2-((1-OXO-2,3-dihydro-1h-inden-5-YL)OXY)acetic acid derivatives and related uses

Abstract

The present disclosure relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The present disclosure also relates to pharmaceutical compositions of the compounds, and methods of preparing and using the compounds.

Description

Cooley Ref. CLBO-002 / 01WO 349489-2004 2-((1-OXO-2,3-DIHYDRO-1H-INDEN-5-YL)OXY)ACETIC ACID DERIVATIVES AND RELATED USES CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 636,543, filed on April 19, 2024, which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Chloride ion channels control a variety of cellular processes that are central to normal function and disease states. The chloride ion channel protein (Clic) family consists of seven members, each with a conserved C-terminal Clic domain. Clic proteins possess both an integral membrane form, which forms an ion channel, and a soluble form.

[0003] Chloride dysregulation has been linked with disrupted inhibition of NPY / AgRP neuronal activity, which is activated by signals associated with hunger and inhibited by signals associated with satiety. In diet-induced obesity, expression and membrane localization of Clic1 is increased in NPY / AgRP neurons. Obesity is a major risk factor for health problems including cardiovascular disease and diabetes. Genetic ablation of Clic1, or inhibition with the Clic1 inhibitor IAA94, reduces food intake and body weight.

[0004] Clic1 has also been implicated in several types of cancer, inflammation, and neurodegeneration. There is a need for new compositions to treat Clic1-related indications including obesity. Compositions with a reduced diuretic effect may be of particular therapeutic value. SUMMARY

[0005] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: X is O or S; n is 1 or 2;Cooley Ref. CLBO-002 / 01WO 349489-2004 R1is C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen; R4is H or halogen; R6is H, halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), or - NH(C=O)-(C1-C6 alkyl); T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; Q is -OH, -C(=O)-Y, or 5- to 10-membered heteroaryl; Y is -OR5, -N(R5)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano; and each R5independently is H, halogen, cyano, -S(=O)2OH, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0006] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

[0007] In some aspects, the present disclosure provides a method of inhibiting chloride intracellular channel 1 (Clic1), comprising contacting a cell with an effective amount of a compound or pharmaceutical composition of the present disclosure.

[0008] In some aspects, the present disclosure provides a method of inhibiting one or more functions of chloride intracellular channel 1 (Clic1) and / or chloride intracellular channel 4 (Clic4), comprising contacting a cell with an effective amount of a compound or pharmaceutical composition of the present disclosure. In some embodiments, the one or more functions of Clic1 and / or Clic4 comprises translocation of Clic1 and / or Clic4 from the cytosol to the plasma membrane of the cell. In some embodiments, the method inhibits one or more functions of Clic1 but does not substantially inhibit one or more functions of Clic4.

[0009] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0010] In some aspects, the present disclosure provides a method of reducing body weight in a subject, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0011] In some aspects, the present disclosure provides a method of reducing food intake in a subject, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0012] In some aspects, the present disclosure provides a compound of the present disclosure for use in inhibiting chloride intracellular channel 1 (Clic1) and / or chloride intracellular channel 4 (Clic4).

[0013] In some aspects, the present disclosure provides a compound of the present disclosure for use in treating or preventing a disease or disorder disclosed herein.

[0014] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for inhibiting chloride intracellular channel 1 (Clic1) and / or chloride intracellular channel 4 (Clic4).

[0015] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0016] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0018] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 shows the effect of Compounds 31a 1a, 33a, and 33b on food intake, as compared to R-indacrinone and to vehicle only, in C57Bl / 6J mice during the 8 hours post- administration of the compound or vehicle.

[0020] FIGS.2A-2B show the effect of Compounds 31a, 1a, 33a, and 33b on diuretic activity measured by flow rate in ml / min during the 24 hours post-administration of the compound or vehicle (FIG. 2A) and measured by sodium (NA) excretion in mmol during the first 8 hours post-administration of the compound or vehicle (FIG. 2B), as compared to R-indacrinone (“(R)-Inda”) and to vehicle only, in Sprague-Dawley rats.

[0021] FIGS.3A-3B show the effect of Compounds 31a, 1a, 33a, and 33b on diuretic activity measured by urine output in grams (g) (FIG.3A) and measured by sodium (NA) excretion in mmol (FIG.3B), as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats at 2 hours post-administration of the compound or vehicle.

[0022] FIGS.4A-4B show the effect of Compounds 31a, 1a, 33a, and 33b on diuretic activity measured by urine output in grams (g) (FIG.4A) and measured by sodium (NA) excretion in mmol (FIG.4B), as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats at 24 hours post-administration of the compound or vehicle.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0023] FIG.5 shows the effect of Compound 33a on diuretic activity measured by flow rate in ml / min, as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats during the 24 hours post-administration of the compound or vehicle.

[0024] FIGS.6A-6B show the effect of Compound 33a on diuretic activity measured by urine output in grams (g) (FIG.6A) and measured by sodium (NA) excretion in mmol (FIG.6B), as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats at 2 hours post- administration of the compound or vehicle.

[0025] FIG.7 shows the effect of Compound 33b on diuretic activity measured by flow rate in ml / min, as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats during the 24 hours post-administration of the compound or vehicle.

[0026] FIGS.8A-8B show the effect of Compound 33b on diuretic activity measured by urine output in grams (g) (FIG.8A) and measured by sodium (NA) excretion in mmol (FIG.8B), compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats at 2 hours post- administration of the compound or vehicle.

[0027] FIGS.9A-9B show the effect of Compound 1a on diuretic activity measured by flow rate in ml / min, as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats during the 24 hours post-administration of the compound or vehicle (FIG.9A), and in Sprague- Dawley rats at 2 hours post-administration of the compound or vehicle (FIG.9B).

[0028] FIGS.10A-10B show the effect of Compound 1a on diuretic activity measured by urine output in grams (g) (FIG.10A) and measured by sodium (NA) excretion in mmol (FIG.10B), as compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats at 2 hours post- administration of the compound or vehicle.

[0029] FIGS.11A-11B show the effect of Compounds 31a, 1a, 33a, and 33b on serum ALT measured by U / L (FIG. 11A) and on serum sodium (Na) measured in mmol / L (FIG. 11B), compared to R-indacrinone and to vehicle only, in Sprague-Dawley rats at 24 hours post- administration of the compound or vehicle.

[0030] FIGS.12A-E show the plasma concentration of Compounds 31a (FIG.12A), 1a (FIG. 12B), 33a (FIG. 12C), and 33b (FIG. 12D), compared to R-indacrinone (FIG. 12E), in Sprague-Dawley rats during the 24 hours post-administration of the compound or vehicle.

[0031] FIGS. 13A-13C shows the effect of Compound 23a on food intake (FIGS. 13A and 13C) and body weight (FIGS. 13A and 13B) in C57Bl / 6J mice during administration of Compound 23a at different doses and dosing regimens.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0032] FIGS.14A-14B show the effect of Compound 1a on body weight (FIG.14A) and food intake (FIGS.14B) in C57Bl / 6J mice during administration of Compound 1a at different doses and dosing regimens.

[0033] FIGS.15A-15B provide data showing body weight (FIG.15A) and food intake (FIG. 15B) in C57Bl / 6J mice during administration of Compounds 23a, 24a, or 25a, compared to vehicle.

[0034] FIGS.16A-16B provide data showing body weight (FIG.16A) and food intake (FIG. 16B) in C57Bl / 6J mice during administration of Compound 26a or Compound 26b, compared to vehicle. DETAILED DESCRIPTION

[0035] Without wishing to be bound by theory, it is understood that compounds of the present disclosure inhibit chloride intracellular channel 1 (Clic1).

[0036] The chloride ion channel protein (Clic) family consists of seven members including Clic1, each with a conserved C-terminal Clic domain. Clic proteins possess both an integral membrane form, which forms an ion channel, and a soluble form. In diet-induced obesity, Clic1 expression and membrane localization are increased in NPY / AgRP neurons. NPY / AgRP neurons are activated by signals associated with hunger and inhibited by signals associated with satiety. However, in diet-induced obesity, NPY / AgRP neurons in the hypothalamic arcuate nucleus – which is critical for regulation of food intake and energy balance – show reduced responsiveness to these signals. Restoring the responsiveness of AgRP / NPY neurons to hunger and satiety cues, potentially by re-polarization of membrane potential, is a potential therapeutic target.

[0037] Obesity is a significant public health issue and is associated with an elevated risk of heart failure and diabetes. Genetic ablation of Clic1, or inhibition with the Clic1 inhibitor IAA94, reduces food intake and body weight. Clic1 has also been implicated in several types of cancer, inflammation, and neurodegeneration.

[0038] Compounds disclosed herein may reduce food intake in a subject and / or may lead to weight loss, reduced body weight, reduced adiposity, and / or increased lean body mass. Compounds disclosed herein may may reduce obesity-related heart failure. Compounds disclosed herein may reduce inflammation and / or neurodegeneration. Compounds disclosed herein may reduce cancer cell proliferation, tumor growth, and / or metastasis. Compounds disclosed herein may reduce liver inflammation, non-alcoholic fatty liver disease activity score (NAS), steatosis hepatocyte ballooning, and / or lobular inflammation. Compounds disclosedCooley Ref. CLBO-002 / 01WO 349489-2004 herein may inhibit translocation of CLIC1 and / or CLIC4 from the cytosol to the plasma membrane. Compounds disclosed herein may cause minimal diuresis or may not cause diuresis. Compounds of the Present Disclosure

[0039] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: X is O or S; n is 1 or 2; R1is C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen; R4is H or halogen; R6is H, halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), or - NH(C=O)-(C1-C6 alkyl); T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-Cooley Ref. CLBO-002 / 01WO 349489-2004 C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; Q is -OH, -C(=O)-Y, or 5- to 10-membered heteroaryl; Y is -OR5, -N(R5)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano; and each R5independently is H, halogen, cyano, -S(=O)2OH, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano.

[0040] In some aspects, the present disclosure provides a compound of Formula (I’’):or a pharmaceutically acceptable salt thereof, wherein: X is O or S; n is 1 or 2; R1is C6-C10aryl, C3-C10cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen; R4is H or halogen;Cooley Ref. CLBO-002 / 01WO 349489-2004 T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; Y is -OR5, -N(R5)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano; and each R5independently is H, halogen, cyano, -S(=O)2OH, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano.

[0041] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen; R4is H or halogen;Cooley Ref. CLBO-002 / 01WO 349489-2004 T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; and R5is H or C1-C6 alkyl.

[0042] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is halogen; R4is halogen; T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-Cooley Ref. CLBO-002 / 01WO 349489-2004 C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; and R5is H or C1-C6 alkyl.

[0043] It is understood that, for a compound of Formula (I’), (I’’), or (I), variables X, n, R1, R1S, R1Sa, R2, R3, R4, R6, T, Ra, Q, Y, and R5can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables X, n, R1, R1S, R1Sa, R2, R3, R4, R6, T, Ra, Q, Y, and R5can be combined, where applicable, with any group described herein for one or more of the remainder of variables X, n, R1, R1S, R1Sa, R2, R3, R4, R6, T, Ra, Q, Y, and R5. Variables X, and n

[0044] In some embodiments, X is O.

[0045] In some embodiments, X is S.

[0046] In some embodiments, n is 1.

[0047] In some embodiments, n is 2. Variables R1, R1S, and R1Sa

[0048] In some embodiments, R1is C6-C10 aryl or 5- to 10-membered heteroaryl.

[0049] In some embodiments, R1is C6-C10 aryl optionally substituted with one or more R1S.

[0050] In some embodiments, R1is C6 aryl optionally substituted with one or more R1S.

[0051] In some embodiments, R1is phenyl optionally substituted with one or more R1S.

[0052] In some embodiments, R1is C6-C10 aryl.

[0053] In some embodiments, R1is C6 aryl.

[0054] In some embodiments, R1is phenyl.

[0055] In some embodiments, R1is C3-C10 cycloalkyl optionally substituted with one or more R1S.

[0056] In some embodiments, R1is C3-C10cycloalkyl.

[0057] In some embodiments, R1is 5- to 10-membered heteroaryl optionally substituted with one or more R1S.

[0058] In some embodiments, R1is 5- to 10-membered heteroaryl.

[0059] In some embodiments, R16-membered heteroaryl.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0060] In some embodiments, R1is .

[0061] In some embodiments, R1is.

[0062] In some embodiments, one or more R1Sis halogen, cyano, -OH, -NH2, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.

[0063] In some embodiments, one or more R1Sis halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, -O(C1-C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -O- (C=O)-(C1-C6 alkyl), -NH-(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)- (C1-C6 alkyl), -NH-(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa.

[0064] In some embodiments, at least one R1Sis halogen. In some embodiments, at least one R1Sis F. In some embodiments, at least one R1Sis Cl. In some embodiments, at least one R1Sis Br. In some embodiments, at least one R1Sis I.

[0065] In some embodiments, at least one R1Sis cyano.

[0066] In some embodiments, at least one R1Sis -OH.

[0067] In some embodiments, at least one R1Sis -NH2.

[0068] In some embodiments, at least one R1Sis -SO2NH2.

[0069] In some embodiments, at least one R1Sis C1-C6 alkyl.

[0070] In some embodiments, at least one R1Sis C2-C6 alkenyl.

[0071] In some embodiments, at least one R1Sis C2-C6 alkynyl.

[0072] In some embodiments, at least one R1Sis -O(C1-C6 alkyl).

[0073] In some embodiments, at least one R1Sis -NH(C1-C6 alkyl).

[0074] In some embodiments, at least one R1Sis -N(C1-C6 alkyl)2.

[0075] In some embodiments, at least one R1Sis -O-(C=O)-(C1-C6alkyl).

[0076] In some embodiments, at least one R1Sis -O-(C=O)-CH3.

[0077] In some embodiments, at least one R1Sis -NH-(C=O)-(C1-C6 alkyl).

[0078] In some embodiments, at least one R1Sis -NH-(C=O)-CH3.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0079] In some embodiments, at least one R1Sis C3-C12 cycloalkyl.

[0080] In some embodiments, at least one R1Sis 3- to 12-membered heterocycloalkyl.

[0081] In some embodiments, at least one R1Sis C6-C10 aryl.

[0082] In some embodiments, at least one R1Sis 5- to 10-membered heteroaryl.

[0083] In some embodiments, at least one R1Sis C1-C6 alkyl, optionally substituted with one or more R1Sa.

[0084] In some embodiments, at least one R1Sis C1-C6 alkyl. In some embodiments, at least one R1Sis C1 alkyl. In some embodiments, at least one R1Sis C2 alkyl. In some embodiments, at least one R1Sis C3 alkyl. In some embodiments, at least one R1Sis C4 alkyl. In some embodiments, at least one R1Sis C5 alkyl. In some embodiments, at least one R1Sis C6 alkyl.

[0085] In some embodiments, at least one R1Sis C1-C6 alkyl, optionally substituted with one or more R1Sa. In some embodiments, at least one R1Sis C1 alkyl, optionally substituted with one or more R1Sa. In some embodiments, at least one R1Sis C2 alkyl, optionally substituted with one or more R1Sa. In some embodiments, at least one R1Sis C3 alkyl, optionally substituted with one or more R1Sa. In some embodiments, at least one R1Sis C4 alkyl, optionally substituted with one or more R1Sa. In some embodiments, at least one R1Sis C5 alkyl, optionally substituted with one or more R1Sa. In some embodiments, at least one R1Sis C6 alkyl, optionally substituted with one or more R1Sa.

[0086] In some embodiments, at least one R1Sis C2-C6 alkenyl, optionally substituted with one or more R1Sa.

[0087] In some embodiments, at least one R1Sis C2-C6 alkynyl, optionally substituted with one or more R1Sa.

[0088] In some embodiments, at least one R1Sis -O(C1-C6 alkyl), optionally substituted with one or more R1Sa.

[0089] In some embodiments, at least one R1Sis -NH(C1-C6 alkyl), optionally substituted with one or more R1Sa.

[0090] In some embodiments, at least one R1Sis -N(C1-C6 alkyl)2, optionally substituted with one or more R1Sa.

[0091] In some embodiments, at least one R1Sis C3-C12 cycloalkyl, optionally substituted with one or more R1Sa.

[0092] In some embodiments, at least one R1Sis 3- to 12-membered heterocycloalkyl, optionally substituted with one or more R1Sa.

[0093] In some embodiments, at least one R1Sis C6-C10 aryl, optionally substituted with one or more R1Sa.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0094] In some embodiments, at least one R1Sis 5- to 10-membered heteroaryl, optionally substituted with one or more R1Sa.

[0095] In some embodiments, at least one R1Sis 5- to 10-membered heteroaryl.

[0096] In some embodiments, at least one R1Sis diazolyl.

[0097] In some embodiments, at least one R1Sis.

[0098] In some embodiments, at least one R1Sais halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0099] In some embodiments, at least one R1Sais halogen. In some embodiments, at least one R1Sais F. In some embodiments, at least one R1Sais Cl. In some embodiments, at least one R1Sais Br. In some embodiments, at least one R1Sais I.

[0100] In some embodiments, at least one R1Sais cyano.

[0101] In some embodiments, at least one R1Sais -OH.

[0102] In some embodiments, at least one R1Sais -OH, -O(C1-C6 alkyl).

[0103] In some embodiments, at least one R1Sais -NH2.

[0104] In some embodiments, at least one R1Sais NH(C1-C6 alkyl).

[0105] In some embodiments, at least one R1Sais -N(C1-C6 alkyl)2. Variables R2, R3, and R4

[0106] In some embodiments, R2is C1-C6 alkyl.

[0107] In some embodiments, R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0108] In some embodiments, R2is methyl.

[0109] In some embodiments, R2is ethyl.

[0110] In some embodiments, R2is propyl (e.g., n-propyl).

[0111] In some embodiments, R2is butyl.

[0112] In some embodiments, R2is pentyl.

[0113] In some embodiments, R2is hexyl.

[0114] In some embodiments, R2is methyl, optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0115] In some embodiments, R2is ethyl, optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0116] In some embodiments, R2is propyl (e.g., n-propyl), optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0117] In some embodiments, R2is butyl, optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0118] In some embodiments, R2is pentyl, optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0119] In some embodiments, R2is hexyl, optionally substituted with one or more halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0120] In some embodiments, R2is -CH3.

[0121] In some embodiments, R2is -CH2CH3.

[0122] In some embodiments, R2is -CH2CH2OH.

[0123] In some embodiments, R2is -CH2CH2CH2CH3.

[0124] In some embodiments, R2is -CH2CH2CH3.

[0125] In some embodiments, R2is -CH2CH2CH(CH3)2.

[0126] In some embodiments, R3is H.

[0127] In some embodiments, R3is halogen.

[0128] In some embodiments, R3is F, Cl, or Br.

[0129] In some embodiments, R3is Cl.

[0130] In some embodiments, R4is H.

[0131] In some embodiments, R4is halogen.

[0132] In some embodiments, R4is F, Cl, or Br.

[0133] In some embodiments, R4is Cl.

[0134] In some embodiments, at least one of R3and R4is halogen.

[0135] In some embodiments, both of R3and R4are halogen.

[0136] In some embodiments, R3is Cl, and R4is Cl. Variable R6

[0137] In some embodiments, R6is H.

[0138] In some embodiments, R6is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, -O(C1-C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -O-(C=O)-(C1- C6 alkyl), or -NH(C=O)-(C1-C6 alkyl).

[0139] In some embodiments, R6is halogen.

[0140] In some embodiments, R6is F. In some embodiments, R6is Cl. In some embodiments, R6is Br.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0141] In some embodiments, R6is cyano.

[0142] In some embodiments, R6is -OH.

[0143] In some embodiments, R6is -NH2.

[0144] In some embodiments, R6is -SO2NH2.

[0145] In some embodiments, R6is C1-C6 alkyl.

[0146] In some embodiments, R6is C2-C6 alkenyl.

[0147] In some embodiments, R6is C2-C6 alkynyl.

[0148] In some embodiments, R6is -O(C1-C6 alkyl).

[0149] In some embodiments, R6is -NH(C1-C6 alkyl).

[0150] In some embodiments, R6is -N(C1-C6 alkyl)2.

[0151] In some embodiments, R6is -O-(C=O)-(C1-C6 alkyl).

[0152] In some embodiments, R6is -NH(C=O)-(C1-C6 alkyl). Variables T and Ra

[0153] In some embodiments, T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *- C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *- C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-.

[0154] In some embodiments, T is *-C(Ra)2-C(Ra)2-.

[0155] In some embodiments, T is *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-.

[0156] In some embodiments, T is *-C(Ra)2-C(Ra)2-O-C(Ra)2-.

[0157] In some embodiments, T is *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-.

[0158] In some embodiments, T is *-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-.

[0159] In some embodiments, T is *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-.

[0160] In some embodiments, T is *-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-C(Ra)2-.

[0161] In some embodiments, T is *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-.

[0162] In some embodiments, T is *-C(Ra)2-C(Ra)2-C(Ra)2- or *-C(Ra)2-.

[0163] In some embodiments, T is *-C(Ra)2-C(Ra)2-C(Ra)2-.

[0164] In some embodiments, T is *-C(Ra)2-.

[0165] In some embodiments, at least one Rais H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0166] In some embodiments, at least one Rais H or C1-C6 alkyl.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0167] In some embodiments, each Rais H.

[0168] In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl.

[0169] In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a C3-C6 cycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a C3 cycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a C4 cycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a C5 cycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a C6 cycloalkyl.

[0170] In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a 3- to 6-membered heterocycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a 3-membered heterocycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a 4-membered heterocycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a 5-membered heterocycloalkyl. In some embodiments, two Ra, together with the one or more intervening atoms they are attached to, form a 6-membered heterocycloalkyl.

[0171] In some embodiments, Rais H.

[0172] In some embodiments, at least one Rais C1-C6 alkyl. In some embodiments, at least one Rais C1 alkyl. In some embodiments, at least one Rais C2 alkyl. In some embodiments, at least one Rais C3 alkyl. In some embodiments, at least one Rais C4 alkyl. In some embodiments, at least one Rais C5 alkyl. In some embodiments, Rais C6 alkyl.

[0173] In some embodiments, at least one Rais -CH3. Variables Q, Y, and R5

[0174] In some embodiments, Q is -OH.

[0175] In some embodiments, Q is -C(=O)-Y.

[0176] In some embodiments, Q is -C(=O)-OH.

[0177] In some embodiments, Q is 5- to 10-membered heteroaryl.

[0178] In some embodiments, Q is tetrazolyl.

[0179] In some embodiments,Cooley Ref. CLBO-002 / 01WO 349489-2004

[0180] In some embodiments, Y is -OR5.

[0181] In some embodiments, Y is -N(R5)2.

[0182] In some embodiments, Y is C1-C6 alkyl optionally substituted with one or more halogen or cyano.

[0183] In some embodiments, Y is C1-C6 alkyl.

[0184] In some embodiments, Y is C1-C6 alkyl substituted with one or more halogen or cyano.

[0185] In some embodiments, R5is H.

[0186] In some embodiments, R5is halogen (e.g., F, Cl, or Br)

[0187] In some embodiments, R5is cyano.

[0188] In some embodiments, R5is -S(=O)2OH.

[0189] In some embodiments, R5is C1-C6 alkyl.

[0190] In some embodiments, R5is C1-C6 alkyl optionally substituted with one or more halogen or cyano.

[0191] In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is C1 alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, R5is C4 alkyl. In some embodiments, R5is C5 alkyl. In some embodiments, R5is C6 alkyl.

[0192] In some embodiments, R5is -CH2CH3. Exemplary Embodiments of the Compounds

[0193] In some embodiments, the compound is of Formula (Ia’) or (Ib’):.or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the compound is of Formula (Ia’’) or (Ib’’):.Cooley Ref. CLBO-002 / 01WO 349489-2004or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the compound is of Formula (Ia) or (Ib):.or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the compound is of Formula (II):or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the compound is of Formula (IIa) or (IIb):or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the compound is selected from the compounds described in Tables 1-3 and pharmaceutically acceptable salts thereof.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0199] In some embodiments, the compound is selected from the compounds described in Table 1-3.

[0200] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0201] In some embodiments, the compound is selected from the compounds described in Table 1.

