GAMMA SECRETASE MODULATORS

FIELD OF THE INVENTION

The present invention relates to certain heterocyclic compounds useful as gamma secretase modulators (including inhibitors, antagonists and the like), pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat various diseases including central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as Aβ) production which is effective in the treatment of diseases caused by Aβ such as, for example, Alzheimers and Down Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change. Presently, treatment of Alzheimer's disease is limited to symptomatic therapies with a symptom-improving agent represented by an acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed. A method of controlling the cause of onset of pathologic conditions needs to be developed for creation of the basic remedy of Alzheimer's disease.

Aβ protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Klein W L, et al Proceeding National Academy of Science USA, Sep. 2, 2003, 100(18), p. 10417-22, suggest a molecular basis for reversible memory loss.

Nitsch R M, and 16 others, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, May 22, 2003, 38(4), p. 547-554) suggest that the main components of Aβ protein are Aβ40 consisting of 40 amino acids and Aβ42 having two additional amino acids at the C-terminal. The Aβ40 and Aβ42 tend to aggregate (for example, see Jarrell J T et al, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, May 11, 1993, 32(18), p. 4693-4697) and constitute main components of senile plaques (for example, (Glenner G G, et al, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, May 16, 1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, June 1985, 82(12), p. 4245-4249.).

Furthermore, it is known that mutations of APP and presenelin genes, which is observed in familial Alzheimer's disease, increase production of Aβ40 and Aβ42 (for example, see Gouras G K, et al, Intraneuronal Aβ142 accumulation in human brain, American Journal of Pathology, January 2000, 156(1), p. 15-20. Also, see Scheuner D, et al, Nature Medicine, August 1996, 2(8), p. 864-870; and Forman M S, et al, Differential effects of the Swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, Journal of Biological Chemistry, Dec. 19, 1997, 272(51), p. 32247-32253.). Therefore, compounds which reduce production of Aβ40 and Aβ42 are expected as an agent for controlling progress of Alzheimer's disease or for preventing the disease.

These Aβs are produced when APP is cleaved by beta secretase and subsequently clipped by gamma secretase. In consideration of this, creation of inhibitors of γ secretase and β secretase has been attempted for the purpose of reducing production of Aβs. Many of these secretase inhibitors already known are peptides or peptidomimetics such as L-685,458. L-685,458, an aspartyl protease transition stale mimic, is a potent inhibitor of amyloid β-protein precursor γ-secretase activity, Biochemistry, Aug. 1, 2000, 39(30), p. 8698-8704).

Also of interest in connection with the present invention are: US 2006/0004013 (Eisai, published Jan. 5, 2006); WO 2005/110422 (Boehringer Ingelheim, published Nov. 24, 2005); WO 2006/045554 (CellZome AG, published May 4, 2006); WO 2004/110350 (Neurogenetics, published Dec. 23, 2004); WO 2004/071431 (Myriad Genetics, published Aug. 26, 2004); US 2005/0042284 (Myriad Genetics, published Feb. 23, 2005) and WO 2006/001877 (Myriad Genetics, published Jan. 5, 2006).

There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with Aβ. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class of heterocyclic compounds as gamma secretase modulators (including inhibitors, antagonists and the like), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the Aβ using such compounds or pharmaceutical compositions.

The compounds of this invention (Formula I) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, Alzheimers disease, mild cognitive impairment (MCI), Downs Syndrome, Glaucoma (Guo et. al., Proc. Natl. Acad. Sci. USA 104, 13444-13449 (2007)), Cerebral amyloid angiopathy, stroke or dementia (Frangione et al., Amyloid: J. Protein folding Disord. 8, suppl. 1, 36-42 (2001), Microgliosis and brain inflammation (M P Lamber, Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998)), Olfactory function loss (Getchell, et. al. Neurobiology of Aging, 663-673, 24, 2003).

In one embodiment, the present application discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, said compound having the general structure shown in Formula I:

wherein U, G, V, R¹, R², R⁶, R⁷, R⁸, R⁹, and R¹⁰are as defined below.

In another embodiment, the present application discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, said compound having the general structure shown in Formula IA:

wherein U, G, V, R¹, R², R⁶, R⁷, R⁸, R^9,and R¹⁰are as defined below.

The compounds of Formula I can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders such as Alzheimers disease and Downs Syndrome.

This invention also provides compounds of formula I.

This invention also provides pharmaceutically acceptable salts of the compounds of formula I.

This invention also provides pharmaceutically acceptable esters of the compounds of formula I.

This invention also provides pharmaceutically solvates of the compounds of formula I.

This invention also provides compounds of formula I in pure and isolated form.

This invention also provides compounds of formula I in pure form.

This invention also provides compounds of formula I in isolated form.

This invention also provides compounds 1 to 164.

This invention also provides compounds 1 to 9.

This invention also provides compounds 10 to 164.

This invention also provides compounds 10 to 162.

This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula I, or a pharmaceutically acceptable salt, ester or solvate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier.

This invention also provides a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of formula I to a patient in need of treatment.

This invention also provides a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula I to a patient in need of treatment.

This invention also provides a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula I to a patient in need of treatment.

This invention also provides a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of formula I to a patient in need of treatment.

This invention also provides a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula I to a patient in need of treatment.

This invention also provides a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of formula I, in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e, donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment.

This invention also provides a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of formula I, in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.

This invention also provides combinations comprising an effective (i.e., therapeutically effective) amount of one or more compounds of formula I, in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e, donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.

This invention also provides a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula I, in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment.

This invention also provides a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula I to a patient in need of treatment.

This invention also provides a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of formula I, in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e, donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment.

This invention also provides a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula I, in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e, donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment.

