Substituted benzofused derivatives and their use as vanilloid receptor ligands   

Abstract: The present invention relates to substituted benzofused derivatives, which can be used as vanilloid receptor ligands, method of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.

This application claims the benefit of Indian Provisional Patent Application Nos. 1269/MUM/2005, filed Oct. 7, 2005, and 996/MUM/2006, filed Jun. 26, 2006, and U.S. Provisional Patent Application No. 60/730,660, filed Oct. 26, 2005, and 60/807,205, filed Jul. 13, 2006, all of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to substituted benzofused derivatives, which can be used as vanilloid receptor ligands, methods of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.

BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limiting, chronic pain persists for 3 months or longer and can lead to significant changes in a patient\'s personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed., 1996). The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to these harmful stimuli are known as “nociceptors”. Nociceptors are primary sensory afferent (C and Aδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities.

Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at vanilloid receptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology 12: 372-379, 2002) to pain processing.

The lipophilic vanilloid, Capsaicin (8-methyl-N-vanillyl-6-nonenamides; CAP) is known to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters via a specific cell surface capsaicin receptor, cloned as the first vanilloid receptor (VR1 now known as TRPV1) (Caterina M J, et. al., Science, April 14; 288 (5464): 306-13, 2000). Capsaicin is the main pungent component in hot pepper. Hot pepper has been used historically not only as a spice, but also as a traditional medicine in the treatment of gastric disorders orally, and applied locally for the relief of pain and inflammation. CAP has a wide spectrum of biological actions and not only exhibits effects on the cardiovascular and respiratory systems, but also induces pain and irritancy on local application. CAP, however, after such induction of pain induces desensitization, both to CAP itself and also to other noxious stimuli, thereby stopping the pain. The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of VR1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Based on this property, CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are either used or are under development as analgesic agents or therapeutic agents for urinary incontinence or skin disorders (Wriggleworth and Walpore, Drugs of the Future, 23: pp 531-538, 1998).

VR1 is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VR1 in various systems are not properly understood at this time. An increasing number of animal studies have revealed the possible involvement of VR1 receptors in a number of pathologies. Based on this information VR1 is now being considered as a molecular target for various indications such as migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington\'s disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn\'s disease, celiac disease and inflammatory diseases such as pancreatitis, and in respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, and in non specific disorders such as fervescence, retinopathy, muscle spasms, emesis, dyskinesias and depression. Specifically VR1 antagonists are likely to be useful in multiple sub-types of pain such as acute, chronic, neuropathic pain or post-operative pain, as well as in pain due to neuralgia (e.g., post herpetic neuralgia, trigeminal neuralgia, and in pain due to diabetic neuropathy, dental pain as well as cancer pain. Additionally, VR1 antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritisor osteoarthritis. VR1 antagonists hold potential benefit in diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere\'s disease, tinnitus, hyperacusis and anxiety disorders.

One class of natural and synthetic compounds that modulate the function of vanilloid Receptor (VR1) have been characterized by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group and the same have been widely studied and is extensively reviewed by Szallasi and Blumberg (The Am. Soc. for Pharmacology and Experimental Therapeutics, Vol. 51, No. 2, 1999).

Various vanilloid agonists and antagonists have been developed for the treatment of pain; the agonists work through desensitizing the receptor while antagonists block its stimulation by (patho) physiological ligands. The first antagonist Capsazepine was developed by Novartis. There are other VR1 antagonists, which are at the preclinical stage, for example, Amore Pacific\'s PAC-20030, Neurogen\'s BCTC, Abbott\'s A-425619 and Amgen\'s AMG-9810.

European Publication No. 0 462 761 discloses certain fused compounds having the formula:

which are potassium channel activators and a method of using them as antiischemic and/or anti-arrhythmic agents. PCT Publication No. WO 2005/075463 describes certain benzopyran derivatives as potassium channel activators. European Patent Publication No. 0 587 180 discloses certain benzofused derivatives for use in the treatment of ischemic conditions and arrythmia. European Patent Publication No. 0 747 374 discloses compounds having the formula:

as potassium channel activators. PCT Publication No. WO 98/045542 discloses chroman derivatives for the treatment of cardiac insufficiency.