[0202] In some embodiments, the compound is selected from the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0203] In some embodiments, the compound is selected from the compounds described in Table 2.

[0204] In some embodiments, the compound is selected from the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0205] In some embodiments, the compound is selected from the compounds described in Table 3. Table 1Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Table 2Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Table 3Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004Cooley Ref. CLBO-002 / 01WO 349489-2004

[0206] In some embodiments, the compound is selected from the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0207] In some embodiments, the compound is selected from the compounds described in Table I.Cooley Ref. CLBO-002 / 01WO 349489-2004 Table ICooley Ref. CLBO-002 / 01WO 349489-2004

[0208] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of a compound disclosed herein.

[0209] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0210] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0211] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0212] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0213] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0214] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0215] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0216] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0217] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0218] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognised techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0219] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the invention. Further, substitution with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0220] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0221] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, formic, citric methane sulphonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0222] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0223] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0224] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents.

[0225] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (RCooley Ref. CLBO-002 / 01WO 349489-2004 or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0226] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0227] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0228] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0229] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0230] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonlyCooley Ref. CLBO-002 / 01WO 349489-2004 observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0231] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0232] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0233] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers).

[0234] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0235] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate.

[0236] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0237] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0238] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0239] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0240] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0241] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. TheCooley Ref. CLBO-002 / 01WO 349489-2004 objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulphonamides, tetrazoles, sulphonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996.

[0242] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate.

[0243] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0244] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0245] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle. N-oxides can be formed by treatment of the corresponding amine withCooley Ref. CLBO-002 / 01WO 349489-2004 an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0246] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the sulphonylurea group in a compound of the any one of the Formulae disclosed herein.

[0247] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.

[0248] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; andH) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0249] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0250] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1- C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0251] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1- ylmethyl.

[0252] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As statedCooley Ref. CLBO-002 / 01WO 349489-2004 hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0253] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis

[0254] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0255] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0256] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0257] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0258] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0259] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0260] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0261] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effectCooley Ref. CLBO-002 / 01WO 349489-2004 removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0262] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0263] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0264] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0265] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removingCooley Ref. CLBO-002 / 01WO 349489-2004 any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0266] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.

[0267] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0268] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0269] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0270] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0271] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied andCooley Ref. CLBO-002 / 01WO 349489-2004 adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). Biological Assays

[0272] Compounds designed, selected and / or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0273] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0274] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0275] In some embodiments, the biological assay is an assay measuring the binding activity for Clic1 protein. In some embodiments, the binding activity is measured by one-dimenstional (1D) saturation transfer difference (STD) NMR.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0276] In some embodiments, the biological assay is an assay measuring food intake. In some embodiments, food intake (i.e., the amount of food eaten by the subject) is measured by (i) manual measurement of food amount prior to, and after, feeding; (ii) automatic measurement of food amount prior to, and after, feeding; (iii) providing pre-measured allotments of food on demand, or (iv) by video-based analysis. Measurement may be conducted by weight or by determining the quantity of pre-measured food allotments consumed.

[0277] In some embodiments, the biological assay is an assay measuring urine flow rate. In some embodiments, urine flow rate is measured by filling cystometry. In some embodiments, urine flow rate is measured by pressure-flow study.

[0278] In some embodiments, the biological assay is an assay measuring urine output. In some embodiments, urine output is measured by weight. In some embodiments, urine output is measured by volume.

[0279] In some embodiments, the biological assay is an assay measuring sodium excretion. In some embodiments, sodium excretion is measured by measuring the concentration of sodium in the urine using an automated clinical chemistry analyzer and multiplying by the volume of the urine.

[0280] In some embodiments, the biological assay is an assay measuring the concentration of one or more analytes in serum obtained from a subject. In some embodiments, the concentration of the one or more analytes in serum is measured by a standard blood chemistry assay. In some embodiments, the concentration of the one or more analytes in serum is measured by a comprehensive metabolic panel. In some embodiments, the standard blood chemistry assay is a Chem20. Non-limiting examples of analytes include alanine aminotransferase (ALT), sodium (Na), TBILI, albumin (ALB), urea nitrogen (BUN), cholesterol (CHOL), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), iron (IRON), glucose (GLUC), phosphate (PHOS), total protein (TP), alkaline phosphatase (ALP), calcium (CA), uric acid (URIC), creatinine (CREAT), triglycerides (TRIG), potassium (K), and chloride (Cl).

[0281] In some embodiments, the biological assay is an assay measuring liver histology and / or liver damage. In some embodiments, liver tissue is sectioned and optionally stained prior to viewing and / or imaging. In some embodiments, the biological assay measures nonalcoholic fatty acid liver disease activity score (NAS), steatosis, hepatocyte ballooning, and / or lbular inflammation.

[0282] In some embodiments, the biological assay is an assay measuring translocation of a CLIC into a membrane. In some embodiments, translocation of a CLIC into a membrane is measured by quantifying the amount of a label associated with lipid vesicles after contactingCooley Ref. CLBO-002 / 01WO 349489-2004 the lipid vesicles with Zn++, wherein the label has been previously associated or linked with the CLIC.

[0283] In some embodiments, the biological assay is an assay measuring translocation of a CLIC from the cytosol of a cell to the plasma membrane of the cell. In some embodiments, translocation of a CLIC from the cytosol of a cell to the plasma membrane of the cell is measured by immunofluorescence staining after contacting the cell with a stimulating agent. In some embodiments, the stimulating agent is hydrogen peroxide, sphingosine-1-phosphate (S1P), or ionomycin. In some embodiments, the immunofluorescence staining comprises contacting the cell with a primary anti-CLIC1 antibody or a primary anti-CLIC4 antibody. In some embodiments, the immunofluorescence staining comprises contacting the cell with a species-specific secondary antibody conjugated to a label. In some embodiments, translocation of a CLIC from the cytosol of a cell to the plasma membrane of the cell is measured by quantifying the amount of the label that colocalizes with the cell membrane. In some embodiments, the label is a fluorescent label. Pharmaceutical Compositions

[0284] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.

[0285] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0286] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0287] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intra-muscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0288] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include thoseCooley Ref. CLBO-002 / 01WO 349489-2004 selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0289] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulphated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulphobutyl ether, branched-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0290] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0291] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0292] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0293] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols -Cooley Ref. CLBO-002 / 01WO 349489-2004 such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0294] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0295] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0296] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0297] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such asCooley Ref. CLBO-002 / 01WO 349489-2004 colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavoring.

[0298] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0299] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0300] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0301] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a disease or disorder referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0302] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use

[0303] In some aspects, the present disclosure provides a method of inhibiting chloride intracellular channel 1 (Clic1), comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition of the present disclosure.

[0304] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0305] In some aspects, the present disclosure provides a compound of the present disclosure for use in inhibiting chloride intracellular channel 1 (Clic1).

[0306] In some aspects, the present disclosure provides a compound of the present disclosure for use in treating or preventing a disease or disorder disclosed herein.

[0307] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for inhibiting chloride intracellular channel 1 (Clic1).

[0308] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0309] In some embodiments the disease or disorder is obesity. Excess adiposity (body fat), including excess weight and obesity, is a major risk factor for cardiovascular disease. As used herein, “excess weight or weight-related” refers to a condition in which the body mass index (BMI) of a subject is 25 to 30. As used herein “obesity” refers to a condition in which the BMI of a subject is at least 30. As used herein, “BMI” is defined as the body mass of a subject in kilograms (kg) divided by the square of the body height in meters (m) and is expressed in units of kg / m2.

[0310] In obesity, inhibition of NPY / AgRP neurons by GABA is impaired by chloride dysregulation. Clic1 increases intracellular chloride, which likely abolishes GABA inhibition. Notably, expression and membrane localization of Clic1 is increased in NPY / AgRP neurons in diet-induced obesity. Increasing chloride permeability can also depolarize the resting membrane potential, increasing nerve activity.

[0311] Obesity is associated with an elevated risk of heart failure. As used herein, “heart failure” refers to any condition characterized by either (a) abnormally low cardiac output in which the heart is unable to pump blood at an adequate rate or in adequate volume, or (b) relatively normal or only slightly reduced cardiac output, but abnormally high diastolic filling pressures.

[0312] Heart failure can be phenotypically classified as heart failure with reduced ejection fraction or heart failure with preserved ejection fraction. As used herein “ejection fraction” refers to a measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each contraction. As used herein, the term “preserved ejection fraction” is understood to mean an ejection fraction of at least about 50%. Heart failure with preserved ejection fraction is a form of heart failure with abnormally high diastolic filing pressures. In some embodiments, a preserved ejection fraction may be between about 50% and about 70%. As used herein, theCooley Ref. CLBO-002 / 01WO 349489-2004 term “reduced ejection fraction” is understood to mean an ejection fraction of less than about 40%. Heart failure with an ejection fraction of 40 to 50% is referred to as “mid-range,” “borderline,” or “mildly reduced” ejection fraction. In some embodiments, the obesity-related heart failure is heart failure with reduced rejection faction. In some embodiments, the obesity- related heart failure is heart failure with preserved rejection faction. In some embodiments, the obesity-related heart failure is heart failure with mildly reduced rejection faction.

[0313] As used herein, the term “obesity-related heart failure” can also include heart failure with diabetic cardiomyopathy. Diabetic cardiomyopathy can be characterized by both heart failure with preserved ejection fraction and also heart failure with reduced ejection fraction. It is generally associated with obesity and type II diabetic related inflammation of the cardiac muscle tissue that leads to abnormal contractility and ventricular stiffness. This inflammation may be mediated by increased inflammasome activity, which can be reduced by Clic1 inhibition.

[0314] Excess adiposity, in the form of excess weight or obesity, is also associated with an elevated risk of hypertension. As used herein, hypertension refers to systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥80 mm Hg. Excess adiposity promotes changes in the myocardium and vasculature, as well as through comorbidities. For example, excess adipose tissue leads to higher blood volume, in part due to elevated renal sodium retention. Excess adipose tissue also leads to higher blood pressure (hypertension) due to activation of the renin-angiotensin-aldosterone and sympathetic nervous systems.

[0315] In some embodiments, the disease or disorder is obesity in the absence of hypertension. In some embodiments, the disease or disorder is uncomplicated obesity. As used herein, “uncomplicated obesity” refers to obesity in a subject, wherein the subject does not also have hypertension or heart failure.

[0316] Further, many obese individuals suffer from at least one comorbidity such as dyslipidemia, glucose intolerance, or diabetes mellitus. In some embodiments, the disease or disorder is obesity with one or more of dyslipidemia, glucose intolerance, or diabetes mellitus.

[0317] In some embodiments, the disease or disorder is liver disease. In some embodiments, the disease or disorder is fatty liver disease. In some embodiments, the disease or disorder is nonalcoholic fatty liver disease (NAFLD), which is also called metabolic dysfunction- associated steatotic liver disease (MASLD). Nonalcoholic fatty liver disease can vary in severity from hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is also called metabolic dysfunction-associated steatotic steatohepatitis (MASH). In some embodiments, the disease or disorder is alcohol-associated fatty liver disease (AALD). Alcohol-associated fattyCooley Ref. CLBO-002 / 01WO 349489-2004 liver disease can vary in severity from hepatic steatosis to alcohol-associated steatohepatitis. In some embodiments, the disease or disorder is hepatic steatosis. In some embodiments, the disease or disorder is NASH (also called MASH). In some embodiments, the disease or disorder is alcohol-associated steatohepatitis. Symptoms or attributes associated with NASH include liver inflammation, liver cell damage, liver enlargement, and hepatic fibrosis.

[0318] In some embodiments, the disease or disorder is rheumatoid arthritis, seropositive rheumatoid arthritis, primary sclerosing cholangitis, autoimmune Addison’s Disease, systemic lupus erythematosus (SLE), latent autoimmune diabetes in an adulttriglye, elevated triglyceride to HDL ratio, abnormal serum apolipoprotein A (ApoA), Graves' disease, multiple sclerosis, early-onset myasthenia gravis, narcolepsy Type 1, Type 1 Diabetes (T1D), T1D with a specified age of onset, T1D with opthalmic manifestaions, or T1D with neurological manifestations.

[0319] Clic1 is highly expressed in several types of cancer, and may contribute to cancer cell proliferation, metastasis, and angiogenesis in some cancers. In some embodiments the disease or disorder is cancer. Non-limiting examples of cancer are acute lymphocytic cancer, acute myeloid leukemia (AML), alveolar rhabdomyosarcoma, B-cell chronic lymphoproliferative disorders, bladder cancer (e.g., bladder carcinoma), blastic plasmacytoid dendritic cell neoplasm, bone cancer, brain cancer (e.g., glioblastoma or medulloblastoma), breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, head and neck cancer (e.g., head and neck squamous cell carcinoma), Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, leukemia, liquid tumors, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma and lung adenocarcinoma), lymphoma, mesothelioma, mastocytoma, melanoma, multiple myeloma, myelodysplastic syndrome, nasopharynx cancer, non-Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, hairy cell leukemia, acute lymphocytic leukemia (ALL), Burkitt’s lymphoma, ovarian cancer, pancreatic cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer, skin cancer, small intestine cancer, soft tissue cancer, solid tumors, synovial sarcoma, gastric cancer, testicular cancer, thyroid cancer, and ureter cancer. In some embodiments, the cancer is characterized by the expression of Clic1.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0320] Clic1 has been associated with inflammation and several inflammation-related diseases and disorders. In some embodiments, the disease or disorder is an inflammation-related disease or disorder. Non-limiting examples of inflammation-related diseases or disorders include rheumatoid arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, Castleman's disease, systemic lupus erythematosus (SLE), lupus nephritis, Crohn's disease, ulcerative colitis, anemia, vasculitis, Kawasaki disease, Still's disease, amyloidosis, multiple sclerosis, transplantation, age-related macular degeneration, ankylosing spondylitis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), IgA nephropathy, osteoarthritis, asthma, diabetic nephropathy, GVHD, endometriosis, hepatitis (NASH), myocardial infarction, arteriosclerosis, sepsis, osteoporosis, diabetes, myocardial infarction, myopic choroidal neovascularization, idiopathic choroidal neovascularization, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis, atopic dermatitis, mesothelioma, polymyositis, dermatomyositis, panuveitis, anterior uveitis, intermediate uveitis, scleritis, keratitis, orbital inflammation, optic neuritis, diabetic retinopathy, proliferative vitreoretinopathy, dry eye, and post-operative inflammation.

[0321] Clic1 has been associated with some neurodegenerative disorders. In some embodiments the disease or disorder is a neurodegenerative disease or disorder. Non-limiting examples of neurodegenerative diseases or disorders include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), frontotemporal dementia, chronic traumatic encephalopathy, Lewy body dementia, neuromyelitis optica spectrum disorder, progressive surpanucleear palsy, Batten disease, and Creutzfeldt-Jakob disease.

[0322] As noted above, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an incretin or an incretin mimetic. In some embodiments, the incretin or incretin mimetic is a glucagon-like peptide receptor (GLP- 1R) agonist, a glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist, an amylin receptor agonist, a GLP-1R / GIPR dual agonist, or a combination thereof. In some embodiments, the GLP-1R agonist is semaglutide or liraglutide. In some embodiments, the GLP-1R / GIPR dual agonist is tirzepatide. In some embodiments, the GLP-1R / amylin receptor dual agonist is amycretin. In some embodiments, the additional therapeutic agent is a glucagon receptor (GcGR) agonist or a GLP-1R / GIPR / GcGR triple agonist. In some embodiments, theCooley Ref. CLBO-002 / 01WO 349489-2004 GLP-1R / GIPR / GcGR triple agonist is retatrutide. In some embodiments, the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an antibody. In some embodiments, the antibody is an anti-GIPR antibody. In some embodiments, the anti-GIPR antibody is conjugated to a GLP-1 analogue.

[0323] In some embodiments, the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent disclosed herein.

[0324] In some embodiments, the subject, having received the method of treatment, will have therapeutic outcomes including, but not limited to, reduced food intake, weight loss, reduction of glycemic index, and / or improved glucose control.

[0325] In some embodiments, the method reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after starting treatment. In some embodiments, reduced food intake is measured over the course of about 30 minutes, about 45 minutes, 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours. In some embodiments, food intake is measured during a single meal that is about 30 minutes, about 45 minutes, or about 60 minutes. In some embodiments, food intake is measured while the subject is allowed food ad libitum.

[0326] In some embodiments, the method reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 17%, at least about 20%, at least about 25%, or at least about 30% within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0327] In some embodiments, the method of treatment has at least two therapeutic effects. In some embodiments, the method of treatment reduces the subject’s food intake and body weight.

[0328] In some embodiments, the method: (i) reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, atCooley Ref. CLBO-002 / 01WO 349489-2004 least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 30 minutes, about 45 minutes, 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours after starting treatment; and (ii) reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 17%, at least about 20%, at least about 25%, or at least about 30%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0329] In some embodiments, the method leads to improved glucose control in the subject, as measured by fasting blood glucose in mg / dL. In some embodiments, improved glucose control in the subject comprises blood glucose ranging from 70-130 mg / dL in a fasted state.

[0330] In some embodiments, improved glucose control in the subject comprises fasting blood glucose that is reduced by at least about 1 mg / dL, at least about 2 mg / dL, at least about 3 mg / dL, at least about 4 mg / dL, at least about 5 mg / dL, at least about 6 mg / dL, at least about 7 mg / dL, at least about 8 mg / dL, at least about 9 mg / dL, at least about 10mg / dL, at least about 12 mg / dL, at least about 15 mg / dL, at least about 17 mg / dL, or at least about 20 mg / dL, compared to that measured before starting treatment.

[0331] In some embodiments, the improvement of glucose control of the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0332] In some embodiments, the method leads to improved glucose control in the subject, as measured by blood glucose in a fed state, in mg / dL. In some embodiments, improved glucose control in the subject comprises blood glucose ranging from 70-180 mg / dL in a fed state. In some embodiments, improved glucose control in the subject comprises blood glucose, in a fed state, that is reduced by at least about 1 mg / dL, at least about 2 mg / dL, at least about 3 mg / dL, at least about 4 mg / dL, at least about 5 mg / dL, at least about 6 mg / dL, at least about 7 mg / dL, at least about 8 mg / dL, at least about 9 mg / dL, at least about 10mg / dL, at least about 12 mg / dL, at least about 15 mg / dL, at least about 17 mg / dL, or at least about 20 mg / dL, compared to that measured before starting treatment. In some embodiments, the improvement of glucose controlCooley Ref. CLBO-002 / 01WO 349489-2004 of the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0333] In some embodiments, the method leads to improved glucose control in the subject, as measured by glycated hemoglobin (HbA1c) test. In some embodiments, HbA1c is reduced by at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.1%, at least about 1.2%, at least about 1.3%, at least about 1.4%, at least about 1.5%, at least about 1.7%, at least about 2.0%, at least about 2.5%, or at least about 3.0%. In some embodiments, the improvement of glucose control of the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0334] In some embodiments, the method increases lean body mass by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10%. In some embodiments, the increase in lean body mass of the subject is measured at about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks after starting treatment.

[0335] In some embodiments, the method does not cause diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by less than about 50%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0336] In some embodiments, the method causes a reduction in at least one symptom of the inflammation-related disease or disorder within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0337] In some embodiments, the method causes a reduction in at least one symptom of the neurodegenerative disease or disorder within about 2 weeks, about 3 weeks, about 4 weeks,Cooley Ref. CLBO-002 / 01WO 349489-2004 about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0338] In some embodiments, the method causes a reduction in tumor size or cancer burden within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0339] In some embodiments of the methods disclosed herein, the subject is a human.

[0340] Subjects with obesity-related heart failure or obesity may have one or more comorbid conditions or diseases. In some embodiments of the method, the subject has a metabolic syndrome, optionally Type 2 diabetes. In some embodiments of the method, the subject has diabetic cardiomyopathy. In some embodiments of the method, the subject has experienced weight gain following treatment with an antipsychotic, optionally clozapine, olanzapine, quetiapine, risperidone, aripiprazole, or ziprasidone. In some embodiments of the method, the subject has a binge eating disorder. In some embodiments of the method, the subject has Prader Willi Syndrome. In some embodiments of the method, the subject has pre-diabetes. Routes of Administration

[0341] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0342] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra- arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Exemplary Embodiments

[0343] Exemplary Embodiment No.1: A compound of Formula (I):Cooley Ref. CLBO-002 / 01WO 349489-2004or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, -O(C1-C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is halogen; R4is halogen; T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; and R5is H or C1-C6 alkyl.

[0344] Exemplary Embodiment No.2: The compound of Exemplary Embodiment 1, wherein R1is C6-C10 aryl optionally substituted with one or more R1S.

[0345] Exemplary Embodiment No. 3: The compound of any one of the preceding Exemplary Embodiments, wherein R1is phenyl optionally substituted with one or more R1S.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0346] Exemplary Embodiment No. 4: The compound of any one of the preceding Exemplary Embodiments, wherein R1is 5- to 10-membered heteroaryl optionally substituted with one or more R1S.

[0347] Exemplary Embodiment No. 5: The compound of any one of the preceding Exemplary Embodiments, wherein R2is C1-C6 alkyl.

[0348] Exemplary Embodiment No. 6: The compound of any one of the preceding Exemplary Embodiments, wherein R3is Cl.

[0349] Exemplary Embodiment No. 7: The compound of any one of the preceding Exemplary Embodiments, wherein R4is Cl.

[0350] Exemplary Embodiment No. 8: The compound of any one of the preceding Exemplary Embodiments, wherein T is *-C(Ra)2-C(Ra)2-.

[0351] Exemplary Embodiment No. 9: The compound of any one of the preceding Exemplary Embodiments, wherein T is *-C(Ra)2-C(Ra)2-C(Ra)2- or *-C(Ra)2-.

[0352] Exemplary Embodiment No. 10: The compound of any one of the preceding Exemplary Embodiments, wherein T is *-C(Ra)2-C(Ra)2-C(Ra)2-.

[0353] Exemplary Embodiment No. 11: The compound of any one of the preceding Exemplary Embodiments, wherein T is *-C(Ra)2-.

[0354] Exemplary Embodiment No. 12: The compound of any one of the preceding Exemplary Embodiments, wherein at least one Rais H or C1-C6 alkyl.

[0355] Exemplary Embodiment No. 13: The compound of any one of the preceding Exemplary Embodiments, wherein each Rais H.

[0356] Exemplary Embodiment No. 14: The compound of any one of the preceding Exemplary Embodiments, wherein two Ra, together with the one or more intervening atoms they are attached to, form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl.

[0357] Exemplary Embodiment No. 15: The compound of any one of the preceding Exemplary Embodiments, wherein R5is H.

[0358] Exemplary Embodiment No. 16: The compound of any one of the preceding Exemplary Embodiments, wherein R5is C1-C6 alkyl.

[0359] Exemplary Embodiment No. 17: The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (Ia) or (Ib):Cooley Ref. CLBO-002 / 01WO 349489-2004or a pharmaceutically acceptable salt thereof.

[0360] Exemplary Embodiment No. 18: The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt thereof.

[0361] Exemplary Embodiment No. 19: The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (IIa) or (IIb):or a pharmaceutically acceptable salt thereof.

[0362] Exemplary Embodiment No. 20: The compound of any one of the preceding Exemplary Embodiments, wherein the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0363] Exemplary Embodiment No.21: A method of preparing the compound of any one of the preceding Exemplary Embodiments.

[0364] Exemplary Embodiment No. 22: A pharmaceutical composition comprising the compound of any one of the preceding Exemplary Embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0365] Exemplary Embodiment No.23: A method of inhibiting chloride intracellular channel 1 (Clic1), comprising contacting a cell with an effective amount of the compound or pharmaceutical composition of any one of the preceding Exemplary Embodiments.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0366] Exemplary Embodiment No. 24: A method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding Exemplary Embodiments.

[0367] Exemplary Embodiment No. 25: The compound of any one of the preceding Exemplary Embodiments for use in inhibiting chloride intracellular channel 1 (Clic1).

[0368] Exemplary Embodiment No. 26: The compound of any one of the preceding Exemplary Embodiments for use in treating or preventing a disease or disorder disclosed herein.

[0369] Exemplary Embodiment No.27: Use of the compound of any one of the preceding Exemplary Embodiments in the manufacture of a medicament for inhibiting chloride intracellular channel 1 (Clic1).

