Methods for treating non-alcoholic steatohepatitis with SCD1 inhibitors - Patent Application 20070123333

Abstract

The present invention relates to compositions and methods for treating patients with non-alcoholic steatohepatitis (NASH) by administration, particularly local administration, of a pharmaceutical composition comprising a therapeutically effective amount of a stearoyl-CoA desaturase (SCD1) inhibitor. In certain preferred embodiments, the method prevents the onset or progression of, or reduces the extent of, liver fibrosis in a patient.

Description

[Technical field]

[0001] This application relates to compositions and methods for treating patients with non-alcoholic steatohepatitis (NASH) by administering stearoyl-CoA desaturase (SCD1). [Background technology]

[0002] Nonalcoholic fatty liver disease (NAFLD) develops when excess lipids accumulate in hepatocytes. Nonalcoholic steatohepatitis (NASH) is a progressive form of NAFLD in which fatty liver is accompanied by hepatocyte damage and inflammation that can occur with or without fibrosis and / or progress to fibrosis and cirrhosis. Both NASH and NAFLD are closely associated with metabolic syndrome comorbidities such as insulin resistance type 2 diabetes, and cardiovascular complications related to hypertension and dyslipidemia. It is estimated that up to 45% of adults in the United States, i.e., 7.5 to 100 million adults, suffer from NAFLD (Clinical Gastroenterology and Hepatology (2015), 13, 655-657). Although NAFLD may be relatively benign, a certain percentage of patients with NAFLD will develop NASH. As with other chronic liver diseases, the severity of underlying hepatic fibrosis progression is associated with clinical outcomes, with patients with bridging fibrosis or cirrhosis at highest risk for future liver disease. Increased hepatic fibrogenesis, evidenced by increased hepatic stellate cell activation, as indicated by increased alpha smooth muscle actin (αSMA) staining, collagen deposition on biopsies, and upregulation of fibrosis markers in serum, is associated with an increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC). A recent meta-analysis estimated a 9.57-, 16.69-, and 42.3-fold increase in liver-related mortality in subjects with fibrosis stages 2, 3, and 4 (cirrhosis), respectively, versus subjects without fibrosis (stage 0), whereas patients with fibrosis stage 1 had only a 1.41-fold increase in mortality (Hepatology (2017), 65, 1557-1565). Other recent estimates suggest that approximately 20% of NASH patients with more advanced fibrosis or compensated cirrhosis may progress to cirrhosis and develop decompensation, respectively, within 2 years (Hepatology (2019), 70(6), 1885-1888). Thus, the natural history of morbidity and mortality in NAFLD-associated liver disease correlates with the presence of NASH and its histological severity, which is determined by the stage of fibrosis.To date, there are no drugs approved for liver fibrosis or cirrhosis, and the only treatment option is liver transplantation for patients with end-stage liver disease (Current Opinion in Pharmacology (2019), 49, 60-70). In light of these findings, therapeutic agents that can prevent or slow the progression of fibrosis from benign NAFLD to NASH and advanced fibrotic stages are highly desirable. Treatment of NASH and NAFLD with the SCD1 inhibitors of the present invention is considered advantageous.

[0003] Stearoyl-CoA desaturase 1 (SCD1) is a microsomal enzyme that catalyzes the de novo biosynthesis of monounsaturated fatty acids from saturated fatty acyl-CoAs in mammals. Specifically, SCD1 introduces a cis double bond at the C9-C10 position of saturated fatty acids such as palmitoyl-CoA (16:0) and stearoyl-CoA (18:0). The resulting monounsaturated fatty acids, palmitoyl-CoA (16:1n7) and oleoyl-CoA (18:1n9), serve as substrates for incorporation into various lipids, including phospholipids, cholesterol esters, and triglycerides. Monounsaturated fatty acids are not only important components of cellular structure, but also mediators of important biological processes, such as signal transduction and cell differentiation. Studies in mice suggest that SCD1 activity is important for maintaining normal skin function due to its key role in synthesizing lipids in the sebaceous gland. Indeed, total deletion of the SCD1 gene in mice (Journal of Nutrition (2001), 131(9), 2260-2268) not only confers resistance to high-fat diet-induced obesity, but also results in significant atrophy of sebaceous glands and a significant reduction in sebum secretion. SCD1 expression has been confirmed in human skin sebaceous glands by immunohistochemistry (Prostaglandins Leukot Essent Fatty Acids (2003), 68(2), 113-21) and in the immortalized sebaceous cell line SZ95 by RT-PCR.

[0004] Systemic inhibition of SCD1 has been an obstacle to the clinical development of oral SCD1 inhibitors, especially due to its important role in the production of meibomian fluid in the gland that corresponds to the sebaceous gland in the eye, where inhibition of this enzyme causes significant dry eye. This problem has led many pharmaceutical companies to abandon SCD1 as a potential drug target to treat various metabolic diseases (Scientific Reports (2018), 8(1), 1-8;Journal of Medicinal Chemistry (2011), 54(14), 5082-5096). Interestingly, skin-specific deletion of SCD1 in mice could also result in a similar resistance to high-fat diet-induced obesity (Journal of Biological Chemistry (2009), 284(30), 19961-19973). This suggests that even 100% inhibition of SCD1 in the skin can affect metabolism and reduce body fat when the entire surface area of ​​the skin (100% body surface area or 100% BSA) is inhibited. However, unexpectedly, the inventors have discovered that local delivery of SCD1 inhibitors to a very small area of ​​the skin can not only affect total body fat throughout the body, but also, surprisingly, affect the development and progression of fibrosis in NASH. The inventors have also discovered that SCD1 is only inhibited at the site of application to the skin, further demonstrating that only partial inhibition of SCD1 in the skin is sufficient for therapeutic effect. Also unexpectedly, these beneficial effects occur without skin or eye toxicity.

[0005] Described herein are compositions of SCD1 inhibitor compounds suitable for topical delivery to the skin and methods of using such compositions. Summary of the Invention

[0006] The present invention provides a method of treating patients with non-alcoholic steatohepatitis (NASH) and preventing or slowing its progression by localized delivery of an SCD1 inhibitor compound.

[0007] Some embodiments of the present invention provide a method of treating non-alcoholic steatohepatitis (NASH) in a patient by locally administering to the patient a therapeutically effective amount of an SCD1 inhibitor compound, or a pharma- ceutically acceptable salt thereof.

[0008] Another embodiment provides a method of treating fibrosis due to non-alcoholic steatohepatitis (NASH) in a patient by locally administering to the patient a therapeutically effective amount of an SCD1 inhibitor compound, or a pharma- ceutically acceptable salt thereof.

[0009] Yet another aspect provides a method of inhibiting the progression of fibrosis due to non-alcoholic steatohepatitis (NASH) in a patient by administering to the patient a therapeutically effective amount of an SCD1 inhibitor compound, or a pharma- ceutically acceptable salt thereof.

[0010] Another embodiment provides a method of treating a patient with non-alcoholic steatohepatitis (NASH) but who is not experiencing fibrosis to inhibit fibrosis, comprising topically applying to the patient's skin an SCD1 inhibitor in an amount effective to inhibit fibrosis in the patient.

[0011] In another aspect, a patient with NASH but no fibrosis is characterized by a NASH CRN fibrosis score of 0, and said inhibition of fibrosis is characterized by a failure of said patient to increase in such histological score.

[0012] Another aspect provides a method of treating a patient with NASH and mild fibrosis to prevent or reduce the rate of fibrosis progression, comprising topically applying to the patient's skin an amount of an SCD1 inhibitor compound effective to prevent or reduce the rate of fibrosis progression in the patient.

[0013] In another aspect, a patient with NASH and mild fibrosis is characterized by a NASH CRN fibrosis score of 1-2, and preventing fibrosis progression in the patient is characterized by a failure to increase in the patient's NASH CRN fibrosis score, or reducing the rate of fibrosis progression in the patient is characterized by a slower rate of increase in the patient's NASH CRN fibrosis score.

[0014] Another embodiment provides a method of treating a patient to reduce the degree of fibrosis in a patient with higher levels of fibrosis due to NASH, comprising topically applying to the patient's skin an amount of an SCD1 inhibitor compound effective to reduce the degree of fibrosis in the patient.

[0015] In some instances of this embodiment, patients with NASH and more severe fibrosis are characterized by a NASH CRN fibrosis score of 3 or 4, and a reduction in the degree of fibrosis is characterized by a reduction in the patient's NASH CRN fibrosis score.

[0016] In another embodiment, patients with NASH and more severe fibrosis are characterized by a NASH CRN fibrosis score of 3, and a reduction in fibrosis is characterized by a reduction in such score in the patient.

[0017] In another embodiment, patients with NASH and more severe fibrosis are characterized by a NASH CRN fibrosis score of 4, and a decrease in the degree of fibrosis is characterized by a decrease in the patient's NASH CRN fibrosis score.

[0018] Another embodiment provides a method of treating a patient with mild fibrosis and a NAS score of 2.

[0019] Another embodiment provides a method of treating patients with higher levels of fibrosis, with a NAS score of 1.

[0020] Another embodiment provides a method of treating patients with higher levels of fibrosis, such as a NASH CRN fibrosis score of 3 or 4.

[0021] Another disclosed embodiment provides a method of preventing progression of fibrosis to a greater extent, including preventing or slowing the rate of progression, compared to patients not treated with an SCD1 inhibitor compound.

[0022] Another embodiment provides the above method, further comprising preventing the progression of or optimally resolving NASH in the patient.

[0023] Another embodiment provides a method of treating a patient with an anti-NASH compound in an amount effective to prevent the progression of or reverse NASH.

[0024] Yet another aspect provides a method for preventing the progression of more severe fibrosis, characterized by no significant change in histological score after one or more of 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years from the start of administration of an SCD1 inhibitor compound.

[0025] In another aspect, a method is provided for reducing histological scores 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years after initiation of administration of an SCD1 inhibitor compound.

[0026] In some embodiments, there is no increase or a slower rate of increase in histological scores 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years after initiation of administration of the SCD1 inhibitor compound.

[0027] In some embodiments, there is no increase or a slower rate of increase in NASH CRN fibrosis score 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years after initiation of administration of the SCD1 inhibitor compound.

[0028] In some embodiments, a reduction in NASH CRN fibrosis score is observed 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years after initiation of administration of the SCD1 inhibitor compound.

[0029] Another embodiment provides a method of treatment with an SCD1 inhibitor compound that improves liver tissue.

[0030] Yet another embodiment provides a method of treatment with SCD1 inhibitor compounds that does not damage liver tissue.

[0031] In yet another aspect, the invention provides a method of preventing, reducing the incidence, delaying onset, reducing the severity, or normalizing hepatic triglycerides in a subject after initiation of treatment.

[0032] Another aspect provides a method for preventing, reducing the incidence, delaying the onset, or reducing the severity of conditions associated with elevated hepatic triglyceride levels in a patient.

[0033] In another aspect, the invention provides a method for preventing, reducing the incidence, delaying onset, reducing the severity, or normalizing the ratio of lipid-containing to non-lipid-containing hepatocytes in a subject after initiation of treatment.

[0034] Another aspect provides a method for preventing, reducing the incidence, delaying onset, or reducing the severity of conditions associated with an alteration in the ratio of lipid-containing to non-lipid-containing liver cells in a patient.

[0035] In another aspect, the invention provides a method for preventing, reducing the incidence, delaying onset, reducing the severity, or normalizing the level of hepatitis in a subject after treatment has begun.

[0036] Another aspect provides a method for preventing, reducing the incidence, delaying the onset, or reducing the severity of conditions associated with altered levels of hepatitis in a patient.

[0037] Another aspect provides a method of preventing, reducing the incidence, delaying onset, reducing the severity, or normalizing fibrillar collagen and matrix-forming collagen (e.g., collagen 1a1 content) in a subject after treatment has begun.

[0038] In yet another aspect, a method is provided for preventing, reducing the incidence, delaying the onset, or reducing the severity of conditions associated with fibrillar collagen and matrix-forming collagen in a patient.

[0039] Another embodiment provides a method of preventing, reducing the incidence, delaying onset, reducing the severity, or normalizing hepatic stellate cell activation (e.g., αSMA content) in a subject after initiation of treatment.

[0040] In another aspect, methods are provided for preventing, reducing the incidence, delaying onset, or reducing the severity of conditions associated with hepatic stellate cell activation (eg, αSMA content) in a patient.

[0041] Another aspect provides a method of preventing, reducing the incidence, delaying onset, reducing the severity, or normalizing liver lipids in a subject after initiation of treatment.

[0042] Yet another aspect provides a method of preventing, reducing the incidence, delaying onset, or reducing the severity of hepatocyte ballooning in a patient.

[0043] Another aspect provides a method for preventing, reducing the incidence, delaying the onset, or reducing the severity of fatty liver in a patient.

[0044] In another embodiment, a method of treating a patient with mild fibrosis with an SCD1 inhibitor compound is provided, wherein the patient's body surface area (BSA) to which the SCD1 inhibitor compound is topically applied is less than 30%. In some embodiments, the patient's BSA to which the SCD1 inhibitor compound is topically applied is less than 20%. In other embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 10%. In some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 5%. In a preferred embodiment, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 2%, and in a particularly preferred embodiment, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 1%.

[0045] Another embodiment provides a method of treating a patient with higher fibrosis with an SCD1 inhibitor compound, wherein the patient's body surface area (BSA) to which the SCD1 inhibitor compound is topically applied is less than 30%, preferably less than 20%. In some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 10%, more preferably less than 5%. In some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is preferably less than 2%, and in some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is more preferably less than 1%.

[0046] In another embodiment, a method of treating a patient with advanced fibrosis with an SCD1 inhibitor compound is provided, wherein the patient's body surface area (BSA) to which the SCD1 inhibitor compound is topically applied is less than 30%, in some embodiments, the patient's BSA to which the SCD1 inhibitor compound is topically applied is less than 20%, in some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 10%, in some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 5%, in some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 2%, and in some embodiments, the patient's BSA to which the SCD1 inhibitor is topically applied is less than 1%.

[0047] Another embodiment provides a method of treating a patient with mild fibrosis with an SCD1 inhibitor compound, where the SCD1 inhibitor compound is applied topically to less than 1-2% of the patient's body surface area (BSA).

[0048] Yet another embodiment provides a method of treating a patient with higher levels of fibrosis with an SCD1 inhibitor compound, wherein the SCD1 inhibitor compound is applied topically to less than 1-2% of the patient's body surface area (BSA).

[0049] Yet another embodiment provides a method of treating a patient with higher levels of fibrosis with an SCD1 inhibitor compound, wherein the SCD1 inhibitor compound is applied topically to less than 1-2% of the patient's body surface area (BSA).

[0050] In another aspect, a method of treating a patient with mild fibrosis with an SCD1 inhibitor compound is provided, wherein the SCD1 inhibitor compound is topically applied to the patient's skin once daily, twice daily, every other day, once weekly, or once every two weeks.

[0051] In another aspect, a method of treating a patient with more advanced fibrosis with an SCD1 inhibitor compound is provided, wherein the SCD1 inhibitor compound is applied topically to the patient's skin once daily, twice daily, every other day, once weekly, or once every two weeks.

[0052] Another embodiment is a method of treating a patient with advanced fibrosis with an SCD1 inhibitor compound, wherein the SCD1 inhibitor compound is topically applied to the patient's skin once daily, twice daily, every other day, once weekly, or once every two weeks.

[0053] Another embodiment provides a method of treating patients with mild fibrosis, characterized by a statistically significant reduction in liver fibrosis as determined by either one or more biomarkers of liver fibrosis or imaging.

[0054] Yet another embodiment provides a method of treating patients with more advanced fibrosis characterized by a statistically significant reduction in liver fibrosis as determined by either one or more biomarkers of liver fibrosis or imaging.

[0055] In yet another aspect, a method is provided for treating patients with advanced fibrosis characterized by a statistically significant reduction in liver fibrosis as determined by either one or more liver fibrosis biomarkers or imaging.

[0056] Another embodiment provides a method of treating a patient with mild fibrosis, characterized by at least a 20% reduction in fibrosis, preferably at least a 25% reduction, compared to before treatment. In some embodiments, the reduction in fibrosis is at least 30%, preferably at least 35%; more preferably, the reduction in fibrosis is at least 40%. In preferred embodiments, the reduction in fibrosis is at least 45%, more preferably at least 50%. In particularly preferred embodiments, the reduction in fibrosis is at least 55%, at least 60%, at least 65%, or at least 70%. In more preferred embodiments, the reduction in fibrosis is at least 75%, at least 80%, or at least 85%. In most preferred embodiments, the reduction in fibrosis is at least 90%, at least 95%, or 100%.

[0057] Another embodiment of the invention provides a method of treating patients with higher levels of fibrosis characterized by at least a 20% reduction in fibrosis compared to before treatment; in some embodiments, the reduction in fibrosis is at least 25%; in some embodiments, the reduction in fibrosis is at least 30%; in some embodiments, the reduction in fibrosis is at least 35%; in some embodiments, the reduction in fibrosis is at least 40%; in some embodiments, the reduction in fibrosis is at least 25%; in some embodiments, the reduction in fibrosis is at least 45%; in some embodiments, the reduction in fibrosis is at least 50%; in some embodiments, The reduction in fibrosis is at least 55%; in some embodiments, the reduction in fibrosis is at least 60%; in some embodiments, the reduction in fibrosis is at least 65%; in some embodiments, the reduction in fibrosis is at least 70%; in some embodiments, the reduction in fibrosis is at least 75%; in some embodiments, the reduction in fibrosis is at least 80%; in some embodiments, the reduction in fibrosis is at least 85%; in some embodiments, the reduction in fibrosis is at least 90%; in some embodiments, the reduction in fibrosis is at least 95%; in some embodiments, the reduction in fibrosis is at least 100%.

