# Patent

## Title
Methods for using carboxamide, sulfonamide and amine compounds

## Abstract

Disclosed are uses of carboxamide, sulfonamide and amine compounds for the treatment and amelioration of disorders and conditions related to oxidative stress, mitochondrial dysfunction, free radical damage and metabolic inefficiency, among others. Also described are methods for increasing exercise endurance, exercise efficiency and aerobic workload using the compounds described herein.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of U.S. provisional patent application No. 61/319,864, filed Mar. 31, 2010, which is incorporated herein by reference.


BACKGROUND
1. Field
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 carboxamide compounds and pharmaceutical compositions thereof, and to methods of treating and ameliorating disorders and conditions related to oxidative stress, mitochondrial dysfunction, free radical damage and metabolic inefficiency, among others.
2. Technical Background
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 5′′-AMP-activated protein kinase (AMPK) pathway. Adiponectin receptors 1 and 2 are membrane-bound proteins found in skeletal muscle and liver tissue. 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). Adiponectin 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, adiponectin decreases glycogen concentration by reducing the activity of glycogen synthase. Adiponectin 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.
SUMMARY
One aspect of the disclosure relates to methods of treating or ameliorating disorders and conditions related to oxidative stress, mitochondrial dysfunction, free radical damage and metabolic inefficiency, using a compound having any of structural formula (1-I), (2-I), (3-I), (4-I), (5-I) and (5-XVII):




or a pharmaceutically acceptable salt, prodrug or N-oxide thereof (or solvate or hydrate thereof), wherein the variables are as described herein.

Another aspect of the present disclosure relates to methods for increasing exercise endurance, exercise efficiency and aerobic workload in subjects using the compounds described herein.
Another aspect of the present disclosure relates to methods for using the compounds described herein as exercise mimetics.
Another aspect of the present disclosure relates to methods for increasing fiber oxidative capacity of muscle fiber using the compounds described herein.


DETAILED DESCRIPTION
One aspect of the disclosure provides 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, the method including administering to the subject an effective amount of a compound having structural formula (1-I):




or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof (or a solvate or hydrate thereof), wherein

    
    
        “B” represents -(aryl or heteroaryl)- substituted by w R3 and k R14;
        E is —C(O)—, —S(O)2— or a single bond, provided that when “B” is phenyl, E is not —C(O)—;
        R1 is H, —(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl);
        R2 is -Hca, -Cak-N(R9)-G-R22 or —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O—, —S— or —N(R9)— and R24 is —R23, -G-R23, or —C(O)O—(C1-C6 alkyl);
        each R3 is substituted on a benzo or pyrido carbon of the ring system denoted by “B” and is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        w is 0, 1, 2 or 3;
        each R14 is substituted on a non-benzo, non-pyrido carbon of the ring system denoted by “B”, and is independently selected from —(C1-C6 alkyl), —(C1-C6 halooalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        k is 0, 1 or 2;
        each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 on the same carbon optionally combine to form oxo;
        x is 0, 1, 2, 3 or 4;
        n is 0, 1, 2 or 3;
        T is —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10 or
    
    






    
    
         in which
        
            Q is —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16, or —S(O)2—;
            the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl;
            each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, —(C0-C6 alkyl)-C(O)R10, -halogen, —NO2 and —CN; and
            y is 0, 1, 2, 3 or 4;
        
        
        in which
        
            each L is independently selected from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—, —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,
            each R6, R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9—(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl),
            each R9 is independently selected from —H, —(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl),
            each G is independently —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16, or —S(O)2—,
            each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo,
            each R20, R22 and R23 is independently Ar or Het,
            each Ar is an optionally substituted aryl,
            each Het is an optionally substituted heteroaryl,
            each Cak is an optionally substituted cycloalkyl,
            each Hca is an optionally substituted heterocycloalkyl, and
            each alkyl is optionally substituted.
        
        
    
    


Various embodiments of compounds of structural formula (1-I) suitable for use in the methods described herein are described below. Information regarding these compounds can also be found in U.S. Patent Application Publication no. 2009/0170829, which is hereby incorporated by reference in its entirety.
In certain embodiments of the presently disclosed compounds of structural formula (1-I), the ring system denoted by “B” is




in which X is O or S, and E is —C(O)—. In certain such embodiments, one R14 can be substituted on the furano or thieno carbon. In one such embodiment, R14 is selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, R14 is selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. R14 can be, for example, halo (e.g., —Cl or —F), cyano, or unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl). In other embodiments, no R14 is substituted on the furano or thieno carbon. In certain embodiments, R14 is H or methyl; in others, R14 is halo (e.g., Cl). In other embodiments, no R14 is substituted on the furano or thieno carbon.

In one embodiment of the presently disclosed compounds of structural formula (1-I), X is O.
In certain embodiments of the presently disclosed compounds of structural formula (1-I), the ring system denoted by “B” is




and E is —C(O)— or —S(O)2—.

In certain embodiments of the presently disclosed compounds of structural formula (1-I), the ring system denoted by “B” is




and E is a single bond. In one embodiment, k is 0. In another embodiment, k is 1 or 2. In certain embodiments, In each R14 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R14 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Each R14 can be, for example, halo (e.g., —Cl or —F), cyano, unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl) or unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl).

In certain embodiments of the presently disclosed compounds of structural formula (1-I), T is




In such embodiments, Q is —S(O)2— or —(C0-C3 alkyl)- in which each carbon of the (C0-C3 alkyl) is optionally and independently substituted with one or two R16, in which each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo. In certain embodiments, each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in particular compounds, each R16 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, Q has at most one R16 or an oxo substituted thereon. Q can be, for example, an unsubstituted —(C0-C3 alkyl)-. In other embodiments, Q is a (C1-C3 alkyl) having as its only substitution a single oxo group. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
In certain embodiments of the presently disclosed compounds of structural formula (1-I), the




moiety is





for example, p-(trifluoromethyl)phenyl. In other embodiments, the





moiety is





in one such embodiment, Q is a single bond.

The number of substituents on the ring system denoted by “A”, y, is 0, 1, 2, 3 or 4. For example, in some embodiments, y is 0, 1, 2 or 3, for example 1. In one embodiment, y is not zero and at least one R5 is halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 or —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 alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.
In certain embodiments of the presently disclosed compounds of structural formula (1-I), each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R5 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In one embodiment of the compounds of structural formula (1-I), y is 0.
In the presently disclosed compounds, 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-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
For example, in certain embodiments of the presently disclosed compounds, the ring system denoted by “A” is a phenyl. In one embodiment, y is 1 and R5 is attached to the phenyl para to Q. In another embodiment, y is 1 and R5 is selected from the group consisting of halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —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-C4 alkyl) or (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R5 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. In another embodiment, the




moiety is a 3,4-dihalophenyl.

In another embodiment of the presently disclosed compounds of structural formula (1-I), 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 one embodiment, when the “A” ring system is heteroaryl, Q is a —(C0-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. In certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
In one embodiment of the presently disclosed compounds, the compound has structural formula (1-II):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-III):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-IV):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-V):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-VI):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-VII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-VIII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-IX):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has the structural formula (1-X):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XI):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XIII):




in which the variables are defined as described above with reference to structural formula (1-I).

In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XIV):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the furano carbon. In other embodiments, no R14 is substituted on the furano carbon.

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XV):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the furano carbon. In other embodiments, no R14 is substituted on the furano carbon.

In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XVI):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the thieno carbon. In other embodiments, no R14 is substituted on the thieno carbon.

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XVII):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the thieno carbon. In other embodiments, no R14 is substituted on the thieno carbon.

The presently disclosed compounds include S-oxidized forms of the benzothiophene compounds described (e.g., with reference to structural formulae (1-XVI) and (1-XVII). S-oxides include, for example, sulfoxides (—SO—) and sulfones (—SO2—). Such compounds may be oxidized chemically or upon administration to e.g. a human subject, may be oxidized biologically. Chemically oxidized compounds may also be biologically reduced to the benzothiophene form.
In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XVIII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XIX):




in which the variables are defined as described above with reference to structural formula (1-I).

In certain embodiments of the compounds disclosed with respect to structural formulae (1-I)-(1-XIX), n is 1 or 2. For example, in one embodiment, n is 2. In another embodiment, n is 1.
In one embodiment of the presently disclosed compounds, the compound has the structural formula (1-XX):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXI):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXIII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXIV):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXV):




in which the variables are defined as described above with reference to structural formula (1-I).

In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XXVI):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXVII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXVIII):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXIX):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXX):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXI):




in which the variables are defined as described above with reference to structural formula (1-I).

In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXII):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the furano carbon. In other embodiments, no R14 is substituted on the furano carbon.

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXIII):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the furano carbon. In other embodiments, no R14 is substituted on the furano carbon.

In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXIV):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the thieno carbon. In other embodiments, no R14 is substituted on the thieno carbon.

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXV):




in which the variables are defined as described above with reference to structural formula (1-I). In certain embodiments, one R14 is substituted on the thieno carbon. In other embodiments, no R14 is substituted on the thieno carbon.

In one embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXVI):




in which the variables are defined as described above with reference to structural formula (1-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (1-XXXVII):




in which the variables are defined as described above with reference to structural formula (1-I).

In certain embodiments of the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), R1 is —H. In other embodiments, R1 is (C1-C4 alkyl), for example methyl, ethyl, n-propyl or isopropyl.
In certain embodiments of the presently disclosed compounds of any structural formulae (1-I)-(1-XXXVII), R2 is -Hca. In certain embodiments, R2 is an optionally-substituted monocyclic heterocycloalkyl. In another embodiment, R2 is not an oxo-substituted heterocycloalkyl.
In certain particular compounds disclosed herein having any of structural formulae (1-I)-(1-XXXVII), R2 is -(optionally-substituted azetidinyl), -(optionally-substituted pyrrolidinyl), -(optionally-substituted piperidinyl), or -(optionally-substituted azepanyl). For example, R2 can be -(optionally substituted piperidinyl) or -(optionally substituted pyrrolidinyl). In one embodiment, R2 is -(optionally substituted piperidinyl). In another embodiment, R2 is -(optionally substituted pyrrolidinyl).
In particular embodiments of the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), R2 is -(optionally-substituted azetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl). For example, in one embodiment, R2 is -(optionally substituted piperidin-4-yl). In another embodiment, R2 is -(optionally substituted pyrrolidin-3-yl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties described above are substituted at their 1-positions. For example, in one embodiment, R2 is substituted at its 1-position with —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het, for example -(unsubstituted C0-C3 alkyl)-Ar or -(unsubstituted C0-C3 alkyl)-Het. For example, in one particular embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with a benzyl substituted with an electron withdrawing group; or with a pyridinylmethyl optionally substituted with an electron withdrawing group. For example, the benzyl or pyridinylmethyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzyl or an unsubstituted phenyl.
In other embodiments of the compounds disclosed herein having any of structural formulae (1-I)-(1-XXXVII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted pyridinylmethyl, an optionally substituted furanylmethyl or an optionally substituted thienylmethyl. For example, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety can be substituted with an unsubstituted pyridinylmethyl, an unsubstituted furanylmethyl, or an unsubstituted thienylmethyl.
In other embodiments of the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—O(C0-C6 alkyl), —C(O)—Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2—O(C0-C6 alkyl).
In certain embodiments of the compounds of any of structural formulae (1-I)-(1-XXXVII), R2 is -Cak-N(R9)-G-R22, as described above. For example, in one embodiment, R2 has the structure




in which b is 0, 1, 2, 3 or 4, and each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R21 on the same carbon optionally combine to form oxo. In certain embodiments of the presently disclosed compounds, each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R21 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, b is 1 or 2. In other embodiments, b is 0. In certain embodiments, R9 is H. In certain embodiments, G is a single bond.

In one embodiment of compounds of any of structural formulae (1-I)-(1-XXXVII), R2 has the structure




In certain embodiments of the compounds of any of structural formulae (1-I)-(1-XXXVII), R2 is —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O— or —N(R9)— and R24 is —R23, -GR23, or —C(O)O—(C1-C6 alkyl). In certain embodiments, the (C2-C8 alkyl) is unsubstituted and no carbon is replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—CH2—N(R9)—R24; or —CH2—CH2—CH2—CH2—N(R9)—R24. In other embodiments, the (C2-C8 alkyl) is substituted and/or one or two carbons are replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—O—CH2—CH2—N(R9)—R24; —CH2—CH(CH3)—N(R9)—R24; or —CH2—CH2—O—CH2—C(O)—N(R9)—R24. In certain embodiments, R9 is H. In certain embodiments, R24 is Ar or Het. In certain embodiments, the (C2-C8 alkyl) is a (C2-C5 alkyl).
In the compounds of any of structural formulae (1-I)-(1-XXXVII), w 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 R3 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 certain embodiments, an R3 is substituted on the “B” ring system at a benzo or pyrido ring position meta to the alicyclic ethereal oxygen.
In certain embodiments of the compounds of any of structural formulae (1-I)-(1-XXXVII), each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R3 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments of the compounds of any of structural formulae (1-I)-(1-XXXVII), w is at least one, and at least one R3 is —NR8R9. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the “B” ring system at a benzo or pyrido ring position meta to the alicyclic ethereal oxygen.
In other embodiments of the compounds of any of structural formulae (1-I)-(1-XXXVII), w is at least one, and at least one R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the “B” ring system at a benzo or pyrido ring position meta to the alicyclic ethereal oxygen. In one particular embodiment, R3 is —CH2—N(CH3)—CH2—C(O)—OCH3.
In the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), the number of substituents on the azacycloalkyl ring, x, is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, x can be 0, or can be 1 or 2.
In certain embodiments of the presently disclosed compounds of any of structural formula (1-I)-(1-XXXVII), two R4s combine to form an oxo. The oxo can be bound, for example, at the position alpha to the nitrogen of the azacycloalkyl ring. In other embodiments, no two R4s combine to form an oxo.
In certain embodiments of the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), when x is 4, not all four R4 moieties are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (1-I)-(1-XXXVII), each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R4 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments, the presently disclosed compounds have the structural formula (1-XXXVIII):




in which Q and G are each independently a bond, —CH2—, —C(H)(R16)—, —C(R16)2— or —S(O)2—; v is 0, 1, 2, 3 or 4; each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R15 on the same carbon optionally combine to form oxo; R17 is Het or Ar, and all other variables are defined as described above with reference to structural formulae (1-I)-(1-XXXVII). In one embodiment, Q is a single bond. In another embodiment, Q is —CH2—. In other embodiments, Q is —C(O)— or —S(O)2—. In certain embodiments, G is —CH2—. In other embodiments, G is —C(O)— or —S(O)2—. In other embodiments, G is —CH(CH3)—. For example, in one embodiment, Q is a single bond and G is —CH2— or —C(O)—. As described above, in certain embodiments, the ring system denoted by “A” is aryl or heteroaryl. In one embodiment, the ring system denoted by “A” is substituted with one or more electron-withdrawing groups. In another embodiment, R17 is substituted with one or more electron-withdrawing groups. In certain embodiments, the ring system denoted by “A”, R17 or both are not substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

In the presently disclosed compounds of structural formula (1-XXXVIII), 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 formula (1-XXXVIII), two R15 is combine to form an oxo. The oxo can be bound, for example, at the position alpha to the nitrogen of the azacycloalkyl ring. In other embodiments, no two R15 is combine to form an oxo.
In certain embodiments of the presently disclosed compounds of structural formula (1-XXXVIII), when v is 4, not all four R15 moieties are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of structural formula (1-XXXVIII), each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R15 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In some embodiments, one R15 is —C(O)NR9R7, which can be bound, for example, at a position alpha to the piperidine nitrogen, or at the position linked to the —N(R1)—.
In certain embodiments of the presently disclosed compounds of structural formula (1-XXXVIII), R17 is an unsubstituted aryl or heteroaryl. In other embodiments, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, R17 is substituted with 1, 2 or 3 substituents selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca. R17 can be substituted with, for example, one such substituent, or two such substituents.
In certain embodiments, the presently disclosed compounds have the structural formula (1-XXXIX):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XL):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLI):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLIII):




in which all variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLIV):




in which R25 is selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl or haloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group; and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII). R25 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLV):




in which G is —C(O)— or —S(O)2— and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLVI):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII). In some embodiments, the compounds of structural formula (1-XLVI) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (1-XLVI) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLVII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with respect to structural formulae (1-I) and (1-XXXVIII). In some embodiments, the compounds of structural formula (1-XLVII) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (1-XLVII) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLVIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-XLIX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-L):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LIV):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LV):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).
In certain embodiments, the presently disclosed compounds have the structural formula (1-LVI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LVII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LVIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LIX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII). In certain embodiments, one R14 is substituted on the furano carbon. R14 can be, for example, as described above with reference to structural formula (1-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl). In other embodiments, no R14 is substituted on the furano carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII). In certain embodiments, one R14 is substituted on the furano carbon. R14 can be, for example, as described above with reference to structural formula (1-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl). In other embodiments, no R14 is substituted on the furano carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII). In certain embodiments, one R14 is substituted on the thieno carbon. R14 can be, for example, as described above with reference to structural formula (1-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl). In other embodiments, no R14 is substituted on the thieno carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII). R5, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII). In certain embodiments, one R14 is substituted on the thieno carbon. R14 can be, for example, as described above with reference to structural formula (1-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl). In other embodiments, no R14 is substituted on the thieno carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXIV):




in which Q, G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formula (1-I). R5, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXV):




in which Q, G, v, R15 and R17 are defined as described above with reference to structural formula (1-XXXVIII), and all other variables are defined as described above with reference to structural formula (1-I). R5, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with respect to any of structural formulae (1-XXXIX)-(1-XLVII).

In certain embodiments of compounds having structural formulae (1-XXXVIII)-(1-LXV), the




moiety has the structure





in which G is —CH2—, —CH(CH3)—, —C(O)— or —S(O)2—. For example, in one embodiment, G is —CH2—. In another embodiment, G is —C(O)— or —S(O)2—.

In other embodiments of compounds having structural formulae (1-XXXVIII)-(1-LXV), the




moiety has the structure





in which G is —CH2—, —C(O)— or —S(O)2—. In such embodiments, the compounds of structural formula (1-XLVII) can be present as racemic mixtures or scalemic mixtures, or in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In other embodiments of compounds having structural formulae (1-XXXVIII)-(1-LXV), the




moiety has the structure





in which G is —CH2—, —C(O)— or —S(O)2—.

In certain embodiments of compounds having structural formulae (1-XXXVIII)-(1-LXV), the R17 moiety has the structure




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca.

In certain embodiments described above, each R27 is selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and each R29 is H, methyl or ethyl, or R27 and R29 together with the nitrogen to which they are bound form Hca.
In certain embodiments of compounds having structural formulae (1-XXXVIII)-(1-LXV), the




moiety is p-(trifluoromethyl)phenyl.

In one embodiment, the presently disclosed compounds have the structural formula (1-LXVI):




in which G, R3 and R17 are as described above with respect to structural formula (1-XXXVIII); R18 is H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., trifluoromethyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and R19 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no alkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R18 and R19 together with the nitrogen to which they are bound form Hca; and R20 is Ar or Het. In certain embodiments, R18 is H or (C1-C4 alkyl), and R19 is —H. In certain embodiments, one R14 is substituted on the furano carbon. R14 can be, for example, as described above with reference to structural formula (1-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., trifluoromethyl). In other embodiments, no R14 is substituted on the furano carbon.

In certain embodiments of compounds of structural formula (1-LXVI), w is 1, and R3 is —NR8R9. In certain such embodiments, R3 is substituted at a benzo or pyrido ring position meta to the alicyclic ethereal oxygen.
In other embodiments of compounds of structural formula (1-LXVI), w is 1, and R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. In certain such embodiments, R3 is substituted at a benzo or pyrido ring position meta to the alicyclic ethereal oxygen.
In another embodiment, the presently disclosed compounds have the structural formula (1-LXVII):




in which R3 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); G and R17 are defined as described above with reference to structural formula (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXVIII):




in which R3 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); G and R17 are defined as described above with reference to structural formula (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXIX):




in which R3 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); G and R17 are defined as described above with reference to structural formula (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXX):




in which Q, R3, R5 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXXI):




in which R3, R5 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXXII):




in which Q, R3, R5 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXXIII):




in which R3, R5 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In another embodiment, the presently disclosed compounds have the structural formula (1-LXXIV):




in which R3, R5 and R14 are defined as described above with reference to structural formulae (1-I) and (1-XXXVIII); and R18 and R19 are defined as described above with reference to structural formula (1-LXVI).

In one embodiment, the presently disclosed compounds have the structural formula (1-LXXV):




in which one J is N and the other is CH; Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXVI):




in which one J is N and the other is CH; Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXVII):




in which one J is N, and the other is CH; Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXVIII):




in which one J is N, and the other three are CH; Q is —CH2— or a single bond; G G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXIX):




in which one J is N and the other is CH; Q is —CH2— or a single bond G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXX):




in which one J is N, and the other three are CH; Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXI):




in which one J is N, and the other is CH; Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXII):




in which one J is N, and the other three are CH; Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXIII):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LX) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXIV):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LXI) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXV):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LX) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXVI):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LXI) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXVII):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LXII) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXVIII):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LXIII) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-LXXXIX):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LXII) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XC):




in which Q is —CH2— or a single bond; G is CH2 or CO; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formulae (1-I) and (1-LXIII) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XCI):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formula (1-I) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XCII):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formula (1-I) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XCIII):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formula (1-I) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

In certain embodiments, the presently disclosed compounds have the structural formula (1-XCIV):




in which Q is —CH2— or a single bond; G is CH2 or C(O); R3 is as described above with respect to structural formulae (1-I) and (1-XXXVIII) (e.g., absent or halo); R14 is as described above with respect to structural formula (1-I) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H.

Examples of compounds presently disclosed for use as described herein include those described in U.S. patent application Ser. No. 11/963,742, filed Dec. 21, 2007, Ser. No. 12/272,581, filed Nov. 17, 2008, Ser. No. 12/334,201, filed Dec. 12, 2008, Ser. No. 12/428,334, filed Apr. 22, 2009, and Ser. No. 12/695,861, filed Jan. 28, 2010, each of which are hereby incorporated herein by reference in their entireties. Further examples of compounds for use as disclosed herein include those according to structural formula (1-I) illustrative examples of which are listed in Table 1. These compounds can be made, for example using a procedure analogous to those described in U.S. Patent Application Publications nos. 2009/0163511, 2009/0170829, 2009/0186894 and 2009/0275609, and in U.S. patent application Ser. No. 12/695,861, each of which is hereby incorporated by reference in its entirety.









