Substituted pyridine, pyridazine, pyrazine and pyrimidine compounds and methods for using the same

Disclosed are substituted pyridine compounds as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structurewherein E, J, T, the ring system denoted by “B”, T, R3, R4, w and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

BACKGROUND

This disclosure relates generally to compounds, pharmaceutical compositions and methods of use of the compounds and compositions containing them. This disclosure relates more particularly to certain substituted pyridine compounds and pharmaceutical compositions thereof, and to methods of treating and preventing metabolic disorders such as type II diabetes, atherosclerosis and cardiovascular disease using certain substituted pyridine compounds.

2. Technical Background

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

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

SUMMARY

Disclosed herein are compounds having structural formula (I)

wherein each of Y1and Y2is N, C or CH, provided that at least one of Y1and Y2is N, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

wherein Y1is N or C and Y2is N, C or CH, provided that at least one of Y1and Y2is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6;T is H, —(C1-C6alkyl), —(C1-C6alkyl)-R23in which R23is Het or Ar and in which one or more non-adjacent carbons of the alkyl is optionally replaced by —O— or —S—, —(C0-C6alkyl)-L-R7, —(C0-C6alkyl)-NR8R9, —(C0-C6alkyl)-OR10, —(C0-C6alkyl)-C(O)R10, —(C0-C6alkyl)-S(O)0-2R10or

Also disclosed herein are pharmaceutical compositions. Examples of such compositions include those having at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound, pharmaceutically acceptable salt, prodrug or N-oxide (or solvate or hydrate) disclosed herein.

Another aspect of the present disclosure includes methods for modulating metabolism in subjects. Accordingly, also disclosed are methods for treating metabolic disorders using the presently disclosed compounds and pharmaceutical compositions.

Another aspect of the present disclosure includes methods for modulating sphingolipid metabolism, for example modulating ceramide signalling in subjects. In one aspect, modulating sphingolipid metabolism includes modulating ceramidase activity, for example by up-regulating ceramidase function. Accordingly, also disclosed are methods for treating ceramide-linked diseases and disorders using the presently disclosed compounds and pharmaceutical compositions.

DETAILED DESCRIPTION

One aspect of the disclosure provides compounds having structural formula (I):

wherein each of Y1and Y2is N, C or CH, provided that at least one of Y1and Y2is N;p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

wherein Y1is N or C and Y2is N, C or CH, provided that at least one of Y1and Y2is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6;T is H, —(C1-C6alkyl), —(C1-C6alkyl)-R23in which R23is Het or Ar and in which one or more non-adjacent carbons of the alkyl is optionally replaced by —O— or —S—, —(C0-C6alkyl)-L-R7, —(C0-C6alkyl)-NR8R9, —(C0-C6alkyl)-OR10, —(C0-C6alkyl)-C(O)R10, —(C0-C6alkyl)-S(O)0-2R10or

In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the compound has structural formula (II):

wherein each of Y1and Y2is N, C or CH, provided that at least one of Y1and Y2is N;p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 2, 3, 4, 5 or 6;T is H, —(C1-C6alkyl), —(C1-C6alkyl)-R23in which R23is Het or Ar and in which one or more non-adjacent carbons of the alkyl is optionally replaced by —O— or —S—, —(C0-C6alkyl)-L-R7, —(C0-C6alkyl)-NR8R9, —(C0-C6alkyl)-OR10, —(C0-C6alkyl)-C(O)R10, —(C0-C6alkyl)-S(O)0-2R10or

In certain embodiments of the presently disclosed compounds of structural formula (I), the compound is not5-(4-(4-cyanobenzyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide;N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide;N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbon yl)picolinamide(S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)pyrrolidin-3-yl)picolinamide;(S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)picolinamide;(S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)pyrrolidin-3-yl)picolinamide;N-(1-(4-chlorobenzyl)pyrrolidin-3-yl)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)picolinamide; or5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)picolinamide.

In one embodiment, the presently disclosed compounds are not compounds disclosed in Darwish et al., International Patent Application no. PCT/US10/22411, filed Jan. 28, 2010, which is hereby incorporated by reference in its entirety.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, D1, D2and D3are independently CH or C substituted by one of the w R3. In other embodiments, D1is N and D2and D3are independently CH or C substituted by one of the w R3. In other embodiments, D2is N and D1and D3are independently CH or C substituted by one of the w R3. In other embodiments, D3is N and D1and D2are independently CH or C substituted by one of the w R3.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, J is —C(O)—, —NR13—, —NR13C(O)— or —C(O)NR13—, in which R13is selected from —H, —(C1-C4alkyl), —C(O)—(C1-C4alkyl) and —C(O)O—(C1-C4alkyl). In certain embodiments of the compounds of structural formula (I) and (II) as described above, R13is H. In other embodiments, R13is unsubstituted (C1-C4alkyl). In certain embodiments of the compounds of structural formula (I) and (II) as described above, J is —C(O)—. In other embodiments, J is —NR13— (for example, —NH—). In still other embodiments, J is —NR13C(O)— (for example, —NHC(O)—). In other embodiments, J is —C(O)NR13— (for example, —C(O)NH—). In still other embodiments, J is absent.

In the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system denoted by “B” is absent, arylene, heteroarylene,

in which each of Y1and Y2is N, C or CH, provided that at least one of Y1and Y2is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6,

wherein Y1is N or C and Y2is N, C or CH, provided that at least one of Y1and Y2is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6.

For example, in certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, (for example, those described below with respect to structural formula (IV)), the ring system denoted by “B” is arylene or heteroarylene. In certain embodiments, the ring system denoted by “B” is arylene (for example, phenylene such as 1,4-phenylene). In other embodiments, the ring system denoted by “B” is heteroarylene (for example, 1H-pyrazolylene, 1H-1,2,3-triazolylene, pyridylene, furanylene or thienylene). In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the ring system denoted by “B” is monocyclic arylene or heteroarylene.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system denoted by “B” is absent.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system denoted by “B” is

wherein each of Y1and Y2is N, C or CH, provided that at least one of Y1and Y2is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 2, 3, 4, 5 or 6. For example, in certain embodiments, Y1is N and Y2is C or CH. (When Y1or Y2is C, it is substituted by one of the x R4.) In other embodiments, Y1is C or CH and Y2is N. In other embodiments, Y1is CF and Y2is N. In other embodiments, Y1and Y2are each N. In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 1 and q is 2. For example, in one embodiment, the ring system denoted by “B” is a piperidine linked to the T moiety through its nitrogen atom. In another embodiment, the ring system denoted by “B” is a piperidine linked to the J moiety through its piperidine nitrogen. In another embodiment, the ring system denoted by “B” is a piperazine. In other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 1 and q is 1. For example, in certain embodiments, the ring system denoted by “B” is a pyrrolidine, for example, linked to the J moiety through its pyrrolidine nitrogen. In still other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 0 and q is 1. For example, in certain embodiments, the ring system denoted by “B” is an azetidine, for example, linked to the J moiety through its azetidine nitrogen.

In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the ring system denoted by “B” is

wherein Y1is N or C and Y2is N, C or CH, provided that at least one of Y1and Y2is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6. For example, in certain embodiments, Y1is N and Y2is C or CH. (When Y2is C, it can be substituted by one of the x R4.) In other embodiments, Y1is C and Y2is N. In other embodiments, Y1and Y2are each N. In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 1 and q is 2. In other embodiments of the presently disclosed compounds of structural formula (I) as described above, p is 1 and q is 1. The heteroarylene can be, for example, a pyridine, a pyrazine, a pyrimidine, a triazine, a pyrrole, a pyrazole, an imidazole, or a triazole. In one example, the ring system denoted by “B” is

In the presently disclosed compounds of structural formula (I) and (II) as described above, x, the number of substituents on the ring system denoted by “B”, is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, in certain embodiments, x is 0. In other embodiments, x can be 1 or 2.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system denoted by “B” is

two R4groups combine to form an oxo. The oxo can be bound, for example, at the position alpha to a nitrogen atom of the ring system. In other embodiments, no two R4groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system denoted by “B” is

two R4groups on different carbons combine to form a —(C0-C4alkylene)-bridge. The alkylene bridge can form bicyclic system, for example, a [3.2.1] system, a [3.2.0] system, a [3.1.0] system, [2.2.2] system, a [2.2.1] system, a [2.1.1] system, a [2.2.0] system or a [2.1.0] system. For example, in one embodiment, ring system denoted by “B” is substituted with R4groups to form

In certain embodiments the —(C0-C4alkylene)-bridge is unsubstituted. In other embodiments, it is substituted only with one or more halogens.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system denoted by “B” is

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, when x is 4, not all four R4groups are (C1-C6alkyl).

In the presently disclosed compounds of structural formula (I) and (II) as described above, E is —R2, —C(O)NR1R2, —NR1R2or —NR1R2, in which R1and R2together with the nitrogen to which they are bound form Hca, or R1is H, —(C1-C4alkyl), —C(O)—(C1-C4alkyl) or —C(O)O—(C1-C4alkyl); and R2is —C(O)Hca, —(C0-C3alkyl)-Ar, —(C0-C3alkyl)-Het, —(C0-C3alkyl)-Cak or —(C0-C3alkyl)-Hca. In certain embodiments, E is —C(O)NR1R2. In other embodiments, E is —NR1R2. In other embodiments, E is —R2. In still other embodiments, E is —NR1C(O)R2.

In certain embodiments of the compounds of structural formula (I) and (II) as described above, R1is H, —(C1-C4alkyl), —C(O)—(C1-C4alkyl) or —C(O)O—(C1-C4alkyl); and R2is —C(O)Hca, —(C0-C3alkyl)-Ar, —(C0-C3alkyl)-Het, —(C0-C3alkyl)-Cak or —(C0-C3alkyl)-Hca. In certain of the compounds of structural formula (I) as described above, R1is H. In other embodiments, R1is (C1-C4alkyl), for example methyl, ethyl, n-propyl or isopropyl. In still other embodiments, R1is —C(O)—O—(C1-C4alkyl), for example —C(O)OCH3or —C(O)—O-t-butyl. In certain embodiments, no alkyl of R1is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, any alkyl of R1is unsubstituted.

In certain particular embodiments, when R2is -(optionally substituted piperidin-4-yl), it is unsubstituted at its 2- and 3-positions.

In other embodiments, when R2is -(optionally substituted piperidin-4-yl), it is substituted with F at a 3-position. For example, R2can be

in which the R group is a further substituent, for example, as described below. Such compounds can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanyl R2moieties described above are substituted, for example, at their 1-positions. In certain alternative embodiments, they can be substituted at their 4-positions (e.g., when a piperidin-1-yl) or 3 positions (e.g., when a pyrrolidin-5-yl). For example, in one embodiment, R2is substituted (e.g., at its 1-position) with —(C0-C3alkyl)-Ar or —(C0-C3alkyl)-Het, for example -(unsubstituted C0-C3alkyl)-Ar or -(unsubstituted C0-C3alkyl)-Het. For example, in one particular embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with a benzyl substituted with an electron withdrawing group; or a phenyl substituted with an electron withdrawing group. For example, the benzyl or phenyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C1-C4fluoroalkyl), —O—(C1-C4fluoroalkyl), —C(O)—(C0-C4alkyl), —C(O)O—(C0-C4alkyl), —C(O)N(C0-C4alkyl)(C0-C4alkyl), —S(O)2O—(C0-C4alkyl), SF5, NO2and —C(O)-Hca in which the Hca includes a nitrogen atom to which the —C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with an unsubstituted benzyl or an unsubstituted phenyl. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with —CH(CH3)Ar, CH(C(O)OCH3)Ar or —C(CH3)2Ar.

In other embodiments of the compounds disclosed herein of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with an optionally substituted pyridinylmethyl, an optionally substituted furanylmethyl, an optionally substituted thienylmethyl, an optionally substituted oxazolylmethyl, or an optionally substituted imidazolylmethyl. For example, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety can be substituted with an unsubstituted pyridinylmethyl, an unsubstituted furanylmethyl, an unsubstituted thienylmethyl, an unsubstituted oxazolylmethyl, or an unsubstituted imidazolylmethyl. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2moiety can be substituted with an pyridinylmethyl, furanylmethyl, thienylmethyl, oxazolylmethyl or imidazolylmethyl substituted with an electron withdrawing group as described above.