[0058] Another embodiment of the invention provides a method of treating a patient with high levels of fibrosis, characterized by at least a 20% reduction in fibrosis compared to before treatment; in some embodiments, the reduction in fibrosis is at least 25%; in some embodiments, the reduction in fibrosis is at least 30%; in some embodiments, the reduction in fibrosis is at least 35%; in some embodiments, the reduction in fibrosis is at least 40%; in some embodiments, the reduction in fibrosis is at least 25%; in some embodiments, the reduction in fibrosis is at least 45%; in some embodiments, the reduction in fibrosis is at least 50%; in some embodiments, the reduction in fibrosis is at least 50%. The reduction in fibrosis is at least 55%; in some embodiments, the reduction in fibrosis is at least 60%; in some embodiments, the reduction in fibrosis is at least 65%; in some embodiments, the reduction in fibrosis is at least 70%; in some embodiments, the reduction in fibrosis is at least 75%; in some embodiments, the reduction in fibrosis is at least 80%; in some embodiments, the reduction in fibrosis is at least 85%; in some embodiments, the reduction in fibrosis is at least 90%; in some embodiments, the reduction in fibrosis is at least 95%; in some embodiments, the reduction in fibrosis is at least 100%.

[0059] One embodiment of the present invention is a compound of formula I: [ka] The present invention includes administering an SCD1 inhibitor compound having the structure:

[0060] In some embodiments of the compounds of formula I, X is selected from the group consisting of O, NH, N-alkyl or N-acyl, S, SO, and SO2; W is independent of CR 4 or N; Z is an independent CR 5 or N; Each R 1 , R 2 , R 3 , R4 and R 5 are independently H, OH, F, Cl, Br, I, C1 to C6 straight or branched chain alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, PO2(OCH3)H or its phosphonic acid, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6 R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 selected from the group consisting of; Here, adjacent substituents R 1 , R 2 , R 3 , R 4 and R 5 may form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring; Each R 6 , R 7 , R 8 , R 9 and R 10is independently selected from the group consisting of H, OH, O-Rx, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl; and Rx is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, or thioester.

[0061] In another embodiment of the compound of formula I, X is O; W is CR 4 and; Z is CR 5 and; R 1 , R 2 , R 4 and R 5 is H; R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0062] In some embodiments, the structure of the compound of formula I is: [ka] or a pharma- ceutically acceptable salt thereof.

[0063] One embodiment disclosed herein is a compound represented by formula II: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0064] One embodiment disclosed herein is a compound represented by formula III: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0065] One embodiment disclosed herein is a compound represented by formula IV: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0066] One embodiment disclosed herein is a compound represented by formula V: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0067] One embodiment disclosed herein is a compound represented by formula VI: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0068] One embodiment disclosed herein is a compound represented by formula VII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0069] One embodiment disclosed herein is a compound represented by formula VIII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0070] One embodiment disclosed herein is a compound represented by formula IX: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0071] One embodiment disclosed herein is a compound represented by formula X: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0072] One embodiment disclosed herein is a compound represented by formula XI: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0073] One embodiment disclosed herein is of formula XII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0074] One embodiment disclosed herein is a compound represented by formula XIII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0075] One embodiment disclosed herein is a compound represented by formula XIV: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0076] One embodiment disclosed herein is a compound represented by formula XV: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0077] One embodiment disclosed herein is a compound represented by formula XVI: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0078] One embodiment disclosed herein is a compound represented by formula XVII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0079] One embodiment disclosed herein is a compound represented by formula XVIII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0080] One embodiment disclosed herein is of formula XIX: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0081] One embodiment disclosed herein is a compound represented by formula XX: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0082] One embodiment disclosed herein is a compound represented by formula XXI: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0083] One embodiment disclosed herein is a compound represented by formula XXII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0084] One embodiment disclosed herein is a compound represented by formula XXIII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0085] One embodiment disclosed herein is a compound represented by formula XXIV: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0086] One embodiment disclosed herein is a compound represented by formula XXV: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0087] One embodiment disclosed herein is a compound represented by formula XXVI: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0088] One embodiment disclosed herein is of formula XXVII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0089] One embodiment disclosed herein is a compound represented by formula XXVIII: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0090] One embodiment disclosed herein is of formula XXIX: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0091] One embodiment disclosed herein is a compound represented by formula XXX: [ka] The present invention includes administration of an SCD1 inhibitor having the structure:

[0092] One embodiment disclosed herein is a compound represented by formula XXXI: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0093] One embodiment disclosed herein is a compound represented by formula XXXII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0094] One embodiment disclosed herein is of formula XXXIII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0095] One embodiment disclosed herein is a compound represented by formula XXXIV: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0096] One embodiment disclosed herein is a compound represented by formula XXXV: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0097] One embodiment disclosed herein is of formula XXXVI: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0098] One embodiment disclosed herein is a compound of formula XXXVII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0099] One embodiment disclosed herein is a compound represented by formula XXXVIII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0100] One embodiment disclosed herein is of formula XXXIX: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0101] One embodiment disclosed herein is a compound of formula XL: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0102] One embodiment disclosed herein is of formula XLI: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0103] One embodiment disclosed herein is of formula XLII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0104] One embodiment disclosed herein is of formula XLIII: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0105] One embodiment disclosed herein is a compound represented by formula XLIV: [ka] The present invention includes the administration of an SCD1 inhibitor having the structure:

[0106] Other aspects of the invention include administering a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV on a continuous daily dosing schedule at least once a week, once daily, twice daily, or three times daily.

[0107] Certain embodiments include methods of treating nonalcoholic steatohepatitis (NASH) with a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLI.

[0108] Some embodiments disclose methods of treating fibrosis due to non-alcoholic steatohepatitis (NASH) with compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV.

[0109] Some embodiments disclose a method of inhibiting the progression of fibrosis due to non-alcoholic steatohepatitis (NASH) with a compound represented by Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV.

[0110] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure as claimed.

[0111] The effect of topical treatment of 10% of the skin with compound 25 for 12 weeks was evaluated in a diet-induced, biopsy-confirmed mouse model of NASH, as described in the literature (World Journal of Gastroenterology (2019), 25(33), 4904-4920). In this model, mice are placed on a high fat-high fructose diet (the so-called GAN [Gubra Amylin novel] diet) for 33 weeks before drug administration to induce NASH. A biopsy is taken before treatment with the drug to exclude mice that do not develop the NASH phenotype. This biopsy is then compared to a biopsy after drug treatment to evaluate changes in NAFLD activity and fibrosis stage. Qualitative scoring is completed using quantitative immunohistochemistry to evaluate effects on hepatic steatosis, inflammation (galectin 3), fibrosis (collagen 1a1 and picrosirius red) and astrocyte activation (αSMA). RNASeq was also performed on liver samples from mice treated with placebo gel and Compound 25 gel to investigate key candidate genes involved in extracellular matrix formation (ECM) and fibrogenesis. Parametric (ANOVA) and non-parametric (Fisher or χ2) statistics were used as appropriate. 2 ) data were analyzed. [Brief description of the drawings]

[0112] [Figure 1] FIG. 1 shows the concentration-dependent inhibition of rat and human SCD1 activity by compound 25 and the IC50 determined for inhibition of rat and human SCD1. [Diagram 2]Figure 2 is a graph showing the effect of Compound 25 on body weight (expressed as a percentage of baseline body weight) and body fat accumulation (expressed as a percentage of body weight). Mice (16 per group) were administered either placebo gel or gel containing 0.05% Compound 25, 0.25% Compound 25, 0.75% Compound 25 or 2.5% Compound 25 for 12 weeks. Body weight and body fat accumulation were significantly (p<0.001) reduced only in the Compound 25 2.5% treatment group. In the low dose group, the improvement of NASH histological parameters can be interpreted as being independent of the pharmacological effect of reducing body weight and body fat accumulation. [Diagram 3] FIG. 3 is a graph showing the number of mice in each treatment group that showed either improvement (low score), no change (same score), or worsening (high score) in the NAFLD Activity Score (NAS), a scoring system used in clinical NASH clinical trials. NAS (score 0-8) is a composite measure of steatosis (liver fat; score 0-3), lobular inflammation (number of inflammatory foci per field; score 0-3), and hepatocyte ballooning (number of cells; score 0-2). Mice (16 per group) were administered either placebo gel, gel containing 0.25% Compound 25, gel containing 0.75% Compound 25, or gel containing 2.5% Compound 25 for 12 weeks. The number of animals with improved NAS was significantly greater in the 0.75% and 2.5% Compound 25 dose groups (p<0.05 vs. placebo), with no animals showing high NAS scores and 15 / 16 animals showing low NAS scores. These results are consistent with a therapeutic benefit in both preventing the progression of NASH and reducing existing NASH. [Figure 4]FIG. 4 is a graph showing hepatic lipid content quantified on hematoxylin and eosin stained sections and hepatic triglyceride content biochemically analyzed at 12 weeks. Mice (16 per group) were administered either placebo gel, gel containing 0.25% Compound 25, gel containing 0.75% Compound 25, or gel containing 2.5% Compound 25. Hepatic lipid content was significantly (p<0.05, p<0.001, respectively) reduced in the 0.75% and 2.5% Compound 25 treatment groups. Similarly, hepatic triglyceride content was significantly (p<0.001) reduced in the 2.5% Compound 25 treatment group. Fatty liver and triglyceride accumulation in the cytoplasm of hepatocytes are characteristic of NAFLD and NASH. [Diagram 5] FIG. 5 is a graph showing the effect of Compound 25 on the worsening (high score) fibrosis stage score of mice in each treatment group during 12 weeks of dosing. Mice (16 per group) were administered either a placebo gel, a gel containing 0.25% Compound 25, a gel containing 0.75% Compound 25, or a gel containing 2.5% Compound 25. The groups treated with 0.25%, 0.75%, and 2.5% Compound 25 dramatically reduced the number of mice with worsening fibrosis stage (6-12%, or 2 / 16, 2 / 16, and 1 / 16 animals, respectively), compared to nearly 50% (7 / 16) in animals treated with placebo gel. These effects of reducing fibrosis stage score suggest that Compound 25 prevents the progression of fibrosis and fibrogenic processes in NASH. [Figure 6]Figure 6 is a graph showing the liver content (mg) of collagen 1a1 in antibody stained sections. Mice (16 per group) were administered either placebo gel or gels containing 0.05% compound 25, 0.25% compound 25, 0.75% compound 25, or 2.5% compound 25 for 12 weeks. Collagen 1a1 is the major fibrous collagen isoform involved in the fibrotic process of NASH. Liver content was determined from collagen 1a1 antibody stained sections as described in a previous publication (WJG (2019) 25(33):4904-4920). There was a clear trend toward a decrease in the amount of collagen 1a1 at all doses of compound 25, with a significant decrease in the 0.75% and 2.5% dose groups (p<0.05 and p<0.01, respectively), consistent with a blockade of the worsening fibrosis stage and a decrease in fibrosis. This was unexpected and again suggests a therapeutic benefit for fibrosis in NASH. [Figure 7] Figure 7 is a graph showing the liver content (mg) of picrosirius red. Mice (16 per group) were administered either a placebo gel, a gel containing 0.25% compound 25, a gel containing 0.75% compound 25, or a gel containing 2.5% compound 25. Picrosirius red is a histological rapid stain commonly used to visualize collagen in paraffin-embedded tissue sections. Compound 25 at 0.75% and 2.5% significantly (p<0.05 and p<0.001, respectively) reduced the amount of picrosirius red. These findings are consistent with the previously described improvement in fibrosis stage score and reduction in hepatic collagen 1a1 content. [Figure 8]FIG. 8 is a graph showing hepatic content of αSMA (mg) in antibody stained sections at 12 weeks. Hepatic stellate cells activated into myofibroblasts become the main collagen and ECM producing cells in fibrotic liver. The extent of myofibroblast activation and its presence in the liver can be determined by measuring the expression of αSMA. Mice (16 per group) were administered either a placebo gel, a gel containing 0.05% Compound 25, a gel containing 0.25% Compound 25, a gel containing 0.75% Compound 25, or a gel containing 2.5% Compound 25. Mice treated with 0.25%, 0.75%, and 2.5% Compound 25 had significantly reduced αSMA activation (p<0.05, p<0.01, and p<0.001, respectively), consistent with reduced collagen markers and reduced fibrotic progression. These findings suggest that even greater antifibrotic activity may be expected with chronic administration of compound 25 beyond 12 weeks. [Figure 9] Graph showing hepatic galectin 3 content (mg) in antibody stained sections at 12 weeks. Galectin 3 is a β-galactoside binding molecule that has an important role in hepatitis, contributing to disease progression, stellate cell activation and fibrogenesis (Gastroenterology (2020): 158:1334-1345). Mice (16 per group) were administered either a placebo gel, a gel containing 0.25% Compound 25, a gel containing 0.75% Compound 25, or a gel containing 2.5% Compound 25. Mice treated with 0.75% and 2.5% Compound 25 had significantly reduced galectin 3 content (p<0.05 and p<0.001, respectively), suggesting an anti-inflammatory therapeutic effect. [Figure 10]Figure 10 is a graph showing the expression levels of mRNA for several genes involved in hepatitis. Chemokine ligand 2 and chemokine ligand 5 are pleiotropic cytokines that induce inflammatory recruitment and fibrosis. Epithelial cell adhesion protein promotes adhesive interactions that mediate the migration of cells to sites of inflammation. CD68 is a common marker of inflammation associated with the involvement of monocytes and macrophages. Integrin X is a heterotrimeric receptor that is activated in inflammatory responses. Mice (16 per group) were administered either a placebo gel or a gel containing 2.5% compound 25. All of these genes were significantly downregulated in the liver by topical administration of compound 25 to the skin of the animals. The reduction in galectin 3 mRNA is highly consistent with the histological findings of galectin 3 (Figure 9). Taken together, these markers further suggest that compound 25 has beneficial effects on multiple inflammatory processes in the liver. [Figure 11] Figure 11 is a graph showing the mRNA expression of hepatic genes involved in NASH fibrogenesis and extracellular matrix formation. Monocyte chemotactic protein 1 attracts other molecules to the extracellular matrix. Osteonectin is an important glycoprotein associated with the basement membrane and is increased in NASH. αSMA is stimulated in activated astrocytes that produce fibrillar collagens (collagen 1a1, collagen 3a1) and matrix-forming collagens (collagen 4a1). Mice (16 per group) were administered either a placebo gel or a gel containing 2.5% compound 25. By topically administering compound 25 to the skin of the animals, all of these genes were significantly downregulated in the liver, which is highly consistent with other measures demonstrating the apparent beneficial effect of compound 25 on fibrosis. [Figure 12]Graph showing plasma alanine transaminase (ALT) (units / L) and plasma aspartate transaminase (AST) (units / L) at 12 weeks. Mice (16 per group) were administered either placebo gel, gel containing 0.25% Compound 25, gel containing 0.75% Compound 25, or gel containing 2.5% Compound 25. ALT and AST are widely used as clinical indicators of liver damage or injury due to various diseases or conditions. Normally, ALT and AST levels in the blood are low, but when the liver is damaged, a lot of ALT and AST are released into the blood. ALT and AST are widely considered clinically reliable and sensitive markers of liver disease progression across multiple indications including NAFLD / NASH, alcoholic liver disease, hepatitis B and C virus infection, drug-induced liver toxicity, autoimmune and cholestatic liver disease. The functional significance of the histological improvement due to treatment is evident in the reduction of these two enzymes in the 0.75% and 2.5% Compound 25 groups. [Figure 13]FIG. 13 is a graph showing mRNA expression levels of hepatic genes associated with NASH progression and poor prognosis in patients by bioinformatics, integrative and text mining approaches in the literature (see, e.g., Int. J. Mol. Sci. (2019), 20, 5594 and Gene (2020) 742, 144549). Many of these genes are involved in lipid metabolism, insulin resistance, inflammation and cancer, and are useful in predicting patients' progression to cirrhosis or liver cancer, which are often fatal sequelae of NASH. Hepatic aldehyde dehydrogenases (such as Aldh8a1 and Aldh7a1) play a key role in catalyzing aldehydes to carboxylic acids, which are important in a wide variety of biological processes. Annexin A2 is an inducible, calcium-dependent, phospholipid-binding protein known to promote hepatic fibrosis via von Willebrand factor secretion. CD36 is a cell surface glycoprotein whose role includes triglyceride uptake in the liver. Cellular nucleic acid-binding proteins (CNBPs) are single-stranded DNA-binding proteins that preferentially bind to sterol regulatory element sequences in several tissues, including the liver. Death-inducing DFFA-like effector C (CIDEC) binds to lipid droplets and regulates their enlargement to promote storage and limit lipolysis, and is also involved in apoptosis. Cyclin D1 is a key regulator of cell cycle progression in somatic cells. Fatty acid synthase (Fasn) catalyzes fatty acid synthesis and is known to be elevated in NASH. Heat shock factor binding protein 1 (Hsbp1) regulates cellular responses to heat and chemical stress. Kinesin family member 6 (KIF6) mediates intracellular trafficking of organelles, complex proteins and mRNAs and has been used as a pharmacogenetic marker for lipid-lowering effects. Nuclear factor erythroid 2-related factor (Nfe2I2) regulates the expression of antioxidants caused by injury and inflammation and is a pleiotropic regulator of metabolism, inflammation, autophagy and other responses. Perilipin 2, also known as adipocyte differentiation-associated protein, is involved in lipid and glucose homeostasis and is known to be elevated in liver disease.Mice (16 per group) were administered either a placebo gel or a gel containing 2.5% compound 25. The significant regulation of these genes by compound 25, together with the histological improvements in hepatic steatosis, inflammation, and fibrosis, suggests that compound 25 may prevent poor prognosis of NASH and improve multiple long-term outcomes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0113] Detailed Description This specification provides compositions and methods for preventing or treating fibrosis due to non-alcoholic steatohepatitis (NASH) and reducing the progression of NASH by topical delivery of SCD1 inhibitor compounds to the skin.

