Functionalized long chain hydrocarbon mono- and dicarboxylic acids and derivatives thereof and their use for the prevention or treatment of disease - Patents.com

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 January 25, 2021, and U.S. Provisional Application No. 63 / 285,890, filed December 3, 2021, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] 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 pharmaceutically acceptable salts and solvates, and compositions thereof. [Background technology]

[0003] Kidney disorders are becoming more common worldwide due to the Western diet and are undertreated. The most common type of kidney disorder is kidney disease or nephropathy, which is characterized by kidney damage. Kidney problems include acute kidney injury, kidney cysts, kidney stones, and kidney infections, which can result in kidney failure, loss of kidney function to some degree, or complete loss of kidney function. Treatments for kidney failure include kidney transplantation or dialysis, but therapy is still needed to treat other kidney conditions.

[0004] When kidney dysfunction or structural damage extends beyond 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 is a condition that affects 13% of the adult population worldwide. CKD is divided into categories according to GFR and urinary albumin:creatinine ratio (UACR). This 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, such as having a family member with kidney disease, being African American, Hispanic, Native American, or Asian, and socioeconomic, drug, or other health conditions. Among patients at higher risk for kidney disease are those with diabetes, high blood pressure, heart disease, or age (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 a higher 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, nonalcoholic fatty liver disease (NAFLD), nonalcoholic 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 for developing NAFLD and nonalcoholic steatohepatitis (NASH), which may be caused by excessive hepatic triglyceride production and accumulation. Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride levels 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), intermediate-density lipoprotein cholesterol (IDL), and small low-density lipoprotein (LDL) in addition to elevated LDL-C and triglyceride levels.

[0008] Current therapeutic options for the treatment of type IIb hyperlipidemia are limited. While statins can be effective in lowering LDL-C and reducing inflammation, they are generally not very effective at lowering triglyceride levels. Furthermore, high-dose statin therapy is often poorly tolerated, potentially causing muscle pain (myalgia) and increasing the risk of serious muscle toxicities, 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 statin blood levels, muscle pain, increased risk of muscle toxicity, and increased safety risks. In fact, the interaction between the statin Baycol (cerivastatin) and the fibrate gemfibrozil resulted in severe muscle toxicity and death, raising safety concerns and leading to Baycol's removal from the U.S. market. Fish oil, used to lower triglyceride levels, must be taken multiple times daily and may cause an oily aftertaste, burping, or reflux. Niacin, especially when given in combination with statins, can cause flushing.

[0009] Gastrointestinal (digestive) cancers can affect the gastrointestinal tract and other organs contained within the digestive system, such as the liver. The origin of digestive cancer has been strongly associated with chronic inflammation of the organ, which develops through a series of histopathological stages depending on the affected organ. In the case of cancer of the gastrointestinal tract or gastrointestinal stromal tumors (GISTs), surgery will likely 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 induced by the pathological accumulation of extracellular matrix (ECM) proteins, resulting in scarring and thickening of affected tissues, as if it were an excessive wound healing response that interferes with normal organ function. Fibrosis can occur in many tissues in the body, typically as a result of inflammation or injury, such as fibrosis in the lungs, liver, brain, heart, kidneys, uterus, etc.

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

[0012] The present invention relates to a method for treating or preventing a disease, the method comprising administering to a subject in need thereof 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, wherein the disease is selected from the group consisting 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 scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, end-stage renal failure, renal clear cell sarcoma, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-related autosomal dominant tubulointerstitial kidney disease, IgG 4-related kidney diseases, MUC1-related autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-related medullary cystic kidney disease, medullary sponge kidney, multicystic dysplastic kidney, multilocular renal cysts, multinodular thyroid cystic kidney polydactyly syndrome, neonatal diabetes mellitus-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidney syndrome, REN-related autosomal dominant tubulointerstitial kidney disease, rare diseases potentially eligible for kidney transplantation, renal cell carcinoma, renal dysplasia and unilateral or bilateral renal dysplasia , renal or urinary tract malformation, sex reversal-renal, adrenal and pulmonary hypoplasia syndrome (SERKAL syndrome), serpentine fibula-polycystic kidney syndrome, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney disease), unilateral polycystic dysplastic kidney, ventriculomegaly-cystic kidney disease, Birt-Hogg-Dube syndrome (BHD), or Peutz-Jeghers syndrome (PJS), or a complication of coal workers' pneumoconiosis.

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

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

[0015] Each composition described herein and useful in the methods of the present invention is a "composition of the present invention." [Brief explanation of the drawings]

[0016] [Figure 1] Schematic diagram of the ADP-Glo ​​assay. [Figure 2A] 1 shows IC50 data for ACC1 inhibition of compound I-32. [Figure 2B] 1 shows IC50 data for ACC1 inhibition of compound I-32-CoA. [Figure 2C] 1 shows IC50 data for ACC1 inhibition of compound I-1-CoA. [Figure 2D] 1 shows IC50 data for ACC1 inhibition for the reference compound CP640186. [Figure 3A] 1 shows IC50 data for ACC2 inhibition of compound I-32-CoA. [Figure 3B] 1 shows IC50 data for ACC2 inhibition of compound I-1-CoA. [Figure 3C] Figure 1 shows IC50 data for ACC2 inhibition for the reference compound CP640186. [Figure 4A] 1 shows IC50 data for ACLY inhibition for compound I-32-CoA. [Figure 4B] 1 shows IC50 data for ACLY inhibition for compound I-1-CoA. [Figure 4C] Figure 1 shows IC50 data for ACLY inhibition for the reference compound BMS-303141. [Figure 4D] 1 shows results for compounds I-1, I-1-CoA, I-32, and I-32-CoA in an ACLY inhibition assay. [Figure 5A] The following measurements are shown in mice treated with vehicle or compounds I-32 or I-1: steatosis (FIG. 5A). [Figure 5B] The following measurements are shown in mice treated with vehicle or compounds I-32 or I-1: inflammation (FIG. 5B). [Figure 5C] The following measurements are shown in mice treated with vehicle or compounds I-32 or I-1: fibrosis (FIG. 5C). [Figure 5D] The following measurements are shown in mice treated with vehicle or compounds I-32 or I-1: NAFLD score (FIG. 5D). [Figure 6A] Representative H&E staining (×1.25 magnification) at the end of the treatment period in mice with vehicle or compound I-32 or compound I-1 is shown. [Figure 6B] Representative H&E staining (×10 magnification) is shown. [Figure 7A] Representative Sirius Red staining (×1.25 magnification) at the end of the treatment period in mice with vehicle or compound I-32 or compound I-1 is shown. [Figure 7B] Representative Sirius Red staining (×10 magnification) is shown, with arrows indicating perisinusoidal and portal vein fibrosis. [Figure 8] Sirius Red % of total liver area in mice treated with vehicle or compound I-32 or compound I-1 is presented. [Figure 9A] The following liver inflammatory gene expression is shown in mice treated with vehicle or compound I-32 or compound I-1: IL-1β (FIG. 9A). [Figure 9B] The following liver inflammatory gene expression is shown in mice treated with vehicle or compound I-32 or compound I-1: MCP-1 (FIG. 9B). [Figure 9C] The following liver inflammatory gene expression is shown in mice treated with vehicle or compound I-32 or compound I-1: IL-6 (FIG. 9C). [Figure 9D] The following liver inflammatory gene expression in mice treated with vehicle or compound I-32 or compound I-1 is shown: NF-κβ (FIG. 9D). [Figure 9E]The following liver inflammatory gene expression is shown in mice treated with vehicle or compound I-32 or compound I-1: TLR-4 (FIG. 9E). [Figure 9F] The following liver inflammatory gene expression is shown in mice treated with vehicle or compound I-32 or compound I-1: TNF-α (FIG. 9F). [Figure 10] A and B show liver fibrosis gene expression in mice treated with vehicle or compound I-32 or compound I-1: TGF-β (FIG. 10A) and Coll1a1 (FIG. 10B). [Figure 11] Representative α-SMA immunostaining (×20 magnification) is shown at the end of treatment in mice with vehicle or compound I-32 or compound I-1. Arrows indicate α-SMA immunostaining. [Figure 12] % α-SMA relative to total liver area in mice treated with vehicle or compound I-32 or compound I-1 is shown. [Figure 13A] 1 shows the creation 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 quantification of renal fibrosis assessed 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-operated control group created by surgical exposure of the left ureter and lower pole of the kidney followed by incision closure, Group UV = vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13C]Representative images and quantification of renal fibrosis assessed 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-operated control group created by surgical exposure of the left ureter and lower pole of the kidney followed by incision closure, Group UV = vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13D] Representative images and quantification of renal fibrosis assessed 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-operated control group created by surgical exposure of the left ureter and lower pole of the kidney followed by incision closure, Group UV = vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13E] Representative images and quantification of renal fibrosis assessed 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-operated control group created by surgical exposure of the left ureter and lower pole of the kidney followed by incision closure, Group UV = vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13F]Representative images and quantification of renal fibrosis assessed 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-operated control group created by surgical exposure of the left ureter and lower pole of the kidney followed by incision closure, Group UV = vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13G] Representative images and quantification of renal fibrosis assessed 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-operated control group created by surgical exposure of the left ureter and lower pole of the kidney followed by incision closure, Group UV = vehicle, Group UA = Compound I-32, Group UB = Compound I-1. [Figure 13H] Representative images and quantification 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 quantification 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 quantification 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 quantification 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] The weights of mice in UUO mice are shown. Group UV = vehicle, group UA = compound I-32, group UB = compound I-1. [Figure 13M] Systolic blood pressure in UUO mice. Inhibitor A = Compound I-32, Inhibitor B = Compound I-1. [Figure 14] Figure 1 shows the inhibition of LPS-induced glycolysis by treatment of bone marrow-derived macrophages (BMDMs) with compound I-1. Differentiated bone marrow-derived macrophages were serum-starved for 2 hours and then treated with vehicle (control), LPS (10 ng / mL), or LPS + ACLYi (I-1) for 4 hours. Glycolytic rates were assessed using a Seahorse bioanalyzer. [Figure 15A] 1 shows the suppression of IL-6 mRNA, a marker of inflammation, by compound I-1 as assessed by RT-qPCR. [Figure 15B] 1 shows the suppression of IL-1b mRNA, a marker of inflammation, by compound IL-1 as assessed by RT-qPCR. [Figure 16] A and B show the plasma levels of alanine aminotransferase (ALT) (FIG. 16A) and aspartate aminotransferase (AST) (FIG. 16B) with compound I-1 or compound I-32. [Figure 17A] Liver weight (FIG. 17A) is shown by compound I-1 or compound I-32. [Figure 17B] The relative liver weight (FIG. 17B) is shown by compound I-1 or compound I-32. [Figure 17C] The liver free fatty acids (FIG. 17C) are shown by compound I-1 or compound I-32. [Figure 17D] The triglycerides (FIG. 17D) are shown by compound I-1 or compound I-32. [Figure 17E] Cholesterol (FIG. 17E) by compound I-1 or compound I-32 is shown. [Figure 18] A and B show hepatic expression of the β-catenin (FIG. 18A) and HIF-1α genes (FIG. 18B). [Figure 19]A to D show liver hepatoma gene expression: VEGFR1-3 (Fig. 19A), FGFR-1 (Fig. 19B), p38 MAP kinase (Fig. 19C), and RIPK4 (Fig. 19D). [Figure 20A] Plasma markers cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E) are shown. [Figure 20B] Plasma markers cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E) are shown. [Figure 20C] Plasma markers cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E) are shown. [Figure 20D] Plasma markers cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E) are shown. [Figure 20E] Plasma markers cholesterol (Figure 20A), HDL (Figure 20B), LDL (Figure 20C), triglycerides (Figure 20D), and free fatty acids (Figure 20E) are shown. [Figure 21] A and B show the plasma markers C-reactive protein CRP (FIG. 21A) and serum amyloid A protein SAA (FIG. 21B). [Figure 22] 1 shows the experimental protocol for the in vivo NAHS-HCC Hepa1-6 liver orthotopic tumor model (Example 11). [Figure 23] Figure 1 shows hepatic de novo lipogenesis in mice treated with compound I-1 or compound I-32 for 7 days. Glucose-derived C-labeled lipids in liver tissue after 7 days of treatment with either 10, 30, or 60 mg / kg of compound I-1 or compound I-32. Each bar represents the mean ± SEM, n = 6-10. * indicates statistically different from the vehicle group with a p-value < 0.05. [Figure 24] The study design for the pharmacokinetic experiments is shown (Example 13). [Figure 25A]These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25B] These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25C]These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25D] These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25E]These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25F] These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25G]These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25H] These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25I]These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 25J] These results show that compound I-32 (A) and compound I-1 (B) do not significantly affect platelet production. Compound I-32 (A) and compound I-1 (B) were added to expanded HSPCs on day 0 (Figures 25A-25E) and cultured for 8 days to develop megakaryocytes, or added on day 6 (Figures 25F-25J). CD41a cell count (Figure 25A), CD41aCd42b+ cell count (Figure 25B), platelet levels (Figure 25C), CD41a MFI (Figure 25D), and CD41a FSC cell size (Figure 25E) were analyzed on day 0. CD41a cell counts (FIG. 25F), CD41aCd42b+ cell counts (FIG. 25G), platelet levels (FIG. 25H), CD41a MFI (FIG. 25I), and CD41a FSC cell size (FIG. 25J) were analyzed on day 6. [Figure 26] Shown are the mean (+SEM) concentrations (ng / mL) of compound I-32 in plasma of male mice after single or repeated oral gavage administration. QD x 1 = once daily, single dose; QD x 4 = once daily for 4 consecutive days. [Figure 27] Shown are the mean (+SEM) concentrations (ng / g) of compound I-32 in the liver of male mice after single or repeated oral gavage administration. QD x 1 = once daily, single dose; QD x 4 = once daily for 4 consecutive days. [Figure 28]Shown are the mean (+SEM) concentrations (ng / g) of compound I-32 in the brain of male mice after single or repeated oral gavage administration. QD x 1 = once daily, single dose; QD x 4 = once daily for 4 consecutive days. [Figure 29] Shown are the mean (+SEM) concentrations (ng / mL) of compound I-1 in plasma of male mice after single or repeated oral gavage administration. QD x 1 = once daily, single dose; QD x 4 = once daily for 4 consecutive days. [Figure 30] Shown are the mean (+SEM) concentrations (ng / g) of compound I-1 in the liver of male mice after single or repeated oral gavage administration. QD x 1 = single dose once daily; QD x 4 = once daily for 4 consecutive days. [Figure 31] Shown are the mean (+SEM) concentrations (ng / g) of compound I-1 in the brain of male mice after single or repeated oral gavage administration. QD x 1 = once daily, single dose; QD x 4 = once daily for 4 consecutive days. [Figure 32] Figures 32A and 32B show the effects of compound I-1 and compound I-32 on the respiratory exchange ratio (RER) in C57B1 / 6 mice fed a high-fructose diet. Figure 32A shows the results as the % change in RER compared to the vehicle control at time 0. Figure 32B shows the % change in RER in each group compared to the respective time point 0. * indicates a significant difference from the vehicle control, p<0.05. [Figure 33] Figures 48A and 48B show the effects of compound I-1 and compound I-32 on heat production in high-fructose-fed C57BL / 6 mice up to 24 hours after treatment with compound I-1 or compound I-32. Figure 48A shows total heat production values ​​(day and night), and Figure 48B shows daytime heat production values ​​compared to nighttime. [Figure 34] Figures 34A and 34B show the effects of compound I-1 and compound I-32 on locomotor activity in fructose-fed C57BL / 6 mice, calculated as the total number of beam breaks in each cage over a 24-hour period. Figure 34A shows the total values, and Figure 34B shows the daytime values ​​compared to the nighttime values ​​for up to 24 hours (daytime + nighttime). * indicates a significant difference from the vehicle control, p<0.05. [Figure 35]Figures 35A and 35B show the effect of compound I-1 and compound I-32 on food intake. Figure 35A shows total food intake values ​​(day and night), and Figure 35B shows daytime food intake values ​​compared to nighttime. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition

[0018] The term "about" immediately preceding a numerical value means up to ±20% of the numerical value. For example, "about" a numerical value means up to ±20% of the numerical value, and in some embodiments, 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 less than ±1%, or any other numerical value or range of values ​​therein.