TABLE 1





No.
Name
Structure







1-1
5-(1-(4-cyanophenyl)piperidin-4- yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)picolinamide






 


1-2
N-(1-(4-cyanobenzyl)piperidin-4- yl)-5-(1-(4-cyanophenyl)piperidin- 4-yloxy)picolinamide






 


1-3
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-4
N-(1-(4-cyanobenzyl)piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-5
N-(1-(pyridin-3-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-6
N-(1-(pyridin-3-ylmethyl)piperidin- 4-yl)-5-(1-(4- cyanophenyl)piperidin-4- yloxy)picolinamide






 


1-7
methyl 4-((4-(5-(1-(4- cyanophenyl)piperidin-4- yloxy)picolinamido)piperidin-1- yl)methyl)benzoate






 


1-8
methyl 4-((4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamido)piperidin-1- yl)methyl)benzoate






 


1-9
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamido)piperidine-1- carboxylate






 


1-10
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-11
N-(1-(4-fluorobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-12
tert-butyl 4-(4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamido)piperidine-1- carboxylate






 


1-13
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-14
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-15
tert-butyl 4-(2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4- yloxy)isonicotinamido)piperidine- 1-carboxylate






 


1-16
N-(1-(4-fluorobenzyl)piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-17
N-(1-(4-cyanobenzyl)piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-18
N-(1-(pyridin-3-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-19
N-(piperidin-4-yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)isonicotinamide






 


1-20
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)isonicotinamide






 


1-21
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)isonicotinamide






 


1-22
N-(1-(4-fluorobenzyl)piperidin-4- yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)isonicotinamide






 


1-23
(R)-tert-butyl 3-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamido)pyrrolidine- 1-carboxylate






 


1-24
(R)-N-(pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-25
(R)-N-(1-(pyridin-4- ylmethyl)pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-26
(S)-tert-butyl 3-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamido)pyrrolidine- 1-carboxylate






 


1-27
(S)-N-(pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-28
N-(1-(4-cyanobenzyl)piperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-29
N-(1-(4-fluorobenzyl)piperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-30
(S)-N-(1-(pyridin-4- ylmethyl)pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-31
(S)-N-(1-(4- cyanobenzyl)pyrrolidin-3-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-32
(S)-N-(1-(4- fluorobenzyl)pyrrolidin-3-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-33
(R)-N-(1-(4- cyanobenzyl)pyrrolidin-3-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-34
(R)-N-(1-(4- fluorobenzyl)pyrrolidin-3-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-35
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide






 


1-36
N-(1-phenethylpiperidin-4-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-37
N-(1-(naphthalen-2- ylmethyl)piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-38
N-(1-benzylpiperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-39
N-(1-(4- (dimethylamino)benzyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-40
N-(1-(4- morpholinobenzyl)piperidin-4-yl)- 5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-41
N-(1-(4-cyanobenzyl)azetidin-3- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-42
N-(1-(pyridin-4-ylmethyl)azetidin- 3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-43
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-44
N-(1-(pyrimidin-5- ylmethyl)piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-45
methyl 4-((4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamido)piperidin-1- yl)methyl)benzoate






 


1-46
4-((4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamido)piperidin-1- yl)methyl)benzoic acid






 


1-47
5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-N-(1-((1-trityl-1H- imidazol-4-yl)methyl)piperidin-4- yl)picolinamide






 


1-48
N-(1-((1H-imidazol-4- yl)methyl)piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-49
tert-butyl 3-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4- yloxy)picolinamido)propylcarbamate






 


1-50
N-(3-(pyridin-4- ylmethylamino)propyl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide






 


1-51
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-52
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- cyanophenyl)piperidin-4- yloxy)pyridine-3-sulfonamide






 


1-53
6-(1-(4-cyanobenzyl)piperidin-4- yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)pyridine-3- sulfonamide






 


1-54
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3- sulfonamido)piperidine-1- carboxylate






 


1-55
N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-56
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-57
N-(1-(3-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-58
N-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-59
N-(1-(3- (trifluoromethyl)benzyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-60
N-(1-(4-fluorobenzoyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine-3-sulfonamide






 


1-61
tert-butyl 4-(3-methyl-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate






 


1-62
3-methyl-N-(piperidin-4-yl)-6-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-63
N-(1-(4-fluorobenzyl)piperidin-4- yl)-3-methyl-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-64
N-(1-(4-cyanobenzyl)piperidin-4- yl)-3-methyl-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-65
3-methyl-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-66
N-(1-(3-cyanobenzyl)piperidin-4- yl)-3-methyl-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-67
N-(1-(2-cyanobenzyl)piperidin-4- yl)-3-methyl-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-68
3-methyl-N-(1-(pyridin-2- ylmethyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-69
3-methyl-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-70
N-(1-benzylpiperidin-4-yl)-5-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzofuran-2-carboxamide






 


1-71
N-(1-benzylpiperidin-4-yl)-5-(1-(4- cyanophenyl)piperidin-4- yloxy)benzofuran-2-carboxamide






 


1-72
N-(1-benzylpiperidin-4-yl)-5-(1-(4- chlorobenzyl)piperidin-4- yloxy)benzofuran-2-carboxamide






 


1-73
N-(1-benzylpiperidin-4-yl)-5-(1-(3- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-74
N-(1-benzylpiperidin-4-yl)-5-(1- (3,4-difluorobenzyl)piperidin-4- yloxy)benzofuran-2-carboxamide






 


1-75
N-(1-benzylpiperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-76
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-77
5-(1-(4-chlorobenzyl)piperidin-4- yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)benzofuran-2-carboxamide






 


1-78
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-79
5-(1-(4-cyanobenzyl)piperidin-4- yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)benzofuran-2-carboxamide






 


1-80
N-(1-benzylpiperidin-4-yl)-5-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-81
tert-butyl 4-(6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate






 


1-82
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate






 


1-83
N-(piperidin-4-yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-84
N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-85
tert-butyl 4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate






 


1-86
N-(piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-87
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-88
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-89
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-90
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-91
N-(1-(4-fluorobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-92
N-(1-(pyridin-2-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-93
N-(1-(pyridin-2-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-94
N-(1-(4-fluorobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-95
N-(1-(pyridin-3-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-96
N-(1-(pyridin-3-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-97
N-(1-(2-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-98
N-(1-(2-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-99
N-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-100
N-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-101
N-(1-(pyridin-3-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-102
tert-butyl 4-(N-methyl-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate






 


1-103
N-methyl-N-(piperidin-4-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-104
N-methyl-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-105
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide, formate salt






 


1-106
N-(1-(pyridin-3- ylsulfonyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-107
N-(1-(4-cyanobenzyl)piperidin-4- yl)-N-methyl-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-108
N-(1-(pyridin-3- ylsulfonyl)piperidin-4-yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide






 


1-109
N-methyl-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-110
N-(1-(3-cyanobenzyl)piperidin-4- yl)-N-methyl-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-111
N-(1-(2-cyanobenzyl)piperidin-4- yl)-N-methyl-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-112
N-(1-isonicotinoylpiperidin-4-yl)-6- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-113
tert-butyl 4-(5-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate






 


1-114
N-(1-benzylpiperidin-4-yl)-5-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzofuran-2-carboxamide






 


1-115
N-(1-isonicotinoylpiperidin-4-yl)-5- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-116
N-(1-benzylpiperidin-4-yl)-5-(1-(4- carbamoylbenzyl)piperidin-4- yloxy)benzofuran-2-carboxamide






 


1-117
N-methyl-N-(1-(pyridin-2- ylmethyl)piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-118
N-(1-isonicotinoylpiperidin-4-yl)- N-methyl-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-119
N-methyl-N-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-120
(R)-tert-butyl 3-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamido)pyrrolidine-1- carboxylate






 


1-121
(R)-N-(pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-122
(R)-N-(1-(pyridin-4- ylmethyl)pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-123
(R)-N-(1-(pyridin-3- ylmethyl)pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-124
(R)-N-(1-(pyridin-2- ylmethyl)pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-125
(R)-N-(1-isonicotinoylpyrrolidin-3- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-126
(R)-N-(1-(pyridin-3- ylsulfonyl)pyrrolidin-3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran-2-carboxamide






 


1-127
(5)-tert-butyl 3-(5-(1-(4- chlorobenzyl)piperidin-4- yloxy)benzofuran-2- carboxamido)pyrrolidine-1- carboxylate






 


1-128
(S)-5-(1-(4-chlorobenzyl)piperidin- 4-yloxy)-N-(pyrrolidin-3- yl)benzofuran-2-carboxamide






 


1-129
(S)-5-(1-(4-chlorobenzyl)piperidin- 4-yloxy)-N-(1-(pyridin-4- ylmethyl)pyrrolidin-3- yl)benzofuran-2-carboxamide






 


1-130
(S)-5-(1-(4-chlorobenzyl)piperidin- 4-yloxy)-N-(1-(pyridin-3- ylmethyl)pyrrolidin-3- yl)benzofuran-2-carboxamide






 


1-131
5-(1-(4-carbamoylbenzyl)piperidin- 4-yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)benzofuran-2-carboxamide






 


1-132
5-(1-(4-carbamoylbenzyl)piperidin- 4-yloxy)-N-(1- isonicotinoylpiperidin-4- yl)benzofuran-2-carboxamide






 


1-133
5-(1-(4-carbamoylbenzyl)piperidin- 4-yloxy)-N-(1-(4- cyanobenzyl)piperidin-4- yl)benzofuran-2-carboxamide






 


1-134
5-(1-(4-carbamoylphenyl)piperidin- 4-yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)benzofuran-2-carboxamide






 


1-135
5-(1-(4-carbamoylphenyl)piperidin- 4-yloxy)-N-(1- isonicotinoylpiperidin-4- yl)benzofuran-2-carboxamide






 


1-136
5-(1-(4-carbamoylphenyl)piperidin- 4-yloxy)-N-(1-(4- cyanobenzyl)piperidin-4- yl)benzofuran-2-carboxamide






 


1-137
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-138
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-139
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- chlorophenyl)piperidin-4- yloxy)benzo[b]thiophene-2- carboxamide






 


1-140
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamido)piperidine-1- carboxylate






 


1-141
N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-142
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-143
N-(1-(pyridin-2-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-144
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-145
N-(1-(3-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-146
N-(1-(2-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-147
tert-butyl 4-(3-chloro-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamido)piperidine-1- carboxylate






 


1-148
3-chloro-N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-149
tert-butyl 4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamido)piperidine-1- carboxylate






 


1-150
N-(piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-151
3-chloro-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-152
3-chloro-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-153
3-chloro-N-(1-(pyridin-2- ylmethyl)piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-154
3-chloro-N-(1-(4- cyanobenzyl)piperidin-4-yl)-6-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-155
3-chloro-N-(1- isonicotinoylpiperidin-4-yl)-6-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide






 


1-156
tert-butyl 4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- ylamino)piperidine-1-carboxylate






 


1-157
N-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- yl)piperidin-4-amine






 


1-158
1-(pyridin-4-ylmethyl)-N-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- yl)piperidin-4-amine






 


1-159
1-(4-fluorobenzyl)-N-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- yl)piperidin-4-amine






 


1-160
4-((4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- ylamino)piperidin-1- yl)methyl)benzonitrile













Another aspect of the disclosure provides 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, the method including administering to the subject an effective amount of a compound having structural formula (2-I):




or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof (or a solvate or hydrate thereof), wherein

    
    
        “B” represents -(aryl or heteroaryl)- substituted by w R3 and k R14;
        the dotted line denoted by “b” is absent, a single bond or a double bond;
        the dotted line denoted by “a” is a bond or absent, provided that if the dotted line denoted by “b” is a double bond, then the dotted line denoted by “a” is absent;
        D is a carbon or N when the dotted line denoted by “a” is absent, and a carbon when the dotted line denoted by “a” is a bond;
        J is —O—, —N(R38)—, —CH2—, —CH(R26)— or —C(R26)2—;
        E is —C(O)—, —S(O)2— or a single bond, provided that when “B” is phenyl, J is —O— and D is a carbon, E is not —C(O)—;
        R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl);
        R2 is -Hca, -Cak-N(R9)-G-R22 or —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O—, —S— or —N(R9)— and R24 is —R23, -G-R23, or —C(O)O—(C1-C6 alkyl), provided that two consecutive carbons of the (C2-C8 alkyl) are not replaced by —O—;
        each R3 is substituted on a benzo, pyrido or pyrazino carbon of the ring system denoted by “B” and is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        w is 0, 1, 2 or 3;
        each R14 is substituted on a non-benzo, non-pyrido, non-pyrazino carbon of the ring system denoted by “B”, and is independently selected from —(C1-C6 alkyl), —(C1-C6 halooalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        k is 0, 1 or 2;
        each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 on the same carbon optionally combine to form oxo;
        x is 0, 1, 2, 3 or 4;
        p is 0, 1, 2, 3 or 4;
        q is 0, 1, 2, 3 or 4;
        the sum of p and q is 1, 2, 3 or 4;
        T is —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10 or
    
    






    
    
         in which
        
            Q is —S(O)2—, L or —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16;
            the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl;
            each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, —(C0-C6 alkyl)-C(O)R10, -halogen, —NO2 and —CN; and
            y is 0, 1, 2, 3 or 4;
        
        
        in which
        
            each L is independently selected from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—, —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,
            each R6, R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9—(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl),
            each R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl),
            each G is independently —S(O)2—, L or —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16, or
            each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo,
            each R26 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R26 on the same carbon combine to form oxo,
            each R38 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl),
            each R22 and R23 is independently Ar or Het,
            each Ar is an optionally substituted aryl,
            each Het is an optionally substituted heteroaryl,
            each Cak is an optionally substituted cycloalkyl,
            each Hca is an optionally substituted heterocycloalkyl, and
            each alkyl is optionally substituted.
        
        
    
    


Various embodiments of compounds of structural formula (2-I) suitable for use in the methods described herein are described below. Information regarding these compounds can also be found in U.S. Patent Application Publication no. 2009/0163511, which is hereby incorporated by reference in its entirety.
In certain embodiments of the presently disclosed compounds of structural formula (2-I), the compound is not

    5-methyl-N,2-bis(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide or
    5-methyl-2-(tetrahydro-2H-pyran-4-yl)-N-(tetrahydrothiophen-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide S,S-dioxide.


In certain embodiments of the presently disclosed compounds of structural formula (2-I), J is —O— or —N(R38)—. In certain such embodiments, D can be, for example, a carbon (for example, it is CH or C substituted with one of the x R4 groups when the bond denoted by “a” is absent, or C when the bond denoted by “a” is present). In other embodiments of the presently disclosed compounds of structural formula (2-I), J is —CH2—, —CH(R26)— or —C(R26)2—, for example, —CH2—. In certain such embodiments, D can be, for example, N.
In certain embodiments of the presently disclosed compounds of structural formula (2-I), R38 is —H. In other embodiments, R38 is —(C1-C4 alkyl), for example methyl, ethyl or propyl. In other embodiments, R38 is —C(O)—(C1-C4 alkyl), for example acetyl. In other embodiments, R38 is —C(O)—O—(C1-C4 alkyl)-, for example —C(O)—O-t-butyl. In certain embodiments, no alkyl of R38 is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments of the presently disclosed compounds of structural formula (2-I), each R26 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R26 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, each R26 is methyl, ethyl, propyl, or two R26 come together to form oxo.
In certain embodiments of the presently disclosed compounds of structural formula (2-I) as described above, the dotted line denoted by “b” is absent. In other embodiments, the dotted line denoted by “b” is a single bond; in one such embodiment, the dotted line denoted by “a” is a bond (thereby forming a double bond between D and the adjacent carbon).
In certain embodiments of the presently disclosed compounds of structural formula (2-I), E is —C(O)—. In other embodiments, E is —S(O)2—
In certain embodiments of the presently disclosed compounds of structural formula (2-I), “B” represents




the dotted line denoted by “b” is a single bond, the dotted line denoted by “a” is a bond, k is 0, J is —N(R38)— and D is a carbon. In one such embodiment, E is —C(O)—.

In other embodiments of the presently disclosed compounds of structural formula (2-I), “B” represents




the dotted line denoted by “b” is absent, the dotted line denoted by “a” is absent, k is 0, J is —N(R38)— and D is a carbon. In one such embodiment, E is —C(O)—.

In other embodiments of the presently disclosed compounds of structural formula (2-I), “B” represents




in which X1 and X2 are independently a carbon (for example, CH or C substituted with one of the w R3 groups) or N, and k is 0. In one such embodiment, E is —C(O)—. In certain embodiments, one of X1 and X2 is N and the other is a carbon. In other embodiments, both X1 and X2 are a carbon. Floating bonds indicate attachment on any carbon of the ring system. In some embodiments, for example, the J moiety is on one ring of the ring system, and the E moiety is on the other ring of the naphthalene, and any R3 groups can be on either ring of the fused ring system.

In other embodiments of the presently disclosed compounds of structural formula (2-I), “B” represents




in which R39 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl). In certain such embodiments, E is —C(O)—. In certain embodiments, one R14 can be substituted on the pyrrolo carbon. In one such embodiment, R14 is selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, R14 is selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3—(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. R14 can be, for example, halo (e.g., —Cl or —F), cyano, unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), or unsubstituted —(C1-C4 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like). In certain embodiments, R14 is H or methyl; in others, R14 is halo (e.g., Cl). In other embodiments, no R14 is substituted on the pyrrolo carbon.

In certain embodiments of the presently disclosed compounds of structural formula (2-I), T is




In such embodiments, Q is —S(O)2—, L or —(C0-C3 alkyl)- in which each carbon of the (C0-C3 alkyl) is optionally and independently substituted with one or two R16, in which each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo. In certain embodiments, each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in particular compounds, each R16 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, Q has at most one R16 or an oxo substituted thereon. Q can be, for example, an unsubstituted —(C0-C3 alkyl)-. In other embodiments, Q is a (C1-C3 alkyl) having as its only substitution a single oxo group. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.

In certain embodiments of the compounds of structural formula (2-I), the




moiety is





for example, p-(trifluoromethyl)phenyl. In other embodiments, the





moiety is





in one such embodiment, Q is a single bond.

The number of substituents on the ring system denoted by “A”, y, is 0, 1, 2, 3 or 4. For example, in some embodiments of the presently disclosed compounds of structural formula (2-I), y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zero and at least one R5 is halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 or —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 certain embodiments of the presently disclosed compounds of structural formula (2-I), each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R5 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In one embodiment of the compounds of structural formula (2-I), y is 0.
In the presently disclosed compounds of structural formula (2-I), 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-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
For example, in certain embodiments of the presently disclosed compounds of structural formula (2-I), the ring system denoted by “A” is a phenyl. In one embodiment, y is 1 and R5 is attached to the phenyl in the para position relative to Q. In another embodiment, y is 1 and R5 is selected from the group consisting of halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —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-C4 alkyl) or (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R5 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. In another embodiment, the




moiety is a 3,4-dihalophenyl.

In another embodiment of the presently disclosed compounds of structural formula (2-I), 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 one embodiment, when the “A” ring system is heteroaryl, Q is a —(C0-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. In certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
In one embodiment of the presently disclosed compounds, the compound has structural formula (2-II):




in which the variables are defined as described above with reference to structural formula (2-I). In certain embodiments, R38 is not H. For example, R38 can in one embodiment be methyl, ethyl or propyl. In another embodiment, R38 can be acetyl. In other embodiments, R38 is H.

In one embodiment of the presently disclosed compounds, the compound has structural formula (2-III):




in which the variables are defined as described above with reference to structural formula (2-I). In certain embodiments, R38 is not H. For example, R38 can in one embodiment be methyl, ethyl or propyl. In another embodiment, R38 can be acetyl. In other embodiments, R38 is H.

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-IV):




in which k is 0, q is 1, 2, 3 or 4, J is —CH2—, —CH(R26)— or —C(R26)2— (e.g., —CH2—), and all other variables are defined as described above with reference to structural formula (2-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-V):




in which k is 0, q is 1, 2, 3 or 4, J is —CH2—, —CH(R26)— or —C(R26)2— (e.g., —CH2—), and all other variables are defined as described above with reference to structural formula (2-I).

In certain embodiments according to structural formulae (2-I)-(2-V), the sum of p and q is 2 or 3. For example, in one embodiment, the sum of p and q is 2 (e.g., p is 1 and q is 1). In another embodiment, the sum of p and q is 3 (e.g., p is 1 and q is 2).
In another embodiment of the presently disclosed compounds, the compound has structural formula (2-VI):




in which k is 0, n is 0, 1, 2 or 3, and all other variables are defined as described above with reference to structural formula (2-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-VII):




in which k is 0, n is 0, 1, 2 or 3, and all other variables are defined as described above with reference to structural formula (2-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-VIII):




in which k is 0, n is 0, 1, 2 or 3, one of X1 and X2 is N and the other is a carbon, and all other variables are defined as described above with reference to structural formula (2-I). In one embodiment, for example, X1 is N and X2 is a carbon. In another embodiment, X1 is a carbon, and X2 is N.

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-IX):




in which k is 0, n is 0, 1, 2 or 3, one of X1 and X2 is N and the other is a carbon, and all other variables are defined as described above with reference to structural formula (2-I). In one embodiment, for example, X1 is N and X2 is a carbon. In another embodiment, X1 is a carbon, and X2 is N.

In one embodiment of the presently disclosed compounds, the compound has structural formula (2-X):




in which n is 0, 1, 2 or 3 and all other variables are defined as described above with reference to structural formula (2-I). In certain embodiments, one R14 is substituted on the pyrrolo carbon. In other embodiments, no R14 is substituted on the pyrrolo carbon.

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XI):




in which the variables are defined as described above with reference to structural formula (2-I). In certain embodiments, one R14 is substituted on the pyrrolo carbon. In other embodiments, no R14 is substituted on the pyrrolo carbon.

In certain embodiments of the compounds disclosed with reference to structural formulae (2-VI)-(2-XI), n is 1 or 2. For example, in one embodiment, n is 2. In another embodiment, n is 1.
In one embodiment of the presently disclosed compounds, the compound has the structural formula (2-XII):




in which the variables are defined as described above with reference to structural formulae (2-I) and (2-II).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XIII):




in which the variables are defined as described above with reference to structural formulae (2-I) and (2-III).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XIV):




in which J is —CH2—, —CH(R26)— or —C(R26)2— (e.g., —CH2—), and all other variables are defined as described above with reference to structural formulae (2-I) and (2-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XV):




in which J is —CH2—, —CH(R26)— or —C(R26)2— (e.g., —CH2—), and all other variables are defined as described above with reference to structural formulae (2-I) and (2-V).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XVI):




in which the variables are defined as described above with reference to structural formulae (2-I) and (2-VI).

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XVII):




in which the variables are defined as described above with reference to structural formulae (2-I) and (2-VII).

In one embodiment of the presently disclosed compounds, the compound has structural formula (2-XVIII):




in which one of X1 and X2 is N, and the other is a carbon; and the other variables are defined as described above with reference to structural formulae (2-I) and (2-VIII). In one embodiment, for example, X1 is N and X2 is a carbon. In another embodiment, X1 is a carbon, and X2 is N.

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XIX):




in which one of X1 and X2 is N, and the other is a carbon; and the other variables are defined as described above with reference to structural formulae (2-I) and (2-IX). In one embodiment, for example, X1 is N and X2 is a carbon. In another embodiment, X1 is a carbon, and X2 is N.

In one embodiment of the presently disclosed compounds, the compound has structural formula (2-XX):




in which the variables are defined as described above with reference to structural formulae (2-I) and (2-X). In certain embodiments, one R14 is substituted on the pyrrolo carbon. In other embodiments, no R14 is substituted on the pyrrolo carbon.

