AMPK-beta-1-activating compounds and methods of using the same

Abstract

Disclosed are compounds or pharmaceutically acceptable salts thereof according to formulae IA, IB, or IC as well as pharmaceutical compositions, and methods of use thereof: Formula (IA), (IB), (IC), wherein moieties A and B are further described herein. In certain embodiments, a compound disclosed herein is a 5'-AMP-activated protein kinase ('AMPK') agonist.

Description

AMPK-beta-l-activating Compounds and Methods of Using the SameField of the Invention

[0001] The present invention relates to compounds activating 5 '-adenosine monophosphate (AMP)-activated protein kinase (AMPK), pharmaceutical compositions, and methods of use thereof. The compounds comprise indole and aza-indole compounds and their pharmaceutically acceptable salts. It also pertains to methods for treating metabolic disorders, inflammatory diseases, and cardiovascular diseases using these compounds.Background

[0002] Metabolic disorders, inflammatory diseases, and cardiovascular diseases are significant health concerns worldwide. There is a need for effective treatments that can address these conditions.

[0003] The kinase 5 '-AMP-activated protein kinase (AMPK) is well established as an important sensor and regulator of cellular energy homeostasis. (B. Viollet et al., Crit Rev Biochem Mol Biol.2010 Aug; 45(4):276-295. (doi: 10.3109 / 10409238.2010.488215)). Being a multi -substrate enzyme, AMPK regulates a variety of metabolic processes, such as glucose transport, glycolysis and lipid metabolism. It acts as a sensor of cellular energy homeostasis and is activated in response to certain hormones and muscle contraction as well as to intracellular metabolic stress signals such as exercise, ischemia, hypoxia and nutrient deprivation. Once activated, AMPK switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis). Activation of the AMPK pathway improves insulin sensitivity by directly stimulating glucose uptake in adipocytes and muscle and by increasing fatty acid oxidation in liver and muscle, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents. Moreover, activation of the AMPK pathway decreases glycogen concentration by reducing the activity of glycogen synthase. Activation of the AMPK pathway also plays a protective role against inflammation and atherosclerosis. It suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory' processes that occur during the early phases of atherosclerosis.

[0004] What is needed are compounds, pharmaceutical compositions and methods of using them to treat disease states wherein AMPK activation is beneficial, such as type II diabetes, atherosclerosis and cardiovascular disease.Summary of the Invention

[0005] The disclosure provides pharmaceutical compositions comprising compounds of formulae IA, IB, or IC, as well as methods for treating type II diabetes, inflammatory diseases, and cardiovascular diseases using these compounds:IA IB ICDetailed Description of the Invention

[0006] In a first aspect, the disclosure includes a compound or a pharmaceutically acceptable salt thereof selected from the group of formula IA, IB, and IC:IA IB IC

[0007] In one embodiment, X can be CRb or N. Substituent Rb can be selected from H, Ci-Ce alkyl, and Ci-Ce haloalkyl. Moreover, Ri can be selected from COORa, SChORa, SO2N(Ra)2, CON(Ra)2, C(OH)(Ra)2, and a 5-membered heterocyclic group, wherein Ra can be, for each occasion independently, selected from hydrogen, a C1-C4 alkyl, a haloalkyl, a C3-C6 cycloalkyl, a three-to-six membered heteroalkyl, a three-to-six membered heterocycloalkyl, a C5-C6 aryl, and a five-to-six membered heteroaryl. Substituent R2, when present, can be selected from hydrogen, a halogen, a Ci-C4 alkyl, a C1-C4 haloalkyl, and a C3-C6 cycloalkyl. R3 can be selected from hydrogen, fluoro, chloro, and bromo. Substituent R4, when present, is selected from hydrogen, fluoro, and a C1-C4 alkyl.

[0008] Moiety Ain formulae IA, IB, or IC can be selected from the following structures:

[0009] Group B in formulae IA, IB, or IC can be selected from:

[0010] Addressing the foregoing substituents for group B, group X has the same meaning as above, group Y can be selected from C(R2a)2, NR2a, CO, O, and S. Substituents R21, R22, R24, and R25, when present and for each occasion, can independently be selected from H, OH, N(R2a)2, F, Cl, Br, CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkoxyalkyl, and Ci-Ce haloalkylalkoxy, wherein R2a is for each occasion independently selected from H and a C1-C4 alkyl. Subsituent R23, when present, can be selected from H, F, Cl, Br, OH, N(R2a)2, C(O)N(R2a)2, CN, and R23a. R23a can be selected from a Ci-Ce alkyl, a C2-C5 alkenyl, a Ci-Ce alkoxy, a hydroxyalkyl, a halogenated alkyl, an alkoxyalkyl, a dialkoxyalkyl, a cyanoalkyl, a six membered aryl, a six membered heteroaryl, a five membered aryl, a five membered heteroaryl, a six membered arylalkyl, a six membered heteroarylalkyl, a five membered arylalkyl, a five membered heteroarylalkyl, a C3-C6 cycloalkyl, a C3-C6 cycloalkylalkyl, a C3-C6 cycloalkyloxy, a C3-C6 cycloalkylcarboxy, a four-to-six memberedheterocycloalkyl, a four-to-six membered heterocycloalkylalkyl, a four-to-six membered heterocycloalkyloxy, a four-to-six membered heterocycloalkylcarboxy, a five-to-ten membered spiroalkyl, a five-to-ten membered heterospiroalkyl, a four-to-six membered lactone, a four-to-six membered lactam, a carboxylate, a carbamide, a sulfonate, and a sulfamide. In embodiments, R 3a can optionally be substituted with a hydroxy, an amine, a halogen, a Ci-Cio alkyl, Ci-Cio alkenyl, a Ci-Ce cycloalkyl, a Ci-Cio alkoxy, or any combination thereof. The optional substituents of R23a include linear, branched, and alkylated derivatives.

[0011] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is selected from the following formulae IA-1 and IA-2:IA-1

[0012] In another embodiment, the compound or a pharmaceutically acceptable salt thereof can be selected from the following formulae IA-1-1 and IA-2-1:

[0013] In yet one further embodiment, the compound or a pharmaceutically acceptable salt thereof can be selected from the following group:-5-o10--11--13-o-16-

[0014] In one embodiment, the present disclosure includes a pharmaceutical composition comprising one of the foregoing compounds or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0015] In yet one further embodiment, the present disclosure includes a method for treating type II diabetes in a subject. The method comprises administering to the subject an effective amount of one of the foregoing compounds or a pharmaceutically acceptable salt thereof. As used herein, an “effective amount” or “therapeutically effective amount” refers to an amount of the compound that, when administered to a subject in need thereof, is sufficient to effect treatment, prevention, oramelioration of the disease or condition. The effective amount will vary depending on the compound, the disease or condition being treated, the severity of the disease or condition, the age, weight, and general health of the subject, and the judgment of the prescribing physician.

[0016] In yet one further embodiment, the present disclosure includes a method for treating an inflammatory disease in a subject. The method comprises administering to the subject an effective amount of one of the foregoing compounds or a pharmaceutically acceptable salt thereof.

[0017] In yet one more embodiment, the present disclosure includes a method for treating a cardiovascular disease in a subject. The method comprises administering to the subject an effective amount of one of the foregoing compounds or a pharmaceutically acceptable salt thereof.

[0018] In another embodiment, the present disclosure includes a compound for use in the treatment of a metabolic disorder, an inflammatory disease, or a cardiovascular disease. In one embodiment, the use for treatment of the metabolic disorder is the treatment of type II diabetes. In one further embodiment, the use for treatment of the inflammatory disease is the treatment of atherosclerosis

[0019] The following Examples are intended to further illustrate certain embodiments and are not intended to limit the scope of the disclosure.Experimental

[0020] Abbreviations:ACN: acetonitrileaq: aqueousBoc: tert-butyloxy carbonyldba: dibenzylideneacetoneDCM: dichloromethaneDME: dimethoxyethaneDMF: N, N-dimethylformamideESI-MS: electrospray ionization mass spectrometryFA: formic acidh: hour(s)HMDS: bis(trimethylsilyl)amideLCMS: liquid chromatography mass spectrometrymin: minute(s)prep: preparative-scaleHPLC: high performance liquid chromatographyPMB: para-methoxybenzylRuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenylRuPhos PdG3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, generation 3RT: room temperatureRt: retention timeTEA: triethylamineTFA: trifluoroacetic acidTHF: tetrahydrofuranXPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0021] Preparation 1: l-bromo-2-((4-methoxybenzyl)oxy)benzene00

[0022] To a solution of 2-bromophenol (5.00 g, 28.9 mmol) and K2CO3 (12.0 g, 86.7 mmol) in DMF (50 m ) was added PMBC1 (5.45 g, 37.4 mmol). The mixture was stirred at RT overnight. It was then diluted with water (400 mb) and extracted with EtOAc (3 x 300 mb). The organic phases were combined, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude material was purified by trituration with MeOH to provide the title compound (8.00 g, 94%) as a white solid.

[0023] Preparation 2: l-(2-((4-methoxybenzyl)oxy)phenyl)piperazineoY N.0 I

[0024] To a solution of l-bromo-2-((4-methoxyphenyl)methoxy)benzene (8.00 g, 27.3 mmol), piperazine (11.8 g, 137 mmol), and CS2CO3 (1.78 g, 5.46 mmol) in anhydrous dioxane (80 mb) was added RuPhos PdG3 (2.31 g, 2.73 mmol) and RuPhos (2.54 g, 5.46 mmol) at RT under nitrogenatmosphere. The mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled and extracted with DCM (3 x 300 mL). The combined organic layers were dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified via reverse phase flash chromatography (C18 silica gel) using 20% to 30% ACN in water (containing 0.1% FA) to provide the title product (3.80 g, 47%) as a white solid. ES / MS (m / z): 299 (M+H).

[0025] Preparation 3: Methyl 5-(4-(tert-butoxycarbonyl)piperazin-l-yl)-6-chloro-lH-indole-3-carboxylateH

[0026] To a solution of methyl 5-bromo-6-chloro-lH-indole-3-carboxylate (9.00 g, 31.2 mmol) and tert-butyl piperazine- 1 -carboxylate (8.70 g, 46.8 mmol) in anhydrous THF (54 mL) was added RuPhos (2.70 g, 6.30 mmol) and RuPhos Pd G3 (2.61 g, 3.12 mmol) at room temperature under nitrogen atmosphere. LiHMDS (93.6 mL, 93.6 mmol, 1.0 M in THF) was then added dropwise at 0 °C. The mixture was stirred at 60 °C for 1 h, cooled to room temperature, quenched with NH4CI (aq) at 0 °C, and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduce pressure to provide the title compound (9.9 g, 81%) as a yellow oil (used in the next step without further purification). ESI-MS m / z 394 and 396 (M+H).

[0027] Preparation 4: Methyl 6-chloro-5-(piperazin-l-yl)-lH-indole-3-carboxylate D

[0028] To a solution of methyl 5-(4-(tert-butoxycarbonyl)piperazin-l-yl)-6-chloro-lH-indole-3-carboxylate (9.9 g, 25.1 mmol) in DCM (66 mL) was added HC1 in 1,4-dioxane (66 mL, 264 mmol, 4.0 M) dropwise at 0 °C. The mixture was stirred at RT for 2 h, diluted with water (500 mL), and extracted with DCM (3 x 150 mL). The water phase was adjusted to pH ~10 with saturated aqueous NaOH at 0 °C and extracted with DCM (3 x 200 mL). The combined organic layers were dried overNa2SO4, filtered, and concentrated under reduced pressure to provide the title compound (4.05 g, 55%) as a yellow solid, which was used directly without further purification. ESI-MS m / z 294 and 296 (M+H).

[0029] Preparation 5: Methyl 6-chloro-5-(4-(2-((4-methoxybenzyl)oxy)phenyl)piperazin-l-yl)-lZ7-indole-3 -carboxylate

[0030] To a solution of l-(2-((4-methoxybenzyl)oxy)phenyl)piperazine (4.70 g, 15.8 mmol), methyl 6-chloro-5-(piperazin-l-yl)-lH-indole-3-carboxylate (3.8 g, 13.2 mmol), RuPhos PdG3 (1.09 g, 1.32 mmol), and RuPhos (1.24 g, 2.64 mmol) in anhydrous THF (50 mL) was added LiHMDS (80 mL, 80 mmol, 1.0 M in THF) at RT under nitrogen atmosphere and stirred at 60 °C for 1 h. The reaction mixture was cooled, quenched with saturated aqueous NH4CI (100 mL) at -10 °C, diluted with water (500 mL), and extracted with DCM (3 x 200 mL). The combined the organic layers were separated, dried over Na SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 40% EtOAc in petroleum ether to provide the title compound (2.85 g, 43%) as a yellow solid. ESI-MS m / z 506 and 508 (M+H).

[0031] Preparation 6: Methyl 6-chloro-5-(4-(2-hydroxyphenyl)piperazin-l-yl)-17 / -indole-3-carb oxy late

[0032] To a solution of methyl 6-chloro-5-(4-(2-((4-methoxybenzyl)oxy)phenyl)piperazin-l-yl)-l / 7-indole-3-carboxylate (200 mg, 0.400 mmol) in DCM (5 mL) was added TFA (1 mL) at 0 °C and stirred at RT for 1 h. Water (30 mL) was added and extracted with DCM (3 >< 15 mL). The combined organiclayers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to provide the title compound (100 mg, 65%) as a yellow oil. ESI-MS m / z 386 and 388 (M+H).

[0033] Preparation 7: (4-bromo-3-((4-methoxybenzyl)oxy)phenyl)methanolOO

[0034] To a solution of 2-bromo-5 -(hydroxymethyl )phenol (5 g, 24.6 mmol) and l-(chloromethyl)-4-methoxybenzene (5.79 g, 36.9 mmol) in DMF (50 mL) was added K2CO3 (10.2 g, 73.9 mmol) at room temperature. The mixture was stirred at 60 °C for 5 h. The reaction mixture was cooled, diluted with water (500 mL), extracted with EtOAc (3 * 300 mL), dried over Na2SO4, filtered, and concentrated the organics under reduced pressure to provide the title compound (7.00 g, crude) as a yellow oil. ESIMS m / z 321 (M-H).

[0035] Preparation 8: l-bromo-2-((4-methoxybenzyl)oxy)-4-(methoxymethyl)benzeneo

[0036] To a solution of (4-bromo-3-((4-methoxybenzyl)oxy)phenyl)methanol (7.00 g, 21.6 mmol) and KOH (3.65 g, 65.1 mmol) in DMSO (70 mL) was added Mel (24.6 g, 173 mmol) at room temperature. The mixture was stirred at RT for 2 h, diluted with water (500 mL), extracted with EtOAc (3 * 300 mL), dried over Na2SO4, filtered, and concentrated the organics under reduced pressure to provide the title compound (8.00 g, crude) as a yellow oil.