[0370] Exemplary Embodiment No.28: Use of the compound of any one of the preceding Exemplary Embodiments in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0371] Exemplary Embodiment No. 29: The method, compound for use, or use of any one of the preceding Exemplary Embodiments, wherein the disease or disorder is obesity.

[0372] Exemplary Embodiment No. 30: The method, compound for use, or use of any one of the preceding Exemplary Embodiments, wherein the disease or disorder is obesity-related heart failure.

[0373] Exemplary Embodiment No. 31: The method, compound for use, or use of any one of the preceding Exemplary Embodiments, wherein the disease or disorder is inflammation, neurodegeneration, or cancer.

[0374] Exemplary Embodiment No. 32: The method, compound for use, or use of any one of the preceding Exemplary Embodiments, wherein the method reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after starting treatme

[0375] Exemplary Embodiment No. 33: The method, compound for use, or use of any one of the preceding Exemplary Embodiments, wherein the method reduces the subject’s body weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least aboutCooley Ref. CLBO-002 / 01WO 349489-2004 10%, at least about 12%, at least about 15%, at least about 17%, or at least about 20%, at least about 25%, or at least about 30%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

[0376] Exemplary Embodiment No. 34: The method, compound for use, or use of any one of the preceding Exemplary Embodiments, wherein the method does not cause diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by less than about 50%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. Definitions

[0377] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0378] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0379] It is to be understood that a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound the present disclosure is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound.

[0380] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0381] As used herein, “alkyl”, “C1, C2, C3, C4, C5 or C6 alkyl” or “C1-C 6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0382] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0383] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0384] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,Cooley Ref. CLBO-002 / 01WO 349489-2004 aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0385] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.

[0386] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0387] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0388] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non- aromatic.

[0389] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic.

[0390] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0391] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (i.e., N→O and S(O)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl).

[0392] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0393] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that theCooley Ref. CLBO-002 / 01WO 349489-2004 designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0394] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0395] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0396] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O- .

[0397] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0398] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0399] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio,Cooley Ref. CLBO-002 / 01WO 349489-2004 thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0400] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0401] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0402] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0403] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated those compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions isCooley Ref. CLBO-002 / 01WO 349489-2004 immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0404] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0405] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art

[0406] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0407] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or preventCooley Ref. CLBO-002 / 01WO 349489-2004 such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0408] As used herein, the term “subject” is interchangeable with the term “subject in need thereof”, both of which refer to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who has (e.g., is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that doesn't respond or hasn’t yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0409] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0410] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition, or disorder, or used to identify suitable candidates for such purposes.

[0411] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0412] As used herein, the term “inhibit,” “inhibiting,” or “inhibition” refers to reducing or eliminating. In some embodiments, inhibiting means reducing or more functions thereof. In some embodiments, the one or more functions may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, atCooley Ref. CLBO-002 / 01WO 349489-2004 least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%. In some embodiments, the one or more functions may be reduced by about 5% to about 95%, about 10% to about 80%, about 20% to about 75%, or about 30% to 70%. In some embodiments, inhibiting a CLIC (e.g., CLIC1 and / or CLIC4) refers to reducing one or more functions of the CLIC. In some embodiments, the one or more functions of the CLIC comprises membrane translocation.

[0413] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0414] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0415] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In oneCooley Ref. CLBO-002 / 01WO 349489-2004 embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0416] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0417] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0418] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0419] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0420] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0421] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0422] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0423] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds intoCooley Ref. CLBO-002 / 01WO 349489-2004 preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0424] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0425] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0426] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrierCooley Ref. CLBO-002 / 01WO 349489-2004 is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0427] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.

[0428] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0429] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0430] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification forCooley Ref. CLBO-002 / 01WO 349489-2004 the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0431] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. In preferred aspects, dosages can range from about 1 mg / kg per day to about 1000 mg / kg per day. In an aspect, the dose will be in the range of about 0.1 mg / day to about 50 g / day; about 0.1 mg / day to about 25 g / day; about 0.1 mg / day to about 10 g / day; about 0.1 mg to about 3 g / day; or about 0.1 mg to about 1 g / day, in single, divided, or continuous doses (which dose may be adjusted for the patient’s weight in kg, body surface area in m2, and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[0432] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0433] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0434] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethaneCooley Ref. CLBO-002 / 01WO 349489-2004 sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0435] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0436] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4- toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0437] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0438] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0439] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilledCooley Ref. CLBO-002 / 01WO 349489-2004 physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0440] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0441] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0442] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0443] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0444] As used herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.Cooley Ref. CLBO-002 / 01WO 349489-2004 EXAMPLES

[0445] Unless indicated otherwise, it is understood that values presented in the examples are approximate and are subject to experimental and instrumental variations. Abbreviations used:

[0446] EA (ethyl acetate); DCM (dichloromethane); FA (formic acid); hr (hour); hrs (hours); PE (petroleum ether);MeOH (methanol); DMF (dimethylformamide); IPA (isopropyl alcohol); ACN (acetonitrile); RT (retention time); OR (optical rotation); TLC (thin-layer SiO2 chromatography); T4P (3-[2,6,8-trioxo-9-[(2R,3R,4R)-2,3,4,5-tetrahydroxypentyl]-3H-purin- 7-yl]propyl dihydrogen phosphate); PPH3 (triphenylphosphine); DIAD (Diisopropyl azodicarboxylate); TFA (trifluoroacetic acid); Xphos Pd G4 ((SP-4-3)-[Dicyclohexyl [2′,4′,6′- tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine] (methane sulfonato -κO)[2′-(methylamino- κN)[1,1′-biphenyl]-2-yl-κC]palladium ); Eaton’s reagent (phosphorus pentoxide, 7.7 wt. % in methanesulfonic acid); OR (optical rotation); SFC (super critical fluid chromatography). Analytical and Chromatography Methods

[0447] LCMS Method 1: Shimadzu LC-40AB &MS 2020; Column: HALO C183.0X30mm, 5 µm. The mobile phase: Aqueous: 0.04% TFA in H2O, Organic: 0.02% TFA in MeCN. A constant gradient from 5% organic to 95% organic mobile phase over the course of 0.5 minutes then hold for 0.3 min, then dropped back to 5% organic over 0.01min and held for 0.19 min. The flow rate was constant at 1.5mL / min.

[0448] LCMS Method 2: Shimadzu LC-20AB &MS 2020; Column: WePure C182.1X30mm, 5 µm, run at 50oC. The mobile phase: Aqueous: 0.04% TFA in H2O, Organic: 0.02% TFA in MeCN. A constant gradient from 5% organic to 95% organic mobile phase over the course of 0.4 minutes then hold for 0.35 min, then dropped back to 5% organic over 0.01min and held for 0.29 min. The flow rate was constant at 2.0 mL / min.

[0449] LCMS Method 3 Shimadzu LC-20AB &MS 2020; Column: WePure C182.1X30mm, 5 µm, run at 50oC. The mobile phase: Aqueous: 0.04% TFA in H2O, Organic: 0.02% TFA in MeCN. A constant gradient from 5% organic to 95% organic mobile phase over the course of 0.8 minutes then hold for 0.4 min, then dropped back to 5% organic over 0.01min and held for 0.29 min. The flow rate was constant at 1.5mL / min. SFC MethodsCooley Ref. CLBO-002 / 01WO 349489-2004

[0450] SFC Method 1: Agilent-1260 equipped with a Chiralpak IG-3150*4.6mm I.D., 3µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.05%DEA); Gradient elution: B in A from 5% to 40% over 3 min; Flow rate: 2.5mL / min; Detector: DAD; Column Temp: 35oC; Back Pressure: 100Bar

[0451] SFC Method 2: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D.,3.5 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH(0.05%DEA);Gradient elution: EtOH(0.05%DEA) in CO2 from 5% to 40% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0452] SFC Method 3: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D.,3.5 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH(0.05%DEA);Gradient elution: EtOH(0.05%DEA) in CO2 from 10% to 60% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0453] SFC Method 4: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D., 3.5µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.05%DEA); Isocratic elution:60% EtOH (0.05%DEA) in CO2; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0454] SFC Method 5: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D.,3.5µm column; Mobile phase: Phase A: CO2; Phase B: EtOH; Gradient elution: EtOH in CO2 from 10% to 60% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0455] SFC Method 6: SHIMADZU LC-30ADsf equipped with a Chiralcel OJ-350*4.6mm I.D.,3µm column; Mobile phase: Phase A: CO2; Phase B: MeOH (0.05%DEA); Gradient elution: MeOH (0.05%DEA) in CO2 from 5% to 40% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0456] SFC Method 7: SHIMADZU LC-30ADsf equipped with a Chiralpak AD-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH (0.05%DEA); Gradient elution: MeOH (0.05%DEA) in CO2 from 5% to 40% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0457] SFC Method 8: SHIMADZU LC-30ADsf equipped with a Chiralpak IG-350×4.6mm I.D., 3 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH (0.05%DEA); Gradient elution: MeOH (0.05%DEA) in CO2 from 5% to 40% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0458] SFC Method 9: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D.,3.5 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH(0.05%DEA);GradientCooley Ref. CLBO-002 / 01WO 349489-2004 elution: MeOH(0.05%DEA) in CO2 from 5% to 40% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC;Back Pressure:100Bar

[0459] SFC Method 10: SHIMADZU LC-30ADsf equipped with a Chiralcel OJ-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.05%DEA); Gradient elution:40% EtOH (0.05%DEA) in CO2 over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0460] SFC Method 11: SHIMADZU LC-30ADsf equipped with a Chiralcel OX-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: IPA (0.05%DEA); Gradient elution: IPA (0.05%DEA) in CO2 from 20% to 60% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0461] SFC Method 12: SHIMADZU LC-30ADsf equipped with a Chiralpak AD-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.05%DEA); Gradient elution: EtOH (0.05%DEA) in CO2 from 10% to 60% over 3 min; Flow rate:4mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0462] SFC Method 13: SHIMADZU LC-30ADsf equipped with a Chiralpak IC-350*4.6mm I.D., 3 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.05%DEA); Gradient elution: EtOH (0.05%DEA) in CO2 from 10% to 60% over 3 min; Flow rate:4mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0463] SFC Method 14: SHIMADZU LC-30ADsf equipped with a Chiralcel OJ-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.05%DEA); Gradient elution: EtOH (0.05%DEA) in CO2 from 10% to 60% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0464] SFC Method 15: SHIMADZU LC-30ADsf equipped with a Chiralpak IG-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH (0.05%DEA); Gradient elution: MeOH (0.05%DEA) in CO2 from 10% to 60% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0465] SFC Method 16: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D., 3.5 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH(0.05%DEA);Gradient elution: MeOH(0.05%DEA) in CO2 from 10% to 60% over 3min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC;Back Pressure:100Bar

[0466] SFC Method 17: SHIMADZU LC-30ADsf equipped with a Kromasil (S,S) Whelk-O1 50×4.6mm I.D., 3.5 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH(0.05%DEA); Isocratic elution: 40%EtOH(0.05%DEA) in CO2; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC;Back Pressure:100BarCooley Ref. CLBO-002 / 01WO 349489-2004

[0467] SFC Method 18: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O150*4.6mm I.D., 3.5 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH(0.05%DEA);Gradient elution: 60%EtOH(0.05%DEA) in CO2 over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC;Back Pressure:100Bar

[0468] SFC Method 19: SHIMADZU LC-30ADsf equipped with a DAICEL CHIRALCEL OJ (250mm*50mm,10um); Mobile phase: Phase A: CO2; Phase B: IPA: ACN = 4:1; Isocratic elution 50%; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0469] SFC Method 20: SHIMADZU LC-30ADsf equipped with a Chiralcel OX-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: IPA (0.05%DEA); Gradient elution: IPA (0.05%DEA) in CO2 from 5% to 40% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0470] SFC Method 21: SHIMADZU LC-30ADsf equipped with a Chiralcel OJ-350*4.6mm I.D.,3 µm column; Mobile phase: Phase A: CO2; Phase B: IPA (0.05%DEA); Gradient elution: IPA (0.05%DEA) in CO2 from 10% to 60% over 3 min; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure:100Bar

[0471] SFC Method 22: SHIMADZU LC-30ADsf equipped with a Kromasil (S,S) Whelk-O1 50×4.6mm I.D., 3.5 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH(0.05%DEA); Isocratic elution: 50%EtOH(0.05%DEA) in CO2; Flow rate:3mL / min; Detector: PDA; Column Temp: 35oC;Back Pressure:100Bar

[0472] SFC Method 23: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O1250*50 mm I.D., 10 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH; Isocratic elution: 50%MeOH in CO2.

[0473] SFC Method 24: SHIMADZU LC-30ADsf equipped with a Chiralcel OJ-3250*30mm I.D.,10 µm column; Mobile phase: Phase A: CO2; Phase B: EtOH (0.1%NH3-H2O); Isocratic elution: 40% EtOH (0.1%NH3-H2O) in CO2

[0474] SFC Method 25: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O1250*50 mm I.D., 10 µm column; Mobile phase: Phase A: CO2; Phase B: IPA; Isocratic elution: 40%IPA in CO2.

[0475] SFC Method 26: SHIMADZU LC-30ADsf equipped with a (S,S) Whelk-O1250*50 mm I.D., 10 µm column; Mobile phase: Phase A: CO2; Phase B: MeOH (0.1% NH3H2O); Isocratic elution: 45%MeOH (0.1% NH3H2O) in CO2. Prep HPLC MethodsCooley Ref. CLBO-002 / 01WO 349489-2004

[0476] Prep HPLC Method 1: Column: Phenomenex Luna C18150*25 mm*10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 42%-72% B over 10.0 min

[0477] Prep HPLC Method 2: Column: Phenomenex luna C18150*25mm* 10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 45%-75% B over 10.0 min

[0478] Prep HPLC Method 3: Column: Phenomenex luna C18150*25mm* 10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 40%-70% B over 10.0 min

[0479] Prep HPLC Method 4: Column: Boston Green ODS 150*30 mm*5 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient:50%-80% B over 11.0 min

[0480] Prep HPLC Method 5: Column: Boston Green ODS 150*30mm*5 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient:43%-73% B over 11.0 min

[0481] Prep HPLC Method 6: Column: Phenomenex Luna C18150*25mm*10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 35%-65% B over 10.0 min

[0482] Prep HPLC Method 7: Column: Phenomenex Luna C18150 * 25 mm * 10 µm; mobile phase: [H2O(0.225% FA) - ACN]; gradient: 47% - 77% B over 10.0 min

[0483] Prep HPLC Method 8: Column: Waters xbridge 150 * 25 mm 10 µm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient:30% - 50% B over 8.0 min

[0484] Prep HPLC Method 9: Column: Waters xbridge 150 * 25 mm 10 µm; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient:10% - 40% B over 15.0 min

[0485] Prep HPLC Method 10: Column: Phenomenex luna C18 (250*70mm, 10 µm); mobile phase: [H2O (0.225% FA)-ACN]; gradient: 34%-64% B over 22.0 min

[0486] Prep HPLC Method 11: Column: Phenomenex luna C18150*40 mm* 15 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 58%-88% B over 15.0 min

[0487] Prep HPLC Method 12: Column: Phenomenex luna C18250*70mm, 10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 40%-70% B over 20.0 min

[0488] Prep HPLC Method 13: Column: Phenomenex luna C18150*40 mm* 15 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 58%-88% B over 10.0 min

[0489] Prep HPLC Method 14: Column: Phenomenex luna C18250*70mm, 10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 43%-73% B over 22.0 min

[0490] Prep HPLC Method 15: Column: Phenomenex Synergi Max-RP 250*50mm, 10 µm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 43%-73% B over 20.0 min

[0491] Prep HPLC Method 16: Column: Phenomenex luna C18250*70mm, 10 µm; mobile phase: [H2O-ACN]; gradient: 50%-80% B over 22.0 min

[0492] Prep HPLC Method 17: Column: Phenomenex luna C18250*70mm, 10 µm; mobile phase: [H2O (FA)-ACN]; gradient: 55%-85% B over 22.0 minCooley Ref. CLBO-002 / 01WO 349489-2004

[0493] Prep HPLC Method 18: Column: Phenomenex luna C18250*70mm, 10 µm; mobile phase: [H2O (FA)-ACN]; gradient: 60%-90% B over 22.0 min Example 1. Synthesis of (R)-2-((6,7-dichloro-2-methyl-1-oxo-2-(4- (trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)oxy)acetic acid (Compound 1a) & (S)-2-((6,7-dichloro-2-methyl-1-oxo-2-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H- inden-5-yl)oxy)acetic acid (Compound 1b)

[0494] Step 1. H2SO4 (120 mL) was added to intermediate 1 (11.0 g, 28.5 mmol, 1.00 eq) at 0 °C and the mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into ice water (800 mL) and extracted with EA (300 mL X 3). The combined organic layers were washed with sat. aq. NaHCO3 (200mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide intermediate 2 (11 g, 24.4 mmol, 85.6% yield, 83.5% purity) as a white solid. LCMS: RT= 0.674 min; m / z = 375 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.96 (s, 1H), 4.01 (s, 3H), 4.00 - 3.98 (m, 1H), 3.63 (q, J = 8.4 Hz, 1H), 3.20 (dd, J1 = 17.6 Hz, J1 = 3.6 Hz, 1H).

[0495] Step 2. A mixture of intermediate 2 (11.0 g, 24.4 mmol, 1.00 eq) and MeI (17.3 g, 122 mmol, 7.62 mL, 5.00 eq) in DMF (51.0 mL) and toluene (51.0 mL) was degassed and purged with N2 (3X), and then NaOMe (1.98 g, 36.7 mmol, 1.50 eq) was added at 0 °C and stirred at 0 °C for 10 min under an atmosphere of N2. The reaction mixture was poured into ice water (500 mL) and extracted with EA (300 mL X 3). The combined organic layers were washed with water (200mL X 4), dried over Na2SO4, filtered and concentrated under reduced pressure to provide intermediate 3 (11 g, crude) as a white solid. LCMS: RT=0.697, m / z = 389.1 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 4.03 (s, 3H), 3.51 (d, J = 17.6 Hz, 1H), 3.26 (d, J = 17.6 Hz, 1H), 1.68 (s, 3H).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0496] Step 3. A mixture of intermediate 3 (9.00 g, 23.1 mmol, 1.00 eq) in Py•HCl (300 g, 2.60 mol, 112 eq) was stirred at 160 °C for 5 hrs then was poured into water (400 mL). The aqueous phase was extracted with EA (300 mL X 3). The combined organic layers were washed with brine (200 mL X 3), dried with anhydrous Na2SO4, filtered and concentrated to provide intermediate 4 (7.80 g, 16.9 mmol, 73.3% yield, 81.6% purity) as a yellow solid. LCMS: RT=0.632m / z = 375.1(LCMS method 2).

[0497] Step 4. To a solution of intermediate 4 (7.80 g, 16.9 mmol, 1.00 eq) in DMF (80.0 mL) were added K2CO3 (9.38 g, 67.8 mmol, 4.00 eq) and intermediate 5 (9.75 g, 33.9 mmol, 20.8 mL, 2.00 eq). After stirring at 60 °C for 1 hr, the mixture was poured into ice water (500 mL). The aqueous phase was extracted with EA (400 mL X 2) and the combined organic layers were washed with water (200mL X 4) and brine (100 mL X 3), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to provide crude material that was purified by column chromatography (SiO2, PE: EA, PE: EA = 1: 0 to 1: 1) to provide intermediate 6 (5.50 g, 10.6 mmol, 62.8% yield, 94.8% purity) as a yellow solid. LCMS: RT= 0.708, m / z =489.1 (LCMS Method 2);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.77 (s, 1H), 4.72 (s, 2H), 3.47 (d, J = 17.6 Hz, 1H), 3.23 (d, J = 18.0 Hz, 1H), 1.67 (s, 3H), 1.51 - 1.49 (m, 9H).

[0498] Step 5. Racemic intermediate 6 was separated by prep-SFC (SFC method 23).

[0499] Intermediate 7A (2.50 g, 4.96 mmol, 46.5% yield, 97.1% purity) was obtained as a yellow oil. LCMS: RT=0.714 min, m / z =489.1 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.77 (s, 1H), 4.72 (s, 2H), 3.47 (d, J = 17.6 Hz, 1H), 3.23 (d, J = 17.6 Hz, 1H), 1.67 (s, 3H), 1.51 (s, 9H). SFC: RT=1.155 min, 100% chiral purity (SFC Method 8).

[0500] Intermediate 7B (2.60 g, 5.18 mmol, 48.6% yield, 97.5% purity) was obtained as a yellow oil. LCMS: RT=0.710, m / z = 489.1 (LCMS Method 2);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 4.72 (s, 2H), 3.47 (d, J = 17.6 Hz, 1H), 3.23 (d, J = 17.6 Hz, 1H), 1.67 (s, 3H), 1.57 - 1.49 (m, 9H). SFC: RT=1.492 min, 100% chiral purity (SFC Method 8).

[0501] Step 6a. To a solution of intermediate 7A (2.00 g, 3.97 mmol, 1.00 eq) in toluene (20.0 mL) was added MsOH (762 mg, 7.94 mmol, 567 μL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The residue was poured into ice water (100 mL). The aqueous phase was extracted with EA (100 mL X 3). The combined organic layers were washed with water (80.0 mL X 3) and brine (100 mL X 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (Prep HPLC method 11) to provideCooley Ref. CLBO-002 / 01WO 349489-2004 Compound 1a (1.23 g, 2.84 mmol, 71.4% yield, 99.9% purity) as a light yellow solid. LCMS: RT=0.625 min, m / z=433.0 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.82 (s, 1H), 4.90 (s, 2H), 3.50 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 1.68 (s, 3H); SFC: RT=1.228 min, chiral purity 100% (SFC method 17).

[0502] Step 6b. To a solution of intermediate 7B (2.10 g, 4.18 mmol, 1.00 eq) in toluene (20.0 mL) was added MsOH (804 mg, 8.37 mmol, 597 μL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The residue was poured into ice water (100 mL). The aqueous phase was extracted with EA (100 mL X 3). The combined organic layers were washed with water (80.0 mL X 3) and brine (100 mL X 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (Prep HPLC method 11) to provide Compound 1b (1.24 g, 2.86 mmol, 68.2% yield, 99.8% purity) as a light-yellow solid. LCMS: RT=0.728, m / z = 431.0 (M-H)+(LCMS Method 2);.1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H), 6.82 (s, 1H), 4.90 (s, 2H), 3.50 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 1.68 (s, 3H); SFC: RT=1.785 min, chiral purity 99.97% (SFC method 17). Example 2. Synthesis of (R)-4-((6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H- inden-5-yl)oxy)butanoic acid (Compound 23a) & (S)-4-((6,7-dichloro-2-methyl-1-oxo-2- phenyl-2,3-dihydro-1H-inden-5-yl)oxy)butanoic acid (Compound 23b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0503] Step 1. Into a mixture of intermediate 1 (48.0 g, 310 mmol, 41.4 mL, 1.10 eq) and AlCl3 (37.7 g, 282 mmol, 15.4 mL, 1.00 eq) in DCM (500 mL) was added intermediate 2 (50 g, 282.44 mmol, 1 eq) at 0 °C. The mixture was degassed and purged with N2 (3X) and then stirred at 25 °C for 12 hrs under an atmosphere of N2. The reaction mixture was poured into 6 M HCl (400 mL) at 0 °C and extracted with DCM (400 mL X 3). The combined organic layers were washed with brine (200 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product that was triturated with PE: DCM = 3: 1 (250 mL) at 25 °C for 30 min to provide Intermediate 3 (39.0 g, 132 mmol, 46.7% yield, - purity) as a white solid. LCMS: RT=0.567 min, m / z=295.1 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.8 Hz, 1H), 7.30 (s, 2H), 7.24 - 7.26 (m, 5H), 4.29 (s, 2H), 3.94 (s, 3H).