[0114] SCD1 inhibitor compounds may be useful in treating fibrosis due to NASH, as well as the progression of inflammatory fibrosis caused by excess body fat.

[0115] The toxicity of fat may be directly related to its ability to synthesize, regulate and secrete cytokines and adipokines. This relationship may be due to the wide range of cytokines and metabolites produced by adipose tissue that display pro-inflammatory and cancer-prone properties. Indeed, cytokines produced by adipose tissue cause insulin resistance and mediate the induction of proliferation, migration, angiogenesis and oxidative stress. There are multiple molecular pathways that metabolize fat in adipocytes. One of the mechanisms to process fat is through peroxidation. However, when cells have to process moderate or high amounts of lipids, the peroxidation becomes toxic, the oxidative stress reduces the DNA repair capacity, and then the cells induce apoptosis leading to disease (Journal of Translational Medicine (2016), 14(21), 1-12). The main pathogenesis of NAFL and NASH is the overwhelming of the liver's ability to process carbohydrates and fatty acids, the main metabolic energy substrates, leading to the accumulation of toxic lipids (Nature Medicine (2018), 24(7), 908-922). These metabolic products induce hepatocyte stress, injury and death, leading to fibrogenesis and genomic instability that predispose to cirrhosis and hepatocellular carcinoma.

[0116] definition Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for a term in this specification, the definition in each section takes precedence unless otherwise stated.

[0117] As used herein, "alkyl" refers to a branched or straight chain substituent containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and neo-pentyl. Alkyl groups can be unsubstituted or substituted with one or more substituents. In some embodiments, an alkyl group contains 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0118] As used herein, "alkylene" means a divalent alkyl, where alkyl is as defined above.

[0119] In this specification, "alkenyl" refers to a linear or branched saturated hydrocarbon group containing a carbon-carbon double bond. For example, the carbon number of the hydrocarbon chain may be 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, 2-4, etc. "Lower alkenyl" may refer to, for example, an alkenyl having 2-6, 2-4, etc. carbon atoms. In some cases, the carbon number of the linear alkenyl may be 2-6, and the carbon number of the branched alkyl may be 3-6, such as vinyl, allyl, butene (including all isomers), pentene (including all isomers), etc. The alkenyl may be optionally substituted. In some cases, the alkenyl may be a C2-C alkyl group having a carbon-carbon double bond. 12 and optionally substituted with oxygen, silicon, or sulfur, or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, or NH-alkyl.

[0120] In this specification, "alkynyl" refers to a linear or branched saturated hydrocarbon group containing a carbon-carbon triple bond. For example, the carbon number of the hydrocarbon chain may be 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, 2-4, etc. "Lower alkynyl" may refer to, for example, an alkynyl having 2-6, 2-4, etc. carbon numbers. In some cases, the linear alkynyl may have 2-6 carbon atoms, and the branched alkyl may have 3-6 carbon atoms, such as acetylene, propargyl, butyne (including all isomers), pentyn (including all isomers), etc. The alkynyl may be optionally substituted. In some cases, the alkynyl may be a C2-C alkyl group having a carbon-carbon triple bond. 12 and optionally substituted with oxygen, silicon, or sulfur, or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, or NH-alkyl.

[0121] As used herein, "cycloalkyl" refers to a ring system in which the ring backbone is made up of only carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Cycloalkyls may include multiple fused rings. Carbocyclyls may be of any degree of saturation, so long as the rings in the ring system are not aromatic. Carbocyclyl groups may be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups contain 3 to 10 carbon atoms, such as 3 to 6 carbon atoms.

[0122] As used herein, "alkylcycloalkyl" refers to a (alkylene)-R group, where R is cycloalkyl as defined above; for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl. In another example, the alkylcycloalkyl has 4 to 12 carbon atoms, i.e., C4 to C6. 12 It is alkylcycloalkyl.

[0123] As used herein, "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having only carbon atoms in a ring backbone with 5 to 14 or 5, 6, 9, or 10 ring atoms, the ring atoms sharing 6, 10, or 14 pi-electrons, and at least one ring of the system being aromatic. Aryl groups may be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, and others. In some embodiments, the aryl is phenyl.

[0124] As used herein, "alkylaryl" refers to the group (alkylene)-R, where R is aryl as defined above. Alkylaryl may be optionally substituted. In some cases, alkylaryl may be alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, or alkyl-substituted naphthyl.

[0125] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 14 or 5, 6, 9 or 10 ring atoms, where the ring atoms share 6, 10 or 14 pi-electrons, at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl. These include quinazolinyl, quinolinyl, thieno[3,2-c]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiane, isoindoline, and others. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0126] As used herein, "halo", "halide" or "halogen" is a chlorine, bromine, fluorine or iodine atom. In some embodiments, halo is chlorine, bromine or fluorine. For example, halide may be fluorine.

[0127] As used herein, "haloalkyl" refers to a hydrocarbon substituent that is a straight or branched chain alkyl, alkenyl, or alkynyl substituted with one or more chlorine, bromine, fluorine, and / or iodine atoms. In some embodiments, the haloalkyl is a fluoroalkyl, in which one or more hydrogen atoms are replaced with fluorine. In some embodiments, the haloalkyl is 1 to about 3 carbons in length (e.g., 1 to about 2 or 1). The term "haloalkylene" refers to a difunctional variant of a haloalkyl, where such a difunctional group may function as a spacer between substituents, other atoms, or between a ring and another functional group.

[0128] In this specification, "heterocyclyl" or "heterocycloalkyl" refers to a non-aromatic ring system containing at least one heteroatom in the ring backbone. Heterocyclyl may include fused polycyclic rings. Heterocyclyl may be unsubstituted or substituted with one or more substituents. In some embodiments, the heterocycle has 3 to 11 members. The heterocyclyl ring is optionally fused to (one) aryl or heteroaryl ring as defined herein. A heterocyclyl ring fused to a monocyclic aryl or heteroaryl ring is also referred to in this application as a "bicyclic heterocyclyl" ring. Furthermore, one or two ring carbons of the heterocyclyl ring may be optionally replaced with a -CO- group. In a 6-membered monocyclic heterocycle, the heteroatoms are selected from 1 to 3 O, N, or S, and when the heterocycle is a 5-membered ring, it may have 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, etc. In some embodiments, heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0129] As used herein, "alkylheterocycloalkyl" refers to a (alkylene)-R group, where R is a heterocyclyl ring as defined above, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, etc. Alkylheterocycloalkyl refers to a heterocyclic ring where the heterocycle contains one or two heteroatoms selected from O, S or N and has 3 to 11 carbon atoms, i.e., C3-C6. 11Also included is alkylheterocycloalkyl, including that when N is present in the heterocycle, the nitrogen atom may be in the form of an amide, carbamate or urea.

[0130] As used herein, "alkylcycloalkyl" refers to a (alkylene)-R group, where R is cycloalkyl as defined above; for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl. In another example, the alkylcycloalkyl has 4 to 12 carbon atoms, i.e., C4 to C6. 12 It is alkylcycloalkyl.

[0131] As used herein, "oxo" or "carbonyl" refers to the =(O) or C=O group respectively.

[0132] As used herein, "O-alkyl" refers to an (oxygen atom)-R group, where R is alkyl as defined above. For example, an O-alkyl can be an oxygen atom bonded to a C1-C6 straight or branched chain alkyl.

[0133] As used herein, "O-cycloalkyl" refers to the group (oxygen atom)-R, where R is cycloalkyl as defined above. For example, O-cycloalkyl is an oxygen atom bonded to a C3-C7 cycloalkyl.

[0134] As used herein, "O-alkylcycloalkyl" refers to the group (oxygen atom)-R, where R is alkylcycloalkyl as defined above. For example, O-cycloalkyl is an oxygen atom bonded to a C4-C8 alkylcycloalkyl.

[0135] The term "substituted" refers to a moiety having a substituent replacing a hydrogen bonded to one or more non-hydrogen atoms of a molecule. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valence of the atom and substituent being substituted, and it is understood that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. Substituents include, for example, one or more of hydroxyl, -NH, -NH(C 1-3 Alkyl) and -N(C 1-3 Alkyl)2-substituted (C 1-9 Alkyl);-(C 1-9 haloalkyl; halide; hydroxyl; carbonyl [e.g., -C(=O)OR and -C(=O)R]; thiocarbonyl [e.g., -C(=S)OR, -C(=O)SR and -C(=S)R]; optionally one or more of halide, hydroxyl, -NH2, -NH(C 1-3 Alkyl) and -N(C 1-3 Alkyl)2-substituted (C 1-9 alkoxy; -OPO(OH); phosphonic acids [e.g., -PO(OH) and -PO(OR')]; -OPO(OR')R"; -NRR'; -C(O)NRR'; -C(NR)NR'R"; -C(NR')R"; cyano; nitro; azido; -SH; -SR; -OSO(OR); sulfonic acids [e.g., -SO(OH) and -SO(OR)]; -SONR'R"; and -SOR, where R, R', and R" are independently H; -(C 1-9 alkyl); optionally substituted with 1 to 3 R'''; 6-10 Aryl; 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 R'''; C 3-7 carbocyclyl; and 3-8 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 R''', where each R''' is independently selected from (C 1-6 alkyl), -(C 1-6 haloalkyl), halide (e.g. F), hydroxyl, -C(O)OR, -C(O)R, -(C1-6 alkoxy), -NRR', -C(O)NRR' (each R and R' is independently H and -(C 1-6 In some embodiments, the substituent is selected from -(C 1-6 alkyl), -(C 1-6 haloalkyl), halide (e.g. F), hydroxyl, -C(O)OR, -C(O)R, -(C 1-6 R and R are independently selected from H and -(C(O)NRR', -C(O)NRR', and cyano. 1-6 alkyl).

[0136] In this specification, when two groups are "linked" or "bonded" to form a "ring", it should be understood that a bond is formed between the two groups and a hydrogen atom of one or both groups may be replaced with a bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. Those skilled in the art will recognize that such rings are readily formed by conventional chemical reactions. In some embodiments, such rings are 3-7 membered (e.g., 5- or 6-membered) rings.

[0137] Those skilled in the art will recognize that some of the chemical structures described herein may be depicted in one or more other resonance forms; or may exist kinetically in one or more other tautomeric forms; and those skilled in the art will recognize that such tautomeric forms represent only a small portion of such compounds. Although such compounds are expressly contemplated as being within the scope of this invention, such resonance forms or tautomers are not expressly disclosed herein.

[0138] The compounds provided herein may include various stereochemical forms. The compounds also include diastereomers and optical isomers, e.g., mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers that arise as a result of structural asymmetry of a particular compound. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, the disclosed compounds are named or depicted by structure without specifying stereochemistry, and when they have one or more chiral centers, they are understood to represent all possible stereoisomers of the compound.

[0139] The present invention includes all pharma- ceutically acceptable isotopically labeled compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g., 2 H (deuterium) and 3 H (tritium)), carbon isotopes (e.g. 11 C. 13 C and 14 C), isotopes of chlorine (e.g. 36 Cl), isotopes of fluorine (e.g. 18 F), isotopes of iodine (e.g. 123 I and 125 I), nitrogen isotopes (e.g. 13 N and 15 N), isotopes of oxygen (e.g. 15 O. 17 O and 18 O), phosphorus isotopes (e.g. 32 P) and sulfur isotopes (e.g. 35S), but are not limited to these.

[0140] The terms "administration" or "administering" and "delivery" refer to a method of providing a dosage of a compound or pharmaceutical composition to a mammal, which method is, for example, localized.

[0141] The term "mammal" is used in its ordinary biological sense, and thus specifically includes humans, cows, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non-human primates, but also many other species.

[0142] The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent" or "pharmaceutically acceptable excipient" includes any biologically or otherwise desirable solvents, cosolvents, complexing agents, dispersion media, coatings, isotonicity agents, and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as a conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition. In addition, various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Brunton et al. (Eds.) (2017); Goodman and Gilman's: The Pharmacological Basis of Therapeutics , 13th Ed., The McGraw-Hill Companies It is described in.

[0143] The term "pharmaceutically acceptable salts" refers to salts that do not lose the biological effectiveness and properties of the compounds provided herein and that are not biologically or otherwise undesirable. In many cases, the compounds provided herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87 / 05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and beryllium; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and ethanolamine. Other acids include dodecylsulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.

[0144] As used herein, a "patient" refers to a human or non-human mammal (e.g., dog, cat, cow, sheep, pig, goat, non-human primate). In some embodiments, the patient is a human.

[0145] The "therapeutically effective amount" of the compound provided herein is an amount sufficient to achieve a desired physiological effect, and may vary depending on the nature and severity of the disease / condition and the potency of the compound. "Therapeutically effective amount" is also intended to include one or more of the compounds represented by formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV in combination with one or more other agents effective for treating the diseases and / or conditions described herein. The combination of compounds may be a synergistic combination. Synergy, as described for example in Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds administered in combination is greater than the additive effect of the compounds administered alone as single agents. In general, synergy is most clearly demonstrated at suboptimal concentrations of the compounds. It is understood that in the prevention of active disease, different concentrations may be used. The amount may also vary depending on the height, weight, sex, age and medical history of the patient.

[0146] A therapeutic effect relieves to some extent one or more of the symptoms of a disease.

[0147] As used herein, "treat" or "treatment" refers to administering a compound or pharmaceutical composition provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to an already afflicted patient to produce a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating an underlying altered cause of symptoms, delaying or preventing further onset of the disorder, and / or reducing the severity of symptoms that will develop or are predicted to develop in the future.

[0148] The term "topical" refers to the application of a suitable compound (e.g., an active agent) or a composition containing a compound (e.g., an active agent) to the skin to treat a disease or condition (e.g., NASH). In some aspects of topical application, the compound or composition penetrates the epidermis or dermis without significant systemic exposure.

[0149] The term "dosing interval" refers to the time between two successive administrations of a pharmaceutical agent in a multiple dose regimen.

[0150] The term "about," when used to refer to a quantitative value, means that the amount identified with this expression may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% more or less than the recited amount.

[0151] compound The compounds and compositions described herein can be used as antifibrotic agents. Additionally, the compounds can be used as inhibitors of stearoyl-CoA desaturase (SCD1). SCD1 is a microsomal enzyme that catalyzes the de novo biosynthesis of monounsaturated fatty acids from the substrate saturated fatty acyl-CoA in mammals.

[0152] The compounds and compositions described herein may also be useful for treating fibrosis due to inflammation caused by fat throughout the body.

[0153] In some embodiments, compounds for use as SCD1 inhibitors include those compounds described in the following articles, US patents, and US patent applications:

[0154] In some embodiments, the SCD1 inhibitor compound is a compound described in U.S. Patent Nos. 8,242,286; 8,524,761 and 8,980,936, which are incorporated by reference herein in their entireties.

[0155] Some embodiments of the present invention relate to a compound of formula I: [ka] or a pharma- ceutically acceptable salt or prodrug thereof.

[0156] In some embodiments of the compound of formula I, X is selected from the group consisting of O, NH, N-alkyl or N-acyl, S, SO, and SO2.

[0157] In some embodiments of the compound represented by formula I, X is O; in some embodiments of the compound represented by formula I, X is NH; in some embodiments of the compound represented by formula I, X is N-alkyl; in some embodiments of the compound represented by formula I, X is N-acyl; in some embodiments of the compound represented by formula I, X is S; in some embodiments of the compound represented by formula I, X is SO; in some embodiments of the compound represented by formula I, X is SO.

[0158] In some embodiments of the compound of formula I, X is selected from the group consisting of NH, N-alkyl, and N-acyl.

[0159] In some embodiments of the compound of Formula I, X is selected from the group consisting of S, SO, and SO2.

[0160] In some embodiments of the compounds of Formula I, W is CR 4 or N; in some embodiments of the compounds of Formula I, W is CR 4 In some embodiments of the compounds of Formula I, W is N.

[0161] In some embodiments of the compounds of Formula I, Z is CR 5 or N; in some embodiments of the compounds of Formula I, Z is CR 5 In some embodiments of the compounds of Formula I, Z is N.