This invention also provides combination therapies for (1) modulating gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of formula I and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs).

This invention also provides a method of treating mild cognitive impairment, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating glaucoma, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating stroke, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating dementia, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating microgliosis, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating brain inflammation, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating olfactory function loss, comprising administering an effective amount of one or more (e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides pharmaceutical compositions comprising a combination of an effective amount of one or more (e.g., one) compounds of formula I, in combination with an effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. The pharmaceutical compositions also comprise a pharmaceutically acceptable carrier.

This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula I in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient, the combined quantities of the compound of formula I and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase.

This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula I in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described below), the combined quantities of the compound of formula I and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase.

This invention also provides any one of the methods disclosed above and below wherein the compound is selected from the group consisting of the compounds 1 to 164.

This invention also provides any one of the above mentioned methods of treatment wherein the compound is selected from the group consisting of compounds in Table 1 (i.e. compounds 1 to 9).

This invention also provides any one of the methods disclosed above and below wherein the compound of formula I is selected from the group consisting of the compounds 10 to 164.

This invention also provides any one of the methods disclosed above and below wherein the compound of formula I is selected from the group consisting of the compounds 10 to 162.

This invention also provides any one of the methods disclosed above and below wherein the compound is any one of the compounds 1 to 164.

This invention also provides any one of the pharmaceutical compositions disclosed above and below wherein the compound is selected from the group consisting of the compounds 1 to 164.

This invention also provides any one of the pharmaceutical compositions disclosed above and below wherein the compound is any one of the compounds 1 to 164.

This invention also provides any one of the methods disclosed above and below wherein the compound is selected from the group consisting of the compounds in Table 14.

This invention also provides any one of the methods disclosed above and below wherein the compound is any one of the compounds in Table 14.

This invention also provides any one of the pharmaceutical compositions disclosed above and below wherein the compound is selected from the group consisting of the compounds in Table 14.

Other embodiments of this invention are directed to any one of the embodiments above or below that are directed to formula I, or the use of formula I (e.g. the embodiments directed to methods of treatment, pharmaceutical compositions and kits), wherein the compound is a compound of formula IA instead of formula I. Those skilled in the art will appreciate that the compounds of formula I and formula IA are isomers of each other.

DETAILED DESCRIPTION

In one embodiment, the present invention discloses compounds which are represented by structural Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

wherein:

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, and N(R¹⁴);

R¹is selected from the group consisting of H, halo, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R²is selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

- or, alternatively, R¹and R²may be joined together to form a C5-C8 cycloalkyl or a 5-8 membered heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;
- or, alternatively, R¹and R⁸are taken together to form a bond (i.e., there is a triple bond between the carbon atom to which R¹was bonded to and the carbon to which R⁸was bonded to, i.e., the compound of formula I is a compound of formula II:

wherein G, U, V, R², R⁶, R⁷, R⁹, and R¹⁰are as defined for formula I);

R⁵, R⁶and R⁷can be the same or different, each being independently selected from the group consisting of H, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

- or alternately, R⁶and R⁷can be joined together to form a carbocyclic spirocyclic moiety or a heterocyclic spirocyclic moiety wherein each of said carbocyclic spirocyclic moiety and heterocyclic spirocyclic moiety can be: (i) unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below, or (ii) fused with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring, wherein each of said carbocyclic spirocyclic moiety, heterocyclic spirocyclic moiety, aryl, heteroaryl, cycloalkyl and heterocycloalkyl ring can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R⁸is selected from the group consisting of H, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, with each of said alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- being unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R¹⁰is selected from the group consisting of a bond, alkyl-, aryl-, arylalkyl-, arylalkenyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclyalkyl- and the moieties:

where X is O, N(R¹⁴) or S;

wherein each of said alkyl-, aryl-, arylalkyl-, arylalkenyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- heterocyclyalkyl- and the above-noted moieties for R¹⁰can be unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of the moieties shown below;

- or, alternatively, R⁸and R¹⁰, together with the carbon atom to which they are bound, can form a C₄-C₇carbocyclic (e.g., cycloalkyl) ring, or a 4-7 membered heterocyclyl ring, or a C₄-C₇carbocyclenyl (e.g., cycloalkenyl) ring, or a 4-7 membered heterocyclenyl ring; and wherein said carbocyclic ring, heterocyclyl ring, carbocyclenylring, or heterocyclenyl ring is optionally substituted with 1-5 independently selected R²¹substituents;

R⁹is selected from the group consisting of alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- can be unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below,

R¹⁴is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶), and wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups is optionally substituted with 1-5 substituents independently selected from the group consisting of the moieties shown below;

R¹⁵, R¹⁶and R¹⁷are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, R¹⁸-alkyl, R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocyclyl, R¹⁸-heterocyclylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl, R¹⁸-heteroaryl and R¹⁸-heteroarylalkyl;

R¹⁸is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂, halo, heteroaryl, —CF₃, —CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl, —O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and —N(alkyl)S(O)₂N(alkyl)(alkyl);

or, alternately, two R¹⁸moieties on adjacent carbons can be linked together to form:

R¹⁹is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;

wherein each of the carbocyclic spirocyclic, heterocyclic spirocyclic, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰and R¹⁴are independently unsubstituted or substituted by 1 to 5 R²¹groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵;

wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R²¹are independently unsubstituted or substituted by 1 to 5 R²²groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —S(O)R¹⁵and —S(O)₂R¹⁵.

