METHODS AND MATERIALS FOR INCREASING LEVEL OF PHOSPHORYLATED AMPK PROTEIN

TECHNICAL FIELD

This document relates to methods and materials for increasing the level of phosphorylated 5′ adenosine monophosphate (AMP)-activated protein kinase (AMPK) polypeptide within cells. For example, this document provides compounds (e.g., organic compounds) having the ability to increase the level of phosphorylated AMPK within cells, formulations containing compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for making compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for increasing the level of phosphorylated AMPK within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in the level of phosphorylated AMPK within cells.

BACKGROUND

AMPK, also known as 5′ adenosine monophosphate (AMP)-activated protein kinase, is an enzyme that plays a role in cellular energy homeostasis. AMPK functions as a metabolic fuel gauge and master metabolic regulator that is activated in response to environmental stressors to restore cellular energy balance. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. In the heart, AMPK coordinates the activation of glucose and fatty acid metabolic pathways to ensure increased production of myocardial ATP when required, such as during cardiac ischemia/reperfusion and hypertrophy, causing an increase in AMPK activity to be viewed as both protective and maladaptive.

AMPK exists as an obligate heterotrimer, composed of three subunits: a catalytic kinase α subunit and two associated regulatory subunits, β and γ subunits, that together make a functional enzyme. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. See Winder W. et al., Am. J. Physiol., 277 (1 Pt 1): E1-10 (1999).

AMPK can act as a metabolic master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids, and the biogenesis of glucose transporter 4 (GLUT4) and mitochondria. See Thomson et al., Am. J. Physiol. Endocrinol. Metab., 292(1): E196-202 (2007); Ojuka E. et al., Proc. Nutr. Soc., 63(2): 275-8 (2004); Durante et al., Am. J Physiol. Endocrinol. Metab., 283(1): E178-86 (2002); Bergeron et al., Am. J Physiol., 276(5 Pt 1): E938-44 (1999); and Winder W. et al, J Appl. Physiol., 91(3): 1017-28 (2001).

SUMMARY

This document provides methods and materials for increasing the level of phosphorylated AMPK within cells. For example, the document provides compounds (e.g., organic compounds) having the ability to increase the level of phosphorylated AMPK within cells, formulations containing compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for making compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for making formulations containing compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for increasing the level of phosphorylated AMPK within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in the level of phosphorylated AMPK.

As described herein, the compounds provided herein can be used to increase the level of phosphorylated AMPK within cells in vitro or in vivo. In some cases, the compounds provided herein can be used to treat mammals (e.g., humans) having a disease, disorder, or condition associated with a low cellular level of phosphorylated AMPK. In some cases, the compounds provided herein can be used to treat mammals (e.g., humans) having a disease, disorder, or condition that is responsive to an increase in the level of phosphorylated AMPK within cells.

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or a pharmaceutically acceptable salt thereof, wherein R¹, L¹, X, L², R², and R³are as described herein.

In Some Embodiments:

R¹is selected from 5-6 membered heteroaryl and a group of formula:

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wherein said 5-6 membered heteroaryl of R¹is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R⁵;

L¹is C_1-4alkylene, which is optionally substituted with halo or OR⁴;

L²is C_1-4alkylene or L²is absent;

X is selected from CR⁷(OR⁴), C═O, and C_3-6cycloalkylene; or X is absent;

R⁷is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl;

R²and R³are each independently selected from H, C_1-6alkyl, Cy¹, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(═O)Cy¹, and S(═O)₂Cy¹, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl are each optionally substituted with 1 or 2 independently selected Cy¹;

provided that at least one of R²and R³is other than H;

R⁴is selected from H, C(O)R^b1, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

or R⁴and R²together with the O atom to which R⁴is attached and N atom to which R²is attached form 5-10 membered heterocycloalkyl, which is optionally substituted with 1 or 2 independently selected Cy¹;

or R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with 1 or 2 substituents independently selected from R⁶;

each R⁶is independently selected from C_1-6alkyl, OR^a1, C(O)NR^c1R^d1, C(O)OR^a1, C_1-6haloalkyl, and Cy¹, wherein said C_1-6alkyl is optionally substituted with a substituent selected from OR^a1, C(O)NR^c1R^d1, and C(O)OR^a1;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

each R⁵is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, thio, C_1-6alkylthio, carboxy, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino;

each Cy¹is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1;

each R^Cy1is independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, Cy², OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each Cy²is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy2.

each R^Cy2is independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

or any R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, C_6-10aryl, C_6-10aryloxy, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, (4-10 membered heterocycloalkyl)-C_1-4alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino,

provided that when R⁴is H, then at least one of R²and R³is selected from C_1-6alkyl, Cy², C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(═O)Cy², and S(═O)₂Cy², wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1 or 2 independently selected Cy², and each of said Cy²is independently selected from C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In Some Embodiments:

R¹is selected from 5-6 membered heteroaryl and a group of formula:

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wherein said 5-6 membered heteroaryl of R¹is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R⁵;

L¹is C_1-4alkylene, which is optionally substituted with halo or OR⁴;

L²is C_1-4alkylene or L²is absent;

X is selected from CR⁷(OR⁴), C═O, and C_3-6cycloalkylene; or X is absent;

R⁷is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl;

provided that at least one of R²and R³is other than H;

R⁴is selected from H, C(O)R^b1, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

each R⁵is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, thio, C_1-6alkylthio, carboxy, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino;

provided that when R⁴is H, then R²and R³are both independently selected from C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, Cy³, C(═O)Cy³, and S(═O)₂Cy³, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl are each substituted with 1 or 2 independently selected Cy³, and each of said Cy³is independently selected from C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In Some Embodiments:

X is selected from CH(OR⁴) and C═O; or X is absent; and

R⁴is selected from C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, L²is C_1-4alkylene.

In some embodiments, L²is methylene.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, L¹is selected from methylene and ethylene.

In some embodiments, L¹is methylene.

In some embodiments, R¹is 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁵.

In some embodiments, the 5-6 membered heteroaryl is selected from pyridinyl and pyrimidinyl.

In some embodiments, m is 0, 1, or 2.

In some embodiments, n is 0, 1, or 2.

In some embodiments, R⁵is selected from halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

In some embodiments, R¹is a group of formula:

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In some embodiments, R¹is a group of formula:

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In some embodiments, the compound of Formula (I) is selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R²and R³are each independently selected from H, C_1-6alkyl, Cy¹, C(═O)Cy¹, and S(═O)₂Cy¹, wherein said C_1-6alkyl, is optionally substituted with 1 or 2 independently selected Cy¹.

In some embodiments, R²and R³are each independently an C_1-6alkyl substituted with 1 or 2 independently selected Cy¹.

In Some Embodiments:

R²is selected from H and C_1-6alkyl; and

R³is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹; and

R³is selected from Cy¹, C(═O)Cy¹and S(═O)₂Cy¹.

In some embodiments, R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with Cy¹.

In some embodiments, the 4-16 membered heterocycloalkyl ring is selected from tetrahydroisoquinolinyl, isoindolinyl, and dihydrodibenzoazepinyl.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula selected from:

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each of which is optionally substituted with a substituent selected from Cy¹, C(O)OR^a1, and an C_1-6alkyl optionally substituted with OR^a1.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula selected from:

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each of which is optionally substituted with Cy¹.

In some embodiments, the compound of Formula (I) is selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, Cy¹is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is selected from phenyl, cyclopropyl, cyclohexyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, quinolinyl, piperidinyl, dihydropyridinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is selected from phenyl, cyclopropyl, cyclohexyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, quinolinyl, piperidinyl, dihydropyridinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, each R^Cy1is independently selected from halo, CN, C(O)NR^c1R^d1, C_1-6alkyl, C_1-6haloalkyl, and 5-10 membered heteroaryl, wherein said 5-10 membered heteroaryl is optionally substituted with halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, and C_1-6haloalkoxy.

In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

text missing or illegible when filed

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

text missing or illegible when filed

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound of formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound of formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, this document provides a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, this document provides a method for increasing the level of phosphorylated AMPK within a cell. The method comprises (or consists essentially of or consists of) administering, to a mammal (e.g., a human) containing the cell, a therapeutically effective amount of any one or more of the compounds described herein (or one or more pharmaceutically acceptable salts thereof).

In some embodiments, this document provides a method of treating a mammal having a disease, disorder, or condition responsive to an increase in the level of phosphorylated AMPK within cells, wherein said method comprises administering, to said mammal, any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

In some embodiments, this document provides a method for treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, (including a cytokine-driven inflammation), sepsis, pneumonia, acute lung injury, metabolic syndrome, diabetic nephropathy, polycystic kidney disease, polycystic ovarian syndrome, and a neurological or neurodegenerative disease. The method comprises (or consists essentially of or consists of) administering, to a mammal (e.g., a human) having the disease, disorder, or condition, a therapeutically effective amount of any one or more of the compounds described herein (or one or more pharmaceutically acceptable salts thereof).

In some embodiments, said mammal is a human. In some embodiments, said method comprises treating a mammal having an inflammation. In some embodiments, the inflammation is a cytokine-driven inflammation. In some embodiments, said method comprises treating a mammal having a sepsis. In some embodiments, said method comprises treating a mammal having a pneumonia. In some embodiments, said method comprises treating a mammal having an acute lung injury. In some embodiments, said method comprises treating a mammal having a metabolic syndrome. In some embodiments, said method comprises treating a mammal having a diabetic nephropathy. In some embodiments, said method comprises treating a mammal having a polycystic kidney disease. In some embodiments, said method comprises treating a mammal having a polycystic ovarian syndrome. In some embodiments, said method comprises treating a mammal having a neurological disease.