In another embodiment of the presently disclosed compounds, the compound has structural formula (2-XXI):




in which the variables are defined as described above with reference to structural formulae (2-I) and (2-XI). In certain embodiments, one R14 is substituted on the pyrrolo carbon. In other embodiments, no R14 is substituted on the pyrrolo carbon.

In certain embodiments of the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), R1 is —H. In other embodiments, R1 is (C1-C4 alkyl), for example methyl, ethyl, n-propyl or isopropyl.
In certain embodiments of the presently disclosed compounds of any structural formulae (2-I)-(2-XXI), R2 is -Hca. In certain embodiments, R2 is an optionally-substituted monocyclic heterocycloalkyl. In another embodiment, R2 is not an oxo-substituted heterocycloalkyl. In certain embodiments (e.g., when the compound has structural formula (2-II) or (2-III)), R2 is not tetrahydro-2H-pyran-4-yl moiety or a tetrahydrothiophene S,S-dioxide moiety.
In certain of the presently disclosed compounds of any structural formulae (2-I)-(2-XXI), R2 is -(optionally-substituted azetidinyl), -(optionally-substituted pyrrolidinyl), -(optionally-substituted piperidinyl), or -(optionally-substituted azepanyl). For example, R2 can be -(optionally substituted piperidinyl) or -(optionally substituted pyrrolidinyl). In one embodiment, R2 is -(optionally substituted piperidinyl). In another embodiment, R2 is -(optionally substituted pyrrolidinyl).
In certain particular embodiments of the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), R2 is -(optionally-substituted azetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl). For example, in one embodiment, R2 is -(optionally substituted piperidin-4-yl). In another embodiment, R2 is -(optionally substituted pyrrolidin-3-yl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties described above are substituted at their 1-positions. For example, in one embodiment, R2 is substituted at its 1-position with —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het, for example -(unsubstituted C0-C3 alkyl)-Ar or -(unsubstituted C0-C3 alkyl)-Het. For example, in one particular embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with a benzyl substituted with an electron withdrawing group; or with a pyridinylmethyl optionally substituted with an electron withdrawing group. For example, the benzyl or pyridinylmethyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzyl or an unsubstituted phenyl.
In other embodiments of the compounds disclosed herein having any of structural formulae (2-I)-(2-XXI), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted 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 or azepanyl R2 moiety 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 R2 moiety 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 having any of structural formulae (2-I)-(2-XXI), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted 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-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het. In one such embodiment, L is —C(O)—NR9—, such as —C(O)—NH—.
In other embodiments of the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—O(C0-C6 alkyl), —C(O)—Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2—O(C0-C6 alkyl), in which Ar and Het can be, for example, as described above with reference to —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—Het or —C(O)—Ar; in another embodiment, it is substituted at its 1-position with —S(O)2-Het or —S(O)2—Ar. For example, in certain embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally-substituted benzoyl (e.g., substituted with an electron withdrawing group as described above); or with an optionally-substituted nicotinyl, isonicotinyl or picolinyl (e.g., optionally substituted with an electron withdrawing group as described above). In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzoyl; or an unsubstituted nicotinoyl, isonicotinoyl or picolinoyl.
In certain embodiments of the compounds of any of structural formulae (2-I)-(2-XXI), R2 is -Cak-N(R9)-G-R22, as described above. For example, in one embodiment of the disclosed compounds, R2 has the structure




in which c is 0, 1, 2, 3 or 4, and each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R21 on the same carbon optionally combine to form oxo. In certain embodiments of the presently disclosed compounds, each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R21 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, c is 1 or 2. In other embodiments, c is 0. In certain embodiments, R9 is H. In certain embodiments, G is a single bond. In certain embodiments of the presently disclosed compounds, each R22 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments of the presently disclosed compounds, each R23 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.

In one embodiment of compounds of any of structural formulae (2-I)-(2-XXI), R2 has the structure




In certain embodiments of the compounds of any of structural formulae (2-I)-(2-XXI), R2 is —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O— or —N(R9)— and R24 is —R23, -GR23 or —C(O)O—(C1-C6 alkyl). In certain embodiments, the (C2-C8 alkyl) is unsubstituted and no carbon is replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—CH2—N(R9)—R24 or —CH2—CH2—CH2—CH2—N(R9)—R24. In other embodiments, the (C2-C8 alkyl) is substituted and/or one or two carbons are replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—O—CH2—CH2—N(R9)—R24; —CH2—CH(CH3)—N(R9)—R24; or —CH2—CH2—O—CH2—C(O)—N(R9)—R24. In certain embodiments, R9 is H. In certain embodiments, R24 is Ar or Het. In certain embodiments, R24 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, the (C2-C8 alkyl) is a (C2-C5 alkyl).
In the compounds of any of structural formulae (2-I)-(2-XXI), the number of substituents on benzo, pyrido or pyrazino carbons of the ring system represented by “B”, w, is 0, 1, 2 or 3. For example, in one embodiment, w is 0, 1 or 2. In another embodiment, such as when the ring system represented by “B” does not include a benzo, pyrido or pyrazino moeity, w is 0. In other embodiments, w is at least 1, and at least one R3 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 R3 is halo (e.g., chloro) or —(C1-C4 alkyl) (e.g., methyl, ethyl or propyl). In certain embodiments, an R3 is substituted on the “B” ring system at a benzo, pyrido or pyrazino ring position in the meta position relative to the J moiety.
In certain embodiments of the compounds of any of structural formulae (2-I)-(2-XXI), each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R3 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in certain embodiments, each R3 is halo (e.g., chloro) or —(C1-C4 alkyl) (e.g., methyl, ethyl or propyl).
In certain embodiments of the compounds of any of structural formulae (2-I)-(2-XXI), w is at least one, and at least one R3 is —NR8R9. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the “B” ring system at a benzo, pyrido or pyrazino ring position in the meta position relative to the J moiety.
In other embodiments of the compounds of any of structural formulae (2-I)-(2-XXI), w is at least one, and at least one R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the “B” ring system at a benzo, pyrido or pyrazino ring position in the meta position relative to the J moiety. In one particular embodiment, R3 is —CH2—N(CH3)—CH2—C(O)—OCH3.
In the compounds of structural formula (2-I), the number of substituents on non-benzo, non-pyrido, non-pyrazino carbons, k, is 0, 1 or 2. For example, in one embodiment, k is 1. In other embodiments, such as when the ring system represented by “B” contains only benzo, pyridino and/or piperazino carbons, k is 0. In certain embodiments of the compounds of structural formula (2-I), each R14 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R14 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Each R14 can be, for example, halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl) or unsubstituted —(C1-C4 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like).
In the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), the number of substituents on the azacycloalkyl ring, x, is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, x can be 0, or can be 1 or 2.
In certain embodiments of the presently disclosed compounds of any of structural formula (2-I)-(2-XXI), two R4 groups combine to form an oxo. The oxo can be bound, for example, at the position alpha to the nitrogen of the azacycloalkyl ring. In other embodiments, no two R4 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), when x is 4, not all four R4 groups are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (2-I)-(2-XXI), each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R4 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments, the presently disclosed compounds have the structural formula (2-XXII):




in which Q and G are each independently a bond, —CH2—, —C(H)(R16)—, —C(R16)2—, L (e.g., —C(O)—NR9— or —NR9—C(O)—) or —S(O)2—; v is 0, 1, 2, 3 or 4; each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R15 on the same carbon optionally combine to form oxo; R17 is Het or Ar, and all other variables are defined as described above with reference to any of structural formula (2-I)-(2-XXI). In one embodiment, Q is a single bond. In another embodiment, Q is —CH2—. In other embodiments, Q is —C(O)— or —S(O)2—. In certain embodiments, G is —CH2—. In other embodiments, G is —C(O)— or —S(O)2—. In other embodiments, G is —CH(CH3)—. In other embodiments, G is —C(O)—NH—. The above-recited 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)—. As described above, in certain embodiments, the ring system denoted by “A” is aryl or heteroaryl. In one embodiment, the ring system denoted by “A” is substituted with one or more electron-withdrawing groups as described above. In another embodiment, R17 is substituted with one or more electron-withdrawing groups as described above. In certain embodiments, the ring system denoted by “A”, R17 or both are not substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In certain embodiments, the azacycloalkyl to which -G-R17 is bound is a piperidinyl; in other embodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formula (2-XXII), 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 formula (2-XXII), two R15 groups combine to form an oxo. The oxo can be bound, for example, at the position alpha relative to the nitrogen of the azacycloalkyl ring. In other embodiments, no two R15 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of structural formula (2-XXII), when v is 4, not all four R15 moieties are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of structural formula (2-XXII), each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R15 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In some embodiments, one R15 is —C(O)NR9R7, which can be bound, for example, at a position alpha relative to the piperidine nitrogen, or at the position linked to the —N(R1)—.
In certain embodiments of the presently disclosed compounds of structural formula (2-XXII), R17 is an unsubstituted aryl or heteroaryl. In other embodiments, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, R17 is substituted with 1, 2 or 3 substituents selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca. R17 can be substituted with, for example, one such substituent, or two such substituents.
In certain embodiments, the presently disclosed compounds have the structural formula (2-XXIII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXIV):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXV):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXVI):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXVII):




in which all variables are as described above with reference to any of structural formulae (2-I)-(2-XXII).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXVIII):




in which R25 is selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl or haloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group; and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). R25 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXIX):




in which G is —C(O)—, —S(O)2— or —C(O)—NH— and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXX):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). In one embodiment, R27 and R29 are both H. In some embodiments, the compounds of structural formula (2-XXX) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (2-XXX) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXI):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (2-I)-(2-XXII). In one embodiment, R27 and R29 are both H. In some embodiments, the compounds of structural formula (2-XXXI) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (2-XXXI) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-II). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-III). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXIV):




in which J is —CH2—, —CH(R26)— or —C(R26)2— (e.g., —CH2—), G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-IV). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXV):




in which J is —CH2—, —CH(R26)— or —C(R26)2— (e.g., —CH2—), G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-V). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXVI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-VI). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXVII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-VII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI).

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXVIII):




in which one of X1 and X2 is N, and the other is a carbon; G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-VIII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI). In one embodiment, for example, X1 is N and X2 is a carbon. In another embodiment, X1 is a carbon, and X2 is N.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XXXIX):




in which in which one of X1 and X2 is N, and the other is a carbon; G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-IX). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI). In one embodiment, for example, X1 is N and X2 is a carbon. In another embodiment, X1 is a carbon, and X2 is N.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XL):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-X). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI). In certain embodiments, one R14 is substituted on the pyrrolo carbon. R14 can be, for example, as described above with reference to structural formula (2-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like). In other embodiments, no R14 is substituted on the pyrrolo carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (2-XLI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (2-XXII), and all other variables are defined as described above with reference to structural formulae (2-I) or (2-XI). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (2-XXIII)-(2-XXXI). In certain embodiments, one R14 is substituted on the pyrrolo carbon. R14 can be, for example, as described above with reference to structural formula (2-I). For example, in one embodiment R14 is halo (e.g., —Cl or —F), cyano unsubstituted —(C1-C4 alkyl) (e.g., methyl or ethyl), unsubstituted —(C1-C4 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like). In other embodiments, no R14 is substituted on the pyrrolo carbon.

In certain embodiments of compounds having structural formulae (2-XXII)-(2-XLI), the




moiety has the structure





in which G is —CH2—, —CH(CH3)—, —C(O)—, —S(O)2— or —C(O)—NH—. For example, in one embodiment, G is —CH2—. In another embodiment, G is —C(O)— or —S(O)2—. In another embodiment, G is —C(O)—NH—.

In other embodiments of compounds having structural formulae (2-XXII)-(2-XLI), the




moiety has the structure





in which G is —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—, R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca. In such embodiments, the compounds can be present as racemic mixtures or scalemic mixtures, or in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In other embodiments of compounds having structural formulae (2-XXII)-(2-XLI), the




moiety has the structure





in which G is —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—.

In certain embodiments of compounds having structural formulae (2-XXII)-(2-XLI), the R17 moiety has the structure




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca.

In certain embodiments of compounds having structural formulae (2-XXII)-(2-XLI), w is 1, and R3 is —NR8R9. In certain such embodiments, R3 is substituted at a benzo, pyrido or pyrazino ring position in the meta position relative to the J moiety.
In other embodiments of compounds having structural formulae (2-XXII)-(2-XLI), w is 1, and R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. In certain such embodiments, R3 is substituted at a benzo, pyrido or pyrazino ring position in the meta position relative to the J moiety.
In certain embodiments described above, each R27 is selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and each R29 is H, methyl or ethyl, or R27 and R29 together with the nitrogen to which they are bound form Hca.
In certain embodiments of compounds having structural formulae (2-XXII)-(2-XLI), at least one R5 moiety is a haloalkyl group, and in exemplary embodiments of these formulae the




moiety is p-(trifluoromethyl)phenyl. By way of further illustration, certain exemplary compounds including such





moieties have structural formula (2-XLII) or (2-XLIII):





in which all variables are as described above with reference to structural formulae (2-XXXII) or (2-XXXIII).

In one embodiment, the presently disclosed compounds have the structural formula (2-XLIV):




in which G, R1, R3, R17 and R38 are as described above with reference to any of structural formulae (2-I), (2-II), (2-XII) or (2-XXII), R18 is H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and R19 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no alkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R18 and R19 together with the nitrogen to which they are bound form Hca. In one embodiment, R18 and R19 are both H.

In one embodiment, the presently disclosed compounds have the structural formula (2-XLV):




in which G, R1, R3, R17 and R38 are as described above with reference to any of structural formulae (2-I), (2-III), (2-XIII) and (2-XXII), and R18 and R19 are defined as described above with reference to structural formula (2-XLIV).

In another embodiment, the presently disclosed compounds have the structural formula (2-XLVI):




in which Q, R1, R3, R5 and R38 are defined as described above with reference to any of structural formulae (2-I), (2-II), (2-XII) and (2-XXII), and R18 and R19 are defined as described above with reference to structural formula (2-XLIV).

In another embodiment, the presently disclosed compounds have the structural formula (2-XLVII):




in which Q, R1, R3, R5 and R38 are defined as described above with reference to any of structural formulae (2-I), (2-III), (2-XIII) and (2-XXII), and R18 and R19 are defined as described above with reference to structural formula (2-XLIV).

In another embodiment, the presently disclosed compounds have the structural formula (2-XLVIII):




in which R1, R3, R5 and R38 are defined as described above with reference to any of structural formulae (2-I), (2-II), (2-XII) and (2-XXII), and R18 and R19 are defined as described above with reference to structural formula (2-XLIV).

In another embodiment, the presently disclosed compounds have the structural formula (2-XLIX):




in which R1, R3, R5 and R38 are defined as described above with reference to any of structural formulae (2-I), (2-III), (2-XIII) and (2-XXII), and R18 and R19 are defined as described above with reference to structural formula (2-XLIV).

In compounds according to any of structural formulae (2-I), (2-IV)-(2-XI) and (2-XIV)-(2-XXI), T and R2 can be defined as described above with reference to structural formulae (2-XLIV)-(2-XLIX).
In certain embodiments, the presently disclosed compounds have the structural formula (2-L):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (2-I), (2-II), (2-XII) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (2-I), (2-II), (2-XII) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (2-I), (2-III), (2-XIII) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (2-I), (2-III), (2-XIII) and (2-XXII); R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In one embodiment, the presently disclosed compounds have the structural formula (2-LIV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with respect to any of structural formulae (2-I), (2-IV), (2-XIV) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central phenyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (2-I), (2-IV), (2-XIV) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central phenyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LVI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with respect to any of structural formulae (2-I), (2-V), (2-XV) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central phenyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LVII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (2-I), (2-V), (2-XV) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central phenyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LVIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (2-I), (2-VI), (2-XVI) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the naphthyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to structural formulae (2-I), (2-VI), (2-XVI) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the naphthyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (2-I), (2-VII), (2-XVII) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the naphthyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to structural formulae (2-I), (2-VII), (2-XVII) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the naphthyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXII):




in which one of X1 and X2 is N and the other is a carbon; Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (2-I), (2-VIII), (2-XVIII) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the quinolinyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXIII):




in which one of X1 and X2 is N and the other is a carbon; Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to structural formulae (2-I), (2-VIII), (2-XVIII) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the quinolinyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXIV):




in which one of X1 and X2 is N and the other is a carbon; Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (2-I), (2-IX), (2-XIX) and (2-XXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the quinolinyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXV):




in which one of X1 and X2 is N and the other is a carbon; Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to structural formulae (2-I), (2-IX), (2-XIX) and (2-XXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the quinolinyl moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXVI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R39 are as described above with reference to any of structural formulae (2-I), (2-X), (2-XX) and (2-XXII); R14 is as described above with reference to structural formulae (2-I), (2-X), (2-XX) and (2-XXII) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXVII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R39 are as described above with reference to any of structural formulae (2-I), (2-X), (2-XX) and (2-XXII); R14 is as described above with reference to structural formulae (2-I), (2-X), (2-XX) and (2-XXII) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXVIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R39 are as described above with reference to any of structural formulae (2-I), (2-XI), (2-XXI) and (2-XXII); R14 is as described above with reference to structural formulae (2-I), (2-XI), (2-XXI) and (2-XXII) (e.g., absent, methyl or halo); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (2-LXIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R39 are as described above with reference to any of structural formulae (2-I), (2-X), (2-XX) and (2-XXII); R14 is as described above with reference to structural formulae (2-I), (2-X), (2-XX) and (2-XXII) (e.g., absent, methyl or halo); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety.

Examples of compounds according to structural formula (2-I) include those listed in Table 2. These compounds can be made, for example using a procedure analogous to those described in U.S. Patent Application Publications nos. 2009/0163511, 2009/0170829, 2009/0186894 and 2009/0275609, and in U.S. patent application Ser. No. 12/695,861, each of which is hereby incorporated by reference in its entirety.









TABLE 2





No.
Name
Structure







2-1
benzyl 8-(1-(4-cyanobenzyl)piperidin-4- ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3- b]indole-2(5H)-carboxylate






 


2-2
benzyl 8-(1-(4-benzyl)piperidin-4- ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3- b]indole-2(5H)-carboxylate






 


2-3
benzyl 8-(1-(tert-butoxycarbonyl)piperidin- 4-ylcarbamoyl)-3,4-dihydro-1H- pyrido[4,3-b]indole-2(5H)-carboxylate






 


2-4
2-benzyl-N-(1-(4-cyanobenzyl)piperidin-4- yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide






 


2-5
2-benzyl-N-(1-(4- trifluoromethylbenzyl)piperidin-4-yl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-6
tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamido)piperidine-1-carboxylate






 


2-7
2-benzyl-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-8
2-(4-fluorobenzyl)-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-9
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4- fluorobenzyl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide






 


2-10
N-(1-(4-trifluoromethylbenzyl)piperidin-4- yl)-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indole-8-carboxamide






 


2-11
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2- (4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-12
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-13
N-(1-(4-trifluoromethylbenzyl)piperidin-4- yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-14
N-(1-phenethylpiperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-15
N-(1-(4-fluorophenyl)piperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-16
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5- methyl-2-(4-(trifluoromethyl)benzyl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-17
N-(1-(4-trifluoromethylbenzyl)piperidin-4- yl)-5-methyl-2-(4-(trifluoromethyl)benzyl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-18
5-methyl-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-19
N-(1-benzylpiperidin-4-yl)-2-(4- (trifluoromethyl)phenylsulfonyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-20
5-acetyl-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-21
N-(1-(4-cyanophenylsulfonyl)piperidin-4- yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-22
N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)- 2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-23
2-(4-(trifluoromethyl)benzyl)-N-(1-(4- (trifluoromethyl)phenylsulfonyl)piperidin- 4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide






 


2-24
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4- (trifluoromethyl)phenylsulfonyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-25
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4- cyanophenylsulfonyl)-2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indole-8-carboxamide






 


2-26
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2- (pyridin-3-ylsulfonyl)-2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indole-8-carboxamide






 


2-27
N-(1-(4-cyanophenylcarbamoyl)piperidin- 4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-28
N-(1-(4-fluorophenylsulfonyl)piperidin-4- yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-29
N-(1-(3-cyanophenylsulfonyl)piperidin-4- yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-30
2-(4-(trifluoromethyl)benzyl)-N-(1-(3- (trifluoromethyl)phenylsulfonyl)piperidin- 4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide






 


2-31
N-(1-(3-fluorophenylcarbamoyl)piperidin- 4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-32
N-(1-(4-chlorophenylsulfonyl)piperidin-4- yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-33
2-(4-(trifluoromethyl)benzyl)-N-(1-(4- (trifluoromethyl)phenylcarbamoyl) piperidin-4-yl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide






 


2-34
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4- fluorophenyl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide






 


2-35
2-(4-fluorophenyl)-N-(1-(4- fluorophenylsulfonyl)piperidin-4-yl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-36
2-(4-fluorophenyl)-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-37
2-(4-fluorophenyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4-yl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-38
tert-butyl 4-(2-(4-fluorophenyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamido)piperidine-1-carboxylate






 


2-39
N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2-(4- fluorophenyl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide






 


2-40
2-(4-fluorophenyl)-N-(1- nicotinoylpiperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-41
2-(4-fluorophenyl)-N-(1-(4- (trifluoromethyl)benzoyl)piperidin-4-yl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-42
N-(1-nicotinoylpiperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-43
tert-butyl 4-(2-(4-carbamoylbenzyl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamido)piperidine-1-carboxylate






 


2-44
2-(4-carbamoylbenzyl)-N-(1-(4- cyanobenzyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-45
2-(4-carbamoylbenzyl)-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-46
2-(4-carbamoylbenzyl)-N-(1- isonicotinoylpiperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-47
2-(4-carbamoylbenzyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4-yl)- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide






 


2-48
2-(4-carbamoylbenzyl)-N-(1-(4- fluorobenzyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-49
2-(4-carbamoylbenzyl)-N-(1-(4- carbamoylbenzyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-50
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2- (4-(trifluoromethyl)benzyl)-2,3,4,5- 2-5tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-51
N-(1-isonicotinoylpiperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-52
N-(1-(4-carbamoylbenzyl)piperidin-4-yl)- 2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-53
N-(1-((1-methyl-1H-imidazol-4- yl)methyl)piperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-54
N-(1-(oxazol-4-ylmethyl)piperidin-4-yl)-2- (4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide






 


2-55
4-((4-benzylpiperazin-1-yl)methyl)-N-(1- benzylpiperidin-4-yl)benzamide






 


2-56
N-(1-benzylpiperidin-4-yl)-4-((4- (cyclohexylmethyl)piperazin-1- yl)methyl)benzamide






 


2-57
N-(1-benzylpiperidin-4-yl)-4-((4-(5- (trifluoromethyl)pyridin-2-yl)piperazin-1- yl)methyl)benzamide






 


2-58
N-(1-benzylpiperidin-4-yl)-4-((4-(pyridin- 2-yl)piperazin-1-yl)methyl)benzamide






 


2-59
4-((4-benzylpiperazin-1-yl)methyl)-N-(1- (pyridin-4-ylmethyl)piperidin-4- yl)benzamide






 


2-60
4-((4-benzylpiperazin-1-yl)methyl)-N-(1- (pyridin-3-ylmethyl)piperidin-4- yl)benzamide






 