PCT Publication No. WO 2003/080578 discloses heteroaromatic ureas as vanilloid receptor (VR1) modulators, in particular antagonists, for treating pain and/or inflammation. PCT Publication No. WO 2005/007652 describes substituted quinolin-4-yl-amine analogues useful in the treatment of conditions related to capsaicin receptor activation. PCT Publication No. WO 05/009977 discloses substituted pyrmidinyl-4-yl-amine analogues used to modulate vanilloid receptor activity. Other vanilloid receptor modulating compounds are disclosed in U.S. Pat. Nos. 6,933,311 and 6,939,891; and PCT Publication Nos. WO 02/08221, 02/16317, 02/16318, 02/16319, 04/035533, 04/103281, 04/108133 and 04/111009.

In efforts to discover better analgesics for the treatment of both acute and chronic pain, and to develop treatments for various neuropathic pain states, there still exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by vanilloid receptors.

SUMMARY

The present invention provides vanilloid receptor ligands of the formula:

analogs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, pharmaceutically acceptable hydrates thereof, N-oxides thereof, tautomers thereof, regioisomers thereof, stereoisomers thereof, prodrugs thereof and polymorphs thereof, wherein:

X and Y are independently O, S(O)m, or NRe;

R1 and R2 are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR9 or S(O)m;

R3 and R4 are independently hydrogen, cyano, halogen, —OR9, substituted or unsubstituted alkyl or —NR9R10, or R3 and R4 together form an oxo group;

(a) R5, R6 and R7 are independently hydrogen, nitro, cyano, halogen, —OR9, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR9R10, —C(=L)-R9, —C(O)O—R9, —C(O)NR9R10, —S(O)m—R9, or —S(O)m—NR9R10; and R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR9R10, —C(=L)-R9, —C(O)O—R9, —C(O)NR9R10, —S(O)m—R9, or —S(O)m—NR9R10; or

(b) R5 and R6 are as defined above; and R7 and R8 are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NRe or S;

each occurrence of R9 and R10 may be the same or different and is independently hydrogen, —ORa, —SRa, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NRaRb, —C(=L)-Ra, —C(O)O—Ra, —C(O)NRaRb, —S(O)m—Ra or —S(O)m—NRaRb, or R9 and R10 taken together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S;

each occurrence of Ra and Rb independently is hydrogen, —ORc, —SRc, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —C(=L)-Rc, —C(O)O—Rc, —C(O)NRcRd, —S(O)m—Rc, —S(O)m—NRcRd, —NRcRd, or a protecting group, or Ra and Rb taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S;

each occurrence of Rc and Rd is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or Rc and Rd taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRc or S;

each occurrence of Re is independently hydrogen or substituted or unsubstituted alkyl;

each occurrence of L is independently O, S, or NRe;

each occurrence of m is independently 0, 1, or 2; and

n is an integer from 0 to 4.

According to one embodiment, the compound meets one or more of criteria (1)-(4) below.

(1) when one of R7 and R8 is hydrogen, the other is not substituted or unsubstituted phenyl, substituted or unsubstituted thienyl or substituted or unsubstituted 2-, 3- or 4-pyridyl;

(2) (a) the bicyclic ring in formula I is not substituted at the 6-position with —S(O)2NRaRb or —S(O)2NR9R10, or (b) when the bicyclic ring in formula I is substituted at the 6-position with —S(O)2NRaRb or —S(O)2NR9R10, then Ra is hydrogen and Rb is methyl, and R9 is hydrogen and R10 is methyl;

(3) (a) R3 and R4 are not —OR9, when R9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, or acyl, (b) R3 and R4 are not —OR9, or (c) when R5 is —NR9R10 and R9 is C(=L)-Ra, then Ra is not substituted or unsubstituted phenyl, napthyl, pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, indolyl, pyrrolidinolinyl, piperidonlyl, azepeneonlyl, or pyridazinone; and

(4) R1 and R2 together form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR9 or S(O)m.

According to one preferred embodiment, the compound meets all of criteria (1)-(4) above. According to another preferred embodiment, the compound meets criteria (4).

