Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof

BACKGROUND OF THE INVENTION
Field of the Invention

The present invention provides substituted fused imidazole derivatives that may be useful for control of an inflammatory response. In addition, the invention provides compounds, pharmaceutical compositions, and methods of use thereof for controlling the activity or the amount, or both the activity and the amount, of heme-oxygenase in a mammalian subject.

Description of Related Art

Cellular damage due to oxidative stress caused by reactive oxygen species (ROS) has been demonstrated to be involved in the onset or progression of various chronic diseases, e.g., cardiovascular disease, including arteriosclerosis and hypertension; diabetes and diabetic related complications, such as glomerular nephropathy; cerebral nerve degenerative diseases, such as Alzheimer's disease, Parkinson's disease, ALS (amyotrophic lateral sclerosis) and multiple sclerosis; asthma, chronic obstructive pulmonary disease, skin diseases, eye diseases, and cancer. Enhancing the capability of protecting from oxidative stress may be useful in one or more of preventing these diseases, delaying their progress, or delaying their onset. Further, with the varied etiology associated with this diverse set of diseases, a general strategy to mitigate oxidative stress would be beneficial.

The basic biochemistry of a cell generates ROS, including superoxide anions, hydroxyl anions, nitric oxide, peroxynitrite, and hydrogen peroxide. All of these products serve critical cellular signaling needs, but also have deleterious effects if overproduced or left unchecked. Many disease conditions induce persistent levels of ROS that are associated with the establishment of chronic pathophysiologic changes seen within a variety of tissues. These complications, in and of themselves, may be the primary drivers of disease morbidity and mortality.

Under normal physiological conditions, production of ROS are counterbalanced by a well defined and conserved set of cellular pathways that respond to, limit, and repair the damage due to ROS. This adaptive set of genes, called the phase II system, encodes enzymes that degrade ROS directly (e.g., superoxide dismutase and catalase) as well as increase levels of a cell's endogenous antioxidant molecules, including glutathione and bilirubin. Examples of known phase II enzymes include glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutamyl-cysteinyl ligase (GCL), heme oxygenase 1 (HMOX1), and thioredoxin reductase 1 (TXNRD1). A common sequence called antioxidant responsive element (ARE) is present in a promoter of each gene of these phase II enzymes, and its expression is induced by the transcription factor Nrf2 (NF-E2 related factor 2).

Of the phase II enzyme system, HMOX1 has been found to be a key component. The role of HMOX1 is to metabolize heme into bilirubin, carbon monoxide, and free iron, as a first step of a two-step process to catabolize heme. The first, and rate-limiting reaction, is the production of biliverdin and carbon monoxide from heme by HMOX1. The second step is the production of bilirubin from biliverdin by biliverdin reductase. Both bilirubin and carbon monoxide have been shown to scavenge ROS and to have potent anti-oxidant and anti-inflammatory activity. Agents that induce production of HMOX1 have been shown to have beneficial activity in models of diabetes, cardiovascular disease, hypertension, and pulmonary function.

HMOX1 is found in the liver, kidneys, spleen, and skin, of humans and has also been localized to specific cell types, notably fibroblasts and macrophages. HMOX1 exists in at least three isoforms, one constitutive and the other two inducible. Heme, heavy metal ions (e.g., tin, gold, platinum, and mercury), transition metal ions (e.g., iron, cobalt, chromium, and nickel), and electrophiles (e.g., natural products such as sulforaphane and curcumin) can all induce production of HMOX1. Induction of HMOX1 and other phase II genes are controlled by a number of transcription factors that are responsive to heavy metals, heme, and electrophiles. The transcription factors Nrf2, Bach1, and Maf are particularly important in this process. In addition, there are cofactors and regulatory molecules that are important in regulating Phase II gene induction. These include Keap1, an adapter molecule targeting Nrf2 for ubiquitination, and two mitochondrial proteins, DJ-1 and frataxin (FXN) that serve to augment Nrf2 activation in the presence of electrophiles. HMOX1 is also induced as part of a generalized stress response to stimuli such as thermal shock, oxidative stress and cytokines such as interleukin-1 (IL-1), tumor necrosis factor and IL-6. The stress response is seen as beneficial in that it results in protection of vulnerable cell enzymes from inactivation.