2-61
4-((4-benzylpiperazin-1-yl)methyl)-N-(1- (4-cyanobenzyl)piperidin-4-yl)benzamide






 


2-62
4-((4-benzylpiperazin-1-yl)methyl)-N-(1- (4-trifluoromethylbenzyl)piperidin-4- yl)benzamide






 


2-63
N-(1-benzylpiperidin-4-yl)-6-(1-(4- (trifluoromethyl)benzyl)piperidin-4-yloxy)- 2-naphthamide






 


2-64
N-(1-benzylpiperidin-4-yl)-6-(1-(4- cyanobenzyl)piperidin-4-yloxy)-2- naphthamide






 


2-65
N-(1-benzylpiperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)-2-naphthamide






 


2-66
tert-butyl 4-(7-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)-2-naphthamido)piperidine-1- carboxylate






 


2-67
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamido)piperidine- 1-carboxylate






 


2-68
N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide






 


2-69
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1- (4-(trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide






 


2-70
N-(1-(4-(trifluoromethyl)benzyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide






 


2-71
N-(1-benzylpiperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide






 


2-72
N-(1-benzylpiperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin-4- yloxy)-1H-indole-2-carboxamide













Another aspect of the disclosure provides 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, the method including administering to the subject an effective amount of a compound having structural formula (3-I):




or a pharmaceutically acceptable salt, prodrug or N-oxides thereof (or a solvate or hydrate thereof), wherein

    
    
        ring system “B” is -(aryl or heteroaryl)-;
        ring system “C” is an azacycloalkyl ring in which
        
            D is C, CH, CR4, or N,
            Z is CH, CR4 or N, provided that at least one of D and Z is N, and
            the bond between D and the carbon at the position denoted by “b” is a single bond or a double bond;
        
        
        J is —O—, —N(R38)—C(O)—, —C(O)— or absent, provided that:
        
            (a) when J is —O— or —N(R38)—C(O)—, D is CH or CR4, Z is N, J links ring systems “B” and “C”, the dotted line connecting ring system “B” to the carbon denoted by “b” in ring system “C” is absent, and the bond between D and the carbon atom at the position denoted by “b” is a single bond,
            (b) when J is —C(O)—, J links ring systems “B” and “C”, the dotted line connecting ring “B” to the carbon denoted by “b” in ring system “C” is absent, and the bond between D and the carbon atom at the position denoted by “b” is a single bond,
            (c) when J is absent, the dotted line connecting ring system “B” to the carbon denoted by “b” in ring system “C” signifies that ring systems “B” and “C” are fused through the bond connecting D and the carbon atom denoted by “b” in ring system “C”, and
            (d) when J is —O—, the ring system denoted by “B” is other than phenyl, that is, the compound does not have the formula
        
        
    
    






    
    
        R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and
        R2 is -Hca, -Cak-N(R9)-G-R22 or —(C2-C8 alkyl)-N(R9)—R24 in which one or two (e.g., non-adjacent) carbons of the (C2-C8 alkyl) are optionally replaced by —O—, —S— or —N(R9)—, and R24 is —R23, -G-R23 or —C(O)O—(C1-C6 alkyl), provided that two consecutive carbons of the (C2-C8 alkyl) are not replaced by —O—, or
        R1 and R2 together with the nitrogen to which they are attached come together to form -Hca;
        each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        w is 0, 1, 2, 3 or 4;
        each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 on the same carbon optionally combine to form oxo;
        p is 0, 1, 2, 3 or 4;
        q is 0, 1, 2, 3 or 4, provided that the sum of p and q is 1, 2, 3 or 4;
        x is 0 or an integer≦p+q, wherein when D or Z is CR4, the R4 of D or Z is one of the x R4 groups on ring system “C”;
        T is —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10 or
    
    






    
    
         in which
        
            Q is —S(O)2—, L, or (C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16;
            the ring denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl;
            each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN; and
            y is 0, 1, 2, 3 or 4;
        
        
        in which
        
            each L is independently selected from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—, —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,
            each R6, R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9—(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl),
            each R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl),
            each G is independently —S(O)2—, L, or —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16,
            each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, or two R16 on the same carbon combine to form oxo,
            R38 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl),
            R22 and R23 are each independently Ar or Het,
            each Ar is an optionally substituted aryl,
            each Het is an optionally substituted heteroaryl,
            each Cak is an optionally substituted cycloalkyl,
            each Hca is an optionally substituted heterocycloalkyl, and
            each alkyl is optionally substituted.
        
        
    
    


Various embodiments of compounds of structural formula (2-I) suitable for use in the methods described herein are described below. Information regarding these compounds can also be found in U.S. Patent Application Publication no. 2009/0275609, which is hereby incorporated by reference in its entirety.
In certain embodiments of the presently disclosed compounds of structural formula (3-I), J is —O— or —N(R38)—C(O)— and D is CH or C— substituted with one of the x R4 groups. In other embodiments of the presently disclosed compounds of structural formula (3-I), J is —C(O)—. In certain such embodiments, D is N.
In certain embodiments of the presently disclosed compounds of structural formula (3-I), Z is N and D is C, CH or C— substituted with one of the x R4 groups. In other embodiments, D is N and Z is CH or C— substituted with one of the x R4 groups. In further embodiments, D is N and Z is N.
In certain embodiments of the presently disclosed compounds of structural formula (3-I), R38 is —H. In other embodiments, R38 is —(C1-C4 alkyl), for example methyl, ethyl or propyl. In other embodiments, R38 is —C(O)—(C1-C4 alkyl), for example acetyl. In other embodiments, R38 is —C(O)—O—(C1-C4 alkyl)-, for example —C(O)—O-t-butyl. In certain embodiments, no alkyl of R38 is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments of the presently disclosed compounds of structural formula (3-I) as described above, ring system “B” is not fused to ring system “C” at the position denoted by “b,” so that the compounds have structural formula (3-II):




In other embodiments, ring system “B” is fused to ring system “C” at the position denoted by “b”; for example, the compounds can have structural formula (3-III):




In certain embodiments of the presently disclosed compounds of structural formula (3-I), “B” represents




in which the benzo ring is linked or fused to ring system “C” and the dotted line is not a bond but merely indicates that the benzo ring is fused to ring system “C” or not. Examples of such compounds wherein ring system “B” is not fused to ring system “C” are represented by the formula





In certain such embodiments, J is —O—, Z is N and D is CH or C— substituted by one of the x R4.

In other embodiments of the presently disclosed compounds of structural formula (3-I), “B” represents




in which the benzo ring is linked or fused to ring system “C” and the dotted line is not a bond but merely indicates that the benzo ring is fused to ring system “C” or not. Examples of such compounds wherein ring system “B” is not fused to ring system “C” are represented by the formula





In certain such embodiments, J is —O—, Z is N and D is CH or C— substituted by one of the x R4.

In other embodiments of the presently disclosed compounds of structural formula (3-I), “B” represents




in which the pyrido ring is linked or fused to ring system “C” and the dotted line is not a bond but merely indicates that the pyrido ring is fused to ring system “C” or not. Examples of such compounds wherein ring system “B” is not fused to ring system “C” are represented by the formula





In certain such embodiments, J is —O—, Z is N and D is CH or C— substituted by one of the x R4. Floating bonds indicate attachment on any carbon of the imidazo[1,2-a]pyridine ring system. In some embodiments, for example, the J moiety is on the pyridine ring of the imidazo[1,2-a]pyridine ring system, and the carboxamide (3-I.e., —C(O)—NR1R2) moiety is on the imidazo ring of the imidazo[1,2-a]pyridine ring system, and any R3 groups can be on either ring of the imidazo[1,2-a]pyridine ring system.

In other embodiments of the presently disclosed compounds of structural formula (3-I), “B” represents




in which the pyrazine ring is linked or fused to ring system “C” and the dotted line is not a bond but merely indicates that the pyrazine ring is fused to ring system “C” or not. Examples of such compounds wherein ring system “B” is not fused to ring system “C” are represented by the formula





In certain such embodiments, J is —O—, Z is N and D is CH or C— substituted by one of the x R4.

In other embodiments of the presently disclosed compounds of structural formula (3-I), “B” represents




and is not fused to ring system “C”, one of E1 and E2 is N and the other is CH, C substituted with the R3, C substituted with the -J-(ring system “C”), or C substituted with the —C(O)—NR1R2), w is 0 or 1. In certain such embodiments, J is —O—, Z is N and D is CH or C— substituted by one of the x R4.

In other embodiments of the presently disclosed compounds of structural formula (3-I), ring system “B” is




and is not fused to ring system “C”. In such embodiments, J is other than O. In certain such embodiments, J is —C(O)—, Z is N, CH or C-substituted by one of the x R4 and D is N. In other such embodiments, J is —N(R38)—C(O)—, Z is N and D is CH or C— substituted by one of the x R4.

In certain embodiments according to structural formulae (3-I)-(3-III), the sum of p and q is 2 or 3. For example, in one embodiment, the sum of p and q is 2 (e.g., p is 1 and q is 1). In another embodiment, the sum of p and q is 3 (e.g., p is 1 and q is 2).
In other embodiments of the presently disclosed compounds of structural formula (3-I), ring system “B” is a phenyl and is fused to ring system “C” (3-I.e., J is absent), Z is N, D is C, q is 2 and p is 1, such that the compound has structural formula (3-IV):




In certain embodiments of the presently disclosed compounds of structural formulae (3-I)-(3-IV), T is




In such embodiments, Q is —S(O)2—, L or —(C0-C3 alkyl)- in which each carbon of the (C0-C3 alkyl) is optionally and independently substituted with one or two R16, in which each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo. In certain embodiments, each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in particular compounds, each R16 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, Q has at most one R16 or oxo substituted thereon. Q can be, for example, an unsubstituted —(C0-C3 alkyl)-. In other embodiments, Q is a (C1-C3 alkyl) having as its only substitution a single oxo group. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.

In certain embodiments of the compounds of structural formulae (3-I)-(3-IV), the




moiety is





for example, p-(trifluoromethyl)phenyl. In other embodiments, the





moiety is





in one such embodiment, Q is a single bond.

The number of substituents on the ring system denoted by “A”, y, is 0, 1, 2, 3 or 4. For example, in some embodiments of the presently disclosed compounds of structural formulae (3-I)-(3-IV), y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zero and at least one R5 is halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 or —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 certain embodiments of the presently disclosed compounds of structural formulae (3-I)-(3-IV), each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R5 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In one embodiment of the compounds of structural formulae (3-I)-(3-IV), y is 0.
In the presently disclosed compounds of structural formulae (3-I)-(3-IV), 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-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
For example, in certain embodiments of the presently disclosed compounds of structural formulae (3-I)-(3-IV), the ring system denoted by “A” is a phenyl. In one embodiment, y is 1 and R5 is attached to the phenyl in the para position relative to Q. In another embodiment, y is 1 and R5 is selected from the group consisting of halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —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-C4 alkyl) or (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R5 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. In another embodiment, the




moiety is a 3,4-dihalophenyl.

In another embodiment of the presently disclosed compounds of structural formulae (3-I)-(3-IV), 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 one embodiment, when the “A” ring system is heteroaryl, Q is a —(C0-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. In certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
In certain embodiments (e.g., when ring system “B” is a phenyl and is fused to ring system “C”, J is absent, Z is N, D is carbon, q is 2 and p is 1), T is not —C(O)O—(C0-C6 alkyl).
In certain embodiments (e.g., when ring system “B” is a phenyl and is fused to ring system “C”, J is absent, Z is N, D is carbon, q is 2 and p is 1), T is not is not —CH2C(O)OH; —NH—CH2—C(O)OH; —O—CH2—C(O)OH; —CH2—CH2—C(O)OH; —CH═CH—C(O)OH; —N(C(O)CH3)—CH2—C(O)OH; ═CH—C(O)OH or ═CH—CH2—CH2—C(O)OH.
In one embodiment of the presently disclosed compounds, the compound has structural formula (3-V):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-VI):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-VII):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-VIII):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-IX):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (2-X):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XI):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XII):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XIII):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XIV):




in which n is 1, 2, 3 or 4, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XV):




in which n is 1, 2, 3 or 4, w is 0 or 1, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV). For example, in one embodiment, E1 is N and E2 is —CH— or —CR3—. In another embodiment, E1 is —CH— or —CR3— and E2 is N.

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XVI):




in which n is 1, 2, 3 or 4, w is 0 or 1, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom.

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XVII):




in which n is 1, 2, 3 or 4, w is 0 or 1, and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom.

In certain embodiments of the compounds disclosed with reference to structural formulae (3-V)-(3-XVII), n is 1 or 2. For example, in one embodiment, n is 2. In another embodiment, n is 1.
For example, in one embodiment of the presently disclosed compounds, the compound has structural formula (3-XVIII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XIX):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XX):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXI):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXIII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXIV):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXV):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXVI):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXVII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXVIII):




in which w is 0 or 1 and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom. In one embodiment, E1 is —CH— or —CR3— and E2 is N. In another embodiment, E1 is N and E2 is —CH— or —CR3—.

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXIX):




in which w is 0 or 1 and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom.

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXX):




in which w is 0 or 1 and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom.

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXI):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV). In one such embodiment, J is —C(O)—, Z is CH or C substituted with one of the x R4 and D is N. In another such embodiment, J is —C(O)—, Z is N and D is N. In a further such embodiment, J is —N(R38)—C(O)— (e.g., —NH—C(O)—), Z is N and D is CH or C substituted with one of the x R4.

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV). In one such embodiment, J is —C(O)—, Z is CH or C substituted with one of the x R4 and D is N. In another such embodiment, J is —C(O)—, Z is N and D is N. In a further such embodiment, J is —N(R38)—C(O)— (e.g., —NH—C(O)—), Z is N and D is CH or C substituted with one of the x R4.

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXIII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV). In one such embodiment, J is —C(O)—, Z is CH or C substituted with one of the x R4 and D is N. In another such embodiment, J is —C(O)—, Z is N and D is N. In a further such embodiment, J is —N(R38)—C(O)— (e.g., —NH—C(O)—), Z is N and D is CH or C substituted with one of the x R4.

In certain embodiments according to structural formulae (3-XXXI)-(3-XXXIII), the sum of p and q is 2 or 3. For example, in one embodiment, the sum of p and q is 2 (e.g., p is 1 and q is 1). In another embodiment, the sum of p and q is 3 (e.g., p is 1 and q is 2).
For example, in one embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXIV):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV). In one such embodiment, Z is N. In another such embodiment, Z is CH or C substituted with one of the x R4.

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXV):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXVI):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV). In one such embodiment, Z is N. In another such embodiment, Z is CH or C substituted with one of the x R4.

For example, in one embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXVII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

For example, in one embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXVIII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV). In one such embodiment, Z is N. In another such embodiment, Z is CH or C substituted with one of the x R4.

In another embodiment of the presently disclosed compounds, the compound has structural formula (3-XXXIX):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XL):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XLI):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XLII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In one embodiment of the presently disclosed compounds, the compound has structural formula (3-XLIII):




in which all variables are defined as described above with reference to structural formulae (3-I)-(3-IV).

In certain embodiments of the presently disclosed compounds of structural formulae (3-I)-(3-XLIII), R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and R2 is -Hca, -Cak-N(R9)-G-R22 or —(C2-C8 alkyl)-N(R9)—R24 in which one or two (for example, non-adjacent) carbons of the (C2-C8 alkyl) are optionally replaced by —O—, —S— or —N(R9)—, and R24 is —R23, -G-R23 or —C(O)O—(C1-C6 alkyl), provided that two consecutive carbons of the (C2-C8 alkyl) are not replaced by —O—. For example, in one embodiment, R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and R2 is -Hca.
In certain embodiments of the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), R1 is —H. In other embodiments, R1 is (C1-C4 alkyl), for example methyl, ethyl, n-propyl or isopropyl.
In certain embodiments of the presently disclosed compounds of any structural formulae (3-I)-(3-XLIII), R2 is -Hca. In certain embodiments, R2 is an optionally-substituted monocyclic heterocycloalkyl.
In certain of the presently disclosed compounds of any structural formulae (3-I)-(3-XLIII), R2 is -(optionally-substituted azetidinyl), -(optionally-substituted pyrrolidinyl), -(optionally-substituted piperidinyl) or -(optionally-substituted azepanyl). For example, R2 can be -(optionally substituted piperidinyl) or -(optionally substituted pyrrolidinyl). In one embodiment, R2 is -(optionally substituted piperidinyl). In another embodiment, R2 is -(optionally substituted pyrrolidinyl).
In certain particular embodiments of the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), R2 is -(optionally-substituted azetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl). For example, in one embodiment, R2 is -(optionally substituted piperidin-4-yl). In another embodiment, R2 is -(optionally substituted pyrrolidin-3-yl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties described above are substituted at their 1-positions. For example, in one embodiment, R2 is substituted at its 1-position with —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het, for example -(unsubstituted C0-C3 alkyl)-Ar or -(unsubstituted C0-C3 alkyl)-Het. For example, in one particular embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with a benzyl substituted with an electron withdrawing group; or with a pyridinylmethyl optionally substituted with an electron withdrawing group. For example, the benzyl or pyridinylmethyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzyl or an unsubstituted phenyl.
In other embodiments of the compounds disclosed herein having any of structural formulae (3-I)-(3-XLIII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted 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 or azepanyl R2 moiety 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 R2 moiety 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 having any of structural formulae (3-I)-(3-XLIII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted 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-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het. In one such embodiment, L is —C(O)—NR9—, such as —C(O)—NH—.
In other embodiments of the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—O(C0-C6 alkyl), —C(O)—Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2—O(C0-C6 alkyl), in which Ar and Het can be, for example, as described above with reference to —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—Het or —C(O)—Ar; in another embodiment, it is substituted at its 1-position with —S(O)2-Het or —S(O)2—Ar. For example, in certain embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally-substituted benzoyl (e.g., substituted with an electron withdrawing group as described above); or with an optionally-substituted nicotinyl, isonicotinyl or picolinyl (e.g., optionally substituted with an electron withdrawing group as described above). In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzoyl; or an unsubstituted nicotinoyl, isonicotinoyl or picolinoyl.
In certain embodiments, R2 is an optionally-substituted bridged azacycloalkyl or diazacycloalkyl, for example, a bridged azabicyclohexyl, a bridged azabicycloheptyl, a bridged azabicyclooctyl, a bridged diazabicyclohexyl, a bridged diazabicycloheptyl or a bridged diazabicyclooctyl. Particular examples of such R2 moieties include optionally substituted azabicyclo[2.2.2]octyl, optionally substituted azabicyclo[3.2.1]octyl, and optionally substituted 2,5-diazabicyclo[2.2.1]heptyl.
When R2 is a bridged azacycloalkyl or diazacycloalkyl, it can be substituted as described above with reference to the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties. For example, a bridged azacycloalkyl or diazacycloalkyl R2 moiety can be substituted (e.g., at a nitrogen) with —(C0-C3 alkyl)-Ar, —(C0-C3 alkyl)-Het, -L-Ar, -L-Het, —C(O)—O(C0-C6 alkyl), —C(O)—Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2—O(C0-C6 alkyl), as described above.
In certain embodiments of the compounds of any of structural formulae (3-I)-(3-XLIII), R2 is -Cak-N(R9)-G-R22, as described above. For example, in one embodiment of the disclosed compounds, R2 has the structure




in which c is 0, 1, 2, 3 or 4, and each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R21 on the same carbon optionally combine to form oxo. In certain embodiments of the presently disclosed compounds, each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R21 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, c is 1 or 2. In other embodiments, c is 0. In certain embodiments, R9 is H. In certain embodiments, G is a single bond. In certain embodiments of the presently disclosed compounds, R22 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments of the presently disclosed compounds, R23 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.

In one embodiment of compounds of any of structural formulae (3-I)-(3-XLIII), R2 has the structure




In certain embodiments of the compounds of any of structural formulae (3-I)-(3-XLIII), R2 is —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O— or —N(R9)— and R24 is —R23, -GR23 or —C(O)O—(C1-C6 alkyl). In certain embodiments, the (C2-C8 alkyl) is unsubstituted and no carbon is replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—CH2—N(R9)—R24 or —CH2—CH2—CH2—CH2—N(R9)—R24. In other embodiments, the (C2-C8 alkyl) is substituted and/or one or two carbons are replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—O—CH2—CH2—N(R9)—R24; —CH2—CH(CH3)—N(R9)—R24; or —CH2—CH2—O—CH2—C(O)—N(R9)—R24. In certain embodiments, R9 is H. In certain embodiments, R24 is Ar or Het. In certain embodiments, R24 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, the (C2-C8 alkyl) is a (C2-C5 alkyl).
In certain embodiments (e.g., when rings system “B” is




when R2 is an azabicycloalkyl moiety (e.g., a 1-azabicycloheptyl, a 1-azabicyclooctyl, a 1-azabicyclononyl or a 1-azabicyclodecyl), R2 is not vicinally substituted (3-I.e., at the position next to the amide nitrogen) with —(C0-C4)-Het.

In certain embodiments (e.g., when rings system “B” is




R2 is not a benzo-, pyrido-, pyrimido-, pyrazino- or pyridazino-fused azacycloalkyl. In other embodiments, R2 is not 7-azabicyclo[2.2.1]hept-2-yl. In other embodiments, R2 is not a quinuclidin-3-yl moiety.

In certain embodiments (e.g., when “B” represents




R2 is not a 4,5-dihydroisoxazol-4-yl moiety or an optionally substituted optionally ring-fused azetidin-2-on-3-yl moiety. In one embodiment, R2 is not an oxo-substituted heterocycloalkyl.

In certain embodiments of the presently disclosed compounds, R1 and R2 together with the nitrogen to which they are attached (3-I.e., the carboxamide nitrogen) come together to form Hca. R1, R2 and the nitrogen can come together to form, for example, an optionally-substituted monocyclic azacycloalkyl or monocyclic diazacycloalkyl, such as a piperidine, a pyrrolidine, a piperazine or an imidazolidine. In other embodiments, R1 and R2 come together to form an optionally-substituted bridged azacycloalkyl or diazacycloalkyl, for example, a bridged azabicyclohexyl, a bridged azabicycloheptyl, a bridged azabicyclooctyl, a bridged diazabicyclohexyl, a bridged diazabicycloheptyl or a bridged diazabicyclooctyl. Particular examples of such R2 moieties include azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, and 2,5-diazabicyclo[2.2.1]heptyl.
When R1, R2 and the nitrogen come together to form Hca, the Hca can be substituted as described above with reference to the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties. For example, the heterocycloalkyl can be substituted with —(C0-C3 alkyl)-Ar, —(C0-C3 alkyl)-Het, -L-Ar, -L-Het, —C(O)—O(C0-C6 alkyl), —C(O)—Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2—O(C0-C6 alkyl), as described above. When R1 and R2 come together to form a diazacycloalkyl, it can be substituted at a nitrogen atom.
For example, in certain embodiments, the —C(O)—NR1R2 moiety is




in which f is 0 or 1; g is 0, 1 or 2; c is 0, 1, 2, 3 or 4; R28 is Ar or Het; E3 is NH, N substituted by one of the c R21, N substituted by the -G-R28, CH2, CH substituted by one of the c R21, CH substituted by the -G-R28, or C substituted by one of the c R21 and the -G-R28; and E4 is absent, NH, N substituted by one of the c R21, N substituted by the -G-R28, CH2, CH substituted by one of the c R21, CH substituted by the -G-R28, or C substituted by one of the c R21 and the -G-R28, provided that both E3 and E4 are not N. When g is 0, R1, R2 and the nitrogen come together to form a monocyclic azacycloalkyl or diazacycloalkyl. In other embodiments, when g is 1 or 2, R1, R2 and the nitrogen come together to form a bridged bicyclic azacycloalkyl or diazacycloalkyl. The c R21 moieties can be disposed anywhere on the azacycloalkyl or diazacycloalkyl ring system. Each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 (C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R21 on the same carbon optionally combine to form oxo. In certain embodiments of the presently disclosed compounds, each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 (C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R21 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, c is 1 or 2. In other embodiments, c is 0. In certain embodiments, G is a single bond, CH2, or C(O). In certain embodiments of the presently disclosed compounds, R28 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In one embodiment, R28 is monocyclic aryl or heteroaryl substituted with 0-3 substitutents selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl) and NO2, in which each alkyl is not further substituted. The -G-R28 moiety, when present, can in some embodiments be as described below for -G-R17.