Thus, one embodiment is directed to a compound of the formula I:

or a pharmaceutically acceptable salt, solvate,or ester thereof, wherein:

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, and N(R¹⁴);

R¹is selected from the group consisting of: H, halo, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- is optionally substituted with 1-5 substituents independently selected from the group consisting of the R²¹groups;

R²is selected from the group consisting of: H, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- is optionally substituted with 1-5 substituents independently selected from the group consisting of the R²¹groups; or

R¹and R²are joined together to form a C5-C8 cycloalkyl or a 5-8 membered heterocyclyl moiety, wherein each of said cycloalkyl or heterocyclyl moiety is optionally substituted with 1-5 substituents independently selected from the group consisting of the R²¹groups; or

R¹and R⁸are taken together to form a bond (i.e., there is a triple bond between the carbon atom to which R¹was bonded to and the carbon to which R⁸was bonded to, i.e., the compound of formula I is a compound of formula II:

wherein G, U, V, R², R⁶, R⁷, R⁹, and R¹⁰are as defined for formula I);

R⁵, R⁶and R⁷are each independently selected from the group consisting of H, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, and wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- is optionally substituted with 1-5 substituents independently selected from the group consisting of the R²¹groups; or

R⁶and R⁷are joined together to form a carbocyclic spirocyclic moiety or a heterocyclic spirocyclic moiety wherein each of said carbocyclic spirocyclic moiety and heterocyclic spirocyclic moiety is: (i) optionally substituted with 1-4 substituents independently selected from the group consisting of the the R²¹groups, or (ii) fused with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring, and wherein each of said carbocyclic spirocyclic moiety, heterocyclic spirocyclic moiety, aryl, heteroaryl, cycloalkyl and heterocycloalkyl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of the the R²¹groups;

R⁸is selected from the group consisting of H, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)(R¹⁶), —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, and wherein each of said alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- moieties is optionally substituted with 1-3 substituents independently selected from the group consisting of the the R²¹groups;

where X is O, N(R¹⁴) or S;

wherein each of said alkyl-, aryl-, arylalkyl-, arylalkenyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclyalkyl-,

is optionally substituted with 1-3 substituents independently selected from the group consisting of the R²¹groups;

- or, alternatively, R⁸and R¹⁰, together with the carbon atom to which they are bound, can form a C₄-C₇carbocyclic (e.g., cycloalkyl) ring, or a 4-7 membered heterocyclyl ring, or a C₄-C₇carbocyclenyl (e.g., cycloalkenyl) ring, or a 4-7 membered heterocyclenyl ring; and wherein said carbocyclic ring, heterocyclyl ring, carbocyclenyl ring, or heterocyclenyl ring is optionally substituted with 1-5 independently selected R²¹substituents;

R⁹is selected from the group consisting of alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, and wherein each of said alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- is optionally substituted with 1-3 substituents independently selected from the group consisting of the R²¹groups;

R¹⁴is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl-, cycloalkenyl, heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, —CN, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶), and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl-, cycloalkenyl, heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl- groups is optionally substituted with 1-5 independently selected R²¹groups;

R¹⁵, R¹⁶and R¹⁷are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, arylcycloalkyl-, arylheterocyclyl-, (R¹⁸)_n-alkyl-, (R¹⁸)_n-cycloalkyl-, (R¹⁸)_n-cycloalkylalkyl-, (R¹⁸)_n-heterocyclyl-, (R¹⁸)_n-heterocyclylalkyl-, (R¹⁸)_n-aryl-, (R¹⁸)_n-arylalkyl-, (R¹⁸)_n-heteroaryl- and (R¹⁸)_n-heteroarylalkyl-;

n is 1 to 5;

Each R¹⁸is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, arylalkyl-, arylalkenyl-, arylalkynyl-, —NO₂, halo, heteroaryl, —CF₃, —CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl, —O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, -N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and —N(alkyl)S(O)₂N(alkyl)(alkyl); or

two R¹⁸moieties on adjacent carbons can be linked together to form:

R¹⁹is selected from the group consisting of: alkyl, cycloalkyl, aryl, arylalkyl and heteroarylalkyl;

R²⁰is selected from the group consisting of: alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl and heteroarylalkyl;

Each R²¹is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵;

wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, heterocycloalkylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, alkenyl and alkynyl R²¹groups is optionally substituted with 1 to 5 independently selected R²²groups; and

Each R²²is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —S(O)R¹⁵and —S(O)₂R¹⁵.

wherein:

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, and N(R¹⁴);

R¹is selected from the group consisting of: H, halo, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R²is selected from the group consisting of: H, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

- or, alternatively, R¹and R²may be joined together to form a C5-C8 cycloalkyl or a 5-8 membered heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;
- or, alternatively, R¹and R⁸are taken together to form a bond (i.e., there is a triple bond between the carbon atom to which R¹was bonded to and the carbon to which R⁸was bonded to, i.e., the compound of formula I is a compound of formula II:

wherein G, U, V, R², R⁶, R⁷, R⁹, and R¹⁰are as defined for formula I;

R⁵, R⁶and R⁷can be the same or different, each being independently selected from the group consisting of H, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

- or alternately, R⁶and R⁷can be joined together to form a carbocyclic spirocyclic moiety or a heterocyclic spirocyclic moiety wherein each of said carbocyclic spirocyclic moiety and heterocyclic spirocyclic moiety can be: (i) unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below, or (ii) fused with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring, wherein each of said carbocyclic spirocyclic moiety, heterocyclic spirocyclic moiety, aryl, heteroaryl, cycloalkyl and heterocycloalkyl ring can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R⁸is selected from the group consisting of H, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵, alkyl, cycloalkyl, aryl and heteroaryl, with each of said alkyl, cycloalkyl, aryl and heteroaryl being unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R¹⁰is selected from the group consisting of a bond, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl-, alkylaryl-, heteroarylalkyl-, heterocyclylalkyl- and the moieties:

where X is O, N(R¹⁴) or S;

wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl and the above-noted moieties for R¹⁰can be unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of the moieties shown below;