[0037] Preparation 9: methyl 6-chloro-5-(4-(2-((4-methoxybenzyl)oxy)-4-(methoxymethyl)phenyl)piperazin-l-yl)-lH-indole-3-carboxylate

[0038] To a solution of l-bromo-2-((4-methoxybenzyl)oxy)-4-(methoxymethyl)benzene (270 mg, 0.801 mmol) and methyl 6-chloro-5-(piperazin-l-yl)-lH-indole-3-carboxylate (259 mg, 0.881 mmol) in THF (5 mL) under nitrogen atmosphere was added RuPhos (75 mg, 0.160 mmol), LiHMDS (4.02 mb, 4.02 mmol, 1.0 M in THF) and RuPhos PdG3 (67 mg, 0.080 mmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to provide the title compound (185 mg, 42%) as a brown solid. ESIMS m / z 550 and 552 (M+H).

[0039] Preparation 10: Methyl 6-chloro-5-(4-(2-hydroxy-4-(methoxymethyl)phenyl)piperazin-l-yl)-lH-indole-3-carboxylate

[0040] To a solution of methyl 6-chloro-5-(4-(2-((4-methoxybenzyl)oxy)-4-(methoxymethyl)phenyl)piperazin-l-yl)-lH-indole-3-carboxylate (180 mg, 0.327 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at RT for 2 h. The mixture was adjusted to pH 10 with NH3 H2O at 0 °C and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to provide the title compound (100 mg, 71%) as a brown solid. ESI-MS m / z 430 and 432 (M+H)

[0041] Preparation 11: 2-(benzyloxy)-l-bromo-4-iodobenzeneBr

[0042] To a solution of 2-bromo-5-iodophenol (2.0 g, 6.71 mmol) and K2CO3 (2.78 g, 20.1 mmol) in DMF (20 mL) was added benzyl bromide (1.69 g, 10.0 mmol). The mixture was stirred at RT for 2 h, diluted with water (200 mL), and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by trituration with MeOH to provide the title compound (1.2 g, 46%) as a white solid.

[0043] Preparation 12: 3-(3-(benzyloxy)-4-bromophenyl)oxetane

[0044] To a solution of 2-(benzyloxy)-l-bromo-4-iodobenzene (1.0 g, 2.57 mmol) in DMA (10 mL) was added 3-iodooxetane (568 mg, 3.08 mmol), (DME)NiCh (57 mg, 129 pmol), pyridine-2-carboximidamide hydrochloride (41 mg, 129 pmol), TFA(29 mg, 129 pmol), Zn (336 mg, 2.57 mmol), and Nal (193 mg, 642 pmol) at RT under nitrogen atmosphere. The reaction mixture was stirred at 60 °C overnight under nitrogen atmosphere, cooled, diluted with water (200 mL), and extracted with DCM (3 x 100 mL). The combined the organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum ether to provide the title compound (280 mg, 34%) as a white solid.

[0045] Preparation 13: Methyl 5-(4-(2-(benzyloxy)-4-(oxetan-3-yl)phenyl)piperazin-l-yl)-6-chloro-17 / -indole-3 -carboxylate

[0046] To a solution of 3-[3-(benzyloxy)-4-bromophenyl]oxetane (170 mg, 533 pmol) and methyl 6-chloro-5-(piperazin-l-yl)-l / 7-indole-3-carboxylate (130 mg, 444 pmol), RuPhos PdG3 (37 mg, 44 pmol), and RuPhos (41 mg, 89 pmol) in anhydrous THF (15 mL) was added LiHMDS (4.4 mL, 4.4 mmol, 1.0 M in THF) at RT under nitrogen atmosphere and stirred at 60 °C for 1 h under nitrogen atmosphere. The reaction mixture was cooled, quenched with saturated aqueous NH4CI (10 mL) at -10 °C, and diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The combined organic layers were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to provide the title compound (120 mg, 44%) as a white solid. ESI-MS m / z 532 and 534 (M+H).

[0047] Preparation 14: Methyl 6-chloro-5-(4-(2-hydroxy-4-(oxetan-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3 -carboxylate

[0048] To a solution of methyl 5-(4-(2-(benzyloxy)-4-(oxetan-3-yl)phenyl)piperazin-l-yl)-6-chloro-177-indole-3 -carboxylate (90 mg, 169 pmol) and isopropanol (10 mL) in EtOAc (10 mL) was added palladium on carbon (10% w / w, 9 mg, 8.5 pmol) at RT under nitrogen atmosphere. The mixture was stirred at 60 °C for 2 h under hydrogen atmosphere. The reaction mixture was cooled and filtered. The filtered solid was washed with MeOH (3 x 10 mL) and concentrated the filtrate under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 40% EtOAc in petroleum ether to provide the title compound (40 mg, 48%) as a yellow solid. ESI-MS m / z 442 and 444 (M+H).

[0049] Preparation 15: 3 -(3 -(benzyl oxy)-4-bromophenyl)tetrahydrofuran-3 -ol

[0050] To a solution of 2-(benzyloxy)-l-bromo-4-iodobenzene (20.0 g, 51.4 mmol) in anhydrous THF (400 mL) was added / r-BuLi (26.8 mL, 66.8 mmol, 2.5 M in w-hexane) dropwise at -78 °C under nitrogen atmosphere for 20 min. Dihydrofuran-3(2J7)-one (5.31 g, 61.7 mmol) was added for 20 min, stirred for another 30 min under nitrogen atmosphere, quenched with saturated aqueous NH4CI (400 mL) at -30 °C, diluted with water (400 mL), and extracted with DCM (3 x 400 mL). The combined organic phases were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to provide the title compound (15.0 g, 84%) as a yellow oil. ESI-MS m / z 347 and 349 (M-H).

[0051] Preparation 16: 3 -(3 -(benzyloxy )-4-bromophenyl)tetrahydrofuranO

[0052] To a solution of 3-(3-(benzyloxy)-4-bromophenyl)tetrahydrofuran-3-ol (20.0 g, 57.2 mmol) in DCM (200 mL) was added EtsSiH (20 mL) and boron trifluoride diethyl etherate (40 mL) at -0 °C. The mixture was stirred at RT for 1 h. The reaction was quenched with ice water (30 mL) at 0 °C, diluted with water (400 mL), extracted with DCM (3 x 600 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to provide the title compound (16.0 g, 84%) as a yellow solid. ESI-MS m / z 331 and 333 (M-H).

[0053] Preparation 17: Methyl 5-(4-(2-(benzyloxy)-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-6-chloro-l / / -indole-3 -carboxylate

[0054] To a solution of 3-(3-(benzyloxy)-4-bromophenyl)tetrahydrofuran (170 mg, 0.51 mmol), methyl 6-chloro-5-(piperazin-l-yl)-lH-indole-3-carboxylate (149 mg, 0.51 mmol), RuPhos PdG3 (42 mg, 0.05 mmol), and RuPhos (47 mg, 0.10 mmol) in anhydrous THF (12 mL) was added LiHMDS (2.55 mL, 2.55 mmol, 1.0 M in THF) at RT under nitrogen atmosphere and stirred at 80 °C for 1 h. The reaction mixture was cooled, quenched with ice water (10 mL) at -10 °C, diluted with water (30 mL), and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography using a gradient of 0 to 60% EtOAc in petroleum ether to provide the title compound (120 mg, 43%) as a yellow solid. ESI-MS m / z 546 and 548 (M+H).

[0055] Preparation 18: Methyl 6-chloro-5-(4-(2-hydroxy-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3-carboxylate

[0056] To a solution of methyl 5-(4-(2-(benzyloxy)-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-6-chloro-17 / -indole-3 -carboxylate (115 mg, 0.21 mmol) in DCM (5 mL) was added BBr3 in DCM (0.63 mL, 0.63 mmol, 1.0 M) at 0 °C under nitrogen atmosphere and stirred at RT for 1 h. The reaction was quenched with MeOH (2 mL) and TEA (2 mL) at -0 °C and concentrated under reduced pressure. The residue was purified via silica gel column chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to provide the title compound (57 mg, 59%) as a yellow solid. ESI-MS m / z 456 and 458 (M+H).

[0057] Preparation 19: 6-chloro-5-(4-(2-hydroxy-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-l / f-indole-3 -carboxylic acidO OH N

[0058] To a solution of methyl 6-chloro-5-(4-(2-hydroxy-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3 -carboxylate (53 mg, 0.11 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (1 mL) at 0 °C and stirred at 60 °C for 1 h. The reaction mixture was cooled, adjusted to pH ~8 with aqueous NH3, and concentrated. The residue was purified via reverse flash chromatography (C 18 silica gel) using a 20% to 30% ACN in water (with 10 mmol / L NH4HCO3) gradient to provide the title compound (26 mg, 51%) as a white solid. ESI-MS m / z 442 and 444 (M+H).

[0059] Preparation 20: l-bromo-4-iodo-2-((4-methoxybenzyl)oxy)benzeneliO

[0060] To a solution of 2-bromo-5 -iodophenol (2.0 g, 6.71 mmol) and K2CO3 (2.78 g, 20.1 mmol) in DMF (30 mL) was added 4-methoxybenzylchloride (1.26 g, 8.05 mmol) at 0 °C. The mixture was stirred at RT overnight, diluted with water (50 mL), and extracted with EtOAc (3 x 150 mL). The organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by trituration with MeOH to provide the title compound (2.0 g, 71%) as a white solid.

[0061] Preparation 21: 5-(4-bromo-3 -((4-methoxybenzyl)oxy )phenyl)-2, 3 -dihydro- 1,4-dioxineo

[0062] To a solution of l-bromo-4-iodo-2-((4-methoxybenzyl)oxy)benzene (2.0 g, 4.78 mmol), 2-(5,6-dihydro-l,4-dioxin-2-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.22 g, 5.74 mmol), and K2CO3 (1.7 g, 12 mmol) in 1,4-dioxane (16 mL) and water (1.6 mL) was added Pd2(dba)3 (440 mg, 0.48 mmol) and XPhos (457 mg, 0.96 mmol) at RT under nitrogen atmosphere and stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled, diluted with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified via reverse phase flash chromatography (Cl 8 silica gel) using a gradient of 50% to 70% ACN in water (with 10 mmol / L NH4HCO3.) to provide the title compound (1.2 g, 66%) as a yellow solid.

[0063] Preparation 22: Methyl 6-chloro-5-(4-(4-(5,6-dihydro-l,4-dioxin-2-yl)-2-((4-methoxybenzyl)oxy)phenyl)piperazin- 1 -yl)- lH-indole-3 -carboxylateOoo II OKV-Q1L.0 L N

[0064] To a solution of 5-(4-bromo-3-((4-methoxybenzyl)oxy)phenyl)-2,3-dihydro-l,4-dioxine (1.2 g, 3.18 mmol), methyl 6-chloro-5-(piperazin-l-yl)-lH-indole-3-carboxylate (1.1 g, 3.74 mmol), RuPhos PdG3 (268 mg, 0.32 mmol), and RuPhos (298 mg, 0.64 mmol) in anhydrous THF (16 mL) was added LiHMDS (15 mL, 15.0 mmol, 1.0 M in THF) at RT under nitrogen atmosphere and stirred at 60 °C for 1 h under nitrogen atmosphere. The reaction mixture was cooled, quenched with saturated aqueous NH4CI (50 mL) at -10 °C, diluted with water (50 mL), extracted with DCM (3 * 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via reverse phase flash chromatography (Cl 8 silica gel) using a gradient of 45% to 60% ACN in water (with 10 mmol / L NH4HCO3) to provide the title compound (1.4 g, 75%) as a light-yellow solid. ESI-MS m / z 590 and 592 (M+H).

[0065] Preparation 23: Methyl 5-(4-(4-(l,4-dioxan-2-yl)-2-((4-methoxybenzyl)oxy)phenyl)piperazin-l-yl)-6-chloro-lH-indole-3-carboxylate

[0066] To a solution of methyl 6-chloro-5-(4-(4-(5,6-dihydro-l,4-dioxin-2-yl)-2-((4-methoxybenzyl)oxy)phenyl)piperazin-l-yl)-lH-indole-3-carboxylate (200 mg, 0.339 mmol) in EtOAc (10 mL) was added palladium on carbon (10% w / w, 30 mg, 28.3 pmol) at RT under nitrogen atmosphere. The mixture was stirred at RT for 0.5 h under hydrogen atmosphere, filtered, and washed the solid with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure to provide the title compound (140 mg, 70%) as a yellow solid, which is used crude. ESI-MS m / z 592 and 594 (M+H).

[0067] Preparation 24: methyl 5-(4-(4-(l,4-dioxan-2-yl)-2-hydroxyphenyl)piperazin-l-yl)-6-chloro-lH-indole-3-carboxylate

[0068] To a solution of methyl 5-(4-(4-(l,4-dioxan-2-yl)-2-((4-methoxybenzyl)oxy)phenyl)-piperazin-l-yl)-6-chloro-lH-indole-3-carboxylate (140 mg, 0.24 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.6 mL) at 0 °C. The mixture was stirred at RT for 0.5 h, adjusted to pH ~7 with saturated aqueous NaOH, and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to provide the title compound (112 mg, crude) as a yellow oil, which is used crude. ESI-MS m / z 472 and 474 (M+H).

[0069] Preparation 25: 5-(4-(4-(l,4-dioxan-2-yl)-2-hydroxyphenyl)piperazin-l-yl)-6-chloro-lH-indole-3 -carboxylic acid

[0070] To a solution of methyl 5-(4-(4-(l,4-dioxan-2-yl)-2-hydroxyphenyl)piperazin-l-yl)-6-chloro-lH-indole-3-carboxylate (112 mg, 0.23 mmol) in MeOH (2 mL) and water (2 mL) was added NaOH (92 mg, 2.3 mmol). The mixture was stirred at 60 °C overnight. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified via reverse phase flash chromatography (Cl 8 silica gel) using a gradient of 20% to 30% ACN in water (with 10 mmol / L NH4HCO3) to provide the title compound (40 mg, 37%) as a white solid. ESI-MS m / z 458 and 460 (M+H).

[0071] Example 1: 6-chloro-5-(4-(2-hydroxyphenyl)piperazin-l-yl)-l / / -indole-3-carboxylic acid

[0072] To a solution of methyl 6-chloro-5-[4-(2-hydroxyphenyl)piperazin-l-yl]-l / 7-indole-3-carboxylate (100 mg, 0.259 mmol) in THF (4 mL) and H2O (1 mL) was added NaOH (51.8 mg, 1.30 mmol) and stirred at 60 °C overnight. The reaction mixture was cooled and purified directly by Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30 * 150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254 nm / 220 nm; Rtl(min): 6.56) to provide the title compound (6.60 mg, 6.9%) as a white solid. ESIMS m / z 372 and 374 (M+H).