BRIEF SUMMARY OF INVENTION

The invention provides substituted fused imidazole derivatives of Formula (I):

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or pharmaceutically acceptable salts thereof, as described herein. In another aspect, the invention provides pharmaceutical compositions which may reduce oxidative stress and/or inflammation. In another aspect, the present invention provides methods for the preparation of compounds of Formula (I) and pharmaceutically acceptable salts thereof. In another aspect, the invention provides pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides methods of treatment comprising: administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof are useful as agents that induce the production of and/or increase the activity of HMOX1, and thus may be useful to treat various chronic diseases that are associated, at least in part, with oxidative stress including, but not limited to: cardiovascular disease including arteriosclerosis and hypertension; diabetes and diabetic related complications such as glomerular nephropathy; cerebral nerve degenerative diseases such as Alzheimers disease, Parkinson's disease, ALS (amyotrophic lateral sclerosis) and multiple sclerosis; asthma; chronic obstructive pulmonary disease; skin diseases; eye diseases including macular degeneration, cataracts, light retinopathy, and retinopathy of prematurity; and cancer.

BRIEF DESCRIPTION OF DRAWINGS

Not applicable

DETAILED DESCRIPTION

The following definitions are intended to clarify the terms defined. If a particular term used herein is not specifically defined, the term should not be considered to be indefinite. Rather, such undefined terms are to be construed in accordance with their plain and ordinary meaning to a person of ordinary skill in the field(s) of art to which the invention is directed.

As used herein the term “alkyl” refers to a straight or branched chain saturated hydrocarbon having one to ten carbon atoms, which may be optionally substituted, as herein further described, with multiple degrees of substitution being allowed. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, n-hexyl, and 2-ethylhexyl.

The number carbon atoms in an alkyl group is represented by the phrase “C_x-yalkyl,” which refers to an alkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Thus, C_1-6alkyl represents an alkyl chain having from 1 to 6 carbon atoms and, for example, includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, and n-hexyl.

As used herein, the term “alkylene” refers to a straight or branched chain divalent saturated hydrocarbon radical having from one to ten carbon atoms, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.

The number of carbon atoms in an alkylene group is represented by the phrase “C_x-yalkylene,” which refers to an alkylene group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, C_1-4alkylene represents an alkylene chain having from 1 to 4 carbons atoms, and, for example, includes, but is not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.

As used herein, the term “cycloalkyl” refers to a saturated, three- to ten-membered, cyclic hydrocarbon ring, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Such “cycloalkyl” groups are monocyclic, bicyclic, or tricyclic. Examples of “cycloalkyl” groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

The number of carbon atoms in a cycloalkyl group will be represented by the phrase “C_x-ycycloalkyl,” which refers to a cycloalkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, C_3-10cycloalkyl represents a cycloalkyl group having from 3 to 10 carbons as described above, and for example, includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

As used herein, the term “heterocycle” or “heterocyclyl” refers to an optionally substituted mono- or polycyclic saturated ring system containing one or more heteroatoms. Such “hetercycle” or “heterocyclyl” groups may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. The term “heterocycle” or “heterocyclyl,” as used herein, does not include ring systems that contain one or more aromatic rings. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides. Typically, the ring is three- to twelve-membered. Such rings may be optionally fused to one or more of another heterocyclic ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” groups, as used herein include, but are not limited to, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene, where attachment can occur at any point on said rings, as long as attachment is chemically feasible. Thus, for example, “morpholine” refers to morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl.

As used herein, when “heterocycle” or “heterocyclyl” is recited as a possible substituent, the “heterocycle” or “heterocyclyl” group can attach through either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible. For example, “heterocyclyl” would include pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. When “heterocycle” or “heterocyclyl” groups contain a nitrogen atom in the ring, attachment through the nitrogen atom can alternatively be indicated by using an “-ino” suffix with the ring name. For example, pyrrolidino refers to pyrrolidin-1-yl.

As used herein the term “halogen” refers to fluorine, chlorine, bromine, or iodine.

As used herein, the term “oxo” refers to a >C═O substituent. When an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group.

As used herein the term “haloalkyl” refers to an alkyl group, as defined herein, that is substituted with at least one halogen. Examples of branched or straight chained “haloalkyl” groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo. The term “haloalkyl” should be interpreted to include groups such as —CF₃, —CH₂—CF₃, and —CF₂Cl.

