METHODS OF TREATING DISEASE WITH MAGL INHIBITORS

BACKGROUND

Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzing endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate based lipid, in the nervous system.

BRIEF SUMMARY OF THE INVENTION

This disclosure provides, for example, methods for treating disease with compounds and pharmaceutical compositions which are modulators of MAGL. The disclosure also provides for the use of disclosed compounds as medicaments and/or in the manufacture of medicaments for the inhibition of MAGL activity in warm-blooded animals such as humans.

In some embodiments is a method for treating a disease or a condition in a patient wherein the disease or condition is selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I) having the structure:

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wherein:

R¹is —C(O)OR¹⁵or —C(O)NR¹⁰R¹¹;
R²is H, halogen, C_1-6alkyl, or C_1-6haloalkyl;
R³is

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A is N or C(H);

X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;

Y is —CH₂— or —C(O)—;

Z is —S—, —O—, or —N(R¹⁸)—;

R⁴is H, halogen, —OR⁷, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_3-8cycloalkyl, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_3-8cycloalkyl, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkoxy, or phenyl;

R⁶is H, halogen or C_1-6alkyl;

R⁷is H, C_1-6alkyl, C_1-6haloalkyl, —C_1-6alkyl-OH, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

each R⁸and each R⁹are independently selected from H and C_1-6alkyl; or R⁸and R⁹together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R¹⁰and R¹¹are each independently H or C_1-6alkyl;

R¹²is H, halogen, or C_1-6alkyl;

R¹³is H or C_1-6alkyl;

each R¹⁴is independently selected from halogen, —OH, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, —C_1-6alkyl-OH, C_3-8cycloalkyl, —C(O)OH, —C(O)NR⁸R⁹, —SO₂—C_1-6alkyl, and —N(R¹⁷)C(O)—C_1-6alkyl;

R¹⁵is H or C_1-6alkyl;

R¹⁶is H, C_1-6alkyl, —C(O)—C_1-6alkyl, —C_1-6alkyl-OH, or —CH₂CO₂H;

R¹⁷is H or C_1-6alkyl;

R¹⁸is H or C_1-6alkyl;

v is 0 or 1;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, or 2; and

q is 0, 1 or 2;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

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wherein:

R¹is —C(O)OR¹⁵or —C(O)NR¹⁰R¹¹;

R²is H, halogen, C_1-6alkyl, or C_1-6haloalkyl;

R³is

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A is N or C(H);

X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;

Y is —CH₂— or —C(O)—;

Z is —S—, —O—, or —N(R¹⁸)—;

R⁴is H, halogen, —OR⁷, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkoxy, or phenyl;

R⁶is H, halogen or C_1-6alkyl;

R⁷is H, C_1-6alkyl, C_1-6haloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

each R⁸and each R⁹are independently selected from H and C_1-6alkyl; or R⁸and R⁹together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R¹⁰and R¹¹are each independently H or C_1-6alkyl;

R¹²is H, halogen, or C_1-6alkyl;

R¹³is H or C_1-6alkyl;

each R¹⁴is independently selected from halogen, —OH, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, —C_1-6alkyl-OH, C_3-8cycloalkyl, —C(O)NR⁸R⁹, —SO₂—C_1-6alkyl, and —N(R¹⁷)C(O)—C_1-6alkyl;

R¹⁵is H or C_1-6alkyl;

R¹⁶is H, C_1-6alkyl, —C(O)—C_1-6alkyl, or —CH₂CO₂H;

R¹⁷is H or C_1-6alkyl;

R¹⁸is H or C_1-6alkyl;

v is 0 or 1;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, or 2; and

q is 0, 1 or 2;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

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In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, A is C(H). In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, A is N. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁶is H. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is halogen, —OR⁷, C_1-6alkyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is halogen, —OR⁷, C_1-6haloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is halogen. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is —Cl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is C_1-6haloalkyl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is —CF₃. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is —OR⁷. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁷is C_1-6haloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_6-10aryl or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁷is phenyl, pyridyl, pyrimidinyl, pyridizinyl, or pyrazinyl, wherein phenyl, pyridyl, pyrimidinyl, pyridizinyl, or pyrazinyl are optionally substituted with halogen or C_1-6haloalkyl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is C_2-9heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is an unsubstituted C_2-9heterocycloalkyl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is C_2-9heterocycloalkyl substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is