For example, in certain embodiments, the —C(O)—NR1R2 moiety is




In the compounds of any of structural formulae (3-I)-(3-XLIII), the number of substituents on ring system “B”, w, 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 R3 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 R3 is halo (e.g., chloro) or —(C1-C4 alkyl) (e.g., methyl, ethyl or propyl). In certain embodiments, an R3 is substituted on the “B” ring system at a 6-membered aromatic ring position in the meta position relative to the J moiety.
In certain embodiments of the compounds of any of structural formulae (3-I)-(3-XLIII), each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R3 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in certain embodiments, each R3 is halo (e.g., chloro) or —(C1-C4 alkyl) (e.g., methyl, ethyl or propyl).
In certain embodiments of the compounds of any of structural formulae (3-I)-(3-XLIII), w is at least one, and at least one R3 is —NR8R9. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the “B” ring system at a 6-membered aromatic ring position in the meta position relative to the J moiety.
In other embodiments of the compounds of any of structural formulae (3-I)-(3-XLIII), w is at least one, and at least one R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the “B” ring system at a 6-membered aromatic ring position in the meta position relative to the J moiety. In one particular embodiment, R3 is —CH2—N(CH3)—CH2—C(O)—OCH3.
In certain embodiments in which ring system “B” is




the imidazo portion of the central imidazo[1,2-a]pyridine ring system has no substitutions other than the carboxamide substitution. In another embodiment, no R3 at the 2-position of the imidazo[1,2-a]pyridine core is —(C1 alkyl)-N(R8)-(5,6,7,8-tetrahydroquinolin-8-yl); —(C1 alkyl)-N(R8)-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl); —(C1 alkyl)-N(R8)-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl); —(C1 alkyl)-N(R8)-(2,3-dihydrofuro[3,2-b]pyridin-3-yl); —(C1 alkyl)-N(R8)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl); or —(C1 alkyl)-N(R8)-(6,7,8,9-tetrahydrooxepino[3,2-b]pyridin-9-yl). In another embodiment, the compound does not have two R3 moieties that include Ar or Het as part of each of the moieties' structure. In another embodiment, no R3 at the 3-position of the imidazo[1,2-a]pyridine core is Het.

In certain embodiments in which ring system “B” is




the compound does not have two R3 moieties that include Ar or Het in the moieties' structure. In another embodiment, when an R3 is —NR9—(C0-C6 alkyl)-Ar, —NR9—(C0-C6 alkyl)-Het, —NR9-Hca, —O—(C0-C6 alkyl)-Ar or —O—(C0-C6 alkyl)-Het, it is not substituted on the pyrazine core at a position ortho to (3-I.e., on the carbon adjacent to) the amide. In another embodiment, when an R3 is —Ar or -Het, it is substituted on the pyrazine core at a position para to (3-I.e., directly across the ring from) the amide.

In certain embodiments in which ring system “B” is




when R3 is (C0-C4 alkyl)-O—(C0-C4 alkyl)-(optionally-substituted phenyl); (C0-C4 alkyl)-S(O)0-2—(C0-C4 alkyl)-(optionally-substituted phenyl) or (C0-C4 alkyl)-S(O)0-2—(C0-C4 alkyl)-O-(optionally-substituted phenyl), it is not at the 2 position of the thiazole core (3-I.e., not on the carbon between the N and the S of the thiazole). In one embodiment, the compound does not have two R3 moieties that include Ar or Het in the moieties' structure.

In the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), the number of substituents on ring system “C”, x, is 0 or an integer less than or equal to the sum of p and q. when D or Z is CR4, the R4 of D or Z is one of the x R4 groups on ring system “C”. In one embodiment, x is 0, 1, 2 or 3. For example, x can be 0, or can be 1 or 2.
In certain embodiments of the presently disclosed compounds of any of structural formula (3-I)-(3-XLIII), two R4 groups combine to form an oxo. The oxo can be bound, for example, at the position alpha to a nitrogen of ring system “C”. In other embodiments, no two R4 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), when x is 4, not all four R4 groups are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII), each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R4 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments, the presently disclosed compounds have the structural formula (3-XLIV):




in which Q and G are each independently a bond, —CH2—, —C(H)(R16)—, —C(R16)2—, L (e.g., —C(O)—NR9— or —NR9—C(O)—) or —S(O)2—; v is 0, 1, 2, 3 or 4; each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R15 on the same carbon optionally combine to form oxo; R17 is Het or Ar, and all other variables are defined as described above with reference to any of structural formula (3-I)-(3-XLIII). In one embodiment, Q is a single bond. In another embodiment, Q is —CH2—. In other embodiments, Q is —C(O)— or —S(O)2—. In certain embodiments, G is —CH2—. In other embodiments, G is —C(O)— or —S(O)2—. In other embodiments, G is —CH(CH3)—. In other embodiments, G is —C(O)—NH—. The above-recited 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)—. As described above, in certain embodiments, the ring system denoted by “A” is aryl or heteroaryl. In one embodiment, the ring system denoted by “A” is substituted with one or more electron-withdrawing groups as described above. In another embodiment, R17 is substituted with one or more electron-withdrawing groups as described above. In certain embodiments, the ring system denoted by “A”, R17 or both are not substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In certain embodiments, the azacycloalkyl to which -G-R17 is bound is a piperidinyl; in other embodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formula (3-XLIV), 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 formula (3-XLIV), two R15 groups combine to form an oxo. The oxo can be bound, for example, at the position alpha relative to the nitrogen of the azacycloalkyl ring. In other embodiments, no two R15 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of structural formula (3-XLIV), when v is 4, not all four R15 moieties are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of structural formula (3-XLIV), each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R15 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In some embodiments, one R15 is —C(O)NR9R7, which can be bound, for example, at a position alpha relative to the piperidine nitrogen, or at the position linked to the —N(R1)—.
In certain embodiments of the presently disclosed compounds of structural formula (3-XLIV), R17 is an unsubstituted aryl or heteroaryl. In other embodiments, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, R17 is substituted with 1, 2 or 3 substituents selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca. R17 can be substituted with, for example, one such substituent, or two such substituents.
For example, in certain embodiments, the presently disclosed compounds have the structural formula (3-XLV):




in which all variables are as defined above with reference to any of structural formulae (3-I)-(3-XLIV).

In other embodiments, the presently disclosed compounds have structural formula (3-XLVI):




in which all variables are as defined above with reference to any of structural formulae (3-I)-(3-XLIV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-XLVII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XLVIII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)— (C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XLIX):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (3-L):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LI):




in which all variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LII):




in which R25 is selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl or haloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group; and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). R25 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LIII):




in which G is —C(O)—, —S(O)2— or —C(O)—NH— and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LIV):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). In one embodiment, R27 and R29 are both H. In some embodiments, the compounds of structural formula (3-LIV) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (3-LIV) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LV):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (3-I)-(3-XLVI). In one embodiment, R27 and R29 are both H. In some embodiments, the compounds of structural formula (3-LV) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (3-LV) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LVI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XVIII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LVII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XIX). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LVIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XX). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LIX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXI). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLVII), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVIII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXIII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXIV). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXV). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXIV):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXVI). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXV):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXVII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXVI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXVIII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV). In one embodiment, E1 is carbon and E2 is N. In another embodiment, E1 is N and E2 is carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXVII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) or (3-XXIX). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXVIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXX). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV). When w is 0, the ring position shown occupied by R3 bears a hydrogen atom.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXIX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXXIV). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV). In certain embodiments, Z is N. In other embodiments, Z is CH or C substituted with one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXXV). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXXVI). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV). In certain embodiments, Z is N. In other embodiments, Z is CH or C substituted with one of the x R4.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXXVII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXXVIII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV). In certain embodiments, Z is N. In other embodiments, Z is carbon (e.g., CH or C substituted with one of the x R4).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXIV):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XXXIX). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXV):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XL). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXVI):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XLI). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXVII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XLII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXVIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (3-XLIV), and all other variables are defined as described above with reference to structural formulae (3-I)-(3-IV) and (3-XLIII). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (3-XLVII)-(3-LV).

In certain embodiments of compounds having structural formulae (3-XLIV)-(3-XLVIII), (3-LIII) and (3-LVI)-(3-LXXVIII), the




moiety has the structure





in which G is —CH2—, —CH(CH3)—, —C(O)—, —S(O)2— or —C(O)—NH—. For example, in one embodiment, G is —CH2—. In another embodiment, G is —C(O)— or —S(O)2—. In another embodiment, G is —C(O)—NH—.

In other embodiments of compounds having structural formulae (3-XLIV)-(3-XLVIII), (3-LIII) and (3-LVI)-(3-LXXVIII), the




moiety has the structure





in which G is —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—, R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca. In such embodiments, the compounds can be present as racemic mixtures or scalemic mixtures, or in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In other embodiments of compounds having structural formulae (3-XLIV)-(3-XLVIII), (3-LIII) and (3-LVI)-(3-LXXVIII), the




moiety has the structure





in which G is —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—.

In certain embodiments of compounds having structural formulae (3-XLIV)-(3-XLVIII), (3-LIII) and (3-LVI)-(3-LXXVIII), the R17 moiety has the structure




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca.

In certain embodiments of compounds having structural formulae (3-XLIV)-(3-LXXVIII), w is 1, and R3 is —NR8R9. In certain such embodiments, R3 is substituted at a 6-membered aromatic ring position in the meta position relative to the J moiety.
In other embodiments of compounds having structural formulae (3-XLIV)-(3-LXXVIII), w is 1, and R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. In certain such embodiments, R3 is substituted at a 6-membered aromatic ring position in the meta position relative to the J moiety.
In certain embodiments described above, each R27 is selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and each R29 is H, methyl or ethyl, or R27 and R29 together with the nitrogen to which they are bound form Hca.
In certain embodiments of compounds having structural formulae (3-XLIV)-(3-XLVI) and (3-XLIX)-(3-LXXVIII), at least one R5 moiety is a haloalkyl group, and in exemplary embodiments of these formulae the




moiety is p-(trifluoromethyl)phenyl.

In one embodiment, the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII) have a T moiety having the structural formula




and an R2 moiety having the structural formula





in which G and R17 are as described above with reference to any of structural formulae (3-I)-(3-LXXVIII), R18 is H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and R19 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no alkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R18 and R19 together with the nitrogen to which they are bound form Hca. In one embodiment, R18 and R19 are both H.

In another embodiment, the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII) have a T moiety having the structural formula




and an R2 moiety having the structural formula





in which Q and R5 are defined as described above with reference to any of structural formulae (3-I)-(3-LXXVIII), R18 is H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and R19 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no alkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R18 and R19 together with the nitrogen to which they are bound form Hca. In one embodiment, R18 and R19 are both H.

In another embodiment, the presently disclosed compounds of any of structural formulae (3-I)-(3-XLIII) have a T moiety having the structural formula




and an R2 moiety having the structural formula





in which Q and R5 are defined as described above with reference to any of structural formulae (3-I)-(3-LXXVIII), R18 is H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and R19 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no alkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R18 and R19 together with the nitrogen to which they are bound form Hca. In one embodiment, R18 and R19 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (3-L)(XIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LVI); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]oxazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]oxazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LVII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]oxazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]oxazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LVI); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]oxazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]oxazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LVI); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]oxazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]oxazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LVIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]thiazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXIV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LIX); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]thiazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LVIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]thiazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXVI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LIX); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the benzo moiety of the central benzo[d]thiazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the benzo moiety of the central benzo[d]thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXVII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LX); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXVIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXI); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-LXXXIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XC):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LX); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXI); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCIV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central imidazo[1,2-a]pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central imidazo[1,2-a]pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXIV); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central pyrazine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyrazine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCVI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXV); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central pyrazine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyrazine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCVII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I) and (3-LXIV); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central pyrazine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyrazine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCVIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXV); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central pyrazine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyrazine.

In certain embodiments, the presently disclosed compounds have the structural formula (3-XCIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; E1, E2, R1, and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXVI); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central thiazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central thiazole. In one embodiment, E1 is carbon and E2 is N. In another embodiment, E1 is N and E2 is carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (3-C):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXVII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central thiazole (3-I.e., the ring position shown occupied by R3 bears a hydrogen atom). In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXVIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central thiazole (3-I.e., the ring position shown occupied by R3 bears a hydrogen atom). In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; E1, E2, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXVI); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central thiazole. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central thiazole. In one embodiment, E1 is carbon and E2 is N. In another embodiment, E1 is N and E2 is carbon.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXVII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central thiazole (3-I.e., the ring position shown occupied by R3 bears a hydrogen atom). In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CIV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXVIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central thiazole (3-I.e., the ring position shown occupied by R3 bears a hydrogen atom). In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central thiazole.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; Z, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXIX); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, Z is N. In another embodiment, Z is CH.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CVI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXX); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, R38 is H. In another embodiment, R38 is methyl, ethyl, propyl or butyl.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CVII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; Z, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXI); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, Z is N. In another embodiment, Z is CH.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CVIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, R38 is H. In another embodiment, R38 is methyl, ethyl, propyl or butyl.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; Z, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, Z is N. In another embodiment, Z is CH.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXIV); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, R38 is H. In another embodiment, R38 is methyl, ethyl, propyl or butyl.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; Z, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXIX); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, Z is N. In another embodiment, Z is CH.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXX); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, R38 is H. In another embodiment, R38 is methyl, ethyl, propyl or butyl.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; Z, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXI); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, Z is N. In another embodiment, Z is CH.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXIV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, R38 is H. In another embodiment, R38 is methyl, ethyl, propyl or butyl.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; Z, R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, Z is N. In another embodiment, Z is CH.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXVI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1, R3 and R38 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXIV); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central phenyl ring. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central phenyl ring. In one embodiment, R38 is H. In another embodiment, R38 is methyl, ethyl, propyl or butyl.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXVII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXV); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXVIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXVI); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXIX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXVII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXVIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXXI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXV); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXXII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXVI); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXXIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXVII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

In certain embodiments, the presently disclosed compounds have the structural formula (3-CXXIV):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (3-I)-(3-IV) and (3-LXXVIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyridine nitrogen is positioned in the para position relative to the G moiety; in another embodiment, the pyridine nitrogen is positioned in the meta position relative to the G moiety. In one embodiment, R1 is H. In another embodiment, R1 is methyl, ethyl, propyl or butyl. In one embodiment, no R3 is substituted on the central benzo moiety. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central benzo moiety.

Examples of compounds according to structural formula (3-I) include those listed below in Table 3. These compounds can be made, for example using a procedure analogous to those described in U.S. Patent Application Publications nos. 2009/0163511, 2009/0170829, 2009/0186894 and 2009/0275609, and in U.S. patent application Ser. No. 12/695,861, each of which is hereby incorporated by reference in its entirety.









TABLE 3





No.
Name
Structure







3-1
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamido)piperidine-1- carboxylate






 


3-2
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamide






 


3-3
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamide






 


3-4
N-(1-(4-fluorobenzoyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamide






 


3-5
N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamide






 


3-6
N-(1-(4-cyanobenzoyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamide






 


3-7
N-(4-isonicotinoylcyclohexyl)-6-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carboxamide






 


3-8
(5-(pyridin-4-ylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)(6- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazol-2- yl)methanone






 


3-9
4-((5-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carbonyl)-2,5- diazabicyclo[2.2.1]heptan-2- yl)methyl)benzamide






 


3-10
4-((5-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carbonyl)-2,5- diazabicyclo[2.2.1]heptan-2- yl)methyl)benzonitrile






 


3-11
(5-isonicotinoyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)(6- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazol-2- yl)methanone






 


3-12
4-(5-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2- carbonyl)-2,5- diazabicyclo[2.2.1]heptane-2- carbonyl)benzonitrile






 


3-13
(5-(4-fluorobenzoyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)(6- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazol-2- yl)methanone






 


3-14
tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]thiazole-2- carboxamido)piperidine-1- carboxylate






 


3-15
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]thiazole-2- carboxamide






 


3-16
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]thiazole-2- carboxamide






 


3-17
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-7-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)imidazo[1,2-a]pyridine-2- carboxamide






 


3-18
N-(1-(4-cyanobenzyl)piperidin-4- yl)-7-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)imidazo[1,2-c]pyridine-2- carboxamide






 


3-19
tert-butyl 4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2- carboxamido)piperidine-1- carboxylate






 


3-20
N-(piperidin-4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2-carboxamide






 


3-21
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2-carboxamide






 


3-22
N-(1-(4-cyanobenzyl)piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2-carboxamide






 


3-23
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)thiazole-5-carboxamide






 


3-24
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(1-(4-cyanophenyl)piperidin- 4-yloxy)thiazole-5-carboxamide






 


3-25
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(1-(4- (trifluoromethyl)benzyl)piperidin-4- yloxy)thiazole-5-carboxamide






 


3-26
tert-butyl 4-(5-(1-(4- cyanobenzyl)piperidin-4- ylcarbamoyl)thiazol-2- yloxy)piperidine-1-carboxylate






 


3-27
N-(1-(4-cyanobenzyl)piperidin-4- yl)-4-(1-(4- ethoxybenzyl)piperidine-4- carbonyl)benzamide






 


3-28
4-(4-(4-chlorobenzyl)piperazine-1- carbonyl)-N-(1-(4- cyanobenzyl)piperidin-4- yl)benzamide






 


3-29
4-(4-(4-chlorophenyl)piperazine-1- carbonyl)-N-(1-(4- cyanobenzyl)piperidin-4- yl)benzamide






 


3-30
N-(1-(4-cyanobenzyl)piperidin-4- yl)-4-(4-(5- (trifluoromethyl)pyridin-2- yl)piperazine-1- carbonyl)benzamide






 


3-31
N1-(1-(4-cyanobenzyl)piperidin-4- yl)-N4-(1-(4- (trifluoromethyl)benzyl)piperidin-4- yl)terephthalamide






 


3-32
N1-(1-(4-cyanobenzyl)piperidin-4- yl)-N4-(1-phenylpiperidin-4- yl)terephthalamide






 


3-33
N1-(1-benzylpiperidin-4-yl)-N4-(1- (4-cyanobenzyl)piperidin-4- yl)terephthalamide






 


3-34
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(4-fluorobenzyl)-1,2,3,4- tetrahydroisoquinoline-7- carboxamide






 


3-35
2-(4-fluorobenzyl)-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-1,2,3,4- tetrahydroisoquinoline-7- carboxamide






 


3-36
2-(4-fluorobenzyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4- yl)-1,2,3,4-tetrahydroisoquinoline- 7-carboxamide






 


3-37
2-(4-cyanobenzyl)-N-(1-(4- cyanobenzyl)piperidin-4-yl)- 1,2,3,4-tetrahydroisoquinoline-7- carboxamide






 


3-38
2-(4-cyanobenzyl)-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-1,2,3,4- tetrahydroisoquinoline-7- carboxamide






 


3-39
2-(4-cyanobenzyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4- yl)-1,2,3,4-tetrahydroisoquinoline- 7-carboxamide






 


3-40
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(4-fluorobenzyl)-1,2,3,4- tetrahydroisoquinoline-7- carboxamide






 


3-41
2-(4-fluorobenzyl)-N-(1-(pyridine- 3-ylmethyl)piperidin-4-yl)-1,2,3,4- tetrahydroisoquinoline-7- carboxamide






 


3-42
2-(4-fluorobenzyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4- yl)-1,2,3,4-tetrahydroisoquinoline- 7-carboxamide













Another aspect of the disclosure provides 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, the method including administering to the subject an effective amount of a compound having structural formula (4-I):




or a pharmaceutically acceptable salt, prodrug or N-oxide thereof (or a solvate or hydrate thereof), in which

    
    
        R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl);
        R2 is -Hca, -Cak-N(R9)-G-R22 or —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O—, —S— or —N(R9)— and R24 is —R23, -G-R23 or —C(O)O—(C1-C6 alkyl), provided that two consecutive carbons of the (C2-C8 alkyl) are not replaced by —O—;
        each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), -(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        w is 0, 1, 2 or 3;
        each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, -(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 on the same carbon optionally combine to form oxo;
        x is 0, 1, 2, 3 or 4;
        p is 0, 1, 2, 3 or 4;
        q is 2, 3 or 4;
        the sum of p and q is 2, 3, 4, 5 or 6;
        T is —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10 or
    
    






    
    
         in which
        
            Q is —S(O)2—, L or (C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16;
            the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl;
            each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN; and
            y is 0, 1, 2, 3 or 4;
        
        
        in which
        
            each L is independently selected from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—, —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,
            each R6, R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9—(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl),
            each R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl),
            each G is independently —S(O)2—, L or —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16,
            each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo,
            each R22 and R23 is independently Ar or Het,
            each Ar is an optionally substituted aryl,
            each Het is an optionally substituted heteroaryl,
            each Cak is an optionally substituted cycloalkyl,
            each Hca is an optionally substituted heterocycloalkyl, and
            each alkyl is optionally substituted.
        
        
    
    


Various embodiments of compounds of structural formula (2-I) suitable for use in the methods described herein are described below. Information regarding these compounds can also be found in U.S. patent application Ser. No. 12/695,861, which is hereby incorporated by reference in its entirety.
In certain embodiments of the presently disclosed compounds of structural formula (4-I), T is




In such embodiments, Q is —S(O)2—, L or —(C0-C3 alkyl)- in which each carbon of the (C0-C3 alkyl) is optionally and independently substituted with one or two R16, in which each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and optionally two of R16 on the same carbon combine to form oxo. In certain embodiments, each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in particular compounds, each R16 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3—(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, Q has at most one R16 or an oxo substituted thereon. Q can be, for example, an unsubstituted —(C0-C3 alkyl)-. In other embodiments, Q is a (C1-C3 alkyl) having as its only substitution a single oxo group. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.

In certain embodiments of the compounds of structural formula (4-I), the




moiety is





for example, p-(trifluoromethyl)phenyl. In other embodiments, the





moiety is





in one such embodiment, Q is a single bond.