As used herein, the term “aryl” refers to a six- to ten-membered cyclic, aromatic hydrocarbon, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of “aryl” groups as used herein include, but are not limited to, phenyl and naphthyl. As used herein, the term “aryl” also includes ring systems in which a phenyl or naphthyl group is optionally fused with one to three non-aromatic, saturated or unsaturated, carbocyclic rings. For example, “aryl” would include ring systems such as indene, with attachment possible to either the aromatic or the non-aromatic ring(s).

As used herein, the term “heteroaryl” refers to a five- to fourteen-membered optionally substituted mono- or polycyclic ring system, which contains at least one aromatic ring and also contains one or more heteroatoms. Such “heteroaryl” groups may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. In a polycyclic “heteroaryl” group that contains at least one aromatic ring and at least one non-aromatic ring, the aromatic ring(s) need not contain a heteroatom. Thus, for example, “heteroaryl,” as used herein, would include indolinyl. Further, the point of attachment may be to any ring within the ring system without regard to whether the ring containing the attachment point is aromatic or contains a heteroatom. Thus, for example, “heteroaryl,” as used herein, would include indolin-1-yl, indolin-3-yl, and indolin-5-yl. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides, where feasible. Examples of “heteraryl” groups, as used herein include, but are not limited to, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, pteridinyl, and phenazinyl, where attachment can occur at any point on said rings, as long as attachment is chemically feasible. Thus, for example, “thiazolyl” refers to thiazol-2-yl, thiazol-4-yl, and thiaz-5-yl.

As used herein, when “heteroaryl” is recited as a possible substituent, the “heteroaryl” group can attach through either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible.

As used herein, the term “heterocyclylene” refers to an optionally substituted bivalent heterocyclyl group (as defined above). The points of attachment may be to the same ring atom or to different ring atoms, as long as attachment is chemically feasible. The two points of attachment can each independently be to either a carbon atom or a heteroatom, as long as attachment is chemically feasible. Examples include, but are not limited to,

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where the asterisks indicate points of attachment.

As used herein, the term “heteroarylene” refers to an optionally substituted bivalent heteroaryl group (as defined above). The points of attachment may be to the same ring atom or to different ring atoms, as long as attachment is chemically feasible. The two points of attachment can each independently be to either a carbon atom or a heteroatom, as long as attachment is chemically feasible. Examples include, but are not limited to,

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where the asterisks indicate points of attachment.

Various other chemical terms or abbreviations have their standard meaning to the skilled artisan. For example: “hydroxyl” refers to —OH; “methoxy” refers to —OCH₃; “cyano” refers to —CN; “amino” refers to —NH₂; “methylamino” refers to —NHCH₃; “sulfonyl” refers to —SO₂—; “carbonyl” refers to —C(O)—; “carboxy” or “carboxyl” refer to —CO₂H, and the like. Further, when a name recited multiple moieties, e.g., “methylaminocarbonyl-methyl”, an earlier-recited moiety is further from the point of attachment than any later-recited moieties. Thus, a term such as “methylaminocarbonylmethyl” refers to —CH₂—C(O)—NH—CH₃.

As used herein, the term “substituted” refers to substitution of one or more hydrogens of the designated moiety with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated, provided that the substitution results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about −80° C. to about +40° C., in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient. As used herein, the phrases “substituted with one or more . . . ” or “substituted one or more times . . . ” refer to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.

As used herein, the various functional groups represented will be understood to have a point of attachment at the functional group having the hyphen or dash (-) or an asterisk (*). In other words, in the case of —CH₂CH₂CH₃, it will be understood that the point of attachment is the CH₂group at the far left. If a group is recited without an asterisk or a dash, then the attachment point is indicated by the plain and ordinary meaning of the recited group.

When any variable occurs more than one time in any one constituent (e.g., R^d), or multiple constituents, its definition on each occurrence is independent of its definition on every other occurrence.

As used herein, multi-atom bivalent species are to be read from left to right. For example, if the specification or claims recite A-D-E and D is defined as —OC(O)—, the resulting group with D replaced is: A-OC(O)-E and not A-C(O)O-E.

As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur.

As used herein, “administer” or “administering” means to introduce, such as to introduce to a subject a compound or composition. The term is not limited to any specific mode of delivery, and can include, for example, intravenous delivery, transdermal delivery, oral delivery, nasal delivery, and rectal delivery. Furthermore, depending on the mode of delivery, the administering can be carried out by various individuals, including, for example, a health-care professional (e.g., physician, nurse, etc.), a pharmacist, or the subject (i.e., self-administration).