In some embodiments, this disclosure provides a method of treating a mammal having a disease, disorder, or condition responsive to an increase in the level of phosphorylated AMPK within cells, wherein said method comprises administering, to said mammal, a compound having formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, this disclosure provides a method for increasing a level of phosphorylated AMPK within cells of a mammal, wherein said method comprises administering, to said mammal, a compound having formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method for treating cancer in a mammal, wherein said method comprises administering, to said mammal, any one of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, the method further comprises administering, to said mammal, a checkpoint inhibitor.

In some embodiments, the present disclosure provides a method for improving function of immune cells in a mammal, wherein said method comprises administering, to said mammal, any one of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, said immune cells are T cells. In some embodiments, said method further comprising administering, to said mammal, a checkpoint inhibitor.

In some embodiments, the present disclosure provides a method for expanding a population of immune cells, said method comprising obtaining a population of immune cells from a mammal and culturing said population of immune cells with any one of the compounds described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, said immune cells are T cells.

In some embodiments, the present disclosure provides a method for treating an infection or reducing the risk of developing an infection in a mammal, said method comprising administering, to said mammal, any one of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

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 the present application pertains. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1A is a graph of the tumor volume in mice over time with no treatment, treatment with an anti-PD-1 antibody, treatment with compound 63, or treated with a combination of an anti-PD-1 antibody and compound 63. In FIGS. 1B, 1C, and 1D, tumor volume is shown for days 6, 13, and 22, respectively.

FIGS. 2A-2D depict the percentage of CD4+ cells (A), CD8+ cells (B), regulatory T cells (C), and leukocytes (D) as determined by fluorescence-activated cell sorting (FACS) of blood from mice with no treatment (1), treatment with 25 mg/kg compound 63 (3), treatment with 20 mg/kg anti-PD-1 antibody (4), or treated with a combination of 20 mg/kg anti-PD-1 antibody and 25 mg/kg compound 63 (6). Leukocytes can include monocytes, neutrophils, granulocytes, natural killer cells (NKCs), and myeloid-derived suppressor cells (MDSCs).

FIG. 3 is a graph of the clearance of methicillin resistant Staphylococcus aureus (strain ATCC 33591) from the lungs of neutropenic BALB/c mice treated with vehicle, vancomycin (16 mg/kg), or compound 63 (25 mg/kg).

FIG. 4 contains a line plot showing mean exposure levels of compound 63 in plasma samples vs. time (semi-log plots).

DETAILED DESCRIPTION

This document provides methods and materials for increasing the level of phosphorylated AMPK. For example, this document provides therapeutic compounds (e.g., therapeutic organic compounds) having the ability to increase the level of phosphorylated AMPK within cells, formulations containing therapeutic compounds having the ability to increase the level of phosphorylated AMPK, methods for making therapeutic compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for making formulations containing therapeutic compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for increasing the level of phosphorylated AMPK within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in the level of phosphorylated AMPK.

Methods of Treatment

Without being bound by theory, it is believed that AMPK is an enzyme involved in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. Increasing the level of phosphorylated AMPK within cells using a compound provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) as described herein can result in one or more benefits for the cell and/or mammal.

In some cases, this document provides methods for increasing the level of phosphorylated AMPK within cells by contacting the cell with one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof).

The increase in phosphorylated AMPK levels can be as compared to the phosphorylated AMPK levels prior to the contacting step. In some cases, methods for increasing the level of phosphorylated AMPK within cells can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase the level of phosphorylated AMPK within cells within that mammal. In some cases, methods for increasing the level of phosphorylated AMPK within cells can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to increase the level of phosphorylated AMPK within those cells. In some cases, such intervention can improve the quality of the cell while in culture or subsequently.

This document also provides methods for treating diseases, disorders, and conditions in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is responsive to an increase in the level of phosphorylated AMPK within cells within the mammal. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is associated with a low level of phosphorylated AMPK within the mammal.

Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) as described herein can include, without limitation, inflammation disorders (including acute or chronic inflammation disorders, cytokine-driven inflammation disorders, or inflammation and tissue damage induced by pathogenic infection), sepsis, pneumonia, acute lung injury, metabolic syndrome, neurodegenerative or neurological conditions, diabetic nephropathy, chronic renal diseases, polycystic kidney disease, polycystic ovarian syndrome, chronic pain syndrome(s), atherosclerosis, atherosclerotic heart disease, malignancies of various cell types, age-related macular degeneration, other age-related pathologies including generalized frailty, sarcopenia, and muscular dystrophies.

Examples of inflammation disorders (e.g., acute or chronic) that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) include, without limitation, asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis (e.g., hypersensitivity pneumonitis or radiation pneumonitis), pneumonia, cystic fibrosis, psoriasis, arthritis/rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergy including hayfever, nephritis, conjunctivitis, encephalitis, meningitis, opthalmitis, uveitis, pleuritis, pericarditis, myocarditis, atherosclerosis, human immunodeficiency virus related inflammation, diabetes, osteoarthritis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), colitis, sepsis, vasculitis, bursitis, connective tissue disease, autoimmune diseases (e.g., systemic lupus erythematosis (SLE)), polymyalgia rheumatica, scleroderma, Wegener's granulomatosis, temporal arteritis, vasculitis, cryoglobulinemia, multiple sclerosis, viral or influenza-induced inflammation, edema, pneumonia, chronic bacterial colonization or persistent intracellular pathogen, and impaired responsiveness to antigenic challenge or vaccines administration. Other examples of inflammation disorders that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) include, without limitation, inflammation and tissue damage induced by pathogenic infection with, for example, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, or Escherichia coli.

In some cases, provided herein are methods to treat sepsis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof).

In some cases, provided herein are methods for treating sepsis in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating pneumonia in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating acute lung injury in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating metabolic disease (or an age-related condition) in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. Examples of metabolic disease include metabolic syndrome, NASH, and diabetes. Examples of age-related conditions include sarcopenia, frailty, macular degeneration, other inherited or acquired retinal degenerative diseases, age-related hearing loss, early cognitive decline, osteoporosis, acute or age-related organ dysfunction (e.g., heart and/or kidney dysfunction), and age-related immune dysfunction (e.g., impaired response to vaccination or immunosenescence).

In some cases, provided herein are methods for treating diabetic nephropathy in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating polycystic kidney disease in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating polycystic ovarian syndrome in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.

In some cases, provided herein are methods for treating neurodegenerative or neurological diseases in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. Examples of neurodegenerative diseases includes Alzheimer's disease, ALS, Huntington's disease, Parkinson's disease, primary age-related tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, acute or chronic traumatic brain injury, and frontotemporal dementia.

In another aspect, this document provides methods for treating cancer in a mammal in need thereof by administering a therapeutically effective amount of one or more compounds described herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) to the mammal. For example, a mammal (e.g., a human) can be treated for a cancer such as melanoma, non-small cell lung cancer, bladder cancer, renal cell cancer, colorectal cancer, or multiple myeloma. In some cases, methods described herein for treating cancer can include administering to a mammal in need thereof one or more compounds provided herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) in combination with a checkpoint inhibitor. Examples of checkpoint inhibitors that can be used in combination with a compound provided herein include, without limitation, PD-1 inhibitors such as Pembrolizumab (KEYTRUDA, Merck &Co., Inc.), Nivolumab (OPDIVO, Bristol-Myers Squibb), or Cemiplimab (LIBTAYO, Regeneron Pharmaceuticals, Inc. and Sanofi), or a small molecule inhibitor of PD-1/PD-L1 such as BMS-1001 or BMS-1166 (see, e.g., Skalniak et al., Oncotarget, 8(42):72167-72181 (2017)), a CTLA4 inhibitor such as Ipilimumab (YERVOY, Bristol-Myers Squibb), or a PD-L1 inhibitor such as Atezolizumab (TECENTRIQ, Genentech/Roche), Avelumab (BAVENCIO, Pfizer), or Durvalumab (IMFINZI, AstraZeneca Pharmaceuticals LP).

In some cases, methods described herein for treating cancer in a mammal (e.g., a human) in need thereof can include administering to the mammal a therapeutically effective amount of one or more compounds described herein such as a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are as described herein. In some cases, methods described herein for treating cancer can include administering to a mammal in need thereof (e.g., a human) a therapeutically effective amount of one or more compounds provided herein (e.g., a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are each independently an C_1-6alkyl, optionally substituted with Cy¹) in combination with a checkpoint inhibitor such as a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor.

In some cases, methods described herein for treating cancer in a mammal (e.g., a human) can include administering a therapeutically effective amount of compound 63:

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or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140). In some cases, methods described herein for treating cancer can include administering to a mammal in need thereof (e.g., a human) a therapeutically effective amount of one or more compounds provided herein such as compound 63 or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140) in combination with a checkpoint inhibitor (e.g., a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor). As shown in Example 3, the combination of compound 63 and a checkpoint inhibitor (e.g., an anti-PD-1 antibody) can result in a synergistic inhibition of tumor growth in an animal model of cancer (e.g., melanoma).

In another aspect, this document provides methods for improving function of immune cells (e.g., T cells) in a mammal (e.g., a human) by administering a therapeutically effective amount of one or more compounds described herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) to the mammal. In some cases, methods described herein for improving function of immune cells (e.g., T cells) can include administering to a mammal in need thereof a therapeutically effective amount of one or more compounds provided herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) in combination with a checkpoint inhibitor (e.g., a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor).

In some cases, methods described herein for improving function of immune cells (e.g., T cells) in a mammal (e.g., a human) in need thereof can include administering a therapeutically effective amount of one or more compounds described herein such as a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are as described herein. In some cases, methods described herein for improving function of immune cells (e.g., T cells) can include administering to a mammal (e.g., a human) in need thereof a therapeutically effective amount of one or more compounds provided herein (e.g., a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are as described herein (e.g., R²and R³are each independently an C_1-6alkyl, optionally substituted with Cy¹) in combination with a checkpoint inhibitor such as a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor.