According to another embodiment, none of the R5 groups are —S(O)2NRaRb or —S(O)2NR9R10.

These compounds may include one or more of the following embodiments. For example, X can be O or S(O)m, [wherein m can be 0 or 2]; R1 and R2 together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatom(s) selected from O, NR9 or S(O)m; R3, R4, R6 and R7 can be hydrogen; in each occurrence R5 can be independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, OR9, NR9R10 or S(O)mR9; R8 can be heteroaryl, heteroarylalkyl, heterocyclyl or arylalkyl; further, R7 and R8, together with the nitrogen atom to which they are attached, may form a saturated or unsaturated C3-C7 cyclic ring which may optionally contain one or more heteroatom(s); and Y can be O or S.

A preferred compound of formula (I) is where X is O.

Another preferred compound of formula (I) is where X is S.

Further preferred is a compound of formula (I) where Y is O.

Further preferred is a compound of formula (I) where R1 and R2 are joined together with the carbon atom to which they are bound to form an optionally substituted 3 to 7 member saturated cyclic ring, which may optionally include a heteroatom selected from O and NR9.

Further preferred is a compound of formula (I) where R1 and R2 are joined together with the carbon atom to which they are bound to form a cyclobutane ring.

Further preferred is a compound of formula (I) where R3 and R4 are independently hydrogen, cyano, halogen, —OR9, substituted or unsubstituted alkyl or —NR9R10.

Further preferred is a compound of formula (I) where R3 and R4 are hydrogen.

Further preferred is a compound of formula (I) where each occurrence of R5 is selected from hydrogen, halogen, unsubstituted alkyl (e.g., methyl) and —OR9 (where R9 is unsubstituted alkyl or alkyl substituted with halogen) (e.g., —OCH3 or —OCHF2).

Further preferred is a compound of formula (I) where R5 is hydrogen.

Further preferred is a compound of formula (I) where R6 is hydrogen.

Further preferred is a compound of formula (I) where R7 is hydrogen.

Further preferred is a compound of formula (I) where R3, R4, R5, R6 and R7 are hydrogen.

Further preferred is a compound of formula (I) where R1 and R2 are joined together to form a cyclobutyl ring, and R3-R7 are hydrogen.

Further preferred is a compound of formula (I) where R8 is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclyl.

Further preferred is a compound of formula (I) where R8 is pyrrolidinyl-3-yl.

Further preferred is a compound of formula (I) where R8 is quinolin-5-yl.

Further preferred is a compound of formula (I) where R8 is isoquinolin-8-yl.

Further preferred is a compound of formula (I) where R8 is (pyridin-4-yl)methyl.

Further preferred is a compound of formula (I) where R8 is 4-trifluoromethylbenzyl.

Further preferred is a compound of formula (I) where R8 is substituted with a substituted or unsubstituted heteroaryl, such as 4-trifluoromethylpyridin-2-yl.

Further preferred is a compound of formula (I) where R7 and R8 are joined together with the nitrogen atom to which they are bound to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NRe or S;

Further preferred is a compound of formula (I) where R7 and R8 are combined to form piperidine.

According to one embodiment, R1 and R2 together with the carbon atom to which they are bound do not form a cyclopentyl or cyclohexyl ring.

According to one preferred embodiment, the vanilloid receptor ligands have the formula:

wherein:

R1, R2, R3, R4, R5 and n are as defined above;

R′ and R″ are independently hydrogen, nitro, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —OR9, —NR9R10, —C(=L)-R9, —C(O)O—R9, —C(O)NR9R10, —S(O)m—R9, or —S(O)m—NR9R10;

p and q are independently 0, 1, 2, or 3,

and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, N-oxides thereof, tautomers thereof, stereoisomers thereof, prodrugs thereof and polymorphs thereof. X is preferably O or S. According to one embodiment, X is O.

According to another embodiment, the compound of formula IIb meets the criteria (3) mentioned above.

According to another preferred embodiment, the VR1 receptor ligands of the invention have the formula:

wherein X, Y, R3-R8, and n are as defined above, and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, N-oxides thereof, tautomers thereof, stereoisomers thereof, prodrugs thereof and polymorphs thereof. X and Y are preferably O. R8 is preferably a substituted or unsubstituted quinolinyl or isoquinolinyl. More preferably, the quinolinyl or isoquinolinyl group is attached to the main structure of the compound at a position on the carbon-only cyclic ring. X is preferably O or S. According to one embodiment, X is O. Y is preferably O.