In certain embodiments of the compounds disclosed herein of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with -L-Ar or -L-Het, in which Ar and Het can be, for example, as described above with reference to —(C0-C3alkyl)-Ar or —(C0-C3alkyl)-Het. In one such embodiment, L is —C(O)—NR9—, such as —C(O)—NH—. In other embodiments of the presently disclosed compounds of structural formula (I) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with —C(O)—O(C0-C6alkyl), —C(O)-Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2-0(C0-C6alkyl), in which Ar and Het can be, for example, as described above with reference to —(C0-C3alkyl)-Ar or —(C0-C3alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with —C(O)-Het or —C(O)—Ar; in another embodiment, it is substituted (e.g., at its 1-position) with —S(O)2-Het or —S(O)2—Ar. For example, in certain embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with an optionally-substituted benzoyl (for example, substituted with an electron withdrawing group as described above); or with an optionally-substituted nicotinyl, isonicotinyl or picolinyl (for example, optionally substituted with an electron withdrawing group as described above). In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with an unsubstituted benzoyl; or an unsubstituted nicotinoyl, isonicotinoyl or picolinoyl.

In other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R2moiety is substituted (e.g., at its 1-position) with —(C0-C3alkyl)-Cak, for example -(unsubstituted C0-C3alkyl)-Cak (e.g, —CH2-Cak) or —C(O)-Cak.

In one embodiment, R2is not an oxo-substituted heterocycloalkyl. In another embodiment, R2is not a tetramethyl-substituted heterocycloalkyl.

In certain embodiments of the compounds of structural formula (I) and (II) as described above (for example, those in which E is —C(O)NR1R2), R1and R2together with the nitrogen to which they are bound form Hca. In such embodiments, Hca can be, for example, an optionally-substituted piperidinyl, an optionally-substituted pyrrolidinyl, or an optionally-substituted piperazinyl. When R1and R2together to form Hca, it can be defined and substituted as described above for R2wherein it is Hca.

In certain embodiments of the compounds of structural formula (I) and (II) as described above (for example, those in which E is —R2, or —NR1R2), R2is —C(O)Hca. In certain such embodiments, the Hca is linked to the —C(O)— through a nitrogen. In other such embodiments, the Hca can be linked to the —C(O)— through a carbon atom. The Hca can be defined and substituted, for example, as described above with respect to R2when it is Hca.

In certain embodiments of the compounds of structural formula (I) as described above (for example, those in which E is —R2, —NR1R2or —C(O)NR1R2), R2is —(C0-C3alkyl)-Ar or —(C0-C3alkyl)-Het. For example, in certain embodiments, R2is Ar, in which the Ar can be, for example, monocyclic, such as optionally-substituted phenyl. In other embodiments, R2is —(C1-C3alkyl)-(optionally-substituted phenyl), for example optionally-substituted benzyl. In other embodiments, R2is Het, in which the Het can be, for example, monocyclic, such as optionally-substituted pyridinyl or optionally-substituted 1H-pyrazolyl. In other embodiments of the compounds of structural formula (I) as described above (for example, those in which E is —C(O)NR1R2), R2is —(C0-C3alkyl)-Cak, in which the Cak can be, for example, monocyclic, such as optionally-substituted cyclohexyl. The aryl, heteroaryl or cycloalkyl of R2can be substituted, for example, as described above with reference to R2when it is Hca. For example, in certain embodiments, the aryl, heteroaryl or cycloalkyl of R2is substituted with —(C0-C3alkyl)-Ar or —(C0-C3alkyl)-Het, substituted as described above. In other embodiments, the aryl, heteroaryl or cycloalkyl of R2is substituted with —O—(C0-C3alkyl)-Ar or —O—(C0-C3alkyl)-Het. In other embodiments, the aryl, heteroaryl or cycloalkyl of R2is substituted with an optionally-substituted heterocycloalkyl, such as a mopholin-1-yl, a 4-methylpiperazin-1-yl, or a pyrrolidin-1-yl. The ring system of the R2moiety can be substituted at any position. For example, in certain embodiments, the ring of a monocyclic R2moiety is substituted at the 4-position, as counted from the attachment to the central pyridine, pyrazine, pyridazine or pyrimidine, or the nitrogen or carbonyl of the E moiety. In other embodiments, the ring of a monocyclic R2moiety is substituted at the 3-position, as counted from the attachment to the central pyridine, pyrazine, pyridazine or pyrimidine, or the nitrogen or carbonyl of the E moiety.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (III)

in which E is —R2, —C(O)NR1R2, —NR1R2or —NR1C(O)R2, in which R1and R2together with the nitrogen to which they are bound form Hca, or R1is H, —(C1-C4alkyl), —C(O)—(C1-C4alkyl) or —C(O)O—(C1-C4alkyl); and R2is —C(O)Hca, —(C0-C3alkyl)-Ar, —(C0-C3alkyl)-Het, —(C0-C3alkyl)-Cak or —(C0-C3alkyl)-Hca. All other variables are as described above with reference to structural formulae (I) and (II). In certain such embodiments, E is R2, —NR1R2or —NR1C(O)R2. In certain embodiments of the compounds of structural formula (III), J is —C(O)—.

In certain embodiments of compounds of structural formulae (I)-(III) as described above, (for example, those in which E is —C(O)NR1R2), when R2is Hca (for example, pyrrolidine or piperidine), it is substituted with at least one fluorine, and further optionally substituted, for example, as described below. In certain embodiments of compounds of structural formula (III) (for example, those in which E is —C(O)NR1R2), when R2is Hca (for example, pyrollidine or piperazine), it is substituted (for example, at the nitrogen) with —C(O)—R22, —S(O)2—R22, —C(O)-Cak, —CH2-Cak, —CH(CH3)—R22, —C(CH3)2—R22, —CH(C(O)-O(C1-C4alkyl))Het, in which R22is Ar or Het, and further optionally substituted, for example, as described below.

In certain embodiments of the compounds of structural formulae (I)-(III) as described above, (for example, those in which E is —C(O)NR1R2), R1and R2together with the nitrogen to which they are bound form Hca, as described below. For example, R1and R2can together to form an optionally substituted piperazine or an optionally-substituted pyrrolidine, as described below. In other embodiments, R1and R2together with the nitrogen to which they are bound form an optionally-substituted spirocyclic heterocycloalkyl (for example, 2,8-diazaspiro[4.5]decanyl), as described below.

In certain embodiments of the compounds of structural formulae (I)-(III) as described above, (for example, those in which E is —C(O)NR1Hca), T is H, —C(O)—(C1-C6alkyl) or (C1-C6alkyl), for example, as described below. In other embodiments of the compounds of structural formula (III) (for example, those in which E is —C(O)NR1Hca), T is —C(CH3)2Ar, —CH2-Het, -Het, —CH2-Cak or Hca, for example, as described below. In other embodiments of the compounds of structural formula (III) (for example, those in which E is —C(O)NR1Hca), T is

in which Q is —C(O)— or —S(O)2—, for example, as described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (IV)

in which J is absent, —NR13—, —NR13C(O)— or —C(O)NR13—; and the ring system denoted by “B” is arylene, heteroarylene, or absent, and all other variables are as described with respect to structural formulae (I)-(III). For example, in certain embodiments of the compounds of structural formula (IV) as described above, J is absent. In other embodiments, J is —NR13—, such as —NH—. In other embodiments, J is —NR13C(O)—, such as —NHC(O)—. In certain embodiments, the ring system denoted by “B” is arylene, such as phenylene); or heteroarylene, such as 1H-pyrazolylene, 1H-1,2,3-triazolylene), with particular examples being described below. In other embodiments, the ring system denoted by “B” is absent, with particular examples being described below. In certain embodiments of the compounds of structural formula (IV), (for example, those in which E is —C(O)NR1R2), R2is Hca, such as piperidinyl, with particular examples being described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (V)

in which the variables are as described above with reference to structural formulae (I)-(III). In certain embodiments of the compounds of structural formula (V), R2is Hca (for example, pyrrolidine or piperidine), for example, described below. In other embodiments of the compounds of structural formula (IV), R2is Cak, such as cyclohexyl, for example, described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VI)

in which Y is N, C, CF or CH, and all other variables are as described above with reference to structural formulae (I)-(III). For example, in certain embodiments, Y is N. In other embodiments, Y is CF or CH. In certain embodiments of the compounds of structural formula (VI), p is 1 and q is 2. In other embodiments (for example, when Y is C, CF or CH), q is 1 and p is 1. In certain embodiments of the compounds of structural formula (VI), R2is Hca, such as pyrrolidine or piperidine.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VII)

in which J is absent, —NR13—, —NR13C(O)— or —C(O)NR13—, and all other variables are as described above with reference to structural formulae (I) (III). For example, in one embodiment, J is —NR13—C(O)—. In other embodiments, J is —NR13—. In certain embodiments of the compounds of structural formula (VII), p is 1 and q is 2. In other embodiments, q is 1 and p is 1. In other embodiments (for example, when Y is C, CF or CH), q is 1 and p is 0. In certain embodiments of the compounds of structural formula (VII), R2is Hca, such as pyrrolidine or piperidine, particular examples of which are further described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VIII)

in which the variables are as described above with reference to structural formulae (I)-(III). In certain embodiments of the compounds of structural formula (VIII), p is 1 and q is 2. In other embodiments, q is 1 and p is 1. In other embodiments (for example, when Y is C, CF or CH), q is 1 and p is 0. In certain embodiments of the compounds of structural formula (VIII), R2is Hca.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, T is

In such embodiments, Q is —O—(C0-C3alkyl)-, —S(O)2—, L or —(C0-C3alkyl)- in which each carbon of the (C0-C3alkyl) is optionally and independently substituted with one or two R16, in which each R16is independently selected from —(C1-C6alkyl), —(C1-C6haloalkyl), —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, —(C0-C6alkyl)-Hca, —(C0-C6alkyl)-L-R7, —(C0-C6alkyl)-NR8R9, —(C0-C6alkyl)-OR10, —(C0-C6alkyl)-C(O)R10, —(C0-C6alkyl)-S(O)0-2R10, -halogen, —NO2and —CN, and optionally two of R16on the same carbon combine to form oxo. In certain embodiments, each R16is independently selected from —(C1-C6alkyl), —(C1-C6haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C0-C6alkyl)-L-R7, —(C0-C6alkyl)-NR8R9, —(C0-C6alkyl)-OR10, —(C0-C6alkyl)-C(O)R10, —(C0-C6alkyl)-S(O)0-2R10, -halogen, —NO2and —CN, and two R16on the same carbon optionally combine to form an oxo, in which each R7, R8and R10is independently selected from H, —(C1-C6alkyl), —(C1-C6haloalkyl), —(C0-C6alkyl)-L-(C0-C6alkyl), —(C0-C6alkyl)-NR9(C0-C6alkyl), —(C0-C6alkyl)-O—(C0-C6alkyl), —(C0-C6alkyl)-C(O)—(C0-C6alkyl), and —(C0-C6alkyl)-S(O)0-2—(C0-C6alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in particular compounds, each R16is —(C1-C3alkyl), —(C1-C3haloalkyl), —(C0-C3alkyl)-L-R7, —(C0-C3alkyl)-NR8R9, —(C0-C3alkyl)-OR10, —(C0-C3alkyl)-C(O)R10, —(C0-C3alkyl)-S(O)0-2R10, -halogen, —NO2and —CN, and two R16on the same carbon optionally combine to form an oxo, in which each R7, R8and R10is independently selected from H, —(C1-C2alkyl), —(C1-C2haloalkyl), —(C0-C2alkyl)-L-(C0-C2alkyl), —(C0-C2alkyl)-NR9(C0-C2alkyl), —(C0-C2alkyl)-O—(C0-C2alkyl), —(C0-C2alkyl)-C(O)—(C0-C2alkyl) and —(C0-C2alkyl)-S(O)0-2—(C0-C2alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, each R16is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH2, —OH, methoxy, ethoxy, trifluoromethoxy, —SO2Me, -halogen, —NO2, N3, —SF5, or —CN, and two R16optionally come together to form oxo. In certain embodiments, Q has at most one R16or an oxo substituted thereon. Q can be, for example, an unsubstituted —(C0-C3alkyl)- (for example, a single bond, —CH2— or —CH2—CH2—). In other embodiments, Q is a (C1-C3alkyl) having as its only substitution a single oxo group. For example, in certain embodiments of the compounds of structural formulae (I)-(VII) as described above, Q is —CH2—; —CH2CH2—; —OCH2CH2—; O; a single bond; —S(O)2—; —C(O)—; —CHF—; —CH(OH)—, —C(CH3)2—, or —CH(CH3)—.

In certain embodiments of the compounds of structural formulae (I)-(VIII) as described above, T is

in which Q is —C(O)— or —S(O)2—. In other embodiments, T is

in which Q is —C(CH3)2—, —CH2CH2—, —CH(CH3)—, —CH(OH)— or —CHF—.

In certain embodiments of the compounds of structural formulae (I)-(VIII) as described above (for example, those in which T is not bound to a nitrogen), T is

in which Q is O.