In some cases, methods described herein for improving function of immune cells (e.g., T cells) in a mammal can include administering a therapeutically effective amount of compound 63:

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or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140). In some cases, methods described herein for improving function of immune cells (e.g. T cells) can include administering to a mammal in need thereof (e.g., a human) a therapeutically effective amount one or more compounds provided herein such as compound 63 or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140) in combination with a checkpoint inhibitor such as a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor.

In another aspect, this document provides methods for expanding a population of immune cells (e.g., T cells) that can include obtaining a population of immune cells from a mammal (e.g., a mammal in need of treatment with a cell based immunotherapy) and culturing the population of immune cells with one or more compounds described herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) to increase the number of immune cells (e.g., T cells such as CD8+ cells).

In some cases, methods described herein for expanding a population of immune cells (e.g., T cells) can include obtaining a population of immune cells from a mammal (e.g., a mammal in need of treatment with a cell based immunotherapy) and culturing the population of immune cells with one or more compounds described herein such as a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are as described herein.

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or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140).

In some cases, the population of immune cells can be obtained from a tumor and cultured to obtain tumor infiltrating lymphocytes. In some cases, the population of immune cells can be obtained from peripheral blood mononuclear cells. In some cases, the expanded immune cells (e.g., T cells) can be further manipulated ex vivo (e.g., to introduce a novel T cell receptor (TCR) or chimeric antigen receptor (CAR)) for a cell based immunotherapy using, for example, methods described elsewhere (see, e.g., Rohaan et al., Virchows Arch. 474(4): 449-461 (2019)).

In some cases, the expanded immune cells can be used for adoptive cell therapy and infused into the mammal in need of treatment with a cell based immunotherapy. In some cases, after adoptive cell therapy, a therapeutically effective amount of one or more compounds provided herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) can be administered to the mammal, optionally in combination with a checkpoint inhibitor (e.g., a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor). In some cases, after adoptive cell therapy, a therapeutically effective amount of one or more compounds provided herein such as a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are as described herein, can be administered to the mammal, optionally in combination with a checkpoint inhibitor (e.g., a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor). In some cases, after adoptive cell therapy, a therapeutically effective amount of one or more compounds provided herein such as compound 63:

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or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140) can be administered to the mammal, optionally in combination with a checkpoint inhibitor (e.g., a PD-1 inhibitor, a CTLA4 inhibitor, or a PD-L1 inhibitor).

In another aspect, this document provides methods for treating an infection and/or reducing the risk of developing an infection in a mammal by administering a therapeutically effective amount of one or more compounds described herein (e.g., a compound set forth in Formula (I) or a pharmaceutically acceptable salt thereof) to the mammal.

In some cases, methods described herein for treating an infection and/or reducing the risk of developing an infection in a mammal (e.g., a human) can include administering a therapeutically effective amount of one or more compounds described herein such as a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof, wherein R²and R³are as described herein.

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or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt such as compound 139 or a tartrate salt such as compound 140) to the mammal.

In some cases, the infection can be a bacterial infection (e.g., with methicillin-resistant Staphylococcus auereus (MRSA)). In some cases, the infection can be a viral infection. In some cases, the methods provided herein can be used for treating, or reducing the risk of developing, an infection in the lungs of the mammal (e.g., a human). For example, the methods described herein can be used for improving clearance of bacteria, viruses, or fungus from the lungs of the mammal, by boosting the host defense through the activation of AMPK. In some cases, the mammal can have cystic fibrosis or chronic obstructive pulmonary disease (COPD). As shown in Example 4, compound 63 can be used to clear the MRSA infection from the lungs of a mouse model of MRSA infection. In some cases, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be used as described herein (e.g., to increase the level of phosphorylated AMPK within cells and/or to treat a disease, disorder, or condition as described herein) as the sole active ingredient(s). For example, a composition containing a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof can lack any other active ingredients that increase the level of phosphorylated AMPK within cells. In some cases, a composition containing a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof can lack any other active ingredients that are effective to treat a disease, disorder, or condition as described herein.

Therapeutic Compounds

As described herein, any one or more of the compounds provided herein can be used to increase the level of phosphorylated AMPK within cells, and/or to treat a disease, disorder, and condition described herein in a mammal.

In some embodiments, this document provides a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein R¹, L¹, X, L², R², and R³are as described herein.

In Some Embodiments:

R¹is selected from 5-6 membered heteroaryl and a group of formula:

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wherein said 5-6 membered heteroaryl of R¹is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R⁵;

L¹is C_1-4alkylene, which is optionally substituted with halo or OR⁴;

L²is C_1-4alkylene or L²is absent;

X is selected from CR⁷(OR⁴), C═O, and C_3-6cycloalkylene; or X is absent;

R⁷is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl;

provided that at least one of R²and R³is other than H;

R⁴is selected from H, C(O)R^b1, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

each R⁵is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, thio, C_1-6alkylthio, carboxy, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino;

each R^Cy2is independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R_d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In Some Embodiments:

R¹is selected from 5-6 membered heteroaryl and a group of formula:

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wherein said 5-6 membered heteroaryl of R¹is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R⁵;

L¹is C_1-4alkylene;

L²is C_1-4alkylene or L²is absent;

X is selected from CH(OR⁴) and C═O; or X is absent;

R²and R³are each independently selected from H, C_1-6alkyl, Cy¹, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(═O)Cy¹, and S(═O)₂Cy¹, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1 or 2 independently selected Cy¹;

provided that at least one of R²and R³is other than H;

R⁴is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

or R⁴and R²together with the 0 atom to which R⁴is attached and N atom to which R²is attached form 5-10 membered heterocycloalkyl, which is optionally substituted with 1 or 2 independently selected Cy¹;

or R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with 1 or 2 independently selected Cy¹;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

each R⁵is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, thio, C_1-6alkylthio, carboxy, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino;

each R^Cy2is independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NRc1R_d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

In some embodiments, when R⁴is H, then at least one of R²and R³is selected from C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(═O)Cy³, and S(═O)₂Cy³, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl are each substituted with 1 or 2 independently selected Cy³, and each of said Cy³is independently selected from C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In some embodiments, when R⁴is H, then R²and R³are both independently selected from C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, Cy³, C(═O)Cy³, and S(═O)₂Cy³, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl are each substituted with 1 or 2 independently selected Cy³, and each of said Cy³is independently selected from C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In some embodiments, when R⁴is H, then at least one of R²and R³is selected from C_1-6alkyl, Cy³, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(═O)Cy³, and S(═O)₂Cy³, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1 or 2 independently selected Cy³, and each of said Cy³is independently selected from C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R_Cy1.

In some embodiments, the compound of Formula (I) is not any one of the following compounds:

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In some embodiments, the compound of Formula (I) is not the following compound:

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In some embodiments, the compound of Formula (I) is not any one of the following compounds:

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In Some Embodiments:

L¹is C_1-4alkylene;

X is selected from CH(OR⁴) and C═O; or X is absent;

R⁴is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with 1 or 2 independently selected Cy¹.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁷is H. In some embodiments, R⁷is C_1-6alkyl.

In some embodiments, Cy³is C_3-10cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy³is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy³is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, L²is C_1-4alkylene (e.g., methylene, ethylene, or propylene). In some embodiments, L²is methylene.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, L¹is selected from methylene, ethylene, and propylene. In some embodiments, L¹is selected from methylene and ethylene. In some embodiments, L¹is selected from methylene and ethylene. In some embodiments, L¹is methylene.

In some embodiments, L¹is methylene and L²is methylene. In some embodiments, L¹is methylene and L²is ethylene. In some embodiments, L¹is ethylene and L²is methylene. In some embodiments, L¹is methylene and L²is propylene. In some embodiments, L¹is propylene and L²is methylene.

In some embodiments, R¹is 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁵. In some embodiments, is R¹is selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl) and pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁵. In some aspects of these embodiments, at least one R⁵is C_1-3haloalkyl (e.g., trifluoromethyl).

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, 3, or 4 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, 3, or 4 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, or 3 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, 3, or 4 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, or 3 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, or 3 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, or 3 independently selected R⁵groups.

In some embodiments, R¹is a group of formula:

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which is optionally substituted with 1, 2, or 3 independently selected R⁵groups.

In some embodiments, R¹is a group of formula (i):

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In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, R¹is a group of formula (ii):

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In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, R⁵is selected from halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy. In some embodiments, R⁵is halo (e.g., F or Cl). In some embodiments, R⁵is selected from C_1-6alkyl, C_1-4haloalkyl and C_1-6alkoxy. In some embodiments, R⁵is C_1-4haloalkyl (e.g., trifluoromethyl). In some embodiments, R⁵is C_1-6alkoxy (e.g., methoxy).

In some embodiments, R¹is a group of formula:

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In some embodiments, R¹is a group of formula:

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In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In Some Embodiments:

R²is C_1-6alkyl substituted with C_6-10aryl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and

R³is C_1-6alkyl substituted with 5-10 membered heteroaryl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, each Cy¹is independently selected from C_6-10aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R^Cy1is selected from C_1-6alkyl, halo, and C_1-6haloalkyl.

In some embodiments, R^Cy1is C_1-6alkyl.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, Cy¹is pyridinyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R²is C_1-6alkyl substituted with C_6-10aryl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof, wherein each R⁸, R⁹, R¹⁰, R¹¹, and R¹²is independently selected from H and R^Cy1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, at least one of R⁸, R⁹, R¹⁰, R¹¹, and R¹²is R^Cy1.

In some embodiments, at least one of R⁸, R⁹, R¹⁰, R¹¹, and R¹²is C_1-6alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, at least one of R⁸, R⁹, R¹⁰, R¹¹, and R¹²is C_1-6alkyl.

In some embodiments, at least one of R⁸, R⁹, R¹⁰, R¹¹, and R¹²is C_1-3alkyl.