The number of substituents on the ring system denoted by “A”, y, is 0, 1, 2, 3 or 4. For example, in some embodiments of the presently disclosed compounds of structural formula (4-I), y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zero and at least one R5 is halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 or —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 certain embodiments of the presently disclosed compounds of structural formula (4-I), each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R5 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In one embodiment of the compounds of structural formula (4-I), y is 0.
In the presently disclosed compounds of structural formula (4-I), 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-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. For example, in certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
For example, in certain embodiments of the presently disclosed compounds of structural formula (4-I), the ring system denoted by “A” is a phenyl. In one embodiment, y is 1 and R5 is attached to the phenyl in the para position relative to Q. In another embodiment, y is 1 and R5 is selected from the group consisting of halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —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-C4 alkyl) or (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R5 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. In another embodiment, the




moiety is a 3,4-dihalophenyl.

In another embodiment of the presently disclosed compounds of structural formula (4-I), 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 one embodiment, when the “A” ring system is heteroaryl, Q is a —(C0-C3 alkyl)- optionally substituted with oxo, and optionally substituted with one or more R16. For example, Q can be a —(C1-C3 alkyl)- having its only substitution a single oxo, or an unsubstituted —(C0-C3 alkyl)-. In certain embodiments, Q is —CH2—; a single bond; —S(O)2—; —C(O)—; or —CH(CH3)—.
In one embodiment of the presently disclosed compounds, the compound has structural formula (4-II):




in which the variables are defined as described above with reference to structural formula (4-I).

In one embodiment of the presently disclosed compounds, the compound has structural formula (4-III):




in which the variables are defined as described above with reference to structural formula (4-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (4-IV):




in which one of X1, X2, X3 and X4 are N, and the others are carbons (for example, independently CH or C substituted with one of the w R3 groups), and all other variables are defined as described above with reference to structural formula (4-I). For example, in one embodiment, X1 is N and X2, X3 and X4 are carbons. In another embodiment, X2 is N and X1, X3 and X4 are carbons. In another embodiment, X3 is N and X1, X2 and X4 are carbons. In another embodiment, X4 is N and X1, X2 and X3 are carbons.

In compounds according to structural formulae (4-I)-(4-IV), p is 0, 1, 2, 3 or 4 and q is 2, 3 or 4. For example, in one embodiment, q is 2. In certain embodiments, p is 1.
In certain embodiments according to structural formulae (4-I)-(4-IV), the sum of p and q is 2 or 3. For example, in one embodiment, the sum of p and q is 2 (e.g., p is 0 and q is 2). In another embodiment, the sum of p and q is 3 (e.g., p is 1 and q is 2). In other embodiments the sum of p and q is 4, 5, or 6. Accordingly the ring containing the p and q carbon atoms can be a 5, 6, 7, 8 or 9-membered ring.
In one embodiment of the presently disclosed compounds, the compound has the structural formula (4-V):




in which the variables are defined as described above with reference to structural formula (4-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (4-VI):




in which the variables are defined as described above with reference to structural formula (4-I).

In another embodiment of the presently disclosed compounds, the compound has structural formula (4-VII):




in which one of X1, X2, X3 and X4 are N, and the others are carbons (for example, independently CH or C substituted with one of the w R3 groups), and all other variables are defined as described above with reference to structural formula (4-I). For example, in one embodiment, X1 is N and X2, X3 and X4 are carbons. In another embodiment, X2 is N and X1, X3 and X4 are carbons. In another embodiment, X3 is N and X1, X2 and X4 are carbons. In another embodiment, X4 is N and X1, X2 and X3 are carbons.

In certain embodiments of the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), R1 is —H. In other embodiments, R1 is (C1-C4 alkyl), for example methyl, ethyl, n-propyl or isopropyl. In still other embodiments, R1 is —C(O)—O—(C1-C4 alkyl), for example —C(O)—O-t-butyl. In certain embodiments, no alkyl of R1 is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments of the presently disclosed compounds of any structural formulae (4-I)-(4-VII), R2 is -Hca. In certain embodiments, R2 is an optionally-substituted monocyclic heterocycloalkyl. In one embodiment, R2 is not an oxo-substituted heterocycloalkyl.
In certain of the presently disclosed compounds of any structural formulae (4-I)-(4-VII), R2 is -(optionally-substituted azetidinyl), -(optionally-substituted pyrrolidinyl), -(optionally-substituted piperidinyl), or -(optionally-substituted azepanyl). For example, R2 can be -(optionally substituted piperidinyl) or -(optionally substituted pyrrolidinyl). In one embodiment, R2 is -(optionally substituted piperidinyl). In another embodiment, R2 is -(optionally substituted pyrrolidinyl).
In certain particular embodiments of the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), R2 is -(optionally-substituted azetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl). For example, in one embodiment, R2 is -(optionally substituted piperidin-4-yl). In another embodiment, R2 is -(optionally substituted pyrrolidin-3-yl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties described above are substituted at their 1-positions. For example, in one embodiment, R2 is substituted at its 1-position with —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het, for example -(unsubstituted C0-C3 alkyl)-Ar or -(unsubstituted C0-C3 alkyl)-Het. For example, in one particular embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with a benzyl substituted with an electron withdrawing group; or with a pyridinylmethyl optionally substituted with an electron withdrawing group. For example, the benzyl or pyridinylmethyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzyl or an unsubstituted phenyl.
In other embodiments of the compounds disclosed herein having any of structural formulae (4-I)-(4-VII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted 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 or azepanyl R2 moiety 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 R2 moiety 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 having any of structural formulae (4-I)-(4-VII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted 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-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het. In one such embodiment, L is —C(O)—NR9—, such as —C(O)—NH—.
In other embodiments of the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—O(C0-C6 alkyl), —C(O)—Het, —C(O)—Ar, —S(O)2-Het, —S(O)2—Ar or —S(O)2—O(C0-C6 alkyl), in which Ar and Het can be, for example, as described above with reference to —(C0-C3 alkyl)-Ar or —(C0-C3 alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —C(O)—Het or —C(O)—Ar; in another embodiment, it is substituted at its 1-position with —S(O)2-Het or —S(O)2—Ar. For example, in certain embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally-substituted benzoyl (e.g., substituted with an electron withdrawing group as described above); or with an optionally-substituted nicotinyl, isonicotinyl or picolinyl (e.g., optionally substituted with an electron withdrawing group as described above). In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzoyl; or an unsubstituted nicotinoyl, isonicotinoyl or picolinoyl.
In certain embodiments of the compounds of any of structural formulae (4-I)-(4-VII), R2 is -Cak-N(R9)-G-R22, as described above. For example, in one embodiment of the disclosed compounds, R2 has the structure




in which c is 0, 1, 2, 3 or 4, and each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R21 on the same carbon optionally combine to form oxo. In certain embodiments of the presently disclosed compounds, each R21 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R21 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, c is 1 or 2. In other embodiments, c is 0. In certain embodiments, R9 is H. In certain embodiments, G is a single bond. In certain embodiments of the presently disclosed compounds, each R22 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments of the presently disclosed compounds, each R23 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.

In one embodiment of compounds of any of structural formulae (4-I)-(4-VII), R2 has the structure




In certain embodiments of the compounds of any of structural formulae (4-I)-(4-VII), R2 is —(C2-C8 alkyl)-N(R9)—R24 in which one or two carbons of the (C2-C8 alkyl) are optionally replaced by —O— or —N(R9)— and R24 is —R23, -GR23 or —C(O)O—(C1-C6 alkyl). In certain embodiments, the (C2-C8 alkyl) is unsubstituted and no carbon is replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—CH2—N(R9)—R24 or —CH2—CH2—CH2—CH2—N(R9)—R24. In other embodiments, the (C2-C8 alkyl) is substituted and/or one or two carbons are replaced by —O— or —N(R9)—. For example, in one embodiment, R2 is —CH2—CH2—O—CH2—CH2—N(R9)—R24; —CH2—CH(CH3)—N(R9)—R24; or —CH2—CH2—O—CH2—C(O)—N(R9)—R24. In certain embodiments, R9 is H. In certain embodiments, R24 is Ar or Het. In certain embodiments, R24 is not substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, the (C2-C8 alkyl) is a (C2-C5 alkyl).
In the compounds of any of structural formulae (4-I)-(4-VII), the number of substituents on the central pyridine, w, 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 R3 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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 R3 is halo (e.g., chloro) or —(C1-C4 alkyl) (e.g., methyl, ethyl or propyl). In certain embodiments, an R3 is substituted on the central pyridine in the meta position relative to the carbonyl bearing the diazacycloalkyl moiety.
In certain embodiments of the compounds of any of structural formulae (4-I)-(4-VII), each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R3 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in certain embodiments, each R3 is halo (e.g., chloro) or —(C1-C4 alkyl) (e.g., methyl, ethyl or propyl).
In certain embodiments of the compounds of any of structural formulae (4-I)-(4-VII), w is at least one, and at least one R3 is —NR8R9. For example, in one embodiment, w is 1. In certain such embodiments, an R3 is substituted on the central pyridine in the meta position relative to the carbonyl bearing the diazacycloalkyl moiety.
In other embodiments of the compounds of any of structural formulae (4-I)-(4-VII), w is at least one, and at least one R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. For example, in one embodiment, w is 1. In certain such embodiments, R3 is substituted on the central pyridine in the meta position relative to the carbonyl bearing the diazacycloalkyl moiety. In one particular embodiment, R3 is —CH2—N(CH3)—CH2—C(O)—OCH3.
In the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), the number of substituents on the diazacycloalkyl ring, x, is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, x can be 0, or can be 1 or 2.
In certain embodiments of the presently disclosed compounds of any of structural formula (4-I)-(4-VII), two R4 groups combine to form an oxo. The oxo can be bound, for example, at the position alpha to a nitrogen of the diazacycloalkyl ring. In other embodiments, no two R4 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), when x is 4, not all four R4 groups are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of any of structural formulae (4-I)-(4-VII), each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R4 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments, the presently disclosed compounds have the structural formula (4-VIII):




in which Q and G are each independently a bond, —CH2—, —C(H)(R16)—, —C(R16)2—, L (e.g., —C(O)—NR9— or —NR9—C(O)—) or —S(O)2—; v is 0, 1, 2, 3 or 4; each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R15 on the same carbon optionally combine to form oxo; R17 is Het or Ar, and all other variables are defined as described above with reference to any of structural formula (4-I)-(4-VII). In one embodiment, Q is a single bond. In another embodiment, Q is —CH2—. In other embodiments, Q is —C(O)— or —S(O)2—. In certain embodiments, G is —CH2—. In other embodiments, G is —C(O)— or —S(O)2—. In other embodiments, G is —CH(CH3)—. In other embodiments, G is —C(O)—NH—. The above-recited 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)—. As described above, in certain embodiments, the ring system denoted by “A” is aryl or heteroaryl. In one embodiment, the ring system denoted by “A” is substituted with one or more electron-withdrawing groups as described above. In another embodiment, R17 is substituted with one or more electron-withdrawing groups as described above. In certain embodiments, the ring system denoted by “A”, R17 or both are not substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In certain embodiments, the azacycloalkyl to which -G-R17 is bound is a piperidinyl; in other embodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formula (4-VIII), 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 formula (4-VIII), two R15 groups combine to form an oxo. The oxo can be bound, for example, at the position alpha relative to the nitrogen of the azacycloalkyl ring. In other embodiments, no two R15 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of structural formula (4-VIII), when v is 4, not all four R15 moieties are (C1-C6 alkyl).
In certain embodiments of the presently disclosed compounds of structural formula (4-VIII), each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R15 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In some embodiments, one R15 is —C(O)NR9R7, which can be bound, for example, at a position alpha relative to the piperidine nitrogen, or at the position linked to the —N(R1)—.
In certain embodiments of the presently disclosed compounds of structural formula (4-VIII), R17 is an unsubstituted aryl or heteroaryl. In other embodiments, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, the R17 Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, R17 is substituted with 1, 2 or 3 substituents selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca. R17 can be substituted with, for example, one such substituent, or two such substituents.
In certain embodiments, the presently disclosed compounds have the structural formula (4-IX):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (4-X):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XI):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). In one embodiment, R27 and R29 are both H.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XIII):




in which all variables are as described above with reference to any of structural formulae (4-I)-(4-VIII).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XIV):




in which R25 is selected from halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl or haloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group; and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). R25 can be, for example, —Cl, —F, cyano, —C(O)CH3, —C(O)OH, —C(O)NH2, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XV):




in which G is —C(O)—, —S(O)2— or —C(O)—NH— and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XVI):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), (C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). In one embodiment, R27 and R29 are both H. In some embodiments, the compounds of structural formula (4-VIII) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (4-XVI) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XVII):




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—O—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca, and all other variables are as described above with reference to any of structural formulae (4-I)-(4-VIII). In one embodiment, R27 and R29 are both H. In some embodiments, the compounds of structural formula (4-VIII) are present as racemic mixtures or scalemic mixtures. In other embodiments, the compounds of structural formula (4-XVII) are present in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XVIII):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (4-VIII), and all other variables are defined as described above with reference to structural formulae (4-I) or (4-II). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (4-IX)-(4-XVII).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XIX):




in which G, v, R15 and R17 are defined as described above with reference to structural formula (4-VIII), and all other variables are defined as described above with reference to structural formulae (4-I) or (4-III). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (4-IX)-(4-XVII).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XX):




in which one of X1, X2, X3 and X4 are N, and the others are carbons (for example, independently CH or C substituted with one of the w R3 groups), as described above with reference to structural formulae (4-IV) and (4-VII); G, v, R15 and R17 are defined as described above with reference to structural formula (4-VIII), and all other variables are defined as described above with reference to structural formulae (4-I) or (4-IV). R5, y, v, R15, R17, Q, G and the ring denoted by “A” can be defined, for example, as described with reference to any of structural formulae (4-IX)-(4-XVII).

In certain embodiments of compounds having structural formulae (4-VIII)-(4-XX), the




moiety has the structure





in which G is —CH2—, —CH(CH3)—, —C(O)—, —S(O)2— or —C(O)—NH—. For example, in one embodiment, G is —CH2—. In another embodiment, G is —C(O)— or —S(O)2—. In another embodiment, G is —C(O)—NH—.

In other embodiments of compounds having structural formulae (4-VIII)-(4-XX), the




moiety has the structure





in which G is —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—, R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca. In such embodiments, the compounds can be present as racemic mixtures or scalemic mixtures, or in an enantiomerically-enriched form, for example as a substantially pure stereoisomer.

In other embodiments of compounds having structural formulae (4-VIII)-(4-XX), the




moiety has the structure





in which G is —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—.

In certain embodiments of compounds having structural formulae (4-VIII)-(4-XX), the R17 moiety has the structure




in which R27 is selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl)-(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R29 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no (C1-C4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R27 and R29 together with the nitrogen to which they are bound form Hca.

In certain embodiments of compounds having structural formulae (4-VIII)-(4-XX), w is 1, and R3 is —NR8R9. In certain such embodiments, R3 is substituted on the central pyridine in a meta position relative to the —C(O)— bearing the diazacycloalkyl moiety.
In other embodiments of compounds having structural formulae (4-VIII)-(4-XX), w is 1, and R3 is —(C0-C3 alkyl)-Y1—(C1-C3 alkyl)-Y2—(C0-C3 alkyl), in which each of Y1 and Y2 is independently L, —O—, —S— or —NR9—. In certain such embodiments, R3 is substituted on the central pyridine in a meta position relative to the —C(O)— bearing the diazacycloalkyl moiety.
In certain embodiments described above, each R27 is selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R21 on the same carbon optionally combine to form oxo, in which each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and each R29 is H, methyl or ethyl, or R27 and R29 together with the nitrogen to which they are bound form Hca.
In certain embodiments of compounds having structural formulae (4-VIII)-(4-XX), at least one R5 moiety is a haloalkyl group, and in exemplary embodiments of these formulae the




moiety is p-(trifluoromethyl)phenyl, p-fluorophenyl or p-cyanophenyl. By way of further illustration, certain exemplary compounds including such





moieties have structural formula (4-XXI), (4-XXII) or (4-XXIII):





in which R26 is trifluoromethyl, chloro, fluoro or cyano and all other variables are as described above with reference to structural formulae (4-XVIII), (4-XIX) and (4-XX).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXIV):




in which G, R1, R3 and R17 are as described above with reference to any of structural formulae (4-I)-(4-XXIII), R18 is H, —(C1-C6 alkyl), —(C1-C6 haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl), in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and R19 is —H, —(C1-C4 alkyl), —CO—(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl) in which no alkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R18 and R19 together with the nitrogen to which they are bound form Hca. In one embodiment, R18 and R19 are both H.

For example, in one embodiment, the presently disclosed compounds have the structural formula (4-XXV):




in which G, R1, R3 and R17 are as described above with reference to any of structural formulae (4-I), (4-VIII), (4-XIII), (4-XIV), (4-XVI) or (4-XXII), and R18 and R19 are defined as described above with reference to structural formula (4-XXIV).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXVI):




in which Q, R1, R3 and R5 are defined as described above with reference to any of structural formulae (4-I)-(4-XXIII), and R18 and R19 are defined as described above with reference to structural formula (4-XXIV).

For example, in one embodiment, the presently disclosed compounds have the structural formula (4-XXVII):




in which Q, R1, R3 and R5 are defined as described above with reference to any of structural formulae (4-I)-(4-XXIII), and R18 and R19 are defined as described above with reference to structural formula (4-XXIV).

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXVIII):




in which R1, R3 and R5 are defined as described above with reference to any of structural formulae (4-I)-(4-XXIII), and R18 and R19 are defined as described above with reference to structural formula (4-XXIV).

For example, in one embodiment, the presently disclosed compounds have the structural formula (4-XXIX):




in which R1, R3 and R5 are defined as described above with reference to any of structural formulae (4-I)-(4-XXIII), and R18 and R19 are defined as described above with reference to structural formula (4-XXIV).

In compounds according to any of structural formulae (4-I)-(4-VII), T and R2 can be defined as described above with reference to structural formulae (4-VIII)-(4-XXIX).
In certain embodiments, the presently disclosed compounds have the structural formula (4-XXX):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (4-I), (4-II), and (4-VIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXXI):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (4-I), (4-II) and (4-VIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXXII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (4-I), (4-III), and (4-VIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXXIII):




in which Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (4-I), (4-III) and (4-VIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXXIV):




in which one of X1, X2, X3 and X4 are N, and the others are carbons (for example, independently CH or C substituted with one of the w R3 groups), as described above with reference to structural formulae (4-IV) and (4-VII); Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (4-I), (4-IV), and (4-VIII); and R11, R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R11, R12 and R13 is not H. In one embodiment, R11 is attached in the para position relative to the G moiety; in another embodiment, R11 is attached in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyridine.

In certain embodiments, the presently disclosed compounds have the structural formula (4-XXXV):




in which one of X1, X2, X3 and X4 are N, and the others are carbons (for example, independently CH or C substituted with one of the w R3 groups), as described above with reference to structural formulae (4-IV) and (4-VII); Q is —CH2—, —C(O)— or a single bond; G is a single bond, —CH2—, —C(O)—, —S(O)2— or —C(O)—NH—; R1 and R3 are as described above with reference to any of structural formulae (4-I), (4-IV) and (4-VIII); and R12 and R13 are independently selected from H, halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2 and —C(O)-Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one particular such embodiment, at least one of R12 and R13 is not H. In one embodiment, the pyrido nitrogen is disposed in the para position relative to the G moiety; in another embodiment, the pyrido nitrogen is disposed in the meta position relative to the G moiety. In one embodiment, no R3 is substituted on the central pyridine. In another embodiment, one R3 (e.g., —Cl, —F, —CH3, —C2H5, —C3H7) is substituted on the central pyridine.

As the person of skill in the art will recognize, the various embodiments described above can be combined to form other embodiments of the disclosure. For example, in one embodiment, Q is —CH2—, as described above, and G is —CH2—, as described above.
Examples of compounds according to structural formula (4-I) include those listed in Table 4. These compounds can be made, for example using a procedure analogous to those described in U.S. Patent Application Publications nos. 2009/0163511, 2009/0170829, 2009/0186894 and 2009/0275609, and in U.S. patent application Ser. No. 12/695,861, each of which is hereby incorporated by reference in its entirety.









TABLE 4





No.
Name
Structure







4-1
5-(4-(4-cyanobenzyl)piperazine-1- carbonyl)-N-(1-(4-cyanobenzyl)piperidin- 4-yl)picolinamide






 


4-2
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-fluorobenzyl)piperazine-1- carbonyl)picolinamide






 


4-3
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-(trifluoromethyl)benzyl)piperazine-1- carbonyl)picolinamide






 


4-4
(S)-5-(4-(4-chlorophenyl)piperazine-1- carbonyl)-N-(1-(4-fluorobenzyl)pyrrolidin- 3-yl)picolinamide






 


4-5
(S)-5-(4-(4-chlorophenyl)piperazine-1- carbonyl)-N-(1-(pyridin-4- ylmethyl)pyrrolidin-3-yl)picolinamide






 


4-6
(S)-5-(4-(4-chlorophenyl)piperazine-1- carbonyl)-N-(1-(4-cyanobenzyl)pyrrolidin- 3-yl)picolinamide






 


4-7
N-(1-(4-chlorobenzyl)pyrrolidin-3-yl)-5-(4- (4-chlorophenyl)piperazine-1- carbonyl)picolinamide






 


4-8
5-(4-(4-chlorophenyl)piperazine-1- carbonyl)-N-(1-(4- (trifluoromethyl)benzyl)pyrrolidin-3- yl)picolinamide













Another aspect of the disclosure provides 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, the method including administering to the subject an effective amount of a compound having structural formula (5-I):




or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof (or a solvate or hydrate thereof), in which

    
    
        R1 is H;
        R2 is -Hca;
        each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar; —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
        w is 0, 1, 2, or 3;
        n is 0, 1 2 or 3;
        each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar; —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 on the same carbon optionally combine to form oxo;
        x is 0, 1, 2, 3 or 4;
        T is —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10; or
    
    






    
    
         in which
        
            Q is —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16;
            each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar; —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form oxo;
            the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl;
            each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar; —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN; and
            y is 0, 1, 2, 3 or 4;
        
        
        in which
        
            each L is independently selected from —NR9C(O)O—, —NR9C(O)—NR9—, —NR9C(O)S—, —NR9C(O)—, —NR9C(S)O—, —NR9C(S)—NR9—, —NR9C(S)S—, —NR9C(S)—, —OC(O)NR9—, —SC(O)NR9—, —C(S)NR9—, —OC(S)NR9—, —SC(S)NR9—, —C(S)NR9—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,
            each R6, R7, R8 and R10 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl) and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl),
            each R9 is independently selected from —H, —(C1-C4 alkyl) and —C(O)—(C1-C4 alkyl),
            each Ar is an optionally substituted aryl,
            each Het is an optionally substituted heteroaryl,
            each Cak is an optionally substituted cycloalkyl,
            each Hca is an optionally substituted heterocycloalkyl, and
            each alkyl is optionally substituted.
        