In certain embodiments of the compounds of structural formulae (I)-(VIII) as described above (for example, those in which the ring system denoted by “B” is absent), T is

in which Q is —O—(C1-C3alkyl)-, for example, —OCH2— or —OCH2CH2—.

The number of substituents, y, on the ring system denoted by “A”, is 0, 1, 2, 3 or 4. For example, in some embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zero and at least one R5is halo, cyano, —(C1-C4haloalkyl), —O—(C1-C4haloalkyl), —(C1-C4alkyl), —O—(C1-C4alkyl), —C(O)—(C0-C4alkyl), —C(O)O—(C0-C4alkyl), —C(O)N(C0-C4alkyl)(C0-C4alkyl), —N3, —SF5, NO2or —C(O)-Hca wherein the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, and wherein no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

In one embodiment of the compounds of structural formulae (I)-(VIII) as described above, y is 0. In another embodiment, y is 1. In another embodiment, y is 2.

In the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, the ring system denoted by “A” is an aryl or a heteroaryl. The ring system denoted by “A” can be, for example, a monocyclic aryl or heteroaryl. In one embodiment, when the “A” ring system is aryl, Q is a —(C0-C3alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3alkyl)-. In certain embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —CH2—; —CH2CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —CF—, —CH(OH)— or —C(CH3)2—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —O—, —OCH2— or —OCH2CH2—.

For example, in certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the ring system denoted by “A” is monocyclic aryl, such as phenyl. In one embodiment, y is 1 and R5is attached to the phenyl in the para position relative to Q. In one embodiment, y is 1 and R5is attached to the phenyl in the meta position relative to Q. In certain embodiments, y is 1 and R5is selected from the group consisting of halo, cyano, —(C1-C4haloalkyl), —O—(C1-C4haloalkyl), —(C1-C4alkyl), —O—(C1-C4alkyl), —C(O)—(C0-C4alkyl), —C(O)O—(C0-C4alkyl), —C(O)N(C0-C4alkyl)(C0-C4alkyl), NO2and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, and in which no (C0-C4alkyl) or (C1-C4alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R5can be, for example, —Cl, —F, cyano, —N3, SF5, —C(O)CH3, —C(O)OH, —C(O)NH2, methoxy, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. In another embodiment, the

moiety is a 3,4-dihalophenyl, a 3,5-dihalophenyl, a 3-cyano-5-methoxyphenyl, a 4-cyano-3-halophenyl, or a 3-halo-4-methoxyphenyl.

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the ring system denoted by “A” is a heteroaryl. For example, in certain embodiments, the ring system denoted by “A” is a pyridyl, a thienyl, or a furanyl. In another embodiment, the ring system denoted by “A” is an isoxazolyl. In one embodiment, when the “A” ring system is heteroaryl, Q is a —(C0-C3alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3alkyl)-. In certain embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —O—, —CF—, —CH(OH)— or —C(CH3)2—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —O—, —OCH2— or —OCH2CH2—.

In another embodiment of the presently disclosed compounds of formulae (I)-(VIII) as described above, the ring system denoted by “A” is a heterocycloalkyl. For example, in certain embodiments, the ring system denoted by “A” is a tetrahydro-2H-pyranyl or a morpholino. In one such embodiment, when the “A” ring system is a heterocycloalkyl, Q is a single bond. In another such embodiment, Q is —CH2— or —C(O)—. In another such embodiment, Q is —O—, —OCH2— or —OCH2CH2—.

In another embodiment of the presently disclosed compounds of formulae (I)-(VIII) as described above, the ring system denoted by “A” is a cycloalkyl. For example, in certain embodiments, the ring system denoted by “A” is a cyclohexyl. In one such embodiment, when the “A” ring system is a cycloalkyl, Q is —CH2— or —C(O)—. In another such embodiment, Q is a single bond. In another such embodiment, Q is —O—, —OCH2— or —OCH2CH2—.

In certain embodiments of the compounds of formulae (I)-(VIII) as described above, T is H, —(C1-C6alkyl) or —C(O)(C1-C6alkyl). In certain such embodiments, the alkyl moieties of T are unsubstituted. In other such embodiments, the alkyl moieties of T are optionally substituted as described below. For example, in certain embodiments, T is H, ispropropyl, or —C(O)-t-butyl.

In certain embodiments of the compounds of formulae (I)-(VIII) as described above, T is —C(CH3)2Ar, —CH2-Het, -Het, —CH2-Cak or -Hca. The —Ar, -Het, -Cak and -Hca moieties can, for example, be substituted with y R5moieties, as described above with reference to the ring system denoted by “A”.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the T moiety is selected from the group consisting of

monocyclic heterocycloalkyl (for example, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl) substituted with 0, 1 or 2 R30, monocyclic heteroaryl (for example, pyridyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl) substituted with 0, 1 or 2 R30; monocyclic heteroarylmethyl- (for example, pyridylmethyl, isoxazolylmethyl, oxazolylmethyl, pyrrolylmethyl, thienylmethyl), in which the heteroaryl is substituted with 0, 1 or 2 R30; or monocyclic heteroaryloxy- (for example, pyridyloxy, isoxazolyloxy, oxazolyloxy, pyrrolyloxy, thienyloxy), in which the heteroaryl is substituted with 0, 1 or 2 R30; in which each R30is independently selected from halogen (e.g., F, Cl), unsubstituted (C1-C6alkoxy) (e.g., methoxy, ethoxy), —(C1-C6haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C1-C6alkyl), —S(C1-C6haloalkyl), —OH, —CN, —NO2, —NH2, —NH(unsubstituted C1-C4alkyl), —N(unsubstituted C1-C4alkyl)2, —N3, —SF5, —C(O)—NH2, C(O)NH(unsubstituted C1-C4alkyl), C(O)N(unsubstituted C1-C4alkyl)2, —C(O)OH, C(O)O(unsubstituted C1-C6alkyl), —(NH)0-1SO2R33, —(NH)0-1COR33, heterocycloalkyl optionally substituted with an (unsubstituted C1-C6alkyl) and heteroaryl optionally substituted with an (unsubstituted C1-C6alkyl), in which each R33is (unsubstituted C1-C6alkyl), (C1-C6haloalkyl(unsubstituted C3-C8cycloalkyl) or (C3-C8heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6alkyl). In certain embodiments, no R30is substituted on the ring of the T moiety. In other embodiments, one R30is substituted on the ring of the T moiety, for example, at a para-position of a phenyl, a meta-position of a phenyl, or at a 3- or 4- position of a heteroaryl or heterocycloalkyl (as counted from the attachment point of the ring system denoted by “B”). Certain particular identities of the T moiety will be found by the person of skill in the art in the compounds described below with respect to Table 1. Those of skill in the art will understand that combinations of such T moieties with other subcombinations of features disclosed herein is specifically contemplated.

For example, in certain embodiments of the compounds of formulae (I)-(VIII) as described above, the T moiety is selected from

In one embodiment of the presently disclosed compounds of structural formulae (I)-(VII) as described above, the compound has structural formula (IX):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII).

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (X):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII). For example, in certain embodiments, R2can be

in which the R group is a further substituent, for example, as described herein.

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (XI):

in which one of X1, X2, X3and X4are N, and the others are carbons (for example, independently CH or C substituted with one of the w R3groups), and all other variables are defined as described above with reference to any of structural formulae (I)-(VIII). For example, in one embodiment, X1is N and X2, X3and X4are carbons. In another embodiment, X2is N and X1, X3and X4are carbons. In another embodiment, X3is N and X1, X2and X4are carbons. In another embodiment, X4is N and X1, X2and X3are carbons.

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (XII):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII).

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (XIII):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII).

In the compounds of any of structural formulae (I)-(XIII) as described above, w, the number of substituents on the central pyridine, pyridazine, pyrazine or pyrimidine, is 0, 1, 2 or 3. For example, in one embodiment, w is 0, 1 or 2. In another embodiment, w is 0. In other embodiments, w is at least 1, and at least one R3is selected from the group consisting of halo, cyano, —(C1-C4fluoroalkyl), —O—(C1-C4fluoroalkyl), —C(O)—(C0-C4alkyl), —C(O)O—(C0-C4alkyl), —C(O)N(C0-C4alkyl)(C0-C4alkyl), —S(O)2O—(C0-C4alkyl), NO2and —C(O)-Hca in which the Hca includes a nitrogen atom to which the —C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. For example, in certain embodiments, at least one R3is halo (for example, chloro) or —(C1-C4alkyl) (for example, methyl, ethyl or propyl). In certain embodiments, an R3is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position relative to the J moiety.

In certain embodiments of the compounds of any of structural formulae (I)-(XIII) as described above, w is at least one, and at least one R3is —NR8R9. For example, in one embodiment, w is 1. In certain such embodiments, an R3is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position relative to the J moiety.

In other embodiments of the compounds of any of structural formulae (I)-(XIII) as described above, w is at least one, and at least one R3is —(C0-C3alkyl)-Y1—(C1-C3alkyl)-Y2—(C0-C3alkyl), in which each of Y1and Y2is independently L, —O—, —S— or —NR9—. For example, in one embodiment, w is 1. In certain such embodiments, R3is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position relative to the J moiety. In one particular embodiment, R3is —CH2—N(CH3)—CH2—C(O)—OCH3.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(XIII) as described above, the compound has the structural formula (XIV):

in which E1is absent, —C(O)—, —C(O)NR1— or —NR1C(O)—; z is 0 or 1; Y3is N, C or CH and Y4is N, C or CH; Q and G are each independently a single bond, —CH2—, —C(H)(R16)—, —C(R16)2—, —CH2CH2—, L (for example, —C(O)—NR9— or —NR9—C(O)—), -L-C(R16)2—, —O—(C0-C3alkyl)- in which the (C0-C3alkyl) is bound to the R17moiety or the ring system denoted by “A”, or —S(O)2—; v is 0, 1, 2, 3 or 4; each R15is independently selected from —(C1-C6alkyl), —(C1-C6haloalkyl), —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, —(C0-C6alkyl)-Hca, —(C0-C6alkyl)-L-R7, —(C0-C6alkyl)-NR8R9, —(C0-C6alkyl)-OR10, —(C0-C6alkyl)-C(O)R10, —(C0-C6alkyl)-S(O)0-2R10, -halogen, —NO2and —CN, and two R15on the same carbon optionally combine to form oxo; and R17is Het or Ar, and all other variables are defined as described above with reference to any of structural formula (I)-(XIII).

In certain embodiments of the presently disclosed compounds of structural formula (XIV) as described above (for example, those in which E1is —C(O)— or absent, Y3is N and Y4is N. In other embodiments, (for example, those in which E1is —C(O)—NR1—), Y3is C or CH and Y4is N. In other embodiments, Y3is N and Y4is C or CH. In other embodiments, Y3is C or CH and Y4is C or CH; in such embodiments, the E1and G moieties can be disposed, for example, cis to one another on the cycloalkyl ring. In certain embodiments of the presently disclosed compounds of structural formula (XIV) as described above, z is 1. In other embodiments, z is 0.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(XIV) as described above, D1, D2and D3are all CH or C substituted by one of the w R3, and the R2moiety is an optionally-substituted piperidine. For example, in one embodiment, a compound has structural formula (XV):

in which all variables are and all as described above with respect to any of structural formulae (I)-(XIV). In one such embodiment, v is 0.

In other embodiments of compounds according to structural formula (XV), one of the R15is F. For example, the F can be substituted at the carbon alpha to the E1moiety. Accordingly, in certain embodiments, a compound has structural formula (XVI):

in which v is 0, 1, 2 or 3 and all other variables are as described above with respect to any of structural formulae (I)-(XIV). In certain such embodiments, v is 0. In one embodiment, the E1moiety and the F are disposed in a cis relationship to one another. In other embodiment, the E1moeity and the F are disposed in a trans relationship to one another. For example, the compound of structural formula (XVI) can be provided as any of the four diastereomers of structural formulae (XVII)-(XX):

in which v is 0, 1, 2 or 3 (e.g., 0), and all other variables are and all as described above with respect to any of structural formulae (I)-(XVI). Compounds can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form, for example, as one of the compounds of structural formulae (XVII)-(XX).

In certain embodiments of the compounds of structural formulae (XV)-(XX), the compound has structural formula (XXI):

in which all variables are as described above with respect to any of structural formulae (I)-(XX). For example, the

moiety can be selected from

in which the G-R17group is as described herein. Such compounds can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In the compounds of structural formulae (XV)-(XXI), the regiochemistry around the central pyridine can be as described with respect to any of claims (IX)-(XI). Moreover, the E1moiety of any such compounds can be absent, —C(O)—, —C(O)NR1— or —NR1C(O)—. In one such embodiment, a compound of any of structural formula (XV)-(XXI) is of structural formula (XXII):

in which all variables are as described above with respect to any of structural formulae (I)-(XXI). For example, the

moiety can be selected from

in which the G-R17group is as described herein.