As used herein, “treat” or “treating” or “treatment” can refer to one or more of delaying the progress of a disease or condition, controlling a disease or condition, delaying the onset of a disease or condition, ameliorating one or more symptoms characteristic of a disease or condition, or delaying the recurrence of a disease or condition or characteristic symptoms thereof, depending on the nature of a disease or condition and its characteristic symptoms.

As used herein, “subject” refers to any mammal such as, but not limited to, humans. In one embodiment, the subject is a human. In another embodiment, the subject is a human who exhibits one or more symptoms characteristic of a disease or condition. The term “subject” does not require one to have any particular status with respect to any hospital, clinic, or research facility (e.g., as an admitted patient, a study participant, or the like).

As used herein, the term “compound” includes free acids, free bases, and any salts thereof. Thus, phrases such as “compound of embodiment 1” or “compound of claim 1” refer to any free acids, free bases, and any salts thereof that are encompassed by embodiment 1 or claim 1, respectively.

As used herein, the term “pharmaceutical composition” is used to denote a composition that may be administered to a mammalian host, e.g., orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations containing conventional non-toxic carriers, diluents, adjuvants, vehicles, and the like. The term “parenteral” includes subcutaneous injections

As used herein, “substituted fused imidazole derivatives” refers to compounds encompassed by Formula (I), described below.

Aspects of the present invention include substituted fused imidazole derivatives, pharmaceutical compositions comprising substituted fused imidazole derivatives, method of making substituted fused imidazole derivatives, methods of making pharmaceutical compositions comprising substituted fused imidazole derivatives, and methods of use thereof.

In a first aspect, the present invention provides substituted fused imidazole derivatives that induce production of HMOX1 and thus may be useful to treat various diseases associated at least in part with oxidative stress.

In a first embodiment (i.e., embodiment 1), the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

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wherein

one of X¹, X², X³, and X⁴is

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and the remaining members of X¹, X², X³, and X⁴are independently N or

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G is hydrogen, —C_1-8alkyl, —C_3-10cycloalkyl, —C_1-6alkylene-C_3-10cycloaklyl, heterocyclyl, —C_1-6alkylene-C_3-10heterocyclyl, phenyl, heteroaryl, or NR^hR^k, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^c; or G is —CH₂Y³, —CH₂CH₂Y³, —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃, —CH(Y³)CH₃, —CH₂C(Y³)(CH₃)₂, —C(Y³)(CH₃)₂, or

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where Y³is cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —Cl, —OH, —O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃, —S(O)₂CH₂CH₃, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH₃, —NH—C(O)—CH₂CH₃, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y⁴, where Y⁴is —OH, —OCH₃, —OCH₂CH₃, —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;