In Some Embodiments:

R⁸is C_1-6alkyl; and

each R⁹, R¹⁰, R¹¹, and R¹²is independently selected from H and R^Cy1.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁸is R^Cy1.

In some embodiments, R⁸is C_1-6alkyl.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof, wherein:

X¹is selected from N and CR¹³;

X²is selected from N and CR¹⁴;

X³is selected from N and CR¹⁵;

X⁴is selected from N and CR¹⁶;

X⁵is selected from N and CR¹⁷; and

each R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷is independently selected from H and R^Cy1.

In some embodiments, not more than three of X¹, X², X³, X⁴, and X⁵are N.

In some embodiments, not more than two of X¹, X², X³, X⁴, and X⁵are N.

In some embodiments, only one of X¹, X², X³, X⁴, and X⁵is N.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹³, R¹⁴, R¹⁵, and R¹⁷is independently selected from H and R^Cy1. In some embodiments, at least one of R¹³, R¹⁴, R¹⁵, and R¹⁷is R^Cy1. In some embodiments, at least one of R¹³, R¹⁴, R¹⁵, and R¹⁷is C_1-6alkyl.

In some embodiments, R¹³is C_1-6alkyl, and R¹⁴, R¹⁵, and R¹⁷are each H.

In some embodiments, R¹⁷is C_1-6alkyl, and R¹⁴, R¹⁵, and R¹³are each H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R²is H. In some embodiments, R²is C_1-6alkyl. In some embodiments, R²is Cy¹. In some embodiments, R²is C(═O)Cy¹. In some embodiments, R²is S(═O)₂Cy¹. In some embodiments, R²is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹. In some embodiments, R²is C_1-6alkyl substituted with Cy¹. In some embodiments, R²is C_1-6alkyl substituted with 2 independently selected Cy¹.

In some embodiments, R³is H. In some embodiments, R³is C_1-6alkyl. In some embodiments, R³is Cy¹. In some embodiments, R³is C(═O)Cy¹. In some embodiments, R³is S(═O)₂Cy¹. In some embodiments, R³is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹. In some embodiments, R³is C_1-6alkyl substituted with Cy¹. In some embodiments, R³is C_1-6alkyl substituted with 2 independently selected Cy¹.

In some embodiments, R²and R³are each independently an C_1-6alkyl substituted with 1 or 2 independently selected Cy¹.

In some embodiments:

R²is C_1-6alkyl substituted with Cy¹; and

R³is C_1-6alkyl substituted with Cy¹.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected C_6-10aryl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and

R³is C_1-6alkyl substituted with 1 or 2 independently selected C_6-10aryl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected C_3-10cycloalkyl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and

R³is C_1-6alkyl substituted with 1 or 2 independently selected C_3-10cycloalkyl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected 5-10 membered heteroaryl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and

R³is C_1-6alkyl substituted with 1 or 2 independently selected 5-10 membered heteroaryl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected C_6-10aryl groups, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and

In Some Embodiments:

R²is selected from H and C_1-6alkyl; and

R³is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹; and

R³is selected from Cy¹, C(═O)Cy¹and S(═O)₂Cy¹.

In Some Embodiments:

R²is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹; and

R³is C(═O)Cy¹.

In some embodiments, R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with Cy¹.

In some embodiments, the 4-16 membered heterocycloalkyl ring is selected from tetrahydroisoquinolinyl, isoindolinyl, and dihydrodibenzoazepinyl.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula selected from:

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each of which is optionally substituted with a substituent selected from Cy¹, C(O)OR^a1, and an C_1-6alkyl optionally substituted with OR^a1.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula:

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which is optionally substituted with Cy¹.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula:

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which is optionally substituted with Cy¹.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula:

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which is optionally substituted with Cy¹.

In some embodiments, R²and R³, together with the N atom to which they are attached, form a ring of formula:

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which is optionally substituted with Cy¹.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁴and R²together with the O atom to which R⁴is attached and N atom to which R²is attached form 5-10 membered heterocycloalkyl, which is optionally substituted with 1 or 2 independently selected Cy¹.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, Cy¹is selected from C_6-10aryl, C_3-10cycloalkyl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1. In some embodiments, Cy¹is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is C_3-10cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1. In some embodiments, Cy¹is selected from cyclopropyl and cyclohexyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy³is selected from cyclopropyl, cyclohexyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, quinolinyl, piperidinyl, dihydropyridinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl), imidazolyl, pyrazolyl, and thiazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy¹is selected from phenyl, cyclopropyl, cyclohexyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, and thiazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, each R^Cy1is independently selected from halo, C_1-6alkyl, C_1-6haloalkyl, and 5-10 membered heteroaryl, wherein said 5-10 membered heteroaryl is optionally substituted with halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, and C_1-6haloalkoxy.

In some embodiments, each R^Cy1is independently selected from halo, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, R^Cy1is 5-10 membered heteroaryl, optionally substituted with halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, and C_1-6haloalkoxy. In some embodiments, R^Cy1is 5-10 membered heteroaryl, optionally substituted with halo or C_1-6haloalkyl.

In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

text missing or illegible when filed

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

text missing or illegible when filed

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a compound of formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a compound of formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a compound selected from:

text missing or illegible when filed

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a compound of formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, a salt of any one of the compounds disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of any Formulae disclosed herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of any Formulae include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH—(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, the compounds of any Formulae disclosed herein, or pharmaceutically acceptable salts thereof, are substantially isolated.

In some embodiments, a compound of any Formulae disclosed herein, or a pharmaceutically acceptable salt thereof, can have the ability to increase the level of phosphorylated AMPK within a cell. Such cells can be in vitro or in vivo. For example, a compound of any Formulae disclosed herein, or a pharmaceutically acceptable salt thereof, can have the ability to increase the level of phosphorylated AMPK within cells present within a mammal (e.g., a human) following administration to that mammal.

Methods of Making Therapeutic Compounds

Compounds of any one of the Formulae disclosed herein, including salts thereof, can be prepared using one or more appropriate organic synthesis techniques and can be synthesized according to any of numerous appropriate synthetic routes. Any appropriate method can be used to select and implement appropriate synthetic protocols. The processes described herein are not the exclusive means by which compounds provided herein may be synthesized, and a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds provided herein.

Suitable synthetic methods of starting materials, intermediates, and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (J. Heterocyclic Chemistry, 1964-2012); Carreira et al., (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations II (Elsevier, 2^ndEdition, 2004); Katritzky et al., (Ed.) Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6^thEd. (Wiley, 2007); Trost et al. (Ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991).

The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be appropriately selected. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be appropriately selected.

Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be appropriately determined. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4^thEd., Wiley & Sons, Inc., New York (2006).

Pharmaceutical Compositions and Formulations

This document also provides pharmaceutical compositions comprising an effective amount of a compound of Formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition also can comprise any one of the additional therapeutic agents and/or therapeutic molecules described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

The compositions or dosage forms can contain any one or more of the compounds or therapeutic agents described herein in the range of 0.005 percent to 100 percent with the balance made up from the suitable pharmaceutically acceptable carriers or excipients. The contemplated compositions can contain from about 0.001 percent to about 100 percent (e.g., from about 0.1 percent to about 95 percent, from about 75 percent to about 85 percent, or from about 20 percent to about 80 percent) of any one or more of the compounds or therapeutic agents provided herein, wherein the balance can be made up of any pharmaceutically acceptable carrier or excipient described herein, or any combination of these carriers or excipients.

Routes of Administration and Dosage Forms

The therapeutic compounds and/or pharmaceutical compositions provided herein (e.g., a composition containing one or more compounds set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can include those suitable for any acceptable route of administration. Acceptable routes of administration include, without limitation, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal or other intraocular routes of administrations.

Compositions and formulations described herein can conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and can be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, Md. (20th ed. 2000). Such preparative methods include, without limitation, the step of bringing into association with the molecule to be administered ingredients such as a carrier that constitutes one or more accessory ingredients. In general, the compositions can be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. Compositions described herein that are suitable for oral administration can be presented as discrete units such as capsules, sachets, granules, or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient(s); a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus. Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include, without limitation, lactose, sucrose, glucose, mannitol, silicic acid, and starches. Other acceptable excipients can include, without limitation, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include, without limitation, lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient(s) can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents can be added. Compositions suitable for oral administration include, without limitation, lozenges comprising ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient(s) in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions or infusion solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, saline (e.g., 0.9% saline solution), or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The injection solutions can be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation also can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including, without limitation, synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables. In some cases, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions, can be used to prepare injectables. These oil solutions or suspensions also can contain a long-chain alcohol diluent or dispersant.

In some cases, a therapeutic compound and/or pharmaceutical composition provided herein can be administered in the form of suppository for rectal administration. These compositions can be prepared by mixing a compound described herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active component(s). Such materials include, without limitation, cocoa butter, beeswax, and polyethylene glycols.

In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, U.S. Pat. No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm. Pharmacol., 56:3-17 (2004); and Ilium, L., Eur. J Pharm. Sci., 11:1-18 (2000).

In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be prepared as a topical composition and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of a therapeutic compounds and/or pharmaceutical composition provided herein can be useful when the desired treatment involves areas or organs readily accessible by topical application. In some cases, a topical composition can include a combination of any one or more of the compounds or therapeutic agents described herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof), and one or more additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.

In some cases, one or more compounds or therapeutic agent described herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be incorporated into a composition for coating an implantable medical device such as a prosthesis, artificial valve, vascular graft, stent, or catheter. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings can be biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, or mixture thereof. In some cases, the coating can optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

In some cases, this document provides an implantable drug release device impregnated with or containing one or more compounds or therapeutic agents described herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) such that the compound(s) or therapeutic agent(s) are released from the device and are therapeutically active.