[0504] Step 2. To a solution of intermediate 3 (40.0 g, 135 mmol, 1 eq) in Ac2O (80 mL) was added intermediate 4 (59.9 g, 586 mmol, 80.0 mL, 4.33 eq) at 0 - 10 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into ice water and filtered. The filtered cake was extracted with DCM (250 mL X 2). The combined organic layers were washed with brine (100 mL X 2), dried over Na2SO4, filtered and concentrated under reducedCooley Ref. CLBO-002 / 01WO 349489-2004 pressure to give intermediate 5 (35.0 g, 113 mmol, 84.08% yield) as a white solid. LCMS: RT=0.979 min, m / z=307.1 (LCMS method 3);1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.8 Hz, 1H), 7.37 - 7.45 (m, 5H), 7.26 (d, J = 8.8 Hz, 1H), 6.32 (s, 1H), 5.78 (s, 1H), 3.95 (s, 3H).

[0505] Step 3. H2SO4 (210 mL) was heated to 60°C and stirred for 0.5 hr. A solution of intermediate 5 (35.0 g, 114 mmol, 1.00 eq) in DCM (105 mL) was added at 60 °C and the mixture was further stirred for 1 hr. The reaction mixture was quenched by the addition of water (200 mL) at 0 °C and then extracted with EA (300 mL X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product that was triturated with MTBE (200 mL) at 25 °C for 15 min to provide intermediate 6 (23 g, crude) as a white solid. LCMS: RT=0.625 min, m / z=307.0 (LCMS method 2).

[0506] Step 4. A mixture of intermediate 6 (20.0 g, 41.6 mmol, 1.00 eq), MeI (23.6 g, 166 mmol, 10.4 mL, 4.00 eq), MeONa (6.08 g, 112 mmol, 2.70 eq) in DMF (180 mL) and toluene (180 mL) was degassed and purged with N2 (3X), and then the mixture was stirred at 0-5 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched by the addition of water (500 mL) at 10 °C and then extracted with EA (400 mL X 3). The combined organic layers were washed with brine (200 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was triturated with MTBE (100 mL) at 25 °C for 30 min., then filtered. The filter cake was collected to provide intermediate 7 (9.00 g, 25.7 mmol, 61.86% yield, 92% purity) as a white solid. LCMS: RT=0.951 min, m / z=321.1 (LCMS method 3);1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.29 - 7.33(m, 2H), 7.23 - 7.26(m, 2H), 4.02 (s, 3H), 2.81 (d, J = 63.2, 2H), 1.56 (s, 3H).

[0507] Step 5. Intermediate 7 was separated by prep-SFC (SFC method 24) to provide intermediate 7a (4.00 g, 12.4 mmol, 44.4% yield) as a yellow solid. LCMS: RT=0.575 min, m / z=321.1 (LCMS Method 2); SFC: RT=1.133 min, chiral purity 100% (SFC method 10). Intermediate 7b (4.00 g, 12.4 mmol, 44.4% yield) was obtained as a yellow solid. LCMS: RT=0.575 min, m / z=321.1 (LCMS Method 2); SFC: RT=1.719 min, chiral purity 100% (SFC method 10).

[0508] Step 6a. To a mixture of intermediate 7a (4.00 g, 12.4 mmol, 1.00 eq) in toluene (40 mL) was added AlCl3(4.98 g, 37.3 mmol, 2.04 mL, 3.00 eq) at 0 - 10 °C. The mixture was degassed and purged with N2 (3X) times and then stirred at 100 °C for 1 hr under an atmosphere of N2. The reaction mixture was quenched by the addition of 6M HCl 100 mL at 0-10 °C and then extracted with EA (200 mL X 3). The combined organic layers were washed with brine (100 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give aCooley Ref. CLBO-002 / 01WO 349489-2004 residue that was triturated with PE (40 mL) at 25 °C for 30 min to provide Intermediate 8a (3.00 g, 9.67 mmol, 77.6% yield, 99% purity) as an off-white solid. LCMS: RT=0.625 min, m / z=307 (LCMS method 2).

[0509] Step 6b. To a mixture of intermediate 7b (4.00 g, 12.4 mmol, 1.00 eq) in toluene (40 mL) was added AlCl3 (4.98 g, 37.3 mmol, 2.04 mL, 3.00 eq) at 0-10 °C. The mixture was degassed and purged with N2 (3X), and then stirred at 100 °C for 1 hr under an atmosphere of N2.The reaction mixture was quenched by the addition of 6M HCl (100 mL) at 0-10 °C and then extracted with EA (200 mL X 3). The combined organic layers were washed with brine (100 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was triturated with PE (40mL) at 25 °C for 30 min to provide Intermediate 8b (3.00 g, 9.67 mmol, 77.6% yield, 99% purity) as an off-white solid. LCMS: RT=0.630 min, m / z=307 (LCMS method 2).

[0510]

[0511] Step 7a. To a solution of intermediate 8a (3.00 g, 9.77 mmol, 1.00 eq) in DMF (30 mL) were added K2CO3 (5.40 g, 39.0 mmol, 4.00 eq) and intermediate 9 (4.36 g, 19.5 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 hrs then was quenched by the addition of water (100 mL) at 15 °C and then extracted with EA (100 mL X 3). The combined organic layers were washed with brine (100 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE: EA = 100: 1 to 5: 1) to provide intermediate 10a (4.00 g, 8.63 mmol, 88.41% yield, 97% purity) as a red oil. LCMS: RT=0.717 min, m / z=449.1 (LCMS method 2).

[0512]

[0513] Step 7b. To a solution of intermediate 8b (3.00 g, 9.77 mmol, 1.00 eq) in DMF (30 mL) were added K2CO3 (5.40 g, 39.0 mmol, 4.00 eq) and intermediate 9 (4.36 g, 19.5 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 hrs then was quenched by the addition of water (100 mL) at 15 °C and then extracted with EA (100 mL X3). The combined organic layers were washed with brine (100 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 5 / 1) to provide intermediate10b (4.00 g, 8.63 mmol, 88.41% yield, 97% purity) as a red oil. LCMS: RT=0.710 min, m / z=449.1 (LCMS method 2).Step 8a. To a solution of intermediate 10a (4.00 g, 8.90 mmol, 1.00 eq) in toluene (40 mL) was added MsOH (1.71 g, 17.8 mmol, 1.27 mL, 2.00 eq) at 0-5 °C. The mixture was stirred at 25 °C for 1 hr then was quenched by the addition of water (240 mL) at 25 °C and then extracted with EA (200 mL X 3). The combined organic layers were washed with brine (200 mL X 3), dried over Na2SO4,Cooley Ref. CLBO-002 / 01WO 349489-2004 filtered and concentrated under reduced pressure to give a residuethat was purified by prep- HPLC (Prep HPLC method 12) to provide Compound 23a (1.00 g, 2.54 mmol, 28.57% yield, >95% purity) as a white solid. LCMS: RT=0.828 min, m / z=393.2 (LCMS method 3);1H NMR (400 MHz, CDCl3) δ 7.30 - 7.33 (m, 4H), 7.21 - 7.25 (m, 1H), 7.23 - 7.26 (m, 2H), 6.90 (s, 1 H), 4.23 (t, J = 5.6 Hz, 2H), 3.37 (d, J = 17.2 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.25 (dt, J1 = 6.4 Hz, J2 = 13.2 Hz, 2H), 1.68(s, 3H); SFC: RT=1.085 min, 100% chiral purity (SFC Method 10).

[0514] Step 8b. To a solution of intermediate 10b (4.00 g, 8.90 mmol, 1.00 eq) in toluene (40 mL) was added MsOH (1.71 g, 17.8 mmol, 1.27 mL, 2.00 eq) at 0-5 °C. The mixture was stirred at 25 °C for 1 hr then was quenched by the addition of water (240 mL) at 25 °C and then extracted with EA (200 mL X 3). The combined organic layers were washed with brine (200 mL X 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC method 12) to provide Compound 23b (1.00 g, 2.54 mmol, 28.57% yield, >95% purity) as a white solid. LCMS: RT=0.864 min, m / z=393.2 (LCMS method 3);1H NMR (400 MHz, CDCl3) δ 7.30 - 7.33 (m, 4H), 7.21 - 7.25 (m, 1H), 7.23 - 7.26 (m, 2H), 6.90 (s, 1H), 4.23 (t, J = 5.6 Hz, 2H), 3.37 (d, J = 17.2 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.25 (dt, J1 = 6.4 Hz, J2 = 13.2 Hz, 2H), 1.68 (s, 3H); SFC: RT=0.532 min, 100% chiral purity (SFC Method 10). Example 3. Synthesis of (R)-4-((6,7-dichloro-2-methyl-1-oxo-2-(4- (trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)oxy)butanoic acid (Compound 24a) & (S)-4-((6,7-dichloro-2-methyl-1-oxo-2-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H- inden-5-yl)oxy)butanoic acid (Compound 24b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0515] Step 1. A solution of intermediate 1 (30.0 g, 147 mmol, 1.00 eq) and intermediate 2 (27.3 g, 154 mmol, 1.05 eq) in Eaton’s reagent (909 g, 3.82 mol, 600 mL, 26.0 eq) was stirred at 20 °C for 10 hrs. The mixture was poured into ice-water (1.50 L) and stirred for 1 hr then filtered. The filter cake was dissolved by EA (500 mL) and DCM (500 mL) and filtered. The organic layer was washed with brine (500 mL X2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was slurried with PE : DCM = 3 : 1 (100mL) to give intermediate 3 (26.0 g, 71.6 mmol, 48.7% yield) as a white solid. LCMS: RT=0.618 min, m / z=not observed (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 4.46 (s, 2H), 3.96 (s, 3H).

[0516] Step 2. To a solution of intermediate 3 (26.0 g, 71.6 mmol, 1.00 eq) in Ac2O (60.0 mL) was added intermediate 4 (31.7 g, 310 mmol, 42.3 mL, 4.33 eq) dropwise at 0 °C. The mixture was stirred at 20 °C for 1 hr then poured into ice-water (500mL), filtered and concentrated in vacuo to give intermediate 5 (22.0 g, 58.6 mmol, 81.9% yield) as a white solid LCMS: RT=0.641 min, m / z=375.1(LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 5.92 (s, 1H), 3.97 (s, 3H).

[0517] Step 3. H2SO4 (220 mL) was added to intermediate 5 (22.0 g, 58.6 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr then poured into ice-water (1.00 L), filtered, and the filter cake was concentrated in vacuo. The crude product was triturated with PE: DCM =Cooley Ref. CLBO-002 / 01WO 349489-2004 3: 1 (120 mL) at 25 °C for 30 min to give intermediate 6 (20.0 g, 53.3 mmol, 90.9% yield) as a white solid. LCMS: RT=0.616 min, m / z=375.0 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.4 Hz, 2H), 7.45 – 7.43 (m, 3H), 4.22 (q, J = 4.0 Hz, 1H), 4.04 (s, 3H), 3.66 (q, J = 4.4 Hz, 1H), 3.21 (dd, J1 = 18.0 Hz, J2 = 4.0 Hz, 1H).

[0518] Step 4. To a mixture of intermediate 6 (20.0 g, 53.3 mmol, 1.00 eq) and MeI (37.8 g, 267 mmol, 16.6 mL, 5.00 eq) in DMF (110 mL) and toluene (110 mL) was added NaOMe (4.32 g, 80.0 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr then was poured into ice water (500mL) and extracted with EA (300 mL X 3). The combined organic layers were washed with water (200mL X 4), dried over Na2SO4, filtered and concentrated. The residue was slurried with PE : DCM = 5 : 1 (120 mL) to give intermediate 7 (20.0 g, 51.4 mmol, 96.4% yield) as a yellow solid. LCMS: RT=0.635 min, m / z=389.1 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H), 4.03 (s, 3H), 3.51 (d, J = 18.0 Hz, 1H), 3.33 (d, J = 17.6 Hz, 1H), 1.60 (s, 3H).

[0519] Step 5. A solution of intermediate 7 (20.0 g, 51.4 mmol, 1.00 eq) in pyridine hydrochloride (60.0 g, 519 mmol, 10.1 eq) was stirred at 160 °C for 2 hrs. The mixture was poured into ice-water (400 mL), and the aqueous phase was extracted with EA (300 mL X 3). The combined organic layers were washed with brine (250 mL X 3), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was slurried with PE: DCM = 5 : 1 (120 mL) to give intermediate 8 (19.0 g, 50.6 mmol, 98.6% yield) as a yellow solid. LCMS: RT=0.589 min, m / z=375.0 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 3.46 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 18.0 Hz, 1H), 1.57 (s, 3H).

[0520] Step 6. To a solution of intermediate 8 (5.00 g, 13.3 mmol, 1.00 eq) in DMF (50.0 mL) were added intermediate 9 (3.57 g, 16.0 mmol, 1.20 eq) and K2CO3 (7.37 g, 53.3 mmol, 4.00 eq). The mixture was stirred at 60°C for 8 hrs then poured into ice-water (50.0 mL) then extracted with EA (20.0 mL X 3). The combined organic layers were washed with brine (20.0 mL X 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was slurried with PE : DCM = 5: 1 (60.0 mL) to give intermediate 10 (4.60 g, 8.89 mmol, 66.7% yield) as a yellow solid. LCMS: RT=0.698 min, m / z=517.1 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 4.26 (t, J = 6.4 Hz, 2H), 3.49 (d, J = 17.6 Hz, 1H), 3.32 (d, J = 17.6 Hz, 1H), 2.43 (t, J = 7.2 Hz, 2H), 2.06 – 1.99 (m, 2H), 1.59 (s, 3H), 1.40 (s, 9H).

[0521] Step 7. Intermediate 10 (4.60 g, 8.89 mmol, 1.00 eq) was purified by SFC seperation (SFC method 19). Intermediate 10a (2.10 g, 4.06 mmol, 45.7% yield) was obtained as aCooley Ref. CLBO-002 / 01WO 349489-2004 yellow solid. LCMS: RT=0.694 min, m / z=517.1 (LCMS method 2);SFC: RT=1.598 min, chiral purity=98.96% (SFC Method 2). Intermediate 10b (2.20 g, 4.25 mmol, 47.8% yield) was obtained as a yellow solid. LCMS: RT=0.695 min, m / z=517.1 (LCMS method 2); SFC: RT=1.955 min, chiral purity=98.76% (SFC Method 2).

[0522] Step 8a. To a solution of intermediate 10a (1.50 g, 3.21 mmol, 1.00 eq) in toluene (15.0 mL) was added MsOH (617 mg, 6.42 mmol, 459 μL, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr then poured into ice-water (50.0 mL) and extracted with EA (20.0 mL X 3). The combined organic layers were washed with brine (20.0 mL X 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Prep HPLC method 13) to give Compound 24a (1.05 g, 2.55 mmol, 79.6% yield, >95% purity) as a white solid. LCMS: RT=0.597 min, m / z=461.1 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.91 (s, 1H), 4.24 (t, J = 7.6 Hz, 2H), 3.49 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.28 – 2.25 (m, 2H), 1.68 (s, 3H); SFC: RT=1.511 min, chiral purity=99.19% (SFC Method 20).

[0523] Step 8b. To a solution of intermediate 10b (1.50 g, 3.21 mmol, 1.00 eq) in toluene (15.0 mL) was added MsOH (617 mg, 6.42 mmol, 458 uL, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr then poured into ice-water (50.0 mL), extracted with EA (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Prep HPLC method 13) to give Compound 24b (1.08 g, 2.63 mmol, 81.8% yield, >95% purity) as a white solid. LCMS: RT=0.597 min, m / z=461.1 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.91 (s, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.49 (d, J = 18.0 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.28 – 2.25 (m, 2H), 1.68 (s, 3H);SFC: RT=1.685 min, chiral purity=99.95% (SFC Method 20).

[0524] Example 4. Synthesis of (R)-4-((6,7-dichloro-2-(4-fluorophenyl)-2-methyl-1-oxo-2,3- dihydro-1H-inden-5-yl)oxy)butanoic acid (Compound 25a) & (S)-4-((6,7-dichloro-2-(4- fluorophenyl)-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)butanoic acid (Compound 25b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0525] Step 1. To a solution of AlCl3 (37.7 g, 282 mmol, 15.4 mL, 1.00 eq) in DCM (400 mL) was added intermediate 1 (53.6 g, 311 mmol, 42.6 mL, 1.10 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr before a solution of intermediate 2 (50.0 g, 282 mmol, 1.00 eq) in DCM (200 mL) was added at 0°C. The resulting mixture was stirred for another 10 hrs at 20°C then was added to ice cold HCl (6 M, 400 mL), and extracted with DCM (200 mL X 3). The combined organic layers were washed with brine (250 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was slurried with PE : EA = 3 : 1 (200 mL) to provide intermediate 3 (45.0 g, 144 mmol, 50.9% yield) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 7.82 (d, J = 8.8 Hz, 1H), 7.28 – 7.24 (m, 3H), 7.14 (t, J = 8.8 Hz, 2H), 4.30 (s, 2H), 3.95 (s, 3H).

[0526] Step 2. To a solution of intermediate 3 (45.0 g, 144 mmol, 1.00 eq) in Ac2O (90.0 mL) was added intermediate 4 (63.6 g, 622 mmol, 84.9 mL, 4.33 eq) at 0°C. The mixture was stirred at 20°C for 1 hr then was poured into ice-water (200 mL), exctracted with EA (50.0 mL X 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide intermediate 5 (40.0 g, 123 mmol, 85.6% yield) as a white solid. LCMS: RT=0.618 min, m / z = 325.1 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.8 Hz, 1H), 7.51 – 7.48 (m, 2H), 7.28 – 7.23 (m, 3H), 6.36 (s, 1H), 5.78 (s, 1H), 3.96 (s, 3H).

[0527] Step 3. A solution of intermediate 5 (35.0 g, 108 mmol, 1.00 eq) in DCM (100 mL) was added to H2SO4 (200 mL) at 60°C. The mixture was stirred at 60°C for 1 hr then wasCooley Ref. CLBO-002 / 01WO 349489-2004 poured into ice-water (2.00 L), filtered and concentrated in vacuo to provide intermediate 6 (34.0 g, 105 mmol, 97.1% yield) as a brown solid. LCMS: RT=0.590 min, m / z = 325.1(LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.25 – 7.22 (m, 2H), 7.17 – 7.13 (m, 3H), 4.08 (q, J = 4.4 Hz, 1H), 4.03 (s, 3H), 3.62 (dd, J1 = 17.6 Hz, J2 = 4.4 Hz, 1H), 3.14 (dd, J1 = 17.6 Hz, J2 = 4.4 Hz, 1H).

[0528] Step 4. To a mixture of intermediate 6 (30.0 g, 92.3 mmol, 1.00 eq) and MeI (65.5 g, 461 mmol, 28.7 mL, 5.00 eq) in DMF (150 mL) and toluene (150 mL) was added NaOMe (7.48 g, 139 mmol, 1.50 eq) in portions at 0°C. The mixture was stirred at 0°C for 0.5 hr then was poured into ice-water (1.00 L), extracted with EA (250 mL X 3). The combined organic layers were washed with brine (500 mL X 3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was slurried with PE : DCM = 3 : 1 (120mL) to give intermediate 7 (27.0 g, 79.6 mmol, 86.3%yield) as a yellow solid. LCMS: RT=0.612 min, m / z = 339.1(LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.31 – 7.28 (m, 2H), 7.16 – 7.10 (m, 3H), 4.02 (s, 3H), 3.47 (d, J = 18.0 Hz, 1H), 3.29 (d, J = 18.0 Hz, 1H), 1.55 (s, 3H).

[0529] Step 5. To a solution of intermediate 7 (10.0 g, 29.5 mmol, 1.00 eq) in toluene (100 mL) was added AlCl3 (11.8 g, 88.5 mmol, 4.83 mL, 3.00 eq) at 0°C. The mixture was stirred at 100°C for 1 hr then was poured into 12M HCl (50.0 mL) at 0 °C, diluted with H2O (100 mL), and extracted with EA (100mL X 3). The combined organic layers were washed with brine (150 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product that was triturated with PE: DCM = 5: 1 (30.0 mL) at 25°C for 30 min to provide intermediate 8 (9.50 g, 29.2 mmol, 99.1% yield) as a brown solid. LCMS: RT=0.553 min, m / z = 325.1 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.30 – 7.27 (m, 2H), 7.15 – 7.09 (m, 3H), 3.41 (d, J = 18.0 Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H), 1.52 (s, 3H).

[0530] Step 6. To a solution of intermediate 8 (5.00 g, 15.4 mmol, 1.00 eq) in DMF (50.0 mL) were added intermediate 9 (6.86 g, 30.8 mmol, 2.00 eq) and K2CO3 (8.50 g, 61.5 mmol, 4.00 eq). The mixture was stirred at 60°C for 3 hrs then was poured into ice-water (300 mL), extracted with EA (50.0 mLX3). The combined organic layers were washed with brine (100 mL X 3), dried over Na2SO4, filtered and concentrated in vacuo to provide a residue that was slurried with PE: DCM = 5: 1 (60.0 mL) to provide intermediate 10 (6.20 g, 13.3 mmol, 86.3% yield) as a yellow solid. LCMS: RT=0.673 min, m / z = 467.1(LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.35 – 7.32 (m, 2H), 7.20 – 7.15 (m, 2H), 4.30 (t, J = 5.6 Hz, 2H), 3.50 (d, J = 17.6 Hz, 1H), 3.22 (d, J = 18.0 Hz, 1H), 3.35 (d, J = 4.0 Hz, 1H), 2.47 (t, J = 7.2 Hz, 2H), 2.10 – 2.03 (m, 2H), 1.59 (s, 3H), 1.44 (s, 9H).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0531] Step 7. Intermediate 10 (7.40 g, 18.8 mmol, 1.00 eq) was purified by SFC seperation (SFC Method 25). Intermediate 10a (3.10 g, 6.63 mmol, 41.9% yield) was obtained as yellow solid. LCMS: RT=0.668 min m / z = 467.1 (LCMS method 2); SFC: RT=1.384 min, chiral purity 97.57% (SFC method 21).

[0532] Intermediate 10b (3.20 g, 6.85 mmol, 43.2% yield) was obtained as yellow solid. LCMS: RT=0.683 min m / z = 467.2(LCMS method 2); SFC: RT=1.582 min, chiral purity 98.56% (SFC method 21).

[0533]

[0534] Step 8a. To a solution of intermediate 10a (1.50 g, 3.21 mmol, 1.00 eq) in toluene (15.0 mL) was added MsOH (617 mg, 6.42 mmol, 459 μL, 2.00 eq) at 0°C. The mixture was stirred at 20°C for 1 hr then was poured in ice-water (50.0 mL), exctracted with EA (20.0 mL X 3). The combined organic layers were washed with brine (20.0 mL X 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Prep HPLC method 14) to provide Compound 25a (1.10 g, 2.67 mmol, 83.2% yield, 99.8% purity) as a white solid. LCMS: RT=0.565 min, m / z = 411.1 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.28 – 7.25 (m, 2H), 7.01 – 6.97 (m, 2H), 6.90 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.47 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.27 – 2.24 (m, 2H), 1.64 (s, 3H). SFC: RT=2.357 min, chiral purity=99.721% (SFC method 6).

[0535] Step 8b. To a solution of intermediate 10b (1.60 g, 3.42 mmol, 1.00 eq) in toluene (16.0 mL) was added MsOH (658 mg, 6.85 mmol, 489 μL, 2.00 eq) at 0°C. The mixture was stirred at 20°C for 1 hr then was poured into ice-water (50.0 mL), extracted with EA (20.0 mL X 3). The combined organic layers were washed with brine (20.0 mL X 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Prep HPLC method 15) to provide Compound 25b (1.20 g, 2.92mmol, 85.2% yield, 100% purity) as a white solid. LCMS: RT=0.581 min, m / z = 411.1(LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.28 – 7.25 (m, 2H), 7.01 – 6.97 (m, 2H), 6.89 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.47 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.27 – 2.24 (m, 2H), 1.64 (s, 3H). SFC: RT=1.899 min, chiral purity=99.277% (SFC method 6). Example 5. Synthesis of (R)-2-((2-butyl-6,7-dichloro-1-oxo-2-phenyl-2,3-dihydro-1H- inden-5-yl)oxy)acetic acid (Compound 31a), (S)-2-((2-butyl-6,7-dichloro-1-oxo-2-phenyl- 2,3-dihydro-1H-inden-5-yl)oxy)acetic acid (Compound 31b), (R)-4-((2-butyl-6,7- dichloro-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy)butanoic acid (Compound 33a),Cooley Ref. CLBO-002 / 01WO 349489-2004 and (S)-4-((2-butyl-6,7-dichloro-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy)butanoic

[0536] Step 1. To a solution of AlCl3 (19.6 g, 147 mmol, 1.00 eq) in DCM (200 mL) was added intermediate 2 (24.0 g, 162 mmol, 1.10 eq) at 0 °C., The mixture was stirred at 0 °C for 0.5 hr. Then to the mixture was added intermediate 1 (25.0 g, 147 mmol, 1.00 eq) in DCM (100 mL) at 0 °C. The mixture was stirred at 25°C for 12 hrs then was poured into 6 M HCl 200Cooley Ref. CLBO-002 / 01WO 349489-2004 mL at 0 °C and extracted with DCM (100 mL X 3). The combined organic layers were washed with brine (150 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was triturated with PE: DCM = 3: 1 (100 mL) at 25 °C for 30 min to provide intermediate 3 (25.0 g, 88.0 mmol, 59.9% yield) as a white solid. LCMS: RT=0.648 min, m / z = 295.0 (LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.8 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.25 - 7.21 (m, 4H), 4.29 (s, 2H), 3.94 (s, 3H).