L is —CH₂—C(O)N(R⁶)—, —C(O)N(R⁶)—, —C(O)—O—, —SO₂—, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from R^x, or heterocyclylene optionally substituted one or more times with substituents independently selected from R^x; or the group -L-G is -cyano;
R¹is hydrogen, R^a, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^x;
R²is R^b;
R³is hydrogen, —C_1-6alkyl, or —C_1-6alkylene-C_3-10cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R^z;
R⁴is —C_1-6alkyl or —C_1-6alkylene-C_3-10cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R^y;
R⁶is hydrogen, —C_1-6alkyl, —C_1-6alkylene-C_3-10cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R^x;
R^ais
- a) -halogen,
- b) —C_1-6alkyl,
- c) —C_3-10cycloalkyl,
- d) -heterocyclyl,
- e) -cyano,
- f) —CF₃,
- g) —OCF₃,
- h) —O—R^d,
- i) —S(O)_w—R^d,
- j) —S(O)₂O—R^d,
- k) —NR^dR^e,
- l) —C(O)—R^d,
- m) —C(O)—O—R^d,
- n) —OC(O)—R^d,
- o) —C(O)NR^dR^e,
- p) —C(O)-heterocyclyl,
- q) —NR^dC(O)R^e,
- r) —OC(O)NR^dR^e,
- s) —NR^dC(O)OR^d, or
- t) —NR^dC(O)NR^dR^e,
- where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R^y;
R^bis
- a) -halogen,
- b) —C_1-6alkyl,
- c) —C_3-10cycloalkyl,
- d) -heterocyclyl,
- e) -phenyl,
- f) -heteroaryl,
- g) -cyano,
- h) —CF₃,
- i) —OCF₃,
- j) —O—R^f,
- k) —S(O)_w—R^f,
- l) —S(O)₂O—R^f,
- m) —NR^fR^g,
- n) —C(O)—R^f,
- o) —C(O)—O—R^f,
- p) —OC(O)—R^f,
- q) —C(O)NR^fR^g,
- r) —C(O)-heterocyclyl,
- s) —NR^fC(O)R^g,
- t) —OC(O)NR^fR^g,
- u) —NR^fC(O)OR^f, or
- v) —NR^fC(O)NR^fR^g,
- where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^z;
R^cis
- a) -halogen,
- b) —C_1-6alkyl,
- c) —C_3-10cycloalkyl,
- d) -heterocyclyl,
- e) -cyano,
- f) —CF₃,
- g) —OCF₃,
- h) —O—R^h,
- i) —S(O)_w—R^h,
- j) —S(O)₂O—R^h,
- k) —NR^hR^k,
- l) —C(O)—R^h,
- m) —C(O)—O—R^h,
- n) —OC(O)—R^h,
- o) —C(O)NR^hR^k,
- p) —C(O)-heterocyclyl,
- q) —NR^hC(O)R^k,
- r) —OC(O)NR^hR^k,
- s) —NR^hC(O)OR^k,
- t) —NR^hC(O)NR^hR^k,
- u) —NR^hS(O)_wR^k,
- v) -phenyl,
- w) -heteroaryl, or
- x) —O—(C_1-4alkylene)-O—(C_1-4alkylene)-N(R^h)C(O)—OR^k,
- where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^x;
R^dand R^eare independently hydrogen, C_1-6alkyl, or C_3-10cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R^y; or, if R^dand R^eare both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R^y;
R^fand R^gare independently hydrogen, C_1-6alkyl, C_3-10cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^z; or, if R^fand R^gare both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R^z;
R^hand R^kare independently hydrogen, C_1-6alkyl, C_3-10cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^x; or, if R^hand R^kare both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R^x;
R^yis
- a) -halogen,
- b) —NH₂,
- c) -cyano,
- d) -carboxy,
- e) -hydroxy,
- f) -thiol,
- g) —CF₃,
- h) —OCF₃,
- i) —C(O)—NH₂,
- j) —S(O)₂—NH₂,
- k) oxo,
- l) —C_1-6alkyl, optionally substituted one or more times with substitutents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- m) -heterocyclyl optionally substituted one or more times with one or more times with substitutents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- n) —C_3-10cycloalkyl optionally substituted one or more times with one or more times with substitutents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- o) —O—C_1-6alkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- p) —O—C_3-10cycloalkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- q) —NH—C_1-6alkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- r) —N(C_1-6alkyl)₂optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- s) —C(O)—C_1-6alkyl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- t) —C(O)—O—C_1-6alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- u) —S—C_1-6alkyl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- v) —S(O)₂—C_1-6alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- w) —C(O)—NH—C_1-6alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- x) —C(O)—N(C_1-6alkyl)₂, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- y) —S(O)₂—NH—C_1-6alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- z) —S(O)₂—N(C_1-6alkyl)₂, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- aa) —NH—C(O)—C_1-6alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂, or
- bb) —NH—S(O)₂—C_1-6alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂;
R^xis
- a) —R^y
- b) -phenyl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- c) -heteroaryl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C_1-6alkyl, —NH₂, —NH—C_1-6alkyl, and —N(C_1-6alkyl)₂,
- d) —O-phenyl,
- e) —O-heteroaryl,
- f) —C(O)-phenyl,
- g) —C(O)-heteroaryl,
- h) —C(O)—O-phenyl, or
- i) —C(O)—O-heteroaryl;
R^zis
- a) —R^y
- b) -phenyl,
- c) -heteroaryl;
- d) —O-phenyl,
- e) —O-heteroaryl,
- f) —C(O)-phenyl,
- g) —C(O)-heteroaryl,
- h) —C(O)—O-phenyl, or
- i) —C(O)—O-heteroaryl;
v is an integer from 0 to 4, and
w is an integer from 0 to 2.