In certain embodiments of the compounds according to structural formula (XV)-(XXII), the ring denoted by “B” is

In certain such embodiments, Y2is N and Y1is CH or C substituted by one of the x R4. In other such embodiments, both Y1and Y2are N. For example, in certain embodiments, compounds according to structural formulae (XV)-(XXII) have structural formula (XXIII):

in which in which all variables are as described above with respect to any of structural formulae (I)-(XXII). In one embodiment, Y1is N. In another embodiment, Y1is CH, or is C substituted by one of the x R4. For example, in certain embodiments, compounds have one of structural formulae (XXIV)-(XXIX):

in which in which all variables are as described above with respect to any of structural formulae (I)-(XXII). In certain embodiments of the compounds of structural formulae (XXIV)-(XXIX), Y1is CH or C substituted by one of the x R4. In certain embodiments of the compounds of structural formulae (XXIV)-(XXIX), w is 0. In other such embodiments, x is 0. In still other such embodiments, both w and x are 0. In any such embodiments, R1can be, for example, H, or unsubstituted (C1-C4alkyl) such as methyl. Compounds according to structural formulae (XXVI)-(XXIX) can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In the compounds of structural formulae (XV)-(XXIX) as described above, G and Q can be as described above with reference to structural formulae (I)-(XIV). For example, in certain embodiments, G is CH2, CO, or SO2. In certain embodiments, Q is CH2, CO, SO2or O.

In the compounds of structural formulae (XV)-(XXIX) as described above, R17and T can be as described above with reference to structural formulae (I)-(XIV). For example, in certain embodiments, R17is an optionally substituted phenyl, for example, substituted with 0-2 R30groups as described above. In other embodiments, R17is an optionally substituted heteroaryl, for example, substituted with 0-2 R30groups as described above. In certain embodiments, T is

in which Q is as described above. The ring system denoted by A and its optional R5substituents can be, for example, phenyl substituted by 0-2 R30groups as described above. In other embodiments, ring system denoted by A and its optional R5substituents are heteroaryl, for example, substituted with 0-2 R30groups as described above.

As examples, in certain embodiments, the compounds have one of structural formulae (XXX)-(XXXV):

in which Q, G, R1and R30are as described above with reference to structural formulae (I)-(XXIX). In certain such embodiments, R1is H. In certain embodiments, G is CH2, CO, or SO2. In certain embodiments, Q is CH2, CO, SO2or O. Compounds according to structural formulae (XXX)-(XXXV) can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In other embodiments of the presently disclosed compounds of structural formulae (I)-(XIII) as described above, the compound has the structural formula (XXXVI):

in which the ring system denoted by “C” is a monocyclic arylene or heteroarylene, or a monocyclic arylene fused to a heterocycloalkyl, and all other variables are as defined above with respect to any of structural formulae (I)-(XIV). For example, in certain embodiments, the ring system denoted by “C” is a phenylene, for example, a 1,4-phenylene. In other embodiments, the ring system denoted by “C” is a monocyclic heteroarylene, such as a pyridylene (for example, a 2,5-pyridylene); a 1,3-pyrazolylene (for example, a 1,3-pyrazolylene); a furanylene (for example, a 2,4-furanylene); or a thienylene (for example, a 2,4-thienylene). In other embodiments, the ring system denoted by “C” is a 1,2,3,4-tetrahydroisoquinolinylene (for example, a 1,2,3,4-tetrahydroisoquinolin-2,6-ylene).

In other embodiments of the presently disclosed compounds of structural formulae (I)-(XIII) as described above, the compound has the structural formula (XVI):

in which z1 is 0 or 1; z2 is 0 or 1; Y5is N, C or CH; Y6is N, C or CH; each of the v R15can be disposed either spiro-fused ring; and all other variables are as defined above with respect to any of structural formulae (I)-(XIV).

In certain embodiments of the presently disclosed compounds of structural formula (XXXVII) as described above (for example, those in which E1is —C(O)— or absent), Y5is N and Y6is N. In other embodiments, (for example, those in which E1is —C(O)—NR1—), Y5is C or CH and Y6is N. In other embodiments, Y5is N and Y6is C or CH. In other embodiments, Y5is C or CH and Y6is C or CH. In certain embodiments of the presently disclosed compounds of structural formula (XXXVII) as described above, z1 is 1 and z2 is 0. In other embodiments, z1 is 0 and z2 is 1.

In one embodiment of the compounds of structural formula (XIV)-(XXXVII) as described above, Q is a single bond. In another embodiment, Q is —CH2—. In other embodiments, Q is —C(O)— or —S(O)2—. In other embodiments, Q is —NH—C(O)— or —CH2—NH—C(O)—. In other embodiments, Q is —C(CH3)2—, —CH2CH2—, —CH(CH3)—, —CH(OH)— or —CHF—. In other embodiments, Q is —O—. In other embodiments, Q is —CH2O— or —OCH2CH2—. In other embodiments, Q is —CH(COOMe)- or —CH(COOEt)-.

In one embodiment of the compounds of structural formula (XIV)-(XXXVII) as described above, G is —CH2—. In other embodiments, G is —C(O)— or —S(O)2—. In other embodiments, G is —CH(CH3)— or —C(CH3)2—. In other embodiments, G is —O—. In other embodiments, G is —C(O)—NH— or —C(O)—NH—CH2—. In other embodiments, G is —CH2CH2—. In other embodiments, G is a single bond. In other embodiments, G is —O—. In other embodiments, G is —OCH2— or —CH2CH2O—. In other embodiments, G is —CH(COOMe)- or —CH(COOEt)-.

In the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, the above-described Q and G moieties can be combined in any possible combination. For example, in one embodiment, Q is a single bond and G is —CH2— or —C(O)—. In another embodiment, Q is —CH2— or —C(O)— and G is a single bond. In yet another embodiment, Q is —CH2— or —C(O)— and G is —CH2— or —C(O)—.

In certain embodiments of the compounds of structural formulae (XIV)-(XXXVII) as described above, the ring system denoted by “A” is aryl or heteroaryl, as described above. In one embodiment, the ring system denoted by “A” is substituted with one or more electron-withdrawing groups as described above. In another embodiment, R17is substituted with one or more electron-withdrawing groups as described above. In certain embodiments, the ring system denoted by “A”, R17or both are not substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In certain embodiments, the azacycloalkyl to which -G-R17is bound is a piperidinyl; in other embodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, v is 0, 1, 2, 3 or 4. In one embodiment, v is 0, 1, 2 or 3. For example, v can be 0, or can be 1 or 2.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, two R15groups combine to form an oxo. The oxo can be bound, for example, at the position alpha relative to the nitrogen of an azacycloalkyl ring. In other embodiments, no two R15groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, v is at least 1 (for example, 1) and at least one R15is F. In certain embodiments, the F can be, for example, disposed at a position alpha to the E1moiety. When the F and E1are both disposed on saturated carbons, they can be disposed in a cis relationship with respect to one another. For example, in certain embodiments, a compound has structural formula (XXXVIII)

in which Y4is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). In other embodiments, a compound has structural formula (XXXIX)

in which Y4is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). In other embodiments, when the F and E1are both disposed on saturated carbons, they can be disposed in a trans relationship with respect to one another. For example, in one embodiment, a compound has structural formula (XL)

in which Y4is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). In another embodiment, a compound has structural formula (XLI)

in which Y4is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). Compounds according to structural formulae (XXXVIII)-(XLI) can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, when v is 4, not all four R15moieties are (C1-C6alkyl).

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, the -G-R17moiety is selected from the group consisting of

monocyclic heterocycloalkyl (for example, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl) substituted with 0, 1 or 2 R30, monocyclic heteroaryl (for example, pyridyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl) substituted with 0, 1 or 2 R30; monocyclic heteroarylmethyl- (for example, pyridylmethyl, isoxazolylmethyl, oxazolylmethyl, pyrrolylmethyl, thienylmethyl), in which the heteroaryl is substituted with 0, 1 or 2 R30; or monocyclic heteroaryloxy- (for example, pyridyloxy, isoxazolyloxy, oxazolyloxy, pyrrolyloxy, thienyloxy), in which the heteroaryl is substituted with 0, 1 or 2 R30; in which each R30is independently selected from halogen (e.g., F, Cl), unsubstituted (C1-C6alkoxy) (e.g., methoxy, ethoxy), —(C1-C6haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C1-C6alkyl), —S(C1-C6haloalkyl), —OH, —CN, —NO2, —NH2, —NH(unsubstituted C1-C4alkyl), —N(unsubstituted C1-C4alkyl)2, —N3, —SF5, —C(O)—NH2, C(O)NH(unsubstituted C1-C4alkyl), C(O)N(unsubstituted C1-C4alkyl)2, —C(O)OH, C(O)O(unsubstituted C1-C6alkyl), —(NH)0-1SO2R33, —(NH)0-1COR33, heterocycloalkyl optionally substituted with an (unsubstituted C1-C6alkyl) and heteroaryl optionally substituted with an (unsubstituted C1-C6alkyl), in which each R33is (unsubstituted C1-C6alkyl), (C1-C6haloalkyl(unsubstituted C3-C8cycloalkyl) or (C3-C8heterocycloalkyl) optionally substituted with an (unsubstituted C1-C6alkyl). In certain embodiments, no R30is substituted on the ring of R17. In other embodiments, one R30is substituted on the ring, for example, at a para-position of a phenyl, a meta-position of a phenyl, or at a 3- or 4-position of a heteroaryl or heterocycloalkyl (as counted from the attachment point of the Y4, Y6or the ring system denoted by “C”). Certain particular identities of the -G-R17moiety will be found by the person of skill in the art in the compounds described below with respect to Table 1. Those of skill in the art will understand that combinations of such -G-R17moieties with other subcombinations of features disclosed herein is specifically contemplated.

For example, in certain embodiments of the compounds of formulae (XIV)-(XLI) as described above, the -G-R17moiety is selected from

heterocycloalkyl optionally substituted by alkyl and/or halogen, -Q-heteroaryl optionally substituted by unsubstituted (C1-C4alkyl) and/or halogen, H, C(O)tBu and isopropyl, in which each X is independently F, Cl or Br (preferably F or Cl), each R33is unsubstituted (C1-C4alkyl), unsubstituted (C1-C4haloalkyl) or cycloalkyl optionally substituted with unsubstituted alkyl, unsubstituted (C1-C4alkyl), unsubstituted (C1-C4haloalkyl) or cycloalkyl optionally substituted with unsubstituted alkyl, and each R35is heterocycloalkyl, optionally substituted with unsubstituted alkyl. In certain such embodiments, Q is a single bond, —CH2—, —CH2O—, —OCH2CH2—, —CH2CH2—, —O—, —CHF—, —CH(CH3)—, —C(CH3)2—, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O)2—. As the person of skill in the art will appreciate, the

moiety and G-R17moieties described above can be combined in virtually any combination, and such combinations are specifically contemplated by this disclosure. For example, in certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XX) as described above, both the

moiety and the -G-R17moiety are

(for example, 4-fluorobenzyl or 4-cyanobenzyl). In other embodiments, the

moiety is

(for example, 4-fluorobenzyl or 4-cyanobenzyl), and the -G-R17moiety is

(for example, 4-methylphenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 4-cyanophenoxy, 4-cyano-2-methoxyphenoxy, 3-methylphenoxy, 3-methoxyphenoxy, 3-fluorophenoxy or 3-cyanophenoxy). Of course, the person of skill in the art will recognize that other combinations of

and -G-R17can be used. Such combinations of

and -G-R17in combination with other combinations of features described herein is specifically contemplated by this disclosure.