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

[0020] The term "pharmaceutically acceptable salts" includes both acid and base addition salts.

[0021] Pharmaceutically acceptable salts can be obtained by reacting a compound of the present invention having a basic, e.g., amino, group with an inorganic or organic acid to form a salt, e.g., a salt with 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, carbonic acid, etc. Pharmaceutically acceptable salts can also be obtained by reacting a compound of the present invention having an acidic, e.g., carboxyl, group with an inorganic or organic base to form a salt, e.g., a salt with sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, trimethylamine, etc. 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 a compound of the present invention having an acidic, e.g., 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 can 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, the pharmaceutically acceptable salt is a meglumine (N-methyl-D-glucamine) salt, an eglumine (N-ethyl-D-glucamine) salt, a D-glucamine salt, a glucosamine salt, a choline salt, a lysine salt, an arginine salt, a histidine salt, or a glutamine salt. In some embodiments, the pharmaceutically acceptable salt is an L-lysine salt, an L-arginine salt, an L-histidine salt, or an 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 the appropriate inorganic or organic acid or base via any of a number of known methods.

[0022] The term "solvate" refers to a solvated complex. A solvate can be formed by solvation (the combination of a solvent molecule with a molecule or ion of a compound of the present invention), or it can be an aggregate containing a solute ion or molecule or a solvent molecule. The solvent can be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. A solvate can be formed through hydration, including the absorption of water. A pharmaceutically acceptable salt can also be a solvate. When the solvate is obtained by crystallization from a solvent, the solvent can 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 asymmetric centers and may therefore be enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of the present invention include all such possible isomers (including geometric isomers), as well as their racemic and optically pure forms, whether or not specifically depicted herein. 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 fractional 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). When a compound of the present invention contains an olefinic double bond or another center of geometric asymmetry, unless otherwise specified, the compound includes both E- and Z-geometric isomers. Similarly, the compounds of the present invention include all tautomeric forms.

[0024] "Effective amount," when used in connection 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, means the amount of the compound, pharmaceutically acceptable salt, or solvate that, when administered to a subject, is effective in the methods of the invention, either alone or together with another pharmaceutically active agent.

[0025] "Effective amount," when used in connection with another pharmaceutically active agent, means the amount of that other pharmaceutically active agent that is effective in the compositions or methods of the 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.

[0026] A "subject" is a human or non-human mammal, such as a cow, horse, cat, dog, rodent, or non-human primate. A human can be male or female, a child, adolescent, or adult. A female can be premenstrual or postmenstrual.

[0027] "Mammals" includes humans, domestic 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-domestic wild animals.

[0028] All weight percentages (i.e., "weight %" and "wt.%" and "w / w") referred to herein are based on the total weight of the mixture or composition, as the case may be, unless otherwise indicated.

[0029] As used herein, the following terms have the following meanings unless otherwise indicated:

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

[0031] "Alkyl" refers to a straight or branched hydrocarbon chain having from 1 to 12 carbon atoms, connected to an atom by a single bond, and fully saturated. Alkyl groups having 1 to 12 carbon atoms are included. Alkyl groups having 1 to 12 carbon atoms include C1-C 12 Alkyl, an alkyl group having 1 to 10 carbon atoms is C1-C 10 An alkyl group having 1 to 6 carbon atoms is a C1-C6 alkyl, and an alkyl group having 1 to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Includes alkyl. C1-C 12 Non-limiting examples of 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 specified, alkyl groups can be unsubstituted or substituted with the substituents disclosed herein.

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

[0033] "Alkenyl" refers to a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to an atom by a single bond. Alkenyl groups having 2 to 12 carbon atoms are included. Alkenyl groups having 2 to 12 carbon atoms are C2-C 12 Alkenyl, an alkenyl group having 2 to 10 carbon atoms, is C2-C 10An alkenyl group having 2 to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl group having 2 to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all of the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Also includes alkenyl. Similarly, C2-C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12Non-limiting examples of alkenyl 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, and 3-nonenyl. , 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 can be unsubstituted or substituted with the substituents disclosed herein.

[0034] "Alkenylene" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. 12 Non-limiting examples of alkenylene include ethenylene, propenylene, butenylene, etc. Each end of the alkenylene chain is connected to an atom by a single bond. The attachment points of the alkenylene chain can be through one or two atoms. Unless otherwise specified, the alkenylene chain can be unsubstituted or substituted with the substituents disclosed herein.

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

[0036] "Alkynylene" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. 12 Non-limiting examples of alkynylene include ethynylene, propynylene, butynylene, etc. Each end of the alkynylene chain is bonded to an atom via a single bond. The attachment points of the alkynylene chain can be through one or two atoms. Unless otherwise specified, the alkynylene chain can be unsubstituted or substituted with the substituents disclosed herein.

[0037] "Alkoxy" means a group of the formula -OR a where R a is an alkyl, alkenyl, or alkynyl radical, as defined herein. Unless otherwise specified, an alkoxy group can be unsubstituted or substituted with the substituents disclosed herein.

[0038] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. The aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aceanthrlenyl, acenaphthylenyl, acephenanthrilenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless otherwise specified, aryl can be unsubstituted or substituted with the substituents disclosed herein.

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

[0040] "Arylalkyl" refers to a group of the formula -R b -R c where R b is an alkylene group as defined herein, and R c is an aryl radical as defined herein, for example, benzyl, diphenylmethyl, and the like. Unless otherwise stated, arylalkyl groups can be unsubstituted or substituted with the substituents disclosed herein. "Arylalkenyl" refers to a group of the formula -R b -R c where Rb is an alkenylene group as defined herein, and R c is an aryl radical, as defined herein. Unless otherwise specified, an arylalkenyl group can be unsubstituted or substituted with the substituents disclosed herein.

[0041] "Arylalkynyl" refers to a group of the formula -R b -R c where R b is an alkynylene group as defined herein, and R c is an aryl radical, as defined herein. Unless otherwise specified, an arylalkynyl group can be unsubstituted or substituted with the 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, which may include fused or bridged ring systems, and is connected to the atoms by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified, cycloalkyl groups can be unsubstituted or substituted with the substituents disclosed herein.

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

[0044] "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 can include fused or bridged ring systems having 3 to 20 carbon atoms, and in some embodiments, 3 to 10 carbon atoms. Cycloalkenyl groups are linked to atoms by single bonds. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specified, cycloalkenyl groups can be unsubstituted or substituted with the substituents disclosed herein.

[0045] "Cycloalkynyl" refers to a non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and which may include fused or bridged ring systems, having from 5 to 20 carbon atoms, in some embodiments from 5 to 10 carbon atoms, and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specified, cycloalkynyl groups can be unsubstituted or substituted with the substituents disclosed herein.

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

[0047] A "cycloalkenylalkyl" is a group of the formula -R b -R d where R b is an alkylene group as defined herein, and R d is a cycloalkenyl radical, as defined herein. Unless otherwise specified, a cycloalkenylalkyl group can be unsubstituted or substituted with the substituents disclosed herein. "Cycloalkenylalkenyl" refers to a group of the formula -R b -R d where R b is an alkenylene group as defined herein, and R d is a cycloalkyl radical, as defined herein. Unless otherwise specified, a cycloalkenylalkynyl group can be unsubstituted or substituted with the substituents disclosed herein. "Cycloalkenylalkynyl" refers to a group of the formula -R b -R d where R b is an alkynylene group as defined herein, and R d is a cycloalkyl radical, as defined herein. Unless otherwise specified, a cycloalkenylalkynyl group can be unsubstituted or substituted with the substituents disclosed herein.

[0048] A "cycloalkynylalkyl" is a group of the formula -R b-R d where R b is an alkylene group as defined herein, and R d is a cycloalkynyl radical, as defined herein. Unless otherwise specified, a cycloalkynylalkyl group can be unsubstituted or substituted with the substituents disclosed herein. "Cycloalkynylalkenyl" refers to a group of the formula -R b -R d where R b is an alkenylene group as defined herein, and R d is a cycloalkyl radical, as defined herein. Unless otherwise specified, a cycloalkynylalkenyl group can be unsubstituted or substituted with the substituents disclosed herein. "Cycloalkynylalkynyl" refers to a group of the formula -R b -R d where R b is an alkynylene group as defined herein, and R d is a cycloalkyl radical, as defined herein. Unless otherwise specified, a cycloalkynylalkynyl group can be unsubstituted or substituted with the substituents disclosed herein.

[0049] "Carbocyclyl," "carbocyclyl ring," or "carbocycle" refers to a cyclic structure in which each atom forming the ring is carbon. A carbocyclyl, carbocyclyl ring, or carbocycle can contain 3 to 20 carbon atoms in the ring. Carbocyclyl, carbocyclyl ring, or carbocycle includes aryl, cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. A carbocyclyl, carbocyclyl ring, or carbocycle can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused, bridged, and helical ring systems. Unless otherwise specified, a carbocyclyl group, carbocyclyl ring, or carbocycle can be unsubstituted or substituted with the substituents disclosed herein.

[0050] "Haloalkyl" refers to an alkyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified, a haloalkyl group can be unsubstituted or substituted with the substituents disclosed herein.

[0051] "Haloalkenyl" refers to an alkenyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise stated, a haloalkenyl group can be unsubstituted or substituted with the substituents disclosed herein.

[0052] "Haloalkynyl" refers to an alkynyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless otherwise stated, a haloalkenyl group can be unsubstituted or substituted with the substituents disclosed herein.

[0053] "Heterocyclyl" refers to a 3- to 20-membered non-aromatic, partially unsaturated, or aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 nitrogen, oxygen, or sulfur heteroatoms. Heterocyclyl includes heteroaryl as defined herein. Unless otherwise specified, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused, bridged, and helical ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise stated, heterocyclyl groups can be unsubstituted or substituted with the substituents disclosed herein.

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

[0055] "Heterocyclylalkenyl" refers to a group of the formula -R b -R e where Rb is an alkenylene group as defined herein, and R e is a heterocyclyl radical, as defined herein. Unless otherwise specified, a heterocyclylalkenyl group can be unsubstituted or substituted with the substituents disclosed herein.

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

[0057] "N-heterocyclyl" refers to a heterocyclyl radical, as defined herein, containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to an atom 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, is through a nitrogen atom in the heterocyclyl radical. Unless otherwise specified, N-heterocyclyl groups can be unsubstituted or substituted with substituents disclosed herein.

[0058] "Heteroaryl" refers to a 5- to 20-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 nitrogen, oxygen, or sulfur heteroatoms, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indo Examples of aryl include aryl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. Unless otherwise specified, a heteroaryl group can be unsubstituted or substituted.

[0059] "N-heteroaryl" refers to a heteroaryl radical, as defined herein, having at least one nitrogen atom, and the point of attachment of the heteroaryl radical to an atom 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, is through a nitrogen atom in the heteroaryl radical. Unless otherwise specified, an N-heteroaryl group can be unsubstituted or substituted with the substituents disclosed herein.

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

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

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

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

[0064] A "thioalkyl" is a group of the formula -SR a where R a is an alkyl, alkenyl, or alkynyl radical, as defined herein. Unless otherwise specified, a thioalkyl group can be unsubstituted or substituted with the substituents disclosed herein.

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

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

[0067] The groups or radicals disclosed herein can be substituted with one or more of the following substituents: 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 containing one or more heteroatoms.

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

[0069] In some embodiments, a group or radical disclosed herein is alternatively or additionally substituted 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 groups, -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 where R g and R hare the same 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, each of the foregoing substituents being 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 chemical synthesis reaction mixture, from an organism that is or was a living 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 a pharmaceutically acceptable salt or solvate thereof, is at least 90% pure. "At least x% pure" means that the compound, pharmaceutically acceptable salt, or solvate contains no more than (100-x)% of one or more other compounds. In some embodiments, the isolated and purified compound, salt, or solvate thereof is at least 95% pure. In some embodiments, the isolated and purified compound, salt, or solvate thereof is at least 96%, at least 97%, at least 98%, or at least 99% pure.

[0071] As used herein, the symbols [ka] ("bond point") denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the bond point and the other of which is not depicted as being attached to the bond point. For example, [ka] indicates that a chemical entity "XY" is attached to another chemical entity through a point of attachment.

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

[0073] The CoA radical, designated herein as "-CoA," has the following structure: [ka]

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

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

[0076] Compounds of formula (I)

[0077] In some embodiments, the compounds of the present invention have the structure of Formula (I): [ka]

[0078] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0079] each p is independently 1, 2, 3, 4, 5, 6, or 7;

[0080] each Z 1 and Z 2 But 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 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently an R bonded to a carbon atom; 1 and R 2 together form a -C3-C7 cycloalkyl group,

[0083] Each R 3 and R 4 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 an R bonded to a carbon atom; 3 and R 4 together form a -C3-C7 cycloalkyl group,

[0084] Q is 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 , heteroaryl, heterocyclyl, or -V-OH, or two Q's independently, together with the carbon atoms to which they are attached, form a heterocyclyl or carbocyclyl group;

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

[0086] Each R 1A and R 2Aare independently 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 is independently -OH, -COOH, -COOR 5 , -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] and

[0089] Each R 6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0090] Each R 7 is independently 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 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is 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 -C(R 1 )(R 2 )-(CH2) c -CO-CoA or Z 1 and Z 2 One or both of the following may be -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA.