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In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is C_1-9heteroaryl optionally substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (F), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is an unsubstituted C_1-9heteroaryl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is C_2-9heteroaryl substituted with 1 or 2 R¹⁴. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁴is

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In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, or C_1-6haloalkoxy. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁵is H. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (F), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁵is halogen. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁵is —Cl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁵is C_1-6haloalkyl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R⁵is —CF₃. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R²is H. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R²is halogen. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R²is C_1-6alkyl. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R¹is —C(O)OR¹⁵. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R¹⁵is H. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R¹is —C(O)NR¹⁰R¹¹. In some embodiments of the methods for treating a disease or a condition with a compound of Formula (I) or (I′), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, R¹⁰and R¹¹are each H.

In some embodiments is method for treating a disease or a condition in a patient wherein the disease is selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain, comprising administering to the patient in need thereof a therapeutically effective amount of a compound having the structure:

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or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

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or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

In some embodiments, the disease or condition is atopic dermatitis. In some embodiments, the disease or condition is bladder dysfunction associated with multiple sclerosis. In some embodiments, the disease or condition is cardiovascular disease. In some embodiments, the disease or condition is contact dermatitis. In some embodiments, the disease or condition is cystic fibrosis. In some embodiments, the disease or condition is dermatomyositis. In some embodiments, the disease or condition is eczema. In some embodiments, the disease or condition is endometriosis. In some embodiments, the disease or condition is enteritis. In some embodiments, the disease or condition is fibromyalgia. In some embodiments, the disease or condition is Tourette syndrome. In some embodiments, the disease or condition is inflammatory bowel disease. In some embodiments, the disease or condition is interstitial cystitis. In some embodiments, the disease or condition is irritable bowel syndrome. In some embodiments, the disease or condition is ischemia. In some embodiments, the disease or condition is labor. In some embodiments, the disease or condition is metabolic disorders. In some embodiments, the disease or condition is musculoskeletal diseases. In some embodiments, the disease or condition is neuropathy. In some embodiments, the disease or condition is osteoarthritis. In some embodiments, the disease or condition is pancreatitis. In some embodiments, the disease or condition is pharyngitis. In some embodiments, the disease or condition is post trigeminal neuralgia. In some embodiments, the disease or condition is renal ischemia. In some embodiments, the disease or condition is rheumatoid arthritis. In some embodiments, the disease or condition is skeletal muscle contusion. In some embodiments, the disease or condition is skin diseases. In some embodiments, the disease or condition is sunburn. In some embodiments, the disease or condition is systemic lupus erythematosus. In some embodiments, the disease or condition is pain selected from acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, abdominal pain, abdominal pain associated with irritable bowel syndrome, post mastectomy pain syndrome, post operative pain, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain.

DETAILED DESCRIPTION OF THE INVENTION

This disclosure is directed, at least in part, to MAGL modulators or inhibitors. For example, provided herein are methods of treating disease with MAGL modulators or inhibitors.

As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that which in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of” or “consist essentially of” the described features.