[0073] Example 2: 6-Chloro-5-(4-(2-hydroxy-4-(methoxymethyl)phenyl)piperazin-l-yl)-lH-indole-3 -carboxylic acid

[0074] To a solution of methyl 6-chloro-5-(4-(2-hydroxy-4-(methoxymethyl)phenyl)piperazin-l-yl)-lH-indole-3-carboxylate (80 mg, 0.186 mmol) in MeOH (2 mL) and H2O (2 mL) was added NaOH (372 mg, 9.30 mmol). The mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled, adjusted the pH to 3 with saturated aqueous citric acid at 0 °C, and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridgePrep OBD C18 Column, 30*150 mm, 5 Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 37% B in 10 min; Wave Length: 254 nm / 220 nm; Rtl(min): 8.03). The desired fractions were concentrated under reduced pressure. The residue was dissolved in ACN and H2O and lyophilized to provide the title compound (4.7 mg, 6%) as a white solid. ESLMS m / z 416 and 418 (M+H).

[0075] Example 3: 6-chloro-5-(4-(2-hydroxy-4-(oxetan-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3-carboxylic acidN OH L. N

[0076] To a solution of methyl 6-chloro-5-(4-(2-hydroxy-4-(oxetan-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3-carboxylate (34 mg, 77 pmol) in MeOH (8 mL) and water (8 mL) was added NaOH (615 mg, 15.4 mmol). The mixture was stirred at 60 °C overnight. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified via reverse phase flash chromatography (Cl 8 silica gel) using a 20% to 30% ACN in water (with 10 mmol / L NH4HCO3) gradient to provide the title compound (11 mg, 32%) as a white solid. ESLMS m / z 428 and 430 (M+H).

[0077] Example 4: 6-chloro-5-(4-(2-hydroxy-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3 -carboxylic acid (Isomer 1)Isomer 1

[0078] Example 5: 6-chloro-5-(4-(2-hydroxy-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-l / f-indole-3 -carboxylic acid (Isomer 2)Isomer 2

[0079] Racemic 6-chloro-5-(4-(2-hydroxy-4-(tetrahydrofuran-3-yl)phenyl)piperazin-l-yl)-l / 7-indole-3 -carboxylic acid (20 mg) was purified by Chiral-HPLC (Column: CHIRALPAK IE 20*250mm, 5 « / »; Mobile Phase A: EtOH, Mobile Phase B: Hexane (0.1% FA); Flow rate: 20 mL / min; Gradient: 80% B to 80% B in 18 min; Wave Length: 220 / 254 nm; Rtl (min): 12.32; Rt2 (min): 15.21). The desired fractions were combined, concentrated, and lyophilized to provide the title compound, Isomer 1 (5.9 mg, 29%) as a white solid and the title compound, Isomer 2 (5.2 mg, 26%) as a white solid. Isomer 1, unknown absolute stereochemistry: LCMS (Method 4) Rt = 0.621 mins (99.5% purity), ESI-MS m / z 442 and 444 (M+H); Chiral HPLC (Method 2) Rt = 2.314 mins (ee = 100%). Isomer 2, unknown absolute stereochemistry: LCMS: (Method 4) Rt = 0.629 mins (99.4% purity), ESI-MS m / z 442 and 444 (M+H); Chiral HPLC (Method 2) Rt = 2.878 mins (ee = 98.3%).

[0080] Example 6: <. S'-5-(4-(4-(l,4-dioxan-2-yl)-2-hydroxyphenyl)piperazin-l-yl)-6-chloro-lH-indole-3 -carboxylic acid (Isomer 1) (69a)Isomer 1

[0081] Example 7: A-5-(4-(4-(l,4-dioxan-2-yl)-2-hydroxyphenyl)piperazin-l-yl)-6-chloro-lH-indole-3 -carboxylic acid (Isomer 2) (69b)Isomer 2

[0082] Racemic 5-(4-(4-( 1,4-dioxan-2-yl)-2-hydroxyphenyl)piperazin- 1 -yl)-6-chloro- lH-indole-3 -carboxylic acid (69a + 69b) (40 mg) was purified by Chiral-SFC (Column: CHIRALPAK IG, 20*250 mm, 5 zzw; Mobile Phase A: EtOH-HPLC, Mobile Phase B: Hexane (0.1% FA) - HPLC; Flow rate: 20 mL / min; Gradient: 70% B to 70% B in 22 min; Wave Length: 220 / 254 nm; Rtl (min): 10.21; Rt2 (min): 18.65; Sample Solvent: EtOH: DCM= 1: 1 - HPLC). Pure fractions were combined, concentrated, and lyophilized to provide the title compound, Isomer 1 (18 mg, 46%) as a light-yellow solid and the title compound, Isomer 2 (12 mg, 31%) as a light-yellow solid.

[0083] Isomer 1: LCMS (Method 5) Rt = 0.713 mins (99% purity), ESLMS m / z 458 and 460 (M+H); Chiral HPLC (Method 1) Rt = 2.394 min (ee = 98%).

[0084] Isomer 2: LCMS: (Method 5) Rt = 0.715 mins (98% purity), ESI-MS m / z 458 and 460 (M+H); Chiral HPLC (Method 1) Rt = 3.872 min (ee = 99%).

[0085] Chiral HPLC Methods:

[0086] Method 1: Column: CHIRALPAKIG IG-3; Mobile Phase A: Hexane (0.1 % FA): EtOH = 70: 30; Flow rate: 1 mL / min; Gradient: isocratic.

[0087] Method 2: Column: CHIRALPAKIE IE-3; Mobile Phase A: Hexane (0.1%FA): EtOH = 80:20; Flow rate: 1 mL / min; Gradient: isocratic.