Embodiment 2

A compound according to embodiment 1 wherein

- G is hydrogen, —C_1-8alkyl, —C_3-10cycloalkyl, —C_1-6alkylene-C_3-10cycloaklyl, heterocyclyl, phenyl, heteroaryl, or NR^hR^k, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^c; or G is —CH₂Y³, —CH₂CH₂Y³, —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃, —CH(Y³)CH₃, —CH₂C(Y³)(CH₃)₂, —C(Y³)(CH₃)₂, or

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where Y³is -cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —Cl, —OH, —O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃, —S(O)₂CH₂CH₃, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH₃, —NH—C(O)—CH₂CH₃, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y⁴, where Y⁴is —OH, —OCH₃, —OCH₂CH₃, —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;

R^cis
- a) -halogen,
- b) —C_1-6alkyl,
- c) —C_3-10cycloalkyl,
- d) -heterocyclyl,
- e) -cyano,
- f) —CF₃,
- g) —OCF₃,
- h) —O—R^h,
- i) —S(O)_w—R^h,
- j) —S(O)₂O—R^h,
- k) —NR^hR^k,
- l) —C(O)—R^h,
- m) —C(O)—O—R^h,
- n) —OC(O)—R^h,
- o) —C(O)NR^hR^k,
- p) —C(O)-heterocyclyl,
- q) —NR^hC(O)R^k,
- r) —OC(O)NR^hR^k,
- s) —NR^hC(O)OR^k,
- t) —NR^hC(O)NR^hR^k,
- u) -phenyl,
- v) -heteroaryl, or
- w) —O—(C_1-4alkylene)-O—(C_1-4alkylene)-N(R^h)C(O)—OR^k,
- where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^x;
R^hand R^kare independently hydrogen, C_1-6alkyl, C_3-10cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R^x; or, if R^hand R^kare both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R^x; and
R^yis
- a) -halogen,
- b) —NH₂,
- c) -cyano,
- d) -carboxy,
- e) —C_1-6alkyl, optionally substituted one or more times with halogen,
- f) -heterocyclyl, optionally substituted one or more times with halogen,
- g) —C_3-10cycloalkyl, optionally substituted one or more times with halogen,
- h) —O—C_1-6alkyl, optionally substituted one or more times with halogen,
- i) —O—C_3-10cycloalkyl, optionally substituted one or more times with halogen,
- j) -hydroxy,
- k) -thiol,
- l) —CF₃,
- m) —OCF₃,
- n) —C(O)—C_1-6alkyl, optionally substituted one or more times with halogen,
- o) —C(O)—O—C_1-16alkyl, optionally substituted one or more times with halogen,
- p) —S—C_1-6alkyl, optionally substituted one or more times with halogen, or
- q) —S(O)₂—C_1-6alkyl, optionally substituted one or more times with halogen.

Embodiment 3

A compound according to embodiment 2, wherein

- R³is hydrogen.

Embodiment 4

A compound according to embodiment 2, wherein

- R³is methyl.

Embodiment 5

A compound according to embodiment 2, wherein

- R³is ethyl.

Embodiment 6

A compound according to embodiment 2, wherein

- R³is isopropyl.

Embodiment 7

A compound according to any one of embodiments 2 to 6, wherein

- X³is

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and X¹, X², and X⁴are

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Embodiment 8

A compound according to any one of embodiments 2 to 6, wherein

- X³is

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and X¹and X⁴are

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and X²is N.

Embodiment 9

A compound according to any one of embodiments 2 to 6, wherein

- X³is

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and X¹and X²are

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and X⁴is N.

Embodiment 10

A compound according to any one of embodiments 2 to 6, wherein

- X³is

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and X²and X⁴are

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and X¹is N.

Embodiment 11

A compound according to any one of embodiments 2 to 6, wherein

- X²is

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and X¹, X³, and X⁴are

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Embodiment 12

A compound according to any one of embodiments 2 to 6, wherein

- X²is

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and X¹and X⁴are

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and X³is N.

Embodiment 13

A compound according to any one of embodiments 2 to 6, wherein

- X²is

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and X¹and X³are

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and X⁴is N.

Embodiment 14

A compound according to any one of embodiments 2 to 6, wherein

- X²is

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and X³and X⁴are

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and X¹is N.

Embodiment 15

A compound according to any one of embodiments 2 to 6, wherein

- X²is

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and two of X¹, X³, and X⁴are N.

Embodiment 16

A compound according to any one of embodiments 2 to 6, wherein

- X³is

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and two of X¹, X², and X⁴are N.

Embodiment 17

A compound according to any one of embodiments 2 to 6, wherein

- X²is

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and X¹, X³, X⁴are N.

Embodiment 18

A compound according to any one of embodiments 2 to 6, wherein

- X³is

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and X¹, X², and X⁴are N.