- or, alternatively, R⁸and R¹⁰, together with the carbon atom to which they are bound, can form a C₄-C₇carbocyclic (e.g., cycloalkyl) ring, or a 4-7 membered heterocyclyl ring, or a C₄-C₇carbocyclenyl (e.g., cycloalkenyl) ring, or a 4-7 membered heterocyclenyl ring; and wherein said carbocyclic ring, heterocyclyl ring, carbocyclenyl ring, or heterocyclenyl ring is optionally substituted with 1-5 independently selected R²¹substituents;

R⁹is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl and heterocyclylalkyl wherein each of said alkyl, aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below;

R¹⁸is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl-, arylalkenyl-, arylalkynyl-, —NO₂, halo, heteroaryl, —CF₃, —CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl, —O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and —N(alkyl)S(O)₂N(alkyl)(alkyl);

or, alternately, two R¹⁸moieties on adjacent carbons can be linked together to form:

R¹⁹is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;

wherein:

U is

or N;

V is selected from the group consisting of a bond, —C(O)—, O and —N(R¹⁴);

R¹is selected from the group consisting of H, halo, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups;

R²is selected from the group consisting of H, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and

alkoxy groups;

- or, alternatively, R¹and R²may be joined together to form a C5-C8 cycloalkyl or a 5-8 membered heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups;
- or, alternatively, R¹and R⁸are taken together to form a bond (i.e., there is a triple bond between the carbon atom to which R¹was bonded to and the carbon to which R⁸was bonded to, i.e., the compound of formula I is a compound of formula II:

wherein G, U, V, R², R⁶, R⁷, R⁹, and R¹⁰are as defined for formula I;

- or alternately, R⁶and R⁷can be joined together to form a carbocyclic spirocyclic moiety or a heterocyclic spirocyclic moiety wherein each of said carbocyclic spirocyclic moiety and heterocyclic spirocyclic moiety can be: (i) unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups, or (ii) fused with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring, wherein each of said carbocyclic spirocyclic moiety, heterocyclic spirocyclic moiety, aryl, heteroaryl, cycloalkyl and heterocycloalkyl ring can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups;

R⁸is selected from the group consisting of H, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵, alkyl, cycloalkyl, aryl and heteroaryl, with each of said alkyl, cycloalkyl, aryl and heteroaryl being unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups;

R¹⁰is selected from the group consisting of a bond, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, heterocyclylalkyl and the moieties:

where X is O, NH or S;

In another embodiment R¹and R²can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below; or, alternatively, R¹and R²may be joined together to form a C5-C8 cycloalkyl or a 5-8 membered heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the R²¹moieties.

In another embodiment R⁵, R⁶and R⁷can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- can be unsubstituted or optionally independently substituted with 1-5 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below; or alternately, R⁶and R⁷can be joined together to form a carbocyclic spirocyclic moiety or a heterocyclic spirocyclic moiety wherein each of said carbocyclic spirocyclic moiety and heterocyclic spirocyclic moiety can be: (i) unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of the moieties shown below, or (ii) fused with an aryl or heteroaryl ring, wherein each of said carbocyclic spirocyclic moiety, heterocyclic spirocyclic moiety, aryl and heteroaryl ring can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of the R²¹moieties.

In another embodiment each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰and R¹⁴are independently unsubstituted or substituted by 1 to 5 R²¹groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)( R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵; wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R²¹are independently unsubstituted or substituted by 1 to 5 R²²groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N—(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —S(O)R¹⁵and —S(O)₂R¹⁵.

In another embodiment the compounds of formula I are compounds of formula II:

wherein G, U, V, R², R⁶, R⁷, R⁹, and R¹⁰are as defined for formula I.

In another embodiment the compounds of formula I are compounds of formula III:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

In another embodiment the compounds of formula I are compounds of formula IV:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

In another embodiment the compounds of formula I are compounds of formula V:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

Examples of formula V include:

In another embodiment the compounds of formula I are compounds of formula VI:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

In another embodiment the compounds of formula I are compounds of formula VII:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

In another embodiment the compounds of formula I are compounds of formula VIII:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

In another embodiment the compounds of formula I are compounds of formula IX:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

In another embodiment the compounds of formula I are compounds of formula X:

wherein R⁶, R⁷, R⁹, R¹⁰and R²¹are as defined in formula I.

Those skilled in the art will appreciate that for the compounds of the invention:

Those skilled in the art will appreciate that in the compounds of the invention R⁶can be:

Those skilled in the art will appreciate that in the compounds of the invention R⁷can be:

Thus, for example, in embodiments of this invention R⁶and R⁷can be:

In other embodiments of this invention R⁶and R⁷can be:

In another embodiment G is O.

In another embodiment G is S.

In another embodiment V is selected from the group consisting of a bond, O, and N(R¹⁴).

In another embodiment V is a bond.

In another embodiment V is —C(O)—.

In another embodiment V is —N(R¹⁴)—.

In another embodiment R⁸is selected from the group consisting of H, alkyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl-, with each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclyalkyl- being unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of the R²¹moieties.

In another embodiment R⁸is selected from the group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl, with each of said alkyl, cycloalkyl, aryl and heteroaryl being unsubstituted or optionally independently substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of the R²¹moieties.

In another embodiment, R⁸and R¹⁰, together with the carbon atom to which they are bound, form a C₄-C₇carbocyclic (e.g., cycloalkyl) ring, or a 4-7 membered heterocyclyl ring, or a C₄-C₇carbocyclenyl (e.g., cycloalkenyl) ring, or a 4-7 membered heterocyclenyl ring; and wherein said carbocyclic ring, heterocyclyl ring, carbocyclenyl ring, or heterocyclenyl ring is optionally substituted with 1-5 independently selected R²¹substituents.