Definitions

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C₁-C₁₃alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C₁-C₈alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C₁-C₆alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C₄alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C₁-C₃alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C₁-C₂alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C₁alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C₅-C₈alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C₅alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^a, —SR^a, —OC(O)R^a, —N(R^a)₂, —C(O)R^a, —C(O)OR^a, —C(O)N(R^a)₂, —N(R^a)C(O)OR^f, —OC(O)—NR^aR^f, —N(R^a)C(O)R^f, —N(R^a)S(O)_tR^f(where t is 1 or 2), —S(O)_tOR^a(where t is 1 or 2), —S(O)_tR^f(where t is 1 or 2) and —S(O)_tN(R^a)₂(where t is 1 or 2) where each R^ais hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R^fis independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of the formula —O— alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In certain embodiments, an alkenyl comprises two to six carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^a, —SR^a, —OC(O)R^a, —N(R^a)₂, —C(O)R^a, —C(O)OR^a, —C(O)N(R^a)₂, —N(R^a)C(O)OR^f, —OC(O)—NR^aR^f, —N(R^a)C(O)R^f, —N(R^a)S(O)_tR^f(where t is 1 or 2), —S(O)_tOR^a(where t is 1 or 2), —S(O)_tR^f(where t is 1 or 2) and —S(O)_tN(R^a)₂(where t is 1 or 2) where each R^ais hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R^fis independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In certain embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^a, —SR^a, —OC(O)R^a, —N(R^a)₂, —C(O)R^a, —C(O)OR^a, —C(O)N(R^a)₂, —N(R^a)C(O)OR^f, —OC(O)—NR^aR^f, —N(R^a)C(O)R^f, —N(R^a)S(O)_tR^f(where t is 1 or 2), —S(O)_tOR^a(where t is 1 or 2), —S(O)_tR^f(where t is 1 or 2) and —S(O)_tN(R^a)₂(where t is 1 or 2) where each R^ais hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R^fis independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C₁-C₈alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C₁-C₅alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C₁-C₄alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C₁-C₃alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C₂-C₂alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C₅-C₈alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C₂-C₅alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C₃-C₅alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^a, —SR^a, —OC(O)—R^a, —N(R^a)₂, —C(O)R^a, —C(O)OR^a, —C(O)N(R^a)₂, —N(R^a)C(O)OR^f, —OC(O)— N R^aR^f, —N(R^a)C(O)R^f, —N(R^a)S(O)_tR^f(where t is 1 or 2), —S(O)_tOR^a(where t is 1 or 2), —S(O)_tR^f(where t is 1 or 2) and —S(O)_tN(R^a)₂(where t is 1 or 2) where each R^ais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R^fis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic or multi cyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl,

heteroarylalkyl, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a) 2, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)_tOR^a(where t is 1 or 2), —R^b—S(O)_tR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenyl ene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“Aryloxy” refers to a radical bonded through an oxygen atom of the formula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —R^c-aryl where R^cis an alkyl ene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^d-aryl where R^dis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^e-aryl, where R^eis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated, (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as “cycloalkyl.” Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C₃-C₈cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C₃-C₇cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C₃-C₆cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C₃-C₅cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C₃-C₄cycloalkyl). An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl,

heteroarylalkyl, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a) 2, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)_tOR^a(where t is 1 or 2), —R^b—S(O)_tR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^c-carbocyclyl where R^cis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a) 2, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)_tOR^a(where t is 1 or 2), —R^b—S(O)_tR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. The terms “heterocyclyl”, “heterocycle”, and “heterocycloalkyl” are used interchangeably.

“Heterocyclylalkyl” refers to a radical of the formula —R^c-heterocyclyl where R^cis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^c-heterocyclyl where R^cis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5.8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1n-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a) 2, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)_tOR^a(where t is 1 or 2), —R^b—S(O)_tR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of the formula —O-heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —R^c-heteroaryl, where R^cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^c-heteroaryl, where R^cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

In some embodiments, he compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

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“Optional” or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

As used herein, “treatment” or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

Embodiments of the Invention

In the following, embodiments of the invention are disclosed. The first embodiment is denoted E1, the second embodiment E2 and so forth.

In a first embodiment E1 the present invention relates to a method of treating a disease with a compound of Formula (I).

E1: A method for treating a disease or a condition in a patient wherein the disease or condition is selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I) having the structure:

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wherein:

R¹is —C(O)OR¹⁵or —C(O)NR¹⁰R¹¹;

R²is H, halogen, C_1-6alkyl, or C_1-6haloalkyl; R³is

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A is N or C(H);

X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;

Y is —CH₂— or —C(O)—;

Z is —S—, —O—, or —N(R¹⁸)—;

R⁴is H, halogen, —OR⁷, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_3-8cycloalkyl, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_3-8cycloalkyl, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkoxy, or phenyl;

R⁶is H, halogen or C_1-6alkyl;

R⁷is H, C_1-6alkyl, C_1-6haloalkyl, —C_1-6alkyl-OH, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

each R⁸and each R⁹are independently selected from H and C_1-6alkyl; or R⁸and R⁹together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R¹⁰and R¹¹are each independently H or C_1-6alkyl;

R¹²is H, halogen, or C_1-6alkyl;

R¹³is H or C_1-6alkyl;

each R¹⁴is independently selected from halogen, —OH, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, —C_1-6alkyl-OH, C_3-8cycloalkyl, —C(O)OH, —C(O)NR⁸R⁹, —SO₂—C_1-6alkyl, and —N(R¹⁷)C(O)—C_1-6alkyl;