Dosages and Regimens

A composition (e.g., pharmaceutical compositions provided herein) containing a compound provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can include that compound in an effective amount (e.g., a therapeutically effective amount).

Effective doses can vary, depending on the diseases being treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents, and the judgment of the treating physician.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.1 mg to about 1000 mg. In some cases, the effective amount can be from about 0.5 mg to about 500 mg of a compound disclosed herein, or any amount in between these two values, for example, one of about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. The effective amount can be an amount sufficient to alleviate or reduce one or more of the symptoms associated with a disease, disorder, or condition being treated as described herein.

In some cases, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg/kg to about 1 mg/kg; from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.5 mg/kg to about 500 mg/kg).

In some cases, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or on a non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, or once a month). In some cases, the dosages can be administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.

Kits

This document also provides pharmaceutical kits useful, for example, to increase the level of phosphorylated AMPK within cells and/or within the nucleus of cells within a mammal (e.g., a human). In some cases, this document provides pharmaceutical kits useful, for example, to treat diseases, disorders, and conditions referred to herein. Such pharmaceutical kits can include one or more containers containing a pharmaceutical composition that includes a therapeutically effective amount of a compound provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof). In some cases, such kits can further include, if desired, one or more of various conventional pharmaceutical kit components such as containers with one or more pharmaceutically acceptable carriers. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components also can be included in a kit provided herein.

Combination Therapy

In some cases, one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) can be combined with one or more therapeutic molecules. Examples of therapeutic molecules that can be used in combination with one or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) include, without limitation, anti-inflammatory agents (e.g., steroids and antibodies against IL-6 or TNF-alpha), antimicrobial agents (e.g., antibiotics, anti-mycobacterial drugs, and anti-viral agents), anti-cancer agents (e.g., chemotherapeutic agents such as immune checkpoint inhibitors (e.g., anti-PD1 antibodies or anti-PD-L1 antibodies) and cellular products such as engineered T cells), anti-aging agents (e.g., nicotinamide riboside, or rapamycin), neurological agents (e.g., L-DOPA, memantine, and riluzole), therapies for a neurodegenerative disease (e.g., edaravone or tetrabenazine), agents used to treat chronic organ dysfunction (e.g., ACE inhibitor and lactulose), therapies for atherosclerosis (e.g. lipid-lowering agents, platelet inhibitors), agents to treat polycystic kidney disease (e.g. tolvaptan), therapies used for metabolic syndrome (e.g. insulin, glucose-lowering therapies), therapies for polycystic ovarian syndrome (e.g. metformin), treatment for muscular dystrophies (e.g. steroids, gene therapy approaches) and therapies for pain relief (e.g., non-steroidal anti-inflammatory medicines, opioids, regional nerve blocks).

One or more compounds provided herein (e.g., a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof) and the one or more therapeutic molecules can be administered in any order or simultaneously. If simultaneously administered, they can be provided in a single, unified, form or in multiple forms (e.g., either as a single pill or as two separate pills). One of the items can be given in multiple doses, or both can be given as multiple doses. If not simultaneous, the timing between the multiple doses can vary from more than zero weeks to less than four weeks.

Definitions

As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

At various places in this document, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that these groups and ranges include each and every individual subcombination of the members of such groups and ranges. For example, the term “C_1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C₃alkyl, C₄alkyl, C₅alkyl, and C₆alkyl.

At various places in this document various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein which are, for brevity, described in the context of a single embodiment, also can be provided separately or in any suitable subcombination.

The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized R (pi) electrons where n is an integer).

The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C_1-4, C_1-6, and the like.

As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, the term “C_n-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_n-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, without limitation, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_n-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, without limitation, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_n-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl-linking group having n to m carbons. Examples of alkylene groups include, without limitation, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_n-malkoxy”, employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, without limitation, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_n-mhaloalkoxy” refers to a group of formula —O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF₃. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “C_n-malkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, without limitation, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

As used herein, the term “di(C_n-m-alkyl)amino” refers to a group of formula —N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkoxycarbonyl” refers to a group of formula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like.

As used herein, the term “C_n-malkylcarbonyl” refers to a group of formula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, without limitation, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and the like.

As used herein, the term “C_n-malkylcarbonylamino” refers to a group of formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonylamino” refers to a group of formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula —S(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonyl” refers to a group of formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonyl” refers to a group of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group of formula —NHS(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonylamino” refers to a group of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonylamino” refers to a group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_n-malkylaminocarbonylamino” refers to a group of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminocarbonylamino” refers to a group of formula —NHC(O)N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “C_n-malkylcarbamyl” refers to a group of formula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-m-alkyl)carbamyl” refers to a group of formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_n-malkylthio” refers to a group of formula —S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfinyl” refers to a group of formula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonyl” refers to a group of formula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a —C(═O)— group, which may also be written as C(O).

As used herein, the term “carboxy” refers to a —C(O)OH group. In some embodiments, the “carboxy” group also refers to a bioisostere replacement group selected from the group consisting of:

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and the like, where R refers to a hydrogen, (C₁-C₈) alkyl, or C₆aryl.

As used herein, the term “cyano-C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-CN.

As used herein, the term “HO—C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-OH.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.

As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term “C_n-maryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups can have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C_3-10). In some embodiments, the cycloalkyl is a C_3-10monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C_3-7monocyclic cycloalkyl. Example cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term “C_n-mcycloalkylene” refers to a divalent C_n-mcycloalkyl group. Examples of cycloalkylene groups include, without limitation, cyclopropylene (e.g., 1,1-cyclopropylene, 1,2,-cyclopropylene), cyclobutylene (1,1,-cyclobutylene, 1,2-cyclobutylene, 1,3-cyclobutylene), cyclopentylene, and cyclohexylene. An example of a cyclopropylene group is shown below:

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As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, without limitation, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, or 16-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include, without limitation, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-16 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C═O), or attached to a heteroatom forming a sulfoxide or sulfone group.

The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Any appropriate method can be used to prepare optically active forms from, for example, optically inactive starting materials. For example, techniques such as resolution of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of a compound provided herein. Many geometric isomers of olefins, C═N double bonds, N═N double bonds, and the like also can be present in a compound described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, a compound provided herein has the (R)-configuration. In some embodiments, a compound provided herein has the (S)-configuration.

Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include, without limitation, ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:

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As readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope provided herein.

In the compounds of the present disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is not specifically designated as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition, or deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium). In some embodiments, a compound of the present disclosure has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated 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 “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal (e.g., a human). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal (e.g., a human).

As used herein, the term “contacting” refers to the bringing together of indicated moieties or items in an in vitro system, an ex vivo system, or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the act of administering that compound to a mammal (e.g., a human) containing that cell as well as, for example, introducing that compound into a cell culture containing that cell.

As used herein, the term “mammal” includes, without limitation, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, elephants, deer, non-human primates (e.g., monkeys and apes), house pets, and humans.

As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, mammal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

As used herein, the term “treating” or “treatment” refers to (a) inhibiting a disease, disorder, or condition, for example, inhibiting a disease, disorder, or condition in a mammal (e.g., human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., arresting further development of the pathology and/or symptomatology), or (b) ameliorating the disease, disorder, or condition, for example, ameliorating a disease, disorder, or condition in a mammal (e.g., a human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., reversing the pathology and/or symptomatology).

As used herein, the term “preventing” or “prevention” of a disease, disorder, or condition refers to decreasing the risk of occurrence of the disease, disorder, or condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed to or susceptible to the disease, disorder, or condition). In some embodiments, preventing a disease, disorder, or condition refers to decreasing the possibility of acquiring the disease, disorder, or condition and/or its associated symptoms. In some embodiments, preventing a disease, disorder, or condition refers to completely or almost completely stopping the disease, disorder, or condition from occurring.

EXAMPLES
Material and Methods

All non-aqueous reactions were carried out under a nitrogen atmosphere in oven- or flame-dried glassware unless otherwise noted. Anhydrous tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl solutions; anhydrous dichloromethane and toluene were distilled from CaH₂; alternatively, the same solvents were obtained from a solvent purification system using alumina columns. All other solvents and reagents were used as obtained from commercial sources without further purification unless noted. Reactions were monitored via TLC using 250 μm pre-coated silica gel 60 F254 plates, which were visualized with 254 nm and/or 365 nm UV light and by staining with KMnO₄(1.5 g KMnO₄, 10 g K₂CO₃, and 1.25 mL 10% NaOH in 200 mL water), cerium molybdate (0.5 g Ce(NH₄)₂(NO₃)₆, 12 g (NH₄)₆Mo₇O₂₄•4H₂O, and 28 mL conc. H₂SO₄in 235 mL water), or vanillin (6 g vanillin and 1.5 mL conc. H₂SO₄in 100 mL EtOH). Flash chromatography was performed with SiliCycle silica gel 60 (230-400 mesh) or with ISCO MPLC. ¹H and ¹³C NMR spectra were recorded on Bruker Avance 300, 400, or 500 MHz spectrometers, using the residual solvent as an internal standard. IR spectra were obtained on a Smiths IdentifyIR or PerkinElmer Spectrum 100. HRMS data were obtained on a Thermo Scientific Exactive HRMS coupled to a Thermo Scientific Accela HPLC system using a 2.1×50 mm 3.5 μm Waters XTerra C18 column eluting with MeCN/H₂O containing 0.1% formic acid. Purity of compounds was assessed using the same HPLC system with either the PDA or an Agilent 385 ELSD. All final screening samples passed QC based on >95% purity by LC/MS/ELSD analysis.

Synthetic Methods

The preparation of the compounds of Formula (I) can be exemplified by the following synthesis of compound BC19856 shown in Scheme 1 from the readily available starting materials.

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Example 1—Compound Structures

The compounds in Table 1 and Table 1a were prepared from readily available starting materials using methods and procedures similar to those described above for compound BC19856.