In another embodiment, R⁸and R¹⁰, together with the carbon atom to which they are bound, form a C₄-C₇carbocyclic (e.g., cycloalkyl) ring; and wherein said carbocyclic ring is optionally substituted with 1-5 independently selected R²¹substituents.

In another embodiment, R⁸and R¹⁰, together with the carbon atom to which they are bound, form a 4-7 membered heterocyclyl ring; and wherein said heterocyclyl ring is optionally substituted with 1-5 independently selected R²¹substituents.

In another embodiment, R⁸and R¹⁰, together with the carbon atom to which they are bound, form a C₄-C₇carbocyclenyl (e.g., cycloalkenyl) ring; and wherein said carbocyclenyl ring is optionally substituted with 1-5 independently selected R²¹substituents.

In another embodiment, R⁸and R¹⁰, together with the carbon atom to which they are bound, form a 4-7 membered heterocyclenyl ring; and wherein said heterocyclenyl ring is optionally substituted with 1-5 independently selected R²¹substituents.

In another embodiment, U is C(R⁵).

In another embodiment, U is N.

In another embodiment R¹is H.

In another embodiment R¹is halo (e.g., Br).

In another embodiment, R²is H.

In another embodiment, R²is alkyl.

In another embodiment, R²is methyl.

In another embodiment, R²is alkoxyalkyl-.

In another embodiment, R²is 3-methoxypropyl-.

In another embodiment, U is N and R²is 3-methoxypropyl-.

In another embodiment, R²is arylalkyl-.

In another embodiment R²is selected from the group consisting of: (a) alkyl, (b) alkyl substituted with an —OR¹⁵group (e.g., —Oalkyl, such as, for example, —OCH₃) or a halo group (e.g., Cl), (c) arylalkyl-substituted with an —OR¹⁵group (e.g., —Oalkyl, such as, for example, —OCH₃) or a halo group (e.g. F), (d) cycloalkyl (e.g., cyclopropyl), (e) heterocycloalkyl (e.g.,

and

(e) cycloalkylalkyl-substituted with a halo substituted alkyl (e.g. wherein the halo substituted alkyl is —CH₂Cl).

In another embodiment R²is selected from the group consisting of: H, —(CH₂)₃OCH₃, —CH₃, —CH₂CH₃, —(CH₂)₂OCH₃, —(CH₂)₂CH(CH₃)₂, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH₃,

In another embodiment, R²is phenylmethyl-.

In another embodiment, R²is (4-alkoxy)phenylmethyl-.

In another embodiment, R²is (4-methoxy)phenylmethyl-.

In another embodiment, R¹is H.

In another embodiment, R¹is alkyl.

In another embodiment, R¹is methyl.

In another embodiment, R¹and R²are joined together to form a cyclopentyl ring, which is unsubstituted.

In another embodiment, R¹and R²are joined together to form a cyclopentyl ring, which is substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R¹and R²are joined together to form a cyclohexyl ring, which is unsubstituted.

In another embodiment, R¹and R²are joined together to form a cyclohexyl ring, which is substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, U is N, and R¹and R²are joined together to form a piperidinyl ring including the N of U as the nitrogen of said piperidinyl ring, which is unsubstituted.

In another embodiment, U is N, and R¹and R²are joined together to form a piperidinyl ring including the N of U as the nitrogen of said piperidinyl ring, wherein said piperidinyl ring is substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, U is N, and R¹and R²are joined together to form a pyrrolidinyl ring including the N of U as the nitrogen of said pyrrolidinyl ring, which is unsubstituted.

In another embodiment, U is N, and R¹and R²are joined together to form a pyrrolidinyl ring including the N of U as the nitrogen of said pyrrolidinyl ring, wherein said pyrrolidinyl ring is substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, U is N, and R¹and R²are joined together to form a piperazinyl ring including the N of U as a nitrogen of said piperazinyl ring, which is unsubstituted.

In another embodiment, U is N, and R¹and R²are joined together to form a piperazinyl ring including the N of U as a nitrogen of said piperazinyl ring, wherein said piperazinyl ring is substituted with 1-3 substituents which can be the same or different, each being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment R⁶is selected from the group consisting of: H, alkyl (e.g. methyl), cycloalkyl (e.g. cyclopropyl), —C(O)OR¹⁵(e.g. —C(O)OR¹⁵wherein R¹⁵is H or alkyl), alkyl substituted with 1-3 halos (e.g. alkyl substituted with 1-3 F), —C(O)R¹⁵(e.g —C(O)R¹⁵wherein R¹⁵is alkyl), and alkyl substituted with —OR¹⁵(e.g. alkyl substituted with —OR¹⁵wherein R¹⁵is H or alkyl, such as, for example, wherein R⁶is —CH₂OH).

In another embodiment, R⁶is H.

In another embodiment, R⁶is alkyl.

In another embodiment, R⁶is methyl.

In another embodiment R⁶is alkyl substituted with 1-5 independently selected R²¹moieties.

In another embodiment R⁶is alkyl substituted with one R²¹moiety.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is selected from the group consisting of: H and alkyl.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is H.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl).

In another embodiment R⁶is methyl substituted with 1-3 independently selected R²¹moieties.

In another embodiment R⁶is methyl substituted with one R²¹moiety.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is selected from the group consisting of: H and alkyl.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said. R²¹moiety is —OR¹⁵, and said R¹⁵is H.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl).