        
    
    


Various embodiments of compounds of structural formula (5-I) suitable for use in the methods described herein are described below. Information regarding these compounds can also be found in U.S. Patent Application Publication no. 2009/0186894, which is hereby incorporated by reference in its entirety.
R1, R2, R3, R4, T, w, x and n may alternatively be as described above with respect to structural formulae (3-I)-(3-CXX).
In one embodiment of compounds of structural formula (5-I), two R4s combine to form an oxo. The oxo can be bound, for example, at the position alpha to the nitrogen of the azacycloalkyl.
In certain embodiments of the compounds of formula (5-I), T is




In these embodiments, Q is —(C0-C3 alkyl)-, in which each carbon of the (C0-C3 alkyl) is optionally and independently substituted with one or two R16, in which each R16 is independently selected from —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar; —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo. Q can be, for example, an unsubstituted (C1-C3 alkyl). In other embodiments, Q is a (C1-C3 alkyl) having as its only substitution a single oxo group. For example, in certain embodiments, Q is —CH2—; a single bond; or —C(O)— or —CH(CH3)—.
The number of substituents on the ring system denoted by “A”, y, in these embodiments is 0, 1, 2, 3 or 4. For example, in some embodiments, y is 0, 1, 2 or 3, for example 0, or 1. In one embodiment, y is not zero and at least one R5 is halo, cyano, trifluoromethyl or trifluoromethoxy.
The ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl. For example, of the compounds of structural formula (5-I), the ring system denoted by “A” is an aryl or a heteroaryl. In one embodiment of the compounds of structural formula (5-I), the ring system denoted by “A” is an aryl. The ring system denoted by “A” can be, for example, a monocyclic aryl or heteroaryl.
For example, in one embodiment of the compounds of structural formula (5-I), the ring system denoted by “A” is an aryl, such as a phenyl. In one embodiment of the compounds of structural formula (5-I), y is 1 and R5 is attached to the phenyl para to Q. In another embodiment of the compounds of structural formula (5-I), y is 1 and R5 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), acyl, carboxylate, carboxamide and nitro. R5 can be, for example, —Cl, —F, cyano, trifluoromethyl or trifluoromethoxy. In another embodiment of the compounds of structural formula (5-I), the




moiety is a 3,4-dihalophenyl.

In another embodiment of the compounds of structural formula (5-I), the ring system denoted by “A” is a heteroaryl. For example, in certain embodiments of the compounds of structural formula (5-I), the ring system denoted by “A” is a pyridiyl, a thienyl, or a furanyl.
In one embodiment of the compounds of structural formula (5-I), the compound has structural formula (5-II):




in which the variables are defined as described above with reference to formula (5-I).

In another embodiment of the compounds of structural formula (5-I), the compound has the structural formula (5-III):




in which the variables are defined as described above with reference to formula (5-I).

For example, compounds according to certain embodiments of the compounds of structural formula (5-I) have structural formula (54V):




in which the variables are defined as described above with reference to formula (5-I).

In other embodiments of the compounds of structural formula (5-I) have structural formula (5-V):




in which the variables are defined as described above with reference to formula (5-I).

In certain embodiments of the compounds of structural formula (5-I), n is 1 or 2. For example, in one embodiment of the compounds of structural formula (5-I), n is 2.
In one embodiment of the compounds of structural formula (5-I), the compound has structural formula (5-VI):




in which the variables are defined as described above with reference to formula (5-I).

In another embodiment, the compound has the structural formula (5-VII):




in which the variables are defined as described above with reference to formula (5-I).

For example, compounds of structural formula (5-I) can have structural formula (5-VIII):




in which the variables are defined as described above with reference to formula (5-I).

In other embodiments of the compounds of structural formula (5-I), compounds of have structural formula (5-IX):




in which the variables are defined as described above with reference to formula (5-I).

According to structural formula (5-I), R1 is —H and R2 is -Hca. In certain embodiments of the compounds of structural formula (5-I), R2 is substituted with (C0-C3 alkyl)-Het or (C0-C3 alkyl)-Ar. In one embodiment of the compounds of structural formula (5-I), R2 is -(optionally-substituted azetidinyl), -(optionally-substituted pyrrolidinyl), -(optionally-substituted piperidinyl), or -(optionally-substituted azepanyl). For example, R2 can be -(optionally substituted piperidinyl) or -(optionally substituted pyrrolidinyl).
In one embodiment of the compounds of structural formula (5-I), R1 is —H and R2 is -(optionally-substituted azetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl). For example, in one embodiment of the compounds of structural formula (5-I), R2 is -(optionally substituted piperidin-4-yl). In another embodiment of the compounds of structural formula (5-I), R2 is -(optionally substituted pyrrolidin-3-yl).
In certain embodiments of the compounds of structural formula (5-I), the azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R2 moieties described above are substituted at their 1-positions. For example, in one embodiment of the compounds of structural formula (5-I), R2 is substituted at its 1-position with (C0-C3 alkyl)-Ar or (C0-C3 alkyl)-Het. For example, in one embodiment of the compounds of structural formula (5-I), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment of the compounds of structural formula (5-I), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with a benzyl substituted with an electron withdrawing group; or with a pyridinylmethyl substituted with an electron withdrawing group. For example, the benzyl or pyridinylmethyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), acyl groups, carboxylate groups, carboxamide groups, cyano groups, sulfonate groups, and nitro groups. In other embodiments of the compounds of structural formula (5-I), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an unsubstituted benzyl or an unsubstituted phenyl.
In other embodiments of the compounds of structural formula (5-I), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with an optionally substituted pyridinylmethyl, an optionally substituted furanylmethyl or an optionally substituted thienylmethyl. For example, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety can be substituted with an unsubstituted pyridinylmethyl, an unsubstituted furanylmethyl, or an unsubstituted thienylmethyl.
In other embodiments of the compounds of structural formula (5-I), the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R2 moiety is substituted at its 1-position with —CO—O—(C0-C6 alkyl), —CO-Het, —CO—Ar or —SO2—(C0-C6 alkyl).
According to structural formula (5-I), the number of substituents on the central phenyl ring, w, is 0, 1, 2, 3 or 4. For example, in one embodiment of the compounds of structural formula (5-I), w is 0, 1 or 2. In another embodiment of the compounds of structural formula (5-I), w is 0. In other embodiments of the compounds of structural formula (5-I), w is at least 1, and at least one R3 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), acyl, carboxylate, carboxamide and nitro.
In certain embodiments of the compounds of structural formula (5-I), R3 is selected from the group consisting of halo, cyano, —(C1-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), acyl, carboxylate, carboxamide and nitro. R3 can be, for example, —Cl or —F. For example, compounds according to these embodiments can have structural formula (5-X):




in which the remaining variables are defined as described above with reference to formula (5-I).

Certain other compounds according to these embodiments have structural formula (5-XI):




in which the remaining variables are defined as described above with reference to formula (5-I).

According to the compounds of structural formula (5-I), the number of substituents on the ethereal azacycloalkane ring, x, is 0, 1, 2, 3 or 4. In one embodiment of the compounds of structural formula (5-I), x is 0, 1, 2 or 3. For example, x can be 0, or can be 1 or 2.
Compounds according to one embodiment of the compounds of structural formula (5-I) have the structural formula (5-XII):




in which Q and G are each independently a bond, —CH2—, —C(H)(R16)— or —C(R16)2—; v is 0, 1, 2, 3 or 4; each R15 is independently selected from —(C1-C6 alkyl), —(C1-C6 fluoroalkyl), —(C0-C6 alkyl)-Ar; —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R15 on the same carbon optionally combine to form oxo; R17 is Het or Ar, and all other variables are defined as described above with reference to formula (5-I). In one embodiment of the compounds of structural formula (5-I), v is 0. In one embodiment of the compounds of structural formula (5-I), Q is a single bond. In another embodiment, G is —CH2— or —CO—. For example, in one embodiment of the compounds of structural formula (5-I), Q is a single bond and G is —CH2— or —CO—. The ethereal linkage of the piperidine to the benzamide can be at any aryl carbon. For example, the ether can be substituted at the 3-position or the 4-position of the benzamide. In one embodiment of the compounds of structural formula (5-I), two R15s combine to form an oxo, which can be bound, for example, at a position alpha to the piperidine nitrogen. As described above, in certain embodiments of the compounds of structural formula (5-I), the ring system denoted by “A” is aryl or heteroaryl. In one embodiment of the compounds of structural formula (5-I), the ring system denoted by “A” is substituted with one or more electron-withdrawing groups. In another embodiment, R17 is substituted with one or more electron-withdrawing groups.

Compounds according to certain embodiments have the structural formula (5-XIII):




in which Q is —CH2— or a single bond; R3 is halo; R11 is H, halo, cyano, or a carboxylate; and R12 and R13 are independently H, trifluoromethyl, trifluoromethoxy, halo or cyano.

Compounds according to other embodiments have structural formula (5-XIV):




in which Q is —CH2— or a single bond; R11 is H, halo, cyano, or a carboxylate; and R12 and R13 are independently H, trifluoromethyl, trifluoromethoxy, halo or cyano.

Compounds according to certain embodiments have the structural formula (5-XV):




in which Q is —CH2— or a single bond; R3 is halo; and R12 and R13 are independently H, trifluoromethyl, trifluoromethoxy, halo or cyano.

Compounds according to other embodiments have the structural formula (5-XVI):




in which Q is —CH2— or a single bond; and R12 and R13 are independently H, trifluoromethyl, trifluoromethoxy, halo or cyano.

Another aspect of the disclosure provides 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, the method including administering to the subject an effective amount of a compound having structural formula (5-XVII):




or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof (or a solvate or hydrate thereof), wherein

    
    
        R1 and R22, together with the nitrogen to which they are attached, form an optionally substituted monocyclic heterocycloalkyl; or
        R1 is H and R22 is selected from —(C2-C4 alkyl)-(morpholin-4-yl) and —(C2-C4 alkyl)-NH—C(O)O—(C1-C6 alkyl), and
        all other variables are as described above with reference to structural formulae (5-I)-(5-XVI).
    
    


In one embodiment of the compounds according to structural formula (5-XVII), R1 and R22, together with the nitrogen to which they are attached, form an optionally substituted monocyclic heterocycloalkyl. The heterocycloalkyl can be, for example, piperidine or piperazine. In certain embodiments of the compounds of structural formula (5-XVII), the heterocycloalkyl is piperazine substituted at its 4-position with —C(O)O—(C1-C6 alkyl), —(C0-C4)-Het or —(C0-C4)—Ar. For example, the piperazine may be substituted at its 4-position with —C(O)O-tBu, -optionally-substituted pyridinylmethyl, optionally-substituted phenyl or optionally-substituted pyridinyl.
In another embodiment of the compounds according to structural formula (5-XVII), R1 is H and R22 is selected from —(C2-C4 alkyl)-(morpholin-4-yl) and —(C2-C4 alkyl)-NH—C(O)O—(C1-C6 alkyl). However, in certain embodiments, when w and x are zero, y is 1 and R5 is methoxy substituted para to the benzyl methylene, R22 is not —(C2-C4 alkyl)-(morpholin-4-yl); and when w is 1, x and y are zero, and R3 is methoxy substituted ortho to the ether oxygen, R22 is not —(C2-C4 alkyl)-(morpholin-4-yl). In certain embodiments, R22 is —(C2-C4 alkyl)-NH—C(O)O—(C1-C6 alkyl). The C1-C6 alkyl can be, for example, a tert-butyl group.
Examples of compounds according to structural formulae (5-I) and (5-XVII) include those listed in Table 5. These compounds can be made, for example using a procedure analogous to those described in U.S. Patent Application Publications nos. 2009/0163511, 2009/0170829, 2009/0186894 and 2009/0275609, and in U.S. patent application Ser. No. 12/695,861, each of which is hereby incorporated by reference in its entirety.









TABLE 5





Cpd
Name
Structure







5-1
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- methoxybenzyl)piperidin-4- yloxy)benzamide






 


5-2
N-(1-benzylpiperidin-4-yl)-4-(1- benzylpiperidin-4-yloxy)-3- methoxybenzamide






 


5-3
N-(1-benzylpiperidin-4-yl)-4-(1- (furan-2-ylmethyl)piperidin-4- yloxy)benzamide






 


5-4
N-(1-benzylpiperidin-4-yl)-4-(1- ((1-methyl-1H-imidazol-5- yl)methyl)piperidin-4- yloxy)benzamide






 


5-5
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-((1-methyl-1H- imidazol-5-yl)methyl)piperidin-4- yloxy)benzamide






 


5-6
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(pyridin-4- ylmethyl)piperidin-4- yloxy)benzamide






 


5-7
N-(1-benzylpiperidin-4-yl)-3- methoxy-4-(1-(3- phenylpropyl)piperidin-4- yloxy)benzamide






 


5-8
N-(1-benzylpiperidin-4-yl)-3- methoxy-4-(1-(thiophen-2- yl)piperidin-4-yloxy)benzamide






 


5-9
N-(1-benzylpiperidin-4-yl)-3- methoxy-4-(1- (methylsulfonyl)piperidin-4- yloxy)benzamide






 


5-10
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(thiophen-2- yl)piperidin-4-yloxy)benzamide






 


5-11
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(furan-2-yl)piperidin- 4-yloxy)benzamide






 


5-12
N-(1-benzylpiperidin-4-yl)-3- methoxy-4-(1-(furan-2- yl)piperidin-4-yloxy)benzamide






 


5-13
N-(1-benzylpiperidin-4-yl)-3-(1- benzylpiperidin-4- yloxy)benzamide






 


5-14
N-(1-benzylpiperidin-4-yl)-4-(1- benzylpiperidin-4-yloxy)-3- chlorobenzamide






 


5-15
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-((2,3- dihydrobenzo[b][1,4]dioxin-6- yl)methyl)piperidin-4- yloxy)benzamide






 


5-16
N-(1-benzylpiperidin-4-yl)-4-(1- (4-tert-butylbenzyl)piperidin-4- yloxy)-3-chlorobenzamide






 


5-17
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-18
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- (trifluoromethyl)benzoyl)piperidin- 4-yloxy)benzamide






 


5-19
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- fluorobenzyl)piperidin-4- yloxy)benzamide






 


5-20
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(4-tert- butylbenzyl)piperidin-4- yloxy)benzamide






 


5-21
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(1- phenylethyl)piperidin-4- yloxy)benzamide






 


5-22
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- fluorobenzoyl)piperidin-4- yloxy)benzamide






 


5-23
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-24
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(2- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-25
3-fluoro-N-(1-phenylpiperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-26
tert-butyl 4-(3-fluoro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamido)piperidine-1- carboxylate






 


5-27
3-fluoro-N-(1-(4- fuorobenzyl)piperidin-4-yl)-4-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-28
3-fluoro-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-29
3-fluoro-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-30
3-fluoro-N-(1-pivaloylpiperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-31
3-fluoro-N-(1-(4- fluorobenzoyl)piperidin-4-yl)-4- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-32
3-fluoro-N-(1-(pyridin-2- ylmethyl)piperidin-4-yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-33
methyl 4-((4-(3-fluoro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamido)piperidin-1- yl)methyl)benzoate






 


5-34
3-fluoro-N-(1- (isopropylsulfonyl)piperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-35
4-((4-(3-fluoro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamido)piperidin-1- yl)methyl)benzoic acid






 


5-36
4-(1-(4-tert- butylbenzyl)piperidin-4-yloxy)-3- fluoro-N-(1-phenylpiperidin-4- yl)benzamide






 


5-37
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(pyridin-4- ylmethyl)piperidin-4- yloxy)benzamide






 


5-38
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(pyridin-3- ylmethyl)piperidin-4- yloxy)benzamide






 


5-39
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(pyridin-2- ylmethyl)piperidin-4- yloxy)benzamide






 


5-40
3-fluoro-N-(1- isonicotinoylpiperidin-4-yl)-4-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-41
N-(1-benzylpiperidin-4-yl)-4-(1- (4-cyanobenzyl)piperidin-4- yloxy)-3-fluorobenzamide






 


5-42
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(4- methylbenzyl)piperidin-4- yloxy)benzamide






 


5-43
N-(1-(4-cyanobenzyl)piperidin-4- yl)-3-fluoro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-44
4-(1-(4-cyanophenyl)piperidin-4- yloxy)-3-fluoro-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)benzamide






 


5-45
N-(1-(4-cyanobenzyl)piperidin-4- yl)-4-(1-(4- cyanophenyl)piperidin-4-yloxy)- 3-fluorobenzamide






 


5-46
N-(1-benzylpiperidin-4-yl)-3-(1- (4- (4-(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-47
N-(1-benzylpiperidin-4-yl)-2- chloro-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-48
N-(1-benzylpiperidin-4-yl)-3-(1- (4-cyanophenyl)piperidin-4- yloxy)benzamide






 


5-49
N-(1-benzylpiperidin-4-yl)-2- chloro-4-(1-(4- cyanophenyl)piperidin-4- yloxy)benzamide






 


5-50
N-(1-benzylpiperidin-4-yl)-3-(1- (4-cyanobenzyl)piperidin-4- yloxy)benzamide






 


5-51
N-(1-benzylpiperidin-4-yl)-2- chloro-4-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzamide






 


5-52
N(1-benzylpiperidin-4-yl)-3-(1- (4- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-53
N-(1-benzylpiperidin-4-yl)-3-(1- (pyridin-4-yl)piperidin-4- yloxy)benzamide






 


5-54
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- (trifluoromethoxy)benzyl)piperidin- 4-yloxy)benzamide






 


5-55
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-56
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-57
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(4- (trifluoromethoxy)benzyl)piperidin- 4-yloxy)benzamide






 


5-58
3-chloro-N-(1-methylpiperidin-4- yl)-4-(1-(4- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-59
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(3- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-60
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(3- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-61
N-(1-benzylpiperidin-4-yl)-3- fluoro-4-(1-(4- fluorobenzyl)piperidin-4- yloxy)benzamide






 


5-62
N-(1-benzylpiperidin-4-yl)-3,5- dichloro-4-(1-(3- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzamide






 


5-63
N(1-benzylpiperidin-4-yl)-4-(1- (4- (trifluoromethoxy)benzyl)piperidin- 4-yloxy)benzamide






 


5-64
N-(1-benzylpiperidin-4-yl)-4-(1- (4-chlorobenzyl)piperidin-4- yloxy)-3-fluorobenzamide






 


5-65
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- chlorobenzyl)piperidin-4- yloxy)benzamide






 


5-66
3-chloro-4-(1-(4- chlorobenzyl)piperidin-4-yloxy)- N-(1-(4-fluorobenzyl)piperidin-4- yl)benzamide






 


5-67
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzamide






 


5-68
3-chloro-N-(1-(4- fluorobenzyl)piperidin-4-yl)-4-(1- (4-methylbenzyl)piperidin-4- yloxy)benzamide






 


5-69
N-(1-benzylpiperidin-4-yl)-4-(1- (3,4-difluorobenzyl)piperidin-4- yloxy)-3-fluorobenzamide






 


5-70
N-(1-(4-chlorobenzyl)piperidin-4- yl)-4-(1-(4- cyanobenzyl)piperidin-4-yloxy)- 3-fluorobenzamide






 


5-71
N-(1-(4-chlorobenzyl)piperidin-4- yl)-4-(1-(3,4- difluorobenzyl)piperidin-4- yloxy)-3-fluorobenzamide






 


5-72
N-(1-(4-chlorobenzyl)piperidin-4- yl)-4-(1-(4- chlorobenzyl)piperidin-4-yloxy)- 3-fluorobenzamide






 


5-73
N-(1-(4-chlorobenzyl)piperidin-4- yl)-3-fluoro-4-(1-(4- methylbenzyl)piperidin-4- yloxy)benzamide






 


5-74
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(3,4- difluorobenzyl)piperidin-4- yloxy)benzamide






 


5-75
N-(1-benzylpiperidin-4-yl)-3,5- dichloro-4-(1-(4- chlorobenzyl)piperidin-4- yloxy)benzamide






 


5-76
N-(1-benzylpiperidin-4-yl)-3,5- dichloro-4-(1-(3,4- difluorobenzyl)piperidin-4- yloxy)benzamide






 


5-77
N-(1-benzylpiperidin-4-yl)-3,5- dichloro-4-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzamide






 


5-78
tert-butyl 4-(4-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzamido)piperidine-1- carboxylate






 


5-79
4-(1-(4-cyanobenzyl)piperidin-4- yloxy)-N-(piperidin-4- yl)benzamide






 


5-80
N-(1-(4-chlorobenzyl)piperidin-4- yl)-4-(1-(3,4- dichlorobenzyl)piperidin-4- yloxy)-3-fluorobenzamide






 


5-81
N-(1-(4-chlorobenzyl)piperidin-4- yl)-4-(1-(4- cyanophenyl)piperidin-4-yloxy)- 3-fluorobenzamide






 


5-82
N-(1-benzylpiperidin-4-yl)-4-(1- (3,4-dichlorobenzyl)piperidin-4- yloxy)-3-fluorobenzamide






 


5-83
4-(1-(4-cyanobenzyl)piperidin-4- yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)benzamide






 


5-84
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-(3,4- dichlorobenzyl)piperidin-4- yloxy)benzamide






 


5-85
4-(1-(4-cyanobenzyl)piperidin-4- yloxy)-N-(1-(pyridin-2- ylmethyl)piperidin-4- yl)benzamide






 


5-86
N-(1-benzylpiperidin-4-yl)-3-(1- (pyridin-2-yl)piperidin-4- yloxy)benzamide






 


5-87
N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-3-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzamide






 


5-88
N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-3-(1-(4- cyanophenyl)piperidin-4- yloxy)benzamide






 


5-89
N-(1-benzylpiperidin-4-yl)-3-(1- (3-cyanobenzyl)piperidin-4- yloxy)benzamide






 


5-90
tert-butyl 4-(4-(1-benzylpiperidin- 4-ylcarbamoyl)-2- chlorophenoxy)piperidine-1- carboxylate






 


5-91
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(1-pivaloylpiperidin-4- yloxy)benzamide






 


5-92
tert-butyl 4-(4-(1-benzylpiperidin- 4-ylcarbamoyl)-2- fluorophenoxy)piperidine-1- carboxylate






 


5-93
N-(1-benzylpiperidin-4-yl)-3- chloro-4-(piperidin-4- yloxy)benzamide






 


5-94
tert-butyl 3-(3-methoxy-4-(1-(4- (trifluoromethyl)benzyl)piperidin- 4- yloxy)benzamido)propylcarbamate






 


5-95
tert-butyl 3-(4-(1-(4- (trifluoromethyl)benzyl)piperidin- 4- yloxy)benzamido)propylcarbamate






 


5-96
tert-butyl 4-(4-(1-(4- methoxybenzyl)piperidin-4- yloxy)benzoyl)piperazine-1- carboxylate






 


5-97
tert-butyl 3-(3-chloro-4-(1-(4- methoxybenzyl)piperidin-4- yloxy)benzamido)propylcarbamate






 


5-98
4-(1-(4-chlorobenzyl)piperidin-4- yloxy)-4-methoxy-N-(3- morpholinopropyl)benzamide






 


5-99
tert-butyl 4-(4-(1-benzylpiperidin- 4-yloxy)benzoyl)piperazine-1- carboxylate






 


5-100
4-(1-(4-chlorobenzyl)piperidin-4- yloxy)-N-(3- morpholinopropyl)benzamide






 