TABLE 1

No.
BC code
Structure

1
BC1618R

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2
BC1618S

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3
BC19801

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4
BC19802

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5
BC19803

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6
BC19804

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7
BC19805

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8
BC19806

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9
BC19807

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10
BC19808

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11
BC19809

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12
BC19810

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13
BC19811

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14
BC19812

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15
BC19813

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16
BC19814

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17
BC19815

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18
BC19816

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19
BC19819

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20
BC19820

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21
BC19821

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22
BC19822

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23
BC19823

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24
BC19824

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25
BC19825

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26
BC19826

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27
BC19827

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28
BC19828

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29
BC19829

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30
BC19830

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31
BC19831

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32
BC19832

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33
BC19833

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34
BC19834

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35
BC19835

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36
BC19836

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37
BC19837

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38
BC19838

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39
BC19839

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40
BC19840

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41
BC19841

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42
BC19842

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43
BC19843

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44
BC19844

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45
BC19845

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46
BC19846

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47
BC19847

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48
BC19848

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49
BC19849

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50
BC19850

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51
BC19851

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52
BC19852

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53
BC19853

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54
BC19854

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55
BC19855

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56
BC19856

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57
BC19857

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58
BC19858

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59
BC19859

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60
BC19860

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61
BC19861

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62
BC19862

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63
BC19863

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64
BC19864

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65
BC19865

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66
BC19866

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67
BC19867

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68
BC19868

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69
BC19869

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70
BC19870

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71
BC19871

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72
BC19872

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73
BC19873

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74
BC19874

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75
BC19875

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76
BC19876

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77
BC19877

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78
BC19878

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79
BC19879

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80
BC19880

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81
BC19881

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82
BC19882

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83
BC19883

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84
BC19884

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85
BC19885

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86
BC19886

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87
BC19887

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Compounds 3-34, 36-44, and 47-60 were isolated and tested as HCl salts.

TABLE 1a

No.
BC code
Structure

88
BC19888

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89
BC19889

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90
BC19890

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91
BC19891

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92
BC19892

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93
BC19893

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94
BC19894

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95
BC19895

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96
BC19896

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97
BC19897

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98
BC19898

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99
BC19899

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100
BC191000

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101
BC191001

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102
BC191002

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103
BC191003

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104
BC191004

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105
BC191005

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106
BC191006

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107
BC191007

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108
BC191008

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109
BC191009

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110
BC191010

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111
BC191011A

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112
BC191011B

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113
BC191011C

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114
BC191011D

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115
BC191011E

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116
BC191011F

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117
BC191012

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118
BC191013

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119
BC191014

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120
BC191015

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121
BC191016

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122
BC191017

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123
BC191018

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124
BC191019

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125
BC191020

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126
BC191021

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127
BC191022

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128
BC191023

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129
BC19856A

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130
BC19856B

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131
BC19856C

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132
BC19856D

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133
BC19856E

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134
BC19856F

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135
BC191024

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136
BC191025

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137
BC191026

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138
BC191027

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139
BC19863A
BC19863 isolated as HCl salt

140
BC19863B
BC19863 isolated as tartrate salt

141
BC191028

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142
BC191029

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143
BC191030

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144
BC191031

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145
BC191032

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146
BC191033

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147
BC191034

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148
BC191035

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149
BC191036

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150
BC19865A

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151
BC19865B

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152
BC191037

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153
BC191038

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154
BC191039

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155
BC191040

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156
BC191041

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157
BC191042

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158
BC191043

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159
BC191044

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160
BC191045

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161
BC191046

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162
BC191047

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163
BC191048

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164
BC191049

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165
BC191050

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166
BC191051

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167
BC191052

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168
BC191053

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169
BC191054

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170
BC191055

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171
BC191056

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172
BC191057

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173
BC191058

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174
BC191059

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175
BC191060

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176
BC191061

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177
BC191062

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178
BC191063

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179
BC191064

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180
BC191065

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181
BC191066

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182
BC191067

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183
BC191068

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184
BC191069

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185
BC191070

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186
BC191071

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187
BC191072

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188
BC191073

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189
BC191074

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190
BC191075

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191
BC191076

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192
BC191077

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193
BC191078

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194
BC191079

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195
BC191080

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196
BC191081

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197
BC191082

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198
BC191083

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199
BC191084

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200
BC191085

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201
BC191086

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Example 2—Assay Results
Assay Protocol

Beas2B cells were plated in 384 white nunc plate (4000 cells per well) for overnight. Compounds were serially diluted in DMEM no glucose media using the liquid handler. Cells were washed once using Biotek EL406 before compound addition for additional 18 hours. Cells were washed and fixed with PFA before immunostained with pAMPK primary antibody and anti-Rabbit HRP secondary antibody. Finally, 25 μl of ECL reagent will be added to cells, and chemical luminescence signal will be counted using plate reader.

Compounds efficacies (μM) were determined by the minimal compound concentration needed to increase pAMPK by 30%. Activity: “+” equals >10 μM; “++” equals between ≤10 μM and >1 μM; and “+++” equals 1 μM. The assay results for compounds 1-87 are shown in Table A. The assay results for compounds 88-201 are shown in Table B.

TABLE A

Compound efficacy results

No.
BC code
efficacy

1
BC1618R
++

2
BC1618S
++

3
BC19801
++

4
BC19802
+++

5
BC19803
++

6
BC19804
++

7
BC19805
+++

8
BC19806
+++

9
BC19807
+

10
BC19808
++

11
BC19809
++

12
BC19810
++

13
BC19811
+++

14
BC19812
+

15
BC19813
+

16
BC19814
++

17
BC19815
+

18
BC19816
+++

19
BC19819
+

20
BC19820
++

21
BC19821

22
BC19822
++

23
BC19823
+++

24
BC19824
+

25
BC19825
+++

26
BC19826
+++

27
BC19827
+++

28
BC19828
+++

29
BC19829
+++

30
BC19830
++

31
BC19831
++

32
BC19832
+++

33
BC19833
++

34
BC19834

35
BC19835
++

36
BC19836
+++

37
BC19837
++

38
BC19838
++

39
BC19839
++

40
BC19840
+++

41
BC19841
++

42
BC19842
+++

43
BC19843
+++

44
BC19844
+++

45
BC19845
+++

46
BC19846
+++

47
BC19847
+++

48
BC19848
+++

49
BC19849
++

50
BC19850
+

51
BC19851
++

52
BC19852
++

53
BC19853
++

54
BC19854
++

55
BC19855
++

56
BC19856
+++

57
BC19857
++

58
BC19858

59
BC19859
++

60
BC19860
++

61
BC19861
++

62
BC19862
++

63
BC19863
+++

64
BC19864
++

65
BC19865
+++

66
BC19866
+++

67
BC19867
+++

68
BC19868
+++

69
BC19869
+++

70
BC19870
+++

71
BC19871
++

72
BC19872
+++

73
BC19873
++

74
BC19874
++

75
BC19875
++

76
BC19876
++

77
BC19877
++

78
BC19878
+++

79
BC19879
++

80
BC19880
++

81
BC19881
+++

82
BC19882
+++

83
BC19883
+++

84
BC19884
+++

85
BC19885
++

86
BC19886
+++

87
BC19887
++

TABLE B

Compound efficacy results.

No.
BC code
efficacy

88
BC19888
+++

89
BC19889
++

90
BC19890
+++

91
BC19891
+++

92
BC19892
++

93
BC19893
++

94
BC19894
++

95
BC19895
+++

96
BC19896
+++

97
BC19897
+++

98
BC19898
++

99
BC19899
+++

100
BC191000
+++

101
BC191001
+++

102
BC191002
+++

103
BC191003
+

104
BC191004
+++

105
BC191005
+++

106
BC191006
+++

107
BC191007
+++

108
BC191008
+++

109
BC191009
+++

110
BC191010
+++

111
BC191011A
++

112
BC191011B
+++

113
BC191011C
++

114
BC191011D
+

115
BC191011E
++

116
BC191011F
+

117
BC191012
++

118
BC191013
+

119
BC191014
+++

120
BC191015
+++

121
BC191016
+++

122
BC191017
+++

123
BC191018
++

124
BC191019
++

125
BC191020
+++

126
BC191021
+

127
BC191022
+++

128
BC191023
++

129
BC19856A
+++

130
BC19856B
+++

131
BC19856C
+++

132
BC19856D
+++

133
BC19856E
+++

134
BC19856F
+++

135
BC191024
+++

136
BC191025
+++

137
BC191026
+++

138
BC191027
+

139
BC19863A
+++

140
BC19863B
+++

141
BC191028
+++

142
BC191029
+++

143
BC191030
+++

144
BC191031
++

145
BC191032
++

146
BC191033
+

147
BC191034
+

148
BC191035
+

149
BC191036
++

150
BC19865A
++

151
BC19865B
+++

152
BC191037
++

153
BC191038
++

154
BC191039
+++

155
BC191040
+++

156
BC191041
+++

157
BC191042
+++

158
BC191043
+++

159
BC191044
+++

160
BC191045
+++

161
BC191046
+++

162
BC191047
+

163
BC191048
+

164
BC191049
+++

165
BC191050
+++

166
BC191051
+

167
BC191052
+

168
BC191053
+

169
BC191054
+++

170
BC191055
+++

171
BC191056
++

172
BC191057
+++

173
BC191058
+++

174
BC191059
+++

175
BC191060
+++

176
BC191061
++

177
BC191062
+

178
BC191063
+++

179
BC191064
++

180
BC191065
++

181
BC191066
+++

182
BC191067
+++

183
BC191068
+++

184
BC191069
+++

185
BC191070
+++

186
BC191071
+++

187
BC191072
+++

188
BC191073
+++

189
BC191074
+

190
BC191075
++

191
BC191076
+++

192
BC191077
+++

193
BC191078
+++

194
BC191079
+++

195
BC191080
+++

196
BC191081
++

197
BC191082
+++

198
BC191083
+

199
BC191084
++

200
BC191085
+++

201
BC191086
++

Example 3—Therapeutic Efficacy in Syngeneic A20 Murine Lymphoma in BALB/c Mice

Groups of (8) immunocompetent (7-8 weeks old), specific pathogen-free (SPF) BALB/c female mice bred in an animal isolator (IVC racks) under specific pathogen free (SPF) condition at 22±2° C. were used in this study. Viable A20 murine melanoma cells (ATCC TIB-208, 1.0×10⁶in 0.1 mL), syngeneic for BALB/c mice, were injected subcutaneously into the right flank of the mice. When group mean tumor volumes reached approximately 40-80 mm³, animals were randomized into five groups, and dosing (denoted as Day 1) was initiated as shown in the following table. For group 1, the animals received no treatment. For Group 2, the animals were administered compound 63 orally, once a day for 21 days. For Group 3, the animals were administered anti-mPD-1 (Clone: RMP1-14, Bio X Cell, Catalog No. BE0146), formulated in phosphate buffered saline (PBS), intraperitoneally (IP) once every four days (repeated three times). For Groups 4 and 5, the animals were administered compound 63 orally, once a day for 21 days, and administered anti-mPD-1 (Clone: RMP1-14, Bio X Cell, Catalog No. BE0146), formulated in PBS, IP, once every four days (repeated three times). Half-life of the antibody is 9 days.