[0088] Table 1 depicts all compounds synthesized similarly to the above-described experimentalTable 1Cpd Chemical Name Structure ES / MS # (m / z) 1 6-chloro-5-(4-(4-(l,3- OH 475 dimethoxypropan-2-yl)-2-0=\(M+H) hydroxyphenyl)piperazin-NHif J1 -yl)- l / f-indole-3 - carboxylic acid ^0 |j^VN^Cl2a (R)-6-chloro-5-(4-(2- 473 hydroxy-4-(3- I D (M+H) methoxytetrahydrofuran-3- J <% ~~OH yl)phenyl)piperazin- 1 -yl)- ^ JL!177-indole-3 -carboxylic O^ / 'Oacid2b (S)-6-chloro-5-(4-(2- 473 hydroxy-4-(3- T(M+H) methoxytetrahy drofuran-3 - ^N. J ^~OH yl)phenyl)piperazin- 1 -yl)-, Qr ^^OHl / 7-indole-3 -carboxylic o^ / ^oacid6-chloro-5-(4-(2-hydroxy- 473 4-(3- I D (M+H) methoxytetrahy drofuran-3 - yl)phenyl)piperazin- 1 -yl)- Hr177-indole-3 -carboxylic0— / oacida (7?)-6-chloro-5-(4-(4-(l,2- 460 dimethoxy ethyl )-2- X X? (M+H) hydroxyphenyl)piperazin- \ J H~0H1 -yl)- l / f-indole-3 - carboxylic acidb (S)-6-chloro-5-(4-(4-(l,2- 460 dimethoxyethyl)-2- T O (M+H) hydroxyphenyl)piperazin- \ > H" OH1 -yl)- l / f-indole-3 -? rrcarboxylic acid 6^6-chloro-5-(4-(4-(l,2- 460 dimethoxyethyl)-2- x o (M+H) hydroxyphenyl)piperazin- \ J H-OHo y — 0l-yl)-l / f-indole-3- carboxylic acid°\6-chloro-5-(4-(2-hydroxy- 498 4-((3S,5S)-l,7- XJO dioxaspiro[4.4]nonan-3- S zz~~OH yl)phenyl)piperazin- 1 -yl)- jQl / / -indole-3-carboxylico-^acid6-chloro-5-(4-(4-(3-CIX -N 472 ethoxyoxetan-3-yl)-2- T O(M+H) hydroxyphenyl)piperazin- / A" OH1 -yl)- l / 7-indole-3 - OZK^^OHcarboxylic acid \y o6-chloro-5-(4-(2-hydroxy- 442 4-(3-methyloxetan-3- XX? (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3 -carboxylic. fracid6-chloro-4-fluoro-5-(4-(2- 434 hydroxy-4- (methoxymethyl)phenyl)pi XX? (M+H) perazin- 1-yl)- l / / -indole-3- J F ^~OHcarboxylic acid_o. A fs. T As / ^OH6-chloro-5-(4-(2-hydroxy- 430 4-(2- methoxyethyl)phenyl)piper XX? (M+H) azin- 1 -yl)- 17 / -indole-3- carboxylic acid5-(4-(2-hydroxy-4-(2- H 396 methoxyethyl)phenyl)piper XX? (M+H) azin- 1 -yl)- 17 / -indole-3- < A~-OH carboxylic acidJDC6-chloro-4-cyclopropyl-5-CI^^N 412 (4-(2-hydroxyphenyl) XX? (M+H) piperazin- 1 -yl)- 17 / -indole- 3 -carboxylic acid f ^^r^OHA 06-chloro-5-(4-(2-fluoro-6- 434 hydroxy-4- T jQ>OH (M+H) (methoxymethyl)phenyl)pi A. ^N. > / %~" OHperazin- 1 -yl)- l / Aindole-3 - carboxylic acid6-chloro-5-(4-(5-fluoro-2- 434 hydroxy-4- X O (M+H) (methoxymethyl)phenyl)pi F. J zZ~-OHperazin- 1 -yl)- l / / -indole-3 - / ^OHcarboxylic acid2-(4-(6-chloro-3-(l -methyl- 408 l / / -pyrazol-3-yl)-l / / -indol- X O (M+H) 5-yl)piperazin- 1 -yl)phenol. N J A? NXT6-chloro-5-(4-(2-hydroxy- 458 4-(3 -methoxy oxetan-3 - T O (M+H) yl)phenyl)piperazin- 1 -yl)- ^N. Jl / / -indole-3 -carboxyliczx JOCacid 06-chloro-5-(4-(2-hydroxy- 444 4-(3 -hydroxy oxetan-3 - T O (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3 -carboxylic / \ jDCO XS^^'OHacid OH6-chloro-5-(4-(2-hydroxy- 416 3 -(methoxy methyl)phenyl) X JQOH ( (M+H) piperazin- 1 -yl)- 1 / f-indole- \ > -X'-OH3 -carboxylic acidu6-chloro-5-(4-(2-hydroxy- 453 4-(3 -methyl- \H- 1,2,4- T ¥>(M+H) triazol-1- yl)phenyl)piperazin- 1 -yl)- rr_ N OH177-indole-3 -carboxylicacid4,6-dichloro-5-(4-(2- 406 hydroxyphenyl)piperazin- X XX (M+H) 1 -yl)- l / f-indole-3 - J'K J Cl / / ~OHcarboxylic acidDC^ CH6-chloro-5-(4-(2-hydroxy-CI^^N 416 5-(methoxymethyl)phenyl) X XX (M+H) piperazin- 1 -yl)- 1 / Z-indole- \ X -Z"~OH3 -carboxylic acid ° CI6-chloro-5-(4-(2-hydroxy- 416 6-(methoxymethyl)phenyl) X XXOH (M+H) piperazin- 1 -yl)- l / / -indole- / X X Xr"~0H3 -carboxylic acidtetrahydro-27 / -pyran-2-yl 456 6-chloro-5-(4-(2-hydroxy- x xx (M+H) pheny l)piperazin- 1 -yl)- \H- J > X~-0indole-3-carboxylate (Q0a (5)-tetrahydro-2Z / -pyran-2- 456 yl 6-chloro-5-(4-(2- X XX (M+H) hydroxyphenyl)piperazin- J ZZ—O1 -yl)- l / f-indole-3 - Q0carboxylateb (A’)-tetrahydro-2 / / -pyran-2-CI^^N 456 yl 6-chloro-5-(4-(2- (M+H) hydroxyphenyl)piperazin- ^N. J / / ~~O1 -yl)- l / f-indole-3 - f Hi Y07 V—oIcarboxylate oiz6-chloro-5-(4-(4-(2- \ / ° 479 cyclopropyl-277-1,2,3- X o (M+H) triazol-4-yl)-2-hydroxy- J zZ~'OH phenyl)piperazin-l-yl)-l / / - fxindole-3-carboxylic acid Y °Ha 6-chloro-5-((17?,67?)-5-(2-CI^^N 398 hy droxy phenyl)-2, 5 - ■|^ N xx> (M+H) diazabicyclo[4.2.0]octan-2- J ZZ—OHyl)-l / / -indole-3 -carboxylicrx— '^OHacidb 6-chloro-5-((lS,6S)-5-(2- 398 hy droxyphenyl)-2, 5 - (M+H) diazabicyclo[4.2.0]octan-2- yl)-l / / -indole-3-carboxylicacid6-chloro-5-(5-(2-hydroxy- 398 phenyl)-2,5-diazabicyclo I Tj (M+H) [4.2.0]octan-2-yl)-l / / - indole-3-carboxylic acidrr6-chloro-5-(4-(2-hydroxy- 450 4-(pyrimidin-4- (M+H) Xyl)phenyl)piperazin- 1 -yl)- Ol / Z-indole-3 -carboxylic IZX x —\ / oacida (7?)-6-chloro-5-(4-(2- 456 hy r x - -(tetrahydro-2 / / - o Z. O > — «3d o y 4 T O(M+H) pyran-2-yl)phenyl) J > Z~~OHpiperazin- 1 -yl)-17 / -indole-.0. Or< — OH3 -carboxylic acidob (S)-6-chloro-5-(4-(2- 456 hydroxy-4-(tetrahydro-27 / - T O (M+H) pyran-2-yl)phenyl) J ^" OHpiperazin- 1 -yl)- l / / -indole- Hr3 -carboxylic acid l^^o6-chloro-5-(4-(3-fluoro-2- 434 hydroxy-4-(methoxy- T O(M+H) methyl)phenyl)piperazin- 1 - J < X~~0Hyl)-l / 7-indole-3-carboxylic YYacid6-chloro-5-(4-(2 -hydroxy430 di 1 -methoxy ethyl) I o (M+H) pheny l)piperazin- 1 -yl)- \H- S X"0Hindole-3-carboxylic acidOH6-chloro-5-(4-(2-hydroxy-CI^^N 469 4-(2-methylthiazol-5- j T)(M+H) yl)phenyl)piperazin- 1 -yl)- 7 -z '" OHl / / -indole-3 -carboxylic_ / sjCC OHacid \\ H6-chloro-5-(4-(6-hydroxy- 474 1,3-dihydroisobenzofuran- HO— ZZ < N Il l j° (M+H) 5-yl)piperazin-l-yl)-l / 7-, / x A _ Jindole-3-carboxylic acid < X JN^^CI6-chloro-5-(4-(2-hydroxy- 495 4-(2-isobutyl-2 / / -l,2,3- X O (M+H) triazol-4-yl)phenyl) S ^"-OH piperazin- 1 -yl)- l / / -indole- 3 -carboxylic acid / -NZNJ YOC6-chloro-5-(4-(2-hydroxy- 453 4-(2-methyloxazol-5- X o (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3 -carboxylicacid. \ / \r / / OC ‘6-chloro-5-(4-(2-hydroxy- 466 4-((5 -methyl- 17 / -py razol - 1 - X o (M+H) yl)methyl)phenyl)piperazin 7 J / % ~~OH-l-yl)-l / / -indole-3- C N OCC ^OHcarboxylic acid06-chloro-5-(4-(2-hydroxy-CIX^-N 463 4-(2-methylpyridin-4- I D (M+H) yl)phenyl)piperazin- 1 -yl)- Xol / / -indole-3 -carboxylic JOC iz\ / °acid N J6-chloro-5-(4-(2-hydroxy- 463 4-(6-methylpyridin-3- O Z 'O -3(M+H) yl)phenyl)piperazin- 1 -yl)- / / l / / -indole-3-carboxylicacid6-chloro-5-(4-(2-hydroxy- 463 4-(2-methylpyridin-3- ’ °K(M+H) yl)phenyl)piperazin- 1 -yl)- / o 'Kl / / -indole-3-carboxylic O ZEacida (S)-6-chloro-5-(4-(2- 469 hydroxyphenyl)piperazin- D JD (M+H) 1 -yl)-A-methyl-Af- / J / / " N(tetrahydro-2 / / -pyran-3-yl)- ex ° XA177-indole-3 -carboxamide O- _ 'b (7?)-6-chloro-5-(4-(2- 469 hydroxyphenyl)piperazin- 1 D (M+H) 1 -yl )- A -methyl -N- / J / Z—N(tetrahydro-2 / / -pyran-3 -yl)- ex ° Al / / -indole-3 -carboxamidea (S)-6-chloro-5-(4-(2- 455 hydroxyphenyl)piperazin- T ¥>(M+H) 1 -yl )-A-(tetrahydro-2 / / -,1+ J ZZ~~NHpyran-3 -y 1)- 17 / -indole-3 - fy ° Acarboxamide o—yb (7?)-6-chloro-5-(4-(2- 455 hydroxyphenyl)piperazin- T H (M+H) 1 -y 1 )- A -(tetrahy dro-2 / 7- _N. J ZZ—NHpy ran-3 -y 1)- l / / -indole-3 - CX0Acarboxamide o — / 6-chloro-5-(4-(2-hydroxy- 466 4-((3 -methyl- 1 / / -py razol - 1 - X X? (M+H) yl)methyl)phenyl)piperazin / I - / OH- 1 -yl)- l / / -indole-3 - A NXJCX ^OHcarboxylic acid06-chloro-5-(4-(5-hydroxy- 414 1,3-dihydroisobenzofuran- XX?(M+H) 4-yl)piperazin- 1 -yl)- 1H- indole-3-carboxylic acid 0NiXjl J6-chloro-5-(4-(4-(l- 478 cyclopropyl-l / / -pyrazol-3- X T? (M+H) yl)-2-hydroxyphenyl) J X~OH piperazin- 1 -yl)- l / / -indole- fK N. A rX Axx3 -carboxylic acid ^NC / ^0H6-chloro-5-(4-(2-hydroxy- 481 4-(3 -i sopropyl- \H- 1,2,4- T O(M+H) tri azol - 1 -y 1 )pheny 1 ) > <%"~OH piperazin- 1 -yl)- 1 / 7-indole-xnr\ \ _ / / IK N OH3 -carboxylic acid6-chl oro-5-(4-(4-(3- 479 cy cl opropyl - 1 H- 1,2,4- T O (M+H) triazol-l-yl)-2- hydroxyphenyl)piperazin- fxIX / / N OH1 -yl)- 1 / / -indole-3 - carboxylic acid3-(6-chloro-5-(4-(2- 496 hydroxy-4-(tetrahydro-2 / / - T Tj(M+H) pyran-4-yl)phenyl) S / / "■NHpiperazin-1 -yl)-l / / -indol-3- f t "- A0yl)-l,2,4-oxadiazol-5(4 / / )- 0^ _ Jone5 -(6-chl oro-5 -(2'-hy droxy-cixO 403 [1,1 '-biphenyl]-4-yl)- 1H- / JO (M+H) indol-3-yl)isoxazol-3-ol°O\^\0H0H6-chl oro-5-(4-(4-hydroxy- 414 rTrT01,3-dihydroisobenzofuran-.0HO~_ / Z < N (M+H) 5-yl)piperazin-l-yl)-l / / - indole-3-carboxylic acid or iN^^CI6-chloro-5-(4-(2-hydroxy- 480I ZE4-( 1 -isopropyl- 1 / / -pyrazol- IX o o OO (M+H) 3 -yl)phenyl)piperazin- 1 - \ / rz oyl)-U7-indole-3 -carboxylic \ / °acid6-chloro-5-(4-(4-(2-ethyl- O Z O O Z Z O ' — O O ' ' — — x X X503467O Z O ' — X52 / / -l,2,3-triazol-4-yl)-2- (M+H) hydroxyphenyl)piperazin- 1 -yl)- l / / -indole-3 - 34 ):=Z ^carboxylic acidA6-chloro-5-(4-(2-hydroxy- 481 4-(2-isopropyl-2 / / -l,2,3- (M+H) triazol-4-yl)phenyl)piperazin- 1 -yl)- l / Z-indole- 3 -carboxylic acid6-chloro-5-(4-(2-hydroxy-CI^^N 453 4-(3-methylisoxazol-5- j T)l+AA / A (M+H) yl)phenyl)piperazin- 1 -yl)- / s. S A-OHl / 7-indole-3 -carboxylic— ^OHacidN-°6-chloro-5-(4-(2-hydroxy- 470 4-(5-methyl-l,2,4- (M+H) thiadiazol-3-yl)phenyl)piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acid5-(4-(4-(carboxymethyl)-2- 430 hydroxyphenyl)piperazin- XO (M+H) 1 -yl)-6-chloro- 17 / -indole-3 - IZcarboxylic acid I jfY \ / o6-chloro-5-(4-(2-hydroxy- 469 4-(2-methylthiazol-4- o z ' — O X3(M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3 -carboxylicacid6-chloro-5-(4-(2-hydroxy- 450 4-(pyrimidin-5-yl)phenyl) X JQ (M+H) piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acid jTYN<X'iXx / 'DH2-(4-(6-chloro-3-(isoxazol-CI^^N 395 5-yl)-l / 7-indol-5- X o (M+H) yl)piperazin- 1 -yl)phenol.hr J / ==>f lOH6-chloro-5-(4-(2-hydroxy- 494 4-(l-isobutyl-l#-pyrazol- X jQ|'X"KN^S— (M+H) 3 -yl)phenyl)piperazin- 1 - yl)-177-indole-3 -carboxylic nacid5-(4-(4-carboxy-2-hydroxyCI^^N 416 pheny l)piperazin- 1 -y 1 ) -6 - XJO (M+H)X X Xchloro- l / / -indole-3- O O OS -Z ~OHcarboxylic acid xz IZ IHO. XT ° Z\ / o— OH \ / \ / ° °06-chloro-5-(4-(2-hydroxy- 470 4-(3 -methyl- 1,2,4- o o o Z Z Z O O — ' — O ' — X X X333T T)(M+H) thi adi azol - 5 -y l)pheny 1) J / Z" OHpiperazin- 1 -yl)- 177-indole- N. Cr_ _ / OH3 -carboxylic acid A z.z. 0 Z ' - / / \\ s-f~ N-s6-chloro-5-(4-(2-hydroxy- 450 4-(pyridazin-4-yl)phenyl)(M+H) piperazin- 1 -yl)- l / / -indole- 3 -carboxylic acid6-chloro-5-(4-(2-hydroxy- 450 4-(pyridazin-3-yl)phenyl)(M+H) piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acid6-chloro-5-(4-(2-hydroxy- 450 4-(pyrazin-2-yl)phenyl)(M+H) piperazin- 1 -yl)- 177-indole- 3 -carboxylic acida (7?)-6-chloro-5-(4-(2- 442 hydroxy-4-(tetrahydrofuran T O(M+H) -2-yl)phenyl)piperazin- 1 - S z / ~~OHyl)-l / / -indole-3 -carboxylico.jCl / OHacidb (S)-6-chloro-5-(4-(2- 442 hydroxy-4- T O (M+H) (tetrahydrofuran-2- J z / ~~OH yl)phenyl)piperazin- 1 -yl)- jQl / / -indole-3 -carboxylicV-0acid6-chloro-5-(4-(4-(5-ethyl- 468 l,2,4-oxadiazol-3-yl)-2- T T)(M+H) hydroxyphenyl)piperazin- ^N. J ^~OHl-yl)-ll / -indole-3- _ / / JTX0Hcarboxylic acid / \-N6-chloro-5-(4-(2-hydroxy- 482 4-(5-isopropyl-l,2,4- (M+H) oxadiazol-3-yl)phenyl)piperazin- 1 -yl)- l / Z-indole- v \ _ Z' NJC OH3 -carboxylic acid C / VN6-chloro-5-(4-(2-hydroxy- 468 4-(2-oxaspiro[3.3]heptan-6- T O (M+H) yl)phenyl)piperazin- 1 -yl)- J ZZ~~OHl / / -indole-3 -carboxylic JCYacido-^y6-chloro-5-(4-(4-(l-ethyl- 466 177-pyrazol-3-yl)-2- X oO (M+H) hydroxyphenyl)piperazin- \ / O1 -yl)- l / 7-indole-3 - carboxylic acid6-chloro-5-(4-(2-hydroxy- O XO. O Z ' —33454 O Z ' —4-(3 -methyl- 1,2,4- X i)(M+H) oxadiazol-5-yl)phenyl)piperazin- 1 -yl)- 1 / 7-indole- / \3 -carboxylic acid J i ”N"°6-chloro-5-(4-(2-hydroxy- 453 4-(5-methylisoxazol-3- yl)phenyl)piperazin- 1 -yl)- l / / -indole-3 -carboxylicacid6-chloro-5-(4-(2-hydroxy- 440 4-(l,2,4-oxadiazol-3-yl) X JQ (M+H) phenyl )piperazin- 1 -y 1)- \H- J A"0Hindole-3-carboxylic acid JCTO'Na (5)-5-(4-(4-( 1,4-dioxan-2- 460 yl)-2-hydroxyphenyl) X o(M+H) piperazin- 1 -yl)-6-chloro- J ZT-OHl / / -indole-3 -carboxylic rxacidXO^b (7?)-5-(4-(4-(l,4-dioxan-2- 460 yl)- - y r x p e Tn I 2 h d o y h nyl) oIiz o (M+H) piperazin- 1 -yl)-6-chloro- J z7~~ \ / 0 °l / 7-indole-3 -carboxylic Of Hacid 0""UoHo "6-chloro-5-(4-(2-hydroxy- O Z o ' —3452 4-(l -methyl- l / / -pyrazol-4- (M+H) yl)phenyl)piperazin- 1 -yl)- l / 7-indole-3 -carboxylic oacida (7?)-6-chloro-5-(4-(2- 497 hy droxy-4-( 1 -i sopropy 1-5 - X X? (M+H) oxopyrrolidin-2- yl)phenyl)piperazin- 1 -yl)- / '" V' ^^^OH17 / -indole-3-carboxylic y, Macid0'X'b (S)-6-chloro-5-(4-(2- 497 hydroxy-4-(l-isopropyl-5- X X? (M+H) oxopyrrolidin-2- J / Z~-'0H yl)phenyl)piperazin- 1 -yl)- fTl / / -indole-3 -carboxylic V—Macid ° 'X'6-chloro-5-(4-(4-(3- 463 cyclopropyl-l / / -l,2,4- (M+H) triazol-1- yl)phenyl)piperazin- 1 -yl)- l / 7-indole-3 -carboxylicacid6-chloro-5-(4-(2-hydroxy-CI^^N X 469 o4-(4-methylthiazol-2- j T)xz (M+H) \ / X X yl)phenyl)piperazin- 1 -yl)- O O °J ^~~0Hl / 7-indole-3 -carboxylic y xz IZX x x\ x - —\ / \ / O o,-XX. "acidV-so36-chloro-5-(4-(2-hydroxy- 449 4-(pyridin-4-yl)phenyl) O O Z Z o o ' ' — —53(M+H) piperazin- 1 -yl)- 17 / -indole- 3 -carboxylic acid# V7 4 >z z — — ' '6-chloro-5-(4-(2-hydroxy- 449 4-(pyridin-3-yl)phenyl)(M+H) piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acid6-chloro-5-(4-(4-(3- 479 i sobutyl- \H- 1,2,4-triazol- 1 - (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3 -carboxylicacid6-chloro-5-(l -(4-(3,3-CI^^N 510 dimethylpiperidine- 1 - xOUQ (M+H) carbonyl)-2-hydroxy- XX S ^"-OH phenyl)piperidin-4-yl)-17 / - jCcCX / XX OHindole-3-carboxylic acid o6-chloro-5-(4-(4-(5-cyclo- 480 propyl-l,2,4-oxadiazol-3- (M+H) yl)-2-hydroxy-phenyl)piperazin- 1 -yl)- l / / -indole- rx3 -carboxylic acid o- N6-chloro-5-(4-(3-hydroxy- 448 [ 1, l'-biphenyl]-4-yl)(M+H) piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acid QXX. °6-chloro-5-(4-(2-hydroxy- 541 4-(2,2,6,6-tetramethyl- XJQ (M+H) morpholine-4-carbonyl)phenyl)piperazin- 1 -yl)- \H- j i rr- A / OHindole-3-carboxylic acid O6-chloro-5-(4-(2-hydroxy- 497 4-( 1 -i sopropyl-5 -oxo- T n(M+H) pyrrolidin-2-yl)phenyl) S ^"-OHpiperazin- 1 -yl)- l / / -indole- — ^OH3 -carboxylic acid M06-chloro-5-(4-(2-hydroxy- 416 4-(methoxymethyl)phenyl) X X? (M+H) piperazin- 1 -yl)- 1 / 7-indole- J ^"-OH3 -carboxylic acid / \0H06-chloro-5-(4-(2-hydroxy- 470 4-(4-methyltetrahydro-2 / 7- T O(M+H) pyran-4-yl)phenyl)piperazin- 1 -yl)- 177-indole- fT3 -carboxylic acid6-chloro-5-(4-(4-(3- 465 i sopropy 1 - 1 H- 1, 2,4-tri azol - 1 D (M+H) 1 -yl)phenyl)piperazin- 1 - J Y" OHyl)-l / / -indole-3-carboxylicK, X+ "acid6-chloro-5-(4-(2-hydroxy- 456 4-(tetrahydro-2 / / -pyran-2- T O (M+H) yl)phenyl)piperazin- 1 -yl)- ^N. J ZZ~~OHl / 7-indole-3 -carboxylic nr.0. Jk< OHacida (7?)