[0095] In some embodiments of compounds of Formula (I), (IA), (IB), or (IC), Z 1 and Z 2 One or both of -C(R 1 )(R 2 )-(CH2) c In some embodiments, Z 1 and Z 2 One or both of the following may be -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 is -C(R 1 )(R 2 )-(CH2) c -CO-CoA, and Z 2 is -C(R 1 )(R 2 )-(CH2) c -COOH, or -C(R 1 )(R2 )-(CH2) c -COOR 5 is.

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

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

[0099] In some embodiments of a compound 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 independently has an R bonded to the carbon atom. 1 and R 2and together form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently selected from the R bonded to the carbon atom. 1 and R 2 Together with

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

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

[0103] In some embodiments of the compounds of Formula (I), (IA), (IB), or (IC), Y is —COOH or —COOR 5 is.

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

[0105] In some embodiments of the compound 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, and Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y and R 3 and R 4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, and 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, and 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 -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, and Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -CO-CoA, -COOH, or -COOR 5 and R 5is -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0106] In some embodiments of a compound 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 a compound 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, the pharmaceutically acceptable salt of a compound of Formula (I), (IA), (IB), or (IC) is a salt of an amino acid, a meglumine salt, an eglumine salt, a D-glucamine salt, a glucosamine salt, or a choline salt. In some embodiments, the pharmaceutically acceptable salt is a salt of a basic amino acid. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I), (IA), (IB), or (IC) is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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 any 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 any 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 any 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 selected from the group consisting of: 1 and C 2 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 selected from the group consisting of: 1 and C 2 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 selected from the group consisting of: 1 and C 2 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 compound of formula (I) is selected from the group consisting of: 1 and C 2 or defined by A-5, C 1 and C 2 or A-6, C 1 and C 2 wherein the phenyl ring of the compound is mono- or di-substituted with -OH or -CH3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has any one of the structures shown in Tables A-1, A-2, A-3, A-4, and C 1 and C 2 or defined by A-5, C 1 and C 2 or A-6, C 1 and C 2 A pharmaceutically acceptable salt of a compound having any one of the structures defined above is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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, the 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 Table A-7, Table A-8, Table A-9, Table A-10, Table A-11, or Table A-12 is a zinc salt. In some embodiments, a pharmaceutically acceptable salt of a compound having any one of the structures shown in Table A-8, Table A-9, or Table A-12 is a zinc salt. For example, the zinc salt of compound I-61 in Table A-9 has the structure depicted immediately 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, 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, is isolated and purified. In some embodiments, a compound of Formula (I), (IA), (IB), or (IC), or a pharmaceutically acceptable salt or solvate thereof, is isolated and purified. In some embodiments, a compound of Formula (I), (IA), (IB), or (IC), or a pharmaceutically acceptable salt or solvate thereof, is ex vivo.

[0131] Compounds of formula (ID)

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

[0133] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0134] each p is independently 1, 2, 3, 4, 5, 6, or 7;

[0135] each Z 1 and Z 2 But 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 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently an R bonded to a carbon atom; 1 and R 2 together form a -C3-C7 cycloalkyl group,

[0138] Each R 3 and R 4 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 an R bonded to a carbon atom; 3 and R 4 together form a -C3-C7 cycloalkyl group,

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

[0140] Each Q 2 are 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 , heteroaryl, heterocyclyl, or -V-OH, or two Q's independently, together with the carbon atoms to which they are attached, form a heterocyclyl or carbocyclyl group;

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

[0142] Each R 1A and R2A are independently 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 is independently -OH, -COOH, -COOR 5 , -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] and

[0145] Each R 6 are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0146] Each R 7 is independently 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 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is 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 the compound of formula (ID), (IE), (IF), or (IG), Z 1 and Z 2 are each independently -C(R 1 )(R 2 )-(CH2) c In some embodiments, Z 1 and Z 2 One or both of the following may be -W-(CH2) c -C(R 3 )(R 4 )-Y.

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

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

[0153] In some embodiments of the compound of formula (ID), (IE), (IF), or (IG), Z 1 and Z 2 One or both of -C(R 1 )(R 2 )-(CH2) c In some embodiments, Z 1 and Z 2 One or both of the following may be -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 is independently —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, each R 1 and R 2 is independently -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, R 1 and R 2 is methyl.

[0155] In some embodiments of the compound of formula (ID), (IE), (IF), or (IG), Z 1 is -C(R 1 )(R 2 )-(CH2) c -CO-CoA, and Z 2 is -C(R 1 )(R 2 )-(CH2) c -X, where X is -CO-CoA, -COOH, or -COOR5 and R 1 and R 2 is methyl.

[0156] In some embodiments of a compound 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 compounds of Formula (ID), (IE), (IF), or (IG), each carbon atom independently has an R bonded to the carbon atom. 1 and R 2 and together form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently selected from the R bonded to the carbon atom. 1 and R 2 Together with

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

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

[0160] In some embodiments of the compound of formula (ID), (IE), (IF), or (IG), Y is —COOH or —COOR 5 is.

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

[0162] In some embodiments of the compound 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 the compound of formula (ID), (IE), (IF), or (IG), Z 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, and Z 2 is -W-(CH2) c -C(R 3 )(R 4 )-Y and R 3 and R 4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. 1 is -W-(CH2) c -C(R 3 )(R 4 )-CO-CoA, and 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, and 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 -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, and 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 -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0163] In some embodiments of a compound 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, the pharmaceutically acceptable salt of a compound of Formula (ID), (IE), (IF), or (IG) is a salt of an amino acid, a meglumine salt, an eglumine salt, a D-glucamine salt, a glucosamine salt, or a choline salt. In some embodiments, the pharmaceutically acceptable salt is a salt of a basic amino acid. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (ID), (IE), (IF), or (IG) is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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, a pharmaceutically acceptable salt of a compound of Formula (ID), (IE), (IF), or (IG) is a zinc salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (IF) or (IG) is a zinc salt.

[0166] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (IF) or (IG) is a zinc salt, wherein p is 3 or 4 and each X and Y is -COOH.

[0167] In some embodiments, the compound of formula (ID), (IE), (IF), or (IG) is selected from the group consisting of: 1 and C 2 defined by, if present, R, R 1 and R 2 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R of the compound of Table A-13 is CH3. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-13 is CH3. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-13 is F. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-13 is Cl. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-13 is Br. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-13 is CF3.

[0168] In some embodiments, the C 1 and C 2 and, if present, a pharmaceutically acceptable salt of a compound having any one of the structures defined by 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, the compound of formula (ID), (IE), (IF), or (IG) is selected from the group consisting of: 1 and C 2 defined by, if present, R, R 1 and R 2 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R of the compound of Table A-14 is CH3. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-14 is CH3. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-14 is F. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-14 is Cl. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-14 is Br. In some embodiments, one or more of R, R1, and R2 of the compound of Table A-14 is CF3.

[0171] In some embodiments, the C 1 and C 2 and, if present, a pharmaceutically acceptable salt of a compound having any one of the structures defined by 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 14-60

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

[0174] In some embodiments, the C 1 and C 2 and, if present, a pharmaceutically acceptable salt of a compound having any one of the structures defined by 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] Compound of formula (IH)

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

[0178] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0179] Z 1 But -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 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently an R bonded to a carbon atom; 1 and R 2 together form a -C3-C7 cycloalkyl group,

[0182] Each R 3 and R 4 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 an R bonded to a carbon atom; 3 and R 4together form a -C3-C7 cycloalkyl group,

[0183] Q is 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 , heteroaryl, heterocyclyl, or -V-OH, or two Q's independently, together with the carbon atoms to which they are attached, form a heterocyclyl or carbocyclyl group;

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

[0185] Each R 1A and R 2A are independently 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 is independently -OH, -COOH, -COOR 5 , -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] and

[0188] Each R 6 are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0189] Each R 7 is independently 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 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is unsubstituted or substituted with one or more of halogen, -OH, It is substituted with -O(C1-C6 alkyl) or phenyl group.

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

[0193] In some embodiments of the compound of Formula (IH), each R 1 and R 2 is independently -C1-C6 alkyl. In some embodiments, R 1 and R 2 is methyl.

[0194] In some embodiments of the compound of Formula (IH), each carbon atom independently has an R bonded to the carbon atom.1 and R 2 and together form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently selected from the R bonded to the carbon atom. 1 and R 2 Together with

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

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

[0201] each p is independently 1 or 2;

[0202] Z1 But -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 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently an R bonded to a carbon atom; 1 and R 2 together form a -C3-C7 cycloalkyl group,

[0205] Each R 3 and R 4 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 an R bonded to a carbon atom; 3 and R 4 together form a -C3-C7 cycloalkyl group,

[0206] Q is 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 , heteroaryl, heterocyclyl, or -V-OH, or two Q's independently, together with the carbon atoms to which they are attached, form a heterocyclyl or carbocyclyl group;

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

[0208] Each R 1A and R 2A are independently 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 is independently -OH, -COOH, -COOR 5 , -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, [ka] and

[0211] Each R 6 are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0212] Each R 7 is independently 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 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is unsubstituted or substituted with one or more of halogen, -OH, It is substituted with -O(C1-C6 alkyl) or phenyl group.

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

[0216] In some embodiments of the compound of Formula (IJ), each R 1 and R 2 is independently -C1-C6 alkyl. In some embodiments, R 1 and R 2 is methyl.

[0217] In some embodiments of compounds of Formula (IJ), each carbon atom independently has an R bonded to the carbon atom. 1 and R 2 and together form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently selected from the R bonded to the carbon atom. 1 and R 2 Together with

[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, wherein each X and Y is -COOH.

[0221] In some embodiments, the compound of Formula (IJ) has any 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 a compound having any one of the structures shown in Table A-17 is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an 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 a compound having any 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 compound of the present invention is a compound having any one of the structures shown in Table A-18, 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-18, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutically acceptable salt of a compound of Table A-18 is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an 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, the pharmaceutically acceptable salt of a compound 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 those shown in Table A-19 and C 1 , C 2 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 1 or C 2 wherein at least one of R is CO-CoA. In some embodiments, the compound of Formula (I), (ID), or (IG) has any 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, R of at least one of the compounds in Table A-19 is CH3. In some embodiments, R of at least one of the compounds in Table A-19 is F. In some embodiments, R of at least one of the compounds in Table A-19 is Cl. In some embodiments, R of at least one of the compounds in Table A-19 is Br. In some embodiments, R of at least one 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 a pharmaceutically acceptable salt or solvate thereof, wherein:

[0232] Each R 1 and R 2 is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently an R bonded to a carbon atom; 1 and R 2 together 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 3is 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, wherein each —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl, and benzyl is unsubstituted or substituted with one or more halogen, —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 is independently -OH, -COOH, -COOR 5 , -CO-CoA, -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, -SO3R 5 , [ka] and

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

[0240] Each R 6 are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0241] Each R 7 is 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 is -CO-CoA.

[0243] In some embodiments of the compound of Formula (II), X is —C(═O)—, —CHR 3 In some embodiments, 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 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 is independently H, —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments, each R 1 and R 2 is independently 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 is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.

[0249] In some embodiments of compounds 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, the pharmaceutically acceptable salt of the compound of Formula (II) is a salt of an amino acid, a meglumine salt, an eglumine salt, a D-glucamine salt, a glucosamine salt, or a choline salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (II) is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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 selected from the group consisting of: 1 and C 2 or a pharmaceutically acceptable salt or solvate thereof.

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

[0254] In some embodiments, C 1 and C 2A pharmaceutically acceptable salt of a compound having any one of the structures shown in Table B1 or Table B2, defined by: 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.

[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 Formulae (III), (IIIA), and (IIIB)

[0259] In some embodiments, the compounds of the present invention have the structure of Formula (III): [ka]

[0260] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0261] R 1 and R 2 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 together with the carbon atom to which they are attached 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 are independently -C1-C6 alkyl, -OH, -COOH, -COOR 5 , -CO-CoA, -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, -SO3R 5 , [ka] and

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

[0268] Each R 6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0269] Each R 7 is 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 a pharmaceutically acceptable salt or solvate thereof,

[0272] R 1 and R 2 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 together with the carbon atom to which they are attached 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 are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups;

[0279] Each R 6 are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0280] Each R 7 is 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 a pharmaceutically acceptable salt or solvate thereof,

[0283] R 1 and R 2 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 together with the carbon atom to which they are attached 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 are independently -C1-C6 alkyl, -OH, -COOH, -COOR 5 , -CO-CoA, -CONH2, -CONHR 5 , -CONHMs, -CONHTs, -SO3H, -SO3R 5 , [ka] and

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

[0290] Each R 6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;

[0291] Each R 7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.

[0292] In some embodiments of compounds of Formula (III), (IIIA), and (IIIB), one or both of Z 1 and Z 2 is —CO—CoA.

[0293] In some embodiments of compounds of Formula (III) and (IIIB), Z 1 is -CO-CoA, and Z 2 is -OH, -COOH, -CO-CoA, or -COOR 5 In some embodiments, Z 2 is -CO-CoA, and Z 1 is -OH, -COOH, -CO-CoA, or -COOR 5 is.

[0294] In some embodiments of compounds of Formula (III), (IIIA), and (IIIB), Z 1 and Z 2 are -CO-CoA, respectively.

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

[0297] In some embodiments of compounds of Formula (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 compounds of Formula (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 compounds of Formula (III), (IIIA), and (IIIB), R 1 and R 2 together with the carbon atoms to which they are attached form a -C3-C7 cycloalkyl group.

[0300] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (III), (IIIA), or (IIIB) is a salt of an amino acid, a meglumine salt, an eglumine salt, a D-glucamine salt, a glucosamine salt, or a choline salt. In some embodiments, the pharmaceutically acceptable salt is a salt of a basic amino acid. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (III), (IIIA), or (IIIB) is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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 any 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 any 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 coenzyme A mono(thioester) or di(thioester) compound having any one of the structures shown in Table B4, or a pharmaceutically acceptable salt or solvate thereof.

[0304] In some embodiments, the compound of Formula (III) or (IIIA) has any 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 coenzyme A mono(thioester) or di(thioester) compound having any one of the structures shown in Table B5, or a pharmaceutically acceptable salt or solvate thereof.

[0306] In some embodiments, C 1 and C 2 A pharmaceutically acceptable salt of a compound having any one of the structures shown in Table B3, Table B4, or Table B5, defined by: is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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 in the Methods of the Invention

[0312] The present invention provides compositions useful in the methods of the invention described herein (each composition is a "composition of the invention").