According to one embodiment, the compound of formula III meets the criteria (1), (2) or (3) mentioned above, or any combination thereof.

According to a more preferred embodiment, the VR1 receptor ligands of the invention have the formula:

wherein:

X, Y, R3, R4, R6, R9, R10, n, p, and q are as defined above;

one of R11-R14 is N and the remaining R11-R14 groups are CH or CRa;

each occurrence of R5 is independently hydrogen, nitro, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —OR9, —NR9R10, —C(=L)-R9, —C(O)O—R9, or —C(O)NR9R10; and

each occurrence of R15 and R16 is independently hydrogen, nitro, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —OR9, —NR9R10, —C(=L)-R9, —C(O)O—R9, —C(O)NR9R10, —S(O)m—R9, or —S(O)m—NR9R10;

and pharmaceutically acceptable salts thereof; pharmaceutically acceptable solvates thereof, hydrates thereof, N-oxides thereof, tautomers thereof; stereoisomers thereof, prodrugs thereof and polymorphs thereof. X is preferably O or S. According to one embodiment, X is O. Y is preferably O.

According to one embodiment, the compound of formula IV meets the criteria (3) mentioned above.

Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, N-oxides, stereoisomers, tautomers, prodrugs or polymorphs thereof. The present invention should not be construed to be limited to them. (±)1-{3,4-Dihydro-1′-(methyl)spiro-[2H-1-benzopyran-2,4′-piperidine]-4-yl}-3-(isoquinoline-5-yl)urea (Compound No. 1), (±)1-(2′,3,3′,4,5′,6′-Hexahydrospiro-[2H-1-benzopyran-2,4′-pyran]-4-yl)-3-(isoquinoline-5-yl)urea (Compound No. 2), (±)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 3), (+)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 4), (−)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 5), (±) 1-(3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(8-chloroisoquinolin-5-yl)urea (Compound No. 6), (±) 1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(3-methylisoquinolin-5-yl)urea (Compound No. 7), (±) 1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(1-methylisoquinolin-5-yl)urea (Compound No. 8), (±) 1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(2-oxoisoquinolin-5-yl)urea (Compound No. 9), (+) 1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(2-oxoisoquinolin-5-yl)urea (Compound No. 10), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(pyridin-3-ylmethyl)urea (Compound No. 11), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(pyridin-2-ylmethyl)urea (Compound No. 12), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(6-chloro-1,3-benzothiazol-2-yl)urea (Compound No. 13), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(6-fluoro-1,3-benzothiazol-2-yl)urea (Compound No. 14), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(1-methyl-1H-indazol-5-yl)urea (Compound No. 15), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(6-methoxy-1,3-benzothiazol-2-yl)urea (Compound No. 16), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(2-methyl-2H-indazol-5-yl)urea (Compound No. 17), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(5-tert-butyl-1,3,4-thiadiazol-2-yl)urea (Compound No. 18), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-y bromophenyl)-1,3-thiazol-2-yl)urea (Compound No. 19), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(6-methyl-1,3-benzothiazol-2-yl)urea (Compound No. 20), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(1-acetyl-1H-indazol-5-yl)urea (Compound No. 21), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(thieno[2,3-c]pyridine-3-yl)urea (Compound No. 22), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-([5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]-)urea (Compound No. 23), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(4,6-dimethylpyrimidin-2-yl)urea (Compound No. 24), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(5-chloro-1,3-benzoxazol-2-yl)urea (Compound No. 25), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)urea (Compound No. 26), (±)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(2-furylmethyl)urea (Compound No. 27), (±) 1-(3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(quinolin-5-yl)urea (Compound No. 28), (±)1-(3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(isoquinolin-8-yl)urea (Compound No. 29), 1-((R)-3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-((S)-1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound No. 30), 1-((R)-3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-((R)-1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound No. 31), 1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-((R)-1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound No. 32), 1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-((S)-1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound No. 33), 1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(pyridin-4-yl)methyl urea (Compound