In certain embodiments, the presently disclosed compounds have the structural formula (XLII):

in which the variables are independently defined as described above with respect to structural formulae (I)-(XLI). In certain embodiments of the compounds of structural formula (XXI), T is H. In certain embodiments of the compounds of structural formula (XLII), T is

as described above with respect to structural formulae (I)-(XLI), and -G-R17is benzoyl, benzenesulfonyl, phenyl, 1-phenylethyl, 1-methyl-1-phenylethyl, —CH(CO(O)(CH2)1-3H)-phenyl substituted with 0, 1 or 2 R30as described above, or 4-methoxybenzyl, —C(O)-Cak or —CH2-Cak. In certain embodiments, G-R17is as described above with respect to structural formulae (I)-(XLI), and T is benzoyl, benzenesulfonyl, 1-methyl-1-phenylethyl, heterocycloalkyl, heteroarylmethyl or heteroaryl substituted with 0, 1 or 2 R30as described above, or 3,5-difluorobenzyl, —C(O)-Cak, (C1-C6alkyl)C(O)— or (C1-C6alkyl). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (XLIII):

in which the variables are independently defined as described above with respect to structural formulae (I)-(XLII). In certain embodiments of the compounds of structural formula (XLIII), T is H. In certain embodiments of the compounds of structural formula (XLIII), T is

as described above with respect to structural formulae (I)-(XLII), and -G-R17is benzoyl, benzenesulfonyl, phenyl, 1-phenylethyl, 1-methyl-1-phenylethyl, —CH(CO(O)(CH2)1-3H)-phenyl substituted with 0, 1 or 2 R30as described above, or 4-methoxybenzyl, —C(O)-Cak or —CH2-Cak. In certain embodiments, G-R17is as described above with respect to structural formulae (I)-(XLII), and T is benzoyl, benzenesulfonyl, 1-methyl-1-phenylethyl, heterocycloalkyl, heteroarylmethyl or heteroaryl substituted with 0, 1 or 2 R30as described above, or 3,5-difluorobenzyl, —C(O)-Cak, (C1-C6alkyl)C(O)— or (C1-C6alkyl). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (XLIV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, T is (C1-C6alkyl). In other embodiments,

In certain embodiments, the T moiety and the G-R17moiety are independently benzyl, 2-phenylethyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (XLV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the Q and the NR13are substituted para from one another on the phenylene. In other embodiments, the Q and the NR13are substituted meta from one another on the phenylene.

In certain embodiments, the presently disclosed compounds have the structural formula (XLVI):

in which the ring system denoted by “C” is heteroarylene (for example, monocyclic heteroarylene), one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the ring system denoted by “C” is a pyrazolylene (for example, a 1,3-pyrazolylene), a pyridylene (for example, a 2,5-pyridylene). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (XLVII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, phenylmethoxy, —C(O)NHCH2-phenyl, heteroaryl, or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the G and the NR1are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (XLVIII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3; each of the v R15can be disposed either spiro-fused ring; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (XLIX):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3; each of the v R15can be disposed either spiro-fused ring; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (L):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, phenylmethoxy, —C(O)NHCH2-phenyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the G and the NR1are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, R31is defined as described above for R30with respect to the

moiety and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. In certain embodiments, R31is Br. In certain embodiments, the

moiety is benzyl with 0, 1 or 2 R30as described above. In certain embodiments, the G and the NR1are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, phenoxy, phenylmethoxy, —C(O)NHCH2-phenyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the G and the NR1are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR1are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LIII):

in which one or two of X1, X2, X3and X4are N; each of the v R15can be disposed either spiro-fused ring; and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LIV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LV):

in which the ring system denoted by “B” is a heteroarylene, one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the ring system denoted by“B” is a pyrazolylene (for example, a 1,3-pyrazolylene).

In certain embodiments, the presently disclosed compounds have the structural formula (LVI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LVII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. The NR1and G-R17moieties can, for example, be substituted cis with respect to one another on the cyclohexane ring. In other embodiments, the NR1and G-R17moieties are substituted trans with respect to one another on the cyclohexane ring. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

certain embodiments, the presently disclosed compounds have the structural formula (LVIII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LIX):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, 2-phenylethyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LX):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. In certain embodiments, the fluorine atom and the —NR1— are disposed cis with respect to one another on the piperidine. In certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXIII):

in which R32is —H, —(C1-C4alkyl), —C(O)—(C1-C4alkyl) or —C(O)O—(C1-C4alkyl), one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. and the other variables are independently defined as described above with respect to structural formulae (I)-(XIV). In certain embodiments, R32is H or methyl. In certain embodiments, the fluorine atom and the —NR1— are disposed cis with respect to one another on the piperidine. In certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXIV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the Q and the NR13are substituted para from one another on the phenylene. In other embodiments, the Q and the NR13are substituted meta from one another on the phenylene.

In certain embodiments, the presently disclosed compounds have the structural formula (LXV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. In certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII), and the G-R17moiety is optional. In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the G-R17moiety is absent. In certain embodiments, the

moiety and the G-R17moiety (if present) are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVIII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the stereogenic center indicated by “*” is racemic. In other embodiments, it is enantiomerically enriched, for example, in the (R)-configuration (i.e., the carbon-NR1bond disposed above the plane of the page). In other embodiments, it is enantiomerically enriched, for example, in the (S)-configuration (i.e., the carbon-NR1bond disposed below the plane of the page). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVIII):

in which the ring system denoted by “B” is a heteroarylene, one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the ring system denoted by“B” is a triazolylene (for example, a 1,2,3-triazol-1,4-ylene).

In certain embodiments, the presently disclosed compounds have the structural formula (LXIX):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXX):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, benzoyl, 1-fluoro-1-phenylmethyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the

moiety is bound at the 4-position of the piperidine. In other embodiments, it is bound at the 3-position of the piperidine. In other embodiments, it is bound at the 2-position of the piperidine.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

In certain embodiments, the presently disclosed compounds have the structural formula (LXXII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXIII):

in which one or two of X1, X2, X3and X4are N and the others are CH or C substituted by one of the w R3; each of the R15is substituted on either ring of the 1,2,3,4-tetrahydroisoquinoline; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXIV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3; each of the R15is substituted on either ring of the 1,2,3,4-tetrahydroisoquinoline; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In other embodiments, the Q moiety is —O—CH2—CH2—.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXVI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, the NR1and the -G-R17are disposed cis with respect to one another on the cyclohexane ring. In other embodiments, the NR1and the -G-R17are disposed trans with respect to one another on the cyclohexane ring. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXVII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. For example, in certain embodiments, the

moiety and the G-R17moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXVIII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the

moiety and the E moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXIX):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, E2is —CONR1— (for example, —CONH—) or —NR1CO— (for example, —NHCO—), and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. The -G-R17moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety and the G-R17moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above. In other embodiments, G is O, CH2, or SO2.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXX):

in which two R4on different carbons combine to form a (C1-C4alkylene) bridge, one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the T moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LVII). For example, in certain embodiments, the T moiety is independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R4. In certain embodiments, the

moiety is

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXI):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. In one embodiment, R1is H. The —R17moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above; and the R17moiety is phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the T moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXIII):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). The A-(R5)ymoiety independently be, for example, described reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXIV):

in which one or two of X1, X2, X3and X4are N, and the others are CH or C substituted by one of the w R3, and all other variables are independently defined as described above with respect to structural formulae (I)-(XXII). In one embodiment, X1is N and X2, X3and X4are CH or C substituted by one of the w R3. In one embodiment, R1is H. The -G-R17moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R30as described above; and the R17moiety is phenyl substituted with 0, 1 or 2 R30as described above.

In certain embodiments of compounds having structural formulae (XIII)-(LXXVIII), the

Another aspect of the disclosure provides compounds of structural formula (LXXXV):

in which each of the variables is independently defined as described above with respect to structural formulae (I)-(LXXXIV). For example, in certain embodiments, a compound has structural formula (LXXXVI):

in which each of the variables is independently defined as described above with respect to structural formulae (I)-(LXXVIII).

As the person of skill in the art will recognize, the various embodiments and features described above can be combined to form other embodiments contemplated by the disclosure. For example, in one embodiment of the compounds of certain of structural formulae (I)-(LXXV) as described above, Q is —CH2—, as described above, and G is —CH2—, as described above. In another embodiment of the compounds of certain of structural formulae (I)-(LXXV) as described above, x is 0 and each w is 0. In another embodiment of the compounds of certain of structural formulae (I)-(LXXVI), x is 0, each w is 0 and each v is 0.

Moreover, the various -E moieties and T-(“B” ring system)-J-moieties described above with respect to any of structural formulae (I)-(LXXVI) can be combined around the central pyridine, pyrazine, pyridazine or pyrimidine (for example, in any of the ways described with respect to structural formulae (IX)-(XIII)) to form additional embodiments of compounds specifically contemplated by this disclosure.

Examples of compounds according to structural formula (I) include those listed in Table 1. These compounds can be made according to the general schemes described below, for example using procedures analogous to those described below in the Examples.

For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (for example, alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety can refer to a monovalent radical (for example CH3—CH2—), in some circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (for example the C2alkylene —CH2—CH2— may be described as a C2alkyl group), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). Nitrogens in the presently disclosed compounds can be hypervalent, for example, an N-oxide or tetrasubstituted ammonium salt. On occasion a moiety may be defined, for example, as (A)a-B—, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B— and when a is 1 the moiety is A-B—.

As used herein, the term “alkyl” includes alkyl, alkenyl and alkynyl groups of a designed number of carbon atoms, desirably from 1 to about 12 carbons (i.e., inclusive of 1 and 12). The term “Cm-Cnalkyl” means an alkyl group having from m to n carbon atoms (i.e., inclusive of m and n). The term “Cm-Cnalkyl” means an alkyl group having from m to n carbon atoms. For example, “C1-C6alkyl” is an alkyl group having from one to six carbon atoms. Alkyl and alkyl groups may be straight or branched and depending on context, may be a monovalent radical or a divalent radical (i.e., an alkylene group). In the case of an alkyl or alkyl group having zero carbon atoms (i.e., “C0alkyl”), the group is simply a single covalent bond if it is a divalent radical or is a hydrogen atom if it is a monovalent radical. For example, the moiety “—(C0-C6alkyl)-Ar” signifies connection of an optionally substituted aryl through a single bond or an alkylene bridge having from 1 to 6 carbons. Examples of “alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, 3-hexenyl and propargyl. If the number of carbon atoms is not specified, the subject “alkyl” or “alkyl” moiety has from 1 to 12 carbons.

The term “haloalkyl” is an alkyl group substituted with one or more halogen atoms, for example F, Cl, Br and I. A more specific term, for example, “fluoroalkyl” is an alkyl group substituted with one or more fluorine atoms. Examples of “fluoroalkyl” include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, hexafluoroisopropyl and the like. In certain embodiments of the compounds disclosed herein, each haloalkyl is a fluoroalkyl.

The term “aryl” represents an aromatic carbocyclic ring system having a single ring (for example, phenyl) which is optionally fused to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. “Aryl” includes ring systems having multiple condensed rings and in which at least one is aromatic, (for example, 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, 2,3-dihydrobenzofuranyl and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as described below.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ring system, which may be saturated (i.e., a cycloalkyl) or partially unsaturated (i.e., a cycloalkenyl). The cycloalkyl ring optionally fused to or otherwise attached (for example, bridged systems) to other cycloalkyl rings. Preferred cycloalkyl groups have from 3 to 7 members in a single ring. More preferred cycloalkyl groups have 5 or 6 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl and bicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, may be substituted in one or more substitutable positions with various groups.

The term “oxa” means a divalent oxygen radical in a chain, sometimes designated as —O—.

The term “oxo” means a doubly bonded oxygen, sometimes designated as ═O or for example in describing a carbonyl “C(O)” may be used to show an oxo substituted carbon.

The term “electron withdrawing group” means a group that withdraws electron density from the structure to which it is attached than would a similarly-attached hydrogen atom. For example, electron withdrawing groups can be selected from the group consisting of halo, cyano, —(C1-C4fluoroalkyl), —O—(C1-C4fluoroalkyl), —C(O)—(C0-C4alkyl), —C(O)O—(C0-C4alkyl), —C(O)N(C0-C4alkyl)(C0-C4alkyl), —S(O)2O—(C0-C4alkyl), —SF5, NO2and —C(O)-Hca in which the Hca includes a nitrogen atom to which the —C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

The term “substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.