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

[0314] In some embodiments, the compositions of the present invention comprise an effective amount of a compound having a structure depicted 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, the pharmaceutically acceptable salt of a compound having a structure depicted 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 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, the compositions of the present invention comprise an effective amount of a coenzyme A ester of an acid having a structure depicted in Table 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 compositions of the present invention comprise an effective amount of a compound having a structure depicted in Table B1. In some embodiments, the compositions of the present invention comprise an effective amount of a mono- or di-coenzyme A ester of an acid having a structure depicted in Table B2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compositions of the present invention comprise an effective amount of a compound having a structure depicted in Table B3. In some embodiments, the compositions of the present invention comprise an effective amount of a mono- or di-coenzyme A ester of an acid having a structure depicted in Table B4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compositions of the invention comprise an effective amount of a mono- or di-Coenzyme A ester of an acid having a structure depicted in Table B5, or a pharmaceutically acceptable salt or solvate thereof.

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

[0316] In some embodiments, the compositions of the present invention further comprise another pharmaceutically active agent, hi 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 comprising another pharmaceutically active agent. In some embodiments, the composition of the present invention and a composition comprising another pharmaceutically active agent are formulated separately. In some embodiments, the composition of the present invention and a composition comprising another pharmaceutically active agent are formulated separately but are administered together. In some embodiments, the composition of the present invention and a composition comprising another pharmaceutically active agent are formulated and administered separately. In some embodiments, the composition of the present invention and a composition comprising another pharmaceutically active agent are useful for adjuvant therapy.

[0318] In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or a fibrate, a bile acid-binding resin, niacin, an anti-obesity drug, a hormone, a tyrphostin, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein AI agonist, an apolipoprotein E agonist, a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-enhancing agent, an HDL enhancer, an agonist of the apolipoprotein AI gene or protein, an agonist of the apolipoprotein A-IV gene or protein, an agonist of an apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, or an acetyl-CoA carboxylase allosteric inhibitor. In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile acid binding resin, niacin, an anti-obesity drug, a hormone, a tyrphostin, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein AI agonist, an apolipoprotein E agonist, a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-enhancing drug, an HDL enhancer, an agonist of the apolipoprotein AI gene or protein, an apolipoprotein A-I V gene or protein agonists, apolipoprotein gene agonists, 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, mammalian target of rapamycin (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 or increases the anti-inflammatory function of IL-6, CRP, TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB, or TGF-β1.

[0320] In some embodiments, the other pharmaceutically active agent affects the expression or function of a fibrotic gene or protein, or a mitotic gene or protein, hi some embodiments, the other pharmaceutically active agent modulates the expression or function of FGF-21, MMP-2, TIMP-1, ASK1, or type 3 collagen.

[0321] In some embodiments, the other pharmaceutically active agent is a regulator of a lipid metabolism-related or transport-related gene, a regulator of PPAR-α target genes such as, but not limited to, HD(ECHS1), PDK4 and Cyp7A1, a regulator 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, hi 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 the free base. In yet some other embodiments, the other pharmaceutically active agent is paclitaxel. In some embodiments, paclitaxel is a pharmaceutically acceptable salt. In some embodiments, paclitaxel is the free base. In yet some other embodiments, the other pharmaceutically active agent is carotuximab. In yet some other embodiments, the other pharmaceutically active agent is pembrolizumab. In yet 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 the free base. In still some other embodiments, the other pharmaceutically active agent is avelumab. In some embodiments, the other pharmaceutically active agent is durvalumab. In still some other embodiments, the other pharmaceutically active agent is tremelimumab. In still some other embodiments, the other pharmaceutically active agent is nivolumab. In still 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 the free base. In yet some other embodiments, the other pharmaceutically active agent is a T cell receptor (TCR) immune cell therapy such as tazemetostat, cemiplimab, ABX196, LioCyx, TBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses or genetically engineered oncolytic viruses, including, but not limited to, telomelysin and imligic, or an immunomodulatory gene therapy such as MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3.

[0325] In yet some other embodiments, the other pharmaceutically active agent is selected from the group consisting of cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnolipid Galacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201 / BMS-986263, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, or nalmafen. In some embodiments, the other pharmaceutically active agent is pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadant, L-alanine, saroglitazar magnesium, vorixibat, filscostat, cilofexor, elafibranor, nalmefene, solithromycin, 99mtechnetium-mebrofenin, tropifexor , S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424,Brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, zotiraclib citrate, sintilimab, camrelizumab, spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab Mumab, atezolizumab, bevacizumab, ramucirumab, IBI305, asclinicalvaccumab, sitravatinib, cytokine-based biologic 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, neoantigen-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, oraxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, BLU-554 (FGFR4 inhibitor), or CMP-001, or a pharmaceutically acceptable salt thereof. In some embodiments, the other pharmaceutically active agent is pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, filscostat, cilofexor, elafibranor, nalmefene, solithromycin, 99mTechnetium-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpar, fisogatinib, doxorubicin,Cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, zotiraclib citrate, sintilimab, camrelizumab spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, asclinicalvacuumab, sitravatinib, 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, neoantigen-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, oraxol, 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, the other pharmaceutically active agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM 282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglita Zar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cistadanone, L-alanine, saroglitazar magnesium, vorixibat, elafibranor, nalmefene, solithromycin, 99m Technetium-mebrofenin, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat,RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, regorafenib, or zotiraclib citrate, or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the compositions of the invention further comprise an anti-cancer agent. In some embodiments, the compositions of the invention further comprise an anti-NASH agent or an anti-cancer agent.

[0329] In some embodiments, the anticancer drug is sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, In some embodiments, the anticancer drug is meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, regorafenib, or zotiraclib citrate, or a pharmaceutically acceptable salt thereof. In some embodiments, the anticancer drug is salsalate or tolvaptan.

[0330] In some embodiments, the anti-NASH agent is cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin , NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602 K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ul In some embodiments, the anti-NASH agent is salsalate or tolvaptan, or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the other pharmaceutically active agent is an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is selected from the group consisting of pembrolizumab, avelumab, durvalumab, nivolumab, cemiplimab, ABX196, sintilimab, camrelizumab, spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, ascribacumab, TCR These include T-cell therapy, sitravatinib, cytokine-based biologic 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 neoantigen-reactive T cells.

[0332] In some embodiments, the compositions of the invention further comprise an immunotherapeutic agent.

[0333] In some embodiments, the other pharmaceutically active agent is an oncogenic virus. In some embodiments, the oncogenic virus is pexastimogene devacirepvec or talimogene laherparepvec. In some embodiments, the compositions of the present invention further comprise an oncogenic virus.

[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 inactivated SARS-CoV-2 virus (CZ02 strain) (Sinovac). In some embodiments, the composition of the invention further comprises a vaccine.

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

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

[0337] In some embodiments, the compositions of the present invention include sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pemetafenib ... Gubelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranol ru, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosine Silmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat,In some embodiments, the composition further comprises a pharmaceutically active agent selected from the group consisting of sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, and prazigastat. , sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, e Rafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cistadanoidan, L -Alanine, saroglitazar magnesium, vorixibat, elafibranor, nalmefene, solithromycin, 99m technetium-mebrofenin, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib,The therapeutic agent further comprises a pharmaceutically active agent that is trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, regorafenib, zotiraclib citrate, salsalate, or tolvaptan, or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the compositions of the present invention comprise (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, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, Filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-068 35919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, 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, saroglitazar magnesium, vorixibat, elafibranor, nalmefene, solithromycin, 99m technetium-mebrofenin, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390,The pharmaceutically active agent is capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, regorafenib, or zotiraclib citrate.

[0339] In some embodiments, the compositions of the present invention comprise 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 that is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, regorafenib, ABX196, a T-cell receptor (TCR) immune cell therapy, TBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, or a genetically engineered oncolytic virus, or an immunomodulatory gene therapy agent.

[0340] In some embodiments, the compositions of the present invention comprise (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 that is sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, regorafenib, ABX196, a T-cell receptor (TCR) immune cell therapy, TBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, or a genetically engineered oncolytic virus, or an immunomodulatory gene therapy agent.

[0341] In some embodiments, the compositions of the present invention comprise 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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise (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 compositions of the present invention comprise 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 compositions of the present invention comprise (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 compositions of the present invention comprise (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, a compound of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), (III), (IIIA), and (IIIB), or Table A-18, or a pharmaceutically acceptable salt or solvate thereof, and another pharmaceutically active agent are synergistic in the compositions or methods of the invention. In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a meglumine salt, a lysine salt, or an arginine salt. 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, a pharmaceutically acceptable amino acid, meglumine, eglumine, D-glucamine, glucosamine, or choline salt of a compound of Formula (I), (IA), (IB), and (IC), or Table A-7, A-8, A-9, A-10, A-11, or A12, and another pharmaceutically active agent are synergistic in a composition or method of the invention. In some embodiments, a pharmaceutically acceptable meglumine, lysine, or arginine salt of a compound of Formula (I), (IA), (IB), and (IC), or Table A-7, A-8, A-9, A-10, A-11, or A12, and another pharmaceutically active agent are synergistic in a composition or method of the 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 a compound of the invention, and (b) another pharmaceutically active agent. For example, composition A1 contains (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 contains (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, glidants, colorants, dye transfer inhibitors, sweetening agents, or flavoring agents.

[0348] Binders or granulating agents give the tablet cohesiveness so that the tablet stays together after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); Microcrystalline cellulose such as RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA), and 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 can be present in the compositions of the present invention at about 2% to about 49% by weight, or any range within these values. In some embodiments, the binder or filler is present in the compositions of the present invention at about 5% to about 15% by weight. In some embodiments, the binder or filler is present in the compositions of the present invention at about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% by weight, or 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 amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets. In some embodiments, the diluent is lactose monohydrate. In some embodiments, the diluent is lactose monohydrate Fast-Flo 316 NF.

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

[0353] Suitable disintegrants include, but are not limited to, agar, bentonite, celluloses such as methylcellulose and carboxymethylcellulose, wood products, natural sponge, cation exchange resins, alginic acid, gums such as guar gum and Veegum HV, citrus pulp, cross-linked celluloses such as croscarmellose, cross-linked polymers such as crospovidone, cross-linked starch, calcium carbonate, microcrystalline cellulose such as sodium starch glycolate, polacrilin potassium, starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch, clays, algins, and mixtures thereof. The amount of disintegrant in the compositions of the present invention can 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 can include a disintegrant, for example, from about 0.5% to about 15% or from about 1% to about 10% by weight of disintegrant, hi some embodiments, the compositions of the present invention include a disintegrant in an amount of about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11%, 12%, 13%, 14%, or 15% by weight of the composition, or 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, glycols such as sorbitol, mannitol, glycerol behenate, and 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 laurate, agar, starch, lycopodium, silica or silica gel, such as AEROSIL® 200 (WR Grace 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 can include a lubricant, for example, about 0.1 to about 5% by weight of a lubricant. In some embodiments, the compositions of the present invention include a lubricant in an amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0% by weight of the composition, or any range within any of these values.

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

[0358] Coloring agents include any of the approved, certified, water soluble FD&C dyes and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes, and mixtures thereof.

[0359] Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which provide a pleasant taste sensation, such as peppermint and methyl salicylate.

[0360] Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweeteners, such as saccharin and aspartame.

[0361] Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid additive, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0362] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.

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

[0364] The compositions of the present invention can be formulated into 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 "parenteral" includes subcutaneous, intravenous, intramuscular, and intraarterial injections by various infusion techniques. As used herein, intraarterial and intravenous infusions include administration via a catheter.

[0365] The compositions of the present invention can be formulated according to routine procedures compatible with the desired route of administration. Thus, the compositions of the present invention can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The compositions of the present invention can be formulated as preparations suitable for implantation or injection. Thus, for example, the compositions of the present invention can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). The compositions of the present invention may also be in powder form for constitution with a suitable vehicle, e.g., 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 can include solid, semi-solid, gel matrix, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated 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 are suitable for oral administration in the form of a tablet or capsule. In some embodiments, the compositions of the present invention are in the form of a tablet. In some embodiments, the compositions of the present invention are in the form of a capsule. In some embodiments, the compound of the present invention is contained in a capsule.

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

[0368] The compositions of the present invention may be in the form of compressed tablets, powder tablets, chewable lozenges, quick-dissolve tablets, multiple compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, 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 can be beneficial for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by multiple compression cycles, including layered tablets and press-coated or dry-coated tablets.

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

[0370] In some embodiments, 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, is contained in a tablet. In some embodiments, the tablet is a compressed tablet. In some embodiments, the tablet is a film-coated compressed tablet.

[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 a fluid bed granulation process can provide tablet formulations with good flowability, good compressibility, rapid dissolution, good stability, and / or minimal to no cracking. In some embodiments, the fluid bed granulation process allows for the preparation of formulations with high drug loading, such as greater than 70% or greater 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 can be in the form of soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), can contain two sections, one slipping over the other, completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by adding glycerin, sorbitol, or similar polyols. Soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are as described herein, including methyl and propyl parabens and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein can be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules can also be coated as known to those skilled in the art to control or maintain dissolution of the active ingredient.

[0373] The compositions of the present invention can be in liquid or semisolid dosage forms, such as emulsions, solutions, suspensions, elixirs, and syrups. Emulsions can be two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid, and can be oil-in-water or water-in-oil. Emulsions can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions can contain a pharmaceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions can contain a pharmaceutically acceptable acetal, e.g., a di-(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), such as acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs can be clear, sweetened, and hydroalcoholic solutions. Syrups can be concentrated aqueous solutions of a sugar, e.g., sucrose, and can contain a preservative. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0374] Compositions of the present invention suitable for oral administration can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms 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-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and a carbon dioxide source.

[0376] Coloring and flavoring agents can be used in all of the above dosage forms, and flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

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

[0378] In some embodiments, the compositions of the present invention include a film coating.

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

[0380] The tablet dosage form can include 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 powdered, crystalline, or granular form, and can further include a carrier or vehicle as described herein, including a binder, disintegrant, controlled-release polymer, lubricant, diluent, or colorant.

[0381] In some embodiments, the compositions of the present invention can further comprise excipients such as diluents, disintegrants, wetting agents, binders, glidants, lubricants, or any combination thereof. In some embodiments, the tablet comprises a binder. Also, in some embodiments, the binder comprises microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyridone, hydroxypropyl cellulose, hydroxymethyl cellulose, or any combination thereof. In other embodiments, the tablet comprises a disintegrant. In other embodiments, the disintegrant comprises croscarmellose sodium, sodium starch glycolate, or any combination thereof. In other embodiments, the tablet comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0382] In some embodiments, a composition of the present invention is in the form of a tablet that includes a binder, eg, any of the binders described herein.

[0383] In some embodiments, the compositions of the present invention are in the form of a tablet that includes a disintegrant, eg, any of the disintegrants described herein.

[0384] In some embodiments, the compositions of the present invention are in the form of a tablet that includes a lubricant, for example, any of the lubricants described herein.