No. 34), 1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1′-cyclobutan]-4-yl)-3-(4-trifluoromethylbenzyl)urea (Compound No. 35), N-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-ylpiperidine-1-carboxamide (Compound No. 36), N-2,1,3-benzothiadiazol-4-yl-N′-3,3′,4,4′-tetrahydro-2′H-spiro[chromene-2,1′-cyclobutan]-4-ylurea (N-2,1,3-benzothiadiazol-4-yl-N′-3,4-dihydro-2H-spiro[chromene-2,1′-cyclobutan]-4-ylurea) (Compound No. 37), N-2,1,3-benzothiadiazol-4-yl-N′-3,3′,4,4′-tetrahydro-2′H-spiro[chromene-2,1′-cyclobutan]-4-ylurea (N-2,1,3-benzothiadiazol-4-yl-N′-3,4-dihydro-2H-spiro[chromene-2,1′-cyclobutan]-4-ylurea) (Compound No. 38), N′-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-3,3′,4,4′-tetrahydro-2′H-spiro[chromene-2,1′-cyclobutan]-4-ylurea (N′-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-3,4-dihydro-2H-spiro[chromene-2,1′-cyclobutan]-4-ylurea) (Compound No. 39), (±) 1-(3,4-Dihydro-6-methyl-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 40), (±) 1-(3,4-Dihydro-7-methyl-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 41), (±) 1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 42), (+) 1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 43), (−) 1-(3,4-Dihydro-6-fluoro spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 44), (±) 1-(3,4-Dihydro-6-hydroxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 45), (±) 1-(3,4-Dihydro-7-hydroxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 46), (±) 1-(3,4-Dihydro-7-methoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 47), 1-(6,8-Difluoro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 48), (±) 1-(8-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 49), (±) 1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 50), (±) 1-(3,4-Dihydro-6-methoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 51), (±) 1-(6-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 52), (±) 1-(7-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 53), (±) 1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea. Hydrochloride salt (Compound No. 54), (±) 1-(3,4-Dihydro-6-methylaminosulfonyl-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 55), (±) 1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(3-methylisoquinolin-5-yl)urea (Compound No. 56), (±) 1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(3-methylisoquinolin-5-yl)urea (Compound No. 57), (±) 1-(8-Cyano-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 58), (+) 1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 59), (−) 1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 60), (±) 1-(3,4-Dihydro-8-hydroxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 61), (±) 1-(3,4-Dihydro-8-difluoromethoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 62), (±) 1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 63), (−) 1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 64), (±) 1-(6-Bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 65), (±) 1-(6,8-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 66), (±) 1-(6-Bromo-3,4-dihydro-7-methylspiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 67), (±) 1-(6,7-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 68), (±) 1-(6-Chloro-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 69), (±) 1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(8-chloroisoquinolin-5-yl)urea (Compound No. 70), (±) 1-(6-Fluoro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(8-chloroisoquinolin-5-yl)urea (Compound No. 71), (±) 1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(3-methylisoquinolin-5-yl)urea (Compound No. 72), (±) 1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(3-methylisoquinolin-5-yl)urea (Compound No. 73), (±) 1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(1-methylisoquinolin-5-yl)urea (Compound No. 74), (±) 1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(1-methylisoquinolin-5-yl)urea (Compound No. 75), (±)1-(6-Acetamido-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 76), (±)1-(6-Amino-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 77), (±) 1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 78), (±) 1-(3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 79), N′-isoquinolin-5-yl-N-3,3′,4,4′-tetrahydro-2′H-spiro[chromene-2,1′-cyclobutan]-4-ylthiourea (N′-isoquinolin-5-yl-N-3,4-dihydro-2H-spiro[chromene-2,1′-cyclobutan]-4-ylthiourea) (Compound No. 80), (±) 1-(3,4-dihydro-spiro[2H-1-benzothiopyran-2,1′-cyclobutan]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 81), (±) 1-(1,1-dioxo-3,4-dihydro-spiro[-2H-1-benzothiopyran-2,1′-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 82), and N′-isoquinolin-8-yl-N-3,3′,4,4′-tetrahydro-2′H-spiro[chromene-2,1′-cyclobutan]-4-ylthiourea (N′-isoquinolin-8-yl-N-3,4-dihydro-2H-spiro[chromene-2,1′-cyclobutan]-4-ylthiourea) (Compound No. 83).