5-101
3-chloro-4-(1-(4- methoxybenzyl)piperidin-4- yloxy)-N-(3- morpholinopropyl)benzamide






 


5-102
tert-butyl 3-(4-(1-benzylpiperidin- 4-yloxy)-3- chlorobenzamido)propylcarbamate






 


5-103
(4-(1-benzylpiperidin-4- yloxy)phenyl)(4-phenylpiperazin- 1-yl)methanone






 


5-104
4-(1-(4-methylbenzyl)piperidin-4- yloxy)-N-(3- morpholinopropyl)benzamide






 


5-105
(4-(1-benzylpiperidin-4- yloxy)phenyl)(4-(pyridin-2- ylmethyl)piperazin-1- yl)methanone













The present disclosure contemplates combinations of particularly described embodiments. For example, paragraph [0013] discloses certain embodiments of ring system “B” and paragraph [0015] discloses certain embodiments of T; also contemplated are embodiments in which ring system “B” is as described as in paragraph [0013], and T is as described in paragraph [0015]. This disclosure contemplates all such combinations, to the extent the definitions of the various structural features do not conflict with one another.
For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., 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 (e.g. 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 (e.g., —CH2—CH2—), 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, e.g., 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-Cn alkyl” means an alkyl group having from m to n carbon atoms (i.e., inclusive of m and n). The term “Cm-Cn alkyl” means an alkyl group having from m to n carbon atoms. For example, “C1-C6 alkyl” 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., “C0 alkyl”), 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-C6 alkyl)-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, e.g. F, Cl, Br and I. A more specific term, e.g., “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 ring system having a single ring (e.g., 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 carbocyclic and aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. In certain examples, aryl groups include those having a first carbocyclic, aromatic ring fused to an aromatic or aliphatic heterocycle, for example, 2,3-dihydrobenzofuranyl. 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 “heteroaryl” refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur in an aromatic ring. The heteroaryl may be fused to one or more cycloalkyl or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. The heteroaryl 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 “heterocycloalkyl” refers to a non-aromatic ring or ring system containing at least one heteroatom that is preferably selected from nitrogen, oxygen and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloalkyl may be saturated (i.e., a heterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups as well as bicyclic and polycyclic ring systems, including bridged and fused systems. The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings. In certain embodiments, the heterocycloalkyl groups have from 3 to 7 members in a single ring. In other embodiments, heterocycloalkyl groups have 5 or 6 members in a single ring. Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (in each case also “quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. Especially desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl), γ-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl, piperazinonyl. The heterocycloalkyl 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 (e.g., bridged systems) to other cycloalkyl rings. Certain examples of cycloalkyl groups present in the disclosed compounds have from 3 to 7 members in a single ring, such as having 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 “ring system” encompasses monocycles, as well as fused and/or bridged polycycles.
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-C4 fluoroalkyl), —O—(C1-C4 fluoroalkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —S(O)2O—(C0-C4 alkyl), NO2 and —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)R70 and —NR70C(NR70)NR80R80. Each R60 is 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)R71 and —NR71C(NR71)NR81R81. Each R70 is independently hydrogen or R60; each R80 is independently R70 or 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-C3 alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each R71 is independently hydrogen or R61, in which R61 is 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)R72 and —NR72C(NR72)NR82R82; and each R81 is independently R71 or 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-C3 alkyl substitution. Each R72 is independently hydrogen, (C1-C6 alkyl) or (C1-C6 fluoroalkyl); each R82 is independently R72 or 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-C3 alkyl 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 e.g. 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, —NR80R80 is meant to include —NH2, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4-methyl-piperazin-1-yl and N-morpholinyl.
Substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, —R60, halo, —O−M+, —OR70, —SR70, —S−M+, —NR80R80, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —SO2R70, —SO3−M+, —SO3R70, —OSO2R70, —OSO3−M+, —OSO3R70, —PO3−2(M+)2, —P(O)(OR70)O−M+, —P(O)(OR70)2, —C(O)R70, —C(S)R70, —C(NR70)R70, —CO2−M+, —CO2R70, —C(S)OR70, —C(O)NR80R80, —C(NR70)NR80R80, —OC(O)R70, —OC(S)R70, —OCO2−M+, —OCO2R70, —OC(S)OR70, —NR70C(O)R70, —NR70C(S)R70, —NR70CO2−M+, —NR70CO2R70, —NR70C(S)OR70, —NR70C(O)NR80R80, —NR70C(NR70)R70 and —NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined.
Substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and heterocycloalkyl groups are, unless otherwise specified, —R60, —O−M+, —OR70, —SR70, —S−M+, —NR80R80, trihalomethyl, —CF3, —CN, —NO, —NO2, —S(O)2R70, —S(O)2O−M+, —S(O)2OR70, —OS(O)2R70, —OS(O)2−M+, —OS(O)2OR70, —P(O)(O−)2(M+)2, —P(O)(OR70)O−M+, —P(O)(OR70)(OR70), —C(O)R70, —C(S)R70, —C(NR70)R70, —C(O)OR70, —C(S)OR70, —C(O)NR80R80, —C(NR70)NR80R80, —OC(O)R70, —OC(S)R70, —OC(O)OR70, —OC(S)OR70, —NR70C(O)R70, —NR70C(S)R70, —NR70C(O)OR70, —NR70C(S)OR70, —NR70C(O)NR80R80, —NR70C(NR70)R70 and —NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined.
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.
In certain preferred embodiments, substituent groups on “substituted” alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are -halo, —OH, —O—(C1-C4 alkyl), —O—(C1-C4 haloalkyl), —N(C0-C4 alkyl)(C0-C4 alkyl), —SH, —S(O)0-2—(C1-C4 alkyl), —(C1-C4 alkyl), —(C1-C4 haloalkyl), —C(O)—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), —N(C0-C4 alkyl)C(O)(C0-C4 alkyl)(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —OC(O)—(C0-C4 alkyl), S(O)2—O(C0-C4 alkyl), and —NO2, in which no alkyl is further substituted.
The compounds disclosed herein can also be provided as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. If the compound is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids. Such salts may be, for example, acid addition salts of at least one of the following acids: benzenesulfonic acid, citric acid, α-glucoheptonic acid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propanoic acid, succinic acid, sulfuric acid, tartaric acid (d, l, or dl), tosic acid (toluenesulfonic acid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, galactaric acid (mucic acid), D-glucuronic acid, 2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, isethionic acid (ethanolsulfonic acid), lactobionic acid, maleic acid, 1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfate, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic acid, (+)-camphoric acid, d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, formic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharine, salicylic acid, gentisic acid, and/or 4-acetamidobenzoic acid.
The compounds described herein can also be provided in prodrug form. “Prodrug” refers to a derivative of an active compound (drug) that undergoes 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. 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.
One of ordinary skill in the art of medicinal chemistry also will appreciate that the disclosed structures are intended to include isotopically enriched forms of the present compounds. As used herein “isotopes” includes those atoms having the same atomic number but different mass numbers. As will be apparent to those of skill in the art upon consideration of the present compounds, certain atoms can be enriched an isotope of that atom. For example, compounds having a fluorine atom, may be synthesized in a form enriched in the radioactive fluorine isotope 18F. Similarly, compounds may be enriched in the heavy isotopes of hydrogen, deuterium and tritium, and can be enriched in a radioactive isotope of carbon, such as 13C. Such compounds can be useful, for example, in studying the AMPK pathway and its role in metabolism.
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 AMPK 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 disclosed herein 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 (e.g., 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.
In the pharmaceutical compositions disclosed herein, one or more of the presently disclosed compounds may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. The pharmaceutical compositions 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 hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Formulations for oral use can also be presented as lozenges.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
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.
Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.
Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The presently disclosed compounds can also be administered in the form of suppositories, e.g., 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.
The presently disclosed compounds 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, for example, in U.S. Patent Application Publications nos. 2009/0163511, 2009/0170829, 2009/0186894 and 2009/0275609, and in U.S. patent application Ser. No. 12/695,861, each of which is hereby incorporated by reference in its entirety. One of skill in the art can adapt the reaction sequences described therein 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 the presently disclosed compounds can be synthesized using different routes altogether.
Compounds suitable for use in the presently disclosed pharmaceutical compositions include compounds of Tables 1-5, above.
Without being limited to any particular theory, it currently is believed that the presently disclosed compounds exert their therapeutic benefits as adiponectin receptor agonists, AMPK activators, or both. For convenience, and without limitation to theory, the present compounds are referred to as “adiponectin receptor agonists” or AMPK activators interchangeably throughout the specification. The presently disclosed adiponectin receptor agonist compounds are useful for increasing metabolic efficiency, for example by increasing fiber oxidative capacity, endurance and aerobic workload. In particular, the present agonists 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 agonists also are useful for treating muscular dystrophic states, such as Duchenne's and Becker's muscular dystrophies and Friedreich's ataxia.
The present agonists 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 adiponectin receptor agonists 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 adiponectin receptor agonists.
Metabolic efficiency is enhanced by the disclosed adiponectin receptor agonists. Thus the agonists 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. In another aspect the present compounds are useful for treating conditions associated with chronic heart failure, including myopathy/muscle atrophy, chronic obstructive pulmonary disease (COPD) and kidney diseases.
In one aspect the present adiponectin receptor agonists stimulate increased nitric oxide production. Such compounds are useful for treating diseases associated with reduced circulation and reduced blood vessel function. For example, the present compounds are useful for the treatment of heart disease and cardiomyopathy.
In another aspect, the present compounds activate autophagy and/or apoptotic pathways. Accordingly the present compounds are useful in halting or slowing the progression of neurodegenerative diseases and hyperproliferative disorders, such as cancer.
Inflammatory disorders and effects can be treated using the present adiponectin receptor agonists. 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 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.
Other aspects of the disclosure relate to the use of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein in the manufacture of a medicament for any of the therapeutic purposes described herein. Still other aspects of the disclosure relate to the use of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein for the treatment of any of the therapeutic purposes described above. In certain embodiments, the compounds used in the methods and uses disclosed herein have EC50 values for AMPK activation less than 10 μM, less than 5 μM, or even less than 1 μM.
EXAMPLES
AMPK Activation
Compounds of Table 1 were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. The EC50 values for AMPK activation for the tested compounds are presented in Table 6 below, in which “A” is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-1 μM; “D” is 1-5 μM; “E” is 5-10 μM; and “F” is >10 μM.










TABLE 6







Cnd No.
AMPK EC50









1-1
B



1-2
A



1-3
A



1-4
A



1-5
A



1-6
B



1-7
A



1-8
A



1-9
B



1-10
A



1-11
A



1-12
C



1-13
B



1-14
A



1-15
D



1-16
A



1-17
A



1-18
A



1-19
D



1-20
C



1-21
B



1-22
D



1-23
B



1-24
E



1-25
B



1-26
B



1-27
F



1-28
A



1-29
B



1-30
A



1-31
A



1-32
B



1-33
C



1-34
C



1-35
B



1-36
C



1-37
C



1-38
D



1-39
B



1-40
A



1-41
B



1-42
D



1-43
D



1-44
B



1-45
F



1-46
D



1-47
D



1-48
D



1-49
A



1-50
D



1-51
B



1-52
B



1-53
B



1-54
D



1-55
D



1-56
E



1-57
C



1-58
A



1-59
B



1-60
F



1-61
B



1-62
E



1-63
A



1-64
A



1-65
A



1-66
A



1-67
A



1-68
A



1-69
A



1-70
A



1-71
A



1-72
B



1-73
C



1-74
B



1-75
A



1-76
B



1-77
B



1-78
A



1-79
B



1-80
A



1-81
B



1-82
B



1-83
B



1-84
E



1-85
C



1-86
F



1-87
A



1-88
A



1-89
A



1-90
A



1-91
F



1-92
C



1-93
B



1-94
A



1-95
A



1-96
A



1-97
A



1-98
A



1-99
A



1-100
A



1-101
A



1-102
D



1-103
D



1-104
B



1-105
A



1-106
B



1-107
A



1-108
B



1-109
A



1-110
A



1-111
B



1-112
A



1-113
B



1-114
B



1-115
A



1-116
B



1-117
A



1-118
B



1-119
A



1-120
D



1-121
F



1-122
B



1-123
B



1-124
D



1-125
D



1-126
D



1-127
D



1-128
F



1-129
D



1-130
D



1-131
D



1-137
A



1-138
A



1-139
A



1-140
C



1-141
B



1-144
A



1-145
B



1-146
B



1-147
D



1-148
F



1-149
A



1-150
D



1-151
A



1-152
A



1-153
B



1-154
A



1-155
A



1-156
B



1-157
D



1-158
B



1-159
B



1-160
A










Compounds of Table 2 were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. The EC50 values for AMPK activation for the tested compounds are presented in Table 7 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; “E” is 10-50 μM; and “F” is >100 μM:










TABLE 7







Cpd No.
AMPK EC50









2-1
C



2-2
E



2-3
E



2-4
C



2-5
C



2-6
B



2-7
D



2-8
D



2-9
A



2-10
B



2-11
A



2-12
A



2-13
A



2-14
A



2-15
A



2-16
A



2-17
B



2-18
C



2-19
F



2-20
C



2-21
B



2-22
B



2-23
C



2-24
C



2-25
E



2-26
E



2-27
C



2-28
C



2-29
C



2-30
C



2-31
C



2-32
C



2-33
C



2-24
C



2-35
E



2-36
F



2-37
D



2-38
E



2-39
E



2-40
F



2-41
E



2-43
F



2-44
E



2-45
F



2-46
F



2-47
E



2-48
F



2-49
F



2-50
A



2-51
B



2-52
C



2-53
E



2-54
A










Compounds of Table 3 were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. The EC50 values for AMPK activation for the tested compounds are presented in Table 8 below, in which “A” is less than 0.1 μM; “B” is 0.1-1 μM; “C” is 1-10 μM; and “D” is 10-100 μM:










TABLE 8







Cpd No.
AMPK EC50









3-1
A



3-2
A



3-3
A



3-4
A



3-5
D



3-6
A



3-7
A



3-8
B



3-9
B



3-10
B



3-11
B



3-12
A



3-13
A



3-14
C



3-15
B



3-16
B



3-17
A



3-18
A



3-19
C



3-20
F



3-21
A



3-22
A



3-23
A



3-24
A



3-25
A



3-26
C



3-27
A



3-28
A



3-29
D



3-30
A



3-31
A



3-32
D



3-33
D



3-34
A



3-35
C



3-36
B



3-37
A



3-38
A



3-39
C



3-40
A



3-41
C



3-42
B










Compounds of Table 4 were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. The EC50 values for AMPK activation for the tested compounds are presented in Table 9 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; “E” is 10-50 μM; and “F” is >100 μM:










TABLE 9







Cpd No.
AMPK EC50









1
A



2
A



3
A



4
C



5
C



6
B



7
C



8
C










Compounds of Table 5 were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. The EC50 values for AMPK activation for the tested compounds are presented in Table 10 below, in which “A” is less than 1 μM; “B” is 1-10 μM; “C” is 10-20 μM; “D” is 20-50 μM; “E” is 50-100 μM, and “F” is >100 μM:










TABLE 10







Cpd No.
AMPK EC50









5-1
A



5-2
A



5-3
B



5-4
F



5-5
E



5-6
A



5-7
A



5-8
B



5-9
D



5-10
B



5-11
B



5-12
B



5-13
D



5-14
A



5-15
A



5-16
A



5-17
A



5-18
A



5-19
A



5-20
A



5-21
B



5-22
B



5-23
A



5-24
C



5-25
F



5-26
A



5-27
A



5-28
A



5-29
A



5-30
A



5-31
A



5-32
A



5-33
A



5-34
A



5-35
B



5-36
A



5-37
A



5-38
B



5-39
B



5-40
A



5-41
A



5-42
A



5-43
A



5-44
A



5-45
A



5-46
A



5-47
A



5-48
A



5-49
A



5-50
B



5-51
A



5-52
B



5-53
C



5-54
A



5-55
A



5-56
A



5-57
A



5-58
B



5-59
A



5-60
A



5-61
A



5-62
A



5-63
A



5-64
A



5-65
A



5-66
A



5-67
A



5-68
A



5-69
A



5-70
A



5-71
A



5-72
A



5-73
A



5-74
A



5-75
A



5-76
A



5-77
A



5-78
A



5-79
F



5-80
A



5-81
A



5-82
A



5-83
A



5-84
A



5-85
A



5-86
A



5-87
A



5-88
B



5-89
B



5-90
B



5-91
A



5-92
B



5-93
F



5-94
A



5-95
A



5-96
B



5-97
B



5-98
B



5-99
B



5-100
B



5-101
C



5-102
C



5-103
D



5-104
C



5-105
C










Endurance Testing

Male C57B/6J mice (8 weeks old) are randomly divided into at least four cohorts for exercise-trained and sedentary control and dosage groups.
Mice are acclimated to moderate treadmill running (10 m/min for 15 min) every other day for 1 week (day 1, 3, 5, 7). After acclimation, basal running endurances for the four groups are determined via a treadmill running test, where the speed is gradually increased from 0 to 15 m/min over the course of 15 min and then maintained constant until exhaustion. Treadmill to be used is 1012M-8-E52 Modular Enclosed Metabolic Treadmill for Mice, 8 Lanes w/Shock for Mice w/Shocker Detection & Software from Columbus Instruments or similar (with attached open-flow calorimeter for the measurement of respiratory metabolic performance while exercising). Exhaustion defined when mice are unable to avoid repetitive electrical shocks. Data are collected on total time and distance run as well as VO2.
On day 8 dosing by gavage with the adiponectin receptor agonist begins for the sedentary and exercise-trained groups and dosing with vehicle only for the control sedentary and exercise-trained groups.
Beginning on day 9, the groups to be exercise-trained are subjected to 4 weeks (5 days/week) of exercise training During all exercise sessions and treadmill tests, VO2 is measured before, during, and after exercise by means of indirect calorimetry in metabolic treadmill chambers. The 5th day of training for each weekly exercise regime is used as a complete treadmill test where the speed is gradually increased from 0 to 15 m/min over the course of 15 min and then maintained constant until exhaustion. Day 9 exercise to consist of treadmill running of 10 m/min for 15 min with a treadmill incline of 5 degrees. Subsequent exercise-training is to be progressive with increasing intensity and time (also incline of 5 degrees on treadmill). Data are collected on total time and distance for each training session, with point of exhaustion noted for mice failing to complete exercise.
Treatment with the present adiponectin receptor agonists results in increased endurance for both the exercise-trained and sedentary groups.

## Claims

1. A method for treating or ameliorating intermittent claudication in a subject who does not have type 2 diabetes, the method comprising administering to the subject an effective amount of a compound having the structural formula




or a pharmaceutically acceptable salt or N-oxide thereof, wherein
each R3 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
w is 0, 1, 2 or 3;
R14 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
each R4 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R4 on the same carbon optionally combine to form oxo;
x is 0, 1, 2, 3 or 4;
each Q is —CH2—, a single bond, —C(O)—, —S(O)2— or —CH(CH3)—;
the ring system denoted by “A” is monocyclic heteroaryl or phenyl;
R5 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN; and
y is 0, 1, 2, 3 or 4;
each R15 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R15 on the same carbon optionally combine to form oxo; and
v is 0, 1, 2, 3 or 4;
G is —CH2—, —C(O)—, —S(O)2— or —CH(CH3)—; and
R17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
in which
each L is independently selected
from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—, —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,
each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl),
each R9 is independently selected from —H, —(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl).

2. A method according to claim 1, wherein
the ring system denoted by “A” is phenyl, pyridyl, thienyl or furanyl; and
R17 is phenyl or pyridinyl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN.

3. A method according to claim 1, wherein
the ring system denoted by “A” is phenyl; and
R17 is phenyl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN.

4. A method according to claim 1, wherein no R14 is substituted on the furano carbon.

5. A method according to claim 1, wherein R14 is halo, cyano, unsubstituted —(C1-C4 alkyl) or unsubstituted —(C1-C4 haloalkyl).

6. A method according to claim 1, wherein G is —CH2—.

7. A method according to claim 1, wherein G is —C(O)— or —S(O)2—.

8. A method according to claim 1, wherein
x is 0;
v is 0;
w is 0; and
no R14 is substituted on the furano carbon, or R14 is halo, cyano, unsubstituted —(C1-C4 alkyl) or unsubstituted —(C1-C4 haloalkyl).

9. A method according to claim 1, wherein
x is 0 or 1;
v is 0, 1 or 2; and
w is 0, 1 or 2.

10. A method according to claim 1, wherein the compound has the structural formula

11. A method according to claim 1, wherein the compound has the structural formula




in which R25 is selected from halo, cyano, —(C1-C3 haloalkyl), —O—(C1-C2 haloalkyl), —(C1-C3 alkyl), —O—(C1-C2 alkyl), —C(O)—(C0-C2 alkyl), —C(O)O—(C0-C2 alkyl), —C(O)N(C0-C4 alkyl)(C0-C2 alkyl) and NO2.

12. A method according to claim 1, wherein the compound has the structural formula

13. A method according to claim 12, wherein
x is 0;
v is 0;
w is 0; and
no R14 is substituted on the furano carbon, or R14 is halo, cyano, unsubstituted —(C1-C4 alkyl) or unsubstituted —(C1-C4 haloalkyl).

14. A method according to claim 1, wherein the compound has the structural formula

15. A method according to claim 14, wherein
x is 0;
v is 0;
w is 0; and
no R14 is substituted on the furano carbon, or R14 is halo, cyano, unsubstituted —(C1-C4 alkyl) or unsubstituted —(C1-C4 haloalkyl).

16. A method according to claim 1, wherein v is 0 and w is 0.

17. A method according to claim 1, wherein
x is 0;
v is 0;
w is 0;
Q is a single bond or —CH2—;
G is —CH2— or —C(O)—; and
no R14 is substituted on the furano carbon, or R14 is halo, cyano, unsubstituted —(C1-C4 alkyl) or unsubstituted —(C1-C4 haloalkyl).

18. A method according to claim 1, wherein
x is 0;
v is 0;
w is 0;
Q is a single bond;
G is —CH2—; and
no R14 is substituted on the furano carbon, or R14 is halo, cyano, unsubstituted —(C1-C4 alkyl) or unsubstituted —(C1-C4 haloalkyl).

19. A method according to claim 1, wherein
Q is a single bond or —CH2—; and
G is —CH2— or —C(O)—.

20. A method according to claim 1, wherein
Q is a single bond; and
G is —CH2—.

21. A method according to claim 1, wherein the compound is
N-(1-(4-fluorobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
3-methyl-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide
N-(1-(3-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
3-methyl-N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
3-methyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoro methyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
5-(1-(4-cyanobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-isonicotinoylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-isonicotinoylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)-N-(1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)-N-(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)-N-(1-isonicotinoylpyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)-N-(1-(pyridin-3-ylsulfonyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(S)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(pyrrolidin-3-yl)benzofuran-2-carboxamide;
(S)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)benzofuran-2-carboxamide;
(S)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)-N-(1-isonicotinoylpiperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylphenyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylphenyl)piperidin-4-yloxy)-N-(1-isonicotinoylpiperidin-4-yl)benzofuran-2-carboxamide; or
5-(1-(4-carbamoylphenyl)piperidin-4-yloxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzofuran-2-carboxamide.