Tumor volumes, body weights, and signs of overt dose related toxicity were monitored in the mice and recorded three times weekly starting on Day 1 and continuing to Day 28 or when the mean tumor volume in the negative control group reached 3000 mm³, whichever came first. Therapeutic efficacy was evaluated for Tumor Growth Inhibition (TGI), or Tumor Growth Delay (TGD), or both TGI and TGD.

Treatment 1
Treatment 2

Group
Test Article
Route
Schedule
mL/kg
mg/kg
Test Article
Route
Schedule
mL/kg
mg/kg
Mice (n)

1^#
No

—

—
No

—

—
8

Treatment

Treatment

2
Compound 63
Oral
qd x 21

25
—

—

—
8

3
PD-1
IP
q4d x 3
10
20
—

—

—
8

4
Compound 63
Oral
qd x 21
10
25
PD-1
IP
q4d x 3
10
20
8

5
Compound 63
Oral
qd x 21
10
25
PD-1
IP
q4d x 3
10
20
2

^#Negative control

For group 5, in-life blood samples (40 μL whole blood per time-point) were collected from both mice via mandibular bleed prior to administering the last dose of compound 63, and at 30 min, 1 hour, 2 hours, and 4 hours post last dose. Terminal blood samples were collected via cardiac puncture from all mice 24 hours post last dose. All blood samples were processed for plasma, flash frozen and stored at −80° C. until analysis. Whole blood samples were analyzed using fluorescence-activated cell sorting (FACS) to determine the percentage of CD4+, CD8+, and T-reg cells.

Upon termination of the mice, tumor samples were collected from all mice, and the tumors divided into two parts. One part was flash frozen and stored at −80° C. until analysis. The second part was homogenized and evaluated for CD4+, CD8+, and T-reg cells using FACS.

Tumor growth inhibition (T/C) was calculated by the following formula: % T/C=(Tn/Cn)×100%, where Cn is the tumor weight measured on Day n in the control group, Tn is the tumor weight measured on Day n in the treated group. % T/C value ≤42% was considered significant antitumor activity (NCI standards).

Percent tumor growth inhibition (% TGI) also was calculated using the following formula: % TGI=(1−(Tn/Cn))×100%. A % TGI value ≥58% was considered significant antitumor activity.

Percent Tumor Growth Delay (% TGD) was expressed as the percentage by which the treated group median tumor volume was delayed in reaching the established tumor volume endpoint compared to the controls using the formula ((T-C)/C))×100, where T and C are median times (days) to reach the established tumor volume endpoint for the treated and control group, respectively. Animal were monitored individually. The tumor volume endpoint for individual animals is 3000 mm³. Responders can be followed longer.

Tumor volume (mm³) was estimated according to the formula for a prolate ellipsoid: length (mm)×[width (mm)]²×0.5.

Tumor volume data is shown in FIGS. 1A-1D. FIG. 1A compares tumor volume over the course of the study, while FIGS. 1B, 1C, and 1D show tumor volume on days 6, 13, and 22, respectively. In mice treated with either compound 63 or anti-PD-1 antibody, tumor volume was reduced but did not reach the ≥58% TGI threshold. However, when mice were treated with a combination of compound 63 and anti-PD-1 antibody, a significant (p<0.005 compared to vehicle and p<0.05 compared to compound 63 alone) decrease in tumor growth was observed (76% TGI), indicating that compound 63 and anti-PD-1 antibody had a synergistic effect. This may underestimate the value of compound 63 since higher doses may be more effective. Similarly, PD-1 therapy was not given after day 12 in this model (q4d×3 dosing). Continuation of PD-1 therapy for longer periods might result in higher levels of synergy.

FIGS. 2A-2D depict the percentage of CD4+ cells (FIG. 2A), CD8+ cells (FIG. 2B), regulatory T cells (FIG. 2C), and leukocytes (FIG. 2D) found in the blood of mice after termination of the study. As shown in FIG. 2B, a significant (p<0.001 compared to vehicle treatment) increase in circulating CD8+ cells was observed in the mice treated with the combination of compound 63 and anti-PD-1 antibody.

Example 4—Antimicrobial Efficacy Against Methicillin Resistant Staphylococcus aureus (MRSA)

Groups of 5-10 female BALB/c mice weighing 20±2 g were used in this study. Animals were rendered immune suppressed by treatment with 250 mg/kg of cyclophosphamide IP at 4 and 2 days before infection (Day −4 and −2). Vehicle 10% DMA (N,N-dimethylacetamide): 40% PEG300: 50% H₂O) and/or test substances were administered on days −4, −3, −2, −1 and 0.

Test
Schedule
Conc.
Dosage
Mice

Group
Article
Route
mg/mL
mL/kg
mg/kg
(Female)

1
Initial counts,
—
—
—
—
5

30 min

Post infection

2
Vehicle^a,b
Once a day,
—
10
—
10

orally

3
Vancomycin
Twice a day,
1.6
10
16
10

IV

4
Compound 63
Once a day,
2.5
10
25
10

orally

On day 0, immediately following the final dose, animals were inoculated intranasally (0.02 mL/lung) with 1-5×10⁶colony forming units (CFU)/mouse of MRSA (ATCC 33591) after being anaesthetized by etomidate (20 mg/kg dose, IV). In addition, following the final dose, blood was collected at 0, 0.5 h, 1 h, 2 h, 4 h and 24 h from three animals of each group, via facial veins. Terminal blood samples were taken by cardiac puncture. Blood samples were drawn into K2EDTA anti-coagulant coated mini collection tubes. The blood was collected from group 1 after sacrifice as the blank for PK analysis. Samples were stored on ice for no more than one hour then centrifuged at 2500×g for 15 min at 4° C. Plasma (˜50 μL) was stored at −80° C. until analysis.

At 24 hours after inoculation, the animals were humanely euthanized with CO₂asphyxiation, and the lung tissue was harvested from each of the test animals. The tissues were homogenized in 1 mL of PBS. Homogenates, 0.1 mL, were used for serial 10-fold dilutions and plated on mannitol salt agar plates for CFU determination. As shown in FIG. 3, compound 63 cleared MRSA from the lung (p<0.01 compared to vehicle treatment).

The plasma samples are processed using acetonitrile precipitation and analyzed by HPLC-MS/MS. A plasma calibration curve is generated. Aliquots of drug-free plasma are spiked with the test compound at the specified concentration levels. The spiked plasma samples are processed together with the unknown plasma samples using the same procedure. The processed plasma samples are stored at −20° C. until the HPLC-MS/MS analysis, at which time peak areas were recorded, and the concentrations of the test compound in the unknown plasma samples are determined using the respective calibration curve. The reportable linear range of the assay is determined, along with the lower limit of quantitation (LLQ).

TABLE 2

The exposure levels of compound 63 in mouse plasma samples-

compound 63 (25 mg/kg, PO QD × 5) group:

Time (h)
Sample concentration (ng/mL)
mean
SD

0
3
0
0
1*
2

0.5
180
243
390
271
108

1
184
95
120
133
46

2
16
36
31
28
10

4
22
38
18
26
11

24
7
0
3
3
4

*The data was excluded from the PK calculation

TABLE 3

The PK parameters of compound 63 in mouse plasma samples

Dose,

AUC_last
AUC_inf
AUC/D

PO
T_max
C_max
(h ×
(h ×
(h × kg ×
AUC_Extr
MTR

(mg/kg)
(h)
(ng/mL)
ng/mL)
ng/mL)
ng/mL/mg)
(%)
(h)

25
0.5
271
593
622
25
5
4.96

ADDITIONAL EMBODIMENTS

Embodiment 1. A compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein:

R¹is selected from 5-6 membered heteroaryl and a group of formula:

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wherein said 5-6 membered heteroaryl of R¹is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R⁵;

L¹is C_1-4alkylene;

L²is C_1-4alkylene or L²is absent;

X is selected from CH(OR⁴) and C═O; or X is absent;

R²and R³are each independently selected from H, C_1-6alkyl, Cy¹, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C(═O)Cy¹, and S(═O)₂Cy¹, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1 or 2 independently selected Cy¹; provided that at least one of R²and R³is other than H;

R⁴is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

or R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with 1 or 2 independently selected Cy¹;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

each R⁵is independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, thio, C_1-6alkylthio, carboxy, amino, C_1-6alkylamino, and di(C_1-6alkyl)amino;

each R^a1, R^b1, R^c1, and R^d1is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C₂-6 alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

provided that the compound of Formula (I) is not any one of the following compounds:

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Embodiment 2. The compound of embodiment 1, wherein the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 3. The compound of embodiment 1, wherein the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 4. The compound of any one of embodiments 1-3, wherein L²is C_1-4alkylene.