Embodiment 19

A compound according to any one of embodiments 2 to 18, wherein

- v is an integer from 0 to 2.

Embodiment 20

A compound according to any one of embodiments 2 to 18, wherein

- v is 0 or 1.

Embodiment 21

A compound according to any one of embodiments 2 to 18, wherein

- v is 1.

Embodiment 22

A compound according to any one of embodiments 2 to 18, wherein

- v is 1, and R²is attached at either the 5-position or the 6-position of the benzothiazole ring.

Embodiment 23

A compound according to any one of embodiments 2 to 18, wherein

- v is 1, and R²is attached at the 6-position of the benzothiazole ring.

Embodiment 24

A compound according to any one of embodiments 2 to 18, wherein

- v is 2, and one R²is attached at the 6-position of the benzothiazole ring.

Embodiment 25

A compound according to any one of embodiments 2 to 18, wherein

- v is 2, and R²is attached at the 5-position and the 6-position of the benzothiazole ring.

Embodiment 26

A compound according to any one of embodiments 2 to 25, wherein

- R²is -halogen, —C_1-6alkyl, —CF₃, —OCF₃, —O—R^f, or —S(O)_w—R^f, where the alkyl group is optionally substituted one or more times with substituents independently selected from R^z.

Embodiment 27

A compound according to any one of embodiments 2 to 25, wherein

- R²is -halogen, -methyl, —CF₃, —OCF₃, —SCF₃, —O-heteroaryl, or —S(O)₂—CH₃.

Embodiment 28

A compound according to any one of embodiments 2 to 25, wherein

- R²is selected from —Cl, —F, —CF₃, and —OCF₃.

Embodiment 29

A compound according to any one of embodiments 2 to 25, wherein

- R²is —OCF₃.

Embodiment 30

A compound according to any one of embodiments 2 to 25, wherein

- R²is —CF₃.

Embodiment 31

A compound according to any one of embodiments 2 to 25, wherein

- R²is —F.

Embodiment 32

A compound according to any one of embodiments 2 to 25, wherein

- R²is —Cl.

Embodiment 33

A compound according to any one of embodiments 2 to 32, wherein

- R⁴is -methyl, -ethyl, -n-propyl, -isopropyl, -n-butyl, -sec-butyl, -isobutyl, -tert-butyl, —(CH₂)_1-2—OCH₃, —(CH₂)_1-2—F, —(CH₂)_1-2—Cl, —(CH₂)_1-2—OCF₃, —(CH₂)_1-2—NH₂, —(CH₂)_1-2—CN, —(CH₂)_1-2—OH, —(CH₂)_1-2—CF₃, —(CH₂)_1-2—CO₂H, —(CH₂)_1-2—SH, —(CH₂)_1-2—SCH₃, —(CH₂)_1-2—S(O)₂CH₃, —(CH₂)_1-2—OCH₂CH₃, —(CH₂)_1-2—SCH₂CH₃, —(CH₂)_1-2—S(O)₂CH₂CH₃, —(CH₂)_1-2—NH—CH₃, or —(CH₂)_1-2—N(CH₃)₂.

Embodiment 34

A compound according to any one of embodiments 2 to 33, wherein

- R⁴is -methyl, -ethyl, -isopropyl, -isobutyl, —CH₂CH₂—OCH₃, —CH₂CH₂—F, or —CH₂CH₂—NH₂.

Embodiment 35

A compound according to any one of embodiments 2 to 34, wherein

- R⁴is -methyl, -ethyl, -isopropyl, or -isobutyl.

Embodiment 36

A compound according to any one of embodiments 2 to 35, wherein

- R⁴is -methyl.

Embodiment 37

A compound according to any one of embodiments 2 to 35, wherein

- R⁴is -ethyl.

Embodiment 38

A compound according to any one of embodiments 2 to 33, wherein

- R⁴is —(CH₂)₂—OCH₃, —(CH₂)₂—F, —(CH₂)₂—Cl, —(CH₂)₂—OCF₃, —(CH₂)₂—NH₂, —(CH₂)₂—CN, —(CH₂)₂—OH, —(CH₂)₂—CF₃, —(CH₂)₂—CO₂H, —(CH₂)₂—SH, —(CH₂)₂—SCH₃, or —(CH₂)₂—S(O)₂CH₃.