R¹⁵is H or C_1-6alkyl;

R¹⁶is H, C_1-6alkyl, —C(O)—C_1-6alkyl, —C_1-6alkyl-OH, or —CH₂CO₂H;

R¹⁷is H or C_1-6alkyl;

R¹⁸is H or C_1-6alkyl;

v is 0 or 1;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, or 2; and

q is 0, 1 or 2;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

E2: A method for treating a disease or a condition in a patient wherein the disease or condition is selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I′) having the structure:

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wherein:

R¹is —C(O)OR¹⁵or —C(O)NR¹⁰R¹¹;

R²is H, halogen, C_1-6alkyl, or C_1-6haloalkyl;

R³is

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A is N or C(H);

X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;

Y is —CH₂— or —C(O)—;

Z is —S—, —O—, or —N(R¹⁸)—;

R⁴is H, halogen, —OR⁷, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkoxy, or phenyl;

R⁶is H, halogen or C_1-6alkyl;

R⁷is H, C_1-6alkyl, C_1-6haloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

each R⁸and each R⁹are independently selected from H and C_1-6alkyl; or R⁸and R⁹together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R¹⁰and R¹¹are each independently H or C_1-6alkyl;

R¹²is H, halogen, or C_1-6alkyl;

R¹³is H or C_1-6alkyl;

each R¹⁴is independently selected from halogen, —OH, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, —C_1-6alkyl-OH, C_3-8cycloalkyl, —C(O)NR⁸R⁹, —SO₂—C_1-6alkyl, and —N(R¹⁷)C(O)—C_1-6alkyl;

R¹⁵is H or C_1-6alkyl;

R¹⁶is H, C_1-6alkyl, —C(O)—C_1-6alkyl, or —CH₂CO₂H;

R¹⁷is H or C_1-6alkyl;

R¹⁸is H or C_1-6alkyl;

v is 0 or 1;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, or 2; and

q is 0, 1 or 2;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

E3: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E4: The method of embodiment 3, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is C(H).

E5: The method of embodiment 3, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is N.

E6: The method of any one of embodiments 3-5, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁶is H.

E7: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E8: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E9: The method of embodiment 7 or embodiment 8, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z is —S—.

E10: The method of embodiment 7 or embodiment 8, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z is —N(H)—.

E11: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E12: The method of embodiment 11, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z is —S—.

E13: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E14: The method of any one of embodiments 11-13, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1.

E15: The method of any one of embodiments 11-13, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1.

E16: The method of any one of embodiments 11-13, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2.

E17: The method of any one of embodiments 11-13, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0.

E18: The method of any one of embodiments 11-17, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is —CH₂—.

E19: The method of any one of embodiments 11-17, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is —C(O)—.

E20: The method of any one of embodiments 1-19, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹³is H.

E21: The method of any one of embodiments 1-20, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H.

E22: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E23: The method of embodiment 22, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹³is H.

E24: The method of embodiment 22, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹³is —CH₃.

E25: The method of any one of embodiments 22-24, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H.

E26: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E27: The method of any one of embodiments 22-26, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein v is 0.

E28: The method of any one of embodiments 22-26, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein v is 1.

E29: The method of any one of embodiments 22-28, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is —O—.

E30: The method of any one of embodiments 22-28, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is —N(CH₃)—.

E31: The method of any one of embodiments 22-28, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is —CH₂N(CH₃)CH₂—.

E32: The method of embodiment 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³is

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E33: The method of any one of embodiments 13-32, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is C(H).

E34: The method of any one of embodiments 13-32, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is N.

E35: The method of any one of embodiments 11-34, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁶is H.

E36: The method of any one of embodiments 1-35, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is halogen, —OR⁷, C_1-6alkyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴.

E37: The method of any one of embodiments 1-35, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is halogen, —OR⁷, C_1-6haloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴.

E38: The method of any one of embodiments 1-37, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is halogen.

E39: The method of embodiment 38, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is —C₁.

E40: The method of any one of embodiments 1-37, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is C_1-6haloalkyl.

E41: The method of embodiment 40, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is —CF₃.

E42: The method of any one of embodiments 1-37, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is —OR⁷.

E43: The method of embodiment 42, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁷is C_1-6haloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_6-10aryl or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴.