Embodiment The compound of any one of embodiments 1-4, wherein L²is methylene.

Embodiment 6. The compound of embodiment 1, wherein the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 7. The compound of embodiment 1, wherein the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 8. The compound of any one of embodiments 1-7, wherein L¹is selected from methylene and ethylene.

Embodiment 9. The compound of embodiment 8, wherein L¹is methylene.

Embodiment 10. The compound of any one of embodiments 1-9, wherein R¹is 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R⁵.

Embodiment 11. The compound of embodiment 10, wherein the 5-6 membered heteroaryl is selected from pyridinyl and pyrimidinyl.

Embodiment 12. The compound of any one of embodiments 1-9, wherein m is 0, 1, or 2.

Embodiment 13. The compound of any one of embodiments 1-9, wherein n is 0, 1, or 2.

Embodiment The compound of any one of embodiments 1-13, wherein R⁵is selected from halo, C_1-6alkyl, C_1-4haloalkyl, C_1-6alkoxy, and C_1-6haloalkoxy.

Embodiment 15. The compound of any one of embodiments 1-9, wherein R¹is a group of formula:

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Embodiment 16. The compound of any one of embodiments 1-9, wherein R¹is a group of formula:

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Embodiment The compound of embodiment 1, wherein the compound of Formula (I) is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiment 18. The compound of any one of embodiments 1-17, wherein R²and R³are each independently selected from H, C_1-6alkyl, Cy¹, C(═O)Cy¹, and S(═O)₂Cy¹, wherein said C_1-6alkyl, is optionally substituted with 1 or 2 independently selected Cy¹.

Embodiment 19. The compound of embodiment 18, wherein R²and R³are each independently an C_1-6alkyl substituted with 1 or 2 independently selected Cy¹.

Embodiment 20. The compound of embodiment 18, wherein:

R²is selected from H and C_1-6alkyl; and

R³is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹.

Embodiment 21. The compound of embodiment 18, wherein:

R²is C_1-6alkyl substituted with 1 or 2 independently selected Cy¹; and

R³is selected from Cy¹, C(═O)Cy¹and S(═O)₂Cy¹.

Embodiment 22. The compound of any one of embodiments 1-17, wherein R²and R³, together with the N atom to which they are attached, form 4-16 membered heterocycloalkyl ring, which is optionally substituted with Cy¹.

Embodiment 23. The compound of embodiment 22, wherein the 4-16 membered heterocycloalkyl ring is selected from tetrahydroisoquinolinyl, isoindolinyl, and dihydrodibenzoazepinyl.

Embodiment 24. The compound of any one of embodiments 1-17, wherein R²and R³, together with the N atom to which they are attached, form a ring of formula selected from:

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each of which is optionally substituted with Cy¹.

Embodiment 25. The compound of embodiment 1, wherein the compound of Formula (I) is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiment 26. The compound of embodiment 1, wherein the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 27. The compound of any one of embodiments 1-26, wherein Cy¹is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

Embodiment 28. The compound of embodiment 27, wherein Cy¹is selected from phenyl, cyclopropyl, cyclohexyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, quinolinyl, piperidinyl, dihydropyridinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

Embodiment 29. The compound of any one of embodiments 1-28, wherein each R^Cy1is independently selected from halo, CN, C(O)NR^c1R^d1, C_1-6alkyl, C_1-6haloalkyl, and 5-10 membered heteroaryl, wherein said 5-10 membered heteroaryl is optionally substituted with halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, and C_1-6haloalkoxy.

Embodiment 30. The compound of embodiment 1, wherein the compound of Formula (I) is selected from any one of the following compounds:

No.
BC code
Structure

3
BC19801

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4
BC19802

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5
BC19803

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6
BC19804

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7
BC19805

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8
BC19806

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9
BC19807

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10
BC19808

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11
BC19809

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12
BC19810

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13
BC19811

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14
BC19812

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15
BC19813

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16
BC19814

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17
BC19815

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18
BC19816

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19
BC19819

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20
BC19820

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21
BC19821

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22
BC19822

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23
BC19823

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24
BC19824

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25
BC19825

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26
BC19826

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27
BC19827

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28
BC19828

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29
BC19829

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30
BC19830

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31
BC19831

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32
BC19832

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33
BC19833

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34
BC19834

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35
BC19835

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36
BC19836

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37
BC19837

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38
BC19838

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39
BC19839

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40
BC19840

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41
BC19841

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42
BC19842

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43
BC19843

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45
BC19845

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46
BC19846

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47
BC19847

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48
BC19848

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49
BC19849

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50
BC19850

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51
BC19851

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52
BC19852

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53
BC19853

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54
BC19854

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55
BC19855

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56
BC19856

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58
BC19858

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59
BC19859

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62
BC19862

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63
BC19863

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64
BC19864

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65
BC19865

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66
BC19866

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67
BC19867

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68
BC19868

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69
BC19869

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70
BC19870

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71
BC19871

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72
BC19872

embedded image

73
BC19873

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74
BC19874

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75
BC19875

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76
BC19876

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77
BC19877

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78
BC19878

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79
BC19879

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80
BC19880

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81
BC19881

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82
BC19882

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83
BC19883

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84
BC19884

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85
BC19885

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86
BC19886

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or a pharmaceutically acceptable salt thereof.

Embodiment 31. A compound of formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 32. A compound of formula:

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or a pharmaceutically acceptable salt thereof.

Embodiment 33. A compound selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiment 34. A pharmaceutical composition comprising a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 35. A method of treating a mammal having a disease, disorder, or condition responsive to an increase in the level of phosphorylated AMPK within cells, wherein said method comprises administering, to said mammal, a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

Embodiment 36. The method of embodiment 35, wherein said mammal is a human.

Embodiment 37. The method of embodiment 35, wherein said method comprises treating a mammal having an inflammation.

Embodiment 38. The method of embodiment 37, wherein the inflammation is a cytokine-driven inflammation.

Embodiment 39. The method of embodiment 35, wherein said method comprises treating a mammal having a sepsis.

Embodiment 40. The method of embodiment 35, wherein said method comprises treating a mammal having a pneumonia.

Embodiment 41. The method of embodiment 35, wherein said method comprises treating a mammal having an acute lung injury.

Embodiment 42. The method of embodiment 35, wherein said method comprises treating a mammal having a metabolic syndrome.

Embodiment 43. The method of embodiment 35, wherein said method comprises treating a mammal having a diabetic nephropathy.

Embodiment 44. The method of embodiment 35, wherein said method comprises treating a mammal having a polycystic kidney disease.

Embodiment 45. The method of embodiment 35, wherein said method comprises treating a mammal having a polycystic ovarian syndrome.

Embodiment 46. The method of embodiment 35, wherein said method comprises treating a mammal having a neurological disease.

Embodiment 47. A method for increasing a level of phosphorylated AMPK within cells of a mammal, wherein said method comprises administering, to said mammal, a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

Embodiment 48. The method of embodiment 47, wherein said mammal is a human.

Embodiment 49. A method of treating a mammal having a disease, disorder, or condition responsive to an increase in the level of phosphorylated AMPK within cells, wherein said method comprises administering, to said mammal, a compound having formula:

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiment 50. A method for increasing a level of phosphorylated AMPK within cells of a mammal, wherein said method comprises administering, to said mammal, a compound having formula:

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiment 51. A method for treating cancer in a mammal, wherein said method comprises administering, to said mammal, a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

Embodiment 52. The method of embodiment 51, said method further comprising administering, to said mammal, a checkpoint inhibitor.

Embodiment 53. The method of embodiment 51 or embodiment 52, wherein said compound is a compound set forth in Formula (A):

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiment 54. The method of any one of embodiments 51-53, wherein said compound is:

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or a pharmaceutically acceptable salt thereof.

Embodiment 55. A method for improving function of immune cells in a mammal, wherein said method comprises administering, to said mammal, a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

Embodiment 56. The method of embodiment 55, wherein said immune cells are T cells.

Embodiment 57. The method of embodiment 55 or embodiment 56, said method further comprising administering, to said mammal, a checkpoint inhibitor.

Embodiment 58. The method of any one of embodiments 55-57, wherein said compound is a compound set forth in Formula (A):

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or a pharmaceutically acceptable salt thereof.

Embodiment 59. The method of any one of embodiments 55-58, wherein said compound is:

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or a pharmaceutically acceptable salt thereof.

Embodiment 60. A method for expanding a population of immune cells, said method comprising obtaining a population of immune cells from a mammal and culturing said population of immune cells with a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

Embodiment 61. The method of embodiment 60, wherein said immune cells are T cells.

Embodiment 62. The method of embodiment 60 or embodiment 61, wherein said compound is a compound set forth in Formula (A):

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiment 63. The method of any one of embodiments 60-62, wherein said compound is:

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or a pharmaceutically acceptable salt thereof.

Embodiment 64. A method for treating an infection or reducing the risk of developing an infection in a mammal, said method comprising administering, to said mammal, a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

Embodiment 65. The method of embodiment 64, wherein said compound is a compound set forth in Formula (A):

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiment 66. The method of embodiment 64 or embodiment 65, wherein said compound is:

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or a pharmaceutically acceptable salt thereof.

OTHER EMBODIMENTS

It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

	Number	Date	Country
	63024283	May 2020	US
	62898285	Sep 2019	US

METHODS AND MATERIALS FOR INCREASING LEVEL OF PHOSPHORYLATED AMPK PROTEIN

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

Claims

CLAIM OF PRIORITY

FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

PCT Information

Provisional Applications (2)