[0162] In some embodiments of the compounds of Formula I, W is CR 4 And Z is CR 5 In some embodiments of the compounds of Formula I, W is CR 4 and Z is N; in some embodiments of the compounds of formula I, W is N and Z is CR 5 in some embodiments of the compounds of Formula I, W is N and Z is N.

[0163] In some embodiments of the compounds of Formula I, each R 1 , R 2 , R 3 , R 4 and R 5 are independently H, OH, F, Cl, Br, I, C1 to C6 straight or branched chain alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, PO2(OCH3)H or its phosphonic acid, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6 R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 is selected from the group consisting of:

[0164] In some embodiments of the compounds of formula I, W is CH and Z is CH; R 1 , R 2 or R 3 is H, OH, F, Cl, Br, I, C1-C6 straight or branched alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, PO2(OCH3)H or its phosphonic acid, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6 R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 is selected from the group consisting of:

[0165] In some embodiments of the compounds of formula I, W is N and Z is CH; R 1 , R 2 or R 3is H, OH, F, Cl, Br, I, C1-C6 straight or branched alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, PO2(OCH3)H or its phosphonic acid, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6 R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 is selected from the group consisting of:

[0166] In some embodiments of the compounds of formula I, W is CH and Z is N; R 1 , R 2 or R 3is H, OH, F, Cl, Br, I, C1-C6 straight or branched alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, PO2(OCH3)H or its phosphonic acid, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6 R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 is selected from the group consisting of:

[0167] In some embodiments of the compounds of formula I, W is N and Z is N; R 1 , R 2 or R 3is H, OH, F, Cl, Br, I, C1-C6 straight or branched alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, PO2(OCH3)H or its phosphonic acid, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6 R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 is selected from the group consisting of:

[0168] In some embodiments of the compounds of Formula I, each R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0169] In some embodiments of the compounds of formula I, W is CH and Z is CH; R 1 , R 2or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of Formula I, W is CH and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is CH and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is CH and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0170] In some embodiments of the compounds of formula I, W is CH and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is CH and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is CH and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0171] In some embodiments of the compounds of formula I, W is N and Z is CH; R 1 , R 2 or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is N and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of Formula I, W is N and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of Formula I, W is N and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0172] In some embodiments of the compounds of formula I, W is N and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is N and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is N and Z is CH; R 2 and R 3 is H;R1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0173] In some embodiments of the compounds of formula I, W is CH and Z is N; R 1 , R 2 or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compound of formula I, W is CH and Z is N; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is CH and Z is N; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is CH and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0174] In some embodiments of the compounds of formula I, W is CH and Z is N; R 1 and R 2 is H;R 3 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is CH and Z is N; R 1 and R 3 is H;R 2is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is CH and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0175] In some embodiments of the compounds of formula I, W is N and Z is N; R 1 , R 2 or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compound of formula I, W is N and Z is N; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is N and Z is N; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, W is N and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0176] In some embodiments of the compounds of formula I, W is N and Z is N; R 1 and R 2 is H;R 3is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is N and Z is N; R 1 and R 3 is H;R 2 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, W is N and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0177] In some embodiments of the compounds of formula I, W is N and Z is CR 5 ;R 1 , R 2 and R 3 is H;R 5 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0178] In some embodiments of the compounds of formula I, W is N and Z is CR 5 ;R 1 , R 2 and R 3 is H;R 5 is selected from the group consisting of CH2F, CHF2, and CF3.

[0179] In some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 1 , R 2 or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 1 and R 2 is H;R 3is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0180] In some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0181] In some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 1 , R 2 or R 3is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0182] In some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 1 and R 2 is H;R 3 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 1 and R 3 is H;R 2 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is CH; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0183] In some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 1 , R 2 or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0184] In some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 1 and R 2 is H;R 3 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 1 and R 3 is H;R 2is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is CH and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0185] In some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 1 , R 2 or R 3 is selected from the group consisting of H, F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 1 and R 2 is H;R 3 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 1 and R 3 is H;R 2 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0186] In some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 1 and R 2 is H;R 3is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 1 and R 3 is H;R 2 is selected from the group consisting of CH2F, CHF2, and CF3; in some embodiments of the compounds of formula I, X is O; W is N and Z is N; R 2 and R 3 is H;R 1 is selected from the group consisting of CH2F, CHF2, and CF3.

[0187] In some embodiments of the compounds of formula I, X is O; W is N and Z is CR 5 ;R 1 , R 2 , and R 3 is H;R 5 is selected from the group consisting of F, Cl, C1-C3 straight or branched chain alkyl, CH2F, CHF2, CF3, O-(C1-3 alkyl), OCH2F, OCHF2, and OCF3.

[0188] In some embodiments of the compounds of formula I, X is O; W is N and Z is CR 5 ;R 1 , R 2 and R 3 is H;R 5 is selected from the group consisting of CH2F, CHF2, and CF3.

[0189] In some embodiments of the compounds of formula I, adjacent substituents R 1 , R 2 , R 3 , R 4 and R 5 may form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring.

[0190] In some embodiments of the compounds of Formula I, each R 6 , R 7 , R 8 , R 9 and R 10is independently selected from the group consisting of H, OH, O-Rx, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl.

[0191] In some embodiments of the compounds of Formula I, Rx is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, or thioester.

[0192] In some embodiments of the compounds of formula I, X is O; W is CR 4 or N; Z is CR 5 or N; each R 1 , R 2 , R 3 , R 4 and R 5 are independently H, OH, F, Cl, Br, I, C1 to C6 straight or branched chain alkyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH2F, CHFCHF2, CHFCF3, CF2CH2F, CF2CHF2, CF2CF3, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCHFCH2F, OCHFCHF2, OCHFCF3, OCF2CH2F, OCF2CHF2, OCF2CF3, O-(CO)-R 6 , O-(CNH)-R 6 , O-(CNR 6 )-R 7 , SO3H or its ester, CO2H or its ester, NO2, NH2, NHCH(O), NR 6 CH(O), NHC(O)R 6 , N.R. 6 C(O)R 7 , C(O)NR 6 R 7 , C(NH)NR 6R 7 , C(NH)NR 6 OH, C(NH)NR 6 NO2 and C(NR 6 )NR 7 C(NR 8 )NR 9 R 10 and the adjacent substituent R 1 , R 2 , R 3 , R 4 and R 5 may form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring; each R 6 , R 7 , R 8 , R 9 and R 10 is independently selected from the group consisting of H, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl.

[0193] Representative compounds of Formula I are shown in Table 1.

[0194] [Table 1-1]

[0195] [Table 1-2]

[0196] [Table 1-3]

[0197] [Table 1-4]

[0198]

Table 1-5

[0199]

Table 1-6

[0200]

Table 1-7

[0201]

Table 1-8

[0202]

Table 1-9

[0203]

Table 1-10

[0204]

Table 1-11

[0205]

Table 1-12

[0206]

Table 1-13

[0207] WO 2006 / 034338, WO 2006 / 034341, WO 2006 / 034440 and WO 2006 / 034441 describe compounds of formulae II, III, IV and V and are hereby incorporated by reference in their entireties.

[0208] Some embodiments of the present invention include a compound represented by formula II: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , G, J, L, M, V, W, x and y are defined in WO 2006 / 034338. or a pharma- ceutically acceptable salt or prodrug thereof.

[0209] Some embodiments of the present invention relate to a compound represented by formula III: [ka] (In the formula, R 2 , R 3 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , G, J, K, L, M, Q, V, W, x and y are defined in WO 2006 / 034341. or a pharma- ceutically acceptable salt or prodrug thereof.

[0210] Some embodiments of the present invention relate to a compound represented by formula IV: [ka] (In the formula, R 2 , R 3 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , G, J, K, L, M, V, x and y are defined in WO 2006 / 034440. or a pharma- ceutically acceptable salt or prodrug thereof.

[0211] Some embodiments of the present invention include a compound represented by formula V: [ka] (In the formula, R 3 , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , J, K, V, W, x and y are defined in WO 2006 / 034441. or a pharma- ceutically acceptable salt or prodrug thereof.

[0212] Representative compounds of formulas II, III, IV and V are shown in Table 2. [Table 2]

[0213] WO 2008 / 024390, WO 2008 / 036715, WO 2008 / 074835, WO 2008 / 127349 and WO 2009 / 103739 describe compounds of formulae VI, VII and VIII and are incorporated herein by reference in their entireties.

[0214] Some embodiments of the present invention relate to a compound represented by formula VI: [ka] (In the formula, R 1 , R 3 , Q, W, X and Y are defined in WO 2008 / 024390 and WO 2008 / 074835. or a pharma- ceutically acceptable salt or prodrug thereof.

[0215] Some embodiments of the present invention include a compound represented by formula VII: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , V, W, X, Y, n and p are defined in WO 2008 / 036715. or a pharma- ceutically acceptable salt or prodrug thereof.

[0216] Some embodiments of the present invention include a compound represented by formula VIII: [ka] (In the formula, R 1 , R 2 , R 3 , Q, V, W, X and Y are defined in WO 2008 / 127349 and WO 2009 / 103739. or a pharma- ceutically acceptable salt or prodrug thereof.

[0217] Representative compounds of formulas VI, VII and VIII are shown in Table 3. [Table 3]

[0218] WO 2009 / 156484, WO 2010 / 112520 and WO 2011 / 039358 and Bioorganic & Medicinal Chemistry (2015), 23(3), 455-465 describe compounds of formulae IX, X and XI, and are incorporated herein by reference in their entireties.

[0219] Some embodiments of the present invention include a compound represented by formula IX: [ka] (In the formula, R 2 , R 2 , P, Q and W are defined in WO 2009 / 156484. or a pharma- ceutically acceptable salt or prodrug thereof.

[0220] Some embodiments of the present invention include a compound represented by formula X: [ka] (In the formula, R 1 , R 2 , R 3 , R 5 , R 6 , Q, W, Z, k, m, n and p are defined in WO 2010 / 112520. or a pharma- ceutically acceptable salt or prodrug thereof.

[0221] Some embodiments of the present invention include compounds of formula XI: [ka] (In the formula, R 1 , R 2 , R 3 , Q, V and W are defined in WO 2011 / 039358. or a pharma- ceutically acceptable salt or prodrug thereof.

[0222] Representative compounds of formulas IX, X and XI are shown in Table 4. [Table 4]

[0223] WO 2006 / 130986 describes a compound represented by formula XII, and is hereby incorporated by reference in its entirety.

[0224] Some embodiments of the present invention include a compound represented by formula XII: [ka] (In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X, Y, Ar and HetAr are defined in WO 2006 / 130986. or a pharma- ceutically acceptable salt or prodrug thereof.

[0225] Some embodiments of the present invention include a compound represented by formula XIII: [ka] (In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X, Y, Ar, W, q and r are defined in WO 2008 / 064474. or a pharma- ceutically acceptable salt or prodrug thereof.

[0226] Representative compounds of formulas XII and XIII are shown in Table 5. [Table 5]

[0227] WO 2007 / 009236, Bioorganic & Medicinal Chemistry Letters (2010), 20, 499-502 and Bioorganic & Medicinal Chemistry Letters (2011), 21, 479-483 describe compounds of formula XIV, and are incorporated herein by reference in their entireties.

[0228] Some embodiments of the present invention include a compound represented by formula XIV: [ka] (In the formula, R a , X, X, Y, Ar and m are defined in WO 2007 / 009236. or a pharma- ceutically acceptable salt or prodrug thereof.

[0229] Representative compounds of formula XIV are shown in Table 6. [Table 6]

[0230] Compound 331 and its analogs are described in Bioorganic & Medicinal Chemistry Letters (2010), 20, 6366-6369, and compound 332 and its analogs are described in Bioorganic & Medicinal Chemistry Letters (2011), 21, 5692-5696, both of which are incorporated by reference in their entireties.

[0231] [Table 7]

[0232] WO 2007 / 143824 describes a compound represented by formula XV, and is hereby incorporated by reference in its entirety.

[0233] Some embodiments of the present invention include a compound represented by formula XV: [ka] (In the formula, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , Y, Ar and HetAr are defined in WO 2007 / 143824. or a pharma- ceutically acceptable salt or prodrug thereof.

[0234] Representative compounds of formula XV are shown in Table 8. [Table 8]

[0235] Compounds 334, 335 and analogs thereof are described in Bioorganic & Medicinal Chemistry Letters (2007), 17(12), 3388-3391, compound 336 and analogs thereof are described in Journal of Medicinal Chemistry (2007), 50(13), 3086-3100, and compound 337 and analogs thereof are described in Bioorganic & Medicinal Chemistry Letters (2008), 18(15), 4298-4302, all of which are incorporated herein by reference in their entireties.

[0236] [Table 9]

[0237] WO 2008 / 135141, WO 2010 / 028761, European Journal of Pharmacology (2013), 707(1-3), 140-146, which are incorporated herein by reference in their entireties, describe compounds of formula XVI.

[0238] Some embodiments of the present invention include a compound represented by formula XVI: [ka] (In the formula, R, R 1 , A, B, D, L, M and n are defined in WO 2008 / 135141 and WO 2010 / 028761. or a pharma- ceutically acceptable salt or prodrug thereof.

[0239] Representative compounds of formula XVI are shown in Table 10. [Table 10]

[0240] WO 2009 / 024287 describes a compound represented by formula XVII, and is hereby incorporated by reference in its entirety.

[0241] Some embodiments of the present invention include a compound represented by formula XVII: [ka] (wherein R, A, B, D, M, W, X and Y are defined in WO 2009 / 024287.) or a pharma- ceutically acceptable salt or prodrug thereof.

[0242] Representative compounds of formula XVII are shown in Table 11. [Table 11]

[0243] WO 2008 / 157844, WO 2009 / 117659, WO 2009 / 117676 and U.S. Patent Application Publication No. 2010 / 0160323 describe compounds of formulas XVIII, XIX, XX and XXI and are incorporated herein by reference in their entireties.

[0244] Some embodiments of the present invention include a compound represented by formula XVIII: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X and Y are defined in WO 2008 / 157844. or a pharma- ceutically acceptable salt or prodrug thereof.

[0245] Some embodiments of the present invention include a compound represented by formula XIX: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X and n are defined in WO 2009 / 117659. or a pharma- ceutically acceptable salt or prodrug thereof.

[0246] Some embodiments of the present invention include a compound represented by formula XX: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5, X, m and n are defined in WO 2009 / 117676. or a pharma- ceutically acceptable salt or prodrug thereof.

[0247] Some embodiments of the present invention include compounds of formula XXI: [ka] (In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, B, Y, and q are defined in U.S. Patent Application Publication No. 2010 / 0160323. or a pharma- ceutically acceptable salt or prodrug thereof.

[0248] Representative compounds of formulas XVIII, XIX, XX and XXI are shown in Table 12. [Table 12]

[0249] WO 2008 / 074832, WO 2008 / 104524, WO 2009 / 010560, WO 2009 / 016216, WO 2009 / 056556, WO 2009 / 060053, WO 2009 / 060054, WO 2009 / 150196 and Clinical Pharmacology in Drug Development (2019), 8(3), 270-280 describe compounds represented by formulas XXII, XXIII, XXIV, XXV, XXVI and XXVII, and are incorporated herein by reference in their entireties.

[0250] Some embodiments of the present invention are represented by formula XXII: [ka] (In the formula, R 1 , R 2 , R3 , R 4 and X are defined in WO 2008 / 074832. or a pharma- ceutically acceptable salt or prodrug thereof.

[0251] Some embodiments of the present invention are of formula XXIII: [ka] (In the formula, R 1 , R 2 , X and Y are defined in WO 2008 / 104524. or a pharma- ceutically acceptable salt or prodrug thereof.

[0252] Some embodiments of the present invention are of formula XXIV: [ka] (In the formula, R 1 , R 2 , R 3 , X and Y are defined in WO 2009 / 016216. or a pharma- ceutically acceptable salt or prodrug thereof.

[0253] Some embodiments of the present invention include a compound represented by formula XXV: [ka] (In the formula, R 1 , W, X and Y are defined in WO 2009 / 056556. or a pharma- ceutically acceptable salt or prodrug thereof.

[0254] Some embodiments of the present invention include compounds of formula XXVI:

[0255] [ka]

[0256] (In the formula, R 1 , R 2 , R 3 and X are defined in WO 2009 / 060053 and WO 2009 / 060054. or a pharma- ceutically acceptable salt or prodrug thereof.

[0257] Some embodiments of the present invention include compounds of formula XXVII: [ka] (wherein Z is defined in WO 2009 / 150196). or a pharma- ceutically acceptable salt or prodrug thereof.

[0258] Representative compounds of formulas XXII, XXIII, XXIV, XV, XXVI and XXVII are shown in Table 13. [Table 13]

[0259] WO 2008 / 044767 and WO 2008 / 096746 describe compounds of formulae XXVIII and XXIX, and are hereby incorporated by reference in their entireties.

[0260] Some embodiments of the present invention include compounds of formula XXVIII: [ka] (wherein R, A, B, C and x are defined in WO 2008 / 044767). or a pharma- ceutically acceptable salt or prodrug thereof.