Embodiment 39

A compound according to any one of embodiments 2 to 38, wherein

- R¹is independently selected from hydrogen, —OCH₃, —F, —Cl, —NH₂, -cyano, —OH, —CF₃, —OCF₃, —SH, —S—C_1-6alkyl, —S(O)₂—C_1-6alkyl, —CO₂H, —NH—C_1-6alkyl, —N(C_1-6alkyl)₂, and —NH—C_1-6alkyl.

Embodiment 40

A compound according to any one of embodiments 2 to 38, wherein

- R¹is independently selected from —OCH₃, —F, —CF₃, —OCF₃, —N(CH₃)₂, —N(CH₂CH₃)₂, and —N(CH₃)(CH₂CH₃).

Embodiment 41

A compound according to any one of embodiments 2 to 38, wherein

- R¹is independently selected from hydrogen, —OCH₃, and —F.

Embodiment 42

A compound according to any one of embodiments 2 to 38, wherein

- R¹is hydrogen.

Embodiment 43

A compound according to any one of embodiments 2 to 41, wherein

- no more than one R¹substituent is not hydrogen.

Embodiment 44

A compound according to any one of embodiments 2 to 43, wherein

- G is hydrogen, —C_1-8alkyl, —C_3-10cycloalkyl, —C_1-6alkylene-C_3-8cycloaklyl, heterocyclyl, or NR^hR^k, where the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R^c; or G is —CH₂Y³, —CH₂CH₂Y³, —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃, —CH(Y³)CH₃, —CH₂C(Y³)(CH₃)₂, —C(Y³)(CH₃)₂, or

- L is —CH₂—C(O)N(R⁶)—, —C(O)N(R⁶)—, —C(O)—O—, —SO₂—, —C(O)—, or heterocyclylene optionally substituted one or more times with substituents independently selected from R^x; or the group -L-G is -cyano;
- R¹is hydrogen or R^a;
- R^cis
  - a) -halogen,
  - b) —C_1-6alkyl,
  - c) —C_3-10cycloalkyl,
  - d) -heterocyclyl,
  - e) -cyano,
  - f) —CF₃,
  - g) —OCF₃,
  - h) —O—R^h,
  - i) —S(O)_w—R^h,
  - j) —S(O)₂O—R^h,
  - k) —NR^hR^k,
  - l) —C(O)—R^h,
  - m) —C(O)—O—R^h,
  - n) —OC(O)—R^h,
  - o) —C(O)NR^hR^k,
  - p) —C(O)-heterocyclyl,
  - q) —NR^hC(O)R^k,
  - r) —OC(O)NR^hR^k,
  - s) —NR^hC(O)OR^k,
  - t) —NR^hC(O)NR^hR^k, or
  - u) —O—(C_1-4alkylene)-O—(C_1-4alkylene)-N(R^h)C(O)—OR^k,
  - where the alkylene, alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R^x;
- R^hand R^kare independently hydrogen, C_1-6alkyl, or C_3-10cycloalkyl, where the alkyl, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R^x; or, if R^hand R^kare both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R^x; and
- R^xis R^y.

Embodiment 45

A compound according to any one of embodiments 2 to 44, wherein

- -L-G is not -cyano.

Embodiment 46

A compound according to any one of embodiments 2 to 45, wherein

- -L-G is —C(O)NR^hR^k.

Embodiment 47

A compound according to any one of embodiments 2 to 45, wherein

- L is —C(O)N(R⁶)— or —C(O)—O—.

Embodiment 48

A compound according to any one of embodiments 2 to 45, wherein

- L is —C(O)N(R⁶)—.

Embodiment 49

A compound according to any one of embodiments 2 to 45, wherein

- L is not —CH₂—C(O)N(R⁶)—.

Embodiment 50

A compound according to any one of embodiments 2 to 45, wherein

- L is —C(O)—O—.

Embodiment 51

A compound according to any one of embodiments 2 to 45, wherein

- L is —C(O)—.

Embodiment 52

A compound according to any one of embodiments 2 to 45, wherein

- L is —S(O)₂—.

Embodiment 53

A compound according to any one of embodiments 2 to 43, wherein

- L is heteroarylene optionally substituted one or more times with substituents independently selected from R^x.

Embodiment 54

A compound according to any one of embodiments 2 to 53, wherein

- R⁶is hydrogen.

Embodiment 55

A compound according to any one of embodiments 2 to 53, wherein

- R⁶is hydrogen or -methyl.

Embodiment 56