-6-chloro-5-(4-(2- 456 hydroxy-4-(tetrahydro-2 / 7- T O (M+H) py ran-3 -y l)phenyl) > A-OHpiperazin- 1 -yl)- 1 / 7-indole-O / XYZZXY^X^OH3 -carboxylic acidb (S)-6-chloro-5-(4-(2- 456 hydroxy-4-(tetrahydro-27 / - T O (M+H) pyran-3 -yl)pheny 1) J zZ~-0Hpiperazin- 1 -yl)- 177-indole- 0^|-' — ^0H3 -carboxylic acida 6-chloro-5-(4-(2-hydroxy- 539 4-(((15',57?)-3,3,5-trimethyl- X JO (M+H) cyclohexyl)carbamoyl) Xk J ^~-OH phenyl)piperazin- 1 -yl)- \H- \hox °— OHindole-3-carboxylic acid0b 6-chloro-5-(4-(2-hydroxy- 539 4-(((17?,5J?)-3,3,5- i o (M+H) trimethylcyclohexyl)carbak V ° moyl)phenyl)piperazin- 1 - \ Hyl)-l / / -indole-3-carboxylic — \ 1 il0H0acid6-chloro-5-(4-(2-hydroxy- 453 4-(5-methyloxazol-2- X (M+H) yl)phenyl)piperazin- 1 -yl)- J ^"-OH1 / / -indole-3 -carboxylicacidv!!6-chloro-5-(4-(2-hydroxy- 469 4-(5-methylthiazol-2- X JO (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3-carboxylic. / rCC °acidv!i6-chloro-5-(4-(2-hydroxy- 453 4-(4-methyloxazol-2- X JO (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3-carboxylicU X "acidk— o6-chloro-5-(4-(2-hydroxy- 398 4-vinylphenyl)piperazin- 1 - I D (M+H) yl)-l / / -indole-3-carboxylic y / % ~~OHacidl-(6-chloro-5-(4-(2- 412 hydroxyphenyl)piperazin- I\ D (M+H) 1 -yl)- l / f-indol-3 -yl)- 1,4- JZNV°dihydro-5 / / -tetrazol-5-one |l J VNH— ^OH5-(4-(2-(((25, 3R, 45,55, 65)- 548 6-carboxy-3,4,5-trihydroxy x o (M+H) tetrahydro-2 / / -pyran-2- J z / ~~OHyl)oxy)phenyl) piperazin- 1- Q\-^Oyl)-6-chloro- l / / -indole-3 -XOHo >•carboxylic acidHO. Js.OH0 OHa (5)-6-chloro-5-(4-(2- 525 hy droxy-4-(methyl( 1,1,1- X o (M+H) trifluoropropan-2- S <^-OH yl)carbamoyl)phenyl)pipera I XV0F OHzin- 1 -yl)- 1 J7-indole-3 - * Ocarboxylic acidb (7?)-6-chloro-5-(4-(2- 525 hydroxy-4-(methyl( 1,1,1- X o (M+H) trifluoropropan-2- J ^~~0H yl)carbamoyl)phenyl)pipera M1rrF OHzin- 1 -yl)- l / / -indole-3 - - Ocarboxylic acid6-chloro-5-(4-(2-hydroxy- 453 4-(4-methyl-477- 1,2,4- X O (M+H) tri azol -3 -y 1 )pheny 1 )piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acid^_-N6-chloro-7-fluoro-5 -(4-(2- F 390 hydroxyphenyl)piperazin- (M+H) l-yl)-177-indole-3- X OJ Z7~~OHcarboxylic acidex6-chloro-5-(4-(4-((l- 525 ethylcyclohexyl)carbamoyl x o (M+H) )-2-hydroxyphenyl) ^N. J ^"-OHh °piperazin- 1 -yl)- 1 / 7-indole-. -H3 -carboxylic acid \ / \' - ' / X | i 0fOH6-chloro-5-(l-(2-hydroxy- 385 4-methylphenyl)piperidin- (M+H) 4-yl)-l / / -indole-3- e / Z'-OHcarboxylic acid6-chloro-5-(4-(2-hydroxy- 456 4-(tetrahy dro-2 / / -py ran-3 - X V} (M+H) yl)phenyl)piperazin- 1 -yl)- J A-0Hl / / -indole-3-carboxylicacid ry6-chloro-5-(4-(4-(5-methyl- 437 \H- 1,2,4-triazol- 1 -yl) T jT> (M+H) phenyl)piperazin-l-yl)-l / / - indole-3-carboxylic acid0€?6-chloro-5-(4-(4-hydroxy- 372 pheny l)piperazin- 1 -yl)- \II- I D (M+H) indole-3-carboxylic acid J zZ" OHx r6-chloro-5-(4-(2-hydroxy- 386 ciJuphenyl)piperazin-l-yl)-7- T O (M+H) methyl-l / / -indole-3- J Z^OHcarboxylic acidex6-chloro-5-(4-(2-hydroxy- 453 4-(2-methyl-277- 1,2,3 - D O (M+H) triazol-4-yl)phenyl) J / Z"-OHpiperazin- 1 -yl)- l / / -indole- NJCX3 -carboxylic acid -N'6-chloro-5-(4-(2-hydroxy- 457 4-(isopropylcarbamoyl) X X? (M+H phenyl)piperazin-l-yl)-177- ^N. J n-OHindole-3-carboxylic acidh°OH1 O6-chloro-5-(4-(2-hydroxy- 0 485 x\ x<^ x+4-((2-methylbutyl) ' TTNH Ti(M+H) k xi^k c> carbamoyl)phenyl)piperazi N > Xx-OH n- 1 -yl)- l / / -indole-3 - 1 Ocarboxylic acidCI^^ H6-chloro-5-(4-(2-hydroxy- 525 4-(((4-methylcyclohexyl) T O (M+H) methyl)carbamoyl)phenyl)piperazin- 1 -yl)- 1 / 7-indole- O kT x'k Jh'k X OxX— — —f OH °3 -carboxylic acid o6-chloro-5-(4-(2-hydroxy- 525 4-(((l -methylcyclohexyl) T O (M+H) methyl)carbamoyl)phenyl) XX x^ xN. x^ -Z"~OH piperazin- 1 -yl)- 177-indole- O k L AH\x^ A o xkr ^OH°3 -carboxylic acid 06-chloro-5-(4-(2-hydroxy- 485 4-(neopentylcarbamoyl) T O (M+H) phenyl )piperazin-l-yl)-l / / - xN^indole-3-carboxylic acid T x>k xHlK X O-k x^fk' OH °o6-chloro-5-(4-(4-(((l-Cl^^-N 511 ethylcyclobutyl)methyl)car T O (M+H) bamoyl)-2-hydroxyphenyl) 1 x^\ xN^ S <^-OH piperazin- 1 -yl)- 17 / -indole- / < O XL xhi'k O x^fkV / OH03 -carboxylic acid 06-chloro-5-(l-(4-fluoro-2- 389 hydroxyphenyl)piperidin-4- ^ TJQ XO (M+H) yl)-l / / -indole-3-carboxylic S zZ^-OH IZ\ / Oacid nr3-(6-chloro-5-(4-(2- 412 hydroxyphenyl)piperazin- J YjO Z ' O — X5(M+H) 1 -yl)- l / 7-indol-3 -yl)- 1,2,4- oxadi azol - 5 (47 / )-on e n11x6-chloro-5-(4-(3-hydroxy- 3721pheny l)piperazin- 1 -yl)- \H- T O (M+H) indole-3-carboxylic acid HO. -N. J Zz ~OHu6-chloro-5-(4-(2-hydroxy- 452 4-( 1 -methyl- 177-py razol-3 - (M+H) yl)phenyl)piperazin-l-yl)- l / 7-indole-3 -carboxylicacid5-(4-(4-carbamoyl-2- 415 hydroxyphenyl)piperazin- T O (M+H) 1 -yl)-6-chloro- l / / -indole-3 - S ^~OHcarboxylic acid H2N^ fX0OH06-chloro-5-(4-(4- 443 (ethylcarbamoyl)-2- T O (M+H) hydroxyphenyl)piperazin- S ^~OH1 -yl)- l / / -indole-3 - H TV °— OHcarboxylic acid06-chloro-5-(4-(2-CI^^N 386 hydroxyphenyl)piperazin-r\ (M+H) 1 -yl)-4-m ethyl- l / / -indole- S ZZ~~OH3 -carboxylic acidex6-chloro-5-(l-(2-hydroxy- 455 4-(tetrahydro-2 / / -pyran-4- (M+H) yl)phenyl)piperidin-4-yl)- l / / -indole-3 -carboxylic rrnvn+nacidO^ / J6-chloro-5-(4-(4-((37?,45)- 497 3,4-dimethylpyrrolidine- 1 - (M+H) carbonyl)-2-hydroxy- pheny l)piperazin- 1 -yl)- \H-. a jQ °— OHindole-3-carboxylic acid 0a 6-chloro-5-(4-(4-((37?,47?)- 497 3,4-dimethylpyrrolidine- 1 - T(M+H) carbonyl)-2-hydroxy- pheny l)piperazin- 1 -yl)- 17 / - z ~i J iTI JYIOHindole-3-carboxylic acid 0b 6-chloro-5-(4-(4-((35,4S)- 497 3,4-dimethylpyrrolidine- 1 - T JQ>(M+H) carbonyl)-2-hydroxy- pheny l)piperazin- 1 -yl)- \H- -OJOC0indole-3-carboxylic acid 06-chloro-5-(4-(4- 442 ((tetrahy drofuran-3 -yl)oxy) T O (M+H) phenyl)piperazin-l-yl)-l / / - indole-3-carboxylic acida (S)-6-chloro-5-(4-(4- 442 ((tetrahy drofuran-3 -yl)oxy) T O (M+H) pheny l)piperazin- 1 -yl)- \H- O / / " OHindole-3-carboxylic acid < i nrb (7?)-6-chloro-5-(4-(4- 442 ((tetrahy drofuran-3 -yl)oxy) T O (M+H) phenyl)piperazin-l-yl)-l / / - O <% " OHindole-3-carboxylic acid o. ry6-chloro-5-(4-(2-hydroxy- 428 4-(oxetan-3 -y l)pheny 1) T O (M+H) piperazin- 1 -yl)- 1 / 7-indole- -N. J ZZ— OH3 -carboxylic acid nro~~J6-chloro-5-(4-(2-hydroxy- 470 4-((tetrahydro-27 / -pyran-4- T O (M+H) yl)methyl)phenyl)piperazinO > r ||- 1 -y 1)- l / 7-indole-3 -0carboxylic acid(25,3S,45,57?,65)-6-((6- 548 chloro-5-(4-(2-hydroxy- T (M+H) phenyl)piperazin-l-yl)-l / 7- indole-3-carbonyl)oxy)- CC HOn°. OH3,4,5 -trihy droxytetrahy dro-0HHO' V o277-pyran-2-carboxylic acid OH6-chloro-5-(4-(4-((35,57?)- 511 3,5-dimethylpiperidine-l- T jQ>(M+H) carbonyl)-2-hydroxy- S ^~0H phenyl)piperazin- 1 -yl)- \H- X ijCt OHindole-3-carboxylic acid o6-chloro-5-(4-(2-hydroxy- 450 4-(pyrimidin-2-yl)phenyl) T O (M+H) piperazin- 1 -yl)- 177-indole- J / / " OH3 -carboxylic acid ex— OH6-chloro-5-(4-(4-cyclo- 426 butoxyphenyl)piperazin- 1 - T O (M+H) yl)-l / / -indole-3 -carboxylic J z / " OHacid n jTT6-chloro-5-(4-(4-(cyclo- 440 pentyloxy)phenyl)piperazin T jQ(M+H) -l-yl)-l / / -indole-3- J zZ~~OH carboxylic acid n fT6-chloro-5-(4-(4-((3,3- 483 dimethylpyrrolidin-1- T O (M+H) yl)methyl)-2-hydroxy- J ^" OHphenyl )piperazin- 1 -y 1)- \H- TTr °''OHindole-3-carboxylic acid6-chloro-5-(4-(4-((3,3-CI^^N 491 difluoropyrrolidin- 1 - 1 X? (M+H) yl)methyl)-2-hydroxy- J Z7---0Hpheny l)piperazin- 1 -y 1)- \H-F> O fxindole-3-carboxylic acid6-chloro-5-(4-(4-((4,4- 505 difluoropiperidin- 1 - XX? (M+H) yl)methyl)-2-hydroxy- \ J ZZ~~OH phenyl)piperazin- 1 -yl)- \H- XT ''QHindole-3-carboxylic acid6-chloro-5-(4-(2-hydroxy- 457 4-((tetrahy drofuran-3 -yl) XX? (M+H) methyl)phenyl)piperazin- 1 - yl)-l / / -indole-3 -carboxylicacid6-chloro-5-(4-(2-hydroxy- 472 4-(4-hydroxytetrahydro- xx? (M+H) 277-pyran-4-yl)phenyl) J ZZ~~OHpiperazin- 1 -yl)- 1 / 7-indole- °h|| 13 -carboxylic acidO^^J5-(6-chloro-5-(4-(2- 411 hy droxyphenyl )piperazi n- xo (M+H) l-yl)-l / 7-indol-3- yl)isoxazol-3-ol f \i^i^OH °X0H2-(4-(6-chloro-3 -( \H- 396 tetrazol-5-yl)-l / / -indol-5- XX? (M+H) y l)piperazin- 1 -yl)phenol Z^NHN 1L I vNOH6-chloro-5-(4-(2-hydroxy- 442 4-(tetrahydrofuran -3- XX? (M+H) yl)phenyl)piperazin- 1 -yl)- J ZT—OHl / / -indole-3 -carboxylic rxacid OQ^^OHa (7?)-6-chloro-5-(4-(2- 442 hydroxy-4-(tetrahydrofuran X O (M+H) -3 -yl)phenyl)piperazin- 1 - J / / —OHyl)-l / / -indole-3 -carboxylic FTacidb (S)-6-chloro-5-(4-(2- 442 hydroxy-4-(tetrahydrofuran X O (M+H) -3 -yl)phenyl)piperazin- 1 - J Z / ~~OHyl)-l / / -indole-3 -carboxylicfracid °Q ^'oh6-chloro-5-(4-(2-hydroxy- 449 4-(pyridin-2-yl)phenyl) T n(M+H) piperazin- 1 -yl)- l / / -indole- _N. J ZZ~-0H3 -carboxylic acid XT6-chloro-5-(4-(2-hydroxy- 381 phenyl)-2-oxopyridin- X o (M+H) 1 (277)-y 1)- l / / -indole-3 - ZZ—OH^0 0carboxylic acid^^^OH6-chloro-5-(4-(4- 411 (cyanomethyl)-2-hydroxy- X o (M+H) phenyl)piperazin- 1 -yl)- \H- J ZZ'-'OHindole-3-carboxylic acid£16-chloro-5-(4-(2-hydroxy- 480X4-(4-methoxypyrimidin-2- o(M+H) yl)phenyl)piperazin- 1 -yl)- \ / X IZ'y x-'-'o O Xl / Z-indole-3 -carboxylic iz\ / °acido O ' — X36-chloro-5-(4-(2-hydroxy- 439O X3O H ' - 4-(l / 7- 1,2, 4-tri azol- 1- (M+H) yl)phenyl)piperazin- 1 -yl)- l / / -indole-3-carboxylico acid6-chloro-5-(4-(2-hydroxy- 523 4-(7-azaspiro[3.5]nonane- (M+H) 7-carbonyl)phenyl)piperazin- 1 -yl)- 1 / 7-indole- Of0L. N. 41OH3 -carboxylic acid 06-chloro-5-(4-(4-((25,67?)- 513T I) 2,6-dimethylmorpholine-4- (M+H) carbonyl)-2-hydroxy- J ^~~0Hpheny l)piperazin- 1 -yl)- \H- O FY'''0Hindole-3-carboxylic acid o6-chloro-5-(4-(4-(3,3- 511CI^^N dimethylpiperidine- 1 - I D (M+H) carbonyl)-2-hydroxy- ^N. J / Z~~0Hpheny l)piperazin- 1 -yl)- 1H- OHindole-3-carboxylic acid O6-chloro-5-(4-(2-hydroxy- 499 4-(methyl(neopentyl) xx? (M+H) carbamoyl)phenyl) S zZ"-OH piperazin- 1 -yl)- 177-indole- 4. N1. J rb' r OH3 -carboxylic acid 06-chloro-5-(4-(2-hydroxy- 522 4-((3 a / ?,7aS)-octahy dro- T X? (M+H) l / Z-isoindole-2-carbonyl) / ”7 S / / " OH pheny l)piperazin- 1 -yl)- 177- +. FL XT OHindole-3-carboxylic acid 06-chloro-5-(4-(2-hydroxy- 509 4-(6-methyl-2-azaspiro[3.3] XX? (M+H) heptane-2-carbonyl)phenyl). N. F < A~-OH piperazin- 1 -yl)- 177-indole- rx OH3 -carboxylic acid O6-chloro-5-(4-(2-hydroxy- 526 4-(4-isopropylpiperazine- 1 - XX? (M+H) carbonyl)phenyl)piperazin- X ^"" OH1 -yl)- 177-indole-3 - / L > F (L| jT — °OHcarboxylic acid06-chloro-5-(4-(2-hydroxy- riH440 phenyl)piperazin-l-yl)-2- XX)H-F(M+H) (trifluorom ethyl)- 1H- J ZZ~~OHindole-3-carboxylic acid e —x OH6-chloro-5-(4-(2-hydroxy- 456 3 -(trifluoromethoxy)OH ID (M+H) phenyl)piperazin-l-yl)-l / / - F. _O. Js. J ZZ— OHindole-3-carboxylic acid v06-chloro-5-(4-(2-hydroxy- 471 4-(morpholinomethyl) ID (M+H) phenyl)piperazin-l-yl)-17 / - indole-3-carboxylic acid Oja.6-chloro-5-(4-(2-hydroxy- 497 4-(3 -isopropylazetidine- 1 - DO (M+H) carbonyl)phenyl)piperazin- 1 X. / Z~-OHl-yl)-l / / -indole-3- V-N. Dr OH °carboxylic acid 06-chloro-5-(4-(4- 440 (tetrahydro-27 / -pyran-4- DO (M+H) yl)phenyl)piperazin- 1 -yl)- J ZZ~~OHl / / -indole-3-carboxylicacid O^^J6-chloro-5-(4-(2-hydroxy- 439 4-(oxazol-2-yl)phenyl) DO (M+H) piperazin- 1 -yl)- 17 / -indole- S ZZ" OH3 -carboxylic acid / oX —i OHVs2-(4-(6-chloro-4-fluoro- 1H- 346 indol-5-yl)piperazin-l- (M+H) yl)phenolFC ^^X^OH6-chloro-4-fluoro-5-(4-(2- 390 hydroxyphenyl)piperazin- T O XO (M+H) 1 -yl)- l / Z-indole-3- / X J F z / ~~OHDv IZ 'carboxylic acid rx \ / o6-chloro-5-(4-( 1 -(hy droxy- p, H 364 methyl)cyclopropyl)-3- o O XNZ. ' — -5(M+H)\oxopiperazin- 1 -y 1)- \H- lx. J X-OHoindole-3-carboxylic acidOH6-chloro-5-(4-(4-cyclo-Cl\^-N 412\propyl-2-hydroxyphenyl) T jQ>- (M+H) piperazin- 1 -yl)- 177-indole- X / / "-OH3 -carboxylic acidrxy— rX-'X^0H6-chloro-5-(4-(2-hydroxy- 454 4-(5-methyl-l,2,4- (M+H) oxadiazol-3-yl)phenyl)piperazin- 1 -yl)- 1 / 7-indole- 3 -carboxylic acida (5)-6-chloro-5-(4-(4-((l -CI^^N 455 methy Ipy rrolidin-3 - I D (M+H) yl)oxy )phenyl)piperazin- 1 - ^x X X"-OHyl)-177-indole-3 -carboxylicacid -NO. JCXb (7?)-6-chloro-5-(4-(4-((l-Cl\^-N 455 methylpyrrolidin-3- I O (M+H) yl)oxy )phenyl)piperazin- 1 - ^NX X X"'OHyl)-l / 7-indole-3-carboxylic - a. Uacid6-chloro-5-(l-phenyl- 355 piperidin-4-yl)- 1 / 7-indole- (M+H) 3 -carboxylic acid6-chloro-5-(4-(4-cyclobutyl ex 426 -2-hydroxyphenyl) T O(M+H) piperazin- 1 -yl)- 177-indole- J / / " OH3 -carboxylic acid jTY6-chloro-5-(4-(2-hydroxy- 489 pheny l)piperazin- 1 -yl)-7V- Y Tj>(M+H) (2,2,2-trifluoroethyl)-l / / -11indole-3-sulfonamide \ YHNA— FF F6-chloro-5-(4-(4-CI^^N 441 (morpholin-2- I o (M+H) yl)phenyl)piperazin- 1 -yl)- 17 / -indole-3-carboxylic fTacidH6-chloro-5-(4-(2-hydroxy-CI^^N 402 4-(hydroxymethyl) I D( (M+H) pheny l)piperazin- 1 -yl)- \H- J Z7~-OHindole-3-carboxylic acid XT0— OH6-chloro-5-(4-(2-hydroxy- 455 4-(pyrrolidin- 1 -ylmethyl) T jQ(M+H) phenyl)piperazin-l-yl)-l / / - J X~~OHindole-3-carboxylic acid O XT^OHa (7?)