Also provided herein is a pharmaceutical composition comprising one or more of the aforementioned compounds together with one or more pharmaceutically acceptable excipients (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present invention. One or more compounds of the present invention may be diluted with carriers or enclosed within a carrier, which can be in the form of a capsule, sachet, paper or other container.

Also provided herein is a method for preventing, ameliorating or treating a disease, disorder or syndrome mediated by vanilloid receptors (such as VR1) in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more compounds of the present invention or a pharmaceutical composition of the present invention. Non-limiting examples of diseases, disorders and syndromes which can be mediated by vanilloid receptor 1 (VR1) include (1) migraine, (2) arthralgia, (3) diabetic neuropathy, (4) neurodegeneration, (5) neurotic skin disorder, (6) stroke, (7) cardiac pain arising from an ischemic myocardium, (8) Huntington\'s disease, (9) memory deficits, (10) restricted brain function, (11) amyotrophic lateral sclerosis (ALS), (12) dementia, (13) urinary bladder hypersensitiveness, (14) urinary incontinence, (15) vulvodynia, (16) pruritic conditions such as uremic pruritus, (17) irritable bowel syndrome including gastro-esophageal reflux disease, (18) enteritis, (19) ileitis, (20) stomach-duodenal ulcer, (21) inflammatory bowel disease including Crohn\'s disease, (22) celiac disease, (23) inflammatory diseases (such as pancreatitis), (24) respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease (COPD), (25) irritation of skin, eye or mucous membrane, (26) dermatitis, (27) fervescence, (28) retinopathy, (29) muscle spasms, (30) emesis, (31) dyskinesias, (32) depression, (33) pain such as acute, chronic, neuropathic pain or post-operative pain, (34) pain due to neuralgia or trigeminal neuralgia, (35) pain due to diabetic neuropathy, (36) dental pain, (37) cancer pain, (38) arthritis, (39) osteoarthritis, (40) diabetes, (41) obesity, (42) urticaria, (43) actinic keratosis, (44) keratocanthoma, (45) alopecia, (46) Meniere\'s disease, (47) tinnitus, (48) hyperacusis, (49) anxiety disorders and (50) benign prostate hyperplasia. According to one preferred embodiment, the compounds of the present invention are administered to treat acute or chronic pain or neuropathic pain.

Also provided herein are processes for preparing compounds described herein.

DETAILED DESCRIPTION

The present invention provides substituted benzofused derivatives, which can be used as vanilloid receptor ligands, and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by vanilloid receptors (such as VR1) are further provided.

The term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term “C1-6 alkyl” refers to an alkyl chain having 1 to 6 carbon atoms.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.

The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are —OCH3 and —OC2H5.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term “cycloalkenyl” refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

The term “aryl” refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., —CH2C6H5 and —C2H5C6H5.

The term “heterocyclic ring” refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term “heteroaryl” refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

Unless otherwise specified, the term “substituted” as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine, —COORx, —C(O)Rx, —C(S)Rx, —C(O)NRxRy, —C(O)ONRxRy, —NRxCONRyRz, —N(Rx)SORy, —N(Rx)SO2Ry, —(═N—N(Rx)Ry), —NRxC(O)ORy, —NRxC(O)Ry, —NRxC(S)Ry, —NRxC(S)NRyRz, —SONRxRy, —SO2NRxRy, —ORx, —ORxC(O)NRyRz, —ORxC(O)ORy, —OC(O)Rx, —OC(O)NRxRy, —RxNRyC(O)Rz, —RxORy, —RxC(O)ORy, —RxC(O)NRyRz, —RxC(O)Ry, —RxOC(O)Ry, —SRx, —SORx, —SO2Rx, and —ONO2, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned “substituted” groups cannot be further substituted. For example, when the substituent on “substituted alkyl” is “substituted aryl”, the substituent on “substituted aryl” cannot be “substituted alkenyl”.