[0537] Step 2. To a solution of intermediate 3 (20.0 g, 67.8 mmol, 1.00 eq) in Ac2O (40.0 mL) was added N,N,N',N'-tetramethylmethanediamine (30.0 g, 293 mmol, 40.0 mL, 4.33 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr then was poured into ice water (200 mL) at 0 °C and the resulting solid was filtered and collected, then concentrated under reduced pressure to provide intermediate 4 (20.0 g, 65.1 mmol, 96.1% yield) as a white solid. LCMS: RT=0.673, m / z = 307.1(LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.47 - 7.45 (m, 2H), 7.42 - 7.37 (m, 4H), 6.91 (d, J = 8.8 Hz, 1H), 6.18 (s, 1H), 5.79 (s, 1H), 3.97 (s, 3H).

[0538] Step 3. Into a solution of intermediate 4 (27.0 g, 87.9 mmol, 1.00 eq) in DCM (50.0 mL) was added H2SO4 (221 g, 2.21 mol, 120 mL, 98% purity, 25.0 eq) at 60 °C. The DCM was removed by distillation. The mixture was stirred at 60 °C for 1 hr then was poured into ice water (300 mL) and extracted with (DCM：MeOH = 10:1) (100 mL X 3). The combined organic layers were washed with brine (250 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product that was triturated with PE: DCM = 3: 1 (100 mL) at 25 °C for 30 min to provide intermediate 5 (13.0 g, 42.3 mmol, 48.1% yield) as a white solid LCMS: RT=0.633 min, m / z = 307.0 (LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.35 - 7.29 (m, 3H), 7.19 - 7.18 (m, 2H), 6.96 (s, 1H), 4.04 (s, 3H), 3.95 - 3.92 (m, 1H), 3.64 - 3.57 (m, 1H), 3.23 - 3.18 (m, 1H).

[0539] Step 4. To a solution of intermediate 5 (13.0 g, 42.3 mmol, 1.00 eq) and intermediate 6 (38.9 g, 212 mmol, 24.1 mL, 5.00 eq) in DMF (130 mL) and toluene (130 mL) was added NaOMe (3.43 g, 63.5 mmol, 1.50 eq) at 0-5 °C. The mixture was stirred at 0-5 °C for 1 hr then was poured into ice water (300 mL) and extracted with EA (200 mL X 3). The combined organic layers were washed with brine (500 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 5 / 1) to provide intermediate 7 (11.5 g, 31.7 mmol, 74.8% yield) as a yellow solid. LCMS: RT=0.723 min, m / z = 363.1(LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.39 - 7.29 (m, 4H), 7.24 - 7.20 (m, 1H), 6.92 (s, 1H), 4.03 (s, 3H),Cooley Ref. CLBO-002 / 01WO 349489-2004 3.56 - 3.51 (m, 1H), 3.33 - 3.28 (m, 1H), 2.16 - 1.96 (m, 2H), 1.36 - 1.10 (m, 4H), 0.86 (t, J = 7.6 Hz, 3H).

[0540] Step 5. To a solution of intermediate 7 (11.5 g, 31.7 mmol, 1.00 eq) in toluene (120 mL) was added AlCl3 (12.7 g, 95.0 mmol, 5.19 mL, 3.00 eq) at 0-5 °C. The mixture was stirred at 100 °C for 1 hr then was poured into 12 M HCl (50.0 mL) at 0 °C, then diluted with H2O (100 mL) and extracted with EA (100 mL X 3). The combined organic layers were washed with brine (150 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product that was triturated with PE: DCM = 5: 1 (30.0 mL) at 25 °C for 30 min to provide intermediate 8 (10.0 g, 28.6 mmol, 90.5% yield) as an off-white solid. LCMS: RT=0.658 min, m / z = 349.1(LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.39 - 7.37 (m, 2H), 7.32 - 7.29 (m, 2H), 7.23 - 7.20 (m, 1H), 7.05 (s, 1H), 6.40 (s, 1H), 3.54 - 3.50 (m, 1H), 3.30 - 3.25 (m, 1H), 2.19 - 1.94 (m, 2H), 1.36 - 1.09 (m, 4H), 0.86 (t, J = 7.6 Hz, 3H).

[0541] Step 6. Intermediate 8 was separated by SFC (SFC method 26) to give intermediate 8A (4.20 g, 12.0 mmol) and intermediate 8B (4.10 g, 11.7 mmol).

[0542] Intermediate 8A (4.20 g, 12.0 mmol) was obtained as a pink solid. LCMS: RT=0.664 min, m / z = 349.1(LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.26 (m, 4H), 7.21 - 7.17 (m, 1H), 6.85 (s, 1H), 3.40 - 3.35 (m, 1H), 3.19 - 3.15 (m, 1H), 2.12 - 1.98 (m, 1H), 1.84 - 1.76 (m, 1H), 1.30 - 1.21 (m, 2H), 1.13 - 0.99 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H). SFC: RT=1.792 min, chiral purity=100% (SFC method 9).

[0543] Intermediate 8B (4.10 g, 11.7 mmol) was obtained as a pink solid. LCMS: RT=0.664 min, m / z = 349.1(LCMS method 2);1H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.26 (m, 4H), 7.20 - 7.16 (m, 1H), 6.82 (s, 1H), 3.38 - 3.33 (m, 1H), 3.18 - 3.13 (m, 1H), 2.08 - 1.99 (m, 1H), 1.83 - 1.76 (m, 1H), 1.30 - 1.19 (m, 2H), 1.14 - 0.98 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H). SFC: RT=2.077 min, chiral purity=99.36% (SFC method 9).

[0544] Step 7a. To a solution of intermediate 8A (1.80 g, 5.15 mmol, 1.00 eq) in DMF (20.0 mL) were added K2CO3 (2.85 g, 20.6 mmol, 4.00 eq) and intermediate 9 (2.01 g, 10.3 mmol, 1.52 mL, 2 eq). The mixture was stirred at 80 °C for 12 hrs then was diluted with H2O (50.0 mL) and extracted with EA (50.0 mL X 3). The combined organic layers were washed with brine (150 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE: EA = 100: 1 to 5: 1) to provide intermediate 10A (2.30 g, 4.96 mmol, 96.3% yield) as a yellow oil. LCMS: RT=0.748 min m / z = 407.1 (LCMS method 2).

[0545] Step 8a. To a solution of intermediate 10A (2.50 g, 5.39 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (12.7 g, 112 mmol, 8.33 mL, 20.7 eq). The mixture was stirred at 20 °CCooley Ref. CLBO-002 / 01WO 349489-2004 for 1 hr then was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Prep HPLC method 16) to provide Compound 31a (1.67 g, 4.07 mmol, 75.4% yield, 99.3% purity) as an off-white solid. LCMS: RT=0.650 min, m / z = 407.1(LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.38 - 7.29 (m, 4H), 7.24 - 7.20 (m, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.55 - 3.51 (m, 1H), 3.32 - 3.28 (m, 1H), 2.17 - 1.94 (m, 2H), 1.35 - 1.09 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H). SFC: RT=0.953 min, chiral purity=99.13% (SFC method 22).

[0546] Step 7b. To a solution of intermediate 8B (1.80 g, 5.15 mmol, 1.00 eq) in DMF (20.0 mL) were added K2CO3 (2.85 g, 20.6 mmol, 4.00 eq) and intermediate 9 (2.01 g, 10.3 mmol, 1.52 mL, 2.00 eq). The mixture was stirred at 80 °C for 12 hrs then was diluted with H2O (50.0 mL) and extracted with EA (50.0mL X 3). The combined organic layers were washed with brine (150mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residueresidue that was purified by column chromatography (SiO2, PE: EA = 100: 1 to 5: 1)) to provide intermediate 10B (2.35 g, 5.07 mmol, 98.40% yield) as a yellow oil. LCMS: RT=0.753, m / z = 463.2 (LCMS method 2).

[0547] Step 8b. To a solution of intermediate 10B (2.50 g, 5.39 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (12.7 g, 112 mmol, 8.33 mL, 20.7 eq). The mixture was stirred at 20 °C for 1 hr then was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC method 16) to provide Compound 31b (1.55 g, 3.78 mmol, 69.9% yield, 99.2% purity) as a yellow solid. LCMS: RT=0.652 min, m / z = 407.1(LCMS method 2);1H NMR (400 MHz, CDCl3) δ 7.38 - 7.29 (m, 4H), 7.24 - 7.20 (m, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.55 - 3.51 (m, 1H), 3.32 - 3.28 (m, 1H), 2.17 - 1.94 (m, 2H), 1.33 - 1.09 (m, 4H), 0.85 (t, J = 7.6 Hz, 3H). SFC: RT=1.278 min, chiral purity=99.68% (SFC method 22).

[0548] Step 9a. To a solution of intermediate 8A (1.80 g, 5.15 mmol, 1.00 eq) in DMF (20.0 mL) were added K2CO3 (2.85 g, 20.6 mmol, 4.00 eq) and intermediate 11 (2.30 g, 10.3 mmol, 2 eq). The mixture was stirred at 80 °C for 12 hrs then was diluted with H2O (50.0 mL) and extracted with EA (30.0 mLX 3). The combined organic layers were washed with brine (50.0 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE: EA = 100: 1 to 5: 1) to provide intermediate 12A (2.3 g, 4.68 mmol, 90.8% yield) as a yellow oil. LCMS:RT=0.787 min, m / z = 491.2 (LCMS method 2).

[0549] Step 10a. To a solution of intermediate 12A (2.60 g, 5.29 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (15.3 g, 134 mmol, 10.0 mL, 25.4 eq). The mixture was stirred at 20 °C for 1 hr then was diluted with H2O (50.0 mL) and extracted with EA (30.0 mL X 3). TheCooley Ref. CLBO-002 / 01WO 349489-2004 combined organic layers were washed with brine (50.0 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC method 17) to provide Compound 33a (1.95 g, 4.46 mmol, 84.2% yield, 99.5% purity) as a white solid. LCMS: RT=0.672 min, m / z = 435.1 (LCMS Method 2);1H NMR (400 MHz, CDCl3) δ 7.39 - 7.37 (m, 2H), 7.32 - 7.28 (m, 2H), 7.23 - 7.19 (m, 1H), 6.91 (s, 1H), 4.22 (t, J = 6.0 Hz, 2H), 3.53 - 3.49 (m, 1H), 3.31 - 3.26 (m, 1H), 2.68 (t, J = 6.8 Hz, 2H), 2.28 - 1.96 (m, 4H), 1.35 - 1.09 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H); SFC: RT=0.765 min, chiral purtity=99.443 % (SFC method 17).

[0550] Step 9b. To a solution of intermediate 8B (1.80 g, 5.15 mmol, 1.00 eq) in DMF (20.0 mL) were added K2CO3 (2.85 g, 20.6 mmol, 4.00 eq) and intermediate 11 (2.30 g, 10.3 mmol, 2.00 eq). The mixture was stirred at 80 °C for 12 hrs then was diluted with H2O (50.0 mL) and extracted with EA (30.0mL X 3). The combined organic layers were washed with brine (50.0mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE: EA = 100: 1 to 5) to provide intermediate 12B (2.3 g, 4.68 mmol, 90.8% yield) as a yellow oil. LCMS: RT=0.781 min, m / z = 491.2 (LCMS method 2).

[0551] Step 10b. To a solution of intermediate 12B (2.60 g, 5.29 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (15.3 g, 134 mmol, 10.0 mL, 25.4 eq). The mixture was stirred at 20 °C for 1 hr then was diluted with H2O (50.0 mL) and extracted with EA (30.0 mL X 3). The combined organic layers were washed with brine (50.0 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC method 18) to provide Compound 33b (1.79 g, 4.00 mmol, 75.6% yield, 97.3% purity) as a white solid. LCMS: RT=0.675 min, m / z=436.8 (LCMS method 2);1H (400 MHz, CDCl3) δ 7.39 - 7.37 (m, 2H), 7.32 - 7.28 (m, 2H), 7.23 - 7.19 (m, 1H), 6.91 (s, 1H), 4.22 (t, J = 6.0 Hz, 2H), 3.53 - 3.49 (m, 1H), 3.31 - 3.26 (m, 1H), 2.68 (t, J = 6.8 Hz, 2H), 2.28 - 1.96 (m, 4H), 1.35 - 1.09 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H); LCMS: RT= 0.675 min, m / z = 435.2. SFC: RT=1.031 min, chiral purity=98.902% (SFC method 17). Example 6. Synthesis of (S)-6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone (Compound 61a) and (R)-6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone (Compound 61b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0552] Step 1. Into a solution of AlCl3 (67.8 g, 508 mmol, 1.00 eq) in DCM (800 mL) was added phenacetyl chloride (86.5 g, 559 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. A solution of 1,2-dichloro-3-methoxybenzene (90.0 g, 508 mmol, 1.00 eq) in DCM (400 mL) was added at 0 °C. The mixture was stirred at 25°C for 12 hrs. The reaction mixture was poured into 800 mL of 6 M HCl at 0°C and extracted with DCM (400 mL X 3). The combined organic layers were washed with brine (600 mLX 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was triturated with PE: DCM = 3: 1 (400 mL) at 25 °C for 30 min to provide intermediate 3 (76.0 g, 251 mmol, 49.4% yield, 97.5% purity) as a white solid. LCMS: RT = 0.660 min, m / z = 295.0 (LCMS Method 1);1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.4 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.26 - 7.18 (m, 4H), 4.29 (s, 2H), 3.94 (s, 3H).

[0553] Step 2. Into a solution of Intermediate 3 (75.0 g, 254 mmol, 1.00 eq) in Ac2O (150 mL) was added N,N,N',N'-tetramethylmethanediamine (112 g, 1.10 mol, 150 mL, 4.33 eq) at 0 °C. The mixture was stirred at 25 °C for 1hr then was poured into 2 L of ice H20 at 0 °C and the resulting solid precipitate was filtered and collected, then concentrated under reduced pressure to give Intermediate 5 (62.0 g, 202 mmol, 79.4% yield) as a white solid. LCMS: RT = 0.679 min, m / z = 309.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.51 - 7.44 (m, 2H), 7.42 - 7.33 (m, 4H), 6.91 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 5.79 (s, 1H),3.97 (s, 3H).

[0554] Step 3. A solution of Intermediate 5 (60.0 g, 195 mmol, 1.00 eq) in DCM (120 mL) was added to H2SO4 (489 g, 4.88 mol, 265 mL, 25.0 eq) at 60 °C. The reaction mixture was concentrated under reduced pressure to remove DCM. The mixture was stirred at 60 °C for 1h then was poured into 3 L of ice water and extracted 3 times with 1L of (DCM: MeOH = 10: 1). The combined organic layers were washed with brine (1 LX 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product that was triturated with PE: DCM = 3: 1 (200 ml) at 25 °C for 30 min to provide Intermediate 6 (39.5 g, 128 mmol, 65.8% yield) as an off-white solid. LC / MS: RT = 0.644 min, m / z = 307.0 (LCMS Method 1);1HNMRCooley Ref. CLBO-002 / 01WO 349489-2004 (400 MHz, CDCl3) δ 7.39 - 7.28 (m, 3H), 7.22 - 7.17 (m, 2H), 6.95 (s, 1H), 4.03 (s, 3H), 3.98 - 3.87 (m, 1H), 3.66 - 3.52 (m, 1H), 3.28 - 3.17 (m,1H).

[0555] Step 4. A mixture of intermediate 6 (39.5 g, 129 mmol, 1.00 eq), MeI (91.2 g, 643 mmol, 5.00 eq) in DMF (200 mL) and toluene (200 mL) was degassed and purged with N2 (3 X). MeONa (10.4 g, 193 mmol, 1.50 eq) was added portion wise at 0°C and the mixture was stirred at 0 to 10 °C for 30 min under N2 atmosphere. The reaction mixture was poured into 2L of ice H2O and extracted with EA (1 LX 3). The combined organic layers were washed with brine (1 LX 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a residue that was triturated with PE: DCM = 5: 1 (300 mL) at 25 °C for 2 h to provide intermediate 7 (33.1 g, 103 mmol, 80.1% yield) as a yellow solid. LCMS: RT = 0.674 min, m / z =321.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.36 – 7.29 (m, 4H), 7.27 – 7.21 (m, 1H), 6.93 (s, 1H), 4.03 (s, 3H), 3.54 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 1.68 (s, 3H).

[0556] Step 5. Intermediate 7 (30.0 g) was separated by prep-SFC (SFC Method 19) to provide:

[0557] Compound 61b (13.6 g, 98.0% purity) was obtained as yellow solid. LCMS:RT = 0.677min, m / z =321.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 6.92 (s, 1H), 4.03 (s, 3H), 3.54 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 1.68 (s, 3H); SFC: RT=1.832 min, chiral purity: 100% (SFC Method 14); OR: Anton Paar MCP 5100; 0.8512 g / 100 mL in acetone; 589 nM wavelength; Optical Rotation= -0.607o, specific rotation -71.3o.

[0558] Compound 61a (16.4 g, 98.9% purity) was obtained as white solid. LCMS:RT = 0.677min, m / z =321.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 6.92 (s, 1H), 4.03 (s, 3H), 3.53 (d, J = 17.6 Hz, 1H), 3.22 (d, J = 17.6 Hz, 1H), 1.67 (s, 3H); SFC: RT=2.212 min, chiral purity= 99.8% (SFC Method 14); OR: Anton Paar MCP 5100; 0.8388 g / 100 mL in acetone, 589 nM wavelength; Optical Rotation= 0.581o; specific rotation 69.3o. Example 7. Synthesis of (R)-6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone (Compound 60b).Cooley Ref. CLBO-002 / 01WO 349489-2004Compound 61b Compound 60b

[0559] Step 1. Into a solution of Compound 61b (11.5 g, 35.0 mmol, 1.00 eq) in toluene (600 mL) was added AlCl3 (37.4 g, 280 mmol, 8.00 eq) at 25°C. The mixture was stirred at 45°C for 2 hrs. The mixture was poured into ice-water (1000 mL) and extracted with EA (800 mLX3). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, then filtered and concentrated in vacuo to give 10.8 g of a brown solid. A sample of the crude product (100 mg) was triturated with PE: DCM = 3:1（2 ml)at 25°C for 10 min. Compound 60b (20.12 mg, 98.7% purity) was obtained as a yellow solid. LCMS:RT = 0.607min, m / z =307.0 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.25 - 7.20 (m, 1H), 7.05 (s, 1H), 6.32 (s, 1H), 3.52 (d, J = 18.0 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 1.66 (s, 3H); SFC: Chiral purity: 100% 1.487 min (SFC Method 2).

[0560] Compound 60a was prepared from Compound 61a using Example 7. Compound 60a was obtained as a yellow solid. LCMS: RT = 0.611 min, m / z = 307.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.41 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 7.05 (s, 1H), 6.29 (s, 1H), 3.52 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 1.66 (s, 3H); SFC: Chiral purity: 100% 1.801 min (SFC Method 2). Example 8. Synthesis of tert-butyl 4-[(R)-6,7-dichloro-2-methyl-1-oxo-2-phenyl-5- indanyloxy]butyrate (Compound 62b)Compound 60b60 C, 4h Compound 62b

[0561] Step 1. Into a solution of Compound 60b (10.0 g, 32.5 mmol, 1.00 eq) in DMF (110 mL) were added tert-butyl 4-bromobutanoate (14.5 g, 65.1 mmol, 2.00 eq) and K2CO3 (18.0 g, 130 mmol, 4.00 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was poured into ice- H2O (1 L) and extracted with EA (600 mL X 3). The combined organic layers were washed with brine (500 mL X 2), dried over Na2SO4, filtered and concentrated to provide 12.6 g of a brown oil. A sample of the residue (100 mg) was purified by prep-TLC (SiO2, PE:Cooley Ref. CLBO-002 / 01WO 349489-2004 EA = 3:1) to provide Compound 62b (10.90 mg, 99.2% purity) as a yellow gum. LCMS: RT = 0.731 min, m / z = 449.1 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 6.90 (s, 1H), 4.20 (t, J = 6.40 Hz, 2H), 3.51 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.51 (t, J = 7.20 Hz, 2H), 2.24 – 2.13 (m, 2H),1.66 (s, 3H),1.47 (s, 9H)); SFC: RT= 1.963 min, Chiral purity=99.89% (SFC Method 2).

[0562] Compound 62a was prepared from Compound 60a using example 8. Yellow gum. LCMS: RT = 0.733 min, m / z = 449.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.33 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 6.90 (s, 1H), 4.20 (t, J = 6.00 Hz, 2H), 3.51 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 2.51 (t, J = 7.60 Hz, 2H), 2.25 – 2.11 (m, 2H),1.66 (s, 3H),1.47 (s, 9H); SFC:RT= 2.388 min (SFC Method 2). Example 9. Synthesis of N-methyl[(R)-6,7-dichloro-2-methyl-1-oxo-2-[p- (trifluoromethyl) phenyl]-5-indanyloxy]acetamide (Compound 59b)Compound 1aCompound 59b

[0563] Step 1. Methanamine hydrochloride (11.7 mg, 173 μmol, 1.5 eq) and DIEA (74.6 mg, 577 μmol, 5 eq) were added into a solution of Compound 1a (50 mg, 115 μmol, 1 eq) in DCM (2 mL). The mixture was cooled to 0 to 5 °C, and T4P (166 mg, 231 μmol, 50% purity, 2 eq) was added. The mixture was stirred at 20 to 25 °C for 1 hr. The reaction mixture was diluted with H2O (5 mL) then extracted with DCM (5 mL X2). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by Prep-HPLC (Prep HPLC Method 1) the desired fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 59b (26.91 mg, 60.30 μmol, 52.25% yield, 100% purity) as a white solid. LCMS: RT=0.638 min, (M+H)+: 446.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.90 (s, 1H), 6.72 (s, 1H), 4.65 (s, 2H), 3.54 (d, J = 17.6 Hz, 1H), 3.28 (d, J = 17.6 Hz, 1H), 2.99 (d, J = 5.2 Hz, 3H), 1.69 (s, 3H); SFC: RT=4.878 min, 100% chiral purity (SFC Method 2).

[0564] Compound 59a was prepared from Compound 1b using example 9. White solid. LCMS: RT=0.637 min, (M+H)+: 446.1(LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.90 (s, 1H), 6.71 (s, 1H), 4.65 (s, 2H), 3.54Cooley Ref. CLBO-002 / 01WO 349489-2004 (d, J = 18.0 Hz, 1H), 3.28 (d, J = 18.0 Hz, 1H), 2.99 (d, J = 4.8 Hz, 3H), 1.69 (s, 3H); SFC: RT=4.188, 100% chiral purity (SFC Method 2).

[0565] Compound 58b was prepared from Compound 1a and N-methylmethanamine hydrochloride using example 9. White solid. LCMS: RT=0.639 min (M+H)+: 460.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 4.93 (s, 2H), 3.49 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 3.16 (s, 3H), 3.01 (s, 3H), 1.67 (s, 3H); SFC: RT=1.429 min, 100% chiral purity (SFC Method 7).