-6-chloro-5-(4-(4-(5- 439 oxopyrrolidin-3-yl)phenyl) T O (M+H) piperazin- 1 -yl)- 1 / 7-indole- J X"'OH3 -carboxylic acid0=x ]■'HN-^b (S)-6-chloro-5-(4-(4-(5- 439 oxopyrrolidin-3-yl)phenyl) T O (M+H) piperazin- 1 -yl)- 1 / 7-indole-. N. J X~~OH3 -carboxylic acid / XHN"J6-chloro-5-(3-oxo-4-r, H 370 phenylpiperazin- 1 -yl)- \H- o^ XX? (M+H) indole-3-carboxylic acid X ZZ -OHO'6-chloro-5-(4-(4-ethyl-2- 400 hydroxyphenyl)piperazin- X X? (M+H) 1 -yl)- l / 7-indole-3 - J X~" OHcarboxylic acidXX6-chloro-5-(4-(2-hydroxy- 414 4-isopropylphenyl) X X? (M+H) piperazin- 1 -yl)- 1 / 7-indole- ^N. J X~~OH3 -carboxylic acidXX6-chloro-5-(4-(4- 422 (difluoromethyl)-2- I D (M+H) hydroxyphenyl)piperazin- 1 -yl)- l / 7-indole-3 - OHcarboxylic acid F6-chloro-5-(4-(4-cyano-2- 397 hydroxyphenyl)piperazin- Y O(M+H) 1 -yl)- 177-indole-3 - carboxylic acidN6-chloro-5-(4-(3-hydroxy- 373 pyridin-4-yl)piperazin- 1 - T O(M+H) yl)-177-indole-3 -carboxylic S ZZ-OHacid ii YOH6-chloro-5-(4-(2-hydroxy- 439 4-(l / 7- 1,2,3-triazol- 1 -yl) I O (M+H) phenyl)piperazin- 1 -yl)- \H- J >7~-0Hindole-3-carboxylic acid rxNvJ °H6-chloro-5-(4-phenyl- 355 piperidin- 1 -yl)- 1 / 7-indole- I O (M+H) 3 -carboxylic acid S ZZ -OH6-chloro-5-(4-(2-hydroxy- 440 4-(trifluoromethyl)phenyl) I D (M+H) piperazin- 1 -yl)-177-indole- J z / ~OH3 -carboxylic acidX OHF 1F6-chloro-5-((2-((2-hydroxy- H 374 phenyl)(methyl)amino)- (M+H) ethyl)(methyl)amino)- 1H- LX1LOH— OH Oindole-3-carboxylic acid2-(4-(6-chl oro-3 -(2,2,2- 426 trifluoro- 1 -hy droxy ethyl)- I O (M+H) l / / -indol-5-yl)piperazin- 1 -FHO \Fyl)phenol r iif— '^'"'OH6-chloro-5-(5-(2 -hydroxy- Pl _ H 384 phenyl)^, 5-diazabicyclo- (M+H) [2.2.1 ]heptan-2-yl)-l H- indole-3-carboxylic acid6-chloro-5-(5-(2-hydroxy- PI H 398 phenyl)-2,5-diazabicyclo- (M+H) [2.2.2]octan-2-yl)-177- indole-3-carboxylic acid^^^OH6-chloro-5-(4-(2-hydroxy-clxO 386 pheny l)piperazin- 1 -yl)-2- I X o (M+H) m ethyl- 17 / -i ndol e-3 - J / Z~-OHcarboxylic acidex^^^OH6-chloro-5-(4-(4-(5-methyl-CI^^N 433 sulfonimidoyl)phenyl)- 1 D (M+H) piperazin- 1 -yl)-177-indole- J ^"-OH3 -carboxylic acid HN |0\\W06-chloro-5-(4-(4-methoxy- 386 pheny l)piperazin- 1 -yl)- \H- XJO (M+H) indole-3-carboxylic acid J ^~~OHrr6-chloro-5-(4-(2-hydroxy- 453 phenyl)piperazin-l -yl)W- XJO (M+H) (2,2,2-trifluoroethyl)-177- J zZ-NHindole-3-carboxamideOC ° S+6-chloro-5-(4-(4-hydrox- 373 ypyri din-3 -yl)piperazin- 1 - XJO (M+H) yl)-17 / -indole-3-carboxylicN 0acid H 1a 6-chloro-5-(4-((1S,2R)-2- p, H 392 hydroxycyclopentane-1- on.. L.(M+H) carbonyl)piperazin-1-yl)-1 / - / - / ~~1 1Ny'indole-3-carboxylic acid \ y / Z-OHob 6-chloro-5-(4-((1R,2R)-2- PI _ n 392chydroxycyclopentane-1-.°H.. JL JL # (M+H) carbonyl)piperazin-1-yl)-1 / - / - / ~~1 1N\indole-3-carboxylic acid S zZ-OHr0c 6-chloro-5-(4-((lS,25)-2- ClH392 hydroxy cyclopentane- 1 - '°hJL^? / 1-' N (M+H) carbonyl)piperazin-l-yl)- \ y zZ~~OHl / 7-indole-3 -carboxylic ll °0acidd 6-chloro-5-(4-((17?,25)-2- Pl Hc392 hydroxy cyclopentane- 1 -SOH JI # (M+H) carbonyl)piperazin-l-yl)- \ / - J 1.', 1 SNZ A'Z--OH177-indole-3 -carboxylic r0acid6-chloro-5-(4-(2-hydroxy- 456 4-(tctrahydro-2 / / -pyran-4- xx? (M+H) yl)phenyl)piperazin- 1 -yl)- S ZZ— OH17 / -indole-3-carboxylicacid rr6-chloro-5-(4-(2-fluoro-6- 390 hydroxyphenyl)piperazin- OH XX? (M+H) 1 -yl)- l / 7-indole-3 - >%~~~OHcarboxylic acid X06-chloro-5-(4-(4-fluoro-2- 390 hydroxyphenyl)piperazin- XX? (M+H) 1 -yl)- l / f-indole-3 - J Z7~-0Hcarboxylic acid fy6-chloro-5-(4-(2-hydroxy- 429 4-(methylcarbamoyl) XX? (M+H) phenyl)piperazin-l-yl)-177- > Zz^OHindole-3-carboxylic acid H Xf °OHO6-chloro-5-(4-(4- 453 (pyrrolidine-1 -carbonyl) T O (M+H) phenyl)piperazin-l-yl)-l / / - J Z / ~~OHindole-3-carboxylic acido6-chloro-5-(4-(4-(3,6- 454 dihydro-27 / -pyran-4-yl)-2- T O (M+H) hydroxyphenyl)piperazin- J ^~~OH1 -yl)- l / 7-indole-3 - rrcarboxylic acid6-chloro-5-(4-(4- 439 (pyrrolidin-l-ylmethyl) T O (M+H) pheny l)piperazin- 1 -yl)- \H- J Z / ~~0Hindole-3-carboxylic acida 6-chloro-5-(4-((17?,27?)-2- PI H 392 hydroxy cyclopentane- 1 - °hJL JL / z (M+H) carbonyl)piperazin-l-yl)- S ZZ~~OH17 / -indole-3-carboxylic 0acidb 6-chloro-5-(4-((15,27?)-2- PI _H392C'V? SVNhydroxy cyclopentane- 1 - °hJL JL z / (M+H) carbony l)piperazin- 1 -yl)- Z' ~OH17 / -indole-3-carboxylic roacid6-chloro-5-(5-(2-hydrox- 398 y pheny 1 )hexahy dropy rrol o T(M+H) [3,4-c]pyrrol-2(177)-yl)- \H- r \— J Z / ~~OHindole-3-carboxylic acid[T T5-(4-(2-aminophenyl) 371 piperazin- 1 -yl)-6-chloro- T n(M+H) l / f-indole-3-carboxylic Xoacid xzcc \ / °6-chloro-5-(4-(2-(methyl- 385 amino)phenyl)piperazin- 1 - T O(M+H) oyl)-l / / -indole-3 -carboxylic5acidci0 H6-chloro-5-(4-(2-hydroxy- 386 6-methylphenyl)piperazin- T OI (M+H) l-yl)-l / / -indole-3- X^ J X~'~OHcarboxylic acid LX5-(4-(4-( 1H- 1,2,4-triazol- 1 - 423 yl)phenyl)piperazin-l-yl)- (M+H) 6-chloro-l / 7-indole-3- carboxylic acid6-chloro-5-(4-(2-(dimethyl- 399 amino)phenyl)piperazin- 1 - I D (M+H) yl)-l / / -indole-3 -carboxylic X X~-OHacid6-chloro-5-(4-(2-hydroxy- PI _H400 benzoyl)piperazin- 1 -yl)- J - - (M+H) 177-indole-3 -carboxylic n Jkr J ZZ--0Hoacid 06-chloro-5-(4-(4-(methyl- 413 carbamoyl)phenyl)piperazi T O(M+H) n- 1 -yl)- 17 / -indole-3 - J / % ~~ IOHocarboxylic acidh 0iz\ / °o6-chloro-5-(4-(2-hydroxy- 469 4-(pyrrolidine- 1 -carbonyl) T O (M+H) o ■phenyl)piperazin-l-yl)-177- J / Z~~OHindole-3-carboxylic acid o fx— OHO6-chloro-5-(4-(2-fluoro-5- 390 hydroxyphenyl)piperazin- T O (M+H) 1 -yl)- 1 / / -indole-3 - HO. J zZ~-OHcarboxylic acid r r6-chloro-5-(4-(2-(difluoro- 407 methyl)pyridin-4-yl)(M+H) piperazin- 1 -yl)- l / / -indole- 3 -carboxylic acid6-chloro-5-(4-(2-hydroxy- 373 phenyl)piperazin- 1 -yl)- \H- T O (M+H) pyrrolo[3,2-Z>]pyridine-3- J A-OHcarboxylic acid ry^x'^''xOH6-chloro-5-(4-(2-oxo-2,3- 413 dihydrobenzo[t / ]oxazol-4- r X^x'-N xTH(M+H) yl)piperazin- 1 -yl)- 1H- indole-3-carboxylic acid 0 Ncl\ / C|Q oHIJ / OH2-(4-(3-carboxy-6-chloro- 373 l / f-indol-5-yl)piperazin-l- T Oyl)pyridine 1 -oxide y < Z ~OH, N+.5-(4-(2-carbamoylphenyl) 399 piperazin- 1 -yl)-6-chloro- T n(M+H) 177-indole-3 -carboxylic ^N. J ^-OHacid Of005-(4-(4-(177- 1,2, 3-tri azol- 1-CI^^N 423 yl)phenyl)piperazin- 1 -yl)- X X? (M+H) 6-chloro-l / f-indole-3- J ZZ~~OHcarboxylic acid / YNvJ6-chloro-5-(4-(2-(difluoro- 407 methyl)pyridin-3-yl) T O(M+H) piperazin- 1 -yl)- 177-indole- J ZY-OH3 -carboxylic acid OCT0NF5-(4-benzoylpiperazin- 1 - riH384 yl)-6-chloro- l / / -indole-3 - (M+H) carboxylic acid06-chloro-5-(4-(l -hydroxy- 364 cyclopropane- 1 -carbonyl) X JO (M+H) piperazin- 1 -yl)- 1 / Z-indole- ^OH1 I \X J ZZ—OH3 -carboxylic acid o6-chloro-5-(4-(2-hydroxy- 386 3-methylphenyl)piperazin- X JOOH N (M+H) 1 -yl)- l / f-indole-3 - \, N. J X~OHcarboxylic acidXr6-chloro-5-(4-(2-(dimethyl- 400 amino)pyridin-4-yl) x xx (M+H) piperazin- 1 -yl)- 1 / Z-indole- I' 1J _N. > <^~~OH3 -carboxylic acid6-chloro-5 -(4-( 5 -fluoro-2- 390CIXXNhydroxyphenyl)piperazin- T O (M+H) 1 -yl)- l / / -indole-3 - F. J z / ~~OHcarboxylic acidXX6-chloro-5-(4-(3-fluoro-2- 390 hydroxyphenyl)piperazin- TOH JO (M+H) l-yl)-l / / -indole-3- J zX~OHcarboxylic acidM6-chloro-5-(4-(2-hydroxy- 402 3 -methoxypheny 1)OH XJO (M+H) piperazin- 1 -yl)-177-indole-.0.. N. / Z~-OH3 -carboxylic acidv6-chloro-5-(l-(2-hydroxy- 371 phenyl)piperidin-4-yl)- 1H- (M+H) indole-3-carboxylic acid y ZZ—OHexa (7?)-6-chloro-5-(l-(2- 357 hydroxyphenyl)pyrrolidin- zT-X I D (M+H) 3 -yl)- l / / -indole-3 -K=< \ _ J Z7--0H\ 0carboxylic acid OHb (5)-6-chloro-5-( 1 -(2- p, H 357 hydroxyphenyl)pyrrolidin- (M+H) 3 -yl)- l / 7-indole-3 - carboxylic acid Q OH-NC" X ^°Ha (7?)-6-chloro-5-(3-(2- PI H 357 hydroxyphenyl)pyrrolidin- (M+H) 1 -yl)- 177-indole-3 - carboxylic acid OHb (S)-6-chloro-5-(3-(2- 357 hydroxyphenyl)pyrrolidin- I D (M+H) l-yl)-17 / -indole-3- \_—J ^~~OH\ Ocarboxylic acid OH6-chloro-5-(4-(3-hydroxy- 362 bicyclo[l.1.1 ]pentan-l -yl) XJO (M+H) piperazin- 1 -yl)- l / / -indole- J Z / ~~OH°3 -carboxylic acidHO^^6-chloro-5-(4-(2-hydrox- PI H 386 yphenyl)-3 -oxopiperazin- 1 - ^ 11 / (M+H) yl)-l / / -indole-3-carboxylic J O' OHacid rr^^''" OH6-chloro-5-(4-(2-methoxy- 386 phenyl)piperazin-l-yl)-l / / - T o (M+H) indole-3-carboxylic acid J O' OHe \ / xO / 6-chloro-5-(4-(6-(dimethyl- 430 amino)-2-methoxypyridin- T n (M+H) 3 -yl)piperazin- 1 -yl)- 1H- 0~OHindole-3-carboxylic acid O NZrXO / 6-bromo-5-(4-(2-hydroxy- 416 phenyl)piperazin- 1 -yl)- 1H- XX? (M+H) indole-3-carboxylic acid J O~0Hrx6-chloro-5-(4-(2-hydroxy- 386 4-methylphenyl)piperazin- XX? (M+H) 1 -yl)- 1 / / -indole-3 - / Z~~0Hcarboxylic acid £X6-chloro-5-(4-(2-hydroxy- 386 5-methylphenyl)piperazin- XX? (M+H) 1 -yl)- l / / -indole-3 - \ ^N. J ^Z"-0Hcarboxylic acid6-chloro-5-(l-(2-hydroxy-CI^^N 357 pheny l)pyrrolidin-3 -yl)- 1H- (M+H) \ \indole-3-carboxylic acid W= / \ J / 7—OH\ OOH6-chloro-5-(4-(2-oxo- 1,4- 4277'V / OHdihy dro-2 / / -benzo[ d\ [1,3](M+H) oxazin-8-yl)piperazin- 1 -3yl)-177-indole-3-carboxylicacid NH 01Tjjj6-chloro-5-(4-(2-(difluoro-CIX^-N 406 methyl)phenyl)piperazin- 1 - X O (M+H) yl)-l / 7-indole-3-carboxylic ^N. J zZ— OHacid OC F / 06-fluoro-5-(4-(2-hydroxy- 356 pheny l)piperazin- 1 -y 1)- \H- (M+H) indole-3-carboxylic acid J Z7— OHrr^^^OH6-chloro-5-(3-(2-hydroxy- p, H 357OHcl^yNphenyl)pyrrolidin-l-yl)-l / 7- (M+H) indole-3-carboxylic acid Y= / \ J z / — 'OH05-(4-(l / / -indazol-7-yl) 7'V / OH396 piperazin- 1 -yl)-6-chloro- (M+H) 17 / -indole-3-carboxylicacid0 Ni HQQNa 6-chloro-5-(4-((17?,27?)-2- 378 hydroxycyclohexyl)piperaz X JO (M+H) in- 1 -yl)- 17 / -indole-3 - 1?r °carboxylic acid^•^ ''OHb 6-chloro-5-(4-((lS,2S)-2- 378 hydroxycyclohexyl)piperaz X JO (M+H) in- 1 -yl)- l / / -indole-3 - carboxylic acid [ 1 —0^^^OH4,6-difluoro-5-(4-(2- 374 hydroxyphenyl)piperazin- T r> (M+H) 1 -yl)- l / / -indole-3 - S F ZZ— OHcarboxylic acidfr^^^OH6-chloro-5-(4-(2-hydroxy- 369 phenyl)-3, 6-dihy dropy ridin T n (M+H) - 1 (27 / )-y 1 )- 17f-indole-3 - JK- J Z / --OHcarboxylic acid cn6-chloro-5-(4-(2-hydroxy- 371 phenyl)piperidin- 1 -yl)- 1H- T O(M+H) indole-3-carboxylic acid Z / -OH( ja (S)-6-chloro-5-(4-(2- 386 hydroxyphenyl)-2- T O (M+H) methy Ipiperazin- 1 -yl)- 1H- indole-3-carboxylic acid fr0b (7?)-6-chloro-5-(4-(2- 386 hydroxyphenyl)-2- T O (M+H) methy Ipiperazin- 1 -yl )- 1H- indole-3-carboxylic acid Q '06-chloro-5-(4-(2- 386 hydroxyphenyl)-2- T O (M+H) methy Ipiperazin- 1-yl)- 1H- ^N- Js. ^"-OHindole-3-carboxylic acid CC06-chloro-5-(4-(2-oxoindolin 411 -7-y l)piperazin- 1 -yl)- 1H- ID (M+H) indole-3-carboxylic acid J ^"-OHQ NH06-chloro-5-(4-(2-(oxetan-3- 412 yl)phenyl)piperazin- 1 -yl)- T O (M+H) l / / -indole-3 -carboxylic J / / — " OHacid CC V-To6-chloro-5-(4-(2-hydroxy-CI\.N^. N 373 pheny l)piperazin- 1 -yl)- \H- 1 D (M+H) pyrrolo[2,3-Z>]pyridine-3- J ZZ—OHcarboxylic acid rx^•^X'0H6-hydroxy-5-(4-(2-hydroxy 355 phenyl)piperazin-l-yl)-l / 7- Y r)(M+H) pyrrolo[2,3-Z>]pyridine-3- J z / " OHcarboxylic acidrx6-chloro-5-(l-(2-hydroxy- 369 phenyl)-l,2,3,6-tetrahydro- (M+H) pyridin-4-yl )- 1 J / -indole-3 - JI / " OHcarboxylic acid C ^ZI^OH6-chloro-5-(4-(2-hydroxy- 457 4-morpholinophenyl) T O (M+H) piperazin- 1 -yl)- 177-indole- > / / --OH3 -carboxylic acid JLXo^^J6-chloro-5-(4-(2-hydroxy- 455 4-(2-oxopyrrolidin-l-yl) T O (M+H) phenyl)piperazin-l-yl)-l / / - J Z7~~ OHindole-3-carboxylic acid rxZ^'N^V^X^OHXO6-chloro-5-(4-(3-hydroxy- 376 1 -methyl- 1 / / -pyrazol-4- X JO (M+H) yl)piperazin- 1 -yl)- 1H-.hr J < / --OHindole-3-carboxylic acid - / V0OHa (S)-6-chloro-5-(4-(2- 386 hydroxyphenyl)-3-methyl- (M+H) piperazin- 1 -yl)-177-indole- / - y X"~OH3 -carboxylic acid rib (7?)-6-chloro-5-(4-(2- PI _ H 386 hy droxyphenyl)-3 -methyl - -. '■ / < - NXX? \ (M+H) piperazin- 1 -yl)- 1 / 7-indole- / -. / N. J X~" OH3 -carboxylic acid ex6-chloro-5-(4-(2- 386 hydroxyphenyl)-3-methyl- (M+H) piperazin- 1 -yl)- 177-indole- / s. X X"-OH3 -carboxylic acidQ^x^X'0H5 -(4-acetylpiperazin- 1 -y 1) - 322 6-chloro-l / f-indole-3- T O (M+H) carboxylic acid \ J X-'-'OH°06-chloro-5-(4-(4-hydroxy- 387 6-methylpyridin-3- X O (M+H) yl)piperazin- 1 -yl)- 1 H- / ^- ^N. J X~-OHN oindole-3-carboxylic acidJO JL6-chloro-5-(4-(2-methyl- 377 thiazol-5-yl)piperazin- 1 -yl) X XJ (M+H) -l / / -indole-3 -carboxylic / N J X~" OHacidN-^5-(4-(2-hydroxyphenyl) 369 piperazin- 1 -yl)-6-methoxy- (M+H) 17 / -pyrrolo[2,3-Z>]pyridine- 3 -carboxylic acidIo6-chloro-5-(5,6-dihydro- H ri 317 imidazof 1,2-«]pyrazin- \ / °(M+H) 7(8 / / )-y 1)- l / / -indole-3 - carboxylic acidH0"\6-chloro-5-(4-(3-(hydroxy-$So O X5386> o Z —methyl)phenyl)piperazin- 1 - X JO (M+H)z\yl)-l / / -indole-3-carboxylic J ZZ~~OHHO / \ oK0acido I6-chloro-5-(4-(2-hydroxy- 371 pheny l)piperazin- 1 -y 1)- \H- X JO (M+H) indole-3-carboxamide TZ~' NH26-chloro-5-(4-(l-(hydroxy- 350 methyl)cyclopropyl)piperaz X JO (M+H) in- 1 -y 1)- l / / -indole-3 - r Lx>< > ZZ—OHocarboxylic acidOH6-chloro-5-(4-(3-hydroxy- 373 pyridin-2-yl)piperazin- 1 - (M+H) yl)-l / 7-indole-3-carboxylicacid6-chloro-5-(4-(2-hydroxy- p, H 373 pheny l)piperazin- 1 -yl)- \H- / XXX?1(M+H) indazole-3 -carboxylic acid J X~OHex Io6-chloro-5-(4-(2-hydroxy- iz 373 \ / °pyri din-3 -yl)piperazin- 1 - (M+H) yl)-l / / -indole-3 -carboxylicacidgOs6-chloro-5-(4-phenyl- b 356 piperazin- 1 -yl)- 1 / 7-indole- (M+H) 3 -carboxylic acid J X~OHex6-chloro-5-(piperazin- 1 -yl)- 280 l / / -indole-3 -carboxylic X JQ (M+H) acid HN J X-OHO6-chloro-5-(4-(2-cyano-CI^^N 381 pheny l)piperazin- 1 -y 1)- \H- XJQ (M+H) indole-3-carboxylic acid X X"~OHOX6-chloro-5-(4-(2-chloro- 390 phenyl)piperazin-l-yl)-l / / - X O (M+H) indole-3-carboxylic acidj'k X X"°fXH6-chloro-5-(4-(4-chloro- 390 pheny l)piperazin- 1 -yl)- \H- ID (M+H) indole-3-carboxylic acid ^N. J / / " OHXT6-chloro-5-(4-(2-fluoro- 374 phenyl)piperazin-l-yl)-l / / - ID (M+H) indole-3-carboxylic acid J zXoHfX6-chloro-5-(4-(3-chloro- 390 pheny l)piperazin- 1 -yl)- \H- ID (M+H) indole-3-carboxylic acid Ck J ' Z A / --0HXT6-chloro-5-(4-(2-(hydroxy- 386 methyl)phenyl)piperazin- 1 - XXI (M+H) yl)-l / 7-indole-3-carboxylic J ZZ—OHacid fY05-(4-(2-hydroxyphenyl) H 338 piperazin- 1 -yl)- 1 / 7-indole- (M+H) 3 -carboxylic acid J X-OHfX6-chloro-5-(4-(l-methyl-2- 387 oxo- 1,2-dihy dropyri din-3 - o X ID (M+H) yl)piperazin- 1 -yl)- 1H- \ JL / Nx. J X'OHindole-3-carboxylic acid U0Methyl 6-chloro-5-(4-(2-CI^^N 388 fluorophenyl)piperazin- 1 - T T)(M+H) yl)-17 / -indole-3- ^N. J / " Ocarboxylate nr0'O'-'6-chloro-5-(4-(pyridin-2- IZ - - 357 \ / °yl)piperazin- 1 -yl)- 1H- x o (M+H) indole-3-carboxylic acid _N.. FL J Zz-OHu Qs6-chloro-5-(4-(3-(trifluoro- 424 tomethyl)phenyl)piperazin- 1 - T(M+H) yl)-l / / -indole-3 -carboxylic R F 1 I I \X J zz ~OHacidFXJMethyl 6-chloro-5-(4-(3- 438 (trifluoromethyl)phenyl)pip X X?F (M+H) erazin-l-yl)-177-indole-3- R | I l \F YY 0 \carb oxy lateMethyl 6-chloro-5-(4- 371 (pyridin-2-yl)piperazin- 1 - (M+H) yl)-l / / -indole-3- carb oxy late6-chloro-5-(4-(2-hydroxy-CI^^N 372 pheny l)piperazin- 1 -yl)- 1H- X X? (M+H) indole-3-carboxylic acidQ273 Methyl 6-chloro-5-(4-(2- hydroxyphenyl)piperazin- 1 -yl)- l / Z-indole-3- carboxylateBiological Assays