Substituent groups for substituting for hydrogens on saturated carbon atoms in the specified group or radical are, unless otherwise specified, —R60, halo, —O−M+, ═O, —OR70, —SR70, —S−M+, ═S, —NR80R80, ═NR70, ═N—OR70, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —SO2R70, —SO2O−M+, —SO2OR70, —OSO2R70, —OSO2O−M+, —OSO2OR70, —P(O)(O−)2(M+)2, —P(O)(OR70)O−M+, —P(O)(OR70)2, —C(O)R70, —C(S)R70, —C(NR70)R70, —C(O)O−M+, —C(O)OR70, —C(S)OR70, —C(O)NR80R80, —C(NR70)NR80R80, —OC(O)R70, —OC(S)R70, —OC(O)O−M+, —OC(O)OR70, —OC(S)OR70, —NR70C(O)R70, —NR70C(S)R70, —NR70CO2−M+, —NR70CO2R70, —NR70C(S)OR70, —NR70C(O)NR80R80, —NR70C(NR70)R70and —NR70C(NR70)NR80R80. Each R60is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halo, —O−M+, ═O, —OR71, —SR71, —S−M+, ═S, —NR81R81, ═NR71, ═N—OR71, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —SO2R71, —SO2O−M+, —SO2OR71, —OSO2R71, —OSO2O−M+, —OSO2OR71, —P(O)(O−)2(M+)2, —P(O)(OR71)O−M+, —P(O)(OR71)2, —C(O)R71, —C(S)R71, —C(NR71)R71, —C(O)O−M+, —C(O)OR71, —C(S)OR71, —C(O)NR81R81, —C(NR71)NR81R81, —OC(O)R71, —OC(S)R71, —OC(O)O−M+, —OC(O)OR71, —OC(S)OR71, —NR71C(O)R71, —NR71C(S)R71, —NR71CO2−M+, —NR71CO2R71, —NR71C(S)OR71, —NR71C(O)NR81R81, —NR71C(NR71)R71and —NR71C(NR71)NR81R81. Each R70is independently hydrogen or R60; each R80is independently R70or alternatively, two R80's, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C1-C3alkyl substitution; and each M+is a counter ion with a net single positive charge. Each R71is independently hydrogen or R61, in which R61is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halo, —O−M+, ═O, —OR72, —SR72, —S−M+, ═S, —NR82R82, ═NR72, ═N—OR72, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —SO2R71, —SO2O−M+, —SO2OR72, —OSO2R72, —OSO2O−M+, —OSO2OR72, —P(O)(O−)2(M+)2, —P(O)(OR72)O−M+, —P(O)(OR72)2, —C(O)R72, —C(S)R72, —C(NR72)R72, —C(O)O−M+, —C(O)OR72, —C(S)OR72, —C(O)NR82R82, —C(NR72)NR82R82, —OC(O)R72, —OC(S)R72, —OC(O)O−M+, —OC(O)OR72, —OC(S)OR72, —NR72C(O)R72, —NR72C(S)R72, —NR72CO2−M+, —NR72CO2R72, —NR72C(S)OR72, —NR72C(O)NR82R82, —NR72C(NR72)R72and —NR72C(NR72)NR82R82; and each R81is independently R71or alternatively, two R81s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C1-C3alkyl substitution. Each R72is independently hydrogen, (C1-C6alkyl) or (C1-C6fluoroalkyl); each R82is independently R72or alternatively, two R82s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include 1, 2, 3 or 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C1-C3alkyl substitution. Each M+may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(R60)4; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5(“subscript 0.5 means for example that one of the counter ions for such divalent alkali earth ions can be an ionized form of a presently disclosed compound and the other a typical counter ion such as chloride, or two ionized presently disclosed molecules can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound can serve as the counter ion for such divalent alkali earth ions). As specific examples, —NR80R80is meant to include —NH2, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4-methyl-piperazin-1-yl and N-morpholinyl. In certain embodiments, each R60is H or (unsubstituted C1-C6alkyl). In certain embodiments, each R70is H or (unsubstituted C1-C6alkyl). In certain embodiments, each R80is H or (unsubstituted C1-C6alkyl).

In certain embodiments as described above, the substituent groups on carbon atoms can also or alternatively be —SF5.

In certain embodiments of the compounds disclosed herein, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

The compounds described herein can also be provided in prodrug form. “Prodrug” refers to a derivative of an active compound (drug) that requires a transformation under the conditions of use, such as within the body, to release the active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug. The cleavage of the promoiety can proceed spontaneously, such as by way of a hydrolysis reaction, or it can be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent can be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it can be supplied exogenously. A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active drugs to yield prodrugs are well-known in the art. For example, a hydroxyl functional group can be masked as a sulfonate, ester or carbonate promoiety, which can be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group can be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which can be hydrolyzed in vivo to provide the amino group. A carboxyl group can be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which can be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.

The compounds disclosed herein can also be provided as N-oxides.

The presently disclosed compounds, salts, prodrugs and N-oxides can be provided, for example, in solvate or hydrate form.

Compounds can be assayed for binding to a membrane-bound adiponectin receptor by performing a competitive binding assay with adiponectin. In one such procedure, HEK 293 cellular membrane is coated onto a COSTAR 384 plate, which is then blocked with 1% casein. Polyhistidine-tagged globular adiponectin and a candidate compound is incubated with the membrane in HEPES buffer. Unbound ligands are washed away and the degree of binding of the adiponectin is determined using horseradish peroxidase-conjugated anti-polyhistidine. Compounds that compete with adiponectin binding to the membrane (i.e., give a reduced signal compared to a control performed without a candidate compound) can be chosen as hits and further screened using the below-described functional assays to identify adiponectin receptor agonists.

An in-cell western assay can be performed to demonstrate the activation of the AMPK pathway in human liver cells by globular adiponectin using glutathione S-transferase (GST). AMPK activity can be measured by the relative concentration of phosphorylated acetyl Co-A carboxylase, which is one of the products of AMPK. An increase in pACC correlates with an increase in the rate of fatty acid oxidation.

The compounds of structural formulae (I)-(LXXXVI) can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (for example, intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.

Pharmaceutical compositions can be made using the presently disclosed compounds. For example, in one embodiment, a pharmaceutical composition includes a pharmaceutically acceptable carrier, diluent or excipient, and compound as described above with reference to structural formulae (I)-(LXXXVI).

In the pharmaceutical compositions disclosed herein, one or more compounds of structural formulae (I)-(LXXXVI) may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. The pharmaceutical compositions containing compounds of structural formulae (I)-(LXXXVI) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

Formulations for oral use can also be presented as lozenges.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

Compounds of structural formulae (I)-(LXXXVI) can be formulated into lotions, oils or powders for application to the skin according to certain methods described below.

Compounds of structural formulae (I)-(LXXXVI) can also be administered in the form of suppositories, for example, for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of structural formula (I)-(LXXXVI) can also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

The compounds disclosed herein can be made using procedures familiar to the person of ordinary skill in the art and as described herein. For example, compounds of structural formula (I) can be prepared according to Schemes 1-6, below, or analogous synthetic schemes:

Referring to Scheme 1, a pyridinedicarboxylic acid monomethyl ester (i), for example, is coupled with an amine (here a substituted 1-benzoylpiperidine-4-amine) to form a carboxymethyl-substituted pyridinecarboxamide (ii). The ester is saponified to form the corresponding carboxylic acid (iii), which is then coupled with a suitable amine (in this case, a substituted 1-benzylpiperazine) to form Compound 4 of Table 1.

Referring to Scheme 2, a bromopyridinedicarboxylic acid, for example, is coupled with an amine (here a substituted 1-benzylpiperidine-4-amine) to form a bromo-substituted pyridinecarboxamide (iv), which is then coupled with a suitable amine (in this case, a substituted 4-phenoxypiperidine) using a palladium catalyst to form Compound 17 of Table 1.

Referring to Scheme 3, a pyridinedicarboxylic acid monomethyl ester (v), for example, is coupled with an amine (here a substituted 1-benzylpiperidine-4-amine) to form a carboxymethyl-substituted pyridinecarboxamide (vi). The ester is saponified to form the corresponding carboxylic acid (vii), which is then coupled with a suitable amine (in this case, a substituted 4-benzoylpiperidine) to form Compound 160 of Table 1.

Referring to Scheme 4, a pyridine dicarboxylic acid (viii), for example, is coupled with one equivalent of an amine (here, a substituted 1-benzylepiperizine), then with methanol and trimethylsilyl(diazomethane) to form a carbomethoxy-substituted pyridinecarboxamide (ix), which is saponified to give a carboxylic acid-substituted pyridinecarboxamide (x). An amine (in this case, 1-phenylpiperazine) is coupled with the carboxylic acid-substituted pyridinecarboxamide (x) to form Compound 94 of Table 1.

Referring to Scheme 5, a bromopyridinecarboxamide (xi) is coupled with a substituted 1-benzylpiperidine-4-carboxamide using a palladium catalyst to form Compound 46 of Table 1. Reactions of this general type are described in more detail, for example, in Wrona, Iwona E. et al., Journal of Organic Chemistry (2010), 75(9), 2820-2835.

Scheme 6 describes a preparation that can be used to make gem-dimethylpiperazines for use in making compounds analogous to Compound 125 of Table 1. A piperazin-2-one is singly protected with trityl chloride, then coupled with an appropriate bromide (here, a substituted benzyl bromide) to form a 4-protected 1-(substituted benzyl)piperazin-2-one. The oxo is converted to a gem-dimethyl using Grignard chemistry, then the trityl is removed to yield the desired gem-dimethyl piperazine. Details are provided in the Examples below, and in Xiao, K-J.; Luo, J-M.; Ye, K-Y.; Wang, Y.; Huang, P-Q.Angew. Chem. Int. Ed.2010, 49, 3037-3040.

One of skill in the art can adapt the reaction sequences of Schemes 1-6 to fit the desired target molecule. Of course, in certain situations one of skill in the art will use different reagents to affect one or more of the individual steps or to use protected versions of certain of the substituents. Additionally, one skilled in the art would recognize that compounds of structural formulae (I)-(LXXXVI) can be synthesized using different routes altogether.

Compounds suitable for use in the presently disclosed pharmaceutical compositions include compounds of Table 1, above. These compounds can be made according to the general scheme described above, for example using a procedure similar to that described below in the Examples.

While not intending to be bound by theory, the inventors surmise that compounds of structural formulae (I)-(LXXXVI) activate the AMPK pathway. Activation of the AMPK pathway has the effect of increasing glucose uptake, decreasing glycogen synthesis and increasing fatty acid oxidation, thereby reducing glycogen, intracellular triglyceride and fatty acid concentration and causing an increase in insulin sensitivity. Because they activate the AMPK pathway, compounds of structural formulae (I)-(LXXXVI) should also inhibit the inflammatory processes which occur during the early phases of atherosclerosis. Accordingly, compounds of structural formulae (I)-(LXXXVI) can be useful in the treatment of type II diabetes and in the treatment and prevention of atherosclerosis, cardiovascular disease, obesity and non-alcoholic fatty liver disease.

In one aspect and without limitation to theory, the present compounds exert AMPK activating activity by binding to an adiponectin receptor, acting as effective adiponectin mimetics. Adiponectin is a protein hormone exclusively expressed in and secreted from adipose tissue and is the most abundant adipose-specific protein. Adiponectin has been implicated in the modulation of glucose and lipid metabolism in insulin-sensitive tissues. Decreased circulating adiponectin levels have been demonstrated in some insulin-resistant states, such as obesity and type 2 diabetes mellitus and also in patients with coronary artery disease, atherosclerosis and hypertension. Adiponectin levels are positively correlated with insulin sensitivity, HDL (high density lipoprotein) levels and insulin stimulated glucose disposal and inversely correlated with adiposity and glucose, insulin and triglyceride levels. Thiazolidinedione drugs, which enhance insulin sensitivity through activation of the peroxisome proliferator-activated receptor-γ, increase endogenous adiponectin production in humans.

Adiponectin binds its receptors in liver and skeletal muscle and thereby activates the AMPK pathway. Similarly, in one aspect, the present compounds act as adiponectin receptor agonists. Adiponectin receptors 1 and 2 are membrane-bound proteins found in skeletal muscle and liver tissue.

Accordingly, another aspect of the present disclosure relates to a method of activating the AMPK pathway. According to this aspect, a method for activating the AMPK pathway in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In one embodiment, a method of increasing fatty acid oxidation in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI). Acetyl Co-A carboxylase (ACC) catalyzes the formation of malonyl Co-A, a potent inhibitor of fatty acid oxidation; phosphorylation of ACC greatly reduces its catalytic activity, thereby reducing the concentration of malonyl Co-A and increasing the rate of fatty acid oxidation. Because the presently disclosed compounds can increase the rate of phosphorylation of ACC, they can reduce the inhibition of fatty acid oxidation and therefore increase its overall rate.

In another embodiment, a method of decreasing glycogen concentration in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of increasing glucose uptake in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of reducing triglyceride levels in a subject includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of increasing insulin sensitivity of a subject includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

Accordingly, the compounds and compositions disclosed herein can be used to treat a variety of metabolic disorders. For example, in one embodiment, a method of treating type II diabetes in a subject in need of such treatment includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, solvate, hydrate, N-oxide or composition described above. In another embodiment, a method of treating or preventing atherosclerosis or cardiovascular disease in a subject includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as compound of one of formulas (I)-(LXXXVI).

As described above, the compounds disclosed herein can act as activators of the AMPK pathway. Accordingly, in another embodiment, a method comprises modulating the AMPK pathway (either in vitro or in vivo) by contacting a cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above, or administering a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above to a mammal (for example, a human) in an amount sufficient to modulate the AMPK activity and study the effects thereby induced. Such methods are useful for studying the AMPK pathway and its role in biological mechanisms and disease states both in vitro and in vivo.