[0261] Some embodiments of the present invention include compounds of formula XXIX: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , R 13 , R 14 , A, B, m and n are defined in WO 2008 / 096746. or a pharma- ceutically acceptable salt or prodrug thereof.

[0262] Representative compounds of formulas XXVIII and XXIX are shown in Table 14. [Table 14]

[0263] Bioorganic & Medicinal Chemistry Letters (2011), 21(6), 1621-1625 describes compounds 363-365 shown in Table 15, which are incorporated herein by reference in their entirety. [Table 15]

[0264] WO 2008 / 029266, WO 2008 / 062276, WO 2009 / 037542 and WO 2010 / 007482 describe compounds of formulae XXX, XXXI, XXXII and XXXIII and are hereby incorporated by reference in their entireties.

[0265] Some embodiments of the present invention include compounds of formula XXX: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, B, Het and n are defined in WO 2008 / 029266. or a pharma- ceutically acceptable salt or prodrug thereof.

[0266] Some embodiments of the present invention include compounds of formula XXXI: [ka] (wherein A, B', Q and U are defined in WO 2008 / 062276). or a pharma- ceutically acceptable salt or prodrug thereof.

[0267] Some embodiments of the present invention include compounds of formula XXXII: [ka] (In the formula, R, B, Y, a, and b are defined in WO 2009 / 037542.) or a pharma- ceutically acceptable salt or prodrug thereof.

[0268] Some embodiments of the present invention include compounds of formula XXXIII: [ka] (In the formula, R, R 1 , R 2 , R 3 , L and n are defined in WO 2010 / 007482. or a pharma- ceutically acceptable salt or prodrug thereof.

[0269] Representative compounds of formulas XXX, XXXI, XXXII and XXXIII are shown in Table 16. [Table 16]

[0270] WO 2008 / 062276, WO 2008 / 123891 and WO 2010 / 045374 describe compounds of formulae XXXIV, XXXV and XXXVI and are hereby incorporated by reference in their entireties.

[0271] Some embodiments of the present invention are represented by formula XXXIV: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X and Y are defined in WO 2008 / 062276. or a pharma- ceutically acceptable salt or prodrug thereof.

[0272] Some embodiments of the present invention include a compound represented by formula XXXV: [ka] (In the formula, R 1 , R 2 , R 3 and Y are defined in WO 2008 / 123891. or a pharma- ceutically acceptable salt or prodrug thereof.

[0273] Some embodiments of the present invention include compounds of formula XXXVI: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , Q, X and Y are defined in WO 2010 / 045374. or a pharma- ceutically acceptable salt or prodrug thereof.

[0274] Representative compounds of formulas XXXIV, XXXV and XXXVI are shown in Table 17. [Table 17]

[0275] WO 2008 / 120744, WO 2008 / 120759 and WO 2008 / 123469 describe compounds of formulae XXXVII, XXXVIII and XXXIX and are hereby incorporated by reference in their entireties.

[0276] Some embodiments of the present invention include compounds of formula XXXVII: [ka] (In the formula, Sa1, Ua1, Rda1, TYa1, TXa1, Lja1 and (Rta1)nta1 are defined in WO 2008 / 120744.) or a pharma- ceutically acceptable salt or prodrug thereof.

[0277] Some embodiments of the present invention include compounds of formula XXXVIII: [ka] (In the formula, Sa1, Ua1, Rdc1, Rtc 10 , Ljc1, (Rtc1)ntc1 and ntc 10 is defined in WO 2008 / 120759.) or a pharma- ceutically acceptable salt or prodrug thereof.

[0278] Some embodiments of the present invention include compounds of formula XXXIX: [ka] (Wherein, Sb0, Ub0, Rdb0, Ldb0, Ljb0, TXb0 and (Rtb0)ntb ois defined in WO 2008 / 123469.) or a pharma- ceutically acceptable salt or prodrug thereof.

[0279] Representative compounds of formulas XXXVII, XXXVIII and XXXIX are shown in Table 18. [Table 18]

[0280] WO 2010 / 006962, WO 2011 / 015629 and WO 2011 / 131593 describe compounds of formulae XL, XLI and XLII and are hereby incorporated by reference in their entireties.

[0281] Some embodiments of the present invention include a compound of formula XL: [ka] (In the formula, R 1 , R 2 , V, W, X, Y, Z, m and n are defined in WO 2010 / 006962. or a pharma- ceutically acceptable salt or prodrug thereof.

[0282] Some embodiments of the present invention include compounds of formula XLI: [ka] (In the formula, R 1 , R 2 , R 3 , U, V, W, Y, m and n are defined in WO 2011 / 015629. or a pharma- ceutically acceptable salt or prodrug thereof.

[0283] Some embodiments of the present invention include compounds of formula XLII: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, R, T, U, V and W are defined in WO 2011 / 131593. or a pharma- ceutically acceptable salt or prodrug thereof.

[0284] Representative compounds of formulae XL, XLI and XLII are shown in Table 19. [Table 19]

[0285] U.S. Patent Application Publication No. 2017 / 0015654 describes a compound represented by formula XLIII, and is incorporated herein by reference in its entirety.

[0286] Some embodiments of the present invention include compounds of formula XLIII: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , L, m, and n are defined in U.S. Patent Application Publication No. 2017 / 0015654. or a pharma- ceutically acceptable salt or prodrug thereof.

[0287] Representative compounds of formula XLIII are shown in Table 20. [Table 20]

[0288] WO 99 / 52932, WO 2015 / 083164 and WO 2020 / 095293 describe compounds represented by formula XLIV, and are incorporated by reference in their entireties herein.

[0289] Some embodiments of the present invention include a compound represented by formula XLIV: [ka] (wherein W, X and G are defined in WO 99 / 52932). and pharma- ceutically acceptable salts and prodrugs thereof, including meglumine and other salts (e.g., aramchol) of formula XLIV. Such compounds are described in U.S. Patent Nos. 11,197,870, 11,166,964, and 10,849,911, which are incorporated herein by reference in their entireties.

[0290] Representative compounds of formula XLIV are shown in Table 21. [Table 21]

[0291] compound preparation The starting materials used in the preparation of the compounds of the present invention are known, prepared by known methods, or are commercially available. It will be apparent to one skilled in the art that the preparation of precursors and functional groups related to the claimed compounds is generally described in the literature. The skilled artisan, having access to such literature and this specification, is fully capable of preparing the compounds.

[0292] Those skilled in the art of organic chemistry will readily recognize that the procedures for preparing compounds can be performed without specific instruction, i.e., these procedures are well within the scope of practice of the skilled artisan. These include reduction of carbonyl compounds to the corresponding alcohols, oxidation, acylation, aromatic substitution, electrophilic and nucleophilic reactions, etherification, esterification, hydrolysis, etc. These procedures are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7th Ed., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2nd Ed., John Wiley & Sons (1999), which are incorporated herein by reference in their entirety.

[0293] Those skilled in the art will readily understand that certain reactions are best performed when other functional groups in the molecule are masked or protected, thereby avoiding undesired side reactions and / or increasing the yield of the reaction. Often, those skilled in the art will utilize protecting groups to increase the yield or avoid undesired reactions. These reactions are described in the literature and are well within the scope of the art. Many examples of these manipulations are described, for example, in P. Wuts Greene's Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons (2014), which is incorporated herein by reference in its entirety.

[0294] The following exemplary schemes are provided for the reader's guidance and summarize exemplary methods for preparing the compounds provided herein. In addition, other methods for preparing the compounds of the present invention will be readily apparent to those skilled in the art upon reference to the following reaction schemes and examples. Those skilled in the art are fully equipped to prepare these compounds by the methods described in the literature and in this specification. The numbering of the compounds used in the synthetic schemes shown below is intended only for these specific schemes and should not be interpreted as the same numbering or confused with the numbering in other sections of this application. Unless otherwise indicated, all variables are as previously described.

[0295] General Procedure General synthetic schemes for preparing compounds of formula I are shown below in Scheme 1 and Scheme 2.

[0296] [ka]

[0297] In Scheme 1, the Boc-protected pyrrolidine is reacted with mesyl chloride, followed by SN2-type displacement with an anion derived from a suitable aromatic alcohol / phenol in the presence of a suitable base such as cesium carbonate to give the Boc-protected derivative, which can then be readily converted to the corresponding 3-substituted pyrrolidine by hydrolysis with p-toluenesulfonic acid in isopropyl acetate. These transformations can be carried out with racemic, partially optically enriched and optically pure materials.

[0298] [ka]

[0299] Scheme 2 outlines two general synthetic routes to prepare representative compounds. In particular, the synthesis utilizes relatively mild amide bond forming reactions such as those using carbodiimides. The first route is completed by reduction of the side chain aldehyde to an alcohol with sodium borohydride, while the second route utilizes an acid that already bears a methyl alcohol. These transformations can also be performed using racemic, partially optically enriched, and optically pure materials.

[0300] Administration and Pharmaceutical Compositions Some embodiments include a pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound described herein, its corresponding enantiomer, diastereoisomer or tautomer, or a pharma- ceutically acceptable salt; and (b) a pharma- ceutically acceptable carrier.

[0301] In some embodiments of the methods described herein, the SCD1 inhibitor is a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV, and can be administered as a lotion, spray, ointment, cream, gel, paste, and patch. In some embodiments, the SCD1 inhibitor compound described herein is prepared as a pharmaceutical composition suitable for topical or local administration.

[0302] In the methods described herein, the SCD1 inhibitor compound is (S)-2-(4-(hydroxymethyl)phenoxy)-1-(3-(2-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)ethan-1-one (25) and can be administered as a lotion, spray, ointment, cream, gel, paste, and patch. In some embodiments, the SCD1 inhibitor compound 25 is prepared as a pharmaceutical composition suitable for topical administration.

[0303] Topical formulations are ointments, creams, emulsions, pomades, powders, impregnated pads, films, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres, nanospheres, lipid or polymer vesicles or polymer patches and hydrogels that allow for controlled release.

[0304] In some embodiments, the drug substance is a salt of the SCD1 inhibitor compound. In some embodiments, the cation is selected from the group consisting of inorganic ions such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and beryllium. The cation may be a protonated organic amine or amino acid.

[0305] In some embodiments, the drug substance is not a salt of the SCD1 inhibitor compound.In some embodiments, the composition is a stable, water-soluble formulation.

[0306] The compounds can be administered alone or in combination with conventional pharmaceutical carriers, additives, etc. Pharmaceutically acceptable additives include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in formulations such as Tween®, poloxamers, or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Chemically modified derivatives such as cyclodextrins, including α-, β-, and γ-cyclodextrin, hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be used to enhance delivery of the compounds described herein. Actual methods for preparing formulations will be known or apparent to those of skill in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK 2012).

[0307] Liquid pharma- ceutically administrable compositions can be prepared, for example, by dissolving, dispersing, etc., a compound described herein and, optionally, a pharmaceutical adjuvant in a carrier (e.g., water, saline, aqueous dextrose, glycerin, glycol, ethanol, etc.) to form a solution, colloid, liposome, emulsion, complex, coacervate, or suspension. If necessary, the pharmaceutical composition can also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, cosolvents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).

[0308] In some embodiments, the pharma- ceutically acceptable carrier that provides a physically and chemically stable environment includes a combination of one or more antioxidants, one or more chelating agents, and a vehicle that includes water and one or more pharma-ceutically acceptable non-aqueous solvents, one or more absorption enhancers, one or more humectants, one or more gelling agents, and one or more pH buffers. The antioxidant is selected from the group consisting of alpha tocopherol, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, coenzyme Q10 (CoQ10), epigallocatechin 3-gallate (EGCG), fumaric acid, idebenone, lycopene, malic acid, methionine, propyl gallate, silymarin sodium ascorbate, sodium metabisulfate, sodium thiosulfate, and sodium bisulfate.

[0309] In some embodiments, the antioxidant is butylhydroxytoluene (BHT) at a concentration of at least 0.05%. In other embodiments, the concentration of butylhydroxytoluene (BHT) is at least 0.1%.

[0310] In some embodiments, the topical formulation is substantially free of oxygen.

[0311] In some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA) and its sodium, potassium, or calcium salts, sodium pyrophosphate, citric acid, gluconic acid, catechol, and various thiol derivatives.

[0312] In some embodiments, the chelating agent is sodium EDTA at a concentration of at least 0.001%. In other embodiments, the concentration of sodium EDTA is at least 0.005%.

[0313] In some embodiments, the one or more non-aqueous solvents are selected from ethanol, acetone, benzyl alcohol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monoethyl ether, glycerin, propylene glycol, propylene carbonate, acetone, hexylene glycol, isopropyl alcohol, polyethylene glycols (PEGs), methoxypolyethylene glycols, diethyl sebacate, dimethyl isosorbide, propylene carbonate, dimethyl sulfoxide (DMSO), diisopropyl adipate, isopropyl myristate, vegetable oil, mineral oil, and isopropyl palmitate. Preferred non-aqueous solvents are ethanol, phenoxyethanol, diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®), propylene glycol, or PEG400.

[0314] In some embodiments, the one or more solvents or penetration enhancers include fatty alcohols. As used herein, the term "fatty alcohol" refers to a straight or branched chain, saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is a mixture of various fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12-20, 14-20, 12-18, 14-18, or 16-18 carbon atoms. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, or mixtures thereof. In some embodiments, the solvent or penetration enhancer comprises one or more fatty alcohols selected from capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleic alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, and lignoceryl alcohol, hi some embodiments, the one or more solvent or penetration enhancer comprises oleyl alcohol.

[0315] In some embodiments, the fatty alcohol is present at about 0.5% to about 20% by weight of the base formulation. In some embodiments, the fatty alcohol is present at 1% to 20% by weight, 1% to 15% by weight, 1% to 10% by weight, 5% to 20% by weight, 5% to 15% by weight, or 5% to 10% by weight of the base formulation. In some embodiments, the fatty alcohol is present at about 10% by weight of the base formulation. In some embodiments, the oleyl alcohol is present at 0.5% to 20% by weight, 1% to 20% by weight, 1% to 15% by weight, 1% to 10% by weight, 5% to 20% by weight, 5% to 15% by weight, or 5% to 10% by weight of the base formulation. In some embodiments, the oleyl alcohol is present at about 10% by weight of the base formulation.

[0316] In some embodiments, the one or more solvents or penetration enhancers include a fatty acid. In some embodiments, the fatty acid is a mixture of various fatty acids. In some embodiments, the fatty acids have an average of about 8 to about 30 carbon atoms. In some embodiments, the fatty acids have an average of about 12 to 20, 14 to 20, 12 to 18, 14 to 18, or 16 to 18 carbon atoms. Suitable fatty acids include capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, caproic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosyl acid, oleic ... The preferred acidic acids include, but are not limited to, oleic acid, erucic acid, brassidic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, alpha-linolenic acid, gamma-linolenic acid, columbic acid, pinolenic acid, alpha-eleostearic acid, beta-eleostearic acid, mead acid, dihomo-gamma-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, or mixtures thereof. In some embodiments, the fatty acid is selected from capric acid, neodecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, caproic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, erucic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquisooctadecanoic acid, behenic acid, isobehenic acid, arachidonic acid, and combinations thereof. In some embodiments, the one or more solvents or penetration enhancers comprise one or more fatty acids selected from neodecanoic acid, isostearic acid, caproic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, and linolenic acid. In some embodiments, the one or more solvents or penetration enhancers include one or more fatty acids selected from neodecanoic acid, isostearic acid, and oleic acid.In some embodiments, the one or more solvents or penetration enhancers include neodecanoic acid. In some embodiments, the one or more solvents or penetration enhancers include isostearic acid. In some embodiments, the one or more solvents or penetration enhancers include oleic acid. In some embodiments, the one or more solvents or penetration enhancers include linoleic acid. In some embodiments, the one or more solvents or penetration enhancers include linolenic acid.

[0317] In one embodiment, the non-aqueous solvent is selected from 1.0-20.0% w / w ethanol, 0.1-5.0% w / w phenoxyethanol, 5.0-40.0% w / w diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®), 5.0-40.0% w / w propylene glycol, or 5.0-40.0% w / w PEG 400. In another embodiment, the pharmaceutical composition comprises three or more, four or more, or all of 1.0-20.0% w / w ethanol, 0.1-5.0% w / w phenoxyethanol, 5.0-40.0% w / w diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®), 5.0-40.0% w / w propylene glycol, or 5.0-40.0% w / w PEG 400. In yet another embodiment, the ethanol is 5.0-15.0% w / w, the phenoxyethanol is 0.5-2.0% w / w, the diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®) is 20.0-30.0% w / w, the propylene glycol is 15.0-25.0% w / w and / or the PEG 400 is 15.0-25.0% w / w.One or more pharma- ceutically acceptable non-aqueous solvents that also function as topical absorption (penetration) enhancers include ethanol, benzyl alcohol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hexylene glycol, PEG 400, diisopropyl adipate, diethylene glycol monoethyl ether (DEGEE or Transcutol P®), dimethyl sulfoxide (DMSO), decyl methyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, The isomers are selected from 5-methyl-2-pyrrolidone, 1,5-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, propylene glycol, ethanol, isopropanol, oleic acid, laurocapram (azone), limonene, cineole, diethyl-m-toluamide (deet), sodium dodecyl sulfate, dimethyl isosorbide, triethyl citrate, tetrahydrofurfuryl alcohol, glyceryl monolaurate, methyl oleate, propylene glycol monolaurate, and oleyl alcohol.