[0385] In some embodiments, the compositions of the present invention can be in a modified-release or controlled-release dosage form. In some embodiments, the compositions of the present invention can include particles that exhibit a specific release profile. For example, the compositions of the present invention can include an immediate-release form 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 also include a modified-release form of a statin or a pharmaceutically acceptable salt thereof, both of which are compressed into a single tablet. Other combinations and modifications of release profiles can be implemented as understood by those skilled in the art. Examples of modified release dosage forms suitable for the pharmaceutical compositions of the present invention include, but are not limited to, those described in U.S. Pat. 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, 5,739,108, Nos. 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, and 6,699,500.

[0386] In some embodiments, the compositions of the present invention are matrix controlled-release dosage forms. For example, the compositions of the present invention can comprise 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 can further comprise 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 are the same or different. Suitable matrix controlled-release dosage forms are described, for example, in Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999.

[0387] In some embodiments, the compositions of the present invention comprise 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 compositions of the present invention comprise 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 compositions are in a matrix-controlled modified-release dosage form.

[0388] In some embodiments, the compositions of the invention comprise 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 dosage form.

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

[0390] In some embodiments, the erodible matrix of the matrix controlled release form is selected from the group consisting of chitin, chitosan, dextran, or pullulan; gum agar, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, or scleroglucan; starch, such as dextrin or maltodextrin; hydrocolloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxyethyl cellulose (HEC), hydroxypropyl ... Hydroxypropyl cellulose (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 hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerin fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm Copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; or other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, or (trimethylaminoethyl) methacrylate chloride; or any combination thereof.

[0391] In other embodiments, the compositions of the present invention are in a matrix-controlled modified-release form comprising a non-erodible matrix. In some embodiments, the statin, 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, is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. In some embodiments, the non-erodible matrix of the matrix controlled-release form is made of 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 epichlorohydrin, butyl rubber. rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, or a hydrophilic polymer such as ethyl cellulose, cellulose acetate, crospovidone or cross-linked partially hydrolyzed polyvinyl acetate, an aliphatic compound (e.g., carnauba wax, microcrystalline wax or triglyceride), or any combination thereof.

[0392] The compositions of the present invention that are modified release dosage forms can be prepared by methods known to those skilled in the art, such as direct compression, dry or wet granulation followed by compression, melt granulation followed by compression, and the like.

[0393] In some embodiments, the compositions of the present invention include a tablet-in-capsule system, which can be a multi-function, multi-unit system containing multiple-use minitablets in a hard gelatin capsule. The minitablets can be immediate-release, sustained-release, pulsed-release, delayed-sustained-release minitablets, or any combination thereof. In some embodiments, combinations of minitablets or combinations of minitablets and minibeads containing multiple active agents can each have a specific lag time for a multiple pulse-release drug delivery system (DDS), a site-specific DDS, a delayed-fast DDS, a fast / delayed DDS, and a zero-order DDS.

[0394] In some embodiments, the compositions of the present invention are in an osmotic controlled release dosage form.

[0395] In some embodiments, the osmotically controlled release device comprises a one-chamber system, a two-chamber system, an asymmetric membrane technology (AMT), an extruded core system (ECS), or any combination thereof. In some embodiments, such a device comprises at least two components: (a) a core containing an active agent(s), and (b) a semipermeable membrane having at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous environment into the core during use to cause drug release by extrusion through the delivery port(s).

[0396] In some embodiments, the core of the osmotic device optionally comprises an osmotic agent, which creates a driving force for the transport of water from the environment of use of the device to the core. One class of osmotic agents useful in the compositions of the present invention comprises water-swellable hydrophilic polymers, also referred to as "osmopolymers" or "hydrogels," including, but not limited to, 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, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0397] Another class of osmogens useful in the compositions of the present invention includes osmogens capable of imbibing water to affect an osmotic pressure gradient across the 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 and sodium chloride), 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] Osmotic agents with different dissolution rates can be used to affect the rapid dissolution 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, following administration. For example, the inclusion of an amorphous sugar, such as Mannogeme EZ (SPI Pharma, Lewis, DE), can provide more rapid delivery during the first few hours (e.g., about 1 to about 5 hours) to rapidly onset prophylactic or therapeutic efficacy, followed by gradual and continuous release of the remaining amount to maintain a desired level of therapeutic or prophylactic efficacy over an extended period of time. In some embodiments, 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, is released from the compositions of the invention at a rate that replaces the amount 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, that is metabolized or excreted by the subject.

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

[0400] Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives, which are either water-permeable and water-insoluble at physiologically relevant pH or readily rendered water-insoluble by chemical alteration, 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 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 copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0401] The semipermeable membrane can be a hydrophobic microporous membrane, the pores of which are substantially gas-filled and not wetted by aqueous media, but which is permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. 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, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0402] The delivery port(s) on the semipermeable membrane can be formed by post-coating, either mechanically or by laser drilling. The delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by a thinner portion of the membrane rupturing over a depression in the core. In addition, the delivery port(s) can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0403] The total amount and release rate 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, released 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 that are osmotic controlled-release dosage forms can further comprise additional conventional excipients as described herein to enhance the performance or processability of the formulation.

[0405] Osmotic controlled release dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy (supra); 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 dosage forms, which comprise an asymmetric osmotic membrane coating a core containing the active ingredient(s) and other pharmaceutically acceptable excipients. See U.S. Patent No. 5,612,059 and WO2002 / 17918. AMT controlled-release dosage forms 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 an ESC controlled-release dosage form comprising an osmotic membrane coating a core comprising 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 dosage forms manufactured as multiparticulate controlled release dosage forms comprising a plurality of particles, granules, or pellets, microparticles, beads, microcapsules, and microtablets ranging in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm.

[0409] Multiparticulate controlled-release dosage forms can provide extended-release dosage forms with improved bioavailability. Carriers suitable for maintaining the release rate 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, include, but are not limited to, ethylcellulose, HPMC, HPMC-phthalate, colloidal silicon dioxide, and Eudragit-RSPM.

[0410] The pellet-form compositions of the present invention may contain 50-80% (w / w) of the drug and 20-50% (w / w) of microcrystalline cellulose or other polymers, including, but not limited to, microcrystalline wax, pregelatinized starch, and maltose dextrin.

[0411] Beads can be prepared in capsule and tablet dosage forms. Beads in tablet dosage forms can 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 comprise sustained-release polymer microcapsules containing a statin and 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, with various solubility characteristics. The sustained-release polymer microcapsules can be prepared by colloidal polymer dispersion 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 made by processes known to those skilled in the art, such as wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and spray coating of seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994, and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989. Excipients for such techniques are commercially available and are described in the United States Pharmacopeia.

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

[0415] In another embodiment, the compositions of the present invention are in a dosage form having an immediate release component and at least one delayed release component, which can provide discontinuous release of the compound in at least two consecutive pulses separated by a time interval of about 0.1 hours to about 24 hours.

[0416] In some embodiments, the compositions of the present invention comprise 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 some embodiments, the compositions of the present invention comprise 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 some embodiments, the compositions of the present invention comprise 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 some embodiments, the compositions of the present invention comprise 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. In some embodiments, the compositions of the invention comprise from 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 ranging from these values.

[0417] In other embodiments, the compositions of the present invention comprise 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 the molar equivalent of 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 ranging from these values. In other embodiments, the compositions of the present invention comprise 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 the molar equivalent of 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 other embodiments, the compositions of the present invention comprise 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 the molar equivalent of 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 other embodiments, the compositions of the present invention comprise 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 the molar equivalent of 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. In other embodiments, the compositions of the present invention comprise 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 the molar equivalent of 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.

[0418] In some embodiments, the compositions of the present invention comprise 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 of about 10% by weight to about 99% by weight of the total weight of the composition of the present invention.

[0419] Methods of the Invention

[0420] The present invention further provides a method for treating or preventing a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention, 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 further provides a method for slowing, inhibiting progression, or delaying the onset of a disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention or a composition of the present invention, 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, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, the CKD is Alport syndrome.

[0422] The present invention further provides a method for treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention, 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 scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or a complication of coal worker's pneumoconiosis. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, the CKD is Alport syndrome.

[0423] The present invention relates to a method for treating or preventing a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention, 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 disease, clear cell sarcoma of the kidney, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-associated autosomal dominant tubulointerstitial kidney disease, IgG4-associated kidney disease, MUC1-associated autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-associated medullary cystic kidney disease, medullary sponge kidney, multicystic dysplastic kidney, multilocular renal cysts, multinodular thyroid carcinoma. Further provided are methods in which the genetic disorder is selected from the group consisting of: adenosalveolar cystic kidney polydactyly syndrome, neonatal diabetes mellitus-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidney syndrome, REN-related autosomal dominant tubulointerstitial kidney disease, rare diseases that may be indicated for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract anomalies, sex reversal-renal, adrenal and pulmonary hypoplasia syndrome (SERKAL syndrome), serpentine fibula-polycystic kidney syndrome, uromodulin-related kidney disease, medullary cystic kidney disease type 2 (UMOD-related autosomal dominant tubulointerstitial kidney disease), unilateral polycystic dysplastic kidney, ventriculomegaly-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 transplant, 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 sponge kidney, multicystic dysplastic kidney, multilocular renal cysts, multinodular cystic thyroid polydactyly syndrome, neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis. Polycystic kidney disease, 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 anomalies, sex reversal-renal, adrenal and pulmonary hypoplasia syndrome (SERKAL syndrome), serpentine fibula-polycystic kidney disease, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney disease), unilateral polycystic dysplastic kidney, ventriculomegaly-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 further provides a method for slowing, inhibiting progression, or delaying the onset of a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention, 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 scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or a complication of coal workers' pneumoconiosis. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, the CKD is Alport syndrome.

[0425] The present invention further provides a method for slowing the progression, inhibiting the progression, or delaying the onset of fibrosis in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention, wherein the fibrosis 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 scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or a complication of coal workers' pneumoconiosis. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, the CKD is Alport syndrome.

[0426] The present invention further provides methods for inhibiting, reducing, or delaying the development of complications of 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 scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or coal worker's pneumoconiosis in a subject.

[0427] In some embodiments, the subject has stage 1 CDK. Stage 1 is defined as a blood glucose level of 90 ml / min / 1.73 m 2 In some embodiments, the subject has stage 2 CDK. Stage 2 is characterized by a glomerular filtration rate (GFR) of 60-89 ml / min / 1.73 m or greater. 2In some embodiments, the subject has stage 3A CDK. Stage 3A is characterized by a GFR of 45-59 ml / min / 1.73 m 2 In some embodiments, the subject has stage 3B CDK. Stage 3B is characterized by a GFR of 30-44 ml / min / 1.73 m 2 In some embodiments, the subject has stage 4 CDK. Stage 4 is characterized by a GFR of 15-29 ml / min / 1.73 m 2 In some embodiments, the subject has stage 5 CDK. Stage 5 is characterized by a GFR of 15 ml / min / 1.73 m 2 characterized by a GFR less than 0.001 or chronic dialysis.

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

[0429] The present invention provides a method for slowing or inhibiting the progression or delaying the onset of a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention, wherein the disease is renal cell carcinoma, autosomal dominant polycystic kidney disease, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis complex, autosomal dominant tubulointerstitial kidney disease, bilateral polycystic dysplastic kidney disease, clear cell sarcoma of the kidney, de novo thrombotic microangiopathy after kidney transplantation, HNF1B-associated autosomal dominant tubulointerstitial kidney disease, IgG4-associated kidney disease, MUC1-associated autosomal dominant tubulointerstitial kidney disease, medullary cystic kidney disease type 1, MUC1-associated medullary cystic kidney disease, medullary sponge kidney, polycystic dysplastic kidney, or multilocular kidney disease. Further provided are methods in which the genetic disorder is selected from the group consisting of: cysts, multinodular cystic thyroid and polycystic kidney syndrome, neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidney syndrome, REN-related autosomal dominant tubulointerstitial kidney disease, rare diseases that may be indicated for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract anomalies, sex reversal-renal, adrenal and pulmonary hypoplasia syndrome (SERKAL syndrome), serpentine fibula-polycystic kidney syndrome, uromodulin-related kidney disease, medullary cystic kidney disease type 2 (UMOD-related autosomal dominant tubulointerstitial kidney disease), unilateral polycystic dysplastic kidney, ventriculomegaly-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 transplant, 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 sponge kidney, multicystic dysplastic kidney, multilocular renal cysts, multinodular cystic thyroid polydactyly syndrome, neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis. Polycystic kidney disease, REN-associated autosomal dominant tubulointerstitial kidney disease, rare diseases potentially eligible for kidney transplantation, renal cell carcinoma, renal dysplasia, unilateral or bilateral renal dysplasia, renal or urinary tract anomalies, sex reversal-renal, adrenal, and pulmonary hypoplasia syndrome (SERKAL syndrome), serpentine fibula-polycystic kidney disease, uromodulin-associated kidney disease, medullary cystic kidney disease type 2 (UMOD-associated autosomal dominant tubulointerstitial kidney disease), unilateral polycystic dysplastic kidney, ventriculomegaly-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, the 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 to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention.

[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-segment elevation ACS (unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI)), ST-segment elevation myocardial infarction (STEMI), dysbetalipoproteinemia, hypoalphalipoproteinemia, risk of pancreatitis, or sitosterolemia. In some embodiments, the hyperlipidemia is primary hyperlipidemia or mixed hyperlipidemia. In some embodiments, the hypercholesterolemia is primary hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), or heterozygous familial hypercholesterolemia (HeFH). In some embodiments, the dysbetalipoproteinemia is primary dysbetalipoproteinemia. In some embodiments, the sitosterolemia is homozygous familial sitosterolemia. In some embodiments, the subject has a previous myocardial infarction, a previous stroke, or established peripheral arterial disease. In some embodiments, the diabetes is type 2 diabetes. In some embodiments, the subject has abnormally high LDL-C. In some embodiments, the subject has type 2 diabetes and does not have CHD.

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

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

[0434] In some embodiments, the fibrosis is liver 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 scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis or adhesive capsulitis, or a complication of coal workers' pneumoconiosis. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease. In some embodiments, the autosomal polycystic kidney disease is autosomal recessive polycystic kidney disease. In some embodiments, the CKD is Alport syndrome.

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

[0436] The present invention further provides a method for slowing, inhibiting the progression, or delaying the onset of de novo lipogenesis or lipid accumulation, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[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 to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention.

[0439] The present 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), discoidin 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 (MEK) Further provided is a method for modulating, directly inhibiting, or allosterically inhibiting IL-1 kinase (MELK), myosin light chain kinase (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 to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0440] The present 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), discoidin 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), NIMA-related kinase 2 (NEK2), and other related kinases. Further provided is a method for modulating, directly inhibiting, or allosterically inhibiting IL-1, the serine-threonine kinase PIM3, receptor-interacting serine / threonine protein kinase 4 (RIPK4), TRAF2- and NCK-interacting protein kinase (TNIK), or vascular intrinsic growth factor receptor 1 (VEGFR1 / FLT1), comprising administering to a subject in need thereof 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. 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 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 to a subject in need thereof 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. 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 an 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 to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention.