In certain embodiments, the compounds disclosed herein affect lipid signaling pathways. For example, in some embodiments, the compounds up-regulate ceramidase activity. Ceramide is a central player in sphingolipid metabolism, and is the immediate precursor of sphingomyelins and glycosphingolipids as well as the bioactive products sphingosine and sphingosine-1-phosphate. Moreover, endogenous ceramide itself mediates, at least in part, the actions of a variety of stimuli on cell differentiation, apoptosis, and growth suppression. Ceramide is deacylated by ceramidase to form sphingosine, which is in turn phosphorylated to sphingosine-1-phosphate by sphingosine kinase.

Elevated ceramide levels have been shown to induce cell apoptosis, differentiation and senescence. Moreover, elevated ceramide levels are linked to a variety of diseases and disorders, including, for example, Batten's disease, inflammatory bowel diseases, diffuse intravascular coagulation, fever, protein catabolism and/or lipid depletion, hepatosplenomegaly associated with inflammatory or metabolic liver diseases, endomyocarditis, endolithial cell and leucocyte activation, capillary thrombosis, meningo-encephalitis due to infectious agents, complications in organ transplantation, rheumatoid arthritis and connective tissue diseases, autoimmune diseases, hyperthyroidism, damage by radiation/chemotherapy agents and chronic fatigue syndrome.

Up-regulating ceramidase function (and therefore reducing the concentration of ceramide) can be used to treat disorders involving deficient cell proliferation (growth) or in which cell proliferation is otherwise desired, for example, degenerative disorders, growth deficiencies, lesions, physical trauma, and diseases in which ceramide accumulates within cells, such as Fabry disease. Other disorders that may benefit from the activation of ceramidase include neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis and disorders of aging such as immune dysfunction, as well as disorders, such as those listed above, linked to elevated ceramide levels.

The compounds, salts, prodrugs, N-oxides, solvates and hydrates described herein can be administered, for example, to a mammalian host to retard cellular responses associated with the activation of the ceramide-mediated signal transduction pathway. The compounds can be useful, for example, in providing protection against cell senescence or apoptosis, such as occurs as a result of trauma (for example, radiation dermatitis) and aging (for example, of the skin or other organs).

Another embodiment is a method for up-regulating ceramidase function in a cell (either in vivo or in vitro), the method including contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method for decreasing ceramide concentration in a cell (either in vivo or in vitro) includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method for inhibiting ceramide-activated responses to stimuli in a cell (either in vivo or in vitro) includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above. The stimuli can be, for example, stimuli for cell senescence and/or apoptosis.

Another embodiment is a method for treating or preventing a disease or disorder in which cell proliferation is deficient or desired in a subject, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, for example, a compound of one of formulas (I)-(LXXXVI). Various applicable diseases and disorders are described above.

Another embodiment is a method for treating a disease or disorder linked to elevated ceramide levels in a subject, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein. Various applicable diseases and disorders are described above. In certain embodiments, the subject has a ceramide level higher than about 50 pmol/106cells.

Moreover, since some drugs can induce high levels of ceramide, the compounds, salts, prodrugs, N-oxides, solvates and hydrates described herein can be usefully co-administered with such drugs in order to at least partially ameliorate this effect. For example, in certain embodiments, an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein is co-administered with a corticosteroid (for example, dexamethasone), an anti-inflammatory (for example, indomethacin), an antiviral (for example, interfereon), an immunosuppressant (for example, cyclosporin), a chemotherapy agent (for example, adriamicin), and immunopotentiant (for example, an immunoglobulin or a vaccine), or an andocrinological agent (for example, metimazole). As the person of skill in the art will appreciate, co-administration contemplates not only administration at the same time, but also administration at different times, but with time-overlapping pharmacological effects.

Another embodiment is a method for reducing the effect of aging in the skin of a subject, the method including contacting the skin with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein.

Another embodiment is a method for treating or preventing radiation dermatitis in the skin of a subject, the method including contacting the skin with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein.

To identify and select therapeutic compounds for use in treating ceramide-associated conditions, cells (or intracellular components such as microsomes) which have not been exposed to a senescence or apoptosis-inducing agent (for example, cytokines such as TNF-α or exogenous stimuli such as heat, radiation or chemical agents) are exposed to such and agent and to the candidate compound. Inhibition of senescence or apoptosis is measured as a function of cell growth. The person of ordinary skill in the art will be familiar with techniques for obtaining such measurements.

For example, inhibition of cell senescence can be measured after serum deprivation in serum-dependent cells. Many cell types are dependent upon serum factors for growth. Thus, deprivation of such cells of serum provides a model for assessment of compounds to modulate cell responses to intracellular ceramide-mediated signal transduction. In particular, withdrawal of serum from serum-dependent cell cultures produces increased intracellular levels of endogenous ceramide and may also increase intracellular levels of endogenous diacyl glycerol (see, e.g., Jayadev, et al., J. Biol. Chem., 270, 2047-2052 (1995)). To evaluate the inhibitory effect of the compounds described herein on ceramide-associated conditions in vitro, the serum withdrawal model can be used. Specifically, 3T3 fibroblast cells can be seeded in 96 well microtiter plates in DMEM in the presence of 10% fetal bovine serum. The cells are incubated to 90% confluence. The medium is removed, and the cells washed and reincubated in serum-free DMEM. A test compound at a variety of concentrations (for example, 0, 4, 40 or 400 μM) and cell permeable ceramide (for example, 0, 5 or 10 μM) are added to the wells. After 24 hrs. incubation, 0.5 μCi of [3H]thymidine is added to each well for 2 hrs. DNA synthesis in the tested cell population is assessed by conventional techniques for detection of [3H]thymidine incorporation. The results of this assay can be used to establish the cell senescence inhibitory efficacy of the test compound.

Inhibition of cell apoptosis can be determined, for example, using CD95 stimulation. Engagement of cell surface receptor CD95 (also known as Fas/Apo-1 antigen) triggers cell apoptosis. DX2 is a functional anti-FAS (CD95) antibody which will, on binding of CD95, activate the sphingomyelinase catalysis of sphingomyelin hydrolysis and production of ceramide (see, with respect to DX2, Cifone, et al., J. Exp. Med., 177, 1547-1552 (1993)). Thus, binding of CD95 is a model for conduction of apoptosis via the sphingomyelin signal transduction pathway. To assess the inhibitory effect of the compounds disclosed herein on ceramide-mediated cell apoptosis, human T lymphoblasts (Jurkat) are suspended at 2×106cells/mL in RPMI-1640 supplemented with insulin, transferrin, selenium and glutamine. After incubation for 2 hrs. at room temperature with a test compound, pentoxifylline or a control compound (Ro-1724), 25 ng/mL of anti-FAS antibody is added to each suspension. After another 2 hrs., cell apoptosis is measured as a function of the number of cells (counted by hemocytometer) that excluded the vital dye erythrosin B. The results of the experiment can be used to establish the apoptosis inhibitory efficacy of the test compound.

To assess the inhibitory effect of the compounds disclosed herein on death of human lymphocytes, human peripheral blood lymphocytes are isolated from normal human blood and depleted of monocytes by adherence to a plastic substrate. Lymphocytes are then cultured in RPMI-1640 medium with 10% autologous plasma at an initial concentration of 2×106cells/mL. Aliquots of the cell samples are divided and one half of the samples are incubated with a test compound or 6,7-dimethoxy-1(2H)-isoquinoline (Aldrich) for four days. The remaining half of the samples are allowed to rest for four days. Cell viability after four days is determined by erythrosin B dye exclusion in a hemocytometer. The results of the experiment can be used to establish the apoptosis inhibitory efficacy of the test compound on human lymphocytes as compared to untreated lymphocytes.

Ceramide-activated protein kinase (CaPK) is a 97 kDa protein which is exclusively membrane-bound and is believed to serve a role in the sphingomyelin signal transduction pathway. In particular, CaPK is believed to mediate phosphorylation of a peptide derived from the amino acid sequence surrounding Thr.sup.669 of the epidermal growth factor receptor (i.e., amino acids 663-681). This site is also recognized by the mitogen-activated kinase MAP (also known as a family of extracellular signal-regulated kinases). Thus, the effect of the compounds disclosed herein on CaPK activity in cells can be indicative of the effect that the compounds exert on signal transduction in the sphingomyelin pathway. Accordingly, Jurkat cells are suspended at 2×106cells/mL in RPMI-1640 medium as described above with respect to the cell apoptosis experiment. After incubation for 2 hrs., either a test compound; 20 μM of ceramide or 25 ng/ml of anti-FAS antibody DX2 are added to each suspension and incubated for 15 mins. After centrifugation and washing, the cells were separately homogenized in a dounce homogenizer. Ceramide kinase levels in each test sample can be assayed as described by Liu, et al., J. Biol. Chem., 269, 3047-3052 (1994), which is hereby incorporated by reference herein in its entirety. Briefly, the membrane fraction is isolated from each test sample of treated cell homogenate by ultracentrifugation and run on a 10% PAGE gel. The gel is washed with guanadine-HCl, and renatured in HEPES buffer. Then [32P]-ATP is added to the gel and left there for 10 mins. Thereafter, the gel is extensively washed with 5% TCA. Autophosphorylated kinase is detected by autoradiography. The results of this assay can be used to establish the CaPK inhibitory efficacy of the compounds disclosed herein.

Ceramidase activity can be measured in a variety of ways. For example, a sample from a subject or a sample of cells can be assayed in vitro for RNA or protein levels, structure, and/or activity of the expressed ceramidase RNA or protein. Many methods standard in the art can be thus employed, including but not limited to ceramidase enzyme assays.

Cellular ceramide levels can be monitored directly, or by indirectly monitoring the concentrations of a ceramide metabolite in a cell. For example, ceramide levels can be directly measured by isolating peripheral blood lymphocytes from a subject. The cells are centrifuged to remove supernatant, and lipids are removed from the cell pellet. The organic phase containing the ceramide can be assayed using the diacylglycerase kinase assay for phosphorylating the ceramide which is then evidenced by autoradiography. Methods for performing diacylglycerase kinase assays are described, for example, in Cifone, M. G. et al., J. Exp. Med., 180(4), 1547-52 (1993), Jayadev et al., J. Biol. Chem., 270, 2047-2052. (1995), and Perry, D. K. et al, Methods Enzymology, 312, 22-31 (2000), each of which is hereby incorporated by reference in its entirety.

The presently disclosed AMPK activating compounds are useful for increasing metabolic efficiency, for example by increasing fiber oxidative capacity, endurance and aerobic workload. In particular, the present compounds are useful for treating and regulating disorders of mitochondrial function, including, without limitation, exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonus epilepsy, such as associated with ragged-red fibers syndrome, Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke (MELAS) syndrome and stroke like episodes. The disclosed compounds also are useful for treating muscular dystrophic states, such as Duchenne's and Becker's muscular dystrophies and Friedreich's ataxia.

The presently disclosed AMPK activating compounds also function to reduce oxidative stress and secondary effects of such stress. Many diseases, including several of those listed above, have secondary effects caused by damage due to excessive oxidative stress which can be treated using the compounds disclosed herein. For example, free radical damage has been implicated in neurological disorders, such as Parkinson's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Alzheimers disease. Additional diseases in which excessive free radical damage occurs generally include hypoxic conditions and a variety of other disorders. More specifically, such disorders include ischemia, ischemic reperfusion injury (such as coronary or cerebral reperfusion injury), myocardial ischemia or infarction, cerebrovascular accidents (such as a thromboembolic or hemorrhagic stroke) that can lead to ischemia in the brain, operative ischemia, traumatic hemorrhage (for example, a hypovolemic stroke that can lead to CNS hypoxia or anoxia), resuscitation injury, spinal cord trauma, inflammatory diseases, autoimmune disorders (such as rheumatoid arthritis or systemic lupus erythematosis), Down's syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy (such as peripheral vascular disease or retinal degeneration), uveitis, chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, asthma, neoplasia, Crohn's disease, inflammatory bowel disease and pancreatitis. Free radical damage is also implicated in a variety of age-related disorders, particularly ophthalmic conditions such as cataracts and age-related macular degeneration.

In particular the present compounds are useful for treating neurological disorders associated with reduced mitochondrial function, oxidative stress, or both. For example, Alzheimer's disease, dementia and Parkinson's disease can be treated using the present AMPK activating compounds.