[0318] In some embodiments, the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG400.

[0319] In some embodiments, the one or more solvents or penetration enhancers do not include DMSO. In some embodiments, the one or more solvents or penetration enhancers include DMSO. In some embodiments, DMSO is present at less than 50% by weight, less than 40% by weight, less than 30% by weight, or 20% by weight of the base formulation. In some embodiments, DMSO is present at 30%-50% by weight, 20%-50% by weight, 10%-50% by weight, 30%-40% by weight, 20%-40% by weight, 10%-40% by weight, 20%-30% by weight, 10%-30% by weight, or 10%-20% by weight of the base formulation. In some embodiments, DMSO is present at 30%-weight, 20%-50% by weight, 30%-40% by weight, 20%-40% by weight, or 20%-30% by weight of the base formulation. In some embodiments, DMSO is present at 20% to 40% or 20% to 30% by weight of the base formulation, hi some embodiments, DMSO is present at about 30% by weight of the base formulation.

[0320] In some embodiments, the topical absorption (penetration) enhancer is selected from diethylene glycol monoethyl ether (DEGEE or Transcutol P®), propylene glycol, and ethanol. In some embodiments, the at least one topical absorption (penetration) enhancer is selected from 5.0-40.0% w / w diethylene glycol monoethyl ether (DEGEE or Transcutol P®), 5.0-40.0% w / w propylene glycol, and 1.0-20.0% w / w ethanol. The one or more humectants are selected from the group consisting of hexylene glycol, glycerin, propylene glycol, sorbitol, lactic acid, sodium lactate, mannitol, butylene glycol, panthenol, hyaluronic acid, urea, chitosan, polyols, methyl gluceth-10, methyl gluceth-20, and polyethylene glycol.

[0321] In some embodiments, the one or more humectants are selected from propylene glycol, polyethylene glycol, and hexylene glycol, hi some embodiments, the one or more humectants are selected from propylene glycol, polyethylene glycol, and hexylene glycol at 5.0-40.0% w / w.

[0322] In some embodiments, water is included at 5-40% v / v along with one or more pH buffers selected from trolamine, sodium hydroxide, or other suitable aqueous bases to solubilize the gelling agent and stabilize the resulting semi-solid formulation. In some embodiments, the trolamine or sodium hydroxide provides an apparent pH of 6.50-7.50.

[0323] Hydrophilic polymeric thickeners (gelling agents) that may be used in the present invention include those known to those skilled in the art, such as hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and pharmaceutical industries. In some embodiments, the one or more hydrophilic and hydrophobic gelling agents are Carbopol® (now known as Carbomer), carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate (Veegum®), methylcellulose, poloxamer (Pluronic® series), polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, or combinations thereof. In some embodiments, the one or more gelling agents include hydroxypropylcellulose. In some embodiments, the molecular weight of the hydroxypropyl cellulose is selected from the group consisting of 40,000 Da, 80,000 Da, 100,000 Da, 140,000 Da, 180,000 Da, 280,000 Da, 370,000 Da, 700,000 Da, 850,000 Da, 1,000,000 Da, 1,150,000 Da, and 2,500,000 Da. In some embodiments, the molecular weight of the hydroxypropyl cellulose is selected from the group consisting of 140,000 Da, 180,000 Da, 280,000 Da, 370,000 Da, 700,000 Da, 850,000 Da, 1,000,000 Da, and 1,150,000 Da. In some embodiments, the molecular weight of the hydroxypropyl cellulose is selected from the group consisting of 700,000 Da, 850,000 Da, 1,000,000 Da, and 1,150,000 Da.

[0324] In some embodiments, the one or more gelling agents are selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, povidone, fatty alcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol, carbomer, carboxymethyl cellulose, xanthan gum, guar gum, chitosan, carrageenan, and alginic acid.

[0325] When one or more gelling agents are present, in some embodiments, the viscosity of the topical formulation is 5,000 to 100,000 cP. When one or more gelling agents are present, in some embodiments, the viscosity of the topical formulation is 5,000 to 50,000 cP. When one or more gelling agents are present, in some embodiments, the viscosity of the topical formulation is 5,000 to 15,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the viscosity of the topical formulation is 5,000 to 100,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the viscosity of the topical formulation is 5,000 to 50,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the viscosity of the topical formulation is 5,000 to 15,000.

[0326] In some embodiments, the one or more gelling agents are present in an amount of about 0.5% to about 30% by weight of the base formulation, and the viscosity of the topical formulation is 5,000 to 100,000 cP. In some embodiments, the one or more gelling agents are present in an amount of about 0.5% to about 30% by weight of the base formulation, and the viscosity of the topical formulation is 5,000 to 50,000 cP. In some embodiments, the one or more gelling agents are present in an amount of about 0.5% to about 30% by weight of the base formulation, and the viscosity of the topical formulation is 5,000 to 15,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of about 0.5% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 20% by weight, or about 20% to about 30% by weight of the base formulation, and the viscosity of the topical formulation is 5,000 to 100,000 cP. When using hydroxypropyl cellulose with an average molecular weight of less than 700,000 Da, in some embodiments, the hydroxypropyl cellulose is present at about 5% to about 30% by weight of the base formulation, and the viscosity of the topical formulation is 5,000 to 100,000 cP. In some embodiments, the hydroxypropyl cellulose is present at 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight of the base formulation, and the viscosity of the topical formulation is 5000 to 15000 cP. In some embodiments, the hydroxypropyl cellulose with an average molecular weight of 700,000 Da or 1,150,000 Da is present at about 2% by weight of the base formulation. In some embodiments, hydroxypropylcellulose having an average molecular weight of 700,000 Da or 1,150,000 Da is present at about 1% by weight of the base formulation.

[0327] In some embodiments, the gelling agent is a carbomer, such as a C980 type carbomer homopolymer, hi some embodiments, the C980 type carbomer homopolymer is 0.5-2.0% w / w.

[0328] In another embodiment, the pharmaceutical composition comprises two or more of: (i) butylhydroxytoluene (BHT) at a concentration of at least 0.05%; (ii) sodium EDTA at a concentration of at least 0.001%; ​​and (iii) trolamine to provide an apparent pH of 6.50 to 7.50.

[0329] In one embodiment, the pharmaceutical composition comprises: (i) butylhydroxytoluene (BHT) in a concentration of at least 0.05%; and (ii) sodium EDTA in a concentration of at least 0.001%.

[0330] In another embodiment, the pharmaceutical composition comprises: (i) butylhydroxytoluene (BHT) at a concentration of at least 0.05%; (ii) sodium EDTA at a concentration of at least 0.001%; ​​and (iii) trolamine to provide an apparent pH of 6.50 to 7.50.

[0331] In some embodiments, the pharmaceutical composition comprises: (i) 1.0-20.0% w / w ethanol; (ii) 0.1-5.0% w / w phenoxyethanol; (iii) 5.0-40.0% w / w diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®); (iv) 5.0-40.0% w / w propylene glycol; (v) 5.0-40.0% w / w PEG 400; and (vi) 0.5-2.0% w / w of a carbomer, such as a C980 type carbomer homopolymer.

[0332] In another embodiment, the pharmaceutical composition comprises: (i) ethanol at 1.0-20.0% w / w; (ii) phenoxyethanol at 0.1-5.0% w / w; (iii) diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®) at 5.0-40.0% w / w; (iv) propylene glycol at 5.0-40.0% w / w; (v) PEG 400 at 5.0-40.0% w / w; (vi) carbomer such as C980 type carbomer homopolymer at 0.5-2.0% w / w; (vii) butylhydroxytoluene (BHT) at a concentration of at least 0.05%; (viii) sodium EDTA at a concentration of at least 0.001%; ​​and (ix) trolamine to provide an apparent pH of 6.50-7.50.

[0333] In another embodiment, the pharmaceutical composition comprises: (i) 5.0-15.0% w / w ethanol; (ii) 0.5-2.0% w / w phenoxyethanol; (iii) 20.0-30.0% w / w diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®); (iv) 15.0-25.0% w / w propylene glycol; (v) 15.0-25.0% w / w PEG 400; and (vi) 0.75-1.5% w / w of a carbomer such as a C980 type carbomer homopolymer.

[0334] In another embodiment, the pharmaceutical composition comprises: (i) ethanol at 5.0-15.0% w / w; (ii) phenoxyethanol at 0.5-2.0% w / w; (iii) diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®) at 20.0-30.0% w / w; (iv) propylene glycol at 15.0-25.0% w / w; (v) PEG 400 at 15.0-25.0% w / w; (vi) carbomer such as C980 type carbomer homopolymer at 0.75-1.5% w / w; (vii) butylhydroxytoluene (BHT) at a concentration of at least 0.1%; (viii) sodium EDTA at a concentration of at least 0.005%; and (ix) trolamine to provide an apparent pH of 6.50-7.50.

[0335] In another embodiment, the pharmaceutical composition comprises: (i) ethanol at a concentration of 10.0% w / w; (ii) phenoxyethanol at a concentration of 1% w / w; (iii) diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®) at a concentration of 25.0% w / w; (iv) propylene glycol at a concentration of 20.0% w / w; (v) PEG400 at a concentration of 21.0% w / w; (vi) C980 type carbomer homopolymer at a concentration of 1.0% w / w; and (vii) water at a concentration of 19.5-22% w / w.

[0336] In yet another particular embodiment, the pharmaceutical composition comprises: (i) ethanol at a concentration of 10.0% w / w; (ii) phenoxyethanol at a concentration of 1% w / w; (iii) diethylene glycol monoethyl ether (also known as DEGEE or Transcutol P®) at a concentration of 25.0% w / w; (iv) propylene glycol at a concentration of 20.0% w / w; (v) PEG 400 at a concentration of 21.0% w / w; (vi) C980 carbomer homopolymer at a concentration of 1.0% w / w; (vii) butylated hydroxytoluene (BHT) at a concentration of 0.1%; (viii) sodium EDTA at a concentration of 0.005%; (ix) trolamine at a concentration of 0.375% w / w; and (x) water at a concentration of 19.02-21.52% w / w.

[0337] In yet another particular embodiment, the pharmaceutical composition of either of the above two embodiments comprises a concentration of (S)-2-(4-(hydroxymethyl)phenoxy)-1-(3-(2-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)ethan-1-one (25) of up to 2.50% w / w, in particular 0.25%, 0.75% or 1.75%. In yet another embodiment, the pharma- ceutically acceptable carrier is a cream or lotion that provides a physically and chemically stable environment, and includes a combination of one or more antioxidants, one or more chelating agents, and a vehicle base comprising water and one or more pharma- ceutically acceptable non-aqueous solvents, one or more oils, one or more structural lipids, one or more absorption enhancers, one or more aqueous surfactants, one or more emollients, one or more wetting agents, one or more gelling agents, and one or more pH buffers.

[0338] In another embodiment, the oil is selected from hydrogenated castor oil, liquid paraffin, white soft paraffin, corn oil, cottonseed oil, ethyl oleate, petrolatum, sesame oil, peanut oil, soybean oil, safflower oil, olive oil, almond oil, coconut oil, walnut oil, and avocado oil.

[0339] In another embodiment, the oil blend is at least 2% liquid paraffin and at least 1% white soft paraffin.

[0340] In other embodiments, the one or more antioxidants are selected from the group consisting of alpha tocopherol, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), fumaric acid, malic acid, methionine, propyl gallate, sodium ascorbate, sodium metabisulfate, sodium thiosulfate, and sodium hydrogen sulfate.

[0341] In another embodiment, the antioxidant is butylhydroxytoluene (BHT) at a concentration of at least 0.05%.In another embodiment, the one or more structured lipids are selected from stearic acid, stearyl alcohol, cetostearyl alcohol, cetrimide, cetyl alcohol, cetyl esters wax, lanolin, lanolin alcohol, emulsifying wax, microcrystalline wax, white wax, yellow wax, and hydrogenated castor oil.

[0342] In another embodiment, the structured lipid is 1% or more cetostearyl alcohol.

[0343] In another embodiment, the one or more oil and aqueous surfactants are selected from medium chain triglycerides, Tween® 60, Tween® 80, Span® 60, Brij® 721, Brij® 72, Aracel 165, polyoxyethylene castor oil derivatives, cetomacrogol 1000, polyoxyethylene stearate. A preferred combination of surfactants is 1% or more Brij® 721 and 2% or more Brij® 72.

[0344] In another embodiment, the one or more emollients are selected from diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetearyl octanoate, isopropyl isostearate, myristyl lactate, octyldodecanol, oleyl alcohol, mineral oil, petrolatum, vegetable oil (e.g., peanut oil, soybean oil, safflower oil, olive oil, almond oil, coconut oil), PPG-15 stearyl ether, PPG-26 oleate, PEG-4 dilaurate, lecithin, lanolin, lanolin alcohol, polyoxyl 75 lanolin, cholesterol, cetyl esters wax, cetostearyl alcohol, glyceryl monostearate, medium chain triglycerides, dimethicone, and cyclomethicone.

[0345] In another embodiment, the combination of emollients is 1% or more cetostearyl alcohol and 6% or more Clodamol® GTCC medium chain triglycerides.

[0346] In another embodiment, the one or more pharma- ceutically acceptable non-aqueous solvents that also act as absorption enhancers include propylene glycol, 2-(2-ethoxyethoxy)ethanol, hexylene glycol, PEG 400, diisopropyl adipate, diethylene glycol monoethyl ether (DEGEE or Transcutol P®), dimethyl sulfoxide (DMSO), decyl methyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, propylene glycol, ethanol, isopropanol, oleic acid, laurocapram ( Azone), limonene, cineole, diethyl-m-toluamide (DEET), sodium dodecyl sulfate, dimethyl isosorbide, triethyl citrate, tetrahydrofurfuryl alcohol, glyceryl monolaurate, methyl oleate, propylene glycol monolaurate and oleyl alcohol, alcohol (ethanol), acetone, benzyl alcohol, phenoxyethanol, diethylene glycol monoethyl ether (Transcutol P), glycerin, hexylene glycol, propylene glycol, isopropyl alcohol, polyethylene glycols (PEGs), methoxypolyethylene glycol, diethyl sebacate, dimethyl isosorbide, propylene carbonate and dimethyl sulfoxide. A preferred combination of non-aqueous solvents is 8% or more ethanol, 20% or more PEG400, 1% or more phenoxyethanol, 12% or more diethylene glycol monoethyl ether (Transcutol P) and 8% or more glycerin. In other embodiments, the one or more pH buffering agents are selected from sodium citrate, monobasic sodium phosphate, sodium acetate, sodium lactate, sodium tartrate, and sodium fumarate, with a pH of about 5.5 to 6. A preferred buffer system is 0.01 M sodium citrate adjusted to pH 5.5.

[0347] In another embodiment, the one or more humectants are selected from glycerin, hexylene glycol, propylene glycol, sorbitol, lactic acid, sodium lactate, mannitol, butylene glycol, panthenol, hyaluronic acid, urea, chitosan, polyols, methyl gluceth-10, methyl gluceth-20, and polyethylene glycols (PEGs).

[0348] In another embodiment, the humectant is 8% or more glycerin and 20% or more PEG400.

[0349] In another embodiment, the one or more gelling agents are selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, povidone, fatty alcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol, carbomer, carboxymethyl cellulose, xanthan gum, guar gum, chitosan, carrageenan, and alginic acid.

[0350] In another embodiment, the gelling agent is a carbomer, such as 0.25% or more of a C980-type carbomer homopolymer. In another embodiment, the concentration of the compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, and XLIV is about 0.005% to about 5% by weight. In one embodiment, the concentration of the compound in the pharmaceutical composition is about 0.01% to about 2.5% w / w, and in another particular embodiment, the concentration of the pharmaceutical composition is 0.25%, 0.75%, or 1.75% w / w. In yet another embodiment, the compound is a racemic mixture, a diastereomeric mixture, a single enantiomer, an enantiomeric diastereomer, a meso compound, a pure epimer, or a mixture of epimers.

[0351] For pharmaceutical use, the SCD1 inhibitor compounds provided herein can be administered as crystalline or amorphous substances, which may be salts, complexes or co-crystals. Another desirable feature of the liquid medium is that it is sterile. Aqueous liquids are subject to significant risk of microbial contamination and growth unless measures are taken to ensure sterility. To provide a substantially sterile liquid, an effective amount of an acceptable antimicrobial agent or preservative can be incorporated, or the liquid can be sterilized and sealed with an airtight seal before being provided. In some embodiments, the liquid is provided as a preservative-free sterile liquid using a suitable airtight container.

[0352] In some embodiments, the compositions may be in the form of patches, hi some embodiments, each patch comprises a single dose for administration to a subject.

[0353] It should be noted that concentrations and dosages may also vary depending on the type of compound and the condition. It should be further understood that a particular patient's specific dosage regimen must be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges given in this specification are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0354] Kits are also provided herein. Typically, the kits include one or more compounds or compositions described herein. In some embodiments, the kits can include one or more delivery systems, e.g., for delivering or administering a compound provided herein, and instructions for using the kit (e.g., instructions for treating a patient). In other embodiments, the kits can include a compound or composition described herein, and labeling indicating that the contents are to be administered to a patient.