[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 to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0444] In some embodiments, the disease associated with increased inflammation is liver inflammation, lung inflammation, cardiac inflammation, uterine inflammation, cystic fibrosis, kidney inflammation, 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, the hepatocellular carcinoma (HCC) is associated with or without cirrhosis. In some embodiments, the hepatocellular carcinoma (HCC) is associated with or without fibrosis.

[0446] In some embodiments of the methods disclosed herein, the disease is a disease caused by steatosis, fibrosis, and cirrhosis. In some embodiments, the disease caused by steatosis is inflammation. In some embodiments, the disease caused by steatosis is NAFLD, NASH, or ASH. In some embodiments, the disease caused by fibrosis is cirrhosis or liver failure. In some embodiments, the disease caused by cirrhosis is hepatocellular carcinoma, liver damage, or hepatic encephalopathy.

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

[0448] In some embodiments of the methods disclosed herein, the disease is inflammatory bowel disease, hi 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, hi some embodiments, the autoimmune disease is systemic lupus erythematosus.

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

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

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

[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 to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0454] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered to a subject in need thereof in an amount ranging from about 1 mg to about 1000 mg, or any amount ranging from these values. In some embodiments, the compounds of the present invention are administered to a subject in need thereof 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 a subject in need thereof at a daily dose ranging from about 1 mg to about 1000 mg, or any amount within these ranges. In some embodiments, the compounds of the present invention are administered to a subject in need thereof at 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 invention are administered to a subject in need thereof once daily at a dose of about 1 mg to about 1000 mg, or any amount within these ranges.

[0457] In some embodiments of the methods disclosed herein, a compound of the invention or a composition of the invention is administered to a subject in need thereof twice daily, with each dose containing about 1 mg to about 500 mg of a compound of the invention, or any amount ranging from these values. In some embodiments, a compound of the invention or a composition of the invention is administered to a subject in need thereof twice daily, with each dose containing 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 of a compound of the invention.

[0458] In some embodiments of the methods disclosed herein, a compound of the invention or a composition of the invention is administered to a subject in need thereof three times daily, with each dose containing about 1 mg to about 400 mg of a compound of the invention, or any amount ranging from these values. In some embodiments, a compound of the invention or a composition of the invention is administered to a subject in need thereof three times daily, with each dose containing 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 of a compound of the invention.

[0459] In some embodiments of the methods disclosed herein, the methods further comprise 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 an adjuvant therapy.

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

[0461] In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile acid-binding resin, niacin, an anti-obesity drug, a hormone, a tyrphostin, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein AI agonist, an apolipoprotein E agonist, a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-enhancing drug, an HDL enhancer, a modulator of the apolipoprotein AI gene, a modulator of the apolipoprotein A-IV gene, a modulator of an apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, or an acetyl-CoA carboxylase allosteric inhibitor. In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile acid-binding resin, niacin, an anti-obesity drug, a hormone, a tyrphostin, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein AI agonist, an apolipoprotein E agonist, a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-enhancing drug, an HDL enhancer, a modulator of the apolipoprotein AI gene, a modulator of the apolipoprotein A-IV gene, a modulator of an apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, an acetyl-CoA carboxylase allosteric inhibitor, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a GLP1R agonist, an mTOR inhibitor, or a TGFβ inhibitor. In some embodiments, the other pharmaceutically active agent is lovastatin.In some embodiments, the other pharmaceutically active agent is sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, regorafenib, ABX196, T-cell receptor (TCR) immune cell therapy, TBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses or genetically engineered oncolytic viruses, such as, but not limited to, telomelysin and imligic, or immunomodulatory gene therapy agents, such as MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3.

[0462] In some embodiments of the methods disclosed herein, the methods further comprise administering two or more other pharmaceutically active agents. In some embodiments, the methods of the present invention comprise administering two or more other pharmaceutically active agents, optionally in combination. In some embodiments, the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir. In other embodiments, the methods of the present invention comprise orally administering a compound of the present invention or a composition of the present invention, and further comprise administering a tumor injection oncolytic treatment. In some embodiments, the combination is administered orally.

[0463] In some embodiments, the other pharmaceutically active agent is selected from the group consisting of cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prasugrel acetaminophen ... Digastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201 / BMS-986263, vorixibat, amlexanox, PF-06835919, leptin, methotrexate Leleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, Na These are lumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, solithromycin, 99m technetium-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, or seladelpar.In some embodiments, the other pharmaceutically active agent is selected from the group consisting of cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, RO5093151, prazigasta ritot, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201 / BMS-986263, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, siragliptin Mutuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalumafen, pentamidine The drugs are benzodiazepine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, solithromycin, technetium-99m-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, salsalate, or tolvaptan.

[0464] In some embodiments of the methods disclosed herein, the methods of the present invention comprise administering to a subject in need thereof 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. 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 arginine salt is an L-arginine salt.

[0465] In some embodiments of the methods disclosed herein, the methods comprise administering to a subject in need thereof effective amounts of (a) a compound of the invention, and (b) sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losal Tan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibrano ol, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, elafi Branol, nalmefene, solithromycin, 99m technetium-mebrofenin, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib,In some embodiments, the methods of the present invention comprise administering to a subject in need thereof an effective amount of (a) a compound of the present invention, and (b) sorafenib, paclitaxel, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin D3, or another pharmaceutically active agent that is temsirolimus, epacadostat, RO7119929, guadecitabine, linlodostat, copanlisib, MIV-818, boranib, RO7070179, axitinib, sunitinib, regorafenib, or zotiraclib citrate. E, cysteamine, selonsertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, vorixibat, amlexanox, PF-06835919, leptin, metreleptin , simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-calcium phosphate Nitin, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, elafibranor, nalmefene, solithromycin, 99m technetium-mebrofenin, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib,and administering another pharmaceutically active agent that is tiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linlodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, regorafenib, zotiraclib citrate, salsalate, or tolvaptan.

[0466] In some embodiments of the methods disclosed herein, the methods comprise administering to a subject in need thereof 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, cenicriviroc, elafibranor, eicosapentaenoic acid, Galunisertib, LY2109761, LDE225, Filsocostat, Aparalenone, Metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, Cysteamine, Selonsertib, Losartan, RO5093151, Pradigastat, Sitagliptin, Vildagliptin, NGM282, Pegbelfermin, PF-05231023, Obeticholic Acid, Cilofexor, Tropifexor, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide Do, vorixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranol, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalumafen, pentamidine, bel Verine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, vorixibat, elafibranor, nalmefene, solithromycin, 99m technetium-mebrofenin, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seladelpal, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, tiauranib, SF1126, anlotinib, P1101,and administering another pharmaceutically active agent that is vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, borolanib, RO7070179, axitinib, sunitinib, regorafenib, or zotiraclib citrate. 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 arginine salt is an L-arginine salt.

[0467] In some embodiments of the methods disclosed herein, the methods of the invention comprise administering to a subject in need thereof effective amounts of (a) a compound of the invention and (b) another pharmaceutically active agent, which is sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, a T-cell receptor (TCR) immune cell therapy, TBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a genetically engineered oncolytic virus, or an immunomodulatory gene therapy agent. In some embodiments of the methods disclosed herein, the methods of the invention comprise administering to a subject in need thereof effective amounts 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 that is sorafenib, paclitaxel, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, regorafenib, ABX196, a T-cell receptor (TCR) immune cell therapy, TBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a genetically engineered oncolytic virus, or an immunomodulatory gene therapy agent. 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 arginine salt is an L-arginine salt.

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

[0469] In some embodiments, a compound of the invention and another pharmaceutically active agent are synergistic in a composition or method of the invention.

[0470] In some embodiments of the methods disclosed herein, the method further comprises administering radiation therapy to the subject. In some embodiments, the radiation therapy is gamma radiation therapy or X-ray radiation therapy. In some embodiments, the radiation therapy is administered via a gamma ray or X-ray radiation device.

[0471] In some embodiments, radiation therapy is administered simultaneously with, before, or after administration of a compound of the invention. In some embodiments, radiation therapy is administered before or after administration of a compound of the 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 comprise administering transarterial chemoembolization (TACE) to the subject.

[0474] In some embodiments of the methods disclosed herein, the method further comprises performing resection, implantation, or percutaneous ablation on the subject.

[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-segment elevation ACS (unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI)), ST-segment elevation myocardial infarction (STEMI), dysbetalipoproteinemia, hypoalphalipoproteinemia, risk of pancreatitis, or sitosterolemia. In some embodiments, the hyperlipidemia is primary hyperlipidemia or mixed hyperlipidemia. In some embodiments, the hypercholesterolemia is primary hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), or heterozygous familial hypercholesterolemia (HeFH). In some embodiments, the dysbetalipoproteinemia is primary dysbetalipoproteinemia. In some embodiments, the sitosterolemia is homozygous familial sitosterolemia. In some embodiments, the subject has a previous myocardial infarction, a previous stroke, or established peripheral arterial disease. In some embodiments, the diabetes is type 2 diabetes. In some embodiments, the subject has abnormally high LDL-C. In some embodiments, the subject has type 2 diabetes and does not have CHD.

[0476] Synthesis Example

[0477] Synthesis and General Protocol

[0478] Compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), and (IJ) can be prepared via the synthetic methodology depicted in Schemes 1-7. Starting materials useful for preparing the compounds of the invention and intermediates thereto are either commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.

[0479] Scheme 1: General synthesis of formula (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 are each independently -O-alkyl, -S-alkyl, -S-aryl, -NR 1A R 2A , NHR 1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A , heteroaryl, or heterocyclyl, or each carbon atom can independently be a Q bonded to a carbon atom. 1 and Q 2 Together with R, they can form a heterocyclyl or carbocyclyl group. 1A and R 2A is as defined herein for formula (I).

[0481] Scheme 2: General synthesis of formula (I) [ka]

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

[0483] Scheme 3: General Synthesis of Formula (I) 1 )(R 2 )-(CH2) c -X, where X is COOR 5 , or COOH, and c is 0. [ka]

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

[0485] Scheme 3 illustrates the reaction of ortho, meta, or para ω-haloalkyl substituted arenes of formula 5, where p is an integer ranging from 2 to 5, and Hal is Cl, Br, or I, with dicarboxylic acids of formula 7, where R 1 and R 2 represents the conversion of a compound of formula R to a compound of formula R 1 R2 CHCO2R 5 an ester of 1 and R 2 is an alkyl and / or aryl moiety or is linked to a 3- to 7-membered ring, and R 5 is typically ethyl or methyl) is deprotonated with a strong base, preferably, but not limited to, butyllithium or lithium diisopropylamide, and then reacted with a 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 a discussion of the scope of this method, see Larock, RC, Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2002). nd ed.; Wiley-VCH, New York, 1999, pp. 1725-1726. For specific examples of this method, see Dasseux et al., US Pat. No. 6,646,170 and US Pat. No. 6,410,802, Oniciu et al., US Pat. No. 10,227,285, 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, 2000). 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 ed.; John Wiley and Sons, New York, 2001, pp. 469-474) to give the diacid of formula 7. Alternatively, this conversion of the dihalide of formula 5 to the diacid of formula 7 can also be carried out by reacting the dihalide of formula R 1 R2 CHCO2H (in the formula, R 1 and R 2 is alkyl and / or aryl) to the above R 1 R 2 CHCO2R 5 This can also be achieved in one step by double deprotonation under conditions similar to the alkylation of , followed by reaction with the dibromide 5 (for a discussion, see Larock, R.C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp. 1717-1718). For example, a 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 temperatures ranging from about −78° C. to room temperature to give the corresponding diester of formula 7 (ortho, p=3). This diester is then hydrolyzed under standard conditions (aqueous ethanol, potassium hydroxide, reflux temperature) and, after reacidification with dilute aqueous hydrochloric acid, the dicarboxylic acid of formula 7 (ortho substitution pattern, R 1 =R 2 = methyl, and p = 3) is obtained. Alternatively, isobutyric acid is deprotonated twice with n-butyllithium and diisopropylamine in THF solution, first at about -20°C and then at about 50°C, as described in Gleiter et al., J. Org. Chem. 1992, 57, 252-258. After recooling to about -20°C, the compound of formula 5 (ortho, R 1 =R 2 = methyl, p = 3, Hal = Br) is added dropwise, maintaining the temperature below 10° C. The mixture is then stirred first at room temperature and then at about 40° C. and worked up in a typical manner to give the corresponding diacid 7. Halogenated derivatives of type 5 can be obtained by several methods, for example as described in 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 are each independently -O-alkyl, -S-alkyl, -S-aryl, -NR 1A R 2A , NHR 1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A , heteroaryl, or heterocyclyl, or each carbon atom can independently be a Q bonded to a carbon atom. 1 and Q 2 Together with R, they can form a heterocyclyl or carbocyclyl group. 1A and R 2A is as defined herein for formula (I).

[0488] Scheme 4 illustrates the synthesis of para-, meta-, and ortho-dibromoalkyl-substituted arene compounds 5-Br from the parent dicarboxylic acid 10, where (p-1) is an integer ranging from 1 to 2. Scheme 4 was first described by Larock, R.C., Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2002. 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 thed.; John Wiley and Sons, New York, 2001, pp. 484-486, outlines the esterification of compounds of formula 10 to diesters of formula 20 (where R is an alkyl moiety such as, but not limited to, methyl, ethyl, or isopropyl). Diols 30 can be prepared from diesters 20 by known synthetic methods (for a discussion of suitable reduction methods, see, e.g., Hudlicky, M. Reductions in Organic Chemistry, 2001). nd ed.; ACS Monograph 188, Washington, DC, 1996, pp. 212-216). In the next step, the conversion of the alcohol functionality in compound 5-Br to a bromo moiety in 30 is carried out according to the procedure described by Larock, R.C., Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2000. ndThis conversion can be carried out by a variety of standard methods, such as those referenced in Schimelpfenig, C.W.J. Org. Chem. 1975, 40, 1493-1494, incorporated herein by reference. For example, a 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 to give the corresponding dimethyl ester of formula 2. Procedures that can be used for this conversion are found, for example, in Schimelpfenig, C.W.J. Org. Chem. 1975, 40, 1493-1494, incorporated herein by reference. Additionally, as disclosed in U.S. Patent Application No. 397,037, filed December 8, 1953, by Reynolds et al., U.S. Pat. No. 2,789,970, 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 aprotic 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 with sodium bromide and concentrated sulfuric acid at elevated temperatures. A useful solvent for this conversion is water, as described by Schimelpfenig, C.W.J. 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 are each independently -O-alkyl, -S-alkyl, -S-aryl, -NR 1A R 2A , NHR 1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A, heteroaryl, or heterocyclyl, or each carbon atom can independently be a Q bonded to a carbon atom. 1 and Q 2 Together with R, they can form a heterocyclyl or carbocyclyl group. 1A and R 2A is as defined herein for formula (I).

