 ml) and extracted with dichloromethane (5 × 50 ml). The organic layers were mixed, washed with brine, dried over Na₂SO₄, concentrated under vacuum, and co-evaporated with Et₂O. The obtained solid was ground with heptane (10 ml), filtered, rinsed with pentane (2 × 5 ml), and air-dried to obtain 385 mg of the desired product. LC-MS: Mass: m / z [M + Na] + 441. 1 H NMR(400MHz,CDCl3 / TMS):δ 7.22-7.13(m,1H),6.99(d,J=6.1Hz,3H),3.64(s,6H),2.58(t,J=9.0,6.7 Hz,4H),2.19(s,4H),1.64-1.51(m,4H),1.33-1.31(m,8H),0.98(s,12H).

[0554] Example 1G: Synthesis of 7,7'-(1,3-phenylene)bis(3,3-dimethylheptanoic acid) (compound I-94) [ka]

[0555] Step 1.2-(benzyloxy)-1,3-dibromobenzene.

[0556] 2,6-Dibromophenol (2.01 g, 7.98 mmol) was dissolved in tetrahydrofuran (5 ml). Benzyl bromide (1.139 ml, 9.58 mmol) and potassium carbonate (2.206 g, 15.96 mmol) were added. The reaction mixture was stirred over a weekend with dichloromethane (10 mL) at room temperature, and saturated aqueous NaHCO3 (10 mL) was added. The aqueous layer was extracted twice more with dichloromethane (10 mL), the organic layers were mixed, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Heptane / siRNA 0=>10% was used as a gradient for flash column chromatography. The product containing the fractions was mixed and concentrated under reduced pressure to obtain 2-(benzyloxy)-1,3-dibromobenzene (1.2 g, 3.51 mmol, yield 44.0%). GCMS >95% mass;m / z[M]+342.0.

[0557] Step 2. Diethyl 6,6'-(2-(benzyloxy)-1,3-phenylene)bis(2,2-dimethylhexanoate).

[0558] A 40 ml screw-cap vial was placed under argon and filled with 2-(benzyloxy)-1,3-dibromobenzene (300 mg, 0.877 mmol) and tetrahydrofuran (dried) (10 ml), followed by S-Phos (36.0 mg, 0.088 mmol) and palladium(II) acetate (9.85 mg, 0.044 mmol). A solution of (6-ethoxy-5,5-dimethyl-6-oxohexyl)-zinc(II) iodide (957 mg, 2.63 mmol, prepared in the same manner as in the above example) in THF was filtered and added dropwise at room temperature (1-2 minutes). The reaction mixture was stirred overnight at 40°C. EtOH (5 mL) was added, followed by the addition of the hydromatrix, and the solvent was removed under reduced pressure. The crude product was pur...

Claims

【Request Item 1】 【Chemistry 1】 A composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prevention of chronic kidney disease (CKD) or renal fibrosis.

2. The aforementioned compound, 【Chemistry 2】 The composition according to claim 1, having the structure of or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing renal fibrosis.

3. The aforementioned compound, 【Transformation 3】 The composition according to claim 1, having the structure of or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing renal fibrosis.

4. The aforementioned compound, 【Chemistry 4】 The composition according to claim 1, having the structure of or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing chronic kidney disease.

5. The aforementioned compound, 【Transformation 5】 The composition according to claim 1, having the structure of or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing chronic kidney disease.

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