[0355] The present compositions containing an SCD1 inhibitor compound may be applied directly or indirectly to various areas of mammalian skin in any convenient or desired manner, such as as a lotion, spray, ointment, cream, gel, paste or patch.

[0356] These compositions may be used in a range of applications, including but not limited to, pinpoint (or smaller) areas to areas of one or several centimeters. 2 , in(inch) 2 or ft (feet) 2 (or larger).

[0357] In some embodiments, topical treatment of the SCD1 inhibitor compound is administered to 1% or less of the total surface area (BSA) of the skin, in some embodiments, topical treatment is administered to about 2% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 3% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 4% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 5% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 6% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 7% of the total BSA of the skin, and in some embodiments, topical treatment is administered to about 8% of the total BSA of the skin. In some embodiments, topical treatment is administered to about 8% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 9% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 10% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 15% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 20% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 25% of the total BSA of the skin, in some embodiments, topical treatment is administered to about 30% of the total BSA of the skin, and in some embodiments, topical treatment is administered to about 35% of the total BSA of the skin.

[0358] In some embodiments, topical treatment with the SCD1 inhibitor compound is administered on a continuous dosing schedule of once daily, twice daily, three times daily, every other day, every third day, once weekly, once every two weeks, once monthly, or once every two months.

[0359] In some embodiments, topical treatment with the SCD1 inhibitor compound is for 1 week; in some embodiments, 2 weeks; in some embodiments, 3 weeks; in some embodiments, 4 weeks; in some embodiments, 5 weeks; in some embodiments, 6 weeks; in some embodiments, 7 weeks; in some embodiments, 8 weeks; in some embodiments, 9 weeks; in some embodiments, 10 weeks; in some embodiments, 11 weeks; in some embodiments, 12 weeks; in some embodiments, 13 weeks; in some embodiments, 14 weeks; in some embodiments, 15 weeks; in some embodiments, 16 weeks; in some embodiments, 17 weeks; in some embodiments, 18 weeks; in some embodiments, for 19 weeks; in some embodiments, for 20 weeks; in some embodiments, for 21 weeks; in some embodiments, for 22 weeks; in some embodiments, for 23 weeks; in some embodiments, for 24 weeks; in some embodiments, for 25 weeks; in some embodiments, for 26 weeks; in some embodiments, for 1 month; in some embodiments, for 2 months; in some embodiments, for 3 months; in some embodiments, for 4 months; in some embodiments, for 5 months; in some embodiments, for 6 months; in some embodiments, for 7 months; in some embodiments, for 8 months; in some embodiments, for 9 months; in some embodiments, for 10 months; in some embodiments, for 11 months, and in some embodiments, for 12 months.

[0360] In some embodiments, the administration of the SCD1 inhibitor compound is applied to the same site or to several different sites of an individual. When applied to different sites, the dosage at each site may be the same or may be adjusted based on factors such as skin thickness and drug penetration differences (if any). In some embodiments, the formulation may be applied to any skin surface, including, for example, the skin of the abdomen, hands, neck, chest, back, arms or legs.

[0361] Treatment Method The compounds and compositions described herein can be used as anti-fibrotic agents. In another aspect, the present invention provides a method for reducing fibrosis in cells or tissues. Furthermore, the compounds can be used as inhibitors of SCD1.

[0362] These methods can be performed in vitro or in vivo. In some embodiments, the methods are performed in vivo, e.g., on a mammal (e.g., an animal model). In some embodiments, the subject is a human. In some embodiments, reducing fibrosis includes (a) reducing or inhibiting the formation or deposition of tissue fibrosis, (b) reducing the size, cellularity (e.g., number of fibroblasts or immune cells), composition, or cellular content of a fibrotic area, (c) reducing collagen or hydroxyproline content in a fibrotic area, (d) reducing the expression or activity of one or more fibrogenic proteins, and / or (e) reducing fibrosis due to an inflammatory response. In some aspects, reducing fibrosis includes (a) reducing or inhibiting the formation or deposition of tissue fibrosis; (b) reducing the size, cellular density (e.g., number of fibroblasts or immune cells), composition or cellular content of fibrotic areas; (c) reducing collagen or hydroxyproline content in fibrotic areas; (d) reducing the expression or activity of one or more fibrogenic proteins; and / or (e) reducing inflammatory fibrosis.

[0363] In some embodiments, the present invention provides a method for reducing loss of liver function or improving liver function, which in some embodiments results in (a) preventing or slowing the formation or deposition of tissue fibrosis in the corresponding organ; (b) reducing the size, cellularity (e.g., number of fibroblasts or immune cells), composition or cellular content of fibrotic areas in the corresponding organ; (c) reducing collagen or hydroxyproline content or degree of cross-linking in fibrotic lesions in the corresponding organ; (d) reducing the expression or activity of one or more fibrogenic proteins (e.g., fibrinogen and collagen) in the corresponding organ; (e) reducing the expression of extracellular matrix and / or EMT in the corresponding organ; (e) reducing fibrosis due to inflammatory response in the corresponding organ; and / or (f) reducing hepatic stellate cells in the liver.

[0364] The present invention also provides a method for treating and / or ameliorating liver fibrosis. In some embodiments, the method comprises administering an effective amount of an SCD1 inhibitor or a pharmaceutical composition comprising an SCD1 inhibitor to a subject with liver fibrosis or at risk of developing liver fibrosis. Further provided is the use of an SCD1 inhibitor provided herein in the manufacture of a medicament for treating or ameliorating liver fibrosis. Liver fibrosis that can be treated using an SCD1 inhibitor provided herein includes one or more of the group consisting of fatty liver (e.g., nonalcoholic steatohepatitis (NASH)), fatty liver disease, cholestatic liver disease (e.g., primary biliary cholangitis (PBC)), cirrhosis, alcoholic liver fibrosis, infection-induced liver fibrosis, bile duct injury, bile duct fibrosis, congenital liver fibrosis, autoimmune hepatitis, and cholangiopathy. In another embodiment, the infection-induced liver fibrosis is bacterial or viral induced.

[0365] In yet another embodiment, the liver fibrosis that can be treated with the SCD1 inhibitors provided herein is one or more of the group consisting of liver fibrosis due to viral infection (e.g., hepatitis (Hepatitis C, B, and D) viruses and COVID19), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, alcoholism, and exposure to toxins or irritants (e.g., alcohol, pharmaceuticals, and environmental toxins).

[0366] According to some embodiments, the present invention provides a method for reducing the loss of liver function in a subject.In some embodiments, the method comprises locally administering SCD1 inhibitor to a subject in need.In some embodiments, the method reduces the loss of liver function in a subject.In another embodiment, the method reduces the progression of liver fibrosis, thereby reducing the loss of liver function in a subject.

[0367] In some aspects, the present invention provides methods of treating, preventing, or slowing the progression of fibrosis due to NASH.

[0368] In addition to fibrosis due to NASH, SCD1 inhibitor compounds may be useful in treating fibrosis due to inflammation, which may or may not be caused by accumulation of liver fat and / or whole body fat.

[0369] Some aspects provided herein relate to methods of preventing fatty liver, which develops in patients following liver transplantation and ultimately impacts the efficacy of the transplant (World Journal of Gastroenterology (2018), 24(14), 1491-1506).

[0370] Fibrosis impedes normal liver metabolic function, impedes portal blood flow, and increases intrahepatic vascular resistance (IHVR) (Scientific Reports (2016), 6, 33453), so patients with NASH cirrhosis are at significant risk for complications of portal hypertension (Gastroenterology (2020), 158(5),1334-1345)).

[0371] Some embodiments provided herein relate to methods of preventing or treating portal hypertension and its complications (eg, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy).

[0372] In some embodiments, the present invention relates to an SCD1 inhibitor for use in the prevention and / or treatment of NASH, said use preventing and / or slowing the increase in relative liver weight, plasma alanine aminotransferase level, liver triglyceride content and / or liver cholesterol. Relative liver weight is defined as the ratio of liver weight to body weight. In some embodiments, said use reducing relative liver weight, plasma alanine aminotransferase level, liver triglyceride content and / or liver cholesterol.

[0373] In some aspects, the invention relates to an SCD1 inhibitor for use in the prevention and / or treatment of NASH, said use preventing, delaying and / or reducing histopathological signs of fatty liver.

[0374] In some aspects, the invention relates to an SCD1 inhibitor for use in the prevention and / or treatment of NASH, said use preventing, delaying and / or reducing hepatic inflammation.

[0375] In some aspects, the invention relates to an SCD1 inhibitor for use in the prevention and / or treatment of NASH, said use preventing or slowing the progression of fibrosis.

[0376] In some embodiments, the present invention relates to an SCD1 inhibitor for use in preventing and / or treating NASH, wherein the SCD1 inhibitor is administered in a therapeutically effective amount to a subject in need thereof. In some embodiments, the subject is obese and / or diabetic. In some embodiments, the subject suffers from obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and / or type 1 diabetes.

[0377] BMI (Body Mass Index) is a measure of body fat based on height and weight. The formula is: BMI=(Weight (kg)) / (Height (m)) 2 In some embodiments, the invention relates to the use of an SCD1 inhibitor in the prevention and / or treatment of NASH, wherein the compound is administered in a therapeutically effective amount to a subject in need thereof, and the subject has a BMI of at least 25 kg / m 2 In some embodiments, the subject's BMI is at least 30 kg / m 2 In some embodiments, the subject's BMI is 30 to 50 kg / m 2 It is.

[0378] Characterization of liver fibrosis Liver fibrosis consists of a variety of pathologies and may be characterized by invasive and non-invasive or minimally invasive tests (Cells (2020), 9(4), 1005) (Wong, V. WS; Chan, H. LY. (2013), Non-invasive methods to determine the severity of NAFLD and NASH. In GC Farrell, AJ McCullough, and CP Day (Ed.) Non-Alcoholic Fatty Liver Disease: A Practical Guide (First Edition, pp. 112-131). Chichester, West Sussex, UK: John Wiley & Sons, Ltd). Liver biopsy is the current gold standard for diagnosis and prognosis. Characterization may be performed by liver needle biopsy, liver ultrasound, transient ultrasound elastography, magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), and / or one of a variety of scoring systems including Child-Turcotte-Pugh score (Journal of Hepatology (2006), 44(1), 217-231), Scheuer, Batts-Ludwig (The American Journal of Surgical Pathology (1995), 19(12), 1409-1417), Knodell, Ishak, METAVIR, International Association for Study of the Liver, FibroSure, HepaScore, Forns Index, FIB4, Fibrolndex, aspartate aminotransferase to platelet count index, and / or other tests. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, the 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin.Biochemical markers of liver fibrosis include alpha-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A and gamma glutamyl transpeptidase (Journal of Hepatology (2007), 47(4), 598-607).

[0379] Multiparametric magnetic resonance imaging (MRI), as a non-invasive tool to assess and monitor liver disease, has recently been shown to accurately distinguish patients with fatty liver from those with fibrosis, regardless of etiology (Journal of Hepatology (2014), 60(1), P69-77). New methods can diagnose liver fibrosis, steatosis and hemosiderosis with high accuracy and may replace liver biopsy in many indications. A new magnetic resonance (MR) protocol (LiverMultiScan (Perspectum Ltd, UK)) quantifies iron-corrected T1 (cT1)20 by removing the effect of elevated iron on liver T1. Liver cT1 has been shown to correlate with features of fibroinflammatory disease and is a promising risk stratification tool in NASH. Proton density fat fraction (PDFF) distinguishes the percentage of MR-visible protons attributable to fat from all MR-visible protons (attributed to both fat and water) and correlates very well with histologically graded hepatic steatosis (Scientific Reports (2020), 10, 15308). Pairing MRI-PDFF and liver histology data showed that a 29% relative reduction in liver fat in MRI-PDFF correlates with histological response in NASH (Therapeutic Advances in Gastroenterology (2016), 9(5), 692-701). Furthermore, MRI-PDFF has been validated against liver histology and shown to be highly sensitive in detecting changes in liver fat content and treatment response in clinical trials (Cells (2020), 9(4), 1005).

[0380] Magnetic resonance elastography (MRE) is a non-invasive medical imaging technique that measures soft tissue stiffness by generating shear waves in tissue, imaging their propagation using MRI, and processing the images to generate stiffness maps. MRE is the most accurate method of liver stiffness measurement (LSM) in non-alcoholic fatty liver disease (NAFLD). Liver stiffness is associated with disease severity, including fibrosis, inflammation, and ballooning (European radiology (2019), 29(11), 5823-5831). MRE was significantly correlated with fibrosis stage. Imaging biomarkers from multiparametric liver MRI / MRE can provide accurate non-invasive prediction of NAFLD activity scores.

[0381] The total NAS score is the sum of the scores for fatty liver, lobular inflammation, cytological ballooning, and fibrosis (stage) and ranges from 0 to 8. The semiquantitative scoring system was validated by the NIH-sponsored Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). In the reference studies, NAS scores of 0 to 2 occurred mostly in cases considered not diagnostic of NASH, and scores of 3 to 4 were evenly divided between cases considered not diagnostic, borderline, or positive for NASH. Scores of 5 to 8 occurred mostly in cases considered diagnostic of NASH (Hepatology (2005), 41(6), 1313-1321). The FDA accepts a NASH Activity Score (NAS) of 4 or more with at least 1 point each in inflammation and ballooning, along with a NASH Clinical Research Network (CRN) fibrosis score greater than stage 1 fibrosis but less than stage 4 fibrosis, as important inclusion criteria in NASH clinical trials.

[0382] In some embodiments, the SCD1 inhibitor compound is administered for 1 week; in some embodiments, 2 weeks; in some embodiments, 3 weeks; in some embodiments, 4 weeks; in some embodiments, 5 weeks; in some embodiments, 6 weeks; in some embodiments, 7 weeks; in some embodiments, 8 weeks; in some embodiments, 9 weeks; in some embodiments, 10 weeks; in some embodiments, 11 weeks; in some embodiments, 12 weeks; in some embodiments, 13 weeks; in some embodiments, 14 weeks; in some embodiments, 15 weeks; in some embodiments, 16 weeks; in some embodiments, 17 weeks; in some embodiments, 18 weeks; in some embodiments, 19 weeks; in some embodiments, 20 weeks; in some embodiments, 21 weeks; in some embodiments, 22 weeks; in some embodiments, 23 weeks; in some embodiments, in some embodiments, there is no significant change in histological score for 24 weeks; in some embodiments, 25 weeks; in some embodiments, 26 weeks; in some embodiments, 40 weeks; in some embodiments, 52 weeks; in some embodiments, 65 weeks; in some embodiments, 72 weeks; in some embodiments, 96 weeks; in some embodiments, 1 month; in some embodiments, 2 months; in some embodiments, 3 months; in some embodiments, 4 months; in some embodiments, 5 months; in some embodiments, 6 months; in some embodiments, 7 months; in some embodiments, 8 months; in some embodiments, 9 months; in some embodiments, 10 months; in some embodiments, 11 months; in some embodiments, 12 months; in some embodiments, 1 year; in some embodiments, 2 years; in some embodiments, 3 years; in some embodiments, 4 years.

[0383] In some embodiments, the SCD1 inhibitor compound is administered for 1 week; in some embodiments, 2 weeks; in some embodiments, 3 weeks; in some embodiments, 4 weeks; in some embodiments, 5 weeks; in some embodiments, 6 weeks; in some embodiments, 7 weeks; in some embodiments, 8 weeks; in some embodiments, 9 weeks; in some embodiments, 10 weeks; in some embodiments, 11 weeks; in some embodiments, 12 weeks; in some embodiments, 13 weeks; in some embodiments, 14 weeks; in some embodiments, 15 weeks; in some embodiments, 16 weeks; in some embodiments, 17 weeks; in some embodiments, 18 weeks; in some embodiments, 19 weeks; in some embodiments, 20 weeks; in some embodiments, 21 weeks; in some embodiments, 22 weeks; in some embodiments, 23 weeks; In some embodiments, the histological score is reduced for 24 weeks; in some embodiments, 25 weeks; in some embodiments, 26 weeks; in some embodiments, 40 weeks; in some embodiments, 52 weeks; in some embodiments, 65 weeks; in some embodiments, 72 weeks; in some embodiments, 96 weeks; in some embodiments, 1 month; in some embodiments, 2 months; in some embodiments, 3 months; in some embodiments, 4 months; in some embodiments, 5 months; in some embodiments, 6 months; in some embodiments, 7 months; in some embodiments, 8 months; in some embodiments, 9 months; in some embodiments, 10 months; in some embodiments, 11 months; in some embodiments, 12 months; in some embodiments, 1 year; in some embodiments, 2 years; in some embodiments, 3 years; in some embodiments, 4 years.

[0384] The FDA currently recommends considering the following liver histological improvements as endpoints that are reasonably likely to predict clinical benefit: Resolution of steatohepatitis on gross histopathology and no worsening of liver fibrosis on NASH CRN fibrosis score. Resolution of steatohepatitis is defined as absence of steatohepatitis or isolated or simple steatosis without steatohepatitis, with NAS scores of 0-1 for inflammation, 0 for ballooning, and any value for steatosis. Improvement of ≥1 stage of liver fibrosis (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis). Both resolution of steatohepatitis and improvement of fibrosis.