[0491] Scheme 5 illustrates the preparation of ortho-, meta-, and para-substituted arene compounds of formula 5A-Br bearing two 3-bromopropyl substituents. Specific examples for the synthesis of meta- and para-substituted compounds 5A-Br 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, compound 50 is treated with malonic acid and piperidine in pyridine solution at approximately 90-110 °C to afford the α,β-unsaturated carboxylic acid of formula 60. The endpoint of this transformation 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 transformation is described in Organikum, Organisch-Chemisches Grundpraktikum, VEB Verlag Deutscher Wissenschaften, Berlin 1984, pp. 572-574. The reduction of compounds of formula 60 to compounds of formula 70 is described in Hudlicky, M. Reductions in Organic Chemistry, 2 ndThis can be achieved by catalytic hydrogenation over colloidal palladium, Raney nickel, or copper chromite, as discussed in [Chem. ed.; ACS Monograph 188, Washington, DC, 1996, pp. 196-197]. Meta-substitution of compound 60 to the corresponding compound 70 by treatment with hydrogen gas in aqueous sodium hydroxide over 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. Further conversion of compound 70 to compound 5A-Br can then be achieved according to the methodology described in Scheme 4.

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

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

[0494] Scheme 6 shows a general method for chain extension of bromides of formula 90, which have an alkyl chain consisting of (p-2) methylene groups, to bromides of formula 5-Br, which have an alkyl chain consisting of p methylene groups. The conversion sequence from alkyl halides (such as 90) to carboxylic acids (such as 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 achieved through deprotonation with a lithium base followed by alkylation with a suitable electrophile according to [Illegible], ... Alternatively, direct decarbalkoxylation of the 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 a salt. However, the decarbalkoxylation rate of these substrates can be improved by adding salts such as KCN, NaCl, or LiCl to the water / DMSO solvent (Fakhri, SA; Yousefi, BH Tetrahedron 2000, 56, 8301-8308). For example, ethyl malonate can be reacted with a solution of sodium metal in ethanol and the compound of formula 90 ((p-2) = 2), followed by the addition of ethyl malonate, to give the corresponding compound of formula 100. This tetraester can then be saponified, for example, using aqueous ethanol and potassium hydroxide, to give the corresponding tetraacid of formula 110. The tetraacid can then be decarboxylated at a temperature of about 200°C to give 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 tetraesters of formula 100 (ortho, (p-2)=1, R=ethyl) to diesters of formula 20 is described in Fakhri, SA; Yousefi, BH Tetrahedron 2000, 56, 8301-8308, which is incorporated herein by reference in its entirety.

[0495] Scheme 7: General synthesis of compounds of formula 7 [ka]

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

[0497] Scheme 7 illustrates the synthesis of ortho-, meta-, and para-substituted arene compounds of formula 7 via ω-carboxyalkyl substitution, where (p-1) is an integer ranging from 2 to 12, and R 1 and R 2is either an alkyl and / or aryl moiety, or two alkyl moieties linked by a 3- to 7-membered ring. The synthesis begins with the double deprotonation of ortho-, meta-, or para-xylene 3 with a strong base, such as, but not limited to, a combination of n-butyllithium and potassium tert-butoxide, in an aprotic solvent, such as, but not limited to, hexane, followed by the reaction of the formed dianion of 3 with a suitable electrophile, A-(CH2). p-1 -CR 1 R 2 -CH2O-PG(in the formula, (p-1), R 1 and R 2 is defined above and A is Cl, Br, or I). "PG" is a hydroxyl protecting group. Examples of hydroxyl protecting groups are described in Greene, TW; Wuts, "PG Protective Groups in Organic Synthesis," 3, which are incorporated herein by reference. rd ed., John Wiley and Sons, New York, 1999, pp. 17-245. Methylarenes are described in Larock, R.C., Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, p. 88, can be alkylated via deprotonation with a lithium base followed by alkylation with a suitable electrophile. For example, for an example of the preparation of xylylene dianions, see Bates et al., J. Am. Chem. Soc. 1981, 103, 5052-5058. In the next step, the protecting group of 190 is removed to liberate the terminal hydroxylmethyl moiety in 200, which is oxidized using a suitable oxidizing agent (Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 200). 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), to obtain the dicarboxylic acid of formula 7. For example, m-xylene (meth-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 = tetrahydropyranyl, prepared according to Dasseux et al., US 6,646,170 and US 6,410,802) is added and the reaction is continued at reflux temperature to obtain the corresponding compound of formula 190 after usual work-up and purification by column chromatography. 1 , R 2 Deprotection of the hydroxyl group (p = methyl, p = 3) is carried out by heating in methanol and concentrated aqueous hydrochloric acid (Vogel, AI Vogel's Textbook of Practical Organic Chemistry, 5 th ed., Longman Scientific and Technical, 1989, p. 552). Compound 200 is then treated with pyridinium dichromate in N,N'-dimethylformamide according to Vedejs, E.; Dent, W.H., III; Gapinski, D.M.; McClure, C.K.J. Am. Chem. Soc. 1987, 109, 5437-5446 to give the dicarboxylic acid of formula 7 (meta, p=3, R 1 , R 2 = methyl).

[0498] Scheme 8 shows an exemplary alternative synthesis method for compounds I-1 and I-32. Commercially available benzene-dicarboxaldehyde (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 (such as, but not limited to, sodium or potassium hydroxide, potassium or sodium tert-butoxide, potassium or sodium carbonate, and sodium hydride) 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. The mixture of cis and trans isomers of formula (230) or (240) can be catalytically reduced by methods known in the art for hydrogenating olefins, 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, FK et al., "Sci. Adv. 2018, 4:eaau1248, 21 September 2018," and the references cited therein. The resulting ester is subjected to hydrolysis after the hydrogenation reaction is deemed substantially complete using an appropriate analytical method. The reaction mixture containing the compound of formula (250) or (260), respectively, is hydrolyzed in refluxing alcohol in the presence of an alkaline earth metal salt or base, or oxide, or alkali metal salt or base for 2 to 96 hours. A typical example includes, but is not limited to, hydrolysis with K2CO3 in a refluxing mixture of DMSO and water.Other suitable procedures are found 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) where X=O, Z 1 , Z 2 =COOH, q=0, and R 1 and R 2 together form a cyclopropyl ring) [ka]

[0501] Compounds of formula (III) or (IIIA) where X=O can be prepared by the 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 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) over an ice bath. After the 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 NaHCO and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 78.27 g of a brown solution. The target was purified four times by flash column chromatography on a 220 g silica column with a gradient of 0-10% EtOAc in heptane. The combined fractions were concentrated to give 56 g of a colorless liquid. The target was stripped with ether and concentrated to dryness again under reduced pressure to give 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: 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 a N atmosphere. Over the course of approximately 4 hours, a solution of 2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (11.80 g, 47 mmol) and tert-butyl cyclopropanecarboxylate (10.02 g, 70.5 mmol) in tetrahydrofuran (dry, 94 mL) was slowly added to the mixture. After the addition, the mixture was slowly warmed to room temperature by removing dry ice from the isopropanol cold bath. Sample analysis showed 73% conversion to the target and approximately 2% remaining starting material. The reaction mixture was poured into a mixture of ice water (20 mL and 60 mL, respectively) and saturated aqueous NaHCO (40 mL), and the product was then extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with a mixture of brine and saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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 0-10% EtOAc in heptane. The second eluate was collected and concentrated to give 12 g of 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, observed 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 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) at room temperature. After 6 h, a sample showed approximately 1% remaining starting material and product at >80% pty. The mixture was stirred at room temperature overnight. Volatiles were removed in vacuo, water (50 mL) was added, and the product was extracted with EtOAc (3 x 50 mL), then washed with brine, dried over sodium sulfate, filtered, and concentrated to give 25 g of a yellow oil. Due to the stability of the product 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 using 2 g of material in 80 g of silica with a gradient of 0-22% EtOAc in heptane. The major component was collected to give 1.37 g of product as a colorless oil. No molecular ion was found by LCMS or GCMS techniques; only [M-OtBu] m / z 155 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 kept at this temperature for 30 minutes. The mixture was then allowed to reach room temperature and then heated to 30 °C. The formation of a methanesulfonic acid intermediate, half an equivalent of the starting material, was controlled by GCMS. A fresh solution of 61% w / w KOH in water was prepared by dissolving potassium hydroxide (70.4 g, 1255 mmol) in demineralized water (45 ml) under stirring and cooling using an ice bath. The resulting total volume was approximately 75 mL and set aside. After an additional hour of reaction, a 55% w / w aqueous solution of tetrabutylammonium hydroxide (0.627 ml, 1.289 mmol) was added, followed by the above KOH (aqueous) solution under vigorous stirring. The mixture was then stirred overnight at 40 °C, and the conversion to the final product was controlled by chromatography or NMR techniques. After 17 hours of heating at 40 °C, the conversion to the final product exceeded 80%, and the reaction was deemed complete, and 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 combined and washed with water, sulfuric acid (2 N), and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to give 7.72 g of a yellow oil, which was further purified by flash column chromatography on 120 g of silica using a gradient elution of 0% to 25% EtOAc in heptane. The product was eluted with 10% EtOAc in heptane fraction. The concentrated fractions yielded 5.5 g of a colorless oil. The nature of the final compound proved incompatible with its detection by UV-LC and GCMS. 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 added slowly at room temperature. Stirring was continued overnight. 2N aqueous sulfuric acid (10 mL) was added and stirred to quench the reaction. After 30 minutes, the original orange mixture became nearly colorless. The organic layer was collected and the aqueous layer was washed with toluene. The combined organic fractions were treated with 2M aqueous NaOH (50 mL) and stirred for 15 minutes, and the aqueous fraction containing the product was collected. The organic layer was washed with additional 2M NaOH (20 mL). The combined aqueous fractions were stirred and 6M HCl (100 mL) was added slowly until the mixture turned cloudy white, and stirring was continued until the pH remained stable. When the mixture began to form an emulsion, diethyl ether (100 mL) 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 diethyl ether (2 x 50 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.85 g of an off-white oil. The product was allowed to solidify overnight, after which it was triturated with diethyl ether and subjected to rotary evaporation at room temperature for 4 hours to give a white crystalline powder (85% yield). 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: 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 min. The mixture was stirred at −78 °C for an additional 1 h while 1,3-dibromopropane (150 g, 743 mmol, 2.88 equiv.) was added dropwise (rapidly) over 5–10 min. The mixture was allowed to warm slowly to room temperature and stirred overnight. After 16 h 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 combined ethyl acetate extracts were washed with 10% HCl (2 × 200 mL), brine (200 mL), dried over magnesium sulfate, filtered, and concentrated on a rotovap. The remaining tan oil (200 g) was filtered through silica gel (800 g), eluting with heptane followed by 2-5% ethyl acetate in heptane. The product containing fractions were combined and concentrated on a rotovap. The experiment produced ethyl 5-bromo-2,2-dimethylpentanoate 3 (49.3 g, 80.5% yield) as a colorless oil. 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 5-bromo-2,2-dimethylpentanoic acid ethyl ester 3 (70.5 g, 0.295 mol) in toluene (600 mL). The solution was heated at reflux for 24 h. The toluene was concentrated to approximately 250 mL on a rotovap. The toluene was decanted and saved. The residue was stirred with heptane (200 mL) under an argon atmosphere at room temperature for 1 h. The heptane was decanted, and the remaining solid was dried under high vacuum. This procedure produced the first crop of intermediate 4 (68.4 g, crop 1). The toluene and heptane washes were combined and concentrated. The remaining residue (75.3 g) was mixed with toluene (200 mL) and heated at reflux under argon for 24 h. After 24 h, the flask was cooled to room temperature and stored in a freezer (-15 °C) for 1 h. The toluene was decanted, and the remaining residue was stirred with heptane (200 mL) under an argon atmosphere for 1 hour. The heptane was decanted, and the solid was dried under high vacuum to prepare a second crop of intermediate 4 (52.5 g). After combining the crops, the experiment produced intermediate 4 (120.9 g, 82% yield) as an off-white solid. 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-oxohex-1-en-1-yl]phenyl}2,2-dimethyl-hex-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) at room temperature under an argon atmosphere. 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, additional intermediate 4 (14.0 g, 28.0 mmol) was added, and the mixture was stirred vigorously 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 combined, dried over magnesium sulfate, filtered, and concentrated. The remaining yellow solid (62.5 g) was dissolved in dichloromethane (200 mL) and filtered through a column of silica gel (400 g), eluting with dichloromethane. The product containing fractions were combined and concentrated. The remaining yellow oil (17.23 g) was purified by column chromatography on silica gel (350 g) eluting with 4% ethyl acetate in heptane. The procedure produced intermediate 7 (10.65 g, 43% yield, E / Z mixture of isomers) as a light yellow oil (retaining some heptane). A second fraction of monoolefinated intermediate (3.28 g) was also collected. (E / Z mixture of isomers): 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-dimethylhexanoic acid diethyl ester

[0521] Intermediate 7 (10.5 g, 25.3 mmol) was dissolved in ethanol (120 mL) and added to 5% palladium on carbon (2.5 g) under a nitrogen atmosphere at room temperature. The nitrogen atmosphere was replaced with hydrogen gas (40-45 psi), and the mixture was hydrogenated on a Parr hydrogenation apparatus at room temperature for 5 h. After 5 h, the hydrogen was replaced with nitrogen, and the mixture was filtered through a pad of Celite. The ethanol was concentrated on a rotovap, and the crude material was used in the final step without purification. The procedure yielded Intermediate 8 (8.59 g, 81% yield, pure by NMR) as a very light yellow oil. 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). Diwater (60 mL) containing potassium hydroxide (8.0 g, 143 mmol) was added, and the mixture was heated to reflux under an argon atmosphere. After 7 h, heating was discontinued, and the mixture was cooled to room temperature and stirred overnight. After 18 h, the solution was concentrated on a rotovap to remove the ethanol. The remaining aqueous solution was diluted with DI 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 x 100 mL). The combined ethyl acetate extracts were washed with brine (100 mL), dried over 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 h, the solid was filtered and dried under high vacuum at 35 °C. The procedure produced 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-32 (6.47 g, 88% yield, 99.4% by HPLC, mp = 99-101 °C) as a white solid. NMR 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-oxohex-1-en-1-yl]phenyl}2,2-dimethyl-hex-5-enoate