In another embodiment R⁷is selected from the group consisting of: (a) aryl substituted with 1-3 R²¹moieties (e.g. phenyl substituted 1-3 halos, such as, 1-3 F), (b) aryl (e.g. phenyl) substituted with —OR¹⁵wherein R¹⁵is (i) an alkyl substituted with 1-3 halos (e.g. F), or (ii) alkyl, (c) aryl (e.g., phenyl), (d) aryl (e.g. phenyl) substituted with alkyl wherein said alkyl is substituted with 1-3 halos (e.g., F), (e) aryl substituted with aryl (e.g. -phenyl-phenyl), (f) alkyl, (g) heteroaryl (e.g. thienyl or pyridyl), (h) arylalkyl-, and (i) cycloalkyl).

In another embodiment, R⁷is aryl.

In another embodiment, R⁷is an unsubstituted phenyl.

In another embodiment, R⁷is a phenyl which is substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment, R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment, R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment, R⁷is phenyl substituted with 1-3 F.

In another embodiment, R⁷is phenyl substituted with 1 F.

In another embodiment R⁷is p-Cl-phenyl.

In another embodiment, R⁷is unsubstituted naphthyl.

In another embodiment, R⁷is naphthyl which is substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment, R⁷is unsubstituted biphenyl.

In another embodiment, R⁷is biphenyl which is substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁷is R⁷is 3-(1,1′-biphenyl)-yl.

In another embodiment, R⁷is R⁷is 4-(1,1′-biphenyl)-yl.

In another embodiment, R⁶is H and R⁷is a biphenyl which can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁶is methyl, and R⁷is a biphenyl which can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁶is H, and R⁷is a phenyl which can be unsubstituted or optionally independently substituted with 1-4 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁶and R⁷are joined to form a spirocyclic unit shown below:

In another embodiment R⁶is alkyl substituted with 1-5 independently selected R²¹moieties, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and R⁷is phenyl substituted with 1-3 F.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and R⁷is phenyl substituted with one F.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl substituted with 1-3 independently selected F.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl one F.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is selected from the group consisting of: H and alkyl, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is H, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is H, and said R¹⁵is selected from the group consisting of: H and alkyl, and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl), and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl), and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is alkyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl), and R⁷is phenyl substituted with one F.

In another embodiment R⁶is methyl substituted with 1-3 independently selected R²¹moieties, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and R⁷is phenyl substituted with 1-3 F.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and R⁷is phenyl substituted with one F.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl substituted with 1-3 independently selected F.

In another embodiment R⁶is methyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵, and R⁷is phenyl one F.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is selected from the group consisting of: H and alkyl, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is H, and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is H, and said R¹⁵is selected from the group consisting of: H and alkyl, and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl), and R⁷is phenyl substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl), and R⁷is phenyl substituted with 1-3 independently selected halos.

In another embodiment R⁶is methyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl (e.g. methyl), and R⁷is phenyl substituted with one F.

In another embodiment R⁶is selected from the group consisting of: H, methyl, cyclopropyl, —C(O)CH₂CH₃, —CHF₂, —CF₃, —C(O)OCH₃, —CH₂OH, —CH₂OCH₃, —CH₂OCH(CH₃)₂, —C(O)OH, —C(CH₃)₃, —C(OH)(CH₃)₂, —C(O)CH₃, —CH(CH₃)OH, —CH₂C(OH)(CH₃)₂, —CH₂CH₂OH and

In another embodiment R⁷is selected from the group consisting of:

In another embodiment R⁶and R⁷taken together with the carbon to which they are bound form a Spiro ring selected from the group consisting of:

and R⁷is selected from the group consisting of:

In another embodiment, R⁸is H.

In another embodiment, R⁸is alkyl.

In another embodiment, R⁸is methyl.

In another embodiment, R¹⁰is aryl.

In another embodiment, R¹⁰is phenyl.

In another embodiment R¹⁰is aryl substituted with 1 to 3 independently selected R²¹moieties.

In another embodiment R¹⁰is aryl substituted with 1 to 3 R²¹moieties, wherein each R²¹moiety is the same or different —OR¹⁵group.

In another embodiment R¹⁰is aryl substituted with 1 R²¹moiety.

In another embodiment R¹⁰is aryl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵.

In another embodiment R¹⁰is aryl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl.

In another embodiment R¹⁰is aryl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, said R¹⁵is alkyl, and said alkyl is methyl (i.e., said R²¹moiety is —OCH₃).

In another embodiment R¹⁰is phenyl substituted with 1 to 3 independently selected R²¹moieties.

In another embodiment R¹⁰is phenyl substituted with 1 to 3 R²¹moieties, wherein each R²¹moiety is the same or different —OR¹⁵group.

In another embodiment R¹⁰is phenyl substituted with 1 R²¹moiety.

In another embodiment R¹⁰is phenyl substituted with one R²¹moiety, and said R²¹moiety is —OR¹⁵.

In another embodiment R¹⁰is phenyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, and said R¹⁵is alkyl.

In another embodiment R¹⁰is phenyl substituted with one R²¹moiety, said R²¹moiety is —OR¹⁵, said R¹⁵is alkyl, and said alkyl is methyl (i.e., said R²¹moiety is —OCH₃).

In another embodiment R¹⁰is:

wherein the —R¹⁰-R⁹moiety is:

In another embodiment R¹⁰is aryl substituted with 1 to 3 R²¹moieties, wherein each R²¹moiety is the same or different halo.

In another embodiment R¹⁰is aryl substituted with 1 to 3 R²¹moieties, wherein each R²¹moiety is F.

In another embodiment R¹⁰is aryl substituted with one R²¹moiety, and said R²¹moiety is halo.

In another embodiment R¹⁰is aryl substituted with one R²¹moiety, said R²¹moiety is -halo, and said halo is F.