[0089] AMPK-beta-1 (AMPK.p i) activity and selectivity over AMPK-beta-2 (AMPKP2) was determined using the ADP-Glo™ Assay by Promega as described in US Patent No.8,183,007.

[0090] Human AMPK enzyme composed of a2, pi and yl isoforms (211) was screened against compounds of interest. AMPK enzyme composed of a2, P2 and yl isoforms (221) was used as a counter screen for selectivity. Activity was performed using 0.6 nM 211 or 0.5 nM 221 in a buffer containing 20 mM HEPES pH 7.0, 10 mM MgCh, 0.02% Brij 35, 0.1 mM NaaVCh and 1 mM EGTA. Experiments were performed with an ATP concentration of 10 pM and a SAMS peptide concentration of 10 pM.

[0091] Buffer and enzyme were added to the plate, followed by addition of compounds at multiple concentrations to generate an ECso curve using * / 2log dilutions with a final concentration of DMSO at 1%. Reaction was initiated by the addition of ATP and SAMS peptide, and incubated for 60 min at 25°C. ADP-Glo reagent was then added and incubated for a further 60 min, followed by detection buffer for a further 60 min. Light emission was measured using an Envision 2104. Table A depicts the measured EC50 on the 211 and 221 isoforms. EC50 values are shown in nM,indicates not determined values.Table AAMPK.pi (211) AMPK02 (221)Ex #EC50 / nM EC50 / nM1 47.7 >100,000a 24.7 >100,000 b 20.0 >100,00023.2 >100,000 a 63.1 >100,000 b 105 >100,00057.7 >100,000 401 >100,000 34.9 >100,000 30.3 >100,000 6.14 1960 13.5 >100,000 2510 >100,000 0 >10,000 >100,000 1 211 >100,000 2 180 >100,000 3 >10,000 >100,000 4 33.2 >100,000 5 17.7 >100,000 6 409 >100,000 7 12.7 >100,000 8 60.6 >100,000 9 693 >100,000 0 >10,000 >100,000 1 103 >100,000 a 110 >100,000 b 198 >100,000 2 52.1 >100,000 a 2100 >100,000 b 59.7 2050 3 155 443021.6 >100,000 a 14.6 18,000 b 10.5 >100,00026.5 4210 1150 >100,000 46 >100,000 188 >100,000 151 >100,000 1080 >100,000 11.7 >100,000 58.9 >100,000 48.6 >100,000 103 >100,000 a 1210 >100,000 b 2170 >100,000 a 610 >100,000 b 1290 >100,00021.8 4440 86.8 >100,000 26.1 >100,000 26.4 >100,000 15.2 3200 66.4 >100,000 138 >100,000 101 >100,000 41 >100,000 24.3 >100,000 48.7 >100,000 >10,000 >100,000 128 >100,00059.6 >100,000 28.3 >100,000 22.5 >100,000 1210 >100,000 70.4 >100,000 117 >100,000 70.1 >100,000 14.1 >100,000 17.9 >100,000 16.0 >100,000 a 13.4 3550 b 9.15 >100,000104 >100,000 273 >100,000 23.8 >100,000 16.8 >100,000 115 >100,000 45.7 >100,000 110 >100,000 a 6.51 8040 b 12.9 303020.9 >100,000 a >10,000 >100,000 b 2390 >100,000499 >100,000 64.2 >100,000 30.8 >100,000 23.4 >100,000 1040 >100,000 35.5 >100,000301 >100,000 152 >100,000 88.9 5160 2780 >100,000 16.1 8080 21.3 >100,000 1010 >100,000 14.5 >100,000 a 21.0 >100,000 b 42.0 >100,000 a 67.2 >100,000 b 90.4 >100,00058.1 >100,000 125 >100,000 76.5 >100,000 30.9 >100,000 155 >100,000 >10,000 >100,000 a 23.5 9860 b 42.5 >100,00026.8 >100,000 27.9 >100,000 40.8 >100,000 133 >100,000 23.7 8010 1980 >100,000 0 1090 >100,000 1 750 >100,000 2 23.9 >100,000 3 8.7 245018.2 2070 36.2 4270 32.2 >100,000 15.2 2240 20.1 >100,000 207 >100,000 45.8 >100,000 >10,000 >100,000 16.7 >100,000 70.5 >100,000 60.8 >100,000 780 >100,000 178 >100,000 38.1 >100,000 a 53.6 >100,000 b 36.6 >100,0001700 >100,000 a 1130 >100,000 b 1380 >100,00024.2 >100,000 35.8 >100,000 54.5 15,440 18.6 >100,000 65.6 >100,000 1180 >100,000 1350 >100,000 26.1 >100,000 21.3 >100,000 32.9 >100,000 19.7 >100,00011.4 >100,000 65.5 >100,000 35.9 >100,000 17.6 9,540 a 18.8 39,250 b 19.3 >100,00012.3 >100,000 991 >100,000 14.8 >100,000 142 >100,000 11.2 >100,000 39.8 >100,000 29.7 >100,000 65.5 >100,000 11.7 >100,000 37.5 >100,000 89.9 >100,000 18.8 >100,000 451 >100,000 253 >100,000 33.1 >100,000 46.4 >100,000 1780 >100,000 41.5 >100,000 1480 >100,000 10.2 13,900 >10,000 >100,000 21.3 >100,000 106 >100,000 a 1090 >100,000b 490 >100,0002490 >100,000 106 >100,000 2300 >100,000 876 >100,000 15.8 >100,000 39.7 >100,000 a 897 >100,000 b 1190 >100,000>10,000 >100,000 36.5 >100,000 45.7 >100,000 92.2 >100,000 80.1 >100,000 594 >100,000 10.6 >100,000 >10,000 >100,000 171 >100,000 >10,000 >100,000 >10,000 >100,000 >10,000 >100,000 >10,000 >100,000 254 >100,000 >10,000 >100,000 1390 >100,000 973 >100,000 >10,000 >100,000 a >10,000 >100,000 b >10,000 >100,000 c >10,000 >100,000d >10,000 >100,00019.8 >100,000 67.6 >100,000 41.8 >100,000 89.7 >100,000 1720 >100,000 18.5 >100,000 1490 >100,000 a >10,000 >100,000 b >10,000 >100,000>10,000 >100,000 >10,000 >100,000 >10,000 >100,000 388 >100,000 492 >100,000 >10,000 >100,000 >10,000 >100,000 1330 >100,000 28.7 >100,000 >10,000 >100,000 >10,000 >100,000 179 >100,000 >10,000 >100,000 >10,000 >100,000 >10,000 >100,000 1330 >100,000 >10,000 >100,000 >10,000 >100,000 >10,000 >100,000 649 >100,000>10,000 >100,000 164 >100,000 60.4 >100,000 42.3 >100,000 43.1 >100,000 a 1560 >100,000 b 1580 >100,000 a >10,000 >100,000 b >10,000 >100,000>10,000 >100,000 >10,000 >100,000 2510 >100,000 >10,000 >100,000 22.7 5830 30.2 >100,000 113 >100,000 >10,000 >100,000 >10,000 >100,000 >10,000 >100,000 443 >100,000 >10,000 >100,000 4450 - / - a >10,000 - / - b >10,000 - / - 190 - / - 150 - / - 950 - / - a 2340 - / - b 238 - / - 892 - / ->10,000 - / - >10,000 - / - 704 - / - >10,000 - / - 16.8 - / - 36.1 - / - 13.1 - / - 878 - / - a >10,000 - / - b 295 - / - 480 - / - >10,000 - / - >10,000 - / - >10,000 - / - >10,000 - / - >10,000 - / - >10,000 - / - 298 - / - >10,000 - / - 219 - / - 38.7 - / - >10,000 - / - 1310 - / - >10,000 - / - >10,000 - / - 3190 - / - 1810 - / - 1340 - / - >10,000 - / - 5480 - / -3000 - / - >10,000 - / - >10,000 - / - 4380 - / - >10,000 - / - >10,000 - / - >10,000 - / - 26 27,000 620 >100,000