[0526] (5-Ethoxy-4,4-dimethyl-5-oxopentyl)(triphenyl)phosphanium bromide 4 (60.0 g, 120.1 mmol), prepared as described in Step 2 of Example 1B, and terephthalaldehyde 5 (8.0 g, 59.6 mmol) were dissolved in dichloromethane (180 mL) at room temperature under an argon atmosphere. 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 min. After 30 min, additional intermediate 4 (14.47 g, 28.97 mmol) was added, and the mixture was stirred vigorously at room temperature for 2 h. Water (DI, 200 mL) was added, and the layers were separated. The aqueous fraction was extracted with dichloromethane (200 mL). The dichloromethane extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The remaining yellow solid (64.2 g) was dissolved in dichloromethane (100 mL) and filtered through a column of silica gel (400 g), eluting with dichloromethane. The product-containing fractions were combined and concentrated. The remaining yellow oil (18.0 g) was purified by column chromatography on silica gel (360 g) eluting with 5% ethyl acetate in heptane. The procedure produced intermediate 9 (9.5 g, 38.5% yield, E / Z mixture of isomers) as a yellow oil (retaining traces of heptane). A second fraction of mono-olefinated intermediate (3.62 g) was also collected. (E / Z mixture of isomers): 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-dimethylhexanoic acid diethyl ester

[0528] Intermediate 9 (11.0 g, 26.5 mmol) was dissolved in ethanol (200 mL) and added to 5% palladium on carbon (3.0 g) 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 hydrogenation apparatus at room temperature for 5 h. After 5 h, the hydrogen was replaced with nitrogen, and the mixture was filtered through a pad of Celite. The ethanol was concentrated on a rotovap, and the crude material was used in the final step without purification. The procedure yielded 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). Diwater (80 mL) containing potassium hydroxide (9.57 g, 170.5 mmol) was added, and the mixture was heated to reflux under an argon atmosphere. After 7 hours, heating was discontinued, and 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 DI 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 x 150 mL). The combined ethyl acetate extracts were washed with brine (100 mL), dried over 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 under high vacuum at 45°C. The procedure produced 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-1 (7.82 g, 88.5% yield, 99.6% by HPLC, mp = 126-127 °C) as a white solid. 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 48-72 hours. The solids were filtered off and rinsed with dichloromethane. The filtrate was concentrated in vacuo to give a slurry of solids. Dichloromethane was added, and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to give ethyl 6-iodo-2,2-dimethylhexanoate (1.125 g, 3.77 mmol, 95% yield). 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(II) iodide.

[0535] An oven-dried 50 mL three-necked round-bottom glass flask equipped with a Teflon stirrer (vacuum outlet, inlet to an argon-filled balloon, stopper) was charged with lithium chloride, anhydrous (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 (dry) (10 mL). The zinc was activated by adding 1,2-dibromoethane (0.024 mL, 0.282 mmol), warmed using a heat gun for a few seconds, and stirred at room temperature for 5 minutes. Trimethylsilyl chloride (0.024 mL, 0.188 mmol) was added, and the mixture was heated with a heat gun for a few seconds 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 about 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 at room temperature within 1-2 minutes. The reaction mixture was stirred at 45 °C (oil bath) under argon for 1 hour, then cooled to room temperature and left 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 charged 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) in THF was filtered and added dropwise (1–2 min) at room temperature. The reaction was stirred overnight at 40 °C. The reaction was quenched and EtOH (5 mL) was added. Hydromatrix was added and the solvent was evaporated. The crude product was purified by linear phase chromatography using heptane / diisopropyl ether 0–20%. The product-containing fractions were combined and concentrated under reduced pressure to give diethyl 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoate) (210 mg). The product was used without further characterization. LCMS: 72% m / z [M+NH] + 436.3.

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

[0539] The crude diethyl 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoate) (210 mg) from above was dissolved in ethanol (1 ml) and 6 M aqueous KOH (1.254 ml, 7.52 mmol) was added. A precipitate formed, and the reaction mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature and acidified to a pH of approximately 8. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was dissolved in HO / acetonitrile / THF and subjected to basic preparation for purification. The product fractions were concentrated in a genevac, reformatted, and lyophilized to give 6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoate) (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-dimethylhept-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(triphenylphosphonium) bromide (3.18 g, 3.58 mmol, prepared as described in U.S. Pat. No. 4,689,344) was coevaporated with dry tetrahydrofuran (THF, 150 mL) to remove solvent residues. To a stirred suspension of (1,4-phenylenebis(ethane-2,1-diyl))bis(triphenylphosphonium) bromide (3.18 g, 3.58 mmol) in dry THF (150 mL) was added n-butyllithium (13.44 mL, 21.50 mmol) at room temperature. A dark orange / brown solution was obtained. After 10 min, a solution of freshly prepared (same day) methyl 3,3-dimethyl-5-oxopentanoate (2.324 g, 14.69 mmol) in dry THF (25 mL) was added dropwise over 2 min. A pale amber solution resulted. The mixture was stirred at room temperature for 30 min for complete conversion. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and partitioned between Et2O (250 mL) and EtOAc (250 mL). The phases were separated, and the organic phase was washed with saturated aqueous NaCl (4 × 500 mL) followed by brine (250 mL). The aqueous phase was then back-extracted with single portions of Et2O (500 mL). This Et2O phase was then washed with brine (250 mL). The combined organic phase was dried over Na2SO4 and allowed to stand overnight. The NaSO was filtered off, and the filtrate was concentrated under reduced pressure to give 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 / EtOAc, 1:0 to 9:1, collected by ELSD, 50 mL fractions). Fractions 28–33 were combined, and the solvent was removed under reduced pressure to give 466 mg of product as a clear, colorless oil (LCMS, m / z 415 [M+H]). 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-dimethylhept-5-enoate) (466 mg, 1.124 mmol) was dissolved in ethanol (Abs) (14.410 mL) in a 20 milliliter Biotage microwave vial and the solution was purged with nitrogen. Pd-C (10 wt % Pd on activated carbon, 50 wt % water wet, non-reduced) (59.8 mg, 0.056 mmol) was added and the vial was capped. The reaction mixture was flushed with hydrogen and then stirred under a hydrogen atmosphere (balloon) at room temperature for 1 h. The reaction mixture was filtered through three high-capacity nylon microfilters. Each filter was rinsed with EtOH (20 mL). The combined filtrate was concentrated under reduced pressure to give 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 / EtOAc, 1:0 to 9:1, 32 mL / min, collection at 220 nm / ELSD, all fractions collected, 25 milliliter fractions). Selected fractions were combined and concentrated under reduced pressure to give 441 mg (94%) of the product as a clear, colorless oil, LCMS m / z 441.4 [M+Na]. + The structure is consistent with 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] 1 M aqueous potassium hydroxide (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 at 70 °C overnight. A clear, colorless solution had formed (LCMS indicates complete and clean conversion. m / z 389.2 [M−H] - and 194.2[M-2H] 2- / 2). The mixture was allowed to cool to room temperature. The reaction mixture was diluted with demineralized water (75 mL) and extracted with dichloromethane (2 x 75 mL). Complete phase separation was not possible because the deprotonated product behaved very soapy in the aqueous phase. The organic phase was discarded. The aqueous phase was acidified with 1 M aqueous KHSO4 (50 mL), dichloromethane (50 mL) was added, and the phases were split. The pH of the aqueous phase was measured at 1. The phases were separated, and the aqueous phase was extracted with dichloromethane (4 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 403.1 mg (98%) of the product as a white solid. The product was placed under reduced pressure to give 398 mg of the product as a white solid (LCMS m / z 389.2 [M H] - . 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-dimethylhept-5-enoate).

[0549] (1,4-Phenylenebis(ethane-2,1-diyl))bis(triphenylphosphonium) bromide (4.1 g, 3.56 mmol, prepared as described in U.S. Pat. No. 4,689,344) was coevaporated with dry tetrahydrofuran (THF) (150 mL) to remove residual solvent. To a stirred suspension of 1,3-bis(2-(bromotriphenyl-15-phosphaneyl)ethyl)benzene (4.1 g, 3.56 mmol) in tetrahydrofuran (dry) (150 mL) in a 250 mL round-bottom flask dried under argon, n-butyllithium (13.37 mL, 21.39 mmol) was added at room temperature. A dark orange solution was obtained, although some small white clumps were still present. After 10 min, methyl 3,3-dimethyl-5-oxopentanoate (2.312 g, 14.62 mmol) diluted in dry THF (25 mL) was added dropwise over 2 min. A yellow solution was obtained. The mixture was stirred for 30 min. TLC (heptane / EtOAc, 9 / 1) showed one new major signal. The mixture was quenched with water (1 mL) and concentrated in vacuo to a small volume (40 mL). Water (100 mL) was added, and the mixture was extracted with EtOAc (2 × 100 mL). The organic layers were combined, washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was dissolved in dichloromethane, coated onto a hydromatrix, and purified by flash column chromatography (80 g silica gel, heptane, 0-10% EtOAc). After a second column chromatography run (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-dimethylhept-5-enoate) (650 mg, 1.568 mmol) was diluted in absolute ethanol (20 ml) and the solution was purged with nitrogen for 5 minutes. Unreduced Pd / C (10% on activated carbon, 50% wet 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 min. The round-bottom flask was sealed under a hydrogen atmosphere and stirred for 1 h. TLC (heptane / EtOAc, 9 / 1) showed spot-to-spot conversion. The mixture was filtered over a pad of Celite. The residue was rinsed with EtOH (10 ml). The filtrate was concentrated in vacuo. The resulting colorless oil was dissolved in dichloromethane, coated onto a hydromatrix, and purified by flash column chromatography (24 g, heptane, EtOAc 0-10%) to give 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 absolute 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 at 60 °C overnight. Complete conversion of the starting material was observed according to LCMS 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 combined, washed with brine, dried over Na2SO4, concentrated in vacuo, and coevaporated with Et2O. The resulting solid was triturated with heptane (10 ml), filtered off, rinsed with pentane (2 x 5 ml) and air dried to give 385 mg of the desired product. LCMS: 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 the weekend in 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 combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. Heptane / EtOAc 0% to 10% was used as the gradient for flash column chromatography. The product-containing fractions were combined and concentrated under reduced pressure to give 2-(benzyloxy)-1,3-dibromobenzene (1.2 g, 3.51 mmol, 44.0% yield). 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 charged with 2-(benzyloxy)-1,3-dibromobenzene (300 mg, 0.877 mmol) and tetrahydrofuran (dry) (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 as in the previous example) in THF was filtered and added dropwise (1–2 min) at room temperature. The reaction mixture was stirred overnight at 40 °C. EtOH (5 mL) was added, followed by hydromatrix, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using heptane / DIPE 0=>20% to give diethyl 6,6'-(2-(benzyloxy)-1,3-phenylene)bis(2,2-dimethylhexanoate) (170 mg). LCMS: 87%, mass: m / z [M+NH]+ 542.7.

[0559] Step 3: 6,6'-(2-(benzyloxy)-1,3-phenylene)bis(2,2-dimethylhexanoic acid).

[0560] Diethyl 6,6'-(2-(benzyloxy)-1,3-phenylene)bis(2,2-dimethylhexanoate) (170 mg) was dissolved in ethanol (1 ml). 6 M aqueous KOH (0.81 ml, 4.86 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature, acidified to pH 2, and extracted with dichloromethane (3 × 15 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product 6,6'-(2-(benzyloxy)-1,3-phenylene)bis(2,2-dimethylhexanoate) (60 mg). LCMS: 90% m / z [MH] -467.6.

[0561] Step 4. 6,6'-(2-hydroxy-1,3-phenylene)bis(2,2-dimethylhexanoic acid).

[0562] To an 8 mL reaction vial was added 6,6'-(2-(benzyloxy)-1,3-phenylene)bis(2,2-dimethylhexanoic acid) (60 mg) and methanol (2 mL). The mixture was purged with N2, then 5% Pd-C (13.63 mg, 6.40 μmol) was added. The mixture was evacuated and refilled with H2 three times. The reaction mixture was stirred overnight, filtered through Celite, and concentrated under reduced pressure. The residue was sent for basic preparation for purification. The product fractions were concentrated in a genevac, reformatted, and lyophilized to give 6,6'-(2-hydroxy-1,3-phenylene)bis(2,2-dimethylhexanoic acid) (8.5 mg, 0.022 mmol, 2.7% yield over three steps). 1 H NMR (400MHz, [MeOD] / TMS): δ6.87(d,J=7.5Hz,2H),6.67(t,J=7.5Hz,1H),2.58(t,4H),1.61-1.49(m,8H),1.39-1.27(m,4H),1.12(s,12H). 13C NMR (100MHz, [MeOD] / TMS): δ184.18,153.38,130.72,128.53,120.85,43.64,42.31,31.93,31.44,26.31,26.22.

[0563] Example 2A: Synthesis of 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid coenzyme A ester (compound I-32-CoA) [ka]

[0564] Step 1: [1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (E2)

[0565] A solution of n-butyllithium (38.8 mL, 2.5 M in hexane / THF / EtPh, 96.9 mmol) was added to a mixture of m-xylene (E1) (5.0 g, 47.1 mmol) and potassium tert-butoxide (5.4 g, 48.1 mmol) in hexane (100 mL) at room temperature. The reaction mixture was heated at reflux for 1 hour. A yellow precipitate formed. The reaction mixture was cooled to 0°C, and 2-(5-bromo-2,2-dimethylpentyloxy)-tetrahydropyran (prepared as described in U.S. Pat. Nos. 6,646,170 and 6,410,802) (30.0 g, 107.5 mmol) was added dropwise. The reaction mixture was heated at reflux for 20 hours. Water (150 mL) was added, and the organic phase was separated. The aqueous solution was extracted with EtOAc (2 x 100 mL). The organic phases were combined, washed with brine (50 mL), and dried over MgSO. The solvent was evaporated, and the residue was puri...

Claims

【Request 1】 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing chronic kidney disease (CKD), autosomal polycystic kidney disease, or renal fibrosis.

2. The compound, 【Chemistry 2】 2. The composition of claim 1, having the structure: or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing autosomal polycystic kidney disease.

3. The compound, 【Chemistry 3】 2. The composition of claim 1, having the structure: or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing autosomal polycystic kidney disease.

4. A composition described in any one of claims 1 to 3, wherein the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis.

5. A composition described in any one of claims 1 to 3, wherein the autosomal polycystic kidney disease is autosomal dominant polycystic kidney disease.

6. The compound, 【Chemistry 4】 or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing renal fibrosis, as described in claim 1.

7. The compound, 【Chemistry 5】 or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing renal fibrosis, as described in claim 1.

8. The compound, 【Chemistry 6】 or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing chronic kidney disease, according to claim 1.

9. The compound, 【Chemistry 7】 or a pharma- ceutically acceptable salt or solvate thereof, for treating or preventing chronic kidney disease, according to claim 1.

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