E44: The method of embodiment 42, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁷is phenyl, pyridyl, pyrimidinyl, pyridizinyl, or pyrazinyl, wherein phenyl, pyridyl, pyrimidinyl, pyridizinyl, or pyrazinyl are optionally substituted with halogen or C_1-6haloalkyl.

E45: The method of any one of embodiments 1-37, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is C_2-9heterocycloalkyl optionally substituted with 1 or 2 R¹⁴.

E46: The method of embodiment 45, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is an unsubstituted C_2-9heterocycloalkyl.

E47: The method of embodiment 45, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is C_2-9heterocycloalkyl substituted with 1 or 2 R¹⁴.

E48: The method of embodiment 44, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is

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E49: The method of any one of embodiments 1-37, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is C_1-9heteroaryl optionally substituted with 1 or 2 R¹⁴.

E50: The method of embodiment 49, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is an unsubstituted C_1-9heteroaryl.

E51: The method of embodiment 49, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is C_2-9heteroaryl substituted with 1 or 2 R¹⁴.

E52: The method of embodiment 49, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴is

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E53: The method of any one of embodiments 1-52, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, or C_1-6haloalkoxy.

E54: The method of embodiment 53, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵is H.

E55: The method of embodiment 53, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵is halogen.

E56: The method of embodiment 55, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵is —C₁.

E57: The method of embodiment 53, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵is C_1-6haloalkyl.

E58: The method of embodiment 57, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵is —CF₃.

E59: The method of any one of embodiments 1-58, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R²is H.

E60: The method of any one of embodiments 1-58, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R²is halogen.

E61: The method of any one of embodiments 1-58, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R²is C_1-6alkyl.

E62: The method of any one of embodiments 1-61, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹is —C(O)OR¹⁵.

E63: The method of embodiment 62, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁵is H.

E64: The method of any one of embodiments 1-61, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹is —C(O)NR¹⁰R¹¹.

E65: The method of embodiment 64, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰and R¹¹are each H.

E66: The method of embodiment 1 or 2, wherein the compound of Formula (I) or Formula (I′) is selected from:

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or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

E67: The method of embodiment 1 or 2, wherein the compound of Formula (I) or Formula (I′) is selected from:

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or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

E68: The method of any one of embodiments 1-67, wherein the disease or condition is atopic dermatitis.

E69: The method of any one of embodiments 1-67, wherein the disease or condition is bladder dysfunction associated with multiple sclerosis.

E70: The method of any one of embodiments 1-67, wherein the disease or condition is cardiovascular disease.

E71: The method of any one of embodiments 1-67, wherein the disease or condition is contact dermatitis.

E72: The method of any one of embodiments 1-67, wherein the disease or condition is cystic fibrosis.

E73: The method of any one of embodiments 1-67, wherein the disease or condition is dermatomyositis.

E74: The method of any one of embodiments 1-67, wherein the disease or condition is eczema.

E75: The method of any one of embodiments 1-67, wherein the disease or condition is endometriosis.

E76: The method of any one of embodiments 1-67, wherein the disease or condition is enteritis.

E77: The method of any one of embodiments 1-67, wherein the disease or condition is fibromyalgia.

E78: The method of any one of embodiments 1-67, wherein the disease or condition is Tourette syndrome.

E79: The method of any one of embodiments 1-67, wherein the disease or condition is inflammatory bowel disease.

E80: The method of any one of embodiments 1-67, wherein the disease or condition is interstitial cystitis.

E81: The method of any one of embodiments 1-67, wherein the disease or condition is irritable bowel syndrome.

E82: The method of any one of embodiments 1-67, wherein the disease or condition is ischemia.

E83: The method of any one of embodiments 1-67, wherein the disease or condition is labor.

E84: The method of any one of embodiments 1-67, wherein the disease or condition is metabolic disorders.

E85: The method of any one of embodiments 1-67, wherein the disease or condition is musculoskeletal diseases.

E86: The method of any one of embodiments 1-67, wherein the disease or condition is neuropathy.

E87: The method of any one of embodiments 1-67, wherein the disease or condition is osteoarthritis.

E88: The method of any one of embodiments 1-67, wherein the disease or condition is pancreatitis.

E89: The method of any one of embodiments 1-67, wherein the disease or condition is pharyngitis.