In another embodiment R¹⁰is phenyl substituted with 1 to 3 R²¹moieties, wherein each R²¹moiety is the same or different halo.

In another embodiment R¹⁰is phenyl substituted with 1 to 3 R²¹moieties, wherein each R²¹moiety is F.

In another embodiment R¹⁰is phenyl substituted with one R²¹moiety, and said R²¹moiety is halo.

In another embodiment R¹⁰is phenyl substituted with one R²¹moiety, said R²¹moiety is -halo, and said halo is F.

In another embodiment R¹⁰is:

wherein the —R¹⁰-R⁹moiety is:

In another embodiment, R¹⁰is unsubstituted heteroaryl.

In another embodiment R¹⁰is unsubstituted heteroaryl wherein said heteroaryl is pyridyl.

In another embodiment R¹⁰is:

wherein the —R¹⁰-R⁹moiety is:

In another embodiment R¹⁰is selected from the group consisting of:

In another embodiment, R⁹is unsubstituted heteroaryl.

In another embodiment of this invention R⁹is selected from the group consisting of heteroaryl and heteroaryl substituted with 1-3 R²¹groups, and wherein each R²¹is independently selected.

In another embodiment, R⁹is heteroaryl which is substituted with 1-3 substituents which can be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, CN, NH₂, NH(alkyl), N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment of this invention R⁹is selected from the group consisting of imidazolyl and imidazolyl substituted with 1-3 R²¹groups, and wherein each R²¹is independently selected.

In another embodiment of this invention R⁹is imidazolyl substituted with 1-3 R²¹groups, and wherein each R²¹is independently selected.

In another embodiment, R⁹is imidazolyl substituted with 1-3 substituents independently selected from the group consisting of halo, alkyl, CN, NH₂, NH(alkyl), N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁹is imidazol-1-yl.

In another embodiment, R⁹is 4-methyl-imidazol-1-yl.

In another embodiment, R⁹is 5-chloro-4-methyl-imidazol-1-yl.

In another embodiment R¹⁰is selected from the group consisting of aryl and aryl substituted with one or more R²¹groups, and R⁹is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more R²¹groups, and wherein each R²¹is independently selected.

In another embodiment R¹⁰is selected from the group consisting of phenyl and phenyl substituted with 1-3 independently selected R²¹groups, and R⁹is selected from the group consisting of imidazolyl and imidazolyl substituted with 1-3 independently selected R²¹groups.

In another embodiment R¹⁰is phenyl substituted with 1-3 independently selected R²¹groups, and R⁹is selected from the group consisting of imidazolyl and imidazolyl substituted with 1-3 independently selected R²¹groups.

In another embodiment R¹⁰is selected from the group consisting of heteroaryl and heteroaryl substituted with 1-3 R²¹groups, and the R⁹group is selected from the group consisting of heteroaryl and heteroaryl substituted with 1-3 R²¹groups, and wherein each R²¹is independently selected.

In another embodiment R¹⁰is selected from the group consisting of pyridyl and pyridyl substituted with 1-3 R²¹groups, and the R⁹group is selected from the group consisting of imidazolyl and imidazolyl substituted with 1-3 R²¹groups, and wherein each R²¹is independently selected.

In another embodiment R¹⁰is pyridyl, and the R⁹group is imidazolyl substituted with 1-3 R²¹groups, and wherein each R²¹is independently selected.

In another embodiment the R⁹-R¹⁰— moiety is:

In another embodiment the R⁹- R¹⁰— moiety is:

In another embodiment the R⁹-R¹⁰— moiety is:

In another embodiment R⁹-R¹⁰— moiety is:

wherein the various moieties are defined above.

In another embodiment, this invention discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, said compound having the general structure shown in the formula:

wherein U is N;

R¹is H;

R²is alkyl;

R⁶is H;

R⁷is 3-(1,1′-biphenyl)-yl;

R⁸is H;

R¹⁰is phenyl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkyl;

R⁶is H;

R⁷is phenyl;

R⁸is H;

R¹⁰is alkoxy-substituted phenyl; and

R⁹is 4-methyl-imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkyl;

R⁶is H;

R⁷is 4-fluoro-phen-1-yl;

R⁸is H;

R¹⁰is phenyl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is methyl;

R⁶is H;

R⁷is 4-fluoro-phen-1-yl;

R⁸is H;

R¹⁰is phenyl; and

R⁹is 5-chloro-4-methyl-imidazol-1-yl.

wherein U is N;

R¹and R²are connected to form a 5-membered ring;

R⁶is H;

R⁷is 3-(1,1′-biphenyl)-yl;

R⁸is H;

R¹⁰is phenyl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkyl;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring wherein said spirocyclic ring is fused with a benzo ring;

R⁸is H;

R¹⁰is phenyl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxyalkyl;

R⁶is alkyl;

R⁷is phenyl;

R⁸is H;

R¹⁰is phenyl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is arylalkyl;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring wherein said spirocyclic ring is fused with a benzo ring;

R⁸is H;

R¹⁰is alkoxy-substituted phenyl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is (alkoxy)aryl-alkyl-;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring wherein said spirocyclic ring is fused with a benzo ring;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶is alkyl;

R⁷is phenyl substituted with halo;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶is alkyl;

R⁷is phenyl substituted with halo;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is 4-alkyl-imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is 4-alkyl-imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring wherein said spirocyclic ring is fused with a benzo ring;

R⁸is H;

R¹⁰(alkoxy-substituted)aryl; and

R⁹is 4-alkyl-imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring wherein said spirocyclic ring is fused with a benzo ring;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is 5-halo-4-alkyl-imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶and R⁷are connected to form a 5-membered spirocyclic ring;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is 4-alkyl-imidazol-1-yl.

wherein U is N;

R¹is H;

R²is alkoxy-alkyl-;

R⁶is alkyl;

R⁷is phenyl substituted with halo;

R⁸is H;

R¹⁰is (alkoxy-substituted)aryl; and

R⁹is 5-halo-4-alkyl-imidazol-1-yl.