[0566] Compound 58a was prepared from Compound 1b and N-methylmethanamine hydrochloride using example 9. White solid. LCMS: RT=0.641 min, (M+H)+: 460.1 (LCMS Method 1).1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 4.93 (s, 2H), 3.49 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 3.16 (s, 3H), 3.01 (s, 3H), 1.67 (s, 3H); SFC: RT=1.600 min, 99.9% chiral purity (SFC Method 7).

[0567] Compound 57b was prepared from Compound 23a and methanamine hydrochloride using example 9. White solid. LCMS: RT = 0.595 min, m / z = 406.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.25 - 7.19 (m, 1H), 6.91 (s, 1H), 5.55 (s, 1H), 4.23 (t, J = 6.00 Hz, 2H), 3.52 (d, J = 18.0 Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H), 2.83 (d, J = 4.80 Hz, 3H), 2.52 – 2.42 (m, 2H), 2.28 – 2.20 (m, 2H), 1.66 (s, 3H); SFC: RT=1.981 min, chiral purity 100% (SFC Method 3).

[0568] Compound 57a was prepared from Compound 23b and methanamine hydrochloride using example 9. Yellow solid. LCMS: RT = 0.602 min, m / z = 406.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.21 (m, 1H), 6.92 (s, 1H), 5.55 (s, 1H), 4.23 (t, J = 6.00 Hz, 2H), 3.52 (d, J = 18.0 Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H), 2.83 (d, J = 4.80 Hz, 3H), 2.52 – 2.42 (m, 2H), 2.28 – 2.20 (m, 2H), 1.66 (s, 3H); SFC: RT=2.231 min, Chiral purity: 100% (SFC Method 3).

[0569] Compound 56a (1041) was prepared from Compound 23a and N-methylmethanamine hydrochloride using example 9. Yellow solid. LCMS: RT = 0.628 min, m / z = 420.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.33 - 7.28 (m, 4H), 7.25 - 7.19 (m, 1H), 6.94 (s, 1H), 4.26 (t, J = 6.00 Hz, 2H), 3.51 (d, J = 17.2 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.61 (d, J = 6.80 Hz, 2H), 2.25 (d, J = 6.00 Hz, 2H), 1.66 (s, 3H); SFC: RT=2.127 min, 100% chiral purity (SFC Method 3).

[0570] Compound 54 was prepared from Compound 23b and N-methylmethanamine hydrochloride using example 9. White solid. LCMS: RT = 0.632 min, m / z = 420.1(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 4H), 7.25 - 7.18 (m, 1H), 6.94 (s, 1H), 4.25 (t, J = 6.00 Hz, 2H), 3.50 (d, J = 17.2 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 3.04 (s,Cooley Ref. CLBO-002 / 01WO 349489-2004 3H), 2.96 (s, 3H), 2.60 (d, J = 6.80 Hz, 2H), 2.24 (d, J = 6.00 Hz, 2H), 1.65 (s, 3H); SFC: RT=2.589 min, 100% chiral purity (SFC Method 3). Example 10. Synthesis of methyl [(R)-6,7-dichloro-2-methyl-1-oxo-2-phenyl-5- indanyloxy] acetate (Compound 55b)

[0571] Step 1. Into a solution of Compound 60b (50.0 mg, 163 μmol, 1.00 eq) in DMF (1 mL) were added methyl bromoacetate (37.4 mg, 244 μmol, 1.50 eq) and K2CO3 (67.5 mg, 488 μmol, 3.00 eq). The mixture was stirred at 60 °C for 1hr then poured into H2O (2 mL) and extracted with EA (1 mLX3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue that was purified by prep-HPLC (Prep HPLC Method 2). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 55b (17.30 mg, 45.62 μmol, 28.03% yield, 100% purity) as a yellow solid. LCMS: RT = 0.648 min, m / z = 379.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 6.77 (s, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 3.51 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 1.66 (s, 3H); SFC: RT=1.830 min, 100% chiral purity (SFC Method 3).

[0572] Compound 55a was prepared from Compound 60a using example 10. White solid. LCMS: RT = 0.651 min, m / z = 379.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 6.77 (s, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 3.51 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 1.66 (s, 3H); SFC: RT=2.414 min, 99.801% chiral purity (SFC Method 3).

[0573] Compound 18a was prepared from Intermediate 8a (Example 2) and methyl bromoacetate using example 10. White solid. LCMS: RT=0.675 min, (M+H) +: 447.0(LCMS Method 1).1H NMR (400 MHz, CDCl3)δ7.56 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.79 (s, 1H), 4.85 (s, 2H), 3.85 (s, 3H), 3.48 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 1.67 (s, 3H); SFC: RT=1.663 min, chiral purity 100% (SFC Method 6).

[0574] Compound 18b was prepared from Intermediate 8B (Example 2) and methyl bromoacetate using example 10. White solid. LCMS: RT=0.670 min, (M+H)+: 447.0(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H),Cooley Ref. CLBO-002 / 01WO 349489-2004 6.79 (s, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 3.48 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 1.67 (s, 3H); SFC: RT=1.872 min, chiral purity 100% (SFC Method 6). Example 11. Synthesis of 2-[(R)-6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy]-2- methylpropionic acid (Compound 53b)

[0575] Step 1. Into a solution of Compound 60b (100 mg, 326 μmol, 1.00 eq) in DMF (1 mL) were added K2CO3 (180 mg, 1.30 mmol, 4.00 eq) and tert-butyl 2-bromo-2-methylpropanoate (218 mg, 977 μmol, 3.00 eq). The mixture was stirred at 90 °C for 24 hrs. The mixture was poured into H2O (2 mL) and extracted with EA (1 mL X3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated to provide intermediate 1 (140 mg, 311.55 μmol, 95.70% yield) as a brown oil. LCMS: RT = 0.736 min, m / z = 449.1 (LCMS Method 1).

[0576] Step 2. Into a solution of intermediate 1 (120 mg, 267 μmol, 1.00 eq) in DCM (1 mL) was added TFA (761 mg, 6.68 mmol, 25.0 eq). The mixture was stirred at 20 °C for 6 hrs. The reaction mixture was quenched by the addition of H2O (2mL) and then extracted with DCM (1mL X2). The combined organic layers were concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC Method 3). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 53b (29.33 mg, 74.58 μmol, 27.93% yield, 100% purity) as a white solid. LCMS: RT = 0.635 min, m / z = 393.1(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.35 - 7.28 (m, 4H), 7.25 - 7.21 (m, 1H), 6.89 (s, 1H), 3.50 (t, J = 17.6 Hz, 1H), 3.19 (d, J = 17.2 Hz, 1H), 1.78 (s, 6H), 1.65 (s, 3H); SFC: RT=1.274 min, 100% chiral purity(SFC Method 2).

[0577] Compound 53a was prepared from Compound 60a using example 11. White solid. LCMS: RT = 0.631 min, m / z = 393.0(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.35 - 7.28 (m, 4H), 7.25 - 7.20 (m, 1H), 6.89 (s, 1H), 3.49 (t, J = 17.6 Hz, 1H), 3.19 (d, J = 17.6 Hz, 1H), 1.78 (s, 6H), 1.65 (s, 3H); SFC: RT=1.743 min, 99.721 % chiral purity (SFC Method 2).

[0578] Compound 47a was prepared from intermediate 8b (Example 2) using example 11. White solid. LCMS: RT=0.674 min, m / z=461.1 (M+H)+(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 3.48 (d, J =Cooley Ref. CLBO-002 / 01WO 349489-2004 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 1.79 (s, 6H), 1.67 (s, 3H); SFC:RT=1.952 min, 99.6% chiral purity (SFC Method 2).

[0579] Compound 47b was prepared from intermediate 8a (Example 2) using example 11. Yellow solid. LCMS: RT=0.671 min, m / z=461.1 (M+H)+(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 3.48 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 1.79 (s, 6H), 1.67 (s, 3H). SFC:RT=1.67 min, 99.96% chiral purity (SFC Method 2).

[0580] Compound 51a was prepared from intermediate 8b (Example 2) and tert-butyl 4- bromobutanoate using example 11. LCMS: RT=0.660 min, m / z=475.1 (M+H)+(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 18.0 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 2.51 (t, J = 7.2 Hz, 2H), 2.01-1.97 (m, 2H), 1.93-1.88 (m, 2H), 1.68 (s, 3H); SFC:RT=2.185 min, 99.9% chiral purity (SFC Method 2).

[0581] Compound 51b was prepared from intermediate 8a (Example 2) and tert-butyl 4- bromobutanoate using example 11. LCMS: RT=0.657 min, m / z=475.1 (M+H)+(LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 18.0 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 2.51 (t, J = 7.2 Hz, 2H), 2.01-1.97 (m, 2H), 1.93-1.88 (m, 2H), 1.68 (s, 3H); SFC:RT=1.81 min, 99.9% chiral purity (SFC Method 2). Example 12. Synthesis of 3-[(R)-6,7-dichloro-2-methyl-1-oxo-2-[p-(trifluoromethyl) phenyl] - 5-indanyloxy] propionic acid (Compound 52b)

[0582] Step 1. To a mixture of compound intermediate 8A (Example 2) (100 mg, 256 μmol, 1 eq), tert-butyl 3-hydroxypropanoate (112.8 mg, 772 μmol, 3 eq) and PPh3 (202 mg, 772 μmol, 3 eq) in THF (1 mL) was added DIAD (156.2 mg, 772 μmol, 3 eq) at 0 to 5 °C under an atmosphere of N2. The mixture was stirred at 20 to 25 °C for 12 hrs then diluted with H2O (10 mL) and extracted with EA (10 mL X 2). The combined organic layers were washed with brine (10 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude residue that was purified by Prep-TLC (SiO2, PE: EA = 3: 1) to provideCooley Ref. CLBO-002 / 01WO 349489-2004 intermediate 1 (70 mg, 94.2% purity) as a yellow oil. LCMS: RT= 0.736, (M+H)+: 503.2 (LCMS Method 1).

[0583] Step 2. Into a solution of intermediate 1 (70 mg, 131 μmol, 1 eq) in toluene (1 mL) was added MsOH (25.2 mg, 262 μmol, 2 eq) at 20 to 25 °C. The mixture was stirred at 20 to 25 °C for 1 hr then poured into ice H2O (5 mL) and extracted with EA (5 mL X2). The combined organic layers were washed with brine (10 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Prep HPLC Method 4), the fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 52b (33.7 mg, 75.35 μmol, 57.5% yield, 100% purity) as a yellow solid. LCMS: RT=0.730, (M-H)+: 445.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 4.44 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 3.02 (t, J = 6.4 Hz, 2H), 1.68 (s, 3H); SFC:RT=1.381 min, chiral purity 99.0% (SFC Method 16).

[0584] Compound 52a was prepared from intermediate 8b (Example 2) using example 12. Yellow solid. LCMS: RT=0.638 min (M-H)+: 445.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 4.44 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 18.0 Hz, 1H), 3.25 (d, J = 18.0 Hz, 1H), 3.02 (t, J = 6.4 Hz, 2H), 1.68 (s, 3H); SFC: RT=1.674 min, chiral purity 99.7% (SFC Method 16).

[0585] Compound 48a was prepared from Compound 60a using example 12. White solid. LCMS: RT=0.609 min (M-H)+: 379.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 6.93 (s, 1H), 4.43 (t, J = 6.00 Hz, 2H), 3.53 (d, J = 17.6 Hz, 1H), 3.22 (d, J = 18.0 Hz, 1H), 3.01 (t, J = 6.40 Hz, 2H), 1.67 (s, 3H); SFC: RT=2.024 min, chiral purity 99.5% (SFC Method 14).

[0586] Compound 48b was prepared from Compound 60b using example 12. White solid. LCMS: RT=0.604 min (M-H)+: 379.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 6.93 (s, 1H), 4.43 (t, J = 6.00 Hz, 2H), 3.53 (d, J = 18.0 Hz, 1H), 3.22 (d, J = 18.0 Hz, 1H), 3.01 (t, J = 6.40 Hz, 2H), 1.67 (s, 3H); SFC: RT=1.82 min, chiral purity 99.5% (SFC Method 14). Example 13. Synthesis of (R)-6,7-dichloro-5-(2-hydroxyethoxy)-2-methyl-2-phenyl-1- indanone (Compound 50b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0587] Step 1. Into a solution of Compound 60b (50.0 mg, 163 μmol, 1.00 eq) in DMF (1 mL) were added K2CO3 (67.5 mg, 488 μmol, 3.00 eq) and 2-hydroxyethyl 4-methylbenzene- 1-sulfonate (70.4 mg, 326 μmol, 2.00 eq). The mixture was stirred at 80 °C for 24 hrs then poured into H2O (2 mL), extracted with EA (1 mL X3). The combined organic layers were washed with H2O (2 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue that was purified by prep-TLC (SiO2, PE: EA=1:1, Rf = 0.25) to provide 50 mg of a brown solid. A 20 mg portion was further purified by prep-HPLC (Prep HPLC Method 5). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 50b (4.93 mg, 13.97 μmol, 8.58% yield, 99.5% purity) as an off-white solid. LCMS: RT = 2.570 min, m / z = 351.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 6.93 (s, 1H), 4.27 (d, J = 4.0 Hz, 2H), 4.08 (d, J = 4.0 Hz, 2H), 3.53 (d, J = 17.6 Hz, 1H), 3.22 (d, J = 17.6 Hz, 1H), 2.15 (s, 1H), 1.67 (s, 3H); SFC: RT= 1.542, chiral purity: 100% (SFC Method 3).

[0588] Compound 50a was prepared from Compound 60a using example 13. Off-white solid. LCMS: RT = 2.572 min, m / z = 351.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 6.93 (s, 1H), 4.27 (d, J = 4.0 Hz, 2H), 4.08 (d, J = 4.0 Hz, 2H), 3.53 (d, J = 17.6 Hz, 1H), 3.22 (d, J = 17.6 Hz, 1H), 2.19 (s, 1H), 1.67 (s, 3H); SFC (RT=1.898 min, chiral purity: 99.7% (SFC Method 3).

[0589] Compound 49a was prepared from intermediate 8B (Example 2) using example 13. White solid. LCMS: RT = 0.642 min, m / z = 419.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 4.28 (t, J = 4.4 Hz, 2H), 4.09 (t, J = 4.4 Hz, 2H), 3.52 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 1.69 (s, 3H); SFC (RT=2.15 min, chiral purity: 99.5% (SFC Method 2).

[0590] Compound 49b was prepared from intermediate 8A (Example 2) using example 13. White solid. LCMS: RT = 0.640 min, m / z = 419.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 4.28 (t, J = 4.4 Hz, 2H), 4.09 (t, J = 4.4 Hz, 2H), 3.52 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 1.69 (s, 3H); SFC (RT=1.753 min, chiral purity: 99.6% (SFC Method 2).Cooley Ref. CLBO-002 / 01WO 349489-2004 Example 14. Synthesis of 4-[(R)-2-methyl-1-oxo-2-phenyl-5-indanyloxy]butyric acid (Compound 46b)Compound 23a Compound 46b

[0591] Step 1. Into a solution of Compound 23a (100 mg, 253 μmol, 1.00 eq) in THF (1 mL) and H2O (0.1 mL) were added KF (29.4 mg, 506 μmol, 2.00 eq), MeSiH(OTMS)2 (225 mg, 1.01 mmol, 4.00 eq) and Pd(OAc)2 (5.68 mg, 25.3 μmol, 0.100 eq). The mixture was stirred at 25 °C for 48 hrs under an atmosphere of N2 then was filtered and concentrated under reduced pressure to give a residue that was diluted with H2O (2 mL) and extracted with EA (2 mL X 3). The combined organic layers were washed with brine 5 mL (2.5 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC Method 6). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 46b (27.01 mg, 82.35 μmol, 32.55% yield, 98.9% purity) as a yellow gum. LCMS: RT =0.581 min, m / z = 325.1 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 1H),7.34 - 7.28 (m, 4H), 7.25 - 7.18 (m, 1H), 7.00 - 6.87 (m, 2H), 4.14 (t, J = 6.0 Hz, 2H), 3.52 (d, J = 17.6.0 Hz, 1H), 3.25 (d, J = 17.2 Hz, 1H), 2.62 (t, J = 7.2 Hz, 2H), 2.26 - 2.12 (m, 2H), 1.66 (s, 3H); SFC: RT=2.312 min, chiral purity: 99.8% (SFC Method 15).

[0592] Compound 46a was prepared from Compound 23b using example 14. Yellow gum. LCMS: RT =0.586 min, m / z = 325.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 1H),7.34 - 7.28 (m, 4H), 7.25 - 7.16 (m, 1H), 6.98 - 6.88 (m, 2H), 4.14 (t, J = 6.0 Hz, 2H), 3.52 (d, J = 17.6.0 Hz, 1H), 3.25 (d, J = 17.2 Hz, 1H), 2.63 (t, J = 7.2 Hz, 2H), 2.26 - 2.12 (m, 2H), 1.65 (s, 3H) SFC: RT=1.779, chiral purity 99.87% (SFC Method 15).

[0593] Compound 45b was prepared from Compound 23a using example 14, but with a shorter reaction time (12 hrs). Off-white solid. LCMS: RT =0.602 min, m / z = 359.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H),7.34 - 7.28 (m, 4H), 7.25 - 7.18 (m, 1H), 6.96 (s, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.51 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 2.68 (t, J = 7.2 Hz, 2H), 2.28 – 2.21 (m, 2H), 1.66 (s, 3H); SFC: RT=2.237 Min, chiral purity: 100% (SFC Method 6).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0594] Compound 45a was prepared from Compound 23b using example 14, with a 12 hr reaction time. Off white solid. LCMS: RT =0.610 min, m / z = 359.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H),7.33 - 7.28 (m, 4H), 7.25 - 7.19 (m, 1H), 6.95 (s, 1H), 4.22 (t, J = 6.0 Hz, 2H), 3.52 (d, J = 17.6 Hz, 1H), 3.24 (d, J = 17.6 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.28 – 2.23 (m, 2H), 1.65 (s, 3H); SFC (RT=2.017 min, 99.88% chiral purity (SFC Method 6). Example 15. Synthesis of N-cyano4-[(R)-6,7-dichloro-2-methyl-1-oxo-2-phenyl-5- indanyloxy]butyramide (Compound 44b)

[0595] Step 1. Into a solution of Compound 23a (50.0 mg, 126 μmol, 1.00 eq) in DCM (1 mL) were added cyanamide (10.6 mg, 253 μmol, 2.00 eq), DMAP (18.6 mg, 152 μmol, 1.20 eq), DIEA (32.7 mg, 253 μmol, 2.00 eq) and EDCI (33.9 mg, 177 μmol, 1.40 eq). The mixture was stirred at 20 °C for 2 hrs then was concentrated under reduced pressure to give a residue that was purified by Prep-HPLC (Prep HPLC Method 3). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 44b (20.48 mg, 48.88 μmol, 38.64% yield, 99.6% purity) as a white solid. LCMS: RT = 0.620 min, m / z =417.1 (LCMS Method 1);1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.39 (s, 1H), 7.34 - 7.28 (m, 2H), 7.26 - 7.20 (m, 3H), 4.27 (t, J = 5.6 Hz, 2H), 3.48 (d, J = 18.0 Hz, 1H), 3.28 (d, J = 18.0 Hz, 1H), 2.61 - 2.50 (m, 2H), 2.15 - 2.02 (m, 2H), 1.56 (s, 3H); SFC: RT=0.922 min, 99.6 % chiral purity (SFC Method 4).

[0596] Compound 44a was prepared from Compound 23b using example 15. LCMS: RT = 0.614min, m / z =417.3(LCMS Method 1);1H NMR ((400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.33 - 7.28 (m, 2H), 7.26 - 7.20 (m, 3H), 4.25 (t, J = 6.4 Hz, 2H), 3.47 (d, J = 18.0 Hz, 1H), 3.27 (d, J = 18.0 Hz, 1H), 2.45 - 2.36 (m, 2H), 2.09 - 1.97 (m, 2H), 1.56 (s, 3H); SFC: RT=1.317, chiral purity 99.8% (SFC Method 4). Example 16. Synthesis of 5-[(R)-6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy]- 1,1,1-trifluoro-2-pentanone (Compound 43b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0597] Step 1. Into a solution of Compound 23a and (COCl)2 (64.2 mg, 506 μmol, 44.3 μL, 2.00 eq) in DCM (2.00 mL) was added DMF (9.25 mg, 126 μmol, 9.73 μL, 0.5 eq) at 0 to 5 °C. The mixture was stirred at 20 to 25 °C for 2 hrs and concentrated under reduced pressure to provide intermediate 1 (104 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0598] Step 2. To a mixture of intermediate 1 (104 mg, 252 μmol, 1.00 eq) in DCM (3.00 mL) were added trifluoroacetic anhydride (318 mg, 1.52 mmol, 210 μL, 6.00 eq) and pyridine (159 mg, 2.02 mmol, 163 μL, 8.00 eq) at -70 to -60 °C. The reaction mixture was stirred at - 70 to -60°C for 2 hr, then at 0 to 10 °C for 2 hrs. The reaction mixture was quenched by adding H2O (5.00 ml) at 0 - 5°C, then further stirred at 35 - 40°C for 2 hr. The reaction mixture was diluted with H2O (5.00 mL) and extracted with DCM (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (0.100 g, a yellow oil). The residue was purified by prep-HPLC (Prep HPLC Method 7). The fractions were concentrated, and the residual aqueous mixture was lyophilized to give the product Compound 43b (18.16 mg, 39.5 μmol, 15.6% yield, 96.9% purity) as a light-yellow solid. LCMS: RT = 1.061 min, (M+1) = 445.1 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.33 - 7.28 (m, 4H), 7.24 - 7.19 (m, 1H), 6.88 (s, 1H), 4.22 - 4.20 (m, 2H), 3.54 - 3.49 (m, 1H), 3.23 - 3.18 (m, 1H), 3.08 - 3.05 (m, 2H), 2.34 - 2.29 (m, 2H), 1.66 (s, 3H); SFC: RT=0.833 min, 88.79% chiral purity (SFC Method 5).

[0599] Compound 43a was prepared from Compound 23b using example 16. Light yellow solid. LCMS: RT = 1.071 min, (M+1) = 445.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.33 - 7.28 (m, 4H), 7.24 - 7.20 (m, 1H), 6.88 (s, 1H), 4.22 - 4.20 (m, 2H), 3.54 - 3.49 (m, 1H), 3.23 - 3.18 (m, 1H), 3.08 - 3.05 (m, 2H), 2.34 - 2.27 (m, 2H), 1.66 (s, 3H); SFC: RT= 0.877, chiral purity 88.58% (SFC Method 5). Example 17. Synthesis of (R)-6,7-dichloro-2-methyl-2-phenyl-5-[3-(1H-tetraazol-5- yl)propoxy]-1-indanone (Compound 40b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0600] Step 1. To a mixture of Compound 60b (50.0 mg, 162 μmol, 1.00 eq) and 4- bromobutanenitrile (48.1 mg, 325 μmol, 2.00 eq) in DMF (1.00 mL) was added K2CO3 (67.4 mg, 488 μmol, 3.00 eq). The reaction mixture was stirred at 60 °C for 2 hrs, then diluted with H2O (5.00 mL) and extracted with EA (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (0.100 g, a yellow oil) that was purified by prep-TLC (PE : EA = 1:1, Rf = 0.5) to provide intermediate 1 (55.0 mg, 146 μmol, 90.2% yield) as a brown solid. LCMS: RT: 0.641 min, m / z = 374.1 (LCMS Method 1).

[0601] Step 2. A mixture of intermediate 1 (55.0 mg, 146 μmol, 1.00 eq), TMSN3 (33.8 mg, 293 μmol, 38.6 μL, 2.00 eq) and dibutyl(oxo)tin (5.58 mg, 22.0 μmol, 0.150 eq) in toluene (0.500 mL) was degassed and purged / refilled with N2 (3X) at 20 to 25 °C, and stirred at 110°C for 12 hrs under an atmosphere of N2. The reaction mixture was diluted with H2O (5.00 mL) and extracted with EA (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (0.100 g, a yellow oil) that was purified by prep-HPLC (Prep HPLC Method 8). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 40a (15.83 mg, 37.7 μmol, 25.6% yield, 99.5% purity) as a white solid. LCMS: RT: 2.533 min, m / z = 417.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.32 - 7.28 (m, 4H), 7.24 - 7.20 (m, 1H), 6.87 (s, 1H), 4.18 - 4.15 (m, 2H), 3.56 - 3.52 (m, 1H), 3.27 - 3.21 (m, 3H), 2.50 - 2.44 (m, 2H), 1.69 (s, 3H); SFC: RT = 2.032 min, 99.923% chiral purity (SFC Method 2).