Claims

What Is Claimed Is:

1. A compound or a pharmaceutically acceptable salt thereof selected from the group of formula IA, IB, and IC:IA IB ICwherein X is CRb or N, wherein Rb is selected from H, Ci-Ce alkyl, and Ci-Ce haloalkyl; Ri is selected from COORa, SO2ORa, SO2N(Ra)2, CON(Ra)2, C(OH)(Ra)2, and a 5-membered heterocyclic group,wherein Rais for each occasion independently selected from hydrogen, a C1-C4 alkyl, a C1-C4 haloalkyl, a C3-C6 cycloalkyl, a three-to-six membered heteroalkyl, a three-to-six membered heterocycloalkyl, a C5-C6 aryl, and a five-to-six membered heteroaryl;R2, when present, is selected from hydrogen, a halogen, a C1-C4 alkyl, a C1-C4 haloalkyl, and a C3-C6 cycloalkyl;R3 is selected from hydrogen, fluoro, chloro, and bromo;R4, when present, is selected from hydrogen, fluoro, and a C1-C4 alkyl;A is selected fromB is selected fromwhereinY is selected from C(R.2a)2, NR.2a, CO, O, and S;R21, R22, R24, and R25, when present and for each occasion, are independently selected from H, OH, N(R2a)2, F, Cl, Br, CN, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6alkoxyalkyl, and Ci-Ce haloalkylalkoxy;R2a is for each occasion independently selected from H, a C1-C4 alkyl, and a C1-C4 haloalkyl;R23, when present, is selected from H, F, Cl, Br, OH, N(R2a)2, C(O)N(R2a)2, CN, and R23a,wherein R23a is selected from a Ci-Ce alkyl, a C2-C5 alkenyl, a Ci-Ce alkoxy, a hydroxyalkyl, a halogenated alkyl, an alkoxyalkyl, a dialkoxyalkyl, a cyanoalkyl, a six membered aryl, a six membered heteroaryl, a five membered aryl, a five membered heteroaryl, a six membered arylalkyl, a six membered heteroarylalkyl, a five membered arylalkyl, a five membered heteroarylalkyl, a C3-C6 cycloalkyl, a C3-C6 cycloalkylalkyl, a C3- Ce cycloalkyloxy, a C3-C6 cycloalkylcarboxy, a four-to-six membered heterocycloalkyl, a four-to-six membered heterocycloalkylalkyl, a four-to-six membered heterocycloalkyloxy, a four-to-six membered heterocycloalkylcarboxy, a five-to-ten membered spiroalkyl, a five-to- ten membered heterospiroalkyl, a four-to-six membered lactone, a four-to-six membered lactam, a carboxylate, a carbamide, a sulfonate, and a sulfamide,wherein R.23a is optionally substituted with a hydroxy, a halogen, a Ci-Cio alkyl, Ci-Cio alkenyl, a Ci-Ce cycloalkyl, a Ci-Cio alkoxy, or any combination thereof.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein formula lAis selected from:

3. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein formulae IA-1 and IA-2 are selected from:

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 selected from:-107--108--109-110--111--112--113--114--116--117-5. A pharmaceutical composition comprisinga compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 through 4, andat least one pharmaceutically acceptable carrier, diluent, or excipient.

6. A method for treating type II diabetes in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 through 4 or a pharmaceutically acceptable salt thereof.

7. A method for treating an inflammatory disease in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims Ithrough 4 or a pharmaceutically acceptable salt thereof.

8. A method for treating a cardiovascular disease in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims Ithrough 4 or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of claims 1 through 4 for use in the treatment of a metabolic disorder, an inflammatory disease, or a cardiovascular disease.

10. The compound according to claim 9, wherein the metabolic disorder is type II diabetes.

Images