Other embodiments are directed to any one of the above embodiments wherein R¹and R⁸cis to each other instead of trans, that is the formulas above have the moiety:

Other embodiments are directed to any one of the above embodiments wherein R⁶has the stereochemistry:

Other embodiments are directed to any one of the above embodiments wherein R⁷has the stereochemistry:

Thus Other embodiments are directed to any one of the above embodiments wherein R⁶and R⁷have the stereochemistry

Other embodiments are directed to any one of the above embodiments wherein R⁶and R⁷have the stereochemistry

An illustrative group of compounds of the invention are shown in Table 1 (Compounds 1 to 9).

TABLE 1

(Compounds 1 to 9)

Representative compounds of the invention also include compounds 10 to 161 (Tables 3 to 13 below), 162 (Method M below), 163 (Method N below), and 164 (Method O below).

Thus, one embodiment of this invention is directed to a compound selected from the group consisting of:

(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-ALPHA,ALPHA-DIMETHYL-3-(3,4,5-TRIFLUOROPHENYL)-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL (ENANTIOMER A)

(−)-(8E)-3-(3-CHLORO-4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE (ENANTIOMER)

(+)-(8′E)-6-FLUORO-2,3,5′,6′,7′,8′-HEXAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]SPIRO[4H-1-BENZOPYRAN-4,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDINE] (ENANTIOMER)

(8E)-3-(3,4-DIFLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE (ENANTIOMER A)

(8Z)-3(R)-(4-FLUOROPHENYL)-5,6-DIHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3,6(S)-DIMETHYL-3H,8H-[1,2,4]OXADIAZOLO[3,4-c][1,4]OXAZINE

(8Z)-3-(4-FLUOROPHENYL)-5,6-DIHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3,6,6-TRIMETHYL-3H,8H-[1,2,4]OXADIAZOLO[3,4-c][1,4]OXAZINE

(8E)-3-(3,5-DIFLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL

(+)-(8′E)-5-FLUORO-2,3,5′,6′,7′,8′-HEXAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE[SPIRO[1H-INDENE-1,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDINE]

(8′E)-6,8-DIFLUORO-2,3,5′,6′,7′,8′-HEXAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]SPIRO[4H-1-BENZOPYRAN-4,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDINE] (ENANTIOMER A)

(8Z)-3(R)-(4-FLUOROPHENYL)-5,6-DIHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3,6(R)-DIMETHYL-3H,8H-[1,2,4]OXADIAZOLO[3,4-c][1,4]OXAZINE

(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-(3,4,5-TRIFLUOROPHENYL)-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL (ENANTIOMER A)

(8E)-3-(3,5-DIFLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE

(−)-(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3-[4-(TRIFLUOROMETHOXY)PHENYL]-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE

(8E)-3-(4-CHLOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-M ETHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3,6(R)-DIMETHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE (SINGLE DIASTEREOMER)

(−)-(8′E)-5′,6′,7′,8′-TETRAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-1-METHYLSPIRO[3H-INDOLE-3,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDIN]-2(1H)-ONE (ENANTIOMER)

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE

5-(4-FLUOROPHENYL)-3-[(E)-2-[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]ETHENYL]ALPHA,ALPHA,5-TRIMETHYL-1,2,4-OXADIAZOLE-4(5H)-ETHANOL

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-3-(METHOXYMETHYL)-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-ALPHA,ALPHA-DIMETHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL (ENANTIOMER A)

(−)-(8′E)-5-FLUORO-5′,6′,7′,8′-TETRAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]SPIRO[3H-INDOLE-3,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDIN]-2(1H)-ONE

(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-(4-METHOXYPHENYL)-3-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-A]PYRIDINE (ENANTIOMER B)

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL (ENANTIOMER A)

(8E)-3-(2,4-DIFLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-ALPHA-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-A]PYRIDINE-3-METHANOL (DIASTEREOMER 2)

(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3-(3,4,5-TRIFLUOROPHENYL)-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE (ENANTIOMER A)

(+)-(8′E)-7-FLUORO-2,3,5′,6′,7′,8′-HEXAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]SPIRO[4H-1-BENZOPYRAN-4,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDINE]

(8Z)-3(R)-(4-FLUOROPHENYL)-5,6-DIHYDRO-8-[[3-M ETHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3H,8H-[1,2,4]OXADIAZOLO[3,4-c][1,4]OXAZINE

(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-3-METHYL-3-[4-(TRIFLUOROMETHYL)PHENYL]-3H-[1,2,4]OXADIAZOLO[4,3-A]PYRIDINE (ENANTIOMER B)

(8E)-3-(4-FLUOROPHENYL)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-ALPHA-METHYL-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL (DIASTEREOMER 4)

(8E)-5,6,7,8-TETRAHYDRO-8-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]METHYLENE]-ALPHA-METHYL-3-(3,4,5-TRIFLUOROPHENYL)-3H-[1,2,4]OXADIAZOLO[4,3-a]PYRIDINE-3-METHANOL (DIASTEREOMER 2); and

(+)-(8′E)-2,3,5′,6′,7′,8′-HEXAHYDRO-8′-[[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]-METHYLENE]SPIRO[4H-1-BENZOPYRAN-4,3′-[3H][1,2,4]OXADIAZOLO[4,3-a]PYRIDINE] (ENANTIOMER B)