[0602] Compound 40a was prepared from Compound 60a using example 17. White solid. LCMS: RT = 0.592 min, (M+1) = 417.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.32 - 7.28 (m, 4H), 7.24 - 7.19 (m, 1H), 6.88 (s, 1H), 4.19 - 4.16 (m, 2H), 3.55 - 3.50 (m, 1H), 3.26 - 3.20 (m, 3H), 2.49 - 2.42 (m, 2H), 1.67 (s, 3H); SFC: RT = 2.302 min, 97.151% chiral purity (SFC Method 2). Example 18. Synthesis of N-sulfo4-[(R)-6,7-dichloro-2-methyl-1-oxo-2-phenyl-5- indanyloxy]butyramide (Compound 42b)Cooley Ref. CLBO-002 / 01WO 349489-2004

[0603] Step 1. To a mixture of Compound 23a (100 mg, 253 μmol, 1.00 eq) and 1- [Bis(dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexa fluoro phosphate (42.3 mg, 278 μmol, 1.1.0 eq) in DMF (2.00 mL) was added 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (63.0 mg, 328 μmol, 1.30 eq) at 20 to 25 °C. The reaction mixture was stirred at 20 to 25 °C for 12 hrs. The reaction mixture was diluted with H2O (5.00 mL) and extracted with EA (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (0.140 g, a yellow oil) that was purified by Prep-TLC (DCM : MeOH = 10:1, Rf = 0.4) to give intermediate 1 (75.0 mg, 191.19 μmol, 75.57% yield) as a white solid. LCMS: RT: 0.583 min, m / z = 392.1 (LCMS Method 1).

[0604] Step 2. Into a solution of 2,6-dimethylpyridine (122.5 mg, 1143 μmol, 133.1 μL, 6.00 eq) in DCE (4.00 mL) was added sulfurochloridic acid (66 mg, 571 μmol, 37.9 μL, 3.00 eq) at -10°C. After the mixture was stirred at 0 °C for 0.5 hr, intermediate 1 (75.0 mg, 191 μmol, 1.00 eq) was added at 0 °C. The mixture was stirred at 75° C for 2 hrs. The reaction mixture was quenched by adding H2O (10 ml) at 0 to 5°C. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (0.100 g, a yellow oil) that was purified by prep-TLC (DCM: MeOH = 10:1, Rf = 0.3). The resulting residue was further purified by prep-HPLC (Prep HPLC Method 9). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide the ammonium salt of Compound 42b (15.39 mg, 32.3 μmol, 23.1% yield, 99.4% purity) as an off-white solid. LCMS: RT =0.765min,(M+1) =472.0 (LCMS Method 1);1H NMR (400 MHz, DMSO) δ 7.39 (s, 1H), 7.32 - 7.28 (m, 2H), 7.25 - 7.22 (m, 3H), 7.07 (s, 4H), 4.25 - 4.21 (m, 2H), 3.49 - 3.38 (m, 3H), 3.30 - 3.25 (m, 1H), 2.04 - 1.92 (m, 2H), 1.55 (s, 3H); SFC: RT=0.744 min, 100% Chiral Purity (SFC Method 18).

[0605] Compound 42a was prepared from Compound 23b using example 18. White solid, ammonium salt. LCMS: RT = 0.761 min, (M+1) =472.1 (LCMS Method 1);1H NMR (400 MHz, DMSO) δ 7.39 (s, 1H), 7.32 - 7.28 (m, 2H), 7.25 - 7.20 (m, 3H), 7.05 (s, 4H), 4.25 - 4.21 (m, 2H), 3.52 - 3.40 (m, 3H), 3.30 - 3.25 (m, 1H), 1.99 - 1.94 (m, 2H), 1.55 (s, 3H); SFC: RT=0.846 min, 100% chiral purity (SFC Method 18).Cooley Ref. CLBO-002 / 01WO 349489-2004 Example 19. Synthesis of 4-(7-chloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)butyric acid

[0606] Step 1. Into a solution of AlCl3 (9.35 g, 70.1 mmol, 1.00 eq) in DCM (80 mL) was added phenylacetyl chloride (11.9 g, 77.2 mmol, 1.10 eq) at 0 °C. After stirring 0 °C for 0.5 hrs, 3-chlorobenzene-1-peroxol (10.0 g, 70.1 mmol, 1.00 eq) in DCM (40 mL) was added at 0°C. The mixture was stirred at 25 °C for 2 hrs then was quenched by the addition ice H2O (500 mL) at 0 °C, and then extracted with DCM (100 mL X3). The combined organic layers were washed with brine (100 mL X2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% EA / PE gradient @ 80 mL / min) to provide intermediate 1 (4.50 g, 17.26 mmol, 24.61% yield, 100% purity) as a colorless oil. LCMS: RT = 0.630 min, m / z = 261.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.28 - 7.23 (m, 3H), 6.94 (d, J = 2.4 Hz, 1H), 6.81 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 4.28 (s, 2H), 3.84 (s, 3H).

[0607] Step 2. Into a solution of intermediate 1 (4.50 g, 17.3 mmol, 1.00 eq) in Ac2O (10 mL) was added N,N,N',N'-tetramethylmethanediamine (7.64 g, 74.7 mmol, 4.33 eq). The mixture was stirred at 25 °C for 1 hr then poured into ice H2O (200 mL) at 0 °C and extracted with EA (100 mL X3). The combined organic layers were washed with brine 200 mL (100 mL X2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide intermediate 2 (4.3 g, 15.77 mmol, 91.35% yield) as a white solid. LCMS: RT = 0.661 min, m / z = 273.0 (LCMS Method 1);1H NMR ((400 MHz, CDCl3)δ 7.50 - 7.43 (m, 3H), 7.42 - 7.34 (m, 3H),Cooley Ref. CLBO-002 / 01WO 349489-2004 6.95 (d, J = 2.4 Hz, 1H), 6.85 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 6.14 (s, 1H), 5.77 (s, 1H), 3.85 (s, 3H)).

[0608] Step 3. A solution of intermediate 2 (4.3 g, 15.71 mmol, 1.00 eq) in DCM (8 mL) was added to H2SO4 (39.5 g, 393mmol, 98% purity, 25.0 eq) at 60 °C. The reaction mixture was concentrated under reduced pressure to remove DCM. The resulting mixture was stirred at 60 °C for 1 h then was poured into ice H2O (3 L) and extracted three times with 1L DCM: MeOH (10: 1). The combined organic layers were washed with brine (100 mL X2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide intermediate 3 (3.2 g, 10.65 mmol, 76.46% yield, 90.8% purity) as a white solid. LCMS: RT = 0.634 min, m / z = 273.0 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.39 - 7.28 (m, 3H), 7.25 - 7.16 (m, 2H), 6.95 – 6.88(m, 2H), 3.98 - 3.85 (m, 4H), 3.66 - 3.53 (m, 1H), 3.20 (dd, J1 = 4.0 Hz, J2 = 17.6 Hz, 1H).

[0609] Step 4. A mixture of intermediate 3 (1.00 g, 3.33 mmol, 1.00 eq), MeI (2.36 g, 16.7 mmol, 5.00 eq) in DMF (5 mL) and toluene (5 mL) was degassed and purged 3 times with N2. NaOMe (540 mg, 9.99 mmol, 3.00 eq) was added portion wise at 0 °C and stirred at 0 to10°C for 1hr under an N2 atmosphere. The reaction mixture was poured into ice H2O (200 mL) and extracted with EA (100 mL X 3). The combined organic layers were washed with brine (100 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was triturated with PE: DCM = 5: 1 (300 mL) at 25 °C for 2 h to give intermediate 4 (0.9 g, 3.14 mmol, 94.27% yield) as a yellow solid. LCMS: RT = 0.658 min, m / z =287.01 (LCMS Method 1);1H NMR((400 MHz, CDCl3)δ 7.34 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 6.93 – 6.79 (m, 2H), 3.90 (s, 3H), 3.53 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 1.66 (s, 3H)).

[0610] Step 5. A solution of intermediate 4 (900 mg, 3.14 mmol, 1.00 eq) in Py•HCl (3.63 g, 31.4 mmol, 10.0 eq) was stirred at 160 °C for 4 hrs. The reaction mixture was poured into ice H2O (200 mL) and extracted with EA (100 mL X 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to provide intermediate 5 (0.8 g, 2.51 mmol, 79.91% yield, 85.5% purity) as a brown solid. LCMS: RT = 0.585 min, m / z =273.0 (LCMS Method 1).

[0611] Step 6. Into a solution of intermediate 5 (800 mg, 2.93 mmol, 1.00 eq) in DMF (10 mL) were added K2CO3 (1.62 g, 11.7 mmol, 4.00 eq) and tert-butyl 4-bromobutanoate (1.31 g, 5.87 mmol, 2.00 eq). The mixture was stirred at 60 °C for 2 hrs, then poured into iced H2O (100 mL) and extracted with EA (60 mL X 3). The combined organic layers were washed with brine (50 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate 6 (1.10 g, 2.03 mmol, 69.23% yield, 76.6% purity) as a brown gum. LCMS: 0.717 min, m / z =415.1 (LCMS Method 1).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0612] Step 7. Into a solution of intermediate 6 (1.1 g, 2.04 mmol, 1.00 eq) in DCM (10 mL) was added TFA (5.78 g, 50.8 mmol, 25.0 eq). The mixture was stirred at 20 °C for 2 hrs, then was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Prep HPLC Method 10). The fractions were concentrated, and the residual aqueous mixture was lyophilized to provide Compound 41 (453.71 mg, 1.25 mmol, 67.94% yield, 99.2% purity) as a white solid. LCMS: RT =0.602 min, m / z = 359.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.35 - 7.27 (m, 4H), 7.25 - 7.18 (m, 1H), 6.94 - 6.88 (m, 1H), 6.85 - 6.78 (m, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.51 (d, J = 17.2 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.61 (t, J = 7.2 Hz, 2H), 2.24 - 2.12 (m, 2H), 1.65 (s, 3H). Example 20. Synthesis of [6,7-dichloro-2-(p-chlorophenyl)-2-methyl-1-oxo-5- indanyloxy]acetic acid (Compound 3)

[0613] Step 1. To a mixture of 1,2-dichloro-3-methoxybenzene (15.0 g, 84.7 mmol, 1.00 eq) and dihydroxyacetyl chloride (9.93 g, 93.2 mmol, 9.77 mL, 1.10 eq) in DCM (75.0 mL) was added AlCl3 (12.4 g, 93.2 mmol, 5.09 mL, 1.10 eq) in portions at 5 °C. The mixture was then stirred at 25 °C for 12 hrs under an atmosphere of N2. The reaction mixture was poured into ice H2O (500 mL) and the mixture was extracted with DCM (500 mL X 2). The combined organic layers were washed with brine (500 mL X 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product (25.0 g, yellow oil). The residue was purified by column chromatography (SiO2, PE : EA = 100 / 1 to 3 / 1) to provide intermediate 1 (14.0 g, 56.6 mmol, 66.8% yield) as a yellow oil. LCMS: RT=0.646 min,Cooley Ref. CLBO-002 / 01WO 349489-2004 (M+H)+: 247.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.26 (d, J= 8.8 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 3.93 (s, 3H), 3.40 - 3.27 (m, 1H), 1.15 (d, J = 6.8 Hz, 1H).

[0614] Step 2. Into a solution of intermediate 1 (14.0 g, 56.6 mmol, 1.00 eq) in AcOH (45.0 mL) was added Br2 (9.51 g, 59.4 mmol, 3.06 mL, 1.05 eq) at 5-10°C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was poured into iced 10% NaHSO3 (200 mL) and extracted with DCM (250 mL X 2). The combined organic layers were washed with brine (200 mL 2), dried over Na2SO4, filtered and concentrated to provide intermediate 2 (15.9 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3)δ 7.63 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 1.98 (s, 6H).

[0615] Step 3. Into a solution of intermediate 2 (14.9 g, 48.8 mmol, 1.00 eq) in DMF (128 mL) was added LiBr (8.90 g, 102.3 mmol, 2.57 mL, 2.10 eq). The mixture was stirred at 100 °C for 2.5 hrs. The reaction mixture was diluted with H2O (500 mL) and extracted with EA (500 mLX 2). The combined organic layers were washed with brine (500 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (15.0 g, a yellow oil) that was purified by column chromatography (SiO2, PE : EA = 100 / 1 to 3 / 1) to provide intermediate 3 (11.0 g, 44.8 mmol, 98.2% yield) as a yellow oil. LCMS: RT = 0.632 min, (M+1) = 244.9 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.18 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.98 (s, 1H), 5.58 (s, 1H), 3.95 (s, 3H), 2.05 (s, 3H).

[0616] Step 4. A solution of intermediate 3 (7.00 g, 28.5 mmol, 1.00 eq) in H2SO4 (50.0 mL) was stirred at 25 °C for 10 hrs. The reaction mixture was diluted with H2O (500 mL) and extracted with EA (200 mL X 2) at 0-5 °C. The combined organic layers were washed with brine (300 mL X 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product (10.0 g, yellow oil) that was purified by column chromatography (SiO2, PE : EA = 100 / 1 to 3 / 1to provide intermediate 4 (5.50 g, 22.4 mmol, 78.5% yield) as a gray solid. LCMS: RT = 0.602 min, (M+1) = 245.0 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 6.87 (s, 1H), 4.00 (s, 3H), 3.34 - 3.28 (m, 1H), 2.82 - 2.70 (m, 1H), 2.69 - 2.61 (m, 1H), 1.31 (d, J = 7.2 Hz, 1H)).

[0617] Step 5. Into a solution of intermediate 4 (320 mg, 1.30 mmol, 1.00 eq) in toluene (3.20 mL) were added 1-bromo-4-iodobenzene (466.3 mg, 1.96 mmol, 1.50 eq), t-BuONa (188 mg, 1.96 mmol, 1.50 eq), quinoline (50.6 mg, 391.6 μmol, 46.3 μL, 0.3 eq) and Pd(dba)2(75 mg, 130.2 μmol, 0.1 eq). The mixture was stirred at 80 °C for 3 hrs under an atmosphere of N2 then was diluted with H2O (5.00 mL) and extracted with EA (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL x 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product (0.700 g, a yellow oil) that wasCooley Ref. CLBO-002 / 01WO 349489-2004 purified by prep-TLC (PE : EA = 3: 1, Rf = 0.45) to provide intermediate 5 (130 mg, 365 μmol, 29.8% yield) as a yellow solid. LCMS: RT = 0.703 min, (M+1) = 357.0 (LCMS Method 1);1H NMR ((400 MHz, CDCl3) δ 7.30 - 7.19 (m, 4H), 6.91 (s, 1H), 4.00 (m, 3H), 3.48 (d, J=17.6 Hz, 1H), 3.22 (d, J=17.2 Hz, 1H), 1.64 (s, 3H)).

[0618] Step 6. A solution of intermediate 5 (130 mg, 365 μmol, 1.00 eq) in pyridine hydrochloride (844 mg, 7.31 mmol, 20.0 eq) was stirred at 160 °C for 2 hrs. The reaction mixture was diluted with H2O (5.00 mL) and extracted with EA (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give crude intermediate 6 (0.115 g, brown solid) that was used without further purification. LCMS: RT = 0.651 min, (M+1) = 342.9 (LCMS Method 1).

[0619] Step 7. Into a solution of intermediate 6 (60.0 mg, 175 μmol, 1.00 eq) in DMF (1.00 mL) were added tert-butyl bromoacetate (68.5 mg, 351 μmol, 51.8 μL, 2.00 eq) and K2CO3 (97.1 mg, 702 μmol, 4.00 eq). The mixture was stirred at 60 °C for 1 hr then was diluted with H2O (5.00 mL) and extracted with EA (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product (0.1 g, yellow oil) that was purified by prep- TLC (PE: EA = 3:1, Rf = 0.45) to provide intermediate 7 (50.0 mg, 109 μmol, 62.4% yield) as a yellow oil. LCMS: RT = 0.738 min, (M+1) = 457.1 (LCMS Method 1).

[0620] Step 8. To a mixture of intermediate 7 (50.0 mg, 109.6 μmol, 1.00 eq) in DCM (0.6 mL) was added TFA (312.5 mg, 2.74 mmol, 203 μL, 25.0 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hr then diluted with H2O (5.00 mL) and extracted with DCM (5.00 mL X 2). The combined organic layers were washed with brine (5.00 mL X 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product that was purified by Prep-HPLC (Prep HPLC Method 7). The fractions were concentrated and the residual aqueous mixture was lyophilized to give Compound 3 (13.0 mg, 32.3 μmol, 36.8% yield, 99.3% purity) as a white solid. LCMS: RT = 0.632 min, (M+1) = 401.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 4.89 (s, 2H), 3.48 (d, J=17.6 Hz, 1H), 3.22 (d, J=17.6 Hz, 1H), 1.64 (s, 3H).

[0621] Compound 79 was prepared using steps 5-8 of example 20 starting from intermediate 4 and 1-iodo-3-(trifluoromethyl)benzene and using tert-butyl 4-bromobutanoate in step 7 instead of tert-butyl bromoacetate. LCMS: RT = 0.626 min, (M+1) = 433.0 (LCMS MethodCooley Ref. CLBO-002 / 01WO 349489-2004 1);1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.54 - 7.47 (m, 2H), 7.46 - 7.40 (m, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.51 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 1.67 (s, 3H).

[0622] Compound 76 was prepared using steps 7-8 of example 20 starting from intermediate 6 and tert-butyl 4-bromobutanoate using. LCMS: RT = 0.646 min, (M+1) = 427.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.45 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.31 - 2.19 (m, 2H), 1.63 (s, 3H).

[0623] Compound 97 was prepared using steps 5-8 of example 20 starting from intermediate 4 (example 20) and 1-iodo-3-(trifluoromethyl)benzene and using tert-butyl 4-bromobutanoate in step 7 instead of tert-butyl bromoacetate. LCMS: RT = 0.651 min, (M+1) = 461.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.53 - 7.46 (m, 2H), 7.44 - 7.39 (m, 1H), 6.91 (s, 1H), 4.24 (t, J=6.0 Hz, 2H), 3.50 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 2.69 (t, J=7.0 Hz, 2H), 2.27 - 2.24 (m, 2H), 1.68 (s, 3H).

[0624] Compound 10 was prepared using steps 5-8 of example 20, starting from intermediate 4 and 1-iodo-4-methylbenzene. LCMS: RT =0.625 min, m / z = 379.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 6.83 (s, 1H), 4.90 (s, 2H), 3.52 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 18.0 Hz, 1H), 2.32 (s, 3H), 1.65 (s, 3H).

[0625] Compound 38 was prepared using steps 5-8 of example 20 starting from intermediate 4 and 1-iodo-4-methylbenzene and using tert-butyl 4-bromobutanoate in step 7 instead of tert- butyl bromoacetate. LCMS: RT =0.647 min, m / z = 407.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.89 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.49 (d, J = 17.6 Hz, 1H), 3.18 (d, J = 17.6 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.30 (s, 3H), 2.29 - 2.21 (m, 2H), 1.64 (s, 3H).

[0626] Compound 82 was prepared using steps 5-8 of example 20 starting from intermediate 4 and 1-iodo-3-methylbenzene. Off-white solid. LCMS: RT=0.611, m / z=379.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3)δ 7.20 (t, J = 7.6 Hz, 1H), 7.12 - 7.01 (m, 3H), 6.81 (s, 1H), 4.89 (s, 2H), 3.51 (d, J = 18.0 Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H), 2.32 (s, 3H), 1.65 (s, 3H).

[0627] Compound 104 was prepared using steps 5-8 of example 20 starting from intermediate 4 and 1-iodo-3-methylbenzene and using tert-butyl 4-bromobutanoate in step 7 instead of tert-butyl bromoacetate. White solid. LCMS: RT=0.631, m / z=407.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 7.6 Hz, 1H), 7.13 - 7.01 (m, 3H), 6.89 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 17.6 Hz, 1H), 3.19 (d, J = 17.6 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 2.30 - 2.21 (m, 2H), 1.64 (s, 3H).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0628] Compound 91 was prepared using steps 5-8 of example 20 starting from intermediate 4 and 5-bromo-2,3-dihydro-1H-indene. Off-white solid. LCMS: RT=0.635, m / z=405.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3)δ 7.19 - 7.11 (m, 2H), 7.07 - 7.00 (m, 1H), 6.81 (s, 1H), 4.88 (s, 2H), 3.51 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 2.93 - 2.79 (m, 4H), 2.12 - 1.95 (m, 2H), 1.64 (s, 3H).

[0629] Compound 83 was prepared using steps 5-8 of example 20 starting from intermediate 4 and 5-bromo-2,3-dihydro-1H-indene and using tert-butyl 4-bromobutanoate in step 7 instead of tert-butyl bromoacetate. White solid. LCMS: RT=0.664, m / z=433.1 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.20 - 7.11 (m, 2H), 7.08 - 6.99 (m, 1H), 6.89 (s, 1H), 4.22 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 17.2 Hz, 1H), 3.18 (d, J = 17.6 Hz, 1H), 2.94 - 2.78 (m, 4H), 2.68 (t, J = 6.8 Hz, 2H), 2.33 - 2.18 (m, 2H), 2.11 - 1.97 (m, 2H), 1.64 (s, 3H)).

[0630] Compound 19 was prepared using steps 5-8 of example 20, starting from intermediate 4 and 1-iodo-4-fluorobenzene. White solid. LCMS: RT =0.599 min, m / z = 383.0 (LCMS Method 1);1H NMR (400 MHz, CDCl3) δ 7.27 - 7.21 (m, 2H), 7.06 - 6.94 (m, 2H), 6.82 (s, 1H), 4.88 (s, 2H), 3.48 (d, J = 17.6 Hz, 1H), 3.22 (d, J = 17.6 Hz, 1H), 1.64 (s, 3H). Example 21. Synthesis of [6,7-dichloro-2-(p-methoxyphenyl)-2-methyl-1-oxo-5- indanyloxy]acetic acid (Compound 7)(example 2) 90oC, 16hrs

[0631] Step 1. A solution of intermediate 6 (example 2) (500 mg, 2.04 mmol, 1.00 eq) in Py•HCl (2.36 g, 20.4 mmol, 10.0 eq) was stirred at 160 °C for 4 hrs. The mixture was poured into H2O (40 mL), extracted with EA (20 mL X3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give intermediate 1(450 mg, 1.95 mmol, 95.46% yield) as an off-white solid. LCMS: RT=0.557, m / z=231.0.

[0632] Step 2. Into a solution of intermediate 1 (400 mg, 1.73 mmol, 1.00 eq) in DMF (4 mL) were added K2CO3 (957 mg, 6.92 mmol, 4.00 eq) and tert-butyl bromoacetate(675 mg, 3.46Cooley Ref. CLBO-002 / 01WO 349489-2004 mmol, 2.00 eq). The mixture was stirred at 60 °C for 2 hrs. then was poured into H2O (50 mL) and extracted with EA(20 mL X3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give intermediate 2(480 mg, 1.26 mmol, 72.7% yield, 90.5% purity) as a yellow solid. LCMS: RT=0.658, m / z=345.0;1H NMR (400 MHz, CDCl3) δ 6.72 (s, 1H), 4.70 (s, 2H), 3.35 - 3.22 (m, 1H), 2.82 - 2.70 (m, 1H), 2.68 - 2.58 (m, 1H), 1.50 (s, 9H), 1.31 (d, J =7.6 Hz, 3H).

[0633] Step 3. A mixture of intermediate 2 (200 mg, 579 μmol, 1.00 eq), 4- methoxyiodobenzene (203 mg, 869 μmol, 1.50 eq) , Cs2CO3 (566 mg, 1.74 mmol, 3.00 eq) , Xphos Pd G4 (49.9 mg, 57.9 μmol, 0.100 eq) in dioxane (2 mL) was degassed and purged with N2 (3 X), and then was stirred at 90 °C for 16 hrs under an atmosphere of N2. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash SiO2 gel chromatography (ISCO®; 1 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% EA / hexanes gradient @ 30 mL / min) to provide intermediate 3 (60 mg, 71.12 μmol, 12.3% yield, 53.5% purity) as a yellow solid. LCMS: RT=0.694 min, m / z=451.2.