E90: The method of any one of embodiments 1-67, wherein the disease or condition is post trigeminal neuralgia.

E91: The method of any one of embodiments 1-67, wherein the disease or condition is renal ischemia.

E92: The method of any one of embodiments 1-67, wherein the disease or condition is rheumatoid arthritis.

E93: The method of any one of embodiments 1-67, wherein the disease or condition is skeletal muscle contusion.

E94: The method of any one of embodiments 1-67, wherein the disease or condition is skin diseases.

E95: The method of any one of embodiments 1-67, wherein the disease or condition is sunburn.

E96: The method of any one of embodiments 1-67, wherein the disease or condition is systemic lupus erythematosus.

E97: The method of any one of embodiments 1-67, wherein the disease or condition is pain selected from acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, abdominal pain, abdominal pain associated with irritable bowel syndrome, post mastectomy pain syndrome, post operative pain, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain.

Methods

In some embodiments disclosed herein are methods of modulating the activity of MAGL. Contemplated methods, for example, comprise exposing said enzyme to a compound described herein. The ability of compounds described herein to modulate or inhibit MAGL is evaluated by procedures known in the art and/or described herein. Another aspect of this disclosure provides methods of treating a disease associated with expression or activity of MAGL in a patient.

Compounds described herein which are modulators of MAGL. In some embodiments, these compounds and pharmaceutical compositions comprising these compounds, are useful for the treatment of atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain.

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wherein:

R¹is —C(O)OR¹⁵or —C(O)NR¹⁰R¹¹;

R²is H, halogen, C_1-6alkyl, or C_1-6haloalkyl;

R³is

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A is N or C(H);

X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;

Y is —CH₂— or —C(O)—;

Z is —S—, —O—, or —N(R¹⁸)—;

R⁴is H, halogen, —OR⁷, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, —C(O)NR⁸R⁹, C_3-8cycloalkyl, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_3-8cycloalkyl, C_2-9heterocycloalkyl, —C_1-6alkyl-C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

R⁵is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkoxy, or phenyl;

R⁶is H, halogen or C_1-6alkyl;

R⁷is H, C_1-6alkyl, C_1-6haloalkyl, —C_1-6alkyl-OH, C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, or C_1-9heteroaryl are optionally substituted with 1 or 2 R¹⁴;

each R⁸and each R⁹are independently selected from H and C_1-6alkyl; or R⁸and R⁹together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R¹⁰and R¹¹are each independently H or C_1-6alkyl;

R¹²is H, halogen, or C_1-6alkyl;

R¹³is H or C_1-6alkyl;

each R¹⁴is independently selected from halogen, —OH, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, —C_1-6alkyl-OH, C_3-8cycloalkyl, —C(O)OH, —C(O)NR⁸R⁹, —SO₂—C_1-6alkyl, and —N(R¹⁷)C(O)—C_1-6alkyl;

R¹⁵is H or C_1-6alkyl;

R¹⁶is H, C_1-6alkyl, —C(O)—C_1-6alkyl, —C_1-6alkyl-OH, or —CH₂CO₂H;

R¹⁷is H or C_1-6alkyl;

R¹⁸is H or C_1-6alkyl;

v is 0 or 1;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, or 2; and

q is 0, 1 or 2;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)OR¹⁵. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)OR¹⁵and R¹⁵is H. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)OR¹⁵and R¹⁵is C_1-6alkyl. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)OR¹⁵and R¹⁵is —CH₃. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)NR¹⁰R¹¹. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)NR¹⁰R¹¹, R¹⁰is H, and R¹¹is H. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)NR¹⁰R¹¹, R¹⁰is H, and R¹¹is C_1-6alkyl. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)NR¹⁰R¹¹, R¹⁰is H, and R¹¹is —CH₃. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)NR¹⁰R¹¹, R¹⁰is C_1-6alkyl, and R¹¹is C_1-6alkyl. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R¹is —C(O)NR¹⁰R¹¹, R¹⁰is —CH₃, and R¹¹is —CH₃.

In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is H. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is halogen. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is —Cl. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is C_1-6alkyl. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is —CH₃. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is C_1-6haloalkyl. In some embodiments of the methods for treating a disease or condition with a compound of Formula (I), R²is —CF₃.