[0385] Current FDA-approved surrogate markers are histologic in nature. Treatment must be demonstrated to improve fibrosis by at least one stage without worsening NASH or cure NASH without worsening liver fibrosis in a substantial proportion of patients. Cure from NASH is defined as any stage of hepatic steatosis, absence of ballooning, and minimal (stage 1) lobular inflammation.

[0386] Other potential non-invasive surrogate endpoints may include circulating biomarkers and / or imaging techniques for liver fat, inflammation, and fibrosis. These have been shown to correlate with histological improvement on a set of biopsies and may one day replace biopsies as endpoints in clinical trials. SCD1 inhibitors that improve histological NASH are likely to improve these novel surrogate endpoints as well.

[0387] Assessment of biological activity Various SCD1 assay methods have been described in the art (Journal of Medicinal Chemistry (2014), 57(12), 5039-5056; Bioorganic & Medicinal Chemistry Letters (2009), 19(15), 4159-4166 and US Patent Application Publication No. 2011 / 0184027).

[0388] The ability of compounds to inhibit isolated SCD1 enzyme activity can be assessed in rat and human microsomes as described in Oncotarget (2018), 9, 3-20. Varying concentrations of compounds are added to liver microsomes and the substrate for SCD1 is cytotoxic. 13 C-labeled stearoyl-CoA for 5 min. The activity of SCD1 was then determined by LC / MS / MS. 13 From C-Stearoyl CoA 13 The ability of a compound to inhibit SCD1 activity is determined by its conversion to C-oleoyl CoA. 50 It is expressed as:

[0389] In order to further illustrate the present invention, examples are described below. These examples should not be interpreted as specifically limiting the present invention, of course. Variations of these examples that fall within the scope of the claims are within the knowledge of a person skilled in the art and are considered to be within the scope of the disclosure described and claimed in this specification. The reader of this specification will recognize that even without the exhaustive examples, a person skilled in the art can carry out the present invention. EXAMPLES

[0390] Example 1 Compound 25 was evaluated for inhibition of SCD1 activity in rat and human liver microsomes as described below.

[0391] Compound 25 is dissolved in DMSO to prepare a 10 mM stock solution.

[0392] Solutions of rat liver microsomes (RLM, BioIVT) and human liver microsomes (HLM, InVitroCYP® H-class, pooled from 25 donors BioIVT) are prepared by adding microsomes to 100 mM sodium phosphate, pH 7.4, at a protein concentration of 1.00 mg / mL.

[0393] Compound 25 stock solution is then added to the RLM and HLM solutions at an initial concentration of 0.2 μM for direct inhibition. Each LM / inhibitor solution is added to a blank LM solution to prepare 8 concentrations by 3-fold serial dilution. These diluted LM / inhibitor solutions are then added to a reaction buffer containing 2 mM NADH, 120 μM coenzyme A, 2 mM ATP, 2 mM DTT and 10 mM MgCl2 in 100 mM sodium phosphate (pH 7.4).

[0394] Stearoyl- 13 C 18 Prepare a 10% solution of stearoyl-CoA in methanol to a final concentration of 3.00 mM. 13 C 18 The reaction is started by adding 200 μL of -CoA to the reaction mixture and incubated at 37° C. for 5 minutes. The oleoyl- 13 C 18 The analysis of -CoA is carried out by liquid chromatography coupled with tandem mass spectrometry (LC / MS / MS).

[0395] Concentration-dependent inhibition of rat and human SCD1 activity by compound 25 and IC values ​​determined for inhibition of rat and human SCD1 50 This is shown in Figure 1.

[0396] Example 2 SCD1 inhibitor compounds can be tested in vivo in a diet-induced rodent model of biopsy-confirmed NASH. In this experiment, the NASH phenotype is induced by feeding mice on a GAN diet for 33 weeks before drug administration (BMC Gastroenterology (2020), 20(1), 210;World Journal of Gastroenterology (2019), 25(33), 4904-4920). Biopsies are taken before drug treatment to exclude mice that do not develop the NASH phenotype and to compare pre- and post-treatment liver biopsies in clinical trials. Metabolism, including body weight, body composition, food intake, and clinical chemistry, are measured during and after the 12-week dosing period, in addition to histological analysis before and after treatment.

[0397] Either a placebo gel or a gel containing compound 25 (at concentrations of 0.05%, 0.25%, 0.75% or 2.5%) was applied topically to 10% of the total BSA of the mouse skin (World Journal of Gastroenterology (2018), 24(2), 179-194).

[0398] [Table 22]

[0399] Animals and diet: The Danish Animal Experimentation Authority approved all experiments, performed according to internationally accepted principles for the use of laboratory animals, under personal license #2013-15-2934-00784. B6.V-Lepob / JRj(ob / ob) mice (6 weeks old) were obtained from Janvier Labs (Le Genest Saint Isle, France) and housed in a controlled environment (12-h light / dark cycle, lights on at 3 am, 21 ± 2 °C, humidity 50 ± 10%). Each animal was identified by a subcutaneously implanted microchip (PetID Microchip, E-vet, Haderslev, Denmark). Mice were given free access to tap water and Gubra Amylin NASH diet [GAN diet; 40 kcal-% fat (with 0% trans fat, 46% saturated fatty acids (by weight)), 22% fructose, 10% sucrose, 2% cholesterol; D09100310, Laboratory Diet]. To induce NASH, mice were fed the GAN diet for 33 weeks prior to the start of the study and continued to be fed the GAN diet for 12 weeks during drug treatment. During the study, mice were weighed daily and body composition was measured by noninvasive EchoMRI scans using an EchoMRI-900 (EchoMRI, Houston, TX).

[0400] Liver biopsy: After 33 weeks of GAN diet feeding, mice were anesthetized with isoflurane (2%-3% in 100% oxygen) and a small incision was made in the midline of the abdomen to expose the left lobe of the liver. A cone of liver tissue (50-100 mg) was excised from the distal lobe. The cut surface was bipolar coagulated using an electrosurgical unit (ERBE VIO® 100C, ERBE, Marietta, GA, USA). The liver was replaced in the abdominal cavity, the abdominal wall was sutured, and the skin was stapled. Carprofen (5 mg / kg, intraperitoneal) was administered at the time of surgery and on postoperative days 1 and 2.

[0401] Histology and digital image analysis: Biopsy and distal liver samples (both from the left lobe) were fixed overnight in 4% paraformaldehyde. Liver tissues were paraffin embedded and sectioned (3 μm thick). Sections were stained with hematoxylin-eosin (HE, Dako, Glostrup, Denmark), picrosirius red (Sigma-Aldrich, Broendby, Denmark), anti-galectin 3 (cat. 125402, Biolegend, San Diego, CA, USA), anti-type I collagen (Col1a1; cat. 1310-01, Southern Biotech, Birmingham, AL, USA) or anti-αSMA (AbCam, cat. no. ab124964) using previously established procedures (World Journal of Hepatology (2016), 8(16), 673-684). The NAS (Figure 3) and fibrosis staging system (Figure 5) were applied before liver biopsy and scored as outlined by Kleiner et al. (Hepatology (2005), 41(6), 1313-1321). Quantitative histomorphometric results were analyzed using digital imaging software (VIS Software, Visiopharm, Hoersholm, Denmark). All histological evaluations were performed by a histologist blinded to the experimental groups.

[0402] Plasma biochemical analysis: Blood is collected in heparinized tubes and plasma is separated and stored at -80°C until analysis. Alanine aminotransferase and aspartate aminotransferase (Figure 12) were measured using commercially available kits (Roche Diagnostics) according to the manufacturer's instructions on a Cobas c 501 autoanalyser.

[0403] Final liver triglyceride content: The animals were sacrificed and small liver pieces (approximately 100 mg) were collected in FastPrep tubes and flash frozen in liquid nitrogen. 1 ml of 5% NH-40 / ddH2O solution was added to the tubes and the samples were homogenized. After homogenization, the samples were slowly heated to 80°C-100°C for 3 min and then returned to room temperature before heating for a second time. The samples were then centrifuged for 2 min to remove insoluble material. Triglyceride content in liver homogenates was measured using a commercial kit (Roche Diagnostics, Germany) on an autoanalyzer Cobas C-111 according to the manufacturer's instructions.

[0404] Statistical analysis: Comparison of data and significant differences for multiple tests are shown on graphs when p<0.05. For continuous data at a single time point, data are fitted to a one-factor linear regression model with treatment group as the categorical independent (predictor) variable, and treatment groups are compared to control groups using Dunnett's test. For continuous data with repeated samples taken over time, data are fitted to a two-factor linear regression model with treatment group and treatment time point as categorical independent (predictor) variables with their interaction. Treatments at each time point were compared to controls using Dunnett's test. Data from categorical endpoints, such as histopathological scoring values, were partitioned into 2x2 contingency tables with responders and non-responders in control and treatment groups, and statistical analyses were performed using Fisher's test or chi-square. 2 Either test was applied.

[0405] result: In a diet-induced mouse model of biopsy-confirmed NASH, topical administration of compound 25 to as little as 10% of the skin's BSA improved multiple features of NASH. A body of evidence suggests that compound 25 can prevent and slow the progression of fibrosis. Compound 25 improved the global NAFLD activity score or NAS (Figure 3) and, quite unexpectedly, prevented the worsening of fibrosis stage (Figure 5). Multiple quantitative markers of collagen (collagen 1a1 immunohistochemistry; PSR histochemical staining and collagen 1a1, collagen 3a1 and collagen 4a1 mRNA expression; Figures 6, 7 and 11, respectively) were shown to be decreased by compound 25. At least in part, this decrease may be due to reduced astrocyte activation as indicated by reduced αSMA expression (Figure 8). These changes were evident even at doses of compound 25 that had no or minimal effect on either total body weight or body fat, strongly suggesting that the effect on fibrosis is not simply a secondary consequence of fat loss. Compound 25 also improved fatty liver, which is known to promote the progression of fibrosis, and reduced inflammation. This is consistent with the significant reduction in serum ALT and AST after local administration. In addition, compound 25 favorably regulated some of the candidate genes whose expression may predict poor outcomes such as cirrhosis and cancer. Taken together, these findings suggest that compound 25 exerts therapeutic effects to prevent, reduce the incidence, delay the onset, reduce the severity, or treat liver fibrosis in subjects.

Claims

1. A pharmaceutical composition for use in a method of treating a patient with non-alcoholic steatohepatitis (NASH) but who is not experiencing fibrosis to inhibit fibrosis, said composition comprising an SCD1 inhibitor compound, said method comprising topically applying to the skin of said patient an amount of said SCD1 inhibitor compound effective to inhibit fibrosis in said patient.

2. 2. The pharmaceutical composition of claim 1, wherein the patient with NASH but no fibrosis is characterized by a NASH CRN fibrosis score of 0 and the inhibition of fibrosis is characterized by the patient's NASH CRN fibrosis score not increasing.

3. A pharmaceutical composition for use in a method of treating a patient with NASH and mild fibrosis to prevent or reduce the rate of fibrosis progression, said composition comprising an SCD1 inhibitor compound, said method comprising topically applying to the skin of said patient an amount of said SCD1 inhibitor compound effective to prevent or reduce the rate of fibrosis progression in said patient.

4. The pharmaceutical composition according to claim 3, wherein the patient with mild fibrosis due to NASH is characterized by a NASH CRN fibrosis score of 1 to 2, and the inhibition of fibrosis progression in the patient is characterized by a lack of increase in the NASH CRN fibrosis score in the patient, or the reduction in the rate of fibrosis progression in the patient is characterized by a slowing down of the rate of increase in the NASH CRN fibrosis score in the patient.

5. A pharmaceutical composition for use in a method of treating a patient with NASH having higher levels of fibrosis to reduce the degree of fibrosis, said composition comprising an SCD1 inhibitor compound, said method comprising topically applying to the skin of said patient an amount of said SCD1 inhibitor compound effective to reduce the degree of fibrosis in said patient.

6. 6. The pharmaceutical composition of claim 5, wherein the NASH patient with higher fibrosis is characterized by a NASH CRN fibrosis score of 3-4, and the degree of fibrosis is characterized by a decrease in the NASH CRN fibrosis score in the patient.

7. The method of claim 4, wherein the patient has a NASH CRN fibrosis score of 1.

8. The method of claim 4, wherein the patient has a NASH CRN fibrosis score of 2.

9. The pharmaceutical composition of claim 6, wherein the patient has a NASH CRN fibrosis score of 3.

10. The pharmaceutical composition of claim 6, wherein the patient has a NASH CRN fibrosis score of 4.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the method further comprises treating the patient with an anti-NASH compound in an amount effective to prevent progression of or resolve NASH.

12. The pharmaceutical composition of claim 2 or 4, wherein no increase in the NASH CRN fibrosis score is observed or a slowdown in the rate of increase is observed 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years after the start of administration of the SCD1 inhibitor compound.

13. The pharmaceutical composition of claim 6, wherein a reduction in the NASH CRN fibrosis score is observed 2 weeks, 4 weeks, 8 weeks, 24 weeks, 40 weeks, 52 weeks, 65 weeks, 72 weeks, or 96 weeks, or 2 years, 3 years, or 4 years after initiation of administration of the SCD1 inhibitor compound.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method improves the patient's liver (as determined by histology).

15. The pharmaceutical composition of any one of claims 1 to 13, wherein the method does not cause liver deterioration in the patient (as determined by histology).

16. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method prevents, reduces the incidence, delays the onset of, or reduces the severity of a condition associated with increased hepatic triglyceride levels in the patient.

17. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method prevents, reduces the incidence, delays the onset of, or reduces the severity of a condition associated with an alteration in the ratio of lipid-containing to non-lipid-containing liver cells in the patient.

18. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method prevents, reduces the incidence of, delays the onset of, or reduces the severity of a condition associated with an altered level of hepatitis in the patient.

19. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method prevents, reduces the incidence of, delays the onset of, or reduces the severity of a condition associated with fibrillar collagen and matrix-forming collagen in the patient.

20. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method prevents, reduces the incidence, delays the onset of, or reduces the severity of a condition associated with hepatic stellate cell activation in the patient.

21. The method of any one of claims 1 to 13, wherein the method prevents, reduces the incidence, delays the onset, or reduces the severity of hepatocyte ballooning in the patient.

22. The method of any one of claims 1 to 13, wherein the method prevents, reduces the incidence, delays the onset, or reduces the severity of fatty liver in the patient.

23. 23. The pharmaceutical composition of any one of claims 1 to 22, wherein the SCD1 inhibitor compound is applied topically to at least 30% of the patient's body surface area (BSA), 20% of the patient's BSA, 10% of the patient's BSA, 5% of the patient's BSA, 2% of the patient's BSA, or 1% of the patient's BSA.

24. The pharmaceutical composition of any one of claims 1 to 22, wherein the SCD1 inhibitor compound is applied topically to 1-2% of the patient's BSA.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein the SCD1 inhibitor compound is topically applied to the skin of the patient once daily, twice daily, every other day, once weekly or once every two weeks.

26. The SCD1 inhibitor compound has formula I; 【Chemistry 1】 (In the formula, X is O, NH, N-alkyl or N-acyl, S, SO and SO ２ selected from the group consisting of: W is an independent CR ４ or N; Z is independently CR ５ or N; Each R １ , R ２ , R ３ , R ４ and R ５ are independently H, OH, F, Cl, Br, I, C １ ~C ６ Straight or branched chain alkyl, CH ２ F, C.H.F. ２ , C.F. ３ , C.H. ２ CH ２ F, C.H. ２ CHF ２ , C.H. ２ CF ３ , C.H.F.C.H. ２ F, CHFCHF ２ , CHFCF ３ , C.F. ２ CH ２ F, C.F. ２ CHF ２ , C.F. ２ CF ３ , O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, OCH ２ F, O.C.H.F. ２ , O.C.F. ３ , O.C.H. ２ CH ２ F, O.C.H. ２ CHF ２ , O.C.H. ２ CF ３ , O.C.F.C.H. ２ F, OCHFCHF ２ , OCHFCF ３ , O.C.F. ２ CH ２ F, O.C.F. ２ CHF ２ , O.C.F. ２ CF ３ , O-(CO)-R ６ , O-(CNH)-R ６ , O-(CNR ６ )-R ７ , S.O. ３ H or its ester, CO ２ H or its ester, PO ２ (O.C.H. ３ ) H or its phosphonic acid, NO ２ , N.H. ２ ,NHCH(O),NR ６ CH(O), NHC(O)R ６ , N.R. ６ C(O)R ７ , C(O)NR ６ R ７ , C(NH)NR ６ R ７ , C(NH)NR ６ OH,C(NH)NR ６ NO ２ and C(NR ６ ) N.R. ７ C (NR ８ ) N.R. ９ R １０ selected from the group consisting of: Here, adjacent substituents R １ , R ２ , R ３ , R ４ and R ５ may form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring; Each R ６ , R ７ , R ８ , R ９ and R １０ is independently selected from the group consisting of H, OH, O-Rx, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl; Rx is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, or thioester. The pharmaceutical composition of any one of claims 1 to 25, wherein the compound is a compound represented by the structure:

27. The SCD1 inhibition according to formula I is 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 【Chemistry 2-12】 【Chemistry 2-13】 or a pharma- ceutically acceptable salt thereof.

28. The SCD1 inhibition according to formula I is 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

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