[0634] Step 4. To a solution of intermediate 3 (60.0 mg, 71.1 μmol, 1.00 eq) in DCM (0.5 mL) was added TFA (186 mg, 1.63 mmol, 25.0 eq). The mixture was stirred at 20 °C for 1 hr then was quenched by addition H2O (2 mL), then extracted with DCM 4 mL (2 mL X2). The combined organic layers were concentrated under reduced pressure to give a residue that was purified by Prep-HPLC (Prep HPLC Method 6). The fractions were concentrated, and the residual aqueous mixture was lyophilized to give Compound 7 (17.26 mg, 43.67 μmol, 66.98% yield, 100% purity) as a white solid. LCMS: RT=0.595, m / z=395.1(LCMS Method 1);1H NMR (400 MHz, CDCl3)δ 7.21 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 4.88 (s, 2H), 3.78 (s, 3H), 3.49 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 1.63 (s, 3H).

[0635] Compound 67 was prepared from intermediate 2 and 1-iodo-3-methoxybenzene using steps 3-4 of example 21. Yellow solid. LCMS: RT=0.585 min, m / z=395.1 (LCMS Method 1);1HNMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.6 Hz, 1H), 6.88 - 6.83 (m, 2H), 6.81 (s, 1H), 6.79 - 6.74 (m, 1H), 4.88 (s, 2H), 3.79 (s, 3H), 3.51 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 1.65 (s, 3H).

[0636] Compound 73 was prepared using steps 3-4 of example 21 from intermediate 2 and 1-iodo-3-chlorobenzene in step 3. White solid. LCMS: RT=0.620 min, m / z=401.1 (LCMS Method 1);1HNMR (400 MHz, CDCl3) δ 7.29 - 7.27 (m, 1H), 7.25 - 7.19 (m, 2H), 7.19 - 7.14 (m, 1H), 6.82 (s, 1H), 4.88 (s, 2H), 3.48 (d, J = 18.0 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 1.64 (s, 3H).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0637] Compound 77 was prepared using steps 2-4 of example 21 from intermediate 1 and tert-butyl 4-bromobutanoate in Step 2 and using 1-iodo-3-chlorobenzene in step 3. White solid. LCMS: RT=0.616 min, m / z=421.1(LCMS Method 1);1HNMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 1H), 6.89 (s, 1H), 6.88 - 6.83 (m, 2H), 6.80 - 6.74 (m, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.50 (d, J = 17.6 Hz, 1H), 3.18 (d, J = 18.0 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.27 - 2.23 (m, 2H), 1.64 (s, 3H).

[0638] Compound 96 was prepared using steps 2-4 of example 21 from intermediate 1 and tert-butyl 4-bromobutanoate in Step 2 and using 1-iodo-3-methoxybenzene in step 3. White solid. LCMS: RT=0.616 min, m / z=423.1(LCMS Method 1);1HNMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 1H), 6.89 (s, 1H), 6.88 - 6.83 (m, 2H), 6.80 - 6.74 (m, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.50 (d, J = 17.6 Hz, 1H), 3.18 (d, J = 18.0 Hz, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.27 - 2.23 (m, 2H), 1.64 (s, 3H). Example 22. Clic1 Binding Activity of Exemplary Compounds.

[0639] The binding activity of exemplary compounds for Clic1 protein was measured by one- dimenstional (1D) saturation transfer difference (STD) NMR. Results are summarized in Table Table 4Cooley Ref. CLBO-002 / 01WO 349489-2004 Example 23. Effect of Exemplary Compounds on Food Intake and Body Weight

[0640] The effects of compounds disclosed herein on food intake were measured in a fasting- induced feeding study. C57Bl / 6J mice were fasted overnight (23 hours) then orally administered 10mg / kg of a compound (Compound 1a, Compound 31a, Compound 33a, or Compound 33b) or vehicle and provided access to normal chow 1 hour after administration. Food intake was measured at regular intervals for 8 hours after administration. Observations are summarized in FIG.1.

[0641] The effects of compounds disclosed herein on food intake and body weight were further measured in a diet-induced obese mouse model. The model involves WT mice fed a high-fat (60%) diet for 8 weeks. These diet-induced obese mice were administered compound or vehicle control, with dose amount and frequency of administration changed at certain intervals, as shown in FIGs. 13A and FIG. 14A. Diet-induced mice initially received Compound 23a, Compound 1a, or Compound 1b at 10 mg / kg once daily (QD) for 7 days, then 5mg / kg twice daily (BID) for 4 days, prior to underoing a washout period during which mice were not administered compound. Dosing resumed after 4 days of washout; mice received 20mg / kg QD for 8 days, 30 mg / kg QD for 8 days, and then 50 mg / kg for 7 days. Body weight was measured daily and is summarized as percentage difference from mice administered vehicle in FIG.13A (Compound 23a) and FIG.14A (Compound 1a). Food intake was measured daily and and is summarized as percentage difference from mice administered vehicle in FIGs.13A (Compound 23a) and FIG.14A (Compound 1a). As shown in FIGs.13A and FIG.14A administration of Compound 23a, Compound 1a, or Compound 1b each reduced food intake and body weight in mice. Quantification of the effects of Compound 23a compared to vehicle on body weight (FIG. 13B) shown as percentage difference from vehicle, demonstrates that Compound 23a reduced body weight by about 3% to about 12%, with the greatest reduction (about 12%) observed with a dose of 50mg / kg QD. Quantification of the effects of Compound 23a compared to vehicle on food intake (FIG.13C), shown as percentage difference from vehicle, demonstrates that Compound 23a reduced food intake by about 0% to about 37%, with the greatest reduction (about 37%) observed with a dose of 50mg / kg QD. Further, the effect of Compound 23a on body weight change and food intake was dose- dependent (FIGS.13B and 13C). Quantification of the effects of Compound 1a compared to vehicle on food intake (FIG. 14B), shown as percentage change from vehicle, demonstrates that Compound 1a reduced food intake by about 12% to about 35%, with the greatest reduction (about 35%) observed with a dose of 50mg / kg QD. While the highest dose of Compound 1a provided the largest effect on food intake, dose-dependency was not statistically significant.Cooley Ref. CLBO-002 / 01WO 349489-2004

[0642] The effects of Compound 23a, Compound 24a, and Compound 25a administered at 25 mg / kg were measured in diet-induced mice. Mice were administered compound for 7 days, and body weight and food intake were measured. Compound 23a, Compound 24a, and Compound 25a decreased body weight (FIG.15A) and food intake (FIG.15B) in diet-induced obese mice.

[0643] The effects of Compound 26a and Compound 26b administered at 25 mg / kg were measured in diet-induced mice. Mice were administered compound for 5 days, and body weight and food intake were measured. Compound 26a and Compound 26b had no significant effect on body weight (FIG.16A) and food intake (FIG.16B) in diet-induced obese mice. Example 24. Reduced Diuretic Effect of Exemplary Compounds

[0644] Sprague-Dawley rats were fasted overnight then provided access to normal chow 4 hours prior to oral administration 10mg / kg of a compound or vehicle. Urine flow rate (measured in ml / min) and sodium excretion (NA, measured in mmol) were measured over time. Observations are summarized in FIGS.2A and 2B.

[0645] Urine output (in grams) and sodium excretion (in mmol) were assessed in these rats at 2 hours post-administration (see FIGS.3A and 3B), and at 24 hours post-administration (see FIGS.4A and 4B).

[0646] A direct comparison of the diuretic effect was made between Compound 33a and indacrinone (see FIGS.5, 6A and 6B). Similar comparison was made between Compound 33b and indacrinone (see FIGS.7, 8A, and 8B), and between Compound 1a and indacrinone (see FIGS.9A-9B and 10A-10B). Example 25. Serum Levels of ALT, Sodium, and Other Analytes Upon Administration of Exemplary Compounds and Liver Histology.

[0647] Serum was collected from Sprague-Dawley rats 24 hours after oral administration of 10mg / kg of a compound or vehicle. Serum levels of alanine aminotransferase (ALT), sodium (Na), TBILI, albumin (ALB), urea nitrogen (BUN), cholesterol (CHOL), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), iron (IRON), glucose (GLUC), phosphate (PHOS), total protein (TP), alkaline phosphatase (ALP), calcium (CA), uric acid (URIC), creatinine (CREAT), triglycerides (TRIG), potassium (K), and chloride (Cl) were measured by a standard blood chemistry assay (Chem20). Serum levels of ALT, sodium, and other measured analytes were not elevated in rats administered with Compounds 31a, 1a, 33a, or 33b as compared to rats administered indacrinone or vehicle (see FIGS.11A-11B).Cooley Ref. CLBO-002 / 01WO 349489-2004

[0648] Diet-induced obese mice are administered a compound disclosed herein. Serum is collected and analyzed by a standard blood chemistry assay, as in the above paragraph. Serum levels of ALT, AST, ALP, LDH, CRP, Cl, Na, K, triglycerides, calcium, and / or phosphate are not elevated in mice administered certain exemplary compounds. Absolute and relative numbers of cell types in blood are measured by any suitable assay known in the art. Absolute and relative numbers of most cell types are not significantly altered in blood in mice administered.

[0649] Liver tissue is extracted from diet-induced mice administered compounds disclosed herein. Liver tissues are sectioned for imaging. Nonalcoholic Fatty Liver Disease Activity Score, (NAS) steatosis, hepatocyte ballooning, and lobular inflammation are quantified. Mice administered certain exemplary compounds disclosed herein have statistically lower NAS score, steatosis, and hepatocyte ballooning, compared to mice administered vehicle. Diet- induced obese mice administered certain exemplary compounds disclosed herein have reduced liver weight, serum ALT and ALP levels, and serum levels of sodium and chloride. Serum levels of AST, LDH, potassium, and CRP are not significantly altered in mice administered certain exemplary compounds disclosed herein, compared to mice administered vehicle. Example 26. Plasma Concentration of Exemplary Compounds Upon Administration

[0650] Serum was collected from Sprague-Dawley rats at various time points after oral administration of 10mg / kg of a compound or vehicle. Time points included 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Serum levels of Compound 31a (FIG. 12A), Compound 1a (FIG.12B), Compound 33a (FIG.12C), Compound 33b (FIG.12D), and R-indacrinone (FIG.12E), are shown. Example 27: Stereoselective Effects of Compounds

[0651] The relative effects of compound R-isomer versus S-isomer are measured in diet- induced obese mice administered compounds disclosed herein. Reductions in body weight and food intake are larger in mice administered the R-isomer compared to the S-isomer of certain exemplary compounds. Example 28: Inhibition by Exemplary Compounds of CLIC Membrane Translocation

[0652] Inhibititory effects of compounds disclosed herein on membrane translocation of CLIC1 and / or CLIC4 may be measured by any suitable assay. One example of a suitable assay is an in vitro system in which lipid vesicles are mixed with labeled CLIC1 and / or CLIC4 proteinCooley Ref. CLBO-002 / 01WO 349489-2004 in the presence of a compound disclosed herein (e.g., at 1 or 10µM), vesicles are contacted with Zn++ to stimulate translocation, and the amount of CLIC1 and / or CLIC4 protein in the lipid vesicles is measured by quantifying the label. Another example of a suitable assay is a cellular assay in which cells (e.g., HEK293, HeLa, MCF7, or U2OS cells) are contacted with a compound disclosed herein (e.g., at 1 or 10µM), cells are stimulated with hydrogen peroxide or sphingosine-1-phosphate (S1P) (e.g., 1µM), and the amount of CLIC1 and / or CLIC4 protein in the plasma membranes of the cells is quantified by immunofluorescent staining. For example, cells are fixed, permeabilized, and stained with a primary anti-CLIC1 antibody or a primary anti-CLIC4 antibody, followed by a species-specific secondary antibody conjugated to a fluorescent label. Translocation of CLIC1 and / or CLIC4 is quantified by measuring relative fluorescence at the plasma membrane, compared to in the cytosol.

[0653] In another example of a suitable assay, cells (e.g., HEK293, HeLa, MCF7, or U2OS cells) are contacted with exemplary compounds. Cells are contacted with hydrogen peroxide (2 mM), ionomycin (10-20µM), or sphingosine-1-phosphate (S1P) (1µM) for 1 hour, 2 hours, 3 hours, or 24 hours, to stimulate translocation of CLIC1 and / or CLIC4 from the cytosol to the plasma membrane. Approximately 24 hours after treatment of cells with compounds, cells are fixed, permeabilized, and stained with a primary anti-CLIC1 antibody or a primary anti-CLIC4 antibody, followed by a species-specific secondary antibody conjugated to a fluorescent label. Translocation of CLIC1 and / or CLIC4 is quantified by measuring relative fluorescence at the plasma membrane, compared to in the cytosol.

[0654] In another example of a suitable assay, cells (e.g., U87 MG cells) are contacted with exemplary compounds (1-100µM). Cells are contacted with sphingosine-1-phosphate (S1P) simultaneously with compound or 30 minutes afterwards, to stimulate translocation of CLIC1 and / or CLIC4 from the cytosol to the plasma membrane. Cells are contacted with ionomycin (3-30µM) for chloride efflux stimulation, then MQAE dye (5-10mM) is added and cells are incubated for 2 hours. Cells are rinsed and fluorescence intensity at a suitable wavelength is recorded at a 0 to 90 minutes by microplate reader. Translocation of CLIC1 and / or CLIC4 is quantified by measuring fluorescence intensity (RFU) at the suitable wavelength.

[0655] In another example of a suitable assay, cells (e.g., U87 MG cells) are contacted with exemplary compounds (1-100µM). Cells are contacted with sphingosine-1-phosphate (S1P) simultaneously with compound or 30 minutes afterwards, to stimulate translocation of CLIC1 and / or CLIC4 from the cytosol to the plasma membrane. Cells are contacted with ionomycin (3-30µM) for chloride efflux stimulation, then cells are trypsinized and prepared in a cell hotel. A patch clamp assay is performed to quantify translocation of CLIC1 and / or CLIC4.CertainCooley Ref. CLBO-002 / 01WO 349489-2004 exemplary compounds inhibit membrane translocation of CLIC1 and / or CLIC 4 as measured by any one or more of these assays. Certain exemplary compounds inhibit membrane translocation of CLIC1, but do not substantially inhibit membrane translocation of CLIC 4, as measured by any one or more of these assays. Example 29: Effect of Exemplary Compounds on Body Weight

[0656] Subjects are administered exemplary compounds disclosed herein, or vehicle control, daily by oral gavage for 14 days. Food intake and body weight are measured daily for 21 days. Baseline body composition are conducted on day 0 (baseline) and day 14 to measure fat versus lean mass. The subject may be overweight or obese. Example 30: Inhibition of Clic1 in a Model of Prader-Willi Syndrome

[0657] Subjects are administered with exemplary compounds disclosed herein, or vehicle control, daily by oral gavage, and food intake and body weight are measured daily. Epididymal white adipose tissue (eWAT) are measured at cessation of treatment. The subject may have Prader-Willi Syndrome. EQUIVALENTS

[0658] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0659] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

Cooley Ref. CLBO-002 / 01WO 349489-2004 CLAIMS:

1. A compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: X is O or S; n is 1 or 2; R1is C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen; R4is H or halogen; R6is H, halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), or - NH(C=O)-(C1-C6 alkyl); T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-;Cooley Ref. CLBO-002 / 01WO 349489-2004 each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; Q is -OH, -C(=O)-Y, or 5- to 10-membered heteroaryl; Y is -OR5, -N(R5)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano; and each R5independently is H, halogen, cyano, -S(=O)2OH, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano.

2. The compound of clam 1, being of Formula (I’’):or a pharmaceutically acceptable salt thereof, wherein: X is O or S; n is 1 or 2; R1is C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10aryl, C3-C10cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen; R4is H or halogen;Cooley Ref. CLBO-002 / 01WO 349489-2004 T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; Y is -OR5, -N(R5)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano; and each R5independently is H, halogen, cyano, -S(=O)2OH, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen or cyano.

3. The compound of claim 1 or claim 2, being of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6- C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is H or halogen;Cooley Ref. CLBO-002 / 01WO 349489-2004 R4is H or halogen; T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-; each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; and R5is H or C1-C6 alkyl.

4. The compound of claim 3, wherein: R1is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one or more R1S; each R1Sindependently is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1- C6 alkyl), -NH(C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), -NH- (C=O)-(C1-C6 alkyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1Sa; each R1Saindependently is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R2is C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; R3is halogen; R4is halogen; T is *-C(Ra)2-, *-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2- C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2- O-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-C(Ra)2-, *-C(Ra)2-C(Ra)2-O-C(Ra)2- C(Ra)2-C(Ra)2-, or *-C(Ra)2-C(Ra)2-C(Ra)2-O-C(Ra)2-C(Ra)2-, wherein * denotes attachment to R5-O-C(=O)-;Cooley Ref. CLBO-002 / 01WO 349489-2004 each Raindependently is H or C1-C6 alkyl; or two Ra, together with the one or more intervening atoms they are attached to, form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl; and R5is H or C1-C6 alkyl.

5. The compound of any one of the preceding claims, wherein X is O.

6. The compound of any one of the preceding claims, wherein X is S.

7. The compound of any one of the preceding claims, wherein n is 1.

8. The compound of any one of the preceding claims, wherein n is 2.

9. The compound of any one of the preceding claims, wherein R1is C6-C10 aryl optionally substituted with one or more R1S.

10. The compound of any one of the preceding claims, wherein R1is phenyl optionally substituted with one or more R1S.

11. The compound of any one of the preceding claims, wherein R1is C3-C10 cycloalkyl optionally substituted with one or more R1S.

12. The compound of any one of the preceding claims, wherein R1is 5- to 10-membered heteroaryl optionally substituted with one or more R1S.

13. The compound of any one of the preceding claims, wherein R2is C1-C6 alkyl.

14. The compound of any one of the preceding claims, wherein at least one of R3and R4is halogen.

15. The compound of any one of the preceding claims, wherein R3is Cl.

16. The compound of any one of the preceding claims, wherein R4is Cl.Cooley Ref. CLBO-002 / 01WO 349489-2004 17. The compound of any one of the preceding claims, wherein T is *-C(Ra)2-C(Ra)2-.

18. The compound of any one of the preceding claims, wherein T is *-C(Ra)2-C(Ra)2- C(Ra)2- or *-C(Ra)2-.

19. The compound of any one of the preceding claims, wherein T is *-C(Ra)2-C(Ra)2- C(Ra)2-.

20. The compound of any one of the preceding claims, wherein T is *-C(Ra)2-.

21. The compound of any one of the preceding claims, wherein at least one Rais H or C1- C6 alkyl.

22. The compound of any one of the preceding claims, wherein each Rais H.

23. The compound of any one of the preceding claims, wherein two Ra, together with the one or more intervening atoms they are attached to, form a C3-C6 cycloalkyl or a 3- to 6- membered heterocycloalkyl.

24. The compound of any one of the preceding claims, wherein Q is -OH.

25. The compound of any one of the preceding claims, wherein Q is -C(=O)-Y.

26. The compound of any one of the preceding claims, wherein Q is tetrazolyl.

27. The compound of any one of the preceding claims, wherein Y is -OR5.

28. The compound of any one of the preceding claims, wherein Y is -N(R5)2.

29. The compound of any one of the preceding claims, wherein Y is C1-C6alkyl optionally substituted with one or more halogen or cyano.

30. The compound of any one of the preceding claims, wherein R5is H.Cooley Ref. CLBO-002 / 01WO 349489-2004 31. The compound of any one of the preceding claims, wherein R5is C1-C6 alkyl.

32. The compound of any one of the preceding claims, wherein R5is halogen.

33. The compound of any one of the preceding claims, wherein R5is cyano.

34. The compound of any one of the preceding claims, wherein R5is -S(=O)2OH.

35. The compound of any one of the preceding claims, wherein R6is H.

36. The compound of any one of the preceding claims, wherein R6is halogen, cyano, -OH, -NH2, -SO2NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O-(C=O)-(C1-C6 alkyl), or -NH(C=O)-(C1-C6 alkyl).

37. The compound of any one of the preceding claims, wherein the compound is of Formula (Ia’) or (Ib’):.or a pharmaceutically acceptable salt thereof.

38. The compound of any one of the preceding claims, wherein the compound is of Formula (Ia’’) or (Ib’’):.Cooley Ref. CLBO-002 / 01WO 349489-2004or a pharmaceutically acceptable salt thereof.

39. The compound of any one of the preceding claims, wherein the compound is of Formula (Ia) or (Ib):or a pharmaceutically acceptable salt thereof.

40. The compound of any one of the preceding claims, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt thereof.

41. The compound of any one of the preceding claims, wherein the compound is of Formula (IIa) or (IIb):Cooley Ref. CLBO-002 / 01WO 349489-2004(IIb), or a pharmaceutically acceptable salt thereof.

42. The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Tables 1-3 and pharmaceutically acceptable salts thereof.

43. A compound being selected from the compounds described in Table I and pharmaceutically acceptable salts thereof.

44. A method of preparing the compound of any one of the preceding claims.

45. A pharmaceutical composition comprising the compound of any one of the preceding claims, and one or more pharmaceutically acceptable carriers or excipients.

46. A method of inhibiting one or more functions of chloride intracellular channel 1 (Clic1) and / or chloride intracellular channel 4 (Clic4), comprising contacting a cell with an effective amount of the compound or pharmaceutical composition of any one of the preceding claims.

47. The method of claim 46, wherein the one or more functions of Clic1 and / or Clic4 comprises translocation of Clic1 and / or Clic4 from the cytosol to the plasma membrane of the cell.

48. The method of claim 46 or 47, wherein the method inhibits one or more functions of Clic1 but does not substantially inhibit one or more functions of Clic4.

49. A method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding claims.Cooley Ref. CLBO-002 / 01WO 349489-2004 50. A method of reducing body weight in a subject, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding claims.

51. A method of reducing food intake in a subject, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding claims.

52. The compound of any one of the preceding claims for use in inhibiting chloride intracellular channel 1 (Clic1) and / or chloride intracellular channel 4 (Clic4).

53. The compound of any one of the preceding claims for use in treating or preventing a disease or disorder disclosed herein.

54. Use of the compound of any one of the preceding claims in the manufacture of a medicament for inhibiting chloride intracellular channel 1 (Clic1) and / or chloride intracellular channel 4 (Clic4).

55. Use of the compound of any one of the preceding claims in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

56. The method, compound for use, or use of any one of the preceding claims, wherein the disease or disorder is obesity.

57. The method, compound for use, or use of any one of the preceding claims, wherein the disease or disorder is obesity-related heart failure.

58. The method, compound for use, or use of any one of the preceding claims, wherein the disease or disorder is fatty liver disease.

59. The method, compound for use, or use of any one of the preceding claims, wherein the disease or disorder is nonalcoholic fatty liver disease (NAFLD) or alcohol-associated fatty liver disease.Cooley Ref. CLBO-002 / 01WO 349489-2004 60. The method, compound for use, or use of any one of the preceding claims, wherein the disease or disorder is rheumatoid arthritis, seropositive rheumatoid arthritis, primary sclerosing cholangitis, autoimmune Addison’s Disease, systemic lupus erythematosus (SLE), latent autoimmune diabetes in an adulttriglye, elevated triglyceride to HDL ratio, abnormal serum apolipoprotein A (ApoA), Graves' disease, multiple sclerosis, early-onset myasthenia gravis, narcolepsy Type 1, Type 1 Diabetes (T1D), T1D with a specified age of onset, T1D with opthalmic manifestaions, or T1D with neurological manifestations.

61. The method, compound for use, or use of any one of the preceding claims, wherein the disease or disorder is inflammation, neurodegeneration, or cancer.

62. The method, compound for use, or use of any one of the preceding claims, wherein the method reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after starting treatme 63. The method, compound for use, or use of any one of the preceding claims, wherein the method reduces the subject’s body weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, or at least about 20%, at least about 25%, or at least about 30%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

64. The method, compound for use, or use of any one of the preceding claims, wherein the method does not cause diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by less than about 50%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3Cooley Ref. CLBO-002 / 01WO 349489-2004 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment.

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