Metabolic efficiency is enhanced by the disclosed AMPK activating compounds. Thus the compounds can be administered to a subject to improve exercise efficiency and athletic performance. Moreover, conditions including, without limitation, hypoxic states, angina pectoris, coronary ischemia and organ damage secondary to coronary vessel occlusion, intermittent claudication, multi-infarct dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure can be treated using the disclosed compounds.

Inflammatory disorders and effects can be treated using the present compounds. For example, in one aspect, the present compounds are particularly useful for treating lung inflammation, such as is involved in asthma, COPD and transplant rejection. Similarly, the present compounds are useful in reducing organ inflammation, particularly macrophage-associated inflammation, such as inflammation of the kidney, liver and other organs. The anti-inflammatory activity of the presently disclosed compounds can be assessed as is known to those of skill in the art, for example, by using the mixed lymphocyte response in vitro.

Accordingly, one aspect of the disclosure relates to a method for treating or ameliorating a disorder or condition related to oxidative stress, mitochondrial dysfunction, free radical damage and/or metabolic inefficiency in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the present disclosure relates to a method for the treatment or amelioration of a disorder of mitochondrial dysfunction in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. In certain embodiments, the disorder is selected from the group consisting of exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonus epilepsy (such as associated with ragged-red fibers syndrome), Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke (MELAS) syndrome and stroke like episodes.

Another aspect of the disclosure relates to a method of increasing metabolic efficiency in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Such methods can be used to increase fiber oxidative capacity, endurance, aerobic workload, or any combination thereof. These methods can be used, for example, to improve exercise efficiency, exercise endurance and/or athletic performance in a subject.

Another aspect of the present disclosure relates to methods for mimicking the effects of exercise in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for treating or ameliorating a disorder in a subject in need thereof, the disorder being selected from the group consisting of hypoxic states, angina pectoris, coronary ischemia and organ damage secondary to coronary vessel occlusion, intermittent claudication, multi-infarct dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for the treatment of amelioration of a muscular dystrophic state in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. In certain embodiments, the muscular dystrophic state is Duchenne's muscular dystrophy, Becker's muscular dystrophy, or Freidreich's ataxia.

Another aspect of the disclosure relates to a method for increasing oxidative capacity of a muscle fiber, the method including contacting the muscle fiber with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure relates to a method for reducing oxidative stress in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for reducing free radical damage in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for treating or ameliorating a disorder or condition in a subject in need thereof, the disorder or condition selected from the group consisting of neurological disorders, hypoxic conditions, ischemia, ischemic reperfusion injury, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, resuscitation injury, spinal cord trauma, inflammatory diseases, autoimmune disorders, Down's syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy, uveitis, chronic obstructive pulmonary disease (COPD), asthma, neoplasia, Crohn's disease, inflammatory bowel disease, pancreatitis and age-related disorders, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Particular examples of such disorders and conditions are discussed above.

Another aspect of the disclosure is a method for treating or ameliorating a neurological disorder in a subject in need thereof, the neurological disorder being associated with reduced mitochondrial function, oxidative stress, or both, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Particular examples of such neurological disorders are discussed above.

Another aspect of the disclosure relates to a method for reducing oxidative stress in a cell, the method including contacting the cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure relates to a method for reducing free radical damage in a cell, the method including contacting the cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure is a method for treating an inflammatory disorder or effect in a subject in need thereof, the method including including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. For example, in one embodiment, the inflammatory disorder or effect is lung inflammation, such as is involved in asthma, COPD and transplant rejection. In another embodiment, the inflammatory disorder or effect is organ inflammation, particularly macrophage-associated inflammation, such as inflammation of the kidney, liver and other organs.

Another embodiment is the use of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described above in the manufacture of a medicament for any of the therapeutic purposes described above. For example, the medicament can be for the reduction of triglyceride levels in a subject, the treatment of type II diabetes in a subject, or the treatment or prevention of atherosclerosis or cardiovascular disease in a subject. In other embodiments, the medicament can be used to reduce the levels of cellular ceramide in a subject, for example in the treatment of Batten's disease.

The compounds disclosed herein can be linked to labeling agents, for example for use in variety of experiments exploring their receptor binding, efficacy and metabolism. Accordingly, another embodiment is a labeled conjugate comprising a compound as disclosed herein covalently linked to a labeling agent, optionally through a linker. Suitable linker and labeling agents will be readily apparent to those of skill in the art upon consideration of the present disclosure. The labeling agent can be, for example, an affinity label such as biotin or strepavidin, a hapten such as digoxigenin, an enzyme such as a peroxidase, or a fluorophoric or chromophoric tag. Any suitable linker can be used. For example, in some embodiments, an ethylene glycol, oligo(ethylene glycol) or poly(ethylene glycol) linker is used. Other examples of linkers include amino acids, which can be used alone or in combination with other linker groups, such as ethylene glycol, oligoethylene glycol or polyethylene glycol. Suitable linkers include, without limitation, single amino acids, as well as di- and tripeptides. In one embodiment, the linker includes a glycine residue. The person of skill in the art will realize, of course, that other linkers and labeling agents can be used. In other embodiments, an alkylene chain is the linker. In other embodiments, the linker has the structure -[(C0-C3alkyl)-Ym—]m—, in which each Ymis —O—, —N(R9)—, or L, and m is in the range of 1-40. For example, in certain embodiments, a labeled conjugate has structural formula (LXXXVII):

in which the “LINK” moiety is a linker and is optional, and the “LABEL” moiety is a labeling agent, the LINK)0-1-LABEL moiety is bound to the bracketed compound at any aryl or heteroaryl carbon (for example, of the central pyridine, pyridazine, pyrimidine or pyrazine, of the E moiety (e.g., of an R17group thereof as in compound 403), or of the T moiety (e.g., of an “A” ring thereof as in compounds 371 and 394)). and all other variables are as described above, for example with reference to structural formula (I). Any of the compounds disclosed with reference to structural formulae (I)-(LXXXVI) can be used in the labeled conjugate of structural formula (LXXXVII).

For example, in one particular embodiment, a labeled conjugate has structural formula (LXXXVIII):

in which all variables are as described above, for example with reference to any of structural formulae (I)-(LXXXVI). The bond to the bracketed compound can be made, for example, at the central pyridine, pyridazine, pyrimidine or pyrazine.

Another disclosed embodiment of a labeled conjugate has the formula (LXXXIX):

The bond to the bracketed compound can be made, for example, at the central pyridine, pyridazine, pyrimidine or pyrazine.

Compounds of formulae (LXXXIX) can be synthesized by those of skill in the art of organic synthesis, for example by reductive amination of N-Boc-glycine aldehyde with a primary amine H2NR2, to yield R2NHCH2CH2NHBoc, which is can be coupled to a pyridinecarboxylic acid to build up the target structure as described herein. The Boc protecting group can be removed, and the resulting amine further elaborated to provide the labeled species.

In another particular embodiment, a labeled conjugate has structural formula (XC):

in which all variables are as described above, for example with reference to any of structural formulae (I)-(LXXXVI). The bond to the bracketed compound can be made, for example, at the central pyridine, pyridazine, pyrimidine or pyrazine. Compound 159 is an example of an embodiment according to structural formula (XC).

Compounds according to structural formula (XC) can be made according to Scheme 7, below, and as described with respect to Examples 159 and 164.

Referring to Scheme 7, a chloropyridinedicarboxylic acid monoethyl ester (xii) is coupled with an amine (here, a substituted 1-benzylpiperazine) to form a carboxymethyl-substituted chloropyridinecarboxamide (xiii), which is coupled with a protected propargyl amine to form a carboxyethyl-substituted alkynylpyridinecarboxamide (xiv). Compound (xiv) is saponified, then coupled with an amine (here, a substituted 1-benzylpiperidine), to form a (3-amino-1-propyne)-substituted pyridinedicarboxamide, Compound 164 of Table 1. Compound 164 is deprotected, and the free amine is coupled with a biotinyl-linked acid to form Compound 159 of Table 1.

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

EXAMPLES

The following compounds were made using methods analogous to those of Schemes 1-7; in certain cases, exemplary synthetic procedures are provided.

Compound 159: N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,20-dioxo-24-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-7,10,13,16-tetraoxa-4,19-diazatetracos-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide. Hydrogen chloride (0.054 mL of a 4.0M solution in dioxane, 0.216 mmol, 5.0 eq) was added to a solution of Compound 164 (see below) (0.030 g, 0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 90 minutes before removing the solvent under a stream of nitrogen. The residue was dried under vacuum to provide 3-(3-aminoprop-1-ynyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide trihydrochloride, which was used without further purification; m/z 594 [M+H]+. To a suspension of the 3-(3-aminoprop-1-ynyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide trihydrochloride (0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL) was added triethylamine (0.018 mL, 0.129 mmol, 3.0 eq) forming a brown solution. 15-[(D)-(+)-Biotinylamino]-4,7,10,13-tetraoxapentadecanoic acid (0.023 g, 0.047 mmol, 1.1 eq) and HATU (0.018 g, 0.047 mmol, 1.1 eq) were added followed by dimethylaminopyridine (0.005 g, 0.043 mmol, 1.0 eq). The reaction was stirred at room temperature for 3 hours before pouring into water (20 mL). The organics were extracted with CH2Cl2(3×25 mL). The combined organics were washed with brine (35 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by RP-HPLC to provide Compound 159; m/z 1068 [M+H]+.

Coupling of the Benzoylpiperidine

Hydrolysis of the Methyl Ester

Coupling of the Benzylaminopiperidine

Synthesis of Compounds 349 and 350

Coupling of the 1-tert-Butyloxycarbonyl-3-Fluoro-4-aminopiperidine

Deprotection of the tert-Butyloxycarbonyl Group

Compound 452: N-((3R,4R)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide. Compound 452 was separated from the racemic mixture of Compound 349 using chiral chromatography on an (R,R)-Whelk-O 1 25 cm×10 mm column (silica modified with covalently bound 4-(3,5-dinitrobenzamido)tetrahydrophenanthrene), available from Regis Technologies. The instrument was a TharSFC semi-preparative HPLC system, and elution was performed isocratically using 50% MeOH with 0.1% diethylamine in supercritical carbon dioxide at 14 mL/min at 30° C. Compound 452 was the later-eluting peak (at about 21 minutes under the conditions described above). The spectral data agree with Compound 349. Compound 452 was independently enantioselectively synthesized as described in the following scheme:

The first step of the synthesis followed the method of Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C., J. Am. Chem. Soc., 2011, 133(6), 1738-1741, which is hereby incorporated herein by reference in its entirety. 9-Epi-DHQA is (1R)-((2R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine. The optical rotation [α] of the (3R,45)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate was −20.0° (c 0.33, CH2Cl2); the literature value for the corresponding (3S,4R) compound is +21.6°. See International Patent Application Publication no. WO 2010/128425.

Compound 453: N-((3S,4S)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide. Compound 453 was separated from the racemic mixture of Compound 349 using chiral chromatography as described above with reference to Compound 452. Compound 452 was the earlier-eluting peak (at about 20 minutes under the conditions described above). The spectral data agree with Compound 349.

6-Chloropyridazine-3-carboxylic acid (0.96 g, 6.2 mMol) was dissolved in dichloromethane (20 mL) and treated with 4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (1.79 g, 6.2 mMol), HATU (2.37 g, 6.2 mMol) and DIEA (3.6 mL, 3.3 eq.). The reaction stirred at RT for 3d. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The crude product was purified by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane.

Synthesis of 1-tert-Butyloxycarbonyl-4-N-methylaminopiperidine

Coupling of the 4-N-methylpiperidine

Synthesis of 1-tert-Butyloxycarbonyl-3,3-difluoro-4-aminopiperidine

Palladium hydroxide (approx. 0.030 g) was added to a solution of the benzylaminopiperidine (0.045 g, 0.138 mmol) in ethanol (3.0 mL). The flask was purged with hydrogen and the reaction stirred under an atmosphere of hydrogen for 2 hours. The flask was purged with nitrogen and the reaction filtered through celite, eluting with 5% MeOH—CH2Cl2(4×5 mL). The filtrate was concentrated under reduced pressure to yield the title compound as a colourless oil, which was used without purification;

Coupling of the 3,3-difluoro-4-aminopiperidine to the pyridine carboxylic acid

For use in the synthesis of various compounds described above, (cis)- and (trans)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate were prepared as described in the scheme below:

Increase in AMPK Activity

Compounds were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. Reagents and procedures for measuring AMPK activation are well known and kits for AMPK activation assays are commercially available. The EC50values for AMPK activation for compounds 1-498 are presented in Table 2 below, in which “A” is less than 0.5 μM; “B” is 0.5-1 μM; “C” is 1-5 μM; and “D” is 5-10 μM; and “E” is >10 μM: