AU2012202687B2

AU2012202687B2 - TRPV1 antagonists and uses thereof

Info

Publication number: AU2012202687B2
Application number: AU2012202687A
Authority: AU
Inventors: Noriyuki Kurose; Laykea Tafesse
Original assignee: Shionogi and Co Ltd; Purdue Pharma LP
Current assignee: Shionogi and Co Ltd; Purdue Pharma LP
Priority date: 2007-04-27
Filing date: 2012-05-08
Publication date: 2013-05-09
Anticipated expiration: 2028-04-25
Also published as: AU2012202687A1; AU2011226773B2; AU2011226773A1; AU2011226773C1

Abstract

The invention relates to compounds of formula I Arl , R4 ---(R3 )m N I X N'-R20 Ar2 (I) and pharmaceutically acceptable derivatives thereof, compositions comprising an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD and IBS, comprising administering to an animal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof.

Description

1 AUSTRALIA Patents Act 1990 PURDUE PHARMA L.P., SHIONOGI & CO., LTD COMPLETE SPECIFICATION STANDARD PATENT Invention Title: TRP V1 antagonists and uses thereof The following statement is a full description of this invention including the best method of performing it known to us:- TRPVI ANTAGONISTS AND USES THEREOF This application claims the benefit of U.S. provisional application no. 60/926,661, filed April 27, 2007, U.S. provisional application no. 60/930,036, filed May 5 11, 2007, U.S. provisional application no. 60/937,003, filed June 21, 2007, and U.S. provisional application no. 60/962,409, filed July 27, 2007, the disclosure of each of which is incorporated by reference herein in its entirety. 1. FIELD OF THE INVENTION 10 The invention relates to compounds of formula I, and pharmaceutically acceptable derivatives thereof, compositions.comprising an effective amount of a compound of formula I and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD, and IBS, comprising administering to an animal in need thereof an 15 effective amount of a compound of formula 1. 2. BACKGROUND OF THE INVENTION Pain is the most common symptom for which patients seek medical advice and 20 treatment. Pain can be acute or chronic. While acute pain is usually self-limited, 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 ofMedicine 100-107 (J.C. Bennett and F. Plum eds., 20th ed. 1 996)). 25 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 peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at vanilloid receptors (V. Di Marzo et al., 30 Current Opinion in Neurobiology 2:372-379 (2002)) to pain processing. Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, 2 ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with anti-epileptics (e.g., gabapentin, 5 carbanazepine, valproic acid, topiramate, phenytoin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline). U! is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. U! affects people of all ages and levels of physical health, both in health care 10 settings and in the community at large. Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic nuscarinic-receptor sites on bladder smooth muscle. Treatments for U! include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity. None of the existing commercial drug treatments for UT has achieved complete 15 success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. 20 Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.

H

2 antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H 2 antagonists promote ulcer healing by reducing gastric acid and 25 digestive-enzyme secretion elicited by histamine and other H 2 agonists in the stomach and duodenum. H 2 antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever. H+, K" - ATPase inhibitors such as omeprazole and lansoprazole are also used to 30 treat ulcers. H 4 , K* - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H 4 , K+ - ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.

3 Inflammatory-bowel disease ("IBD") is a chronic disorder in which the bowel becomes inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are Crohn's disease and ulcerative colitis. Crohn's disease, which can include regional enteritis, granulomatous ileitis, and 5 ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastem-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the 10 large intestine, but can occur in any part of the digestive tract. Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. When Crohn's disease causes the intestine to be obstructed or when abscesses or 15 fistulas do not heal, surgery can be necessary to remove diseased sections of the intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In almost half of the cases a second operation is needed. The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997). Ulcerative colitis is a chronic disease in which the large intestine becomes 20 inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30; however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine. The disease usually begins in the rectum and the sigmoid colon and 25 eventually spreads partially or completely throughout the large intestine. The cause of ulcerative colitis is unknown. Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients. Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more 30 intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered. Irritable-bowel syndrome ("IBS") is a disorder of motility of the entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more women than men. In IBS, stimuli such as stress, diet, drugs, 4 hormones, or irritants can cause the gastrointestinal tract to contract abnormally. During an episode of IBS, contractions of the gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food and feces through the small intestine, often leading to diarrhea. Cramps result from the strong contractions of the large intestine and 5 increased sensitivity of pain receptors in the large intestine. Treatment of IBS typically involves modification of an IBS-patient's diet. Often it is recommended that an IBS patient avoid beans, cabbage, sorbitol, and fructose. A low-fat, high-fiber diet can also help some IBS patients. Regular physical activity can also help keep the gastrointestinal tract functioning properly, Drugs such as 10 propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997). International publication no. WO 98/31677 describes a class of aromatic amines 15 derived from cyclic amines that are useful as antidepressant drugs. International publication no. WO 01/027107 describes a class of heterocyclic compounds that are sodium/proton exchange inhibitors. International publication no. WO 99/37304 describes substituted oxoazaheterocycly compounds useful for inhibiting factor Xa. 20 U.S. Patent No. 6,248,756 to Anthony et al. and international publication no. WO 97/38665 describe a class of piperidine-containing compounds that inhibit farnesyl protein transferase (Ftase). International publication no. WO 98/31669 describes a class of aromatic amines derived from cyclic amines useful as antidepressant drugs. 25 International publication no. WO 97/28140 describes a class of piperidines derived from I -(piperazin- I -yl)aryl(oxy/amino)carbonyl-4-aryl-piperidine that are useful as 5-HT IDb receptor antagonists. International publication no. WO 97/38665 describes a class of piperidine containing compounds that are useful as inhibitors of famesyl-protein transferase. 30 U.S. Patent No. 4,797,419 to Moos et al. describes a class of urea compounds for stimulating the release of acetylcholine and useful for treating symptoms of senile cognitive decline.

5 U.S. Patent No. 5,891,889 describes a class of substituted piperidine compounds that are useful as inhibitors of famesyl-protein transferase, and the farnesylation of the oncogene protein Ras. U.S. Patent No. 6,150,129 to Cook et al. describes a class of dinitrogen 5 heterocycles useful as antibiotics. U.S. Patent No. 5,529,998 to Habich el al. describes a class of benzooxazolyl and benzothiazolyloxazolidones useful as antibacterials. International publication no. WO 01/57008 describes a class of 2-benzothiazolyl urea derivatives useful as inhibitors of serine/threonine and tyrosine kinases. 10 International publication no. WO 02/08221 describes aryl piperazine compounds useful for treating chronic and acute pain conditions, itch, and urinary incontinence. International publication no. WO 00/595 10 describes aminopyrimidines useful as sorbitol dehydrogenase inhibitors. Japanese patent application no. I1 -199573 to Kiyoshi et al. describes 15 benzothiazole derivatives that are neuronal 5HT3 receptor agonists in the intestinal canal nervous system and useful for treating digestive disorders and pancreatic insufficiency. German patent application no 199 34 799 to Rainer et al. describes a chiral smectic liquid crystal mixture containing compounds with 2 linked (hetero)aromatic rings or compounds with 3 linked (hetero)aromatic rings. 20 M. Chu-Moyer el al., J. Med. Chem. 45:511-528 (2002) describes heterocycle substituted piperazino-pyrimidines useful as sorbitol dehydrogenase inhibitors. B.G. Khadse et a/., Bull. Haff Instt. l(3):27-32 (1975) describes 2-(N 4 substituted-N'-piperazinyl) pyrido(3,2-d)thiazoles and 5-nitro-2-(N 4 -substituted N'-piperazinyl)benzthiazoles useful as anthelmintic agents. 25 U.S. Patent Application Publication No. US 2004/0186111 A l and International publication no. WO 2004/058754 Al describe a class of compounds that are useful for treating pain. U.S. Patent Application Publication No. US 2006/0199824-A l and International publication no. WO 2005/009987 Al describe a class of compounds that are useful for 30 treating pain. U.S. Patent Application Publication No. US 2006/0128717 Al and International publication no. WO 2005/009988 A l describe a class of compounds that are useful for treating pain.

There remains, however, a clear need in the art for new drugs useful for treating or preventing pain, UI, an ulcer, IBD, and IBS. Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application. 5 Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of 10 each claim of this application. 3. SUMMARY OF THE INVENTION Disclosed herein are compounds of formula I: 15 Arl..W

R

4 (R3)m N X. N N'R20 Ar 2 (I) or a pharmaceutically acceptable derivative thereof, where 20 X is 0, S, N-CN, N-OH, or N-ORIO; W is N or C; the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R4 is -H, OH, -OCF 3 , -halo, -(Ci-C 6 )alkyl, -CH 2 OH, -CH 2 CI, -CH 2 Br, -CH 2 I, -CH 2 F, -CH(halo) 2 , 25 -CF 3 , -ORio, -SRio, -COOH, -COORio, -C(O)Rio, -C(O)H, -OC(O)Rio, -OC(O)NHRIO,

-NHC(O)R

3 , -CON(RI 3

)

2 , -S(0) 2 Rio, or -NO 2 ; Rio is -(Ci-C 4 )alkyl; each R13 is independently -H, -(Ci-C 4 )alkyl, -(Ci-C 4 )alkenyl, -(Ci-C 4 )alkynyl, or phenyl; 6 ? Ari is (R2), (R2)n (R2)n .N (R2)n -N .N R1 N 'R N R1 ' R ' (R2)PN (R 2 ) N (R2 R 'NN R N ' NN

R

1

R

1 1 N , N (R 2 )P NN (R2) N 2por r 'N N Ar is Ni, N-R2o NJ S N O Y / \/ I R1i 2 a

R

8

R

9

R

8 R, R 8 R, I -(R 1 4)1 -(R 1 4)t

Y

1

Y

1

Y

2

Y

2 )cE (Y3)c N -or (R14)q (R14)q (R14)q (R14), (R1)r 5 c is the integer 0, 1, or 2;

Y

1 , Y 2 , Y 3 are independently C, N, or 0; wherein no more than one of Y 1 , Y 2 , or Y 3 can be 0, and for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R2 1 group and for each YI, Y 2 , and Y 3 that is C, the C is 8 bonded to two R 20 groups, provided that there are no more than a total of two (Ci

C

6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ; R1 2 , and R12b are independently -H or -(CI-C 6 )alkyl; E is =0, =S, =CH(CI-C 5 )alkyl, =CH(CI-CS)alkenyl, -NH(CI-C 6 )alkyl, or =N 5 OR 2 0 ; R, is -H, -halo, -(CI-C 4 )alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo)3, -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , or -OCH 2 (halo); each R 2 is independently: (a) -halo, -OH, -O(CI-C 4 )alkyl, -CN, -NO 2

.-NH

2 , -(CI-Cio)alkyl, -(C 2 10 CIO)alkenyl, -(C 2 -Cjo)alkynyl, -phenyl, or (b) a group of formula Q; wherein Q is J 0 J S Z3 Z1 Z 3 0 Z4 Z Z4 Z3 , : Z Z3, , Z 4 Z3 O0 R20 HNR20 O0 --- R2_ 0 Y HW S R 20

Z

3 NH, Z3j O, Z NjH 0 H H N O 0 H,2 0 N.. N R 20 R20 N R 20 Z:f Z3 , 2

Z

3 or Z 2 Z3 15 ZI is -H, -OR 7 , -SR 7 , -CH 2

-OR

7 , -CH 2

-SR

7 , -CH 2

-N(R

20

)

2 , or -halo;

Z

2 is -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, -CH 2

-OR

7 , -phenyl, or -halo; each Z 3 is independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, or 20 -phenyl;

Z

4 is -H, -OH, -OR 20 , -(Ci-C 6 )alkyl, or -N(R 2 0

)

2 ; J is -OR 2 0 , -SR 2 0 , -N(R 20

)

2 , or -CN; 9 provided that at least one R 2 group is a group of formula Q, and provided that when Z, is -OR 7 or -SR 7 , then Z 2 is not -halo; each R 3 is independently: (a) -H, CH 2

OR

7 , or (C1-C 6 )alkyl; or 5 (b) two R 3 groups together form a (C-C 6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains -HC=CH- within the (C-C 6 )bridge; or (c) two R 3 groups together form a -CH-N(R,)-CHr- bridge, a Rb Rb C=O O--s=0 10 -CH 2 -N CH 2 - bridge, or a - CH 2

-N--CH

2 - bridge; R, is selected from -H, -(CI-C)alkyl, -(C 3 -C8)cycloalkyl, -CHr-C(O)-Re,

-(CH

2 )-C(O)-ORc, -(CH 2 )-C(O)-N(Rc) 2 , -(CH 2

)

2 -0-Re, -(CH 2

)

2

-S(O)

2 -N(Rc) 2 , or -(CH2)r-N(Rc:)S(O)r Rc:; 1 5 Rb is selected from: (a) -H, -(CI-C 6 )alkyl, -(C 3

-C

8 )cycloalkyl, -(3- to 7 membered)heterocycle, -N(Rc) 2 , -N(Rc)-(C 3 -C8)cycloalkyl, or -N(Re)-(3- to 7 membered)heterocycle; or (b) -phenyl, -(5- or 6-membered)heteroaryl, -N(Rc)-phenyl, or -N(Re)-(5 20 to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R7 groups; each Re is independently selected from -H or -(CI-C 4 )alkyl; each R 7 is independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C-C 6 )alkynyl,

-(C

3

C

8 )cycloalkyl, -(C-Cs)cycloalkenyl, -phenyl, -(CI-C 6 )haloalkyl, -(C 25 C 6 )hydroxyalkyl, -(CI-C 6 )alkoxy(Ci-C 6 )alkyl, -(C1-C 6 )alkyl-N(R 2 0) 2 , or -CON(R 20

)

2 ; each R 8 and R9 is independently; (a) -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2 -C)alkynyl, -(C 3 -Cs)cycloalkyl, (C 5

-C

8 )cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with I or 2 -OH groups; or 10 (b) -H, -CH- 2 C(halo) 3 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , -OCH 2 (halo), -SC(halo) 3 , -SCH(halo) 2 , -SCH 2 (halo), -CN, -O-CN, -OH, -halo, -N 3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 . -NR 7 0H, -OR 7 , -C(O)R,, -C(O)OR 7 , -OC(O)R 7 ,

-OC(O)OR

7 , -SR 7 , -S(O)R 7 , or -S(O) 2

R

7 ; 5 each R, is independently -CN, -OH, -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -halo, -N 3 ,

-NO

2 , -N(R 7

)

2 , -CH=NR 7 , -NR 7 0H, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , or -OC(0)OR 7 ; each R 1 4 is independently -H, -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2

-C

6 )alkynyl, (C 3 -Cs)cycloalkyl, -(Cs-C 8 )cycloalkenyl, -(CI-C 6 )alkoxy-(CI-C 6 )alkyl, -phenyl, 10 -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(3- to 7-membered)heterocycle, -(Ci-C 6 )haloalkyl,

-(C

2

-C

6 )haloalkenyl, -(C 2

-C

6 )haloalkynyl, -(C 2

-C

6 )hydroxyalkenyl, -(C

C

6 )hydroxyalkynyl, -(Ci-C 6 )alkoxy(C-C 6 )alkyl, -(CI-C 6 )alkoxy(C-C 6 )alkenyl, -(C 1 C 6 )alkoxy(C-C 6 )alkynyl, -(CI-C 6 )alkoxy(C 3

-C

8 )cycloalkyl,-CN, -OH, -halo, -OC(halo) 3 , -N 3 , -NO,, -CH=NR 7 , -N(R 7 )2, -NR 7 0H, -OR7, -SR 7 , -O(CH2)bOR7, 15 O(CH2)bSR7, -O(CH2)bN(R7)2, -N(R7)(CH2)bOR7, -N(R7)(CH,)bSR7, -N(R7)(CH2)bN(R7)2, -N(R7)COR7, -C(O)R 7 , -C(O)OR7, -OC(O)R7, -OC(O)OR7, -S(O)R7, or -S(0)2R7, -S(O)2N(R7)2, -SO2C(halo) 3 , SO2(3-to 7- neibered)heterocycle, -CON(R7)2, -(C 1 -Cs)alkyl-C=NOR7, -(C,-Cs)alkyl-C(O)-N(R7)2, -(CI-C 6 )alkyl NHSO2N(R7)2, or -(CI -C 6 )alkyl-C(=NH)-N(R7)2; 20 each R, 0 is independently -H, -(C -C 6 )alkyl, or -(C 3

-C

8 )cycloalkyl; each R 2 is independently -H, -(C -C 6 )alkyl, 1^1 N(CH3)2 ND or N> 0 25 each halo is independently -F, -Cl, -Br, or -1; n is the integer 1, 2, or 3; p is the integer I or 2 each b is independently the integer I or 2; q is the integer 0, 1, 2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2. 5 According to one aspect of the present invention there is provided a compound of formula I: Arl. , R 4 W--(R3)m N Xl N'-R20 Ar 2 (1) 10 or a pharmaceutically acceptable derivatives thereof, where X is 0, S, N-CN, N-OH, or N-ORio; W is N or C; the dashed line denotes the presence or absence of a bond, and when the dashed 15 line denotes the presence of a bond or W is N then R 4 is absent, otherwise R4 is -H, OH, -OCF 3 , -halo, -(Ci-C 6 )alkyl, -CH 2 OH, -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 F, -CH(halo) 2 ,

-CF

3 , -ORio, -SRio, -COOH, -COORio, -C(O)Rlo, -C(O)H, -OC(O)Ri 0 , -OC(O)NHRio,

-NHC(O)RI

3 , -CON(R] 3

)

2 , -S(0) 2 Rio, or -NO 2 ; Rio is -(Ci-C 4 )alkyl; 20 each R 13 is independently -H, -(Ci-C 4 )alkyl, -(Ci-C 4 )alkenyl, -(Ci-C 4 )alkynyl, or -phenyl; 11 Arn is (R2), (R2),(R2) N R) N N (R).N NN' N

N(R

2 )P NR) N (R2)p N or NN Ar 2 is 5 NJ NR20 N-, S N~ 0 N R4

Y

1 "' " \I Ri 2 a

R

8

R

9

R

8 Rg R 8 Rg R,2bC y E

N

3 )CE (y3)C NN , or7 (R14)q (R14)q (R14)q (1) R ) c is the integer 0, 1, or 2; YI, Y 2 , Y 3 are independently C, N, or 0; wherein no more than one of YI, Y 2 , or Y 3 can be 0, and for each YI, Y 2 , and

Y

3 that is N, the N is bonded to one R 21 group, and for each Y 1 , Y 2 , and Y 3 that is C, the 5 C is bonded to two R 20 groups, provided that there are no more than a total of two (CI

C

6 )alkyl groups substituted on all of Y, Y 2 , and Y 3 ; Ri 2 a and R12b are independently -H or -(Ci-C 6 )alkyl; E is =0, =S, =CH(Ci-C 5 )alkyl, =CH(Ci-C 5 )alkenyl, -NH(Ci-C 6 )alkyl, or

=N-OR

20 ; 10 R, is -H, -halo, -(Ci-C 4 )alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , or -OCH 2 (halo); each R 2 is independently: (a) -halo, -OH, -O(CI-C 4 )alkyl, -CN, -NO 2 . -NH 2 , -(CI-Cio)alkyl, -(C 2 Co)alkenyl, -(C 2 -CIo)alkynyl, -phenyl, or 15 (b) a group of formula Q; wherein Q is J O Z4 , rO Z3 or jz 3 each Z 3 is independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, or 20 -phenyl;

Z

4 is -H, -OH, -OR 20 , -(CI-C 6 )alkyl, or -N(R 20

)

2 with the proviso that -OR 20 is not -OCH 2

CH

3 ; J is -OR 2 0 , -SR 20 , -N(R 20

)

2 , or -CN; provided that at least one R 2 group is a group of formula Q; 25 each R 3 is independently: (a) (CI-C 6 )alkyl, or CH 2 0R 7 ; or (b) two R 3 groups together form a (C 2

-C

6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge; or 30 (c) two R 3 groups together form a -CH 2 -N(Ra)-CH 2 - bridge, a Rb Rb 0C0

-CH

2

-N-CH

2 - bridge, or a -- CH 2

-N-CH

2 - bridge; Ra is selected from -H, -(CI-C 6 )alkyl, -(C 3

-C

8 )cycloalkyl, -CH 2 -C(O)-R,

-(CH

2 )-C(O)-ORe, -(CH 2 )-C(O)-N(Rc) 2 , -(CH 2

)

2 -O-Re, -(CH 2

)

2

-S(O)

2 -N(Re) 2 , or -(CH2)r-N(Re)S(O)r-e; 5 Rb is selected from: (a) -H, -(Ci-C 6 )alkyl, -(C 3

-C

8 )cycloalkyl, -(3- to 7-membered)heterocycle, -N(Rc) 2 , -N(Rc)-(C 3 -Cs)cycloalkyl, or -N(Rc)-(3- to 7-membered)heterocycle; or (b) -phenyl, -(5- or 6-membered)heteroaryl, -N(Rc)-phenyl, or -N(Rc)-(5 to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 10 independently selected R 7 groups; each Re is independently selected from -H or -(Ci-C 4 )alkyl; each R 7 is independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl,

-(C

3 -Cs)cycloalkyl, -(C 5

-C

8 )cycloalkenyl, -phenyl, -(Ci-C 6 )haloalkyl, -(C

C

6 )hydroxyalkyl, -(CI-C 6 )alkoxy(CI-C 6 )alkyl, -(C-C 6 )alkyl-N(R 20

)

2 , or -CON(R 2 0) 2 ; 15 each R 8 and R 9 is independently: (a) -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, -(C 3

-C

8 )cycloalkyl, (C-C 8 )cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with 1 or 2 -OH groups; or (b) -H, -CH 2 C(halo) 3 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , 20 -OCH(halo) 2 , -OCH 2 (halo), -SC(halo) 3 , -SCH(halo) 2 , -SCH 2 (halo), -CN, -O-CN, -OH, -halo, -N 3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 , -NR70H, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 ,

-OC(O)OR

7 , -SR 7 , -S(O)R 7 , or -S(O)2R7; each RI is independently -CN, -OH, -(Ci-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -halo, -N 3 ,

-NO

2 , -N(R 7

)

2 , -CH=NR 7 , -NR 7 0H, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , or 25 -OC(O)OR 7 ; each R 1 4 is independently -H, -(Ci-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, (C 3

-C

8 )cycloalkyl, -(Cs-C 8 )cycloalkenyl, -(CI-C 6 )alkoxy-(CI-C 6 )alkyl, -phenyl, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(3- to 7-membered)heterocycle, -(Ci-C 6 )haloalkyl, -(C2-C 6 )haloalkenyl, -(C2-C 6 )haloalkynyl, -(C 2

-C

6 )hydroxyalkenyl, -(C 2 30 C 6 )hydroxyalkynyl, -(Ci-C 6 )alkoxy(C 2

-C

6 )alkyl, -(CI-C 6 )alkoxy(C 2

-C

6 )alkenyl, -(Ci C6)alkoxy(C 2

-C

6 )alkynyl, -(C I-C6)alkoxy(C 3 -Cs)cycloalkyl, -CN, -OH, -halo, -OC(halo) 3 , -N 3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 , -NR 7 0H, -OR 7 , -SR 7 , -O(CH 2 )bOR 7 , O(CH 2 )bSR 7 , -O(CH 2 )bN(R 7

)

2 , -N(R 7

)(CH

2 )bOR 7 , -N(R 7

)(CH

2 )bSR 7 ,

-N(R

7

)(CH

2 )bN(R 7

)

2 , -N(R 7

)COR

7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OC(O)OR 7 , 35 -S(O)R 7 , or -S(0) 2

R

7 , -S(0) 2

N(R

7

)

2 , -SO 2 C(halo) 3 , -S0 2 (3- to 7 11c membered)heterocycle, -CON(R 7

)

2 , -(CI-C 5 )alkyl-C=NOR 7 , -(CI-Cs)alkyl-C(O)

N(R

7

)

2 , -(C -C 6 )alkyl-NHSO 2

N(R

7

)

2 , or -(Ci -C 6 )alkyl-C(=NH)-N(R 7

)

2 ; each R 20 is independently -H, -(CI-C 6 )alkyl, or -(C 3

-C

8 )cycloalkyl; each R 2 1 is independently -H, -(C i-C 6 )alkyl, 5

N(CH

3

)

2 N or each halo is independently -F, -Cl, -Br, or -I; n is the integer 1, 2, or 3; 10 p is the integer I or 2; each b is independently 1 or 2; q is the integer 0, 1, 2, 3 or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; 15 t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2. Compounds of formula I are potent at TRPVI receptors, and are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2. 20 A compound of formula I, or a pharmaceutically acceptable derivative thereof, is useful for treating or preventing pain, UI, an ulcer, IBD, or IBS (each being a "Condition") in an animal. The invention also relates to compositions comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof, and a 25 pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing a Condition in an animal. The invention further relates to methods for treating a Condition comprising administering to an animal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof. 30 The invention further relates to use of a compound of formula I in the manufacture of a medicament for treating and/or preventing a Condition. 11D The invention further relates to methods for preventing a Condition comprising administering to an animal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof. 5 The invention still further relates to methods for inhibiting Transient Receptor Potential Vanilloid I ("TRPV1," formerly known as Vanilloid Receptor 1 or VR1) function in a cell, comprising contacting a cell capable of expressing TRPV1 with an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof. 10 The invention still further relates to a method for preparing a composition comprising the step of admixing a compound of formula I, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier or excipient. The invention still further relates to a kit comprising a container containing an effective amount of a compound of formula I, or a pharmaceutically acceptable 15 derivative thereof. Preferred compounds of formula I are compounds of formula II: 11E 12 Ar 1 , W'R 4 -(R3)m N> X N'R20 Ar 2 (II) or a pharmaceutically acceptable derivative thereof, where the dashed line, W, X, Ar 1 , 5 Ar 2 , R 3 , R 4 , R 2 0 , and m are as defined above for compounds of formula I, wherein Q is J

Z

2

Z

3 Z, is -OH, -SH, -N(R2 0

)

2 , -CH 2 -OH, -CH 2 -SH, or -CH-N(R 20

)

2 ; 10 Z 2 is -H, -CH 3 , or -CH 2 -0R 7 ; each Z 3 is independently -H or -CH 3 ; and J is -OH, -SH, or -N(R20) 2 . Compounds of formula I are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2, are very potent at the TRPV I receptor, have good bioavailability, and have a 15 good therapeutic index. Preferred compounds of formula I are compounds of formula III: Aris W R 4 (R3)m N X N'H Ar 2 (Ill) 20 or a pharmaceutically acceptable derivative thereof, where the dashed line, W, X, Arl, Ar 2 , R 3 , R 4 , and m are as defined above for compounds of formula I, wherein Arl is: HO OH R1N

R

1 is -Cl, -F, or -CF3; wherein Ar 2 is: 5 N N S OF1 ,

CF

3 O, O0CF '3SO 2 CF 3 or

CF

3

R

8

R

9

R

14 is -H, -Cl, -F, -Br, -OCF 3 , -(Ci-C 6 )alkyl, -SO 2

CF

3 , -S0 2 (Ci-C 6 )alkyl,

-OCH

3 , -OCH 2

CH

3 , or -OCH(CH 3

)

2 , and preferably is -CF 3 , -OCF 3 , -Cl, or -F; 10 R 14 . is -H, -Cl, -F, -Br, -CH 3 , -CH 2

CH

3 , -OCH 3 , -OCF 3 , or -OCH 2

CH

3 ; and each R 8 and R 9 is independently -H, -Cl, -Br, -F, -CH 3 , -OCH 3 , -OCH 2

CH

3 ,

-CF

3 , -OCF 3 , iso-propyl, or tert-butyl. Compounds of formula III are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2, are exceptionally potent at TRPV1 receptors, have excellent 15 bioavailability, have a high therapeutic index, and are believed to be highly efficacious in animals for the treatment of pain. The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non limiting embodiments of the invention. 20 Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. 13 BRIEF DESCRIPTION OF THE FIGURES Fig 1. 96-well plate with different agonist solutions (Agonist Plate). Seven different 5 sulfuric acid solutions, or agonist solutions, with different sulfuric acid (H 2

SO

4 ) concentrations (of from 15.0 mM to 18 mM as indicated) were used for the pH assay as indicated. For the wells in row A, measuring buffer alone was used. The final 13A 14 concentration of sulfuric acid in the wells for each row, after a 1:4 dilution of the agonist solution, is also indicated in each row in parenthesis. Fig 2. pH dependent Ca 2 responses in TRPVI/CHO cells. Ca2+ influx into 5 TRPVI/CHO cells as measured by Fura-2 AM fluorescence is indicated by the graph within each rectangular field. The graph presents the fluorescence intensity over time starting from the addition of agonist solution. Each rectangular field presents one experiment performed in one well of a 96-well plate. Each row presents six experiments performed at the same final sulfuric acid concentration; the final sulfuric acid 10 concentration is indicated at the left. Actual pH values were measured after the experiment and are indicated above the graph. No antagonists were added to the cell culture. Final sulfuric acid concentrations of 3.2 and 3.3 mM produced an appropriate Ca 2+ response and were selected for subsequent assays. These final sulfuric acid concentrations can be obtained by 1:4 dilutions of agonist solution with sulfuric acid 1 5 concentrations of 16.0 mM or 16.5 mM, respectively (see Fig. 1). Fig 3. (A) A 96-well plate with two different sulfuric acid concentrations. Wells in columns I to 6 had one final sulfuric acid concentration; wells in columns 7 to 12 had a different final sulfuric acid concentration. The final sulfuric acid concentration was 20 reached by 1:4 dilution of two different agonist solutions with sulfuric acid concentrations of X mM and (X + 0.5) mM, respectively. In the experiment described in Section 2 of Protocol 2, X was determined to be 16 mM. (B) A 96-well plate with different test compound, or antagonist, concentrations indicated in nM. Only one kind of test compound was applied per 96-well plate. Since two different sulfuric acid 25 concentrations were used (columns 1-6 vs. columns 7-12), seven wells were tested for each combination of test compound concentration and agonist solution (e.g., wells Al, BI, C1, El, Fl, GI, and H I were tested for test compound concentration 0.977 nM and agonist solution with sulfuric acid solution X mM). The wells in row D did not include an antagonist in order to measure the maximal Ca 2 + response. 30 15 5. DETAILED DESCRIPTION OF THE INVENTION 5.1 COMPOUNDS OF FORMULA I 5 The invention encompasses compounds of formula 1: ArW..

R

4 -(R3)m N) X N'-R20 Ar 2 (I) 10 or a pharmaceutically acceptable derivative thereof, where W, X, Ar 1 , Ar 2 , R 3 , R 4 , Rao, and m are as defined above for compounds of formula I. Certain embodiments of fonnula I are presented below. In one embodiment, a compound of formula I is a pharmaceutically acceptable 15 derivative of a compound of formula 1. In another embodiment, a compound of formula I is a compound of formula I whererein the derivative is a pharmaceutically acceptable salt. In another embodiment, a compound of formula I is a pharmaceutically acceptable salt of a compound of formula 1. 20 In another embodiment, Ari is a pyridyl group. In another embodiment, Arl is a pyrimidinyl group. In another embodiment, Ari is a pyrazinyl group. In another embodiment, Ari is pyridazinyl group. In another embodiment, W is C. 25 In another embodiment, W is N. In another embodiment, X is 0. In another embodiment, X is S. In another embodiment, X is N-CN. In another embodiment, X is N-OH.

16 In another embodiment, X is N-OR 1 0 . In another embodiment, Ar 2 is a benzoimidazolyl group. In another embodiment, Ar 2 is a benzothiazolyl group. In another embodiment, Ar 2 is a benzooxazolyl group. 5 In another embodiment, Ar 2 is N (Rl 4 )q In another embodiment, Ar, is 10 N

(R

1 4 )q In another embodiment, Ar 2 is 15 (R A In another embodiment, Ar 2 is N\ (Rl )q 20 In another embodiment, Ar 2 is 17 5 (Ri)r In another embodiment, Ar 2 is N R 2 1 N 5 In another embodiment, Ar2 is N, R21 10 In another embodiment, Ar 2 is 0 15 In another embodiment, n or p is 1. In another embodiment, n or p is 2. In another embodiment, n is 3. In another embodiment, m is 2. In another embodiment, each R 3 is independently -H, or (CI-C 6 )alkyl.

18 In another embodiment, two R 3 groups together form a (C 2

-C

6 )bndge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge. In another embodiment, two R 3 groups together form a (C 2

-C

6 )bridge, which is 5 unsubstituted or substituted with an R 8 group, and which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge. In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains -HC=CH- within the (C 2

-C

3 )bridge. 10 In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted and which bridge optionally contains -HC=CH- within the (C 2 -C3)bridge. In another embodiment, two R 3 groups together form a (C 2 )bridge, a -HC=CH bridge, or a (C 3 )bridge each of which is unsubstituted. In another embodiment, two R 3 groups together form a (C-C 6 )bridge, which is 15 unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (C-C 6 )bridge, which is unsubstituted or substituted with an Rg group, which bridge optionally contains 20 -HC=CH- within the (C-C 6 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains -HC=CH- within the (C-C3)bridge, and which bridge joins positions 2 and 6 of the 25 piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted, which bridge optionally contains -HC=CH- within the (C 2

-C

3 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. 30 In another embodiment, two R 3 groups together form a (C 2 )bridge, a -HC=CH bridge, or a (C 3 )bridge each of which is unsubstituted, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a -CH 2

-N(R.)-CH

2 - bridge (BI), a 19 Rb Rb -- C N-CH 2 - bridge (B2), or a - CH 2

-N-CH

2 - bridge (B3); wherein Ra is selected from -H, -(CI-C 6 )alkyl, -(C 3

-C

8 )cycloalkyl, -CH 2

-C(O)

Rc, -(C H 2 )-C(0)-ORc, -(CH 2 )-C(O)-N(Rc) 2 , -(CH 2

)

2 -O-Re, -(CH 2

)

2

-S(O)

2 -N(Rc) 2 , or 5 -(CH 2

)

2 -N(Re)S(O) 2 -Rc; RI is selected from: (a) -H, -(CI-C 6 )alkyl, -(C 3 -Cg)cycloalkyl, -(3- to 7 membered)heterocycle, -N(Re) 2 , -N(Re)-(C 3 -Cs)cycloalkyl, or -N(Re)-(3- to 7 membered)heterocycle; or 10 (b) -phenyl, -(5- or 6-membered)heteroaryl, -N(Rc)-phenyl, or -N(Rc)-(5 to I 0-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups; and each Re is independently selected from -H or -(C 1 -C4)alkyl; In another embodiment, the BI, B2, or B3 bridge joins positions 2 and 6 of the 15 piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups form a bicyclo group to give one of the following structures, Ar 1 sW R 4 Ar 1 sW R 4 or N N X NR20 X NR20 Ar 2 Ar 2 20 In another embodiment, m is 1. In another embodiment, m is 0. In another embodiment, s or q is 0. In another embodiment, s or q is 1. 25 In another embodiment, s or q is 2.

20 In another embodiment, R, is -H. In another embodiment, R, is -halo. In another embodiment, R, is -Cl. In another embodiment, R, is -F. 5 In another embodiment, R, is -CH 3 . In another embodiment, R, is -NO 2 . In another embodiment, R, is -CN. In another embodiment, R, is -OH. In another embodiment, R, is -OCH 3 . 10 In another embodiment, R, is -NH 2 . In another embodiment, R, is -C(halo) 3 . In another embodiment, R, is -CF 3 . In another embodiment, R, is -CH(halo) 2 . In another embodiment, R, is -CH 2 (halo). 15 In another embodiment, Ari is a pyridyl group and n is 1. In another embodiment, Ari is a pyrazinyl group and p is 1. In another embodiment, Ari is a pyrimidinyl group and p is 1. In another embodiment, Arl is a pyridazinyl group and p is 1. In another embodiment, when n and p are 1, then R 2 must be Q. 20 In another embodiment, Q is J J Z ~ 3Z Z Z 3 0 4 Z3 0 O HN' .-- R20 Z H Z3 Z 3 0 H 0 0N0 H N R O H,.. Si 20 R20 N R 20 Z3z 3 Z3Z 3 orZ In another embodiment, Q is 21 J 0 J 0 Z2 Z 0 Z4 Z 3 z Z 3

Z

3 ~ or ~~ In another embodiment, Q is J J 5 Z 23, Z Z3 or Z 3 In another embodiment, Q is J Z Z 2 3 or Z 3 10 In another embodiment, Q is J or Z3 15 In another embodiment, Q is 22 0 J 0 O Z 4 Z O Z 3 Z 2 ZZ N Zz 3 Z Z 3

Z

3 0 0 0 H::S-SR0

R

20 y o Z 3 ~ O H

HN'R

20 H N R 20 R20 z 3 Z3z ZI Z Z3 0 , Z: Z3 or Z Z3 In another embodiment, Q is J O Z4 0 Z

±Z

3 0 -- R20 N R20 Z Nf H Z Z 3 Nf H 0 H R0 Hs A O2 N, HN'R20 2 ZZ Z3,Z or Z2 5 Z3 0 , Z:Z2o Z3 5 In another embodiment, Q is 23 00 0 0 O0Z.--R 20 'N'R2 0 R 2 0 0 H HNR20 N R 20 R2

Z

3 o 5N Z3HorZ Z3 In another embodiment, Q is 0 H0 O R0HN' R20 H N R20 0 N R20 NHZ3 0 ,:2 Z 3 or Z Z3 N10 2 In another embodiment, Q is Z0 H 15 In aoro Hin QRs0 In ~ anohe embdimntQ i 1 5 In another embodiment, Q is 24 J Z Z 3 In another embodiment, Q is 50 Z4 5 2 In another embodiment, Q is 0 10 In another embodiment, Q is OZ3 15 In another embodiment, Q is 0

Z

2 Z Z3 In another embodiment, J is -OR 20 , -SR 2 0 or -N(R 2 0

)

2 . 20 In another embodiment, J is -OR 2 0 . In another embodiment, J is -OH. In another embodiment, J is -CN. In another embodiment, Z, is -H. In another embodiment, Z, is -OH.

25 In another embodiment, Zi is -OCH 3 . In another embodiment, Z, is -CH 2 OH. In another embodiment, Z 2 is -CH 2

-OR

7 . In another embodiment, Z 2 is -CH 2 OH. 5 In another embodiment, Z 2 is -H, -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -(Cr

C

6 )alkynyl, -phenyl, or -halo. In another embodiment, Z 2 is -H. In another embodiment, Z 2 is -CH 3 . In another embodiment, Z 3 is -H. 10 In another embodiment, Z 3 is -CH 3 . In another embodiment, Z 4 is -H. In another embodiment, Z 4 is -(C I-C 6 )alkyl. In another embodiment, Z 4 is -N(R 20

)

2 . In another embodiment Z 4 is -OR 2 0 . 15 In another embodiment, Z 4 is -OH. In another embodiment, Q is H OH H NH 2 N0 OH OH OH OH OH OH HO HO HO± HO OH N OH OH OH F HO , H O OH O=S=O OH O or NH 20 In another embodiment, Q is 26 -f , jL ,fLH 1 or In another embodiment, Q is OH OH OH OH OH OH HO HO HO HO OH N OH OH OH H o 0 OH In another embodiment, Q is OH OH OH OH OH OH OH OH HO HO HO,, HO or OH 10 In another embodiment, Q is OH OH OH OH OH OH HO Hj HO HO or 15 In another embodiment, Q is OH OH OH OH HOW HO,) HO.o) HO? or In another embodiment, Q is 27 0 0 O O H O O H o O In another embodiment, Q is O=s=O NH 51 In another embodiment, m is I and R 3 is -(CI-C 6 )alkyl. In another embodiment, m is I and R 3 is -CH 3 . In another embodiment, n is 0. 10 In another embodiment, R 4 is -OH. In another embodiment, R 4 is -OCF 3 In another embodiment, R 4 is -halo. In another embodiment, R 4 is -F. In another embodiment, R 4 is -Cl. 15 In another embodiment, R 4 is -(C-C 6 )alkyl. In another embodiment, R 4 is -CH 3 . In another embodiment, R 4 is -CH 2 OH. In another embodiment, R4 is -CH 2 Cl. In another embodiment, R 4 is -CH 2 Br. 20 In another embodiment, R 4 is -CH 2 1 In another embodiment, R 4 is -CH 2 F. In another embodiment, R 4 is -CH(halo) 2 . In another embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -NO 2 . 25 In another embodiment, R 4 is -ORIO. In another embodiment, R 4 is -SR, 0 . In another embodiment, R 4 is -C(O)R1 0 . In another embodiment, R 4 is -COOH. In another embodiment, R 4 is -C(O)H.

28 In another embodiment, R 4 is -COORio. In another embodiment, R 4 is -OC(O)Rio. In another embodiment, R 4 is -S0 2 RIO. In another embodiment, R 4 is -OC(O)NHR 1 o. 5 In another embodiment, R 4 is -NHC(O)R, 3 . In another embodiment, R 4 is -CON(Ri 3

)

2 . In another embodiment, each R 20 is independently -H or -(Ci-C 6 )alkyl. In another embodiment, each R 2 o is -H. In another embodiment, each R 2 0 is -(CI-C 6 )alkyl. 10 In another embodiment, Ar, is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is -H. In another embodiment, Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is not -H. In another embodiment, Ar 2 is a benzothiazolyl, benzoimidazolyl, or 15 benzooxazolyl group; and at least one of R 8 and Rq is -halo. In another embodiment, Ar 2 is

(R

14 )s 20 s is I and R1 4 is -(CI-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -S0 2

R

7 , or

-SO

2 C(halo)3. In another embodiment, Ar 2 is (R64)S 25 s is 2, and each R 1 4 group independently is -(CI-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 ,

-OR

7 , -N(R 7

)

2 , -SO 2

R

7 , or -SO 2 C(halo) 3 . In another embodiment, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 29 Z±Z3 wherein J is -OR2O. In another embodiment, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is J Z Z 3 z 2

Z

3 5 wherein J is -OR 20 and ZI is -OR 7 . In another embodiment, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is J zi Z 3 2 : Z 3 10 wherein J is -ORao and Zi is -CH2OR 7 . In another embodiment, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 15 wherein Z 4 is -OR2 0 . In another embodiment, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 20 -~ wherein J is -OH. In another embodiment, R 4 is -halo, n or p is I, R 2 is Q, wherein Q is 30 J ZI Z 3 2 : Z 3 wherein J is -OH and Z, is -OH. In another embodiment, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 5 J Z Z 3 2 : Z 3 wherein J is -OH and Zi is -CH 2 OH. In another embodiment, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 10 J Z Z 3 2 f Z 3 wherein J is -OH and Z, is -OH. In another embodiment, R4 is -F, n or p is 1, R 2 is Q, wherein Q is 15 J

Z

2

Z

3 wherein J is -OH and Z, is -CH 2 OH. In another embodiment, R, is -halo, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 20 Z fZ3 wherein J is -OR 20 . In another embodiment, R, is -halo, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 31 J Z

Z

3 wherein J is -OR 2 0 and Zi is OR7. In another embodiment, R, is -halo, R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is 5 J Z Z 3 2 : Z 3 wherein J is -OR2o and Z, is -CH 2

OR

7 . In another embodiment, R, is -halo, R 4 is -halo, n or p is 1, R2 is Q, wherein Q is 10 O Z4 wherein Z 4 is -OR 20 . In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 15 Z Z3 wherein J is -OR 20 . In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 20 J Z Z 3 2 : Z 3 wherein J is -OR 20 and Z, is -OR 7 . In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 32 Z Z 3 2 : Z 3 wherein J is -OR 20 and Z, is -CH 2 0R 7 . In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 5 0 Z4 wherein Z 4 is -OR 20 . In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 10 Z~e Z3 wherein J is -OH. In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 15 ZZ3 wherein I is -OH and Z, is -OH. In another embodiment, R, is -Cl, R 4 is -F, n or p is 1, R 2 is Q, wherein Q is 20 J Z Z 3 2 : Z 3 wherein J is -OH and Zi is -CH 2 OH. In another embodiment, Arl is a pyridyl group, wherein n is 1, and R 2 is Q. 25 In another embodiment, Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 33 wherein J is -OH. In another embodiment, Arl is a pyridyl group, wherein n is I, R 2 is Q, and Q is 5 J Z Z 3 wherein J is -OR 20 , and Z, is -OR 7 . In another embodiment, Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 10 ZI Z 3 wherein J is -OH, and Z, is -OH. In another embodiment, Ari is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 15 J Z Z 3 wherein J is -OR 20 , and Z, is -CH 2

OR

7 . In another embodiment, Ari is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 20 J zi Z 3 Z Z3 wherein J is -OH, and Z, is -CH 2 OH. In another embodiment, Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 34 O Z4 wherein Z 4 is -OR 20 . In another embodiment, R, is -halo, R 4 is -halo, and Arl is a pyridyl group, 5 wherein n is 1, R2 is Q, and Q is J

Z

2

Z

3 wherein J is -OR 2 0 , ZI is -OR 7 . 10 In another embodiment, R, is -halo, R 4 is -halo, and Arl is a pyridyl group, wherein n is 1, Ri is Q, and Q is J

Z

2

Z

3 15 wherein J is -OH, Z, is -OH. In another embodiment, R, is -halo, R4 is -halo, and Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is J zi Z 3

Z

2

Z

3 20 wherein J is -OR 20 , ZI is -CH 2 0R 7 . In another embodiment, R, is -halo, R4 is -halo, and Arl is a pyridyl group, wherein n is 1, R, is Q, and Q is 35 J Z Z3 wherein J is -OH, Z, is -CH 2 OH. In another embodiment, Ri is -halo, R4 is -halo, and Arl is a pyridyl group, 5 wherein n is 1, R 2 is Q, and Q is J Z Z3 2 : Z 3 wherein J is -OH, Z, is -OH, Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is 10 not -H. In another embodiment, R, is -halo, R 4 is -halo, and Ar is a pyridyl group, wherein n is 1, R2 is Q, and Q is J

Z

2

Z

3 15 wherein J is -OH, Z, is -CH 2 OH, Ar 2 is benzothiazolyl, wherein at least one of R 8 or R is not -H. In another embodiment, R, is -halo, R4 is -halo, and Ari is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 20 J Z Z 3 2 : Z 3 wherein J is -OH, Z, is -OH, Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not -H. 25 In another embodiment, R, is -halo, R4 is -halo, and Ar is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 36 J Z Z 3 wherein J is -OH, Z, is -CH 2 OH, Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not -H. 5 In another embodiment, R, is -halo, R 4 is -halo, and Ar is a pyridyl group, wherein n is I, R 2 is Q, and Q is Z3 Z2 Z3 10 wherein J is -OH, Z, is -OH, Ar 2 is benzoimidazolyl, wherein at least one of R 8 or Rq is not -H. In another embodiment, R, is -halo, R4 is -halo, and Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is J Z1 Z 3

Z

2

Z

3 15 wherein J is -OH, Z, is -CH2OH, Ar 2 is benzoimidazolyl, wherein at least one of R 8 or

R

9 is not -H. In another embodiment, R, is -halo, R4 is -halo, and Ar, is a pyridyl group, 20 wherein n is 1, R 2 is Q, and Q is J Z Z 3 2 f Z 3 wherein J is -OH, Z, is -OH, Ar 2 is phenyl, wherein s is 0 or 1. 25 In another embodiment, R, is -halo, R4 is -halo, and Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 37

Z

2

Z

3 wherein J is -OH, ZI is -CH 2 OH, Ar 2 is phenyl, wherein s is 0 or 1. In another embodiment, RI is -halo, R 4 is -halo, and Arl is a pyridyl group, 5 wherein n is 1, R 2 is Q, and Q is J Z Z 3 2 : Z 3 wherein J is -OH, ZI is -OH, Ar 2 is phenyl, wherein s is 2. 10 In another embodiment, R, is -halo, R 4 is -halo, and Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is J Zi Z 3 15 wherein J is -OH, ZI is -CH 2 OH, Ar 2 is phenyl, wherein s is 2. In another embodiment, the dashed line is a double bond, n or p is 1, R 2 is Q, wherein Q is 20 wherein J is -OR 20 . In another embodiment, the dashed line is a double bond, n or p is 1, R 2 is Q, wherein Q is J Z Z 3 z 2

Z

3 38 wherein J is -OR 20 and Zi is OR 7 . In another embodiment, the dashed line is a double bond, n or p is I, R2 is Q, wherein Q is J Zi 3 5Z: Z3 5 wherein J is -OR 2 0 and Z, is -CH2OR 7 . In another embodiment, the dashed line is a double bond, n or p is 1, R 2 is Q, wherein Q is 10 0 Z4 wherein Z 4 is -OR 20 . In another embodiment, the dashed line is a double bond, n or p is 1, R 2 is Q, 15 wherein Q is Z~w Z3 wherein J is -OH. 20 In another embodiment, the dashed line is a double bond, n or p is 1, R 2 is Q, wherein Q is J

Z

2

Z

3 wherein J is -OH and Zi is -OH. In another embodiment, the dashed line is a double bond, n or p is 1, R 2 is Q, 25 wherein Q is 39 Z Z 3 2 : Z 3 wherein J is -OH and ZI is -CH 2 OH. In another embodiment, the dashed line is a double bond, R, is -halo, n or p is 1, 5 R 2 is Q, wherein Q is Z fZ3 Z1~1 wherein J is -OH. 10 In another embodiment, the dashed line is a double bond, R, is -halo, n or p is 1,

R

2 is Q, wherein Q is J

Z

2

Z

3 15 wherein J is -OH and Z, is -OH. In another embodiment, the dashed line is a double bond, RI is -halo, n or p is 1,

R

2 is Q, wherein Q is J Z Z 3 2 f Z 3 20 wherein J is -OH and ZI is -CH 2 OH. In another embodiment, the dashed line is a double bond, R, is -halo, and Ar is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 40 J Z

Z

3 wherein J is -OH, Zi is -OH. In another embodiment, the dashed line is a double bond, R 1 is -halo, and Ari is 5 a pyridyl group, wherein n is 1, R 2 is Q, and Q is J

Z

2

Z

3 wherein J is -OH, Z, is -CH 2 OH. 10 In another embodiment, the dashed line is a double bond, R, is -halo, and Ar, is a pyridyl group, wherein n is 1, R 2 is Q, and Q is ZI Z 3 15 wherein J is -OH, ZI is -OH Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not a -H. In another embodiment, the dashed line is a double bond, R, is -halo, and Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is J Zi 3

Z

2 : Z 3 20 wherein J is -OH, Z, is -CH 2 OH, Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not a -H. In another embodiment, the dashed line is a double bond, R, is -halo, and Ari is 25 a pyridyl group, and Q is 41 J

Z

2

Z

3 wherein J is -OH, Z, is -OH Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not a -H. 5 In another embodiment, the dashed line is a double bond, R, is -halo, and Ar, is a pyridyl group, wherein n is 1, and Q is J

Z

2

Z

3 10 wherein J is -OH, Z, is -CH 2 OH, Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not a -H. In another embodiment, the dashed line is a double bond, R, is -halo, and Ar, is a pyridyl group, wherein n is I, R 2 is Q, and Q is J Zi 3

Z

2

Z

3 15 wherein J is -OH, Z, is -OH, Ar 2 is benzoimidazolyl, wherein at least one of R3 or R 9 is not a -H. In another embodiment, the dashed line is a double bond, R, is -halo, and Ar is 20 a pyridyl group, wherein n is 1, R 2 is Q, and Q is J z 3

Z

2

Z

3 wherein J is -OH, Z, is -CH 2 OH, Ar 2 is benzoimidazolyl, wherein at least one of R 8 or 25 R 9 is not a -H.

42 In another embodiment, the dashed line is a double bond, R, is -halo, and Ar is a pyridyl group, wherein n is 1, R 2 is Q, and Q is J Z Z 3 2 : Z 3 5 wherein J is -OH, ZI is -OH Ar 2 is phenyl, wherein s is 0 or I and R1 4 is -(CI-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -SO 2

R

7 , or -SO 2 C(halo) 3 , and preferably is -F, -Cl, -CF 3 , or -OCF 3 . In another embodiment, the dashed line is a double bond, R, is -halo, and Ar is 10 a pyridyl group, wherein n is 1, R 2 is Q, and Q is J Z Z 3 2 : Z 3 wherein J is -OH, ZI is -CH 2 OH, Ar 2 is phenyl, wherein s is 0 or I and R 14 is -(C 15 C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR7, -N(R 7

)

2 , -SO 2 R7, or -SO 2 C(halo) 3 , and preferably is -F, -Cl, -CF 3 , or -OCF3.. In another embodiment, the dashed line is a double bond, R, is -halo, and Ar is a pyridyl group, wherein n is 1, R 2 is Q, and Q is J Zi Z 3

Z

2

Z

3 20 wherein J is -OH, ZI is -OH Ar 2 is phenyl, wherein s is 2, and each R 1 4 is independently

-(CI-C

6 )alkyl, -halo, -C(halo)3, -OC(halo) 3 , -OR7, -N(R 7

)

2 , -SO 2 R7, or -SO 2 C(halo) 3 , and preferably is -F, -Cl, -CF 3 , or -OCF3.. 25 In another embodiment, the dashed line is a double bond, R, is -halo, and Arl is a pyridyl group, wherein n is 1, R 2 is Q, and Q is 43 J Z Z 3 wherein J is -OH, Z, is -CH 2 OH, Ar 2 is phenyl, wherein s is 2, and each R 14 is independently -(Ci-C 6 )alkyl, -halo, -C(halo)3, -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -SO 2

R

7 , or 5 -SO 2 C(halo) 3 , and preferably is -F, -Cl, -CF 3 , or -OCF 3 .. In another embodiment Q is HO OH 10 wherein the compound of formula I is racemic. In another embodiment Q is HO OH HO,., OH and 1 5 wherein the % ee of the R enantiomer is greater than 60%. In another embodiment Q is HO OH HO,, OH and ~ 20 wherein the % ee of the R enantiomer is greater than 70%. In another embodiment Q is HO OH HO,.. OH and ~' , 25 wherein the % ee of the R enantiomer is greater than 80%. In another embodiment Q is 44 HO OH HO,' OH and wherein the % ee of the R enantiomer is greater than 90%. In another embodiment Q is 5 HO OH HO,. OH and wherein the % ee of the R enantiomer is greater than 99%. In another embodiment Q is 10 HO OH HO,,. OH and wherein the % ee of the S enantiomer is greater than 60%. In another embodiment Q is 15 HO OH HO OH and wherein the % ee of the S enantiomer is greater than 70%. In another embodiment Q is 20 HO OH HO OH and wherein the % ee of the S enantiomer is greater than 80%. In another embodiment Q is 25 HO OH HO,'. OH and ~ 45 wherein the % ee of the S enantiomer is greater than 90%. In another embodiment Q is HO OH HO,,. OH and 5 wherein the % ee of the S enantiomer is greater than 99%. In another embodiment, the invention encompasses compounds of formula I.4: Ar 1 . W R 4 -- (R36m N> X N' R20 Ar 2 10 (1.4) or a pharmaceutically acceptable salt thereof, where X is 0, S, N-CN, N-OH, or N-ORio; W is N or C; 15 the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R 4 is -H, -OH,

-OCF

3 , -halo, -(CI-C 6 )alkyl, -CH 2 OH, -CH 2 CI, -CH 2 Br, -CH 2 1, -CH 2 F, -CH(halo) 2 , CF 3 , -ORio, -SRjo, -COOH, -COORo, -C(O)Ro, -C(O)H, -OC(O)Rio, -OC(O)NHRo. NHC(O)R 1 3. -CON(R 1 3

)

2

.-S(O)

2

R

0 , or -NO 2 ; 20 Rio is -(Ci-C 4 )alkyl; each R 1 3 is independently: -H, -(Ci-C 4 )alkyl, -(Ci-C 4 )alkenyl, -(Ci-C 4 )alkynyl, or -phenyl; Arn is 46

(R

2 )n (R 2 )n (R2).N R2)n N R1,'R R1, R1 N (R2)\ N (R 2 )P 1 j(R2)P N or N Ar2 is Ni N-R20 N S NJ 0

-(R

4 ) Y R12a1) R" 0 \ ( , /3) Ri 2 a

R

8

R

9

R

8

R

9

R

8

R

9

-(R

1 4 ) -(R4)t

Y

2 Y2 E (Y3)c (Y3)c NN N N or (R14)q (R14)q (R14)q (R 14 )s (Rii)r 5 c is the integer 0, 1, or 2; YI, Y 2 , Y 3 are independently C, N, or 0; wherein no more than one of Y 1 , Y 2 , or Y3 can be 0, and for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R 21 group, and for each YI, Y 2 , and Y 3 that is C, the C is 47 bonded to two R 20 groups, provided that there are no more than a total of two (C 1 C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ; R1 2 a and R12b are independently -H or -(CI-C 6 )alkyl; E is =0, =S, =C(CI-Cs)alkyl, =C(CI-Cs)alkenyl, =NH(Ci-C 6 )alkyl, or =N-OR 20 ; 5 R, is -H, -halo, -(CI-C4)alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , or -OCH 2 (halo); each R 2 is independently: (a) -halo, -OH, -O(CI-C 4 )alkyl, -CN, -NO, -NH 2 , -(CI-Clo)alkyl, -(C 2 CIo)alkenyl, -(C 2 -CIo)alkynyl, -phenyl, or 10 (b) a group of formula Q; wherein Q is J J Z3i Z3,Z Z 3 Z4 O± Z 2 : Z 3 , 2Cj, 3Z 0 OyR~O O R20 HN' R20 Ozz---I__R20 NH ,NH

Z

3 jjj Z3ZJ O z 3 j3 0 H N~ ~ R 2 H.. .S SN R20 R20 H S R 20 Z:L Z3 Z2

Z

3 or Z 2 Z3 15 Z, is -H, -OR 7 , -SR 7 , -CH 2 -OR,, -CH 2

-SR

7 , -CH 2

-N(R

2 0

)

2 , or -halo;

Z

2 is -H, -(CI-C 6 )alkyl, -(C-C)alkenyl, -(C 2

-C

6 )alkynyl, -phenyl, or -halo; each Z 3 is independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, or -phenyl;

Z

4 is -H, -OH, -OR 20 , -(Ci-C 6 )alkyl, or -NR 2 O; 20 J is -OR 20 , -SR 20 , or -N(R 2 0) 2 ; provided that at least one R 2 group is a group of formula Q, and provided that when Z, is -OR 7 or -SR 7 , then Z 2 is not -halo; each R 3 is independently: 48 (a) -H, (CI-C 6 )alkyl, or two R 3 groups form a bicyclo group to give one of the following structures, Arl,.W R 4 Arl..W R 4 or N N x NR20 X NR20 Ar 2 Ar 2 5 each R 7 is independently -H, -(C -C 6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl,

-(C

3

-C

8 )cycloalkyl, -(CS-Cs)cycloalkenyl, -phenyl, -(CI-C 6 )haloalkyl, -(C

C

6 )hydroxyalkyl, -(C,-C 6 )alkoxy(CI-C 6 )alkyl, -(C -C 6 )alkyl-N(R 2 0) 2 , or -CON(R 2 0

)

2 ; each R 8 and R 9 are independently -H, -(C,-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C, 10 C 6 )alkynyl, -(C 3 -Cs)cycloalkyl, -(C 5 -Cs)cycloalkenyl, -phenyl, -CH 2 C(halo) 3 .-C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo)3, -OCH(halo) 2 , -OCH2(halo), -O-CN, -OH, -halo,

-N

3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 . -NR 7 OH, -OR 7 , -C(O)Ry, -C(O)OR 7 , -OC(O)R 7 , -OC(O)OR7, -SR 7 , -S(O)R 7 , or -S(O)2R7; each R, I is independently -CN, -OH, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -halo, -N 3 , 15 -NO 2 , -N(R 7

)

2 , -CH=NR 7 , -NR 7 0H, -OR 7 , -C(O)R7,

-C(O)OR

7 , -OC(O)R 7 , or -OC(O)OR 7 ; each R 1 4 is independently -(C ,C 6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl, -(C 3 C8)cycloalkyl, -(CS-Cs)cycloalkenyl,-(CI-C 6 )alkoxy-(C,-C 6 )alkyl, -phenyl, C(halo) 3 , CH(halo) 2 , CH 2 (halo), -(3- to 7-membered)heterocycle, -(C 1

-C

6 )haloalkyl, -(C 2 20 C)haloalkenyl, -(C 2

-C

6 )haloalkynyl, -(C 2

-C

6 )hydroxyalkenyl, -(C-C 6 )hydroxyalkynyl, (C -C 6 )alkoxy(C 2

-C

6 )alkyl, (CI -C 6 )alkoxy(C 2

-C

6 )alkenyl, (CI -C 6 )alkoxy(C 2

-C

6 )alkynyl, -CN, -OH, -halo, OC(halo) 3 , -N 3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 , -NR 7 0H, -OR 7 , -SR 7 , O(CH2)bOR7, -O(CH 2 )bSR7, -O(CH2)bN(R7) 2 , -N(R 7

)(CH

2 )bOR 7 , -N(R 7

)(CH

2 )bSR 7 , N(R 7 )(CH2)bN(R7) 2 , -N(R 7

)COR

7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OC(O)OR, 25 -S(O)R 7 , or -S(O) 2

R

7 , -S(O) 2

N(R

7

)

2 , SO 2 C(halo) 3 , -CON(R 7

)

2 , -(C-C 5 )alkyl-C=NOR 7 , (C-C 5 )alkyl-C(O)-N(R 7

)

2 , -(C 1

-C

6 )alkyl-NHSO 2

N(R

7

)

2 , or -(C 1

-C

6 )alkyl-C(=NH) N(Re)2; each R 2 0 is independently -H or -(C -C 6 )alkyl; each R21 is independently -H, -(CI-C6)alkyl, 49

<-_N(CH

3

)

2 N or N N 0 each halo is independently -F, -Cl, -Br, or -1; n is the integer 1, 2, or 3; 5 p is the integer 1 or 2; each b is independently the integer 1 or 2; q is the integer 0, 1, 2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; 10 t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2. In another embodiment relating to formula 1.4, E is =0, =S, =CH(Ci-CS)alkyl,

=CH(C

1 -C5)alkenyl, or =N-OR 20 . In another embodiment relating to formula 1.4, E is =0, =S, or =N-OR 20 . 15 In another embodiment, the invention encompasses compounds of formula 1.3: ArisW

R

4 -(R36m N> X N'- R20 Ar 2 (1.3) 20 or a pharmaceutically acceptable salt thereof, where X is 0, S, N-CN, N-OH, or N-OR 1 0 ; W is N or C; the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R 4 is -H, -OH, 25 -OCF 3 , -halo, -(C -C 6 )alkyl, -CH 2 OH, -CH 2 CI, -CH 2 Br, -CH 2 1, -CH 2 F, -CH(halo)2, - 50

OF

3 , -O 0 o, -SR, 0 , -GOOH, -COOR if), -G(O)Rlo, -C(O)H, -OC(O)RIO, -OC(O)NHR, NHC(O)R1 3 .-CON(R13) 2 .- S(O)2R0, or -NO,-;

R,

0 is -(C 1

-C

4 )alkyl; each R1 3 is independently: -H, -(C,-C 4 )alkyl, -(C,-C 4 )alkenyi, -(CI-G 4 )alkynyl, or 5 -phenyl; Arl is (2n(R 2 )n (R2)n.N R (R)PN(R))(2)n NN V N N (R)N (R 2 )P~ NR) NN-N N N or 10 Ar 2 is 51 N N-R20 N S N o (R1)t / R12a

R

8

R

9

R

8

R

9

R

8

R

9 R12b -(R 1) (R ) E 2 (Y3)c (Y3)c , 1Ij or N (R14)q (R 1 )q (R4)q (R14)s (R11), c is the integer 0, 1, or 2; YI, Y 2 , Y 3 are independently C or N; 5 wherein for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R 2 o group, and for each YI, Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (Ci-C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ; R1 2 , and R12b are independently -H or -(CI-C 6 )alkyl; E is =0, =S, =C(Cg-Cs)alkyl, =C(CI-Cs)alkenyl, =NH(CI-C 6 )alkyl, or =N-OR 2 0 ; 10 R 1 1 is -H, -halo, -(CI-C 4 )alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , or -OCH 2 (halo); each R 2 is independently: (a) -halo, -OH, -O(CI-C 4 )alkyl, -CN, -NO 2 . -NH 2 , -(Ci-Cio)alkyl, -(C 2 Cgo)alkenyl, -(C 2

-C

1 o)alkynyl, -phenyl, or 15 (b) a group of formula Q; wherein Q is 52 J J Z3, Z3, Z3 O Z4 0± Z3 O R20 HN' R20 0 1 -- R20 Z NH Z 3 0, Z z 3 I

Z

3 NH 0 H H'NA 0 H N R 20 R 20 N R 20 Z Z3 Z Z 3 Z 3 ZL Z3 ,Z2

Z

3 or Z 2 Z3 Zi is -H, -OR 7 , -SR7, -CH 2 -OR7, -CH 2

-SR

7 , -CH,-N(R 20

)

2 , or -halo;

Z

2 is -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, -phenyl, or -halo; 5 each Z 3 is independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, or -phenyl;

Z

4 is -H, -OH, -OR 20 , -(CI-C 6 )alkyl, or -NR 2 ; J is -OR 20 , -SR 20 , or -N(R 20

)

2 ; provided that at least one R 2 group is a group of formula Q, and provided that 10 when Z, is -OR 7 or -SR 7 , then Z 2 is not -halo; each R 3 is independently: (a) -H, (CI-C 6 )alkyl, or two R 3 groups form a bicyclo group to give one of the following structures, Ar,-sW R 4 ArW' R 4 or x N'R20 x N R20 15 Ar 2 Ar 2 53 each R 7 is independently -H, -(Ci-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl,

-(C

3 -CS)cycloalkyl, -(C 5 -Cs)cycloalkenyl, -phenyl, -(CI-C 6 )haloalkyl, -(C 1 C 6 )hydroxyalkyl, -(C 1

-C

6 )alkoxy(C 1

-C

6 )alkyl, -(C,-C 6 )alkyl-N(R 2 0) 2 , or -CON(R 2 0) 2 ; each Rs and R 9 are independently -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2 5 C 6 )alkynyl, -(C 3 -C8)cycloalkyl, -(Ci-Cs)cycloalkenyl, -phenyl, -CH 2 C(halo) 3 .-C(halo) 3 , -CH(halo)2, -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , -OCH2(halo), -O-CN, -OH, -halo,

-N

3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 . -NR 7 0H, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 ,

-OC(O)OR

7 , -SR 7 , -S(O)R 7 , or -S(O)2R7; each R I I is independently -CN, -OH, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -halo, -N 3 , 10 -NO 2 , -N(R-7) 2 , -CH=NR 7 , -NR 7 0H, -OR 7 , -C(O)R, -C(O)OR 7 , -OC(O)R 7 , or -OC(O)OR?; each R1 4 is independently -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(Cr-C 6 )alkynyl, -(C 3 C 8 )cycloalkyl, -(Cs-Cs)cycloalkenyl,-(CI-C 6 )alkoxy-(CI-C 6 )alkyl, -phenyl, C(halo) 3 , CH(halo) 2 , CH 2 (halo), -(3- to 7-membered)heterocycle, -(CI-CW)haloalkyl, -(Ci 15 C 6 )haloalkenyl, -(C-C 6 )haloalkynyl, -(C 2

-C

6 )hydroxyalkenyl, -(C 2

-C

6 )hydroxyalkynyl,

(CI-C

6 )alkoxy(C 2

-C

6 )alkyl, (CI-C 6 )alkoxy(C 2

-C

6 )alkenyl, (CI-C 6 )alkoxy(C-C 6 )alkynyl, -CN, -OH, -halo, OC(halo) 3 , -N 3 , -NO 2 , -CH=NR 7 , -N(R7) 2 , -NR 7 0H, -OR 7 , -SR 7 , O(CH2)bOR7, -O(CH 2 )bSR 7 , -O(CH2)bN(R 7 )2, -N(R 7 )(CH2)bOR 7 , -N(R 7

)(CH

2 )bSR 7 , N(R 7

)(CH

2 )bN(R7)2, -N(R 7

)COR

7 , -C(O)R 7 , -C(O)OR7, -OC(O)R 7 , -OC(O)OR 7 , 20 -S(O)R7, or -S(O) 2

R

7 , -S(O) 2

N(R

7

)

2 , SO 2 C(halo)3, -CON(R 7

)

2 , -(C -Cs)alkyl-C=NOR 7 , (CI-C 5 )alkyl-C(O)-N(R7) 2 , -(Ci-C 6 )alkyl-N HSO 2 N(R7) 2 , or -(CI-C 6 )alkyl-C(=NH)

N(R

7

)

2 ; each R 20 is independently -H or -(CI-C 6 )alkyl; each halo is independently -F, -Cl, -Br, or -1; 25 n is the integer 1, 2, or 3; p is the integer I or 2; each b is independently the integer I or 2; q is the integer 0, 1, 2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; 30 s is the integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and rm is the integer 0, 1, or 2.

54 In another embodiment relating to formula 1.3, E is =0, =S, =CH(CI-C5)alkyl, =CH(CI-C,)alkenyl, or =N-OR 2 0 . In another embodiment relating to formula 1.3, E is =0, =S, or =N-OR 2 0 . In another embodiment, the invention encompasses compounds of formula 1.2: 5 Ar 1 s R 4 -(R3)m N) x R20 Ar 2 (1.2) or a pharmaceutically acceptable salt thereof, where 10 X is 0, S, N-CN, N-OH, or N-OR 1 0 ; W is N or C; the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R4 is absent, otherwise R 4 is -H, -OH,

-OCF

3 , -halo, -(CI-C 6 )alkyl, -CH- 2 OH, -CH 2 CI, -CH 2 Br, -CH 2 I, -CH 2 F, -CH(halo) 2 , 15 CF 3 , -ORIO, -SRIo, -COOH, -COORjo, -C(O)RIO, -C(O)H, -OC(O)Rio, -OC(O)NHR o.

NHC(O)R

1 3

.-CON(R

1 3

)

2 . -S(O) 2 R jo, or -NO 2 ; RIO is -(CI-C 4 )alkyl; each R13 is independently: -H, -(C,-C 4 )alkyl, -(Ci-C 4 )alkenyl, -(CI-C 4 )alkynyl, or -phenyl; 20 Arl is 55

(R

2 )n (R 2 )n - (R2)n.NR I I (R2)P '-N

(R

2 )P " (2) N (R2)P N (R 2 )P\ T(R2)P or '. Ar 2 is N~ N-R20 N.5 S N~ 0 I I12 R83) R((Y)c 5 (R1A ~- (R 4) -(R 14 )s R 1 ) c ~ ~ Y is th negr02Ir2

Y

1

,Y

2

,Y

3 re ndeenElCorN 56 wherein for each Y I, Y 2 , and Y 3 that is N, the N is bonded to one R2 0 group. and for each Yi, Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (C -C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ; R1 2 a and R12b are independently -H or -(CI-C 6 )alkyl; 5 E is =0, =S, =C(CI-C 5 )alkyl, =C(C 1 -CS)alkenyl, =NH(CI-C 6 )alkyl, or =N-OR 20 ; Ri is -H, -halo, -(C 1

-C

4 )alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo)2, or -OCH 2 (halo); each R 2 is independently: (a) -halo, -OH, -O(Ci-C 4 )alkyl, -CN, -NO 2 , -NH 2 , -(CI-Clo)alkyl, -(C 10 CIO)alkenyl, -(C 2 -Cj 0 )alkynyl, -phenyl, or (b) a group of formula Q; wherein Q is JJ Z3, 3, Z Z 1 Z3 0 Z4 0 Z3 Z NH , Z3 03 Z N 0 Y ~HN'SR2 Z3 Z3O 0 H 0 N 0 N R 20 R 20 H S R z Z3 z 2 zi3Z32 Z Z , Z2 Z3 or Z 2 15 ZI is -H, -OR 7 , -SR 7 , -CH-OR 7 , -CH-SR 7 , -CH 2

-N(R

2 0

)

2 , or -halo;

Z

2 is -H, -(Ci-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, or -phenyl; 20 Z4 is -H, -OH, -OR 20 , -(C-C 6 )alkyl, or -NR 2 0; J is -OR 20 , -SR 2 0, or -N(R 20

)

2 ; provided that at least one R 2 group is a group of formula Q, and provided that when Zi is -OR 7 or -SR 7 , then Z2 is not -halo; 57 each R 3 is independently: (a) -H, (CI-C 6 )alkyl, or two R 3 groups form a bicyclo group to give one of the following structures, Ari, W R 4 Ar 1 .,W R 4 or x NR20 X N R20 5 Ar 2 Ar 2 each R 7 is independently -H, -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl,

-(C

3

-C

8 )cycloalkyl, -(C 5 -Cs)cycloalkenyl, -phenyl, -(Ci-C 6 )haloalkyl, -(C,

C

6 )hydroxyalkyl, -(Ci-C 6 )alkoxy(CI-C 6 )alkyl, -(CI-C 6 )alkyl-N(R 2 0

)

2 , or -CON(R 20

)

2 ; 10 each R 8 and R 9 are independently -H, -(Ci-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2 C 6 )alk ynyl, -(C 3 -C8)cycloalkyl, -(C 5

-C

8 )cycloalkenyl, -phenyl, -CH 2 C(halo) 3 .-C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , -OCH 2 (halo), -O-CN, -OH, -halo,

-N

3 , -NO 2 , -CH=NR 7 , -N(R 7 ) -NR 7 OH, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 ,

-OC(O)OR

7 , -SR 7 , -S(O)R 7 , or -S(O)2R7; 15 each R11 is independently -CN, -OH, -(Ci-C)alkyl, -(C 2

-C

6 )alkenyl, -halo, -N 3 ,

-NO

2 , -N(R 7

)

2 , -CH=NR 7 , -NR 7 0H, -OR 7 , -C(O)R7,

-C(O)OR

7 , -OC(O)R 7 , or -OC(O)OR 7 ; each R 14 is independently -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, -(C 3 C 8 )cycloalkyl, -(C 5

-C

8 )cycloalkenyl,-(CI-C 6 )alkoxy-(Ci-C 6 )alkyl, -phenyl, C(halo) 3 , 20 CH(halo) 2 , CH 2 (halo), -(3- to 7-membered)heterocycle, -(CI-C 6 )haloalkyl, -(C

C

6 )haloalkenyl, -(C 2

-C

6 )haloalkynyl, -(C-C 6 )hydroxyalkenyl, -(C 2

-C

6 )hydroxyalkynyl, (C i-C 6 )alkoxy(C 2

-C

6 )alkyl, (CI-C 6 )alkoxy(C -C 6 )alkenyl, (C I-C 6 )alkoxy(C 2

-C

6 )alk ynyl, -CN, -OH, -halo, OC(halo) 3 , -N 3 , -NO 2 , -CH=NR 7 , -N(R7) 2 , -NR 7 0H, -OR 7 , -SR 7 , O(CH2)bOR 7 , -O(CH 2 )bSR 7 , -O(CH 2 )bN(R 7

)

2 , -N(R 7 )(CH2)bOR 7 , -N(R 7

)(CH

2 )bSR 7 , 25 N(R7)(CH2)bN(R?) 2 , -N(R7)COR 7 , -C(O)R 7 , -C(0)OR 7 , -OC(O)R 7 , -OC(O)OR7,

-S(O)R

7 , or -S(O) 2

R

7 , -S(O) 2

N(R

7

)

2 , SO 2 C(halo) 3 , -CON(R 7

)

2 , -(CI-C5)alkyl-C=NOR7, (Ci-C5)alkyl-C(O)-N(R 7

)

2 , -(C -C 6 )alkyl-NHSO 2

N(R

7

)

2 , or -(CI-C 6 )alkyl-C(=NH) N(R7) 2 ; each R 2 0 is independently -H or -(CI-C 6 )alkyl; 58 each halo is independently -F, -Cl, -Br, or -1; n is the integer 1, 2, or 3; p is the integer I or 2; each b is independently the integer I or 2; 5 q is the integer 0, 1, 2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2. 10 In another embodiment relating to formula 1.2, E is =0, =S, =CH(CI-CS)alkyl, =CH(CI-Cs)alkenyl, or =N-OR 20 . In another embodiment relating to formula 1.2, E is =0, =S, or =N-OR 2 0 . In another embodiment, the invention encompasses compounds of formula 1.1: ArW

'R

4

-(R

3 )m N 1 X N'R20 15 Ar 2 (I.1) or a pharmaceutically acceptable salt thereof, where X is 0, S, N-CN, N-OH, or N-ORlo; 20 W is N or C; the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R 4 is -H, -OH,

-OCF

3 , -halo, -(CI-C 6 )alkyl, -CH 2 OH, -CH 2 Cl, -CH 2 Br, -CH 2 1, -CH 2 F, -CH(halo) 2 , CF 3 , -OR 10 , -SRjo, -COOH, -COORjo, -C(O)R 1 0 , -C(O)H, -OC(O)RIO, -OC(O)NHRIo 25 NHC(O)R3. -CON(R 1 3

)

2 . -S(0) 2 RIO, or -NO 2 ;

R

10 is -(Ci-C 4 )alkyl; each R 1 3 is independently: -H, -(CI-C 4 )alkyl, -(CI-C 4 )alkenyl, -(C 1

-C

4 )alkynyl, or -phenyl; Arl is 59 (R2) (R 2 ), (R2)p N (R2)P R1 N R1, N' R1 N or R1 Ar 2 is N N-R2O N S N O R2b

R

8

R

9

R

8

R

9

R

8

R

9 -(R 14)1 (R 1)1

Y

1 ,Y1

Y

2 Y2 3)C (Y 3 )c N N or 5 (R14)q ( ) (R,4)q (R 14 )s (Rii), c is the integer 0, 1, or 2; YI, Y 2 , Y 3 are independently C or N; wherein for each YI, Y 2 , and Y 3 that is N, the N is bonded to one R 20 group, and 10 for each YI, Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (CI-C 6 )alkyl groups substituted on all of YI, Y 2 , and Y 3 ;

R

12 and R12b are independently -H or -(CI-C 6 )alkyl; E is =0, =S, =C(CI-C 5 )alkyl, =C(C 1 -Cs)alkenyl, =NH(C 1 -C 6 )alkyl, or =N-OR 2 0 ; R, is -H, -halo, -(CI-C 4 )alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , 15 -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , or -OCH 2 (halo); each R 2 is independently: 60 (a) -halo, -OH, -O(Ci-C 4 )alkyl, -CN, -NO 2

-NH

2 , -(CI-C o)alkyl, -(C 2 C o)alkenyl, -(C -CIo)alkynyl, -phenyl, or (b) a group of formula Q; wherein Q is 5 J J z i z Z 3 Z 3 O Z 4 0 Z O R20 HN R 2 0 O -R 2 0

Z

3 NH ZNH3 0 H 0 N.0 H,N RO H S 20 R20 N R 2 0

Z

2 , Z Z , ZI is -H, -OR 7 , -SR 7 , -CH 2

-OR

7 , -CH 2

-SR

7 , -CH 2

-N(R

2 0

)

2 , or -halo;

Z

2 is -H, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -(C 2

-C

6 )alkynyl, -phenyl, or -halo; 10 each Z 3 is independently -H, -(CI-C 6 )alkyl, -(Cr-C 6 )alkenyl, -(Cr-C 6 )alkynyl, or -phenyl;

Z

4 is -H, -OH, -ORio, -(CI-C 6 )alkyl, or -NR 2 0; J is -OR 20 , -SR 2 a, or -N(R 20 )2; provided that at least one R 2 group is a group of formula Q, and provided that 15 when Z, is -OR 7 or -SR 7 , Z 2 in not -halo; each R 3 is independently: (a) -H, (Ci-C 6 )alkyl, or two R 3 groups may form bicyclo group, which gives the following structures, 61 ArlW 'R 4 ArlW ' R 4 or N N R20 X 'R2O Ar 2 Ar 2 each R 7 is independently -H, -(Ci-C 6 )alkyl, -(Cl-C 6 )alkenyl, -(C 2

-C

6 )alkynyl,

-(C

3 -Cs)cycloalkyl, -(Cs-Cs)cycloalkenyl, -phenyl, -(Ci-C 6 )haloalkyl, -(C 1 5 C 6 )hydroxyalkyl, -(CI-C 6 )alkoxy(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl-N(R 20

)

2 , or -CON(R 2 0

)

2 ; each R 8 and R9 are independently -H, -(CI-C 6 )alkyl, -(C 2 -C6)alkenyl, -(C 2 C 6 )alkynyl, -(C 3

-C

8 )cycloalkyl, -(CS-Cs)cycloalkenyl, -phenyl, -CH 2 C(halo) 3 .-C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , -OCH 2 (halo), -O-CN, -OH, -halo,

-N

3 , -NO 2 , -CH=NR7, -N(R7) 2 . -NR 7 OH, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)Ry, 10 -OC(O)OR 7 , -SR 7 , -S(O)R 7 , or -S(0) 2 R?; each R is independently -CN, -OH, -(CI-C 6 )alkyl, -(C 2

-C

6 )alkenyl, -halo, -N 3 ,

-NO

2 , -N(R 7

)

2 , -CH=NR 7 , -NR 7 OH, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , or

-OC(O)OR

7 ; each R 14 is independently -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2

-C

6 )alkynyl, -(C 3 15 Cs)cycloalkyl, -(C 5

-C

8 )cycloalkenyl,-(CI-C 6 )alkoxy-(Ci-C 6 )alkyl, -phenyl, C(halo) 3 , CH(halo) 2 , CH 2 (halo), -(3- to 7-membered)heterocycle, -(CI-C 6 )haloalkyl, -(C 2 C 6 )haloalkenyl, -(C 2

-C

6 )haloalkynyl, -(C 2

-C

6 )hydroxyalkenyl, -(C 2

-C

6 )hydroxyalkynyl, -(C -C 6 )alkoxy(C 2

-C

6 )alkyl, -(C -C 6 )alkoxy(C 2

-C

6 )alkenyl, -(CI-C 6 )alkoxy(C 2 C 6 )alkynyl, -CN, -OH, -halo, OC(halo) 3 , -N 3 , -NO 2 , -CH=NR 7 , -N(R 7

)

2 , -NR 7 OH, -OR 7 , 20 -SR 7 , -O(CH2)bOR7, -O(CH 2 )bSR 7 , -O(CH2)bN(R 7

)

2 , -N(R 7 )(CH?)bOR 7 , N(R 7 )(CH2)bSR 7 , -N(R 7

)(CH

2 )bN(R7) 2 , -N(R 7

)COR

7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 ,

-OC(O)OR

7 , -S(O)R 7 , or -S(0) 2

R

7 , -S(0) 2

N(R

7

)

2 , SO 2 C(halo) 3 , -CON(R 7

)

2 , -(Ci

C

5 )alkyl-C=NOR 7 , -(CI-C 5 )alkyl-C(O)-N(R) 2 , -(Ci-C 6 )alkyl-NHSO 2

N(R

7

)

2 , or -(C|

C

6 )alkyl-C(=NH)-N(R 7

)

2 ; 25 each R 20 is independently -H or -(CI-C 6 )alkyl; each halo is independently -F, -Cl, -Br, or -1; n is the integer 1, 2, or 3; p is the integer I or 2; each b is independently the integer I or 2; 62 q is the integer 0, 1, 2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and 5 m is the integer 0, 1, or 2. In another embodiment relating to fonnula 1.1, E is =0, =S, =CH(Ci-C5)alkyl, =CH(Ci-C5)alkenyl, or =N-OR20. In another embodiment relating to fonnula 1.1, E is =0, =S, or =N-OR 20 . In other embodiments, the compound of formula I is 10 OH HO OH HO HO HO,, CI N F CI F N NN 0 NH 0 NH NH F F F OCF 3

CF

3 Q5 Ss R6 63 N

NH

2 CN CI CN CN N N N O NH O NH 0 NH

CF

3

CF

3 or OCF 3 S6 T6 U6 Other compounds of interest include I N N N N C1 C1 F F N N N N 0 NH 0 NH 0 NH 0 NH F CI

CF

3

OCF

3

CF

3

CF

3 5 213 214 208 215 64 F cl ci cl F F F F F F N N N N N HN 0 0 NH 0 NH 0 NH 0 NH F F

CF

3 CF, ' oS - ' OCF 3

CF

3 212 209 211 207 210 Aqueous solubility of compounds is often a desirable feature. For example, 5 aqueous solubility of a compound permits that compound to be more easily formulated into a variety of dosage forms that may be administered to an animal. When a compound is not fully soluble in the blood, it may precipitate in the blood, and the animal's exposure to the drug will accordingly not correspond to the administered dose. Aqueous solubility increases the likelihood that a compound will not precipitate in an 10 animal's blood, and increases the ability to predict exposure at the target sight of the compound. Compounds of formula I are highly soluble in aqueous solution. For example, at either pH 6.8 or pH 1.2, compound 200 isinsoluble in aqueous solution, i.e., has an aqueous solubility <0. I pM. In contrast, the aqueous solubility at pH 6.8, in PM, of 15 compounds of formula I F2, E6, F6, and G2 is 3.0, 9.0, 9.2, and 38.2, respectively. The aqueous solubility at pH 1.2, in pM, of compounds of formula I F2, E6, F6 and G2 is 1.0, 27.2, >50 and >50, respectively. Additionally, the aqueous solubility at either pH 6.8 or pH 1.2 of each of compounds of formula I G6, H6, J2, and ZI is >50 pM. The following compounds are aqueous insoluble at pH 6.8: 203, 207, 200, and 208. The 20 following compounds have very low aqueous solubility at pH 6.8: 209, 210, 211, 212, 213, 214, and 215 have aqueous solubility, in lM, of 1.0, 0.4, 0.4, 1.9, 0.8, 1.8, and 0.6, 65 respectively. The aqueous solubility, in pM, at pH 1.2 of compounds 209, 210, 211, 212, 213, 214 and 215 is 9.3, 2.0, 1.3, 10.3, 39.6, >50 and 9.6, respectively. In contrast, the aqueous solubility at pH 6.8, in pM, of compounds of formula I NI, F1, C1, Y3, and U3 is 28.0, 22.6, 15.7, 17.4, and 26.4, respectively.At pH 1.2, compounds of formula I 5 N1, F1, Cl, Y3 and U3 all have an aqueous solubility of>50 pM. The aqueous solubility, at either pH 6.8 or pH 1.2, is >50 pM for each of the following compounds of formula I: H1, N6, Z1, S1, E2, and UI. 5.2 COMPOUNDS OF FORMULA 11 10 Preferred compounds of formula I are compounds of fonnula Il: ArW..

R

4 -(R3)m N> X N-R20 Ar 2 (11) 15 or a pharmaceutically acceptable derivative thereof, where the dashed line, W, X, Ari, Ar 2 , R 3 , R 4 , R 2 o, and m are as defined above for compounds of formula 1, wherein Q is J ZI Z 3 20 Z Z Zi is -OH, -SH, -N(R 20

)

2 , -CH 2 -OH, -CH 2 -SH, or -CH 2

-N(R

20

)

2 ;

Z

2 is -H, -CH 3 , or -CH 2 -OR ; each Z 3 is independently -H or -CH 3 ; and 25 J is -OH, -SH, or -N(R 2 0

)

2 . In addition to being highly soluble in aqueous solution, compounds of formula 11 are preferred because side effects are less severe (e.g., attenuation or removal of central 66 nervous system side effects) in animals administered a compound of formula II. For example, muscle relaxation is attenuated or absent in animals administered a compound of formula II. Sedation is attenuated or absent in animals administered a compound of formula 11. Ataxia is attenuated or absent in animals administered a compound of 5 formula II. Flat body posture is attenuated or absent in animals administered a compound of formula II. Tremor is attenuated or absent in animals administered a compound of formula 11. When a compound induces less severe side effects, the therapeutic index, which is the difference between an effective dose and a dose that causes adverse effects, is increased. Therapeutic index is a measure of the safety of a 10 compound when administered to an animal. The greater the therapeutic index, the safer the compound. Compounds of formula 11 also have excellent pharmacokinetic properties. Specifically, the plasma level of a compound of fornula 11 in an animal is dose proportionate. Therefore, the amount of compound in the plasma of an animal can be 15 more readily controlled according to the dose of the compound administered to the animal. Moreover, for a given dose administered, the animal plasma concentration is greater and is achieved more rapidly for a compound of formula 11. For example; compound 200 achieves its maximum plasma concentration 3.1 h after administration. In contrast, compound of formula 11 Z1 achieves its maximum plasma concentration 2.5 20 h after administration and that maximum plasma concentration is 2.5 times greater than the maximum for compound 200. Additionally, compound of formula II R6 achieves its maximum plasma concentration 1.85 h after administration and that maximum plasma concentration is 5.3 times greater than the maximum for compound 200. For each of compounds of formula II ZI and R6, the plasma concentration up to 24 h is consistently 25 greater for each when compared with compound 200. Compound R6 has the following structure: 67 O H N O ~~"NH CF3 Compounds of formula II are also preferred because they have a high therapeutic index. Therapeutic index is the difference between the amount of a compound that is 5 effective for treating a Condition and the amount of that same compound that induces adverse effects. Other embodiments of formula I are presented below. In one embodiment, a compound of formula II is a pharmaceutically acceptable derivative of a compound of formula 11. 10 In another embodiment, a compound of formula II is a compound of formula II whererein tlie derivative is a pharmaceutically acceptable salt. In another embodiment, a compound of formula II is a pharmaceutically acceptable salt of a compound of formula II. In another embodiment, Ar, is a pyridyl group. 15 In another embodiment, Ari is a pyrimidinyl group. In another embodiment, Ar, is a pyrazinyl group. In another embodiment, Ar, is pyridazinyl group. In another embodiment, W is C. In another embodiment, W is N. 20 In another embodiment, X is 0. In another embodiment, X is S. In another embodiment, X is N-CN. In another embodiment, X is N-OH. In another embodiment, X is N-ORi,.

68 In another embodiment, Ar 2 is a benzoimidazolyl group. In another embodiment, Ar 2 is a benzothiazolyl group. In another embodiment, Ar 2 is a benzooxazolyl group. In another embodiment, Ar 2 is 5 N

(R

1 4)q In another embodiment, Ar 2 is N 10 (R 14) In another embodiment, Ar 2 is 15 In another embodiment, Ar 2 is (R 1 )q 20 In another embodiment, Ar 2 is 69 (Rii)r In another embodiment, n or p is 1. In another embodiment, n or p is 2. 5 In another embodiment, n is 3. In another embodiment, m is 2. In another embodiment, two R 3 groups together form a (C 2

-C

6 )bridge. 10 In another embodiment, two R 3 groups together form a (C 2

-C

6 )bridge, which is unsubstituted or substituted with an Rg group, and which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge. In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted or substituted with an R8 group, and which bridge optionally contains 15 -HC=CH- within the (C 2

-C

3 )bridge. In another embodiment, two R 3 groups together form a (Cr-C 3 )bridge, which is unsubstituted and which bridge optionally contains -HC=CH- within the (C-C 3 )bridge. In another embodiment, two R 3 groups together form a (C3)bridge, a -HC=CH bridge, or a (C 3 )bridge each of which is unsubstituted. 20 In another embodiment, two R 3 groups together form a (C 2

-C

6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, which bridge optionally contains -HC=CH- within the (C-C 6 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (C 2

-C

6 )bridge, which is 25 unsubstituted or substituted with an R 8 group, which bridge optionally contains -HC=CH- within the (C-C 6 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyrdine or piperazine ring. In another embodiment, two R 3 groups together form a (C 2

C

3 )bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains 30 -HC=CH- within the (C 2

-C

3 )bridge, and which bridge joins positions 2 and 6 of the piperidine, I,2,3,6-tetrahydropyridine or piperazine ring.

70 In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted, which bridge optionally contains -HC=CH- within the (Cr-C 3 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. 5 In another embodiment, two R 3 groups together form a (C 2 )bridge, a -HC=CH bridge, or a (C 3 )bndge each of which is unsubstituted, and which bridge joins positions 2 and 6 of the pipendine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a -CHr-N(Ra)-CH 2 r bridge (B1), a 10 Rb Rb N-CH2- bridge (B2), or a - CH2-- CH2- bridge (B3); wherein Ra is selected from -H, -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, -CH 2

C(O)

Rc, -(CH 2 )-C(O)-ORc, -(CH 2 )-C(O)-N(Rc) 2 , -(CH 2

)O

2 -- Re, -(CH 2

)

2

-S(O)

2 -N(Re) 2 , or 15 -(CH 2

)

2 -N(Rc)S(O) 2 -Re; Rb is selected from: (a) -H, -(CI-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, -(3- to 7 membered)heterocycle, -N(Rc) 2 , -N(R)-(C 3 -Cs)cycloalkyl, or -N(Re)-(3- to 7 membered)heterocycle; or 20 (b) -phenyl, -(5- or 6-membered)heteroaryl, -N(Re)-phenyl, or -N(Re)-(5 to I 0-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups; and each Re is independently selected from -H or -(Ci-C 4 )alkyl; In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6 of the 25 piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups form a bicyclo group to give one of the following structures, 71 Ar. ,R 4 Ar, -R 4 w w or N N X N'R20 X N'R20 Ar 2 Ar 2 In another embodiment, in is 1. In another embodiment, m is 0. 5 In another embodiment, s or q is 0. In another embodiment, s or q is 1. In another embodiment, s or q is 2. In another embodiment, R, is -H. In another embodiment, R, is -halo. 10 In another embodiment, R, is -CL. In another embodiment, R, is -F. In another embodiment, R, is -CH 3 . In another embodiment, R, is -NO 2 . In another embodiment, R, is -CN. 15 In another embodiment, RI is -OH. In another embodiment, R, is -OCH 3 . In another embodiment, R, is -NH 2 . In another embodiment, R, is -C(halo) 3 . In another embodiment, R, is CF 3 . 20 In another embodiment, R, is -CH(halo) 2 . In another embodiment, RI is -CH 2 (halo). In another embodiment, Art is a pyridyl group and n is 1. In another embodiment, Arl is a pyrazinyl group and p is 1. In another embodiment, Arl is a pyrimidinyl group and p is 1. 25 In another embodiment, Ari is a pyridazinyl group and p is 1. In another embodiment, Q is 72 OH OH OH OH OH HO,, HO± HO OH N OH OH OH F, HO , or OH In another embodiment, J is -OR 2 0 . In another embodiment, J is -OH. 5 In another embodiment, Z, is -OR 7 . In another embodiment, Z, is -OH. In another embodiment, Z, is - CH 2

-OR

7 . In another embodiment, Z, is -CH2OH. In another embodiment, Z 2 is -CH 2

-OR

7 . 10 In another embodiment, Z 2 is -CH 2 OH. In another embodiment, Z 2 is -H or -CH 3 . In another embodiment, Z 2 is -H. In another embodiment, Z 2 is -CH 3 . In another embodiment, Z 3 is -H. 15 In another embodiment, Z 3 is -CH 3 . In another embodiment, m is I and R 3 is -(CI-C 6 )alkyl. In another embodiment, m is I and R 3 is -CH 3 . In another embodiment, R 4 is -OH. In another embodiment, R 4 is -OCF 3 20 In another embodiment, R 4 is -halo. In another embodiment, R4 is -F. In another embodiment, R 4 is -Cl. In another embodiment, R 4 is -(CI-C 6 )alkyl. In another embodiment, R 4 is -CH 3 . 25 In another embodiment, R4 is -CH 2 OH. In another embodiment, R 4 is -CH 2 CL. In another embodiment, R 4 is -CH 2 Br. In another embodiment, R 4 is -CH 2

I.

73 In another embodiment, R 4 is -CH 2 F. In another embodiment, R 4 is -CH(halo) 2 . In another embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -NO 2 . 5 In another embodiment, R 4 is -ORIO. In another embodiment, R 4 is -SRIO. In another embodiment, R 4 is -C(O)RIO. In another embodiment, R 4 is -COOH. In another embodiment, R 4 is -C(O)H. 10 In another embodiment, R 4 is -COORio. In another embodiment, R 4 is -OC(O)Rio. In another embodiment, R 4 is -SO 2

R

10 . In another embodiment, R 4 is -OC(O)NHR 1 O. In another embodiment, R 4 is -NHC(O)R 3 . 15 In another embodiment, R 4 is -CON(R 13

)

2 . In another embodiment, each R 2 0 is independently -H or -(Ci-C 6 )alkyl. In another embodiment, each R 20 is independently -H or -(C 3 -Cs)cycloalkyl. In another embodiment, each R 2 0 is independently -(Ci-C 6 )alkyl or -(C 3 Cg)cycloalkyl. 20 In another embodiment, each R 2 0 is -H. In another embodiment, each R 20 is -(Ci-C 6 )alkyl. In another embodiment, each R 20 is -(C 3 -Cs)cycloalkyl. In another embodiment, Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is -H. 25 In another embodiment, Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is not -H. In another embodiment, Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is -halo. In another embodiment, Ar 2 is 30 (R14)S 74 s is I and R 1 4 is -(CI-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -SO 2

R

7 , or

-SO

2 C(halo) 3 . In another embodiment, Ar is 5 (R14),, s is 2, and each R 14 group independently is -(C -C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 ,

-OR

7 , -N(R 7

)

2 , -SO 2 R7, or -SO 2 C(halo) 3 . 10 In another embodiment, J is -OH, and ZI is -OH. In another embodiment, J is -OH and Z, is -CH 2 OH. In another embodiment, J is -OH, Zi is -OH, Z 2 is -H, and Z 3 is -H. In another embodiment, J is -OH, Zi is -CH 2 OH, Z 2 is -H, and Z 3 is -H. In another embodiment, R4 is -halo, J is -OH, ZI is -OH, Z 2 is -H, and Z 3 is -H. 15 In another embodiment, R 4 is -halo, J is -OH, Zi is -CH 2 OH, Z 2 is -H, and Z 3 is -H. In another embodiment, R4 is -F, J is -OH, Zi is -OH, Z 2 is -H, and Z 3 is -H. In another embodiment, RA is -F, J is -OH, ZI is -CH 2 OH, Z 2 is -H, and Z 3 is -H. 20 In another embodiment, R, is -halo, R 4 is -halo, J is -OH, ZI is -OH, Z- is -H, and Z 3 is -H. In another embodiment, Ri is -halo, R4 is -halo, J is -OH, ZI is -CH 2 OH, Z 2 is -H, and Z 3 is -H. In another embodiment, R, is -Cl, R 4 is -F, J is -OH, Z, is -OH, Z 2 is -H, and 25 Z 3 is -H. In another embodiment, R, is -Cl, R 4 is -F, J is -OH, ZI is -CH 2 OH, Z 2 is -H, and Z 3 is -H. In another embodiment Arl is 75 Q R1 -N In another embodiment, R, is -halo, R 4 is -halo, Arl is Q -N

R

1 5 J is -OH, Z, is -OH, Z 2 is -H, and Z 3 is -H. In another embodiment, R, is -halo, R 4 is -halo, Ar is Q -N R1 10 J is -OH, Z, is -CH 2 OH, Z 2 is -H, and Z 3 is -H. In another embodiment, R, is -halo, R 4 is -halo, Arl is Q R N 15 J is -OH, Z, is -OH, Z- is -H, Z 3 is --H, Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not -H. In another embodiment, R, is -halo, R 4 is -halo, Ari is 76 Q N R, J is -OH, Zi is -CH 2 OH, Z 2 is -H, Z3 is -H, Ar 2 is benzooxazolyl, wherein at least one of R 8 or Rq is not -H. 5 In another embodiment, R, is -halo, R 4 is -halo, Arl is Q N R, N J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzothiazolyl, wherein at least one of R 8 10 or Rq is not -H. In another embodiment, R, is -halo, R 4 is -halo, Ar, is Q N R, 15 J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not -H. In another embodiment, R, is -halo, R 4 is -halo, Arl is Q N R1 20 77 J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar2 is benzoimidazolyl, wherein at least one of R8 or Rg is not -H. In another embodiment, R, is -halo, R 4 is -halo, Ari is Q N R1 5 J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not -H. In another embodiment, R, is -halo, R 4 is -halo, Arl is, 10 N R1 J is -OH, ZI is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 1. In another embodiment, R, is -halo, R 4 is -halo, Ar, is 15 Q -N R1 J is -OH, ZI is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar- is phenyl, wherein s is 2. In another embodiment, the dashed line is a double bond, RI is -halo, Ari is 20 Q N R1 78 J is -OH, Zi is -OH, Z 2 is -H, and Z 3 is -H. In another embodiment, the dashed line is a double bond, R, is -halo, Ari is Q N 5 J is -OH, Z, is -CH 2 OH, Z 2 is --H, and Z 3 is -H. In another embodiment, the dashed line is a double bond, R, is -halo, Arl is Q N R, 10 J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not -H. In another embodiment, the dashed line is a double bond, R, is -halo, Arl is 15 Q N J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzooxazolyl, wherein at least one of Rs or R 9 is not -H. 20 In another embodiment, the dashed line is a double bond, R, is -halo, Arl is Q N R

,

79 J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzothiazolyl, wherein at least one of Rs or R 9 is not -H. In another embodiment, the dashed line is a double bond, R, is -halo, Arl is 5 Q -N J is -OH, ZI is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not -H. 10 In another embodiment, the dashed line is a double bond, R, is -halo, Ari is Q N R1 J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzoimidazolyl, wherein at least one of 15 R 8 or Re is not -H. In another embodiment, the dashed line is a double bond, R, is -halo, Arl is Q R1 -N 20 J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not -H. In another embodiment, the dashed line is a double bond, R, is -halo, Ari is 80 Q R1 -N I is -OH, Z, is -OH, Z 2 is -H, Z, is -H, Ar 2 is phenyl, wherein s is 1. In another embodiment, the dashed line is a double bond, R, is -halo, Arl is 5 Q R1 -N J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 2. In another embodiment, the dashed line is a double bond, R, is -halo, Ari is 10 -N R1 J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 1. In another embodiment, the dashed line is a double bond, R, is -halo, Arl is 15 Q R1 -N J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 2. In another embodiment, the dashed line is a double bond, R, is -halo, Ar, is 81 Q A N R, J is -OH, Z, is -OH, Z 2 is -H, Z3 is -H, Ar 2 is phenyl, wherein s is 1, and R 14 is -(C,

C

6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -S0 2

R

7 , or -SO 2 C(halo) 3 . 5 In another embodiment, the dashed line is a double bond, R, is -halo, Arl is Q AN R, J is -OH, Zi is -CH 2 OH, Z is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 1, and 10 R 1 4 is -(CI-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R7) 2 , -SO 2

R

7 , or

-SO

2 C(halo) 3 . In another embodiment, the dashed line is a double bond, R, is -halo, Arn is Q AN

R

1 15 J is -OH, Z, is -OH, Z 2 is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 2, and each R1 4 is independently -(CI-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -SO 2

R

7 , or

-SO

2 C(halo) 3 . In another embodiment, the dashed line is a double bond, R, is -halo, Arl is 20 a R N 82 J is -OH, Z, is -CH 2 OH, Z 2 is -H, Z 3 is -H, Ar 2 is phenyl, wherein s is 2, and each R 1 4 is independently -(Ci-C 6 )alkyl, -halo, -C(halo) 3 , -OC(halo) 3 , -OR 7 , -N(R 7

)

2 , -S0 2

R

7 , or

-SO

2 C(halo) 3 . 5 In another embodiment Q is HO OH wherein the compound of formula II is racemic. 10 In another embodiment Q is HO OH HO,. OH and wherein the % ee of the R enantiomer is greater than 60%. 15 In another embodiment Q is HOHO HO OH HO. OH and wherein the % ee of the R enantiomer is greater than 70%. 20 In another embodiment Q is HO OH HO,. OH and wherein the % ee of the R enantiomer is greater than 80%. 25 In another embodiment Q is HO OH HO,, OH ~~ and 83 wherein the % ec of the R enantioner is greater than 90%. In another embodiment Q is H OH HO,, OH and 5 wherein the % ee of the R enantiomer is greater than 99%. In another embodiment Q is HO HO,, OH HO, OH and I0 wherein the o ee of the S enantiomer is greater than 60%. In another embodiment Q is HOHO HO OH HO, OH and 15 wherein the % ee of the S enantiomer is greater than 70%. In another embodiment Q is HO OH HO,, OH and 20 wherein the % ee of the S enantiomer is greater than 80%. In another embodiment Q is H OH HO,.. OH ~~ and 25 wherein the % ee of the S enantiomer is greater than 90%. In another embodiment Q is 84 HO OH HO,, OH and wherein the % ee of the S enantiomer is greater than 99%. In another embodiment Q is 5 HO OH In another embodiment Q is HOr H OH 10 In another embodiment, the invention encompasses compounds formula 11.4: Ar 1 sW

R

4 -(R3)m N X N'-R20 Ar 2 15 (11.4) or a pharmaceutically acceptable salt thereof, where the dashed line, W, X, Ari, Ar 2 , R 3 , RA, R 20 , and m are as defined above for compounds of formula 1.4, wherein Q is 20 J Z Z 3 2 : Z 3 Z, is -OH, -SH, N(R20) 2 , -CH2-OH, -CH 2 -SH, or -CH 2

-N(R

2 0) 2 ;

Z

2 is -H or -CH 3

;

85 each Z 3 is independently -H or -CH 3 ; and J is -OH, -SH, or -N(R 20

)

2 . In another embodiment, the invention encompasses compounds formula 11.3: ArW

'R

4 (R3)m N) X N' R20 5 Ar 2 (11.3) or a pharmaceutically acceptable salt thereof, where the dashed line, W, X, Ari, Ar 2 , R 3 ,

R

4 , R 20 , and in are as defined above for compounds of formula 1.3, 10 wherein Q is J Z Z 3 2 : Z 3 Z, is -OH, -SH, N(R 20

)

2 , -CH 2 -OH, -CH 2 -SH, or -CH 2

-N(R

2 0) 2 ;

Z

2 is -H or -CH 3 ; 15 each Z 3 is independently -H or -CH 3 ; and J is -OH, -SH, or -N(R20) 2 . In another embodiment, the invention encompasses compounds formula 11.2: Arl, W R 4

-

(R3)m SN> X' N'R20 Ar 2 20 (11.2) or a pharmaceutically acceptable salt thereof, where the dashed line, W, X, Ari, Ar 2 , R 3 ,

R

4 , R 2 0 , and m are as defined above for compounds of formula 1.2, 86 wherein Q is J Z Z 3 Zi is -OH, -SH, N(R 20

)

2 , -CH 2 -OH, -CH 2 -SH, or -CH 2

-N(R

2 0

)

2 ; 5 Z 2 is -H or -CH 3 ; each Z 3 is independently -H or -CH 3 ; and J is -OH, -SH, or -N(R20)2. In another embodiment, the invention encompasses compounds formula II. 1: Ar 1 W .R 4

(R

3 )m XN2 X N.,R20 10 Ar 2 (11.1) or a pharmaceutically acceptable salt thereof, where the dashed line, W, X, Arl, Ar7, R 3 ,

R

4 , R2 0 , and n are defined above for compounds of formula 1.1, 15 wherein Q is J Z Z 3 Zi is -OH, -SH, N(R 20

)

2 , -CH 2 -OH, -CH 2 -SH, or -CH 2

-N(R

2 0

)

2 ; 20 Zis-H or-CH 3 ; each Z3 is independently -H or -CH 3 ; and J is -OH, -SH, or -N(R 20

)

2

.

87 5.3 COMPOUNDS OF FORMULA III Preferred compounds of formula 11 are compounds of formula III: 5 Ar 1 s WR 4 -(R3)m N> X NH Ar 2 (Ill) or a pharmaceutically acceptable derivative thereof, where the dashed line, W, X, R 3 , R 4 , 10 and m are as defined above for compounds of formula 1, wherein Arl is: HO OH R1N 15 R, is -Cl, -F, or -CF 3 ; wherein Ar 2 is:

CF

3

R

14 . R 14 .

R

14 , R14- CF 3 ,O\ , F 3 C-"SO2 , CF 3 or

CF

3

R

8 Rg

R

1 4 is -H, -Cl, -F, -Br, -OCF 3 , -(Ci-C 6 )alkyl, -SO 2

CF

3 , -SO 2 (CI-C)alkyl, 20 -OCH 3 , -OCH 2

CH

3 , or -OCH(CH 3

)

2 , and preferably is -CF 3 , -OCF 3 , -Cl, or -F;

R

1 4 is -H, -Cl, -F, Br, -CH 3 , -CH 2

CH

3 , -OCH 3 , -OCF 3 , or -OCH 2

CH

3 ; and 88 each R 8 and R 9 is independently -H, -Cl, -Br, -F, -CH 3 , -OCH 3 , -OCH 2

CH

3 ,

-CF

3 , -OCF 3 , iso-propyl, or tert-butyl. In addition to being highly soluble in aqueous solution at both pH 6.8 and pH 1.2, having a very high therapeutic index, and having excellent pharmacokinetic 5 parameters as described for formulae I and 11, compounds of formula Ill are preferred because they are also very bioavailable, and are believed to be highly efficacious in animals for the treatment of pain. Bioavailability is a measure of how much of the dose administered reaches systemic circulation after oral administration. For example, compounds of formula III R6 and GI are 68.9% and 70.7% bioavailable following oral 10 administration, respectively. The compound of formula Ill D2 produced a 78.7% maximum reversal of FCA-induced hyperalgesia at 5 hours post-administration, with an EDSO of 1.63 mg/kg. Certain embodiments of formula III are presented below. In one embodiment, a compound of formula Ill is a pharmaceutically acceptable 15 derivative of a compound of formula I11. In another embodiment, a compound of formula I is a compound of formula Ill whererein the derivative is a pharmaceutically acceptable salt. In another embodiment, a compound of formula III is a pharmaceutically acceptable salt of a compound of formula Ill. 20 In another embodiment, Arl is: HO OH N

R

1 In a preferred embodiment, Ar is: 25 HO,, O OH R1

N

89 In another embodiment, n is 2. In another embodiment, two R 3 groups together form a (Cl-C 6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge. 5 In another embodiment, two R 3 groups together form a (C-C 6 )bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains -HC=CH- within the (Cr-C 6 )bridge. In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains 10 -HC=CH- within the (C-C 3 )bridge. In another embodiment, two R 3 groups together form a (C 2

-C

3 )bridge, which is unsubstituted and which bridge optionally contains -HC=CH- within the (C-C 3 )bridge. In another embodiment, two R 3 groups together forn a (C 2 )bridge, a -HC=CH bridge, or a (C 3 )bridge each of which is unsubstituted. 1 5 In another embodiment, two R 3 groups together form a (C 2

-C

6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (C-C 6 )bridge, which is 20 unsubstituted or substituted with an R 8 group, which bridge optionally contains -HC=CH- within the (C 2

-C

6 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (Cr-C 3 )bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains 25 -HC=CH- within the (C 2

-C

3 )bndge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups together form a (C 2

-C

C

3 )bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or 30 piperazine ring. In another embodiment, two R 3 groups together form a (C 2 )bridge, a -HC=CH bridge, or a (C 3 )bridge each of which is unsubstituted, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

90 In another embodiment, two R 3 groups together form a -CH 2 -N(Ra)-CH 2 - bridge (B I), a Rb Rb I I C=0 O= S o S-CH2- bridge (B2), or a - CH 2 -- N--CH 2 - bridge (B3); 5 wherein R, is selected from -H, -(CI-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, -CH 2

-C(O)

Re, -(CH 2 )-C(O)-ORc, -(CH 2 )-C(O)-N(Rc) 2 , -(CH 2

)

2 -0-Re, -(CH 2

)

2

-S(O)

2 -N(Rc) 2 , or -(CH2)2-N(Rc)S(O)2-Rc; Rb is selected from: 10 (a) -H, -(C -C 6 )alkyl, -(C 3 -Cs)cycloalkyl, -(3- to 7 membered)heterocycle, -N(Rc) 2 , -N(Re)-(C 3 -Cs)cycloalkyl, or -N(Rc)-(3- to 7 nembered)heterocycle; or (b) -phenyl, -(5- or 6-membered)heteroaryl, -N(Rj-phenyl, or -N(Re)-(5 to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 15 independently selected R7 groups; and each Re is independently selected from -H or -(Ci-C 4 )alkyl; In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring. In another embodiment, two R 3 groups form a bicyclo group to give one of the 20 following structures, Arl, ,FR 4 Ar 1 ,R4 or N N X N'H X N'H Ar 2 Ar 2 In another embodiment, m is 1. 25 In another embodiment, m is 0.

91 In another embodiment X is 0. In another embodiment the dashed line denotes the presence of a bond and R 4 is absent. In another embodiment W is N and R 4 is absent. 5 In another embodiment R 4 is -H, -OH, -Cl, or F. In another embodiment, each R 20 is independently -H or -(CI-C 6 )alkyl. In another embodiment, each R 20 is -H. In another embodiment, each 120 is -(Ci-C 6 )alkyl. In another embodiment Ar2 is selected from N N S R14.

R

14 R14 CF 3 ,OC F3C-SO 2 , CF 3 or 10 CF 3 R8 Rg In another embodiment Ar is HO OH N 15 wherein the compound of formula III is racemic. In another embodiment Ar, is HO HOH H OH OH O I N

R

1 N R1 N - and 20 wherein the % ee of the R enantiomer is greater than 60%. In another embodiment Arl is 92 HO H,. OH HO OH AN N and wherein the % ee of the R enantiomer is greater than 70%. In another embodiment Arl is 5 HO HO, OH OH IN R N AN -N and wherein the % ee of the R enantiomer is greater than 8 0 %. In another embodiment Arl is 10 HO OH HO,, OH RT'N R, N AN AN and wherein the % ee of the R enantiomer is greater than 90%. In another embodiment Arl is 15 HOHO OH HO OH N 'N R1 R1 and wherein the % ee of the R enantiomer is greater than 99%. In another embodiment Arl is 93 HO H,, OH HO,, OH N 'N

R

1 R and wherein the % ee of the S enantiorner is greater than 60%. In another embodiment Ar is 5 HO OH HO,. OH AN AN and wherein the % ee of the S enantiorner is greater than 70%. In another embodiment Ar, is 10 HO HO,. OH OH O RN RN R1 R1 and wherein the % ee of the S enantiomer is greater than 80%. In another embodiment Ar, is 15 HO OH HO,' OH RN AN and wherein the % ee of the S enantioner is greater than 90%. In another embodiment Ar is 94 HO HO,, OH '- OH I | R1 N R -N and wherein the % ee of the S enantiomer is greater than 99%. In another embodiment Ar, is 5 HO OH R 1 N In another embodiment Ar, is HO,, O -OH R1 Ix N 10 In another embodiment the compound of formula III is 95 OH C'N ONH C, 'N R. or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula IlI is ONH NN or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of fonnula 1. In another embodiment the compound of formula III is 96 OH O,N C. N 0 NH or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of fonnula I. 5 In another embodiment the compound of formula III is OH HO N 0 NH or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula IlIl is 97 OH HO, C1 N 0 NH CF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula III is OH HO, F N N CF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula Ill is 98 OH HO CI N 0 NH CF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula Il is OH N O NH CF, R., or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula Ill is 99 OH HO,, CI ONH O N CFa or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula III is OH HON N N RI, CF, or a phanrmaceutically acceptable derivative thereof, where R1 4 is as defined above for 10 the compounds of fonnula 1. In another embodiment the compound of formula Il1 is 100 OH HO,,. N N 0 NH R,. CF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula III is OH N ONH CF 3 or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula Ill is 101 OH ClN C11 O N R,4 OCF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula Ill is OH HON N 0 N H N o N R,, OCF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula Ill is 102 OH HC C, N O N OCF3 or a pharmaceutically acceptable derivative thereof, where R14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula IlI is OH N O NH R,. CF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 103 OH HO, F N or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula II is OH F N NH or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula I. In another embodiment the compound of fonnula III is 104 OH O,N N 0 NH or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula I is OH HO. FN N ONH or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 105 OH HO, CI F N 0 NH CF1 or a pharmaceutically acceptable derivative thereof, where R1 4 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH HO N F F N 0 NH CF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula Ill is 106 OH HO, F N 0 NH R ,. or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH HO, F N O NH CF) or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula III is 107 OH HO, N C'3 N O NH C F 3 or a pharmaceutically acceptable derivative thereof, where R1 4 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH H, FN F N O NH R,. or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 108 OH HON CI F N 0 NH R,. CF, or a pharmaceutically acceptable derivative thereof, where R1 4 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula IIl is OH HO, FN F N O NH CF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula Ill is 109 OH HO, C. N R,. OCF or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula III is OH HO, N F N O NH N R,4 OCF3 or a pharmaceutically acceptable derivative thereof, where R1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 110 OM HO C N 0 NH R,, OC F, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula Ill is OH N F N R,,

OCF

3 or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula Ill is 111 OH MO CNN N NH R or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula Ill is OH HO FN N ONH 7N or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula III is 112 OH HO, N C. CN N o NH R,. or a pharmaceutically acceptable derivative thereof, where R1 4 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH F N O NH or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula III is 113 OH HO. 0 CI N N ONH CF, R.. or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH HO, N F N N CF3 or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 114 OH HO C1N N N NH CF, R, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH HO N N ONH CF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 115 OH ciN C1 N 0 NH N N R,,

CF

3 or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula III is OH HO, N N N O NH N

C

3 or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula III is 116 OH HOQ cN N N 0 NH CF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula I. 5 In another embodiment the compound of formula Ill is OH HO, FN N O' NH R,. CF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula I. In another embodiment the compound of formula III is 117 OH C N N O" NH OCF, or a phar-naceutically acceptable derivative thereof, where R 1 4 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula Ill is OH H N F N N OCF, or a pharmaceutically acceptable derivative thereof, where R 1 4 is as defined above for 10 the compounds of formula 1. In another embodiment the compound of formula III is 118 OH N NI 0 ;"N H OCF, or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for the compounds of formula 1. 5 In another embodiment the compound of formula IlII is OH HO, N o NH OCF ' or a pharmaceutically acceptable derivative thereof, where R 14 is as defined above for 10 the compounds of formula 1. In another embodiment, the invention encompasses compounds of formula 111.4: 119 Ar 1 , W R 4 -(R3)m N> X N',H Ar 2 (111.4) or a pharmaceutically acceptable salt thereof, where'the dashed line, W, X, Ari, Ar 2 , R 3 , 5 R 4 , and m are as defined above for compounds of formula 1.4, wherein Arl is: HO OH -N R, N 10 R 1 is -Cl, -F, or -CF 3 ; wherein Ar 2 is: I N N S

R

14

.

R

14 .

R

14 . F F O\ ,SO 2 FF F CF 3 FF F ' F 3 C or 15 R 1 4 is -H, -Cl, -F, -Br, -CH 3 , -CH 2

CH

3 , -OCH 3 , or -OCH 2

CH

3 ;

R

9 is -Cl, F, or CH 3 . In another embodiment, the invention encompasses compounds of formula 111.3: 120 Ar 1 . WR 4 N-(R3)m" X N H Ar 2 (111.3) or a pharmaceutically acceptable salt thereof, where the dashed line, W, X, Ari, Ar 2 , R 3 , 5 R 4 , and m are as defined above for compounds of formula 1.3, wherein Arl is: HO OH R1, R, is -Cl, -F, or -CF3; 10 wherein Ar, is: SIN N S R14 R14~~ FF F ' CF 3 FF F 3 C- 2 or

R

1 4 is -Cl, -F, -CH 3 , -CH 2

CH

3 , -OCH 3 , or -OCH 2

CH

3 ; 15 R is -Cl, F, or CH 3 . Illustrative compounds of formula Ill are listed below in Tables 1-30: 121 Table 1 OH OH R1N F N O NH

R

1 4 FF F 5 (IIa) and phannaceutically acceptable derivatives thereof, where: Compound Ri R 14 AAA -Cl -Cl AAB -Cl -F AAC -Cl -OCH 3 AAD -Cl -OCH 2

CH

3 AAE -F -Cl AAF -F -F AAG -F -OCH 3 AAH -F -OCH 2

CH

3 AAI -CF 3 -Cl AAJ -CF 3 -F AAK -CF 3

-OCH

3 AAL -CF 3

-OCH

2

CH

3 122 Table 2 OH OH N NH

R

14 FF F 5 (IIIb) and pharmaceutically acceptable derivatives thereof, where: Compound R, R w AAM -Cl -Cl AAN -Cl -F AAO -Cl -OCH 3 AAP -Cl -OCH 2

CH

3 AAQ -F -Cl AAR -F -F AAS -F -OCH 3 AAT -F -OCH 2

CH

3 AAU -CF 3 -Cl AAV -CF 3 -F AAW -CF 3

-OCH

3 AAX -CF 3

-OCH

2

CH

3 123 Table 3 OH OH N (N) N O -NH

R

1 4 FF F 5 (IIIc) and pharmaceutically acceptable derivatives thereof, where: Compound Ri R14 AAY -Cl -Cl AAZ -CI -F ABA -Cl -OCH 3 ABB -Cl -OCH 2

CH

3 ABC -F -Cl ABD -F -F ABE -F -OCH 3 ABF -F -OCH 2

CH

3 ABG -CF 3 -CI ABH -CF 3 -F ABI -CF 3

-OCH

3 ABJ -CF 3

-OCH

2

CH

3 124 Table 4 OH OH R,N F N O -NH R14. FF F (1i1d) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, Ria ABK -Cl -Cl ABL -Cl -F ABM -Cl -OCH 3 ABN -Cl -OCH 2

CH

3 ABO -F -Cl ABP -F -F ABQ -F

-OCH

3 ABR -- F -OCH 2

CH

3 ABS -CF 3 -Cl ABT -CF 3 -F ABU -CF 3

-OCH

3 ABV

-CF

3

-OCH

2

CH

3 125 Table 5 OH OH N NH R1 4 FF F (IIe) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, R14 ABW -Cl -Cl ABX -Cl -F ABY -Cl -OCH 3 ABZ -Cl -OCH 2

CH

3 ACA -F -Cl ACB -F -F ACC -F -OCH 3 ACD -F -OCH 2

CH

3 ACE -CF 3 -Cl ACF -CF 3 -F ACG -CF 3

-OCH

3 ACH -CF 3

-OCH

2

CH

3 126 Table 6 OH OH R1 N N O -NH R 1 4 FF F (IlIf) 5 and phannaceutically acceptable derivatives thereof, where: Compound R, R 14 ACI -CI -CI ACJ -Cl -F ACK -Cl -OCH 3 ACL -Cl -OCH 2

CH

3 ACM -F -Cl ACN -F -F ACO -F -OCH 3 ACP -F -OCH 2 CH3 ACQ -CF 3 -Cl ACR -CF 3 -F ACS -CF 3

-OCH

3 ACT -CF 3

-OCH

2

CH

3 127 Table 7 OH OH N F N O NH

R

1 4 ' 0,

CF

3 (1l1g) 5 and pharmaceutically acceptable derivatives thereof, where: Compound RI R w BAA -Cl -CH 3 BAB -Cl -CH 2

CH

3 BAC -Cl -CI BAD -F -CH 3 BAE -F -CH 2

CH

3 BAF -F -Cl BAG -CF 3

-CH

3 BAH -CF 3

-CH

2

CH

3 BAI -CF 3 -Cl 128 Table 8 OH OH N R, N O NH R14.

CF

3 (I1Ih) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, R 14 BAJ -Cl -CH 3 BAK -Cl -CH 2

CH

3 BAL -Cl -Cl BAM -F -CH 3 BAN -F -CH 2 CH3 BAO -F -Cl BAP -CF 3

-CH

3 BAQ -CF 3

-CH-

2 CH 3 BAR -CF 3 -Cl 129 Table 9 OH, OH RN CN) N O NH

R

14 . 0,

CF

3 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, R14 BAS -Cl -CH3 BAT -Cl -CH 2

CH

3 BAU -Cl -Cl BAV -F -CH 3 BAW -F -CH 2

CH

3 BAX -F -Cl BAY -CF 3

-CH

3 BAZ -CF 3

-CH

2

CH

3 BBA -CF 3 -Cl 130 Table 10 OH OH F N N R14' 0,

CF

3 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, RIw BBB -Cl -CH BBC -Cl -CH 2

CH

3 BBD -Cl -Cl BBE -F -CH 3 BBF -F -CH 2

CH

3 BBG -F -Cl BBH -CF 3

-CH

3 BBI -CF 3

-CH

2

CH

3 BBJ -CF 3 -Cl 131 Table 11 OH OH 'N R,N N O NH

R

14 0'

CF

3 (111k) 5 and pharmaceutically acceptable derivatives thereof, where: Compound Ri Rw BBK -Cl -CH 3 BBL -Cl -CH 2

CH

3 BBM -Cl -Cl BBN -F -CH 3 BBO -F -CH 2

CH

3 BBP -F -Cl BBQ -CF3 -CH3 BBR -CF 3

-CH

2

CH

3 BBS -CF 3 -Cl 132 Table 12 OH OH N (N) N O -NH R 1

CF

3 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, R 14 BBT -Cl -CH 3 BBU -Cl -CH 2

CH

3 BBV -Cl -Cl BBW -F -CH 3 BBX -F -CIH 2

CH

3 BBY -F -Cl BBZ -CF 3

-CH

3 BCA -CF 3

-CH

2

CH

3 BCB -CF 3 -Cl In other embodiments, substituent R1 4 of Tables 1-12 can be H.

133 Table 13 OH OH N F N N FF F (11im) 5 and phannaceutically acceptable derivatives thereof, where: Compound R, CAA -Cl CAB -F CAC

-CF

3 134 Table 14 OH OH N R1 N O--, N H N FF F (II1n) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, CAD -Cl CAE -F CAF

-CF

3 135 Table 15 OH OH N N O -NH N FF F (1110) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, CAG -Cl CAH -F CAI

-CF

3 136 Table 16 OH OH N

R

1 F N O- N H N FF F (1Ip) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, CAJ -Cl CAK -F CAL

-CF

3 137 Table 17 OH OH N R1 N O- N H N FF F (IIIq) 5 and pharmaceutically acceptable derivatives thereof, where: Compound Ri CAM -Cl CAN -F CAO

-CF

3 138 Table 18 OH OH N R1 N N O--, N H N FF F (IIIr) 5 and pharnaceutically acceptable derivatives thereof, where: Compound R, CAP -Cl CAQ -F CAR

-CF

3 139 Table 19 OH OH N F N O NH

F

3

C-S

0 2 (Ills) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, DAA -Cl DAB -F DAC -CF 3 140 Table 20 OHOH OH RN N O NH

F

3 C-SO2 (lilt) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, DAD -Cl DAE -F DAF

-CF

3 141 Table 21 OH OH N N O NH

F

3 C-SO2 (Illu) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, DAG -Cl DAH -F DAI

-CF

3 142 Table 22 OH OH N R1 F N S N H

F

3

S

0 2 (IIv) 5 and pharmaceutically acceptable derivatives thereof, where: Compound Ri DAJ -Cl DAK -F DAL -CF 3 143 Table 23 OH OH N R1 N O--, N H

F

3 C-SO2 (IIIV) 5 and pharmaceutically acceptable derivatives thereof, where: Compound RI DAM -Cl DAN -F DAO -CF 3 144 Table 24 OH OH RN NH N O -NH

F

3 C'So2 (Ilx) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, DAP -Cl DAQ -F DAR

-CF

3 145 Table 25 OH OH R1N F N O NH N S Rg (Illy) 5 and phannaceutically acceptable derivatives thereof, where: Compound R, Rg EAA -Cl -Cl EAB -Cl -F EAC -Cl -CH 3 EAD -F -Cl EAE -F -F EAF -F -CH 3 EAG -CF 3 -Cl EAH -CF 3 -F EAI

-CF

3

-CH

3 146 Table 26 OH" OH N R, N O NH N S

R

9 (IIhz) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, R< EAJ -CI -Cl EAK -Cl -F EAL -Cl -CH 3 EAM -F -Cl EAN -F -F EAO -F -CH 3 EAP -CF 3 -Cl EAQ -CF 3 -F EAR -CF 3

-CH

3 147 Table 27 OH OH OH OH R N R 1 N N (N) N N CH3 O NH O NH N SN S

R

8 R o R 8 Rg or (Illaa) (IIlab) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, Rs R 8 EASI aa or ab -Cl -H -H EAS2 aa or ab -Cl -H -Cl EAS3 aa or ab -Cl -H -Br EAS4 aa or ab -Cl -H -F EAS5 aa or ab -Cl -H -CH 3 EAS6 aa or ab -Cl -H -OCH 3 EAS7 aa or ab -Cl -H -OCH 2

CH

3 EAS8 aa or ab -Cl -H -CF 3 EAS9 aa or ab -Cl -H -OCF 3 EASIO aa or ab -Cl -H iso-propyl EAS I I aa or ab -Cl -H tert-butyl EAS12 aa or ab -Cl -Cl -H EAS13 aa or ab -Cl -Cl -Cl EAS14 aa or ab -Cl -Cl -Br EAS15 aa or ab -Cl -Cl -F EAS16 aa or ab -Cl -Cl -CH 3 EAS17 aa or ab -Cl -Cl -OCH 3 EAS18 aa or ab -Cl -Cl -OCH 2

CH

3 EASI9 aa or ab -Cl -Cl

-CF

3 EAS20 aa or ab -Cl -Cl -OCF 3 EAS21 aa or ab -Cl -Cl iso-propyl EAS22 aa or ab -Cl -Cl tert-butyl 148 Compound R, R 8

R

9 EAS23 aa or ab -Cl -Br -H EAS24 aa or ab -Cl -Br -Cl EAS25 aa or ab -Cl -Br -Br EAS26 aa or ab -Cl -Br -F EAS27 aa or ab -Cl -Br -CH3 EAS28 aa or ab -Cl -Br -OCH 3 EAS29 aa or ab -Cl -Br -OCH2CH 3 EAS30 aa or ab -Cl -Br -CF 3 EAS3I aa or ab -Cl -Br -OCF 3 EAS32 aa or ab -Cl -Br iso-propyl EAS33 aa or ab -Cl -Br tert-butyl EAS34 aa or ab -Cl -F -H EAS35 aa or ab -Cl -F -Cl EAS36 aa or ab -Cl -F -Br EAS37 aa or ab -Cl -F -F EAS38 aa or ab -Cl -F -CH 3 EAS39 aa or ab -Cl -F -OCH 3 EAS40 aa or ab -Cl -F -OCH 2

CH

3 EAS41 aa or ab -Cl -F -CF 3 EAS42 aa or ab -Cl -F -OCF 3 EAS43 aa or ab -Cl -F iso-propyl EAS44 aa or ab -Cl -F tet-butyl EAS45 aa or ab -Cl -CH 3 -H EAS46 aa or ab -Cl -CH 3 -Cl EAS47 aa or ab -Cl -CH 3 -Br EAS48 aa or ab -Cl -CH 3 -F EAS49 aa or ab -Cl -CH 3

-CH

3 EAS50 aa or ab -Cl -CH 3 -OCH3 EAS51 aa or ab -Cl -CH 3

-OCH

2

CH

3 EAS52 aa or ab -Cl -CH 3

-CF

3 EAS53 aa or ab -Cl -CH 3

-OCF

3 EAS54 aa or ab -Cl -CH 3 iso-propyl EAS55 aa or ab -Cl -CH 3 tert-butyl EAS56 aa or ab -Cl -OCH 3 -H EAS57 aa or ab -Cl -OCH 3 -Cl EAS58 aa or ab -Cl -OCH 3 -Br EAS59 aa or ab -Cl -OCH 3 -F EAS60 aa or ab -Cl -OCH 3

-CH

3 EAS61 aa or ab -Cl -OCH 3

-OCH

3 EAS62 aa or ab -Cl -OCH 3 -OCH2CH 3 EAS63 aa or ab -Cl -OCH 3

-CF

3 EAS64 aa or ab -Cl -OCH 3

-OCF

3 EAS65 aa or ab -Cl -OCH 3 iso-propyl EAS66 aa or ab -Cl -OCH 3 tert-butyl EAS67 aa or ab -Cl -OCH 2

CH

3 -H EAS68 aa or ab -Cl -OCH 2

CH

3 -Cl EAS69 aa or ab -Cl -OCH 2

CH

3 -Br 149 Compound Ri Rg R 8 EAS70 aa or ab -Cl -OCH 2

CH

3 -F EAS71 aa or ab -Cl -OCH 2

CH

3 -CH3 EAS72 aa or ab -Cl -OCH 2

CH

3 -OCH3 EAS73 aa or ab -Cl -OCH 2

CH

3

-OCH

2

CH

3 EAS74 aa or ab -Cl -OCH 2

CH

3

-CF

3 EAS75 aa or ab -Cl -OCH 2

CH

3

-OCF

3 EAS76 aa or ab -Cl -OCH 2

CH

3 iso-propyl EAS77 aa or ab -Cl -OCH 2

CH

3 tert-butyl EAS78 aa or ab -Cl -CF 3 -H EAS79 aa or ab -Cl -CF 3 -Cl EASSO aa or ab -Cl -CF 3 -Br EAS81 aa or ab -Cl -CF 3 -F EAS82 aa or ab -Cl -CF 3

-CH

3 EAS83 aa or ab -Cl -CF 3

-OCH

3 EAS84 aa or ab -Cl -CF 3

-OCH

2

CH

3 EAS85 aa or ab -Cl -CF 3

-CF

3 EAS86 aa or ab -Cl -CF 3

-OCF

3 EAS87 aa or ab -Cl -CF 3 iso-propyl EAS88 aa or ab -Cl -CF 3 tet-butyl EAS89 aa or ab -Cl -OCF 3 -H EAS90 aa or ab -Cl -OCF 3 -Cl EAS91 aa or ab -Cl -OCF 3 -Br EAS92 aa or ab -Cl -OCF 3 -F EAS93 aa or ab -Cl -OCF 3 -CH3 EAS94 aa or ab -Cl -OCF 3

-OCH

3 EAS95 aa or ab -Cl -OCF 3

-OCH

2

CH

3 EAS96 aa or ab -Cl -OCF 3

-CF

3 EAS97 aa or ab -Cl -OCF 3

-OCF

3 EAS98 aa or ab -Cl -OCF 3 iso-propyl EAS99 aa or ab -Cl -OCF 3 tert-butyl EAS 100 aa or ab -Cl iso-propyl -H EAS10I aa or ab -Cl iso-propyl -Cl EAS 102 aa or ab -Cl iso-propyl -Br EAS 103 aa or ab -Cl iso-propyl -F EAS 104 aa or ab -Cl iso-propyl -CH 3 EAS 105 aa or ab -Cl iso-propyl -OCH 3 EAS 106 aa or ab -Cl iso-propyl -OCHi 2

CH

3 EAS 107 aa or ab -Cl iso-propyl -CF 3 EAS 108 aa or ab -CI iso-propyl -OCF 3 EAS 109 aa or ab -Cl iso-propyl iso-propyl EASI 10 aa or ab -Cl iso-propyl tert-butyl EASI I I aa or ab -Cl lert-butyl -H EAS 112 aa or ab -Cl tert-butyl -Cl EAS 113 aa or ab -Cl tert-butyl -Br EAS1 14 aa or ab -Cl tert--butyl -F EAS 115 aa or ab -Cl tert-butyl -CH3 EAS 116 aa or ab -Cl tert-butyl -OCH 3 150 Compound R, R 8

R

9 EAS 117 aa or ab -Cl tert-butyl -OCH 2

CH

3 EAS 118 aa or ab -Cl tert-butyl -CF 3 EASI 19 aa or ab -Cl tert-butyl -OCF 3 EAS 120 aa or ab -Cl tert-butyl iso-propyl EAS 121 aa or ab -Cl tert-butyl tert-butyl EATI aa or ab -F -H -H EAT2 aa or ab -F -H -Cl EAT3 aa or ab -F -H -Br EAT4 aa or ab -F -H -F EAT5 aa or ab -F -H -CH 3 EAT6 aa or ab -F -H -OCH 3 EAT7 aa or ab -F -H -OCH 2

CH

3 EAT8 aa or ab -F -H -CF 3 EAT9 aa or ab -F -H -OCF 3 EATIO aa or ab -F -H iso-propyl EATI I aa or ab -F -H tert-butyl EATl 2 aa or ab -F -Cl -H EATI3 aa or ab -F -Cl -Cl EATI4 aa or ab -F -Cl -Br EATI5 aa or ab -F -Cl -F EATl6 aa or ab -F -Cl -CH 3 EAT]7 aa or ab -F -Cl -OCH 3 EAT]8 aa or ab -F -Cl -OCH 2

CH

3 EATl9 aa or ab -F -Cl -CF 3 EAT20 aa or ab -F -Cl -OCF 3 EAT21 aa or ab -F -Cl iso-propyl EAT22 aa or ab -F -Cl tert-butyl EAT23 aa or ab -F -Br -H EAT24 aa or ab -F -Br -Cl EAT25 aa or ab -F -Br -Br EAT26 aa or ab -F -Br -F EAT27 aa or ab -F -Br -CH 3 EAT28 aa or ab -F -Br -OCH 3 EAT29 aa or ab -F -Br -OCH2CH 3 EAT30 aa or ab -F -Br -CF 3 EAT31 aa or ab -F -Br -OCF 3 EAT32 aa or ab -F -Br iso-propyl EAT33 aa or ab -F -Br tert-butyl EAT34 aa or ab -F -F -H EAT35 aa or ab -F -F -Cl EAT36 aa or ab -F -F -Br EAT37 aa or ab -F -F -F EAT38 aa or ab -F -F -CH 3 EAT39 aa or ab -F -F -OCH 3 EAT40 aa or ab -F -F -OCH 2

CH

3 EAT41 aa or ab -F -F -CF 3 EAT42 aa or ab -F -F -OCF 3 151 Compound R, R 8

R

9 EAT43 aa or ab -F -F iso-propyl EAT44 aa or ab -F -F tert-butyl EAT45 aa or ab -F -CH 3 -H EAT46 aa or ab -F -CH 3 -Cl EAT47 aa or ab -F -CH 3 -Br EAT48 aa or ab -F -CH 3 -F EAT49 aa or ab -F -CH 3

-CH

3 EAT50 aa or ab -F -CH 3

-OCH

3 EAT5 aa or ab -F -CH 3

-OCH

2

CH

3 EAT52 aa or ab -F -CH 3

-CF

3 EAT53 aa or ab -F -CH 3

-OCF

3 EAT54 aa or ab -F -CH 3 iso-propyl EAT55 aa or ab -F -CH 3 tert-butyl EAT56 aa or ab -F -OCH 3 -H EAT57 aa or ab -F -OCH 3 -Cl EAT58 aa or ab -F -OCH 3 -Br EAT59 aa or ab -F -OCH 3 -F EAT60 aa or ab -F -OCH 3

-CH

3 EAT61 aa or ab -F -OCH 3

-OCH

3 EAT62 aa or ab -F -OCH 3

-OCH

2

CH

3 EAT63 aa or ab -F -OCH 3

-CF

3 EAT64 aa or ab -F -OCH 3

-OCF

3 EAT65 aa or ab -F -OCH 3 iso-propyl EAT66 aa or ab -F -OCH 3 tert-butyl EAT67 aa or ab -F -OCH 2

CH

3 -H EAT68 aa or ab -F -OCH 2

CH

3 -Cl EAT69 aa or ab -F -OCH 2

CH

3 -Br EAT70 aa or ab -F -OCH 2

CH

3 -F EAT71 aa or ab -F -OCHCH 3

-CH

3 EAT72 aa or ab -F -OCH 2

CH

3

-OCH

3 EAT73 aa or ab -F -OCH 2

CH

3

-OCH

2

CH

3 EAT74 aa or ab -F -OCH 2

CH

3

-CF

3 EAT75 aa or ab -F -OCH 2

CH

3

-OCF

3 EAT76 aa or ab -F -OCH 2

CH

3 iso-propyl EAT77 aa or ab -F -OCH 2

CH

3 tert-butyl EAT78 aa or ab -F -CF 3 -H EAT79 aa or ab -F -CF 3 -Cl EAT80 aa or ab -F -CF 3 -Br EAT81 aa or ab -F -CF 3 -F EAT82 aa or ab -F -CF 3

-CH

3 EAT83 aa or ab -F -CF 3

-OCH

3 EAT84 aa or ab -F -CF 3

-OCH

2

CH

3 EAT85 aa or ab -F -CF 3

-CF

3 EAT86 aa or ab -F -CF 3

-OCF

3 EAT87 aa or ab -F -CF 3 iso-propyl EAT88 aa or ab -F -CF 3 tert-butyl EAT89 aa or ab -F -OCF 3

-H

152 Compound Ri Rs Rg EAT90 aa or ab -F -OCF 3 -Cl EAT91 aa or ab -F -OCF 3 -Br EAT92 aa or ab -F -OCF 3 -F EAT93 aa or ab -F -OCF 3

-CH

3 EAT94 aa or ab -F -OCF 3 -OCH3 EAT95 aa or ab -F -OCF 3

-OCH

2

CH

3 EAT96 aa or ab -F -OCF3 -CF 3 EAT97 aa or ab -F -OCF 3

-OCF

3 EAT98 aa or ab -F -OCF 3 iso-propyl EAT99 aa or ab -F -OCF 3 tert-butyl EAT100 aa or ab -F iso-propyl -H EATIO aa or ab -F iso-propyl -Cl EAT]02 aa or ab -F iso-propyl -Br EAT]03 aa or ab -F iso-propyl -F EAT104 aa or ab -F iso-propyl -CH3 EAT 105 aa or ab -F iso-propyl -OCH3 EAT 106 aa or ab -F iso-propyl -OCH 2

CH

3 EAT107 aa or ab -F iso-propyl -CF 3 EAT]08 aa or ab -F iso-propyl -OCF 3 EAT109 aa or ab -F iso-propyl iso-propyl EAT] 10 aa or ab -F iso-propyl tert-butyl EATI I I aa or ab -F tert-butyl -H EAT 112 aa or ab -F tert-butyl -Cl EAT 113 aa or ab -F tert-butyl -Br EATl 14 aa or ab -F tert-butyl -F EATI 15 aa or ab -F tert-butyl -CH3 EAT] 16 aa or ab -F tert-butyl -OCH 3 EAT] 17 aa or ab -F tert-butyl -OCH 2

CH

3 EAT] 18 aa or ab -F iert-butyl -CF 3 EATI 19 aa or ab -F iert-butyl -OCF 3 EAT120 aa or ab -F tert-butyl iso-propyl EAT121 aa or ab -F tert-butyl tert-butyl EAUI aaorab -CF 3 -H -H EAU2 aa or ab -CF 3 -H -Cl EAU3 aa or ab -CF 3 -H -Br EAU4 aa or ab -CF 3 -H -F EAU5 aa or ab -CF 3 -H -CH 3 EAU6 aa or ab -CF 3 -H -OCH 3 EAU7 aa or ab -CF 3 -H -OCH 2

CH

3 EAU8 aa or ab -CF 3 -H -CF 3 EAU9 aa or ab -CF 3 -H -OCF 3 EAU 10 aa or ab -CF 3 -H iso-propyl EAU I I aa or ab -CF 3 -H tert-butyl EAU]2 aa or ab -CF 3 -Cl -H EAUI3 aa or ab -CF 3 -Cl -Cl EAU 14 aa or ab -CF 3 -Cl -Br EAUl5 aaor ab -CF 3 -Cl -F 153 Compound Ri R 8

R

9 EAU 16 aa or ab -CF 3 -Cl -CH 3 EAU 17 aa or ab -CF 3 -Cl -OCH 3 EAU 18 aa or ab -CF 3 -Cl -OCH 2

CH

3 EAU19 aa or ab -CF 3 -Cl -CF 3 EAU20 aa or ab -CF 3 -Cl -OCF 3 EAU21 aa or ab -CF 3 -Cl iso-propyl EAU22 aa or ab -CF 3 -Cl tert-butyl EAU23 aa or ab -CF 3 -Br -H EAU24 aa or ab -CF 3 -Br -Cl EAU25 aa or ab -CF 3 -Br -Br EAU26 aa or ab -CF 3 -Br -F EAU27 aa or ab -CF 3 -Br -CH 3 EAU28 aa or ab -CF 3 -Br -OCH 3 EAU29 aa or ab -CF 3 -Br -OCH 2

CH

3 EAU30 aa or ab -CF 3 -Br -CF 3 EAU31 aa or ab -CF 3 -Br -OCF 3 EAU32 aa or ab -CF 3 -Br iso-propyl EAU33 aa or ab -CF 3 -Br tert-butyl EAU34 aa or ab -CF 3 -F -H EAU35 aa or ab -CF 3 -F -Cl EAU36 aa or ab -CF 3 -F -Br EAU37 aa or ab -CF 3 -F -F EAU38 aa or ab -CF 3 -F -CH 3 EAU39 aa or ab -CF 3 -F -OCH 3 EAU40 aa or ab -CF 3 -F -OCH 2

CH

3 EAU41 aa or ab -CF 3 -F -CF 3 EAU42 aa or ab -CF 3 -F -OCF 3 EAU43 aa or ab -CF 3 -F iso-propyl EAU44 aa or ab -CF 3 -F tert-butyl EAU45 aa or ab -CF 3

-CH

3 -H EAU46 aa or ab -CF 3

-CH

3 -Cl EAU47 aa or ab -CF 3

-CH

3 -Br EAU48 aa or ab -CF 3

-CH

3 -F EAU49 aa or ab -CF 3

-CH

3

-CH

3 EAU50 aa or ab -CF 3

-CH

3

-OCH

3 EAU51 aa or ab -CF 3

-CH

3 -OCH2CH 3 EAU52 aa or ab -CF 3

-CH

3

-CF

3 EAU53 aa or ab -CF 3

-CH

3

-OCF

3 EAU54 aa or ab -CF 3

-CH

3 iso-propyl EAU55 aa or ab -CF 3

-CH

3 tert-butyl EAU56 aa or ab -CF 3

-OCH

3 -H EAUS7 aa or ab -CF 3

-OCH

3 -Cl EAU58 aa or ab -CF 3

-OCH

3 -Br EAU59 aa or ab -CF 3

-OCH

3 -F EAU60 aa or ab -CF 3

-OCH

3

-CH

3 EAU61 aa or ab -CF 3

-OCH

3

-OCH

3 EAU62 aa or ab -CF 3

-OCH

3

-OCH

2

CH

3 154 Compound R, R 8 R< EAU63 aa or ab -CF 3

-OCH

3

-CF

3 EAU64 aa or ab -CF 3

-OCH

3

-OCF

3 EAU65 aa or ab -CF 3

-OCH

3 iso-propyl EAU66 aa or ab -CF 3

-OCH

3 zert-butyl EAU67 aa or ab -CF 3 -OCH2CH 3 -H EAU68 aa or ab -CF 3

-OCH

2

CH

3 -Cl EAU69 aa or ab -CF 3

-OCH

2

CH

3 -Br EAU70 aa or ab -CF 3

-OCH

2

CH

3 -F EAU71 aa or ab -CF 3

-OCH

2

CH

3

-CH

3 EAU72 aa or ab -CF 3

-OCH

2

CH

3 -OCH3 EAU73 aa or ab -CF 3

-OCH

2

CH

3

-OCH

2

CH

3 EAU74 aa or ab -CF 3

-OCH

2

CH

3

-CF

3 EAU75 aa or ab -CF3 -OCH 2

CH

3

-OCF

3 EAU76 aa or ab -CF 3

-OCH

2

CH

3 iso-propyl EAU77 aa or ab -CF 3

-OCH

2

CH

3 tert-butyl EAU78 aa or ab -CF 3

-CF

3 -H EAU79 aa or ab -CF 3

-CF

3 -Cl EAU80 aa or ab -CF 3

-CF

3 -Br EAU81 aa or ab -CF 3

-CF

3 -F EAU82 aa or ab -CF 3

-CF

3 -CH3 EAU83 aa or ab -CF 3

-CF

3

-OCH

3 EAU84 aa or ab -CF 3

-CF

3 -OCH2CH 3 EAU85 aa or ab -CF 3

-CF

3

-CF

3 EAU86 aa or ab -CF 3

-CF

3

-OCF

3 EAU87 aa or ab -CF 3

-CF

3 iso-propyl EAU88 aa or ab -CF 3

-CF

3 tert-butyl EAU89 aa or ab -CF 3

-OCF

3 -H EAU90 aa or ab -CF 3

-OCF

3 -Cl EAU91 aa or ab -CF 3

-OCF

3 -Br EAU92 aa or ab -CF 3

-OCF

3 -F EAU93 aa or ab -CF 3

-OCF

3 -CH3 EAU94 aa or ab -CF 3

-OCF

3 -OCH3 EAU95 aa or ab -CF 3

-OCF

3

-OCH

2

CH

3 EAU96 aa or ab -CF 3

-OCF

3

-CF

3 EAU97 aa or ab -CF 3

-OCF

3

-OCF

3 EAU98 aa or ab -CF 3

-OCF

3 iso-propyl EAU99 aa or ab -CF 3

-OCF

3 tert-butyl EAU 100 aa or ab -CF 3 iso-propyl -H EAU 101 aa or ab -CF 3 iso-propyl -Cl EAU 102 aa or ab -CF 3 iso-propyl -Br EAU 103 aa or ab -CF 3 iso-propyl -F EAU 104 aa or ab -CF 3 iso-propyl -CH 3 EAU 105 aa or ab -CF 3 iso-propyl -OCH3 EAU 106 aa or ab -CF 3 iso-propyl -OCH 2

CH

3 EAU] 07 aa or ab -CF 3 iso-propyl -CF 3 EAU 108 aa or ab -CF 3 iso-propyl -OCF 3 EAU 109 aa or ab -CF 3 iso-propyl iso-propyl 155 Compound R, R 8 Rg EAU] 10 aa or ab -CF 3 iso-propyl tert-butyl EAUl I I aa or ab -CF 3 tert-butyl -H EAU 112 aa or ab -CF 3 tert-butyl -Cl EAU 113 aa or ab -CF 3 tert-butyl -Br EAU 114 aa or ab -CF 3 tert-butyl -F EAU 115 aa or ab -CF 3 tert-butyl -CH 3 EAUI 16 aa or ab -CF 3 tert-butyl -OCH 3 EAU 117 aa or ab -CF 3 tert-butyl -OCH 2

CH

3 EAU 118 aa or ab -CF 3 tert-butyl -CF 3 EAU 119 aa or ab -CF 3 tert-butyl -OCF 3 EAU 120 aa or ab -CF 3 tert-butyl iso-propyl EAU 121 aa or ab -CF 3 tert-butyl tert-butyl EAVI aa or ab -CH 3 -H -H EAV2 aa or ab -CH 3 -H -Cl EAV3 aa or ab -CH 3 -H -Br EAV4 aa or ab -CH 3 -H -F EAV5 aa or ab -CH 3 -H -CH 3 EAV6 aa or ab -CH 3 -H -OCH 3 EAV7 aa or ab -CH 3 -H -OCH 2

CH

3 EAV8 aa or ab -CH 3 -H -CF 3 EAV9 aa or ab -CH 3 -H -OCF 3 EAVlO aa or ab -CH 3 -H iso-propyl EAV I I aa or ab -CH 3 -H tert-but yl EAV12 aa or ab -CH 3 -Cl -H EAV13 aa or ab -CH 3 -Cl -Cl EAV14 aa or ab -CH 3 -Cl -Br EAVl5 aa or ab -CH 3 -Cl -F EAVl6 aa or ab -CH 3 -Cl -CH 3 EAV17 aa or ab -CH 3 -Cl -OCH 3 EAV18 aa or ab -CH 3 -Cl -OCH 2

CH

3 EAV19 aa or ab -CH 3 -Cl -CF 3 EAV20 aa or ab -CH 3 -Cl -OCF 3 EAV21 aa or ab -CH 3 -Cl iso-propyl EAV22 aa or ab -CH 3 -Cl tert-butyl EAV23 aa or ab -CH 3 -Br -H EAV24 aa or ab -CH 3 -Br -Cl EAV25 aa or ab -CH 3 -Br -Br EAV26 aa or ab -CH 3 -Br -F EAV27 aa or ab -CH 3 -Br -CH 3 EAV28 aa or ab -CH 3 -Br -OCH 3 EAV29 aa or ab -CH 3 -Br -OCH 2

CH

3 EAV30 aa or ab -CH 3 -Br -CF 3 EAV31 aa or ab -CH 3 -Br -OCF 3 EAV32 aa or ab -CH 3 -Br iso-propyl EAV33 aa or ab -CH 3 -Br tert-butyl EAV34 aa or ab -CH 3 -F -H EAV35 aa or ab -CH 3 -F -Cl 156 Compound R, Rs R 9 EAV36 aa or ab -CH 3 -F -Br EAV37 aa or ab -CH3 -F -F EAV38 aa or ab -CH 3 -F -CH 3 EAV39 aa or ab -CH 3 -F -OCH 3 EAV40 aa or ab -CH3 -F -OCH 2

CH

3 EAV41 aa or ab -CH 3 -F -CF 3 EAV42 aa or ab -CH 3 -F -OCF 3 EAV43 aa or ab -CH 3 -F iso-propyl EAV44 aa or ab -CH 3 -F tert-butyl EAV45 aa or ab -CH 3

-CH

3 -H EAV46 aa or ab -CH 3

-CH

3 -Cl EAV47 aa or ab -CH 3

-CH

3 -Br EAV48 aa or ab -CH 3

-CH

3 -F EAV49 aa or ab -CH 3

-CH

3 -CH3 EAV50 aa or ab -CH 3

-CH

3

-OCH

3 EAV51 aa or ab -CH 3

-CH

3 -OCH2CH 3 EAV52 aa or ab -CH 3

-CH

3

-CF

3 EAV53 aa or ab -CH 3

-CH

3

-OCF

3 EAV54 aa or ab -CH 3

-CH

3 iso-propyl EAV55 aa or ab -CH 3

-CH

3 tert-butyl EAV56 aa or ab -CH 3

-OCH

3 -H EAV57 aa or ab -CH 3 -OCH3 -Cl EAV58 aa or ab -CH 3

-OCH

3 -Br EAV59 aa or ab -CH 3

-OCH

3 -F EAV60 aa or ab -CH 3

-OCH

3

-CH

3 EAV61 aa or ab -CH 3

-OCH

3 -OCH3 EAV62 aa or ab -CH 3

-OCH

3 -OCH2CH 3 EAV63 aa or ab -CH 3

-OCH

3

-CF

3 EAV64 aa or ab -CH 3

-OCH

3

-OCF

3 EAV65 aa or ab -CH 3

-OCH

3 iso-propyl EAV66 aa or ab -CH 3

-OCH

3 tert-butyl EAV67 aa or ab -CH 3 -OCH2CH 3 -H EAV68 aa or ab -CH 3

-OCHCH

3 -Cl EAV69 aa or ab -CH 3

-OCH

2

CH

3 -Br EAV70 aa or ab -CH 3

-OCH

2

CH

3 -F EAV71 aa or ab -CH 3

-OCH

2

CH

3 -CH3 EAV72 aa or ab -CH 3

-OCH

2

CH

3 -OCH3 EAV73 aa or ab -CH 3

-OCHCH

3

-OCH

2

CH

3 EAV74 aa or ab -CH 3 -OCH2CH 3

-CF

3 EAV75 aa or ab -CH 3

-OCHCH

3

-OCF

3 EAV76 aa or ab -CH 3

-OCH

2

CH

3 iso-propyl EAV77 aa or ab -CH 3

-OCH

2

CH

3 tert-butyl EAV78 aa or ab -CH 3

-CF

3 -H EAV79 aa or ab -CH 3

-CF

3 -Cl EAV80 aa or ab -CH 3

-CF

3 -Br EAV81 aa or ab -CH 3

-CF

3 -F EAV82 aa or ab -CH 3

-CF

3 -CH3 157 Compound R, Rs Ro EAV83 aa or ab -CH 3

-CF

3 -OCH3 EAV84 aa or ab -CH 3

-CF

3

-OCHCH

3 EAV85 aa or ab -CH 3

-CF

3

-CF

3 EAV86 aa or ab -CH 3

-CF

3

-OCF

3 EAV87 aa or ab -CH 3

-CF

3 iso-propyl EAV88 aa or ab -CH 3

-CF

3 tert-butyl EAV89 aa or ab -CH 3

-OCF

3 -H EAV90 aa or ab -CH 3

-OCF

3 -Cl EAV91 aa or ab -CH 3

-OCF

3 -Br EAV92 aa or ab -CH 3

-OCF

3 -F EAV93 aa or ab -CH3 -OCF 3 -CH3 EAV94 aa or ab -CH 3

-OCF

3

-OCH

3 EAV95 aa or ab -CH 3

-OCF

3

-OCH

2

CH

3 EAV96 aa or ab -CH 3

-OCF

3

-CF

3 EAV97 aa or ab -CH 3

-OCF

3

-OCF

3 EAV98 aa or ab -CH 3

-OCF

3 iso-propyl EAV99 aa or ab -CH 3

-OCF

3 tert-butyl EAV 100 aa or ab -CH 3 iso-propyl -H EAVIGI aa or ab -CH 3 iso-propyl -Cl EAV 102 aa or ab -CH 3 iso-propyl -Br EAV 103 aa or ab -CH 3 iso-propyl -F EAV 104 aa or ab -CH 3 iso-propyl -CH 3 EAV 105 aa or ab -CH 3 iso-propyl -OCH3 EAV 106 aa or ab -CH 3 iso-propyl -OCH 2

CH

3 EAV 107 aa or ab -CH 3 iso-propyl -CF 3 EAV 108 aa or ab -CH 3 iso-propyl -OCF 3 EAV 109 aa or ab -CH 3 iso-propyl iso-propyl EAVI 10 aa or ab -CH 3 iso-propyl tert-bulyl EAVI I I aa or ab -CH 3 tert-butyl -H EAV 112 aa or ab -CH 3 tert-butyl -Cl EAV 113 aa or ab -CH 3 tert-butyl -Br EAV 114 aa or ab -CH 3 tert-butyl -F EAVI 15 aa or ab -CH 3 tert-butyl -CH 3 EAV 116 aa or ab -CH 3 tert-butyl -OCH3 EAVI 17 aa or ab -CH 3 tert-butyl -OCH 2

CH

3 EAV 118 aa or ab -CH 3 tert-butyl -CF 3 EAV 119 aa or ab -CH 3 tert-butyl -OCF 3 EAV1 20 aa or ab -CH 3 tert-butyl iso-propyl EAV121 aa or ab -CH 3 tert-butyl tert-butyl 158 Table 28 OH OH R1N F N O NH N S R9 (IIIbb) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, Ro EBB -Cl -CI EBC -Cl -F EBD -Cl -CH 3 EBE -F -Cl EBF -F -F EBG -F -CH 3 EBH -CF 3 -Cl EBI -CF 3 -F EBJ -CF 3

-CH

3 159 Table 29 OH OH N O'NH N S Rg (IIIcc) 5 and phannaceutically acceptable derivatives thereof, where: Compound Ri Re EBK -Cl -Cl EBL -Cl -F EBM -Cl -CH 3 EBN -F -Cl EBO -F -F EBP -F -CH 3 EBQ -CF 3 -Cl EBR -CF 3 -F EBS -CF 3

-CH

3 160 Table 30 OH OH N N O -NH N~ S Rg (Ilidd) 5 and phannaceutically acceptable derivatives thereof, where: Compound R, R 9 EBT -CI -Cl EBU -Cl -F EBV -Cl

-CH

3 EBW -F -Cl EBX -F -F EBY -F

-CH

3 EBZ -CF 3 -Cl ECA -CF 3 -F ECB

-CF

3 -CH 3 161 Table 31 OH OH R,N F N O NH

CF

3 R14 (1IIee) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, Rw FAA -Cl -Cl FAB -Cl -F FAC -Cl -Br FAD -Cl -OCH 3 FAE -Cl -OCH 2

CH

3 FAF -F -Cl FAG -F -F FAH -F -Br FAI -F -OCH3 FAJ -F -OCH 2

CH

3 FAK -CF 3 -Cl FAL -CF 3 -F FAM -CF 3 -Br FAN -CF 3

-OCH

3 FAO -CF 3

-OCH

2

CH

3 Table 32 162 OH OH N N O- N H

CF

3 R14 (II1ff) and phannaceutically acceptable derivatives thereof, where: Compound RI R 14 FAP -Cl -Cl FAQ -Cl -F FAR -Cl -Br FAS -Cl -OCH 3 FAT -Cl -OCH 2

CH

3 FAU -F -Cl FAV -F -F FAW -F -Br FAX -F -OCH 3 FAY -F -OCH 2

CH

3 FAZ -CF 3 -Cl FBA -CF 3 -F FBB -CF 3 -Br FBC -CF 3

-OCH

3 FBD -CF 3

-OCH

2

CH

3 5 163 Table 33 OH OH R,N NH N O -NH

CF

3 R14 (IIIgg) 5 and phannaceutically acceptable derivatives thereof, where: Compound R 1 i R1w FBE -Cl -Cl FBF -CI -F FBG -Cl -Br FBH -Cl -OCH3 FBI -Cl -OCH 2

CH

3 FBJ -F -Cl FBK -F -F FBL -F -Br FBM -F -OCH 3 FBN -F -OCH 2

CH

3 FBO -CF 3 -Cl FBP -CF 3 -F FBQ -CF 3 -Br FBR -CF 3

-OCH

3 FBS -CF 3

-OCH

2

CH

3 164 Table 34 OH OH RN F N O -NH

CF

3 R14' (IIIhh) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R R 14 FBT -Cl -Cl FBU -Cl -F FBV -Cl -Br FBW -Cl -OCH 3 FBX -Cl -OCH 2

CH

3 FBY -F -Cl FBZ -F -F FCA -F -Br FCB -F -OCH 3 FCC -F -OCH 2

CH

3 FCD -CF 3 -Cl FCE -CF 3 -F FCF -CF 3 -Br FCG -CF 3

-OCH

3 FCH -CF 3

-OCH

2

CH

3 165 Table 35 OH OH N NH

CF

3 R14. (Ilii) 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, R w FCI -Cl -Cl FCJ -Cl -F FCK -Cl -Br FCL -Cl -OCH 3 FCM -Cl -OCH 2

CH

3 FCN -F -Cl FCO -F -F FCP -F -Br FCQ -F -OCH 3 FCR -F -OCH 2

CH

3 FCS -CF 3 -Cl FCT -CF 3 -F FCU -CF 3 -Br FCV -CF 3

-OCH

3 FCW -CF 3

-OCH

2

CH

3 166 Table 36 OH OH R N NH N O ,NH

CF

3 R14. 5 and pharmaceutically acceptable derivatives thereof, where: Compound R, RIw FCX -Cl -Cl FCY -Cl -F FCZ -Cl -Br FDA -Cl -OCH 3 FDB -Cl -OCH 2

CH

3 FDC -F -Cl FDD -F -F FDE -F -Br FDF -F -OCH 3 FDG -F -OCH 2

CH

3 FDH -CF 3 -Cl FDI -CF 3 -F FDJ -CF 3 -Br FDK -CF 3

-OCH

3 FDL -CF 3

-OCH

2

CH

3 167 5.4 DEFINITIONS As used herein, the terms used above having following meaning: "-(Ci-Cio)alkyl" means a straight chain or branched non-cyclic hydrocarbon 5 having from I to 10 carbon atoms. Representative straight chain -(Ci-CIo)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative branched -(C Clo)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, I -methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1 -methylpentyl, 10 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1 -dimethylbutyl, I,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, I -methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, I,3-dimethylpentyl, 1,2-dimethylhexyl, I,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 15 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

"-(C-C

6 )alkyl" means a straight chain or branched non-cyclic hydrocarbon having from I to 6 carbon atoms. Representative straight chain -(CI-C 6 )alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative branched

-(CI-C

6 )alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, 20 -neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, I-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, I -ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1 -dimethtylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

"-(CI-C

6 )haloalkyl" means a straight chain or branched non-cyclic hydrocarbon 25 having from I to 6 carbon atoms as defined above for -(C-C 6 )alkyl that is substituted with 1, 2 or 3 independently selected halo groups.

"-(CI-C

6 )hydroxyalkyl" means a straight chain or branched non-cyclic hydrocarbon having from I to 6 carbon atoms as defined above for -(C -C 6 )alkyl that is substituted with 1, 2 or 3 hydroxyl groups. 30 "-(C -C 4 )alkyl" means a straight chain or branched non-cyclic hydrocarbon having from I to 4 carbon atoms. Representative straight chain -(CI-C 4 )alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched -(Cr-C 4 )alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.

168

"-(C

2 -ClO)alkenyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C 2 -CIo)alkenyls include -vinyl, -allyl, - I -butenyl, -2-butenyl, -iso-butylenyl, -1 -pentenyl, -2-pentenyl, -3-methyl-I -butenyl, 5 -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -I -hexenyl, -2-hexenyl, -3-hexenyl, - I -heptenyl, -2-heptenyl, -3-heptenyl, -I -octenyl, -2-octenyl, -3-octenyl, -I -nonenyl, -2-nonenyl, -3-nonenyl, -I-decenyl, -2-decenyl, -3-decenyl and the like.

"-(C

2

-C

6 )alkenyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond. 10 Representative straight chain and branched (C 2

-C

6 )alkenyls include -vinyl, -allyl, - I -butenyl, -2-butenyl, -iso-butylenyl, -1 -pentenyl, -2-pentenyl, -3-methyl-I -butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl and the like.

"-(C

2

-C

6 )haloalkenyl" means a straight chain or branched non-cyclic 15 hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond as defined above for -(C 2

-C

6 )alkenyl that is substituted with 1, 2 or 3 independently selected halo groups.

"-(C

2

-C

6 )hydroxyalkenyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon 20 double bond as defined above for -(C-C)alkenyl that is substituted with 1, 2 or 3 hydroxyl groups.

"-(C

2 -CIo)alkynyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Representative straight chain and branched -(C 2 -CIo)alkynyls include -acetylenyl, 25 -propynyl, -I -butynyl, -2-butynyl, -I -pentynyl, -2-pentynyl, -3-methyl-I -butynyl, -4-pentynyl, -I -hexynyl, -2-hexynyl, -5-hexynyl, - I -heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -I-decynyl, -2-decynyl, -9-decynyl and the like.

"-(C

2

-C

6 )alkynyl" means a straight chain or branched non-cyclic hydrocarbon 30 having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond. Representative straight chain and branched (C 2

-C

6 )alkynyls include -acetylenyl, -propynyl, -I -butynyl, -2-butynyl, -I -pentynyl, -2-pentynyl, -3-methyl-I -butynyl, -4-pentynyl, -I-hexynyl, -2-hexynyl, -5-hexynyl and the like.

169

"-(C

2

-C

6 )haloalkynyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond that is substituted with 1, 2 or 3 independently selected halo groups. " -(C 2

-C

6 )hydroxyalkynyl" means a straight chain or branched non-cyclic 5 hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond that is substituted with 1, 2 or 3 hydroxyl groups. "-(Ci-Cs)alkoxy" means a straight chain or branched non cyclic hydrocarbon having one or more ether groups and from I to 6 carbon atoms. Representative straight chain and branched -(CI-C 6 )alkoxys include methoxy, ethoxy, propoxy, butoxy, 10 pentoxy, hexoxy, methoxymethyl, 2-methoxyethyl, 5-methoxypentyl, 3-ethoxybutyl, and the like.

"-(CI-C

6 )alkoxy(C-C 6 )alkyl" means a straight chain or branched non cyclic hydrocarbon having one or more ether groups and from I to 6 carbon atoms as defined above for -(CI-C 6 )alkoxy group that is substituted with a -(C-C 6 )alkyl group. 15 "-(CI-C 6 )alkoxy(C-C 6 )alkenyl" means a straight chain or branched non cyclic hydrocarbon having one or more ether groups and from I to 6 carbon atoms as defined above for -(C -C 6 )alkoxy group that is substituted with a -(C-C 6 )alkenyl group. "-(CI-C)alkoxy(C 2

-C

6 )alkynyl" means a straight chain or branched non cyclic hydrocarbon having one or more ether groups and from I to 6 carbon atoms that is 20 substituted with a -(C-C 6 )alkynyl group.

"-(CI-C

6 )alkoxy(C 3 -CS)cycloalkyl" means a straight chain or branched non cyclic hydrocarbon having one or more ether groups and from I to 6 carbon atoms as defined above for -(C -C 6 )alkyl group that is substituted with a -(C 3 -CS)cycloalkyl group 25 "-(C 3

-C

1 o)cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Representative (C 3 -CIo)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl.

"-(C

3

-C

8 )cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative (C-C8)cycloalkyls include -cyclopropyl, -cyclobutyl, 30 -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl. "-(Cs-Cs)cycloalkenyl" means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms. Representative -(C5-C 8 )cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, 170 -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cycloociatrienyl, -cyclooctatetraenyl and the like. "-(3- to 7-membered)heterocycle" or "-(3- to 7-membered)heterocyclo" means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated 5 non-aromatic, or aromatic. A 3-membered heterocycle can contain up to 1 heteroatorn, a 4-membered heterocycle can contain up to 2 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 4 heteroatons, and a 7-membered heterocycle can contain up to 5 heteroatoms. Each heteroatorn is independently selected from nitrogen, which can be quatemized; oxygen; 10 and sulfur, including sulfoxide and sulfone. The -(3- to 7-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 7-mernbered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3 15 dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. "-(5- to I 0-membered)heteroaryl" means an aromatic heterocycle ring of 5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon 20 atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. In another embodiment, both of the -(5- to 10 25 membered)heteroaryl's rings contain at least one carbon atom. Representative -(5- to 1 0-membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl, 30 triazinyl, thienyl, cinnolinyl, phthalazinyl, and quinazolinyl. "-(5- or 6-membered)heteroaryl" means a monocyclic aromatic heterocycle ring of 5 or 6 members where at least one carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- or 6-membered)heteroaryl's ring contains at least one carbon atom.

171 Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrinidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl. 5 "-CH 2 (halo)" means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen. Representative -CH 2 (halo) groups include

-CH

2 F, -CH 2 Cl, -CH 2 Br, and -CHI. "-CH(halo) 2 " means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen. Representative -CH(halo) 2 groups include 10 -CHF 2 , -CHCI 2 , -CHBr 2 , CHBrCl, CHCII, and -CHI. "-C(halo) 3 " means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen. Representative -C(halo) 3 groups include -CF 3 , -CCl 3 , -CBr 3 , and -C1 3 . "-Halogen" or "-Halo" means -F, -Cl, -Br, or -1. 15 "(C 2

-C

6 )bridge" as used herein means a hydrocarbon chain containing 2 to 6 carbon atoms joining two atoms of the piperidine, 1,2,3,6-tetrahydropyridiine or piperazine ring of the compounds of formulas I, Il and/or Ill to form a fused bicyclic ring system. The positions of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring are denoted as follows: 20 A r l , , R 4 A r , , R 4 A r , -R 4 N ()m(R3) R3m 2' (R3) X~NR N N X NR20' X N- R20 X 1,N' H Ar 2 Ar 2 Ar 2 For example, compounds of the invention can comprise a (C 2

-C

6 )bridge joining positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring (two R 3 25 groups can together form a (C 2

-C

6 )bridge). Examples of compounds where two R 3 groups can together form a (C 2

-C

6 )bridge include compounds comprising the following ring systems: 8-aza-bicyclo[3.2. l]octane; 8-azabicyclo[3.2. I ]oct-3-ene; 3,8 diazabicyclo[3.2.1 ]octane; 8-azabicyclo[3.2. I ]oct-6-ene; 8-azabicyclo[3.2. I Jocta-3,6- 172 diene; 3,8-diazabicyclo[3.2. I ]oct-6-ene; 9-aza-bicyclo[3.3.1 ]nonane; 9 azabicyclo[3.3.1 ]non-3-ene; 9-azabicyclo(3.3.1 ]non-6-ene; 9-azabicyclo[3.3. I ]nona-3,6 diene; 9-azabicyclo[3.3. I ]nona-3,7-diene; 3,9-diazabicyclo[3.3. I Inonane; 3,9 diazabicyclo[3.3. I ]non-6-ene; 3,9-diazabicyclo[3.3.1 ]non-7-ene; 1 0-aza 5 bicyclo[4.3.1 I]decane; I 0-azabicyclo[4.3.1 ]dec-8-ene; 8,1 0-diazabicyclo[4.3. I ]decane; 8,1 0-diazabicyclo[4.3.1 ]dec-3-ene; 8,1 0-diazabicyclo[4.3. I ]dec-4-ene; 8 azabicyclo[4.3. 1]dec-4-ene; 8-azabicyclo[4.3.1 ]dec-3-ene; 8-azabicyclo[4.3. 1 deca 2,6(1 0)-diene; 8-azabicyclo[4.3.1 ]deca-3,6(1 0)-diene; 8-azabicyclo[4.3.1 Ideca-4,6(10) diene; II -aza-bicyclo[5.3. I ]undecane; I I-azabicyclo[5.3.1 ]undec-8-ene; 9,11 10 diazabicyclo(5.3.l]undecane; 12-aza-bicyclo[6.3.1]dodecane; 12 azabicyclo[6.3.l]dodec-9-ene; and 10,12-diazabicyclo[6.3.l]dodecane. In connection with the Ar 2 group -(R1 )t

Y

1

Y

2 (Y3)cE 15 when E is -NH(Ci-C 6 )alkyl it is to be understood that the dashed line in the above Ar, group is absent, i.e., the Ar 2 group is -(R1 )t

Y

1

Y

2 (y 3 )C NH(C,-C6 )alkyl 20 where Y 1 , Y 2 , Y 3 , R 14 , c and t are as defined above for compounds of fonnula 1. When E is =0, =S, =C(CI-Cs)alkyl, =C(CI-C 5 )alkenyl, or =N-OR 2 0 , it is to be understood that the dashed line in the above Ar 2 group is present, i.e., the Ar 2 group is 173 - (R1 )t - (R 1)( (R14)t

Y

1 1 Y I 1 1 Y2' Y2 ' Y2 (Y3)C 0 (Y3(Y 3 )c CH(C-C 5 )alkyl (R 1 )t |-(R4)1 Y1 ,or Y2 Y2 y CH(CC)alkeny (y N-OR 2 respectively, where YI, Y-2, Y 3 , R 1 4 , R2 0 , c and t are as defined above for compounds of foninula 1. 5 The phrase "pyridyl group" means (R2)n (R2)n (R2)n. N (R2)n R1 N R N R or R N where RI, R 2 , and n are as defined above for compounds of fonnula 1, and where the 10 numbers designate the position of each atom in the ring. The phrase "pyrazinyl group" means (R2)p N R1N 15 where R I, R 2 , and p are as defined above for compounds of fonnula I. The phrase "pyrimidinyl group" means 174 (R2)P N (R 2 p N N N or where R 1 , R 2 , and p are as defined above for compounds of formula I. The phrase "pyridazinyl group" means 5 NN (R2)P.NN (R2)P N N R -(R2)p, R or 1 N where R I, R 2 , and p are as defined above for compounds of formula I. The phrase "benzoimidiazolyl group" means 10 N N'R20

R

8 Rg where R 8 , R 9 , and R 2 0 are as defined above for compounds of formula I. The phrase "benzothiazolyl group" means 15 N S

R

8 R9 where R 8 and R, are as defined above for compounds of formula I. The phrase "benzooxazolyl group" means 175 N Ra

R

9 where Rg and R 9 are as defined above for compounds of formula I. The phrase phenyl group means (R 1 4 )5 where R 14 and s are as defined for compounds of formula I. The phrase "tetrahydropyridyl" means 3 ~~ 2 (R 3 )m . N where the numbers designate the position of each atom of the tetrahydropyridyl ring. The term "animal," includes, but is not limited to, a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, and human, The phrase "pharmaceutically acceptable derivative," as used herein, includes any pharmaceutically acceptable salt, solvate, radiolabeled, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer. e.g., of a compound of formula I of the invention. In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, solvate, radiolabeled, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer, e.g., of a compound of formula I of RECTIFIED SHEET (RULE 91) ISA/EP 176 the invention. In another embodiment, the pharmaceutically acceptable derivative is a phanraceutically acceptable salt, e.g., of a compound of formula I of the invention. The phrase "pharmaceutically acceptable salt," as used herein, is any pharmaceutically acceptable salt that can be prepared from a compound of formula 1 5 including a salt formed from an acid and a basic functional group, such as a nitrogen group, of a compound of formula I. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, 10 gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also includes a salt prepared from a compound of formula I having an acidic functional group, such as a carboxylic acid functional group, and a 15 pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, cesium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; 20 tributyl amine; pyridine; picoline; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-(C-C 3 )alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-teri-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-[(C-C 3 )alkyl] -N-(hydroxy-(C

C

3 )alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)ainine, or 25 tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. One skilled in the art will recognize that, e.g., acid addition salts of a compound of formula I can be prepared by reaction of the compounds with the appropriate acid via a variety of known methods. Compounds of formula I encompass all solvates of compounds of formula 1. 30 "Solvates" are known in the art and are considered to be a combination, physical association and/or solvation of a compound of formula I with a solvent molecule, e.g., a disolvate, monosolvate or hemisolvate when the ratio of the solvent molecule to the molecule of the compound of formula I is 2:1, 1:1 or 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen 177 bonding. In certain instances, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate," as used herein, encompasses both solution-phase and isolatable solvates. A compound of formula I of the invention may be present as a solvated form with a 5 pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the invention include both solvated and unsolvated compound of formula I forms. As "hydrate" relates to a particular subgroup of solvates, i.e., where the solvent molecule is water, hydrates are included within the solvates of the invention. Preparation of solvates is known in the art. For example, M. Caira et al., J. Pharmaceut. 10 Sci., 93(3):601-611 (2004), describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparations of solvates, hemisolvate, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech,, 5(J), article 12 (2004), and A.L. Bingham etal., Chem. Cominun., 603-604 (2001). A typical, non-limiting, process involves dissolving the compound of formula I in a desired 15 amount of the desired solvent (organic, water or mixtures thereof) at temperatures above about 20 0 C to about 25'C, cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques, for example, infrared spectroscopy, can be used to show the presence of the solvent in a crystal of the solvate. 20 The invention disclosed herein is also meant to encompass all prodrugs of the compounds of the invention. "Prodrugs" are known in the art and, while not necessarily possessing any pharmaceutical activity as such, are considered to be any covalently bonded carrier(s) that releases the active parent drug in vivo. In general, such prodrugs will be a functional derivative of a compound of formula 1, 11 and/or III which is readily 25 convertible in vivo, e.g., by being metabolized, into the required compound of formula 1, 11 and/or Ill. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, Design ofProdrugs, H. Bundgaard ed., Elsevier (1985); "Drug and Enzyme Targeting, Part A," K. Widder et al. eds., Vol. 112 in Methods in Enzymology, Academic Press (1985); Bundgaard, "Design and 30 Application of Prodrugs," Chapter 5 (pp. 113-191) in A Textbook of Drug Design and Development, P. Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers (1991); Bundgaard et al., Adv. Drug Delivety Revs. 8:1-38 (1992); Bundgaard et al., J. Pharmaceut. Sci, 77:285 (1988); and Kakeya et al., Chem. Pharm. Bull. 32:692 (1984).

178 In addition, one or more hydrogen, carbon or other atoms of a compound of formula I can be replaced by an isotope of the hydrogen, carbon or other atoms. Compounds of formula I include all radiolabeled forms of compounds of formula 1. Such a "radiolabeled," "radiolabeled form", and the like of a compound of formula 1, 5 each of which is encompassed by the invention, is useful as a research and/or diagnostic tool in metabolism phannacokinetic studies and in binding assays. Examples of isotopes that can be incorporated into a compound of formula I of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 1 3 C, ' 4 C, 1 5 N, o, 0, 3P, 3P, 3S, "F, and 36Cl, respectively. Radiolabeled 10 compounds of the invention can be prepared by methods known in the art. For example, tritiated compounds of formula I can be prepared by introducing tritium into the particular compound of Formula I, for example, by catalytic dehalogenation with tritium. This method may include reacting a suitably halogen-substituted precursor of a compound of Formula I with tritium gas in the presence of a suitable catalyst, for 15 example, Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Filer, Isotopes in the Physical and Biomedical Sciences. Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). '4C-labeled compounds can be prepared by employing starting materials having a 14C carbon. 20 A compound of formula I can contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Compounds of formula I encompass all such possible forms as well as their racemic and resolved forms or any mixture thereof. When a compound of formula I contains an olefinic double bond or other center of geometric asymmetry, and unless specified 25 otherwise, it is intended to include all "geometric isomers," e.g., both E and Z geometric isomers. All "tautomers," e.g., ketone-enol, amide-imidic acid, lactam-lactim, enamine imine, amine-imine, and enamine-enimine tautomers, are intended to be encompassed by the invention as well. As used herein, the tens "stereoisomer," "stereoisomeric form", and the like are 30 general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another ("diastereomers"). The term "chiral center" refers to a carbon atom to which four different groups are attached.

179 The tern "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction. 5 The term "racemic" refers to a mixture of equal parts of enantiorners which is optically inactive. The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule. Optical isomers of a compound of formula I can be obtained by known 10 techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base. Optical purity can be stated in terms of enantiomeric excess (% ee), which is determined by the formula: % ee =maior enantiomer(mol) - minor enantiomer(mol) X 100% 15 = [ major enantiomer(mol) + minor enantiomer(mol) The phrase "effective amount," when used in connection with a compound of formula I means an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting TRPVI function in a cell. 20 The phrase "effective amount," when used in connection with the another therapeutic agent means an amount for providing the therapeutic effect of the therapeutic agent. The phrase "therapeutic index," describes the gap between the dose that is effective, and the dose that induces adverse effects. 25 When a first group is "substituted with one or more" second groups, one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups. When the number of second groups is two or greater, each second group can be the same or different. In one embodiment, the number of second groups is one or two. In another embodiment, the number of second groups is one. 30 The term "MeOH" means methanol, i.e., methyl alcohol. The term "EtOH" means ethanol, i.e., ethyl alcohol. The term "t-BuOH" means tert-butyl alcohol, i.e., 2-methylpropan-2-ol. The term "THF" means tetrahydrofuran.

180 The term "DMF" means N.N-dimethylformamide. The term "DCM" means methylene chloride, i.e., dichloromethane. The term "DCE" means dichloroethane. The term "DME" means 1,2-dimethoxyethane, i.e., ethylene glycol dimethyl 5 ether. The term "EtOAc" means ethyl acetate. The term "NH 4 0H" means arnmonium hydroxide. The term "TEA" means triethylamine. The term "MeCN" means acetonitrile. 10 The term "NaH" means sodium hydride. The term "AcOH" means acetic acid. The term "DIEA" means NN-diisopropylethylamine or N ethyldiisopropylamine, i.e., N-ethyl-N-isopropylpropan-2-amine. The term "DMSO" means dimethylsulfoxide, i.e., methylsulfinylmethane. 15 The term "DAST" means (diethylamino) sulfur trifluoride. The term "LiH-MDS" means lithium hexamethyldisilazide. The term "BuLi" means butyl lithium. The term "DPPP" means 1,3-bis(diphenylphosphino)propane. The term "BOC" means tert-butyloxycarbonyl: 20 0 Hac

CH

3 The term "TBS" means tert-butyldimethylsilyl:

CH

3 CH 3 S CH3 25

CH

3

CH

3 The term "TsOH" means p-toluenesulfonic acid or toluene-4-sulfonic acid. The term "TMSBr" means trimethylsilyl bromide or (CH 3

)

3 SiBr.

181 The term "TMSCI" means trimethylsilyl chloride or (CH 3

)

3 SiCl. The term "IBD" means inflammatory-bowel disease. The term "IBS" means irritable-bowel syndrome. The term "ALS" means amyotrophic lateral sclerosis. 5 The phrases "treatment of," "treating" and the like include the amelioration or cessation of a Condition or a symptom thereof. In one embodiment, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or a symptom thereof. The phrases "prevention of," "preventing" and the like include the avoidance of 10 the onset of a Condition or a symptom thereof. 5.5 METHODS FOR MAKING COMPOUNDS OF FORMULA I The compounds of formula I can be made using conventional organic synthesis 15 or by the illustrative methods shown in the schemes below. 5.5.1 Methods for Making Compounds of Formula I where W is C and the Dashed Line is Absent 20 The compounds of formula I where W is C and the dashed line is absent, i.e., "Piperidine Compounds," can be made using conventional organic synthesis or by the illustrative methods shown in the schemes below. 5.5.1.1 Methods for Making the Piperidine Compounds where X is 0 and R 4 25 is -OH or -F The compounds of formula I where X is 0 and R 4 is -OH can be obtained by the illustrative inethod shown below in scheme 1.1: 182 Scheme 1.1 0 Rl

(R

2 -- R ), -- (R t-butyl lithium/-78 0 C ( N N THF KN 01 "N H L Ar 2 Ar 2 2aPiperidine Compound 3a

(R

2 ) ' N\' OH (R2)p\ Nl,) (R3> ~NI t-butyl Iithium/-78 0 !Q C +L Ar 2 2b Pipe ridine Compound 3b (R22)l\N

N(

3 N (_ _ _ _ NN,0O + R N t-butyl lithium-78 0 CQ +L THF 0-JNH 2c Ar 2 Piperidine Compound Rc /OH (R2)p' N R,

(R

3 )m R, t-butyl lithiuni-78'CQ 2d Piperidine Compound 3d 183 where Ar 2 , RI, R 2 , R 3 , n, m, and p are as defined for compounds of formula I and L is a halogen. To a solution of 2a-d in the presence of tert-butyl lithium (1.7M in heptane, 6.45mL, 11 .1 2mmol) in THF (20mL) at -78 0 C is added dropwise compound I in 5 anhydrous THF (OmL). The reaction mixture is stirred at -78"C for about 3h and is quenched with aqueous NH 4 Cl at about 0*C, and then the organic and aqueous layers are separated. The aqueous layer is extracted with THF, the organic portions are combined, and dried (Na 2

SO

4 ). The resulting solution is concentrated under reduced pressure to provide a residue. The residue is chromatographed using silica gel column 10 chromatography that is eluted with ethyl acetate/hexane (gradient elution from 30:70 to 70:30) to provide a Piperidine Compound where X is 0 and R 4 is -OH (3a-d). The compounds of formula 2a-d are commercially available or can be prepared by methods known in the art. Compound 1 can be obtained by reacting 4 with an isocyanate as shown below 15 in scheme 1.2: Scheme 1.2 0

(R

3 )m 1) Ar-NCO N N 2) 4N HCI O NH H 4 1 k 2 20 where R 3 , and m are as defined above and R is Ar 2 . Compound 4 (20mmol) in chloroform is added to a solution of an isocyanate of formula R-NCO in chloroform (30mL) at about 25*C. The resultant reaction mixture is stirred for about 3 h at about 25'C then concentrated under reduced pressure to provide a residue. The residue is suspended in THF (50mL) and 4N HCI (50mL) is added to the 25 resulting solution. The reaction mixture allowed to stir for about 12h. The reaction mixture is then poured into water (200mL), and the pH is adjusted to 10 or greater with aqueous potassium carbonate base. The resulting solution is extracted with ethyl acetate and the ethyl acetate layers are combined, dried (MgSO 4 ) and concentrated under 184 reduced pressure to provide a residue that can be chromatographed using flash chromatography on a silica gel column eluted with ethyl acetate/hexane (gradient elution from 30:70 to 70:30) to provide compound 1. Isocyanates of formula Ar 2 -NCO are commercially available or are can be 5 prepared by reacting an amine Ar 2

NH

2 with phosgene according to known methods (See, e.g., H. Eckert and B. Foster, Angew. Chem. Int. Ed. Engi., 26, 894 (1987); H. Eckert, Ger. Offen. DE 3 440 14 1; Chiem. Abstr. 106, 4294d (1987); and L. Contarca et al., Synthesis, 553-576 (1996). For example, an amine Ar 2

NH

2 can be reacted with triphosgene as shown below. 10 Triphosgene DCM R-NH2 IM R-NCO Typically a solution of triphosgene (about 0.3 equivalents or 0.3eq.) in DCM (about 0.3M) is slowly added to a stirred solution of the amine (about I.Oeq.) in DCM 15 (about 0.3M) at about 25 0 C. The reaction mixture is then stirred at about 25'C for about 10 min. and the temperature is raised to about 70*C. After stirring at 70'C for 3h., the reaction mixture is cooled to 25*C, filtered, and the filtrate is concentrated to provide the isocyanate. Cyclic acetals of formula 4 are commercially available or can be prepared by 20 methods known in the art. The Piperidine Compounds where X is 0 and R 4 is -OH can also be obtained by the illustrative method shown below in schemes 1.3 and 1.4: 185 Scheme 1.3

(R

2 )n-;. N 0 OH (RA) -(R + i-butyl lithium n/ -78C R -(R3)m N NW N P L NP 5 2a 6a

(R

2 )P- '\ N N~N\ OH (R2)P OH 5 t-butyl lithium / -78'C

R

R N THF N L NP 2b 6b

(R

2 )p-s N

(R

2 p N OH R N t-butyl lithium / -78"C - 7

(R

3 )m THF N L NP 2c 6c N

(R

2 )n,- N (R2)p OH R N t-butyl lithium / -78 0 C THF N L NP 2d 6d 5 where RI, R 2 , R 3 , n, m, and p are as defined above, L is a halogen, and NP is a nitrogen protecting group (see, for example, T.W. Greene et at., Protective Groups in Organic Synthesis 494-653 (3d ed. 1999). To a solution of t-BuLi (1.7M in heptane, 18.4nL, 31.3mmol) or n-BuLi (1.6M in heptane, 19.5mL, 31.3mmol) in ether (30mL) is added dropwise a solution of a 10 compound of formula 2a-d (31.3mmol) in ether (20mL) at -78"C under a nitrogen 186 atmosphere. The resulting solution is stirred at -78'C for about I hour. To the resulting solution is added dropwise a compound of formula 5 (25.Ommol) dissolved in ether (20mL) at -78"C and the resulting mixture is allowed to stir at about -50*C for 3 h. The reaction mixture is then quenched with aqueous NH 4 Cl at 0"C and the reaction mixture 5 is extracted with ether. The organic portions are combined, dried (Na 2

SO

4 ), and concentrated under reduced pressure to provide a residue that can be chromatographed using flash chromatography on a silica gel column eluted with ethyl acetate/hexane (gradient elution 30/70 to 70/30) to provide a compound of formula 6a-d. The nitrogen protecting group is then removed to provide a compound of formula 7a-d, respectively. 10 The compound of formula 7a-d is then reacted with an isocyanate of formula R-NCO to provide the compound of formula 3a-d, as shown below in scheme 1.4: 187 Scheme 1.4

(R

2 )n N ROH Ar,-NCO Piperidine (R3m Compound 3a N H 7a

(R

2 )p'>. N N OH Ar 2 -NCO Piperidine

-(R

3 )m Compound 3b N H 7b (R2) N O H Ar,-NCO R O Piperidine (R3)m. Compound 3c N H 7c

(R

2 )p,-.- N OH Ar-,-NCO ~OA N Piperidine R (R 3 Compound 3d N H 7d 5 where Ar 2 , R I, R 2 , R 3 , n, m, and p are as defined above. To a solution of a compound of formula 7a-d (Immol) in DCM (lmL) is added dropwise a solution of isocyanate Ar 2 -NCO (Immol) in DCM (ImL) at the about 25 0 C. The resultant mixture is allowed to stir at 25*C for 3h and concentrated under reduced pressure to provide a residue that can be chromatographed using a silica gel column 10 eluted with ethyl acetate/hexane (gradient elution 10/90 to 70/30) to provide a compound of fonnula 3a-d.

188 A compound of formula 5 is commercially available or can be prepared by protecting the nitrogen atom of a compound of formula 8, shown below: 0 e)-(R3)m N H 8 5 Compounds of formula 8 are commercially available or can be prepared by methods known in the art. Any nitrogen protecting group known in the art can be used to protect the nitrogen atom in the compound of formula 8. Suitable protecting groups are described 10 in T.W. Greene et al., Protective Groups in Organic Synthesis, 494-653 (3d ed. 1999). Isocyanates of formula Arr-NCO are commercially available or can be prepared as described above. 5.5.1.2 Methods for Making Piperidine Compounds where X is S and 15 R 4 is -OH The Piperidine Compound where X is S and R 4 is -OH can be obtained by a method analogous to that described above in Scheme 1.1 to provide the Piperidine Compounds where X is 0 and R 4 is -OH (3a-d) except that a compound of fonnula 9, 20 shown below, 0

-;-(R

3 )m N S NH Ar 2 9 where R 3 and n are as defined above, is used in place of compound 1.

189 The compound of formula 9 can be obtained by a method analogous to that described above in Scheme 1.2 to provide I except that an isothiocyanate of formula Ar 2 -NCS is used in place of the isocyanate Ar 2 -NCO. Isothiocyanates are commercially available or can be prepared by reacting an 5 amine of formula Ar 2

NH

2 with thiophosgene as shown in the scheme below (See, e.g., Tett. Lett., 41(37), 7207-7209 (2000); Org. Prep. Proced., Int., 23(6), 729-734 (1991); J. Heterocycle Chem., 28(4), 1091-1097 (1991); J. Fluorine Chem., 41(3), 303-310 (1988); and Tett. Lett., 42(32), 5414-5416 (2001). 10 Ar,-NH, C(S)Cl2 - Ar,-NCS Alternatively, isothiocyanates of formula Ar 2 -NCS can be prepared by reacting an amine of formula Ar 2

NH

2 with carbon disulfide in the presence of triethylamine (TEA) in THF, followed by reaction with hydrogen peroxide and hydrochloric acid in 15 water as shown in the scheme below (See. e.g., J. Org. Chem., 62(13), 4539-4540 (1997)). 1. TEA, THF, CS, 2. H 2 02 Ar 2 -NH, 3. HCI, Water Ar 2 -NCS 20 The Piperidine Compound where X is S and R 4 is -OH can be obtained by a method analogous to that described above in Schemes 1.3 and 1.4 to provide the Piperidine Compounds where X is 0 and R 4 is -OH (3a-d) except that an isothiocyanate of formula Ar 2 -NCS is used in place of the isocyanate of formula Ar 2 -NCO. 25 5.5.1.3 Methods for Making Piperidine Compounds where X is N-CN and R 4 is -OH The Piperidine Compound where X is N-CN and R 4 is -OH can be obtained as shown below in scheme 1.5: 190 Scheme 1.5 Ar 1 OH Ar 1 OH N (R 3 )m 7 R) N Ar 2 NH2 N-(R3)m NC-N O N NC-N NH Ar 2 Piperidine 10 Compound 5 where Ari, Ar2, R 3 and m are as defined above. A compound of fonula 10 is reacted with an amine of formula Ar 2

-NH

2 in an aprotic organic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene at a temperature of from about 25*C to about the reflux temperature of the solvent for a period of from about 0.5 h to about 24 h to provide the Piperidine Compound where X is 10 N-CN and R 4 is -OH. In one embodiment, the aprotic organic solvent is di-n-propyl ether. In another embodiment, a reaction mixture of di-n-propyl ether, a compound of formula 10 and the amine of formula Ar 2

-NH

2 is heated at a temperature of about 70* to about 80* C. In another embodiment, the reaction mixture of di-n-propyl ether, a compound of formula 10 and the amine of formula Ar 2

-NH

2 is heated at a temperature of 15 about 75'C for about 12 h. The compound of fon-nula 10 can be obtained as shown below in scheme 1.6: 191 Scheme 1.6 Ar 1 OH N

-(R

3 )m 7a-d + 0 0 NC-N 0 35 10 5 where Arn is defined above for the Piperidine Compounds. A compound of formula 7a-d is reacted with diphenyl cyanocarbonimidate 35 (commercially available from Sigma-Aldrich, St. Louis, MO) in an aprotic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene to provide the compound of 10 formula 10. In one embodiment, the aprotic solvent is DCM and the reaction mixture of the compound of formula 7a-d and diphenyl cyanocarbonimidate 35 is allowed to react at about 25"C. In another embodiment, the aprotic solvent is toluene and the reaction mixture of the compound of formula 7a-d and diphenyl cyanocarbonimidate 35 is allowed to react at about I 10*C. The compound of formula 7a-d and diphenyl 15 cyanocarbonimidate 35 is typically allowed to react for a period of about 0.5 h to about 24 h. Typically the compound of formula 10 is used without further purification. The compounds of formula 7a-d can be obtained as described above in section 5.5.1.1. 20 5.5.1.4 Methods for Making Piperidine Compounds where X is N-OH and

R

4 is -OH The Piperidine Compound where X is N-OH and R4 is -OH can be prepared by a method analogous to that described above in Scheme 1.1 to provide the Piperidine 25 Compounds where X is 0 and R 4 is -OH (3a-d) except that a compound of formula 11, shown below, 192 0

-(R

3 )m N PO-N N H R 11 where R 3 and m are as defined above, R is Ar 2 , and P is an oxygen/hydroxyl protecting group, is used in place of compound 1 followed by removal of the oxygen/hydroxyl 5 protecting group. The compound of formula 11 can be obtained as shown below in scheme 1.7: Scheme 1.7 0 O O Protecting -(R3)m NH->OH , -(R3)m group -(R3)m N Ethanol 80 0 C N N

H

3 C-S N HO-N NH OP-O-N NH R RR R 12 13 11 10 where R 3 and m are as defined above, R is Ar 2 , and OP is an oxygen/hydroxyl protecting group. A compound of formula 12 (about 0.3mmol) is reacted with hydroxylamine (50 15 weight percent in water, about 5.8mmol) in about 1.5mL of ethanol with stirring at a temperature of about 80'C for about 2 h. The mixture is then concentrated under reduced pressure to provide a compound of formula 13. The hydroxyl group of the compound of formula 13 is then protected using an oxygen/hydroxyl protecting group to provide the compound of formula 11. An oxygen/hydroxyl protecting group known in 20 the art can be used to protect the oxygen atom in the compound of formula 13. Suitable oxygen/hydroxyl protecting groups are disclosed in T.W. Greene er al., Protective Groups in Organic Synthesis 17-200 (3d ed. 1999). In one embodiment, the compound of formula I1 is further treated using column chromatography or recrystallized.

193 The compound of formula 12 can be obtained as shown below in scheme 1.8: Scheme 1.8 0 0

N)-(R

3 )m CH31 7 (R)m N TEA N S NH H 3 C-S N R R 9 12 5 where R 3 and m are as defined above and R is Ar. A solution of a compound of formula 9 (about 0.6mmol), obtained as described above, in DCM is reacted with iodomethane (about 0.9mmol) in about 3mL of tetrahydrofuran with stirring at about 25 0 C for about 12 h. Excess iodomethane is 10 removed from the mixture under reduced pressure. A solution of triethylamine (about 1.74mmol) in about 2.5mL of ethyl acetate is then added to the mixture and the mixture is allowed to stir for about 2 h. The mixture is then concentrated under reduced pressure to provide the compound of formula 12 that can then be further treated if desired. In one embodiment, the compound of formula 12 is further treated using column 15 chromatography or recrystallization. 5.5.1.5 Methods for Making Piperidine Compounds where X is N-OR 10 and R4 is -OH 20 The Piperidine Compound where X is N-ORIO and R 4 is -OH can be obtained by a method analogous to that described above in Scheme 1.1 to provide the Piperidine Compounds where X is 0 and R 4 is -OH (3a-d) except that a compound of formula 14, shown below, 194 0

-(R

3 )m N

R

10 0-N NH R 14 where R 3 , RIO and m are as defined above and R is Ar 2 is used in place of compound 1. The compound of formula 14 can be prepared by reacting the compound of 5 formula 13, obtained as described above in Scheme 1.7, with L-(CI-C 4 )alkyl, where L is -1, -Br, -Cl, or -F in the presence of sodium hydride in DMF at about 25 0 C. In one embodiment, L is -1 or -Br. 5.5.1.6 Methods for Making Piperidine Compounds where R4 is a Group 10 Other Than -OH The Piperidine Compounds where R4 is -halo, -OCF 3 , -(C IC 6 )alkyl, -CH 2 OH,

-CH

2 CI, -CH 2 Br, -CH 2 I, -CH 2 F, -CH(halo) 2 , -CF 3 , -OR Io, -SR 1 o, -COOH, -COORio, -C(O)Rlo, -C(O)H, -OC(O)Rio, -OC(O)NHR 10 . -NHC(O)RI 3 , -SOR 10 , -CON(R] 3

)

2 or 15 -NO 2 can be obtained from the Piperidine Compounds where R.4 is -OH. The Piperidine Compounds where R4 is -F can be obtained by reacting a Piperidine Compound where R 4 is -OH with fluorinating reagents such as DAST, Deoxo-Fluor, SF 4 , HF, KF, CsF, Yarovenko's reagent, Ishikawa's reagent, according to the procedure described in M. Schlosser et al., Tetrahedron 52(24):8257-8262 (1996). 20 The Piperidine Compounds where R4 is -Cl can be obtained by reacting a Piperdine Compound where RA is -OH with SOC 2 or PCI 5 according to the procedure described in J. Amer. Chem. Soc. 120(4):673-679 (1998) or with CH 3 COCl according to the procedure described in Tett. Lett. 41(47):9037-9042 (2000). The Piperidine Compounds where R4 is -Br can be obtained by reacting a 25 Piperidine Compound where R4 is -OH with pyridine and SOBr 2 according to the procedure described in J Organometallic Chemistirv 627(2):179-88 (2001) or by 195 reacting a Piperidine Compound where RA is -OH with pyridine and PPh 3 /Br 2 according to the procedure described in J. Amer. Chem. Soc. J12 (9):3607-14 (1990). The Piperidine Compounds where R 4 is -1 can be obtained by reacting a Piperidine Compound where R 4 is -OH with H I in acetic anhydride according to the 5 procedure described in J. A mer. Chem. Soc. 87(3):539-542 (1965). The Piperidine Compounds where R 4 is -CH 3 can be obtained by reacting a Piperidine Compound where R 4 is -OH with PC 5 and CH 3 TiC 3 according to the procedure described in Angewandte Chemie, 92(11), 933-4 (1980). The Piperidine Compounds where R 4 is -(CI-C 6 )alkyl can be obtained by 10 reacting a Piperidine Compound where R 4 is -OH with p-toluenesulfonic acid in toluene followed by n-butyl lithium and X-(Ci-C 6 )alkyl, where X is a halogen, according to the procedure described in Charles J. Bamett, el al, J. Org. Chem., 54(20) 4795-4800 (1989) followed by hydrogenating the product according to the procedure described in Thomas E. D'Ambra et al, J. Org. Chem,, 54(23) 5632-5 (1989) as described below. 15 N 1) p-TsOH/Toluene, reflux N Pd/H N OHFR4R 2) n-BuLi/THF, R 4 X R 4 N N N II I NP NP NP The Piperidine Compounds where R4 is -CH 2 OH can be obtained by reacting a Piperidine Compound where R4 is -COOH with LiAlH 4 according to procedures known 20 in the art. The Piperidine Compounds where R 4 is -CH2OH can be obtained by reacting a Piperidine Compound where R 4 is -C(O)H with NaBH 4 according to procedures known in the art. The Piperidine Compounds where R4 is -COOH can be obtained by reacting a Piperidine Compound where R 4 is -CN with KOH according to procedures known in the 25 art. The Piperidine Compounds where R 4 is -CN can be obtained by reacting a Piperidine Compound where R 4 is -OH with KCN and SOC1 2 according to the procedure described in A rmyanskii Khimicheskii Zhurnal. 30(9):723-727 (1977).

196 The Piperidine Compounds where R 4 is -C(O)H can be obtained by reacting a Piperidine Compound where R 4 is -CN with di-iso-butylaluminum hydride (DIBAL-H) according to procedures known in the al. The Piperidine Compounds where R4 is -OCF 3 can be obtained by reacting a 5 Piperidine Compound where R 4 is -OH with CS 2 ; methyl idodide; and bromosuccinimide and pyridine/HF in DCM according to the procedure described in Chemical Communications (Cambridge) 3:309-310 (1997) or Bulletin of the Chemical Society ofJapan, 73(2):471-484 (2000). The Piperidine Compounds where R 4 is -CH 2 Cl can be obtained by reacting a 10 Piperidine Compound where R 4 is -CH 2 OH, obtained as described above, with PCl5 according to the procedure described in J. Armer. Chem. Soc., 120(4):673-679 (1998). The Piperidine Compounds where R4 is -CH 2 Br can be obtained by reacting a Piperidine Compound where R 4 is -CH 2 OH, obtained as described above, with SOBr2 according to the procedure described in J. Organomet. Chem., 627(2): 179-188 (2001) or 15 with PPh 3 /Br 2 according to the procedure described in J. Amer. Chem. Soc., S12(9):3607-3614 (1990). The Piperidine Compounds where R4 is -CH 2 F can be obtained by reacting a Piperidine Compound where R4 is -CH 2 OH, obtained as described above, with I eq. of DAST according to the procedure described in M. Schlosser et al., Tetrahedron 20 52(24):8257-8262 (1996) and Organic Letters. 3(17):2713-2715 (2001). The Piperidine Compounds where R4 is -CH 2 1 can be obtained by reacting a Piperidine Compound where R4 is -CH 2 OH, obtained as described above, with PPh 3 /l according to the procedure described in Organic Process Research and Development 6(2):190-191 (2002). 25 The Piperidine Compounds where R 4 is -CH(halo) 2 can be obtained by reacting a Piperidine Compound where R 4 is -C(O)H, obtained as described above, with

(F

3

CSO

2

)

2 0 followed by Mg(halo) 2 in CS 2 according to the procedure described in Synthesis 12:1076-1078 (1986). The Piperidine Compounds where R4 is -CHF 2 can also be obtained by reacting a 30 Piperidine Compound where R 4 is -C(O)H, obtained as described above, with 2eq. of DAST according to the procedure described in M. Schlosser et al., Tetrahedron 52(24):8257-8262 (1996) and Organic Letters. 3(1_7):2713-2715 (2001). The Piperidine Compounds where R 4 is -CF 3 can be obtained by reacting a Piperidine Compound where R 4 is -C(O)H, obtained as described above, with copper (I) 197 iodide and sodium trifluoroacetate according to the procedure described in U.S. Patent No. 4,866,197 to Bauman. The Piperidine Compounds where R 4 is -ORjo can be obtained by reacting a Piperidine Compound where R 4 is -OH, obtained as described above, with Rio-X where 5 X is a halogen in the presence of NaOH according to the procedure described in European Journal of Medicinal Chemistry 24(4):391-396 (1989). The Piperidine Compounds where R 4 is -SR 1 3 can be obtained by reacting a Piperidine Compound where R 4 is -OH, obtained as described above, with R 13 -SH according to the procedure described in U.S. Patent No. 4,409,229 to Ong et al. or 10 Journal of Medicinal Chemistry 24(l):74-79 (198 1). The Piperidine Compounds where R4 is -COOR 10 can be obtained by esterifying a Pipendine Compound where R 4 is -COOH, obtained as described above, with Rio-OH. Methods to esterify carboxylic acids are known in the art. The Piperidine Compounds where R 4 is -OC(O)RIo can be obtained by reacting a 15 Piperidine Compound where R4 is -OH, obtained as described above, with R 1 OC(O)CI according to the procedure described in European Journal of Medicinal Chemistrv 24(4):391-396 (1989). The acid chlorides, RjoC(O)Cl, can be prepared from the corresponding carboxylic acid, RjoCOOH, using procedures known in the art. The Piperidine Compounds where R 4 is -NHC(O)R 3 can be obtained by reacting 20 a Piperidine Compound where R 4 is -OH with RIOCN in the presence of H 2 S0 4 followed by K 2

CO

3 in DCM as described in Bioorganic and Medicinal Chemistry Letters 10(17):2001-2014 (2000). The Piperidine Compounds where R 4 is -OC(O)NH 2 can be obtained by reacting a Piperidine Compound where R 4 is -OH with C1 3 CCONCO in DCM at 0"C with stirring 25 for about 2 h and then adding to the resulting mixture K 2

CO

3 in methanol-water and allowing the resulting mixture to stir for about 4 h at 0*C and about 2 h at about 25'C according to the procedure described in Christopher P. Holmes et al, J. Org. Chem., 54(_):98-108 (1989). The Piperidine Compounds where R 4 is -OC(O)NHRn can be obtained by 30 reacting a Piperidine Compound where R 4 is -OH with an isocyanate of formula RIONCO in refluxing THF for about 24 h at about 25 0 C according to the procedure described in Andre Hallot et al, J. Med. Cheni., 29(3):369-375 (1986). The Piperidine Compounds where R 4 is -SO2RIo, -NO,, -CN, -CORio, -COORio, and CON(RI 3

)

2 can be prepared by the illustrative methods described below.

198 A compound of formula 15 is reacted with a compound of formula 16a-d in the presence of a base according to the procedure described in Journal of Heterocycle Chemistrv, 23(1 ):73-75 (1986) or Organic Chemistry and Procedures International 28(4):478-480 (1996) to provide a compound of formula 17a-d, as described below in 5 scheme 1.9: Scheme 1.9 (R2)n r--N

(R

2 )n \ / Base R N + R 1 N 1(R3)m NN NP Y 15 16a NP . 17a (R2)pN

(R

2 )P N y base ~ N ~ 7

(R

3 )M 15 + RN NP 16b 17b (R2)p N,- N (R2)p N bas base R 15 + RN

-(R

3 )m N 16c NP 17c

(R

2 )n rNN (R2)p \ N Base R 15 + R1 N ,(R 3 )m N 16d NP 17d where RI, R 2 , R 3 , n, m, and p are as defined above; Y is -S0 2 Rj 0 , -NO 2 , -CN, -CORI,, 10 -COORIO, or CON(R 3

)

2 ; and NP is a nitrogen protecting group.

199 The nitrogen protecting group is then removed from the compound of formula 17a-d to provide a compound of formula 18a-d. Any nitrogen protecting group known in the art can be used to protect the nitrogen in the compound of formula 15. To provide the Piperidine compounds of formula I where X is 0 and R4 is 5 -SO 2 Ro, -NO 2 , -CN, -CORj 0 , -COORIo, or CON(R 3

)

2 , the compound of formula 18a-d is then reacted with an isocyanate of formula R-NCO according to a procedure analogous to that described above in scheme 1.4 and described below in Scheme 1.10: 200 Scheme 1.10 (R)nN(R2 )n -N R1 R, (R3),, (R3 + R-NCO NN HNH 18a R (R2)p (R2)P N y R N (R3k + R-NCO R -- (R3n N N HO CNH 18b

(R

2 )p N

(R

2 )pl N R Y Y R -(R 3 )m + R-NCO - N (R 3 )m N N H O- NH 18c

(R

2 ) N,N

(R

2 )n N N Y Y R1 7

-(R

3 )m + R-NCO -(R3 N HOCNH 18d 5 where R1, R 2 , R 3 , n, m, and p are as defined above; Y is -SO2R 10 , -NO 2 , -CORIO, or

-CON(R

1 3

)

2 ; and R is Ar2 A compound of formula 18a-d is reacted with a compound of formula R-NCO according to a procedure analogous to that described above in Scheme 1.4.

201 To provide the Piperidine Compounds where X is S and R 4 is -S0 2 RIo, -NO 2 , -CN, -CORIo, -COOR 10 , or CON(R 3

)

2 , the compound of formula 18a-d is reacted with an isothiocyanate of formula R-NCS according to a procedure analogous to that described above in Section 5.5.1.2. 5 To provide the Piperidine Compounds where X is N-CN and R 4 is -SO 2 Rio,

-NO

2 , -CN, -COR o, -COORio, or CON(R, 3

)

2 , the compound of formula 18a-d is reacted with diphenyl cyanocarbonimidate 35 and then an amine of formula R-NH 2 according to a procedure analogous to that described above in Section 5.5.1.3. To provide the Piperidine Compounds where X is N-OH and R 4 is -S0 2

R

0 , 10 -NO 2 , -CN, -COR 10 , -COOR 10 , or CON(R 3

)

2 , the Piperidine Compound where X is S and R 4 is -SO 2 Rj 0 , -NO 2 , -CN, -CORIO, -COORio, and CON(R 3

)

2 is reacted with methyl iodide according to a procedure analogous to that described above in scheme 1.8 to provide a compound of formula 19, Ar 1

-(R

3 )m N

H

3 C-S' N R 15 19 where Arl, R 3 , n, and Y are as defined above and R is Ar 2 . The compound of formula 19 is then reacted with hydroxylarnine in ethanol according to a procedure analogous to that described above in Scheme 1.8 to provide the 20 Piperidine Compounds where X is N-OH and R4 is -S0 2

RI

0 , -NO 2 , -CN, -CORio, -COORIo, or CON(R 3

)

2 . To provide the Piperidine Compounds where X is N-OR 10 and R 4 is -S0 2 R,

-NO

2 , -CN, -COR 10 , -COORIO, or CON(R 3

)

2 , the Piperidine Compound where X is NOH and R 4 is -SO 2

R

1 0 , -NO 2 , -CN, -CORjo, -COORjo, and CON(R 3

)

2 is reacted with 25 X-(CI-C 4 )alkyl, where X is -1, -Br, -Cl, or -F in the presence of triethylamine according to a procedure analogous to that described above in Section 5.5.1.6. The compound of formula 15 is commercially available or can be prepared by methods known in the art.

202 The compounds of formula 16a-d where Y is -S0 2

R

10 can be obtained by reacting a compound of formula 16a-d, where Y is a halogen, with RIOSOH according to the procedure described in J. Org. Chiem. 67(13):4387-4391 (2002) or international publication no. WO 02/48098. 5 The compounds of formula 16a-d where Y is -CN can be obtained by reacting a compound of formula 16a-d, where Y is a halogen, with potassium cyanide according to the procedure described in Farmaco 45(9):945-953 (1990). The compounds of formula 16a-d where Y is -COOR 10 can be obtained by reacting a compound of formula 16a-d, where Y is a halogen, with (a) potassium 10 cyanide, (b) water, and (c) RIOH and SO 2 Cl according to the procedure described in Farmaco 45(9):945-953 (1990). The compounds of fonrula 16a-d where Y is -COR 1 0 can be obtained by reacting a compound of formula 16a-d, where Y is a halogen, with RIOC(O)H and trimethylsilyl cyanide according to the procedure described in international publication 15 no. WO 01/81333. The compounds of formula 16a-d where Y is -CON(Ri 3

)

2 can be obtained by reacting a compound of formula 16a-d, where Y is a halogen, with (a) potassium cyanide, (b) water, and (c) NH(R 13 )2 and SO 2 CI according to the procedure described in Farmaco 45(9):945-953 (1990). 20 The compounds of formula 16a-d where Y is -NO 2 can be obtained by reacting a compound of formula 2a-d where X is -CH 3 with NaNH 2 in liquid NH 3 followed by

CH

3

CH

2

CH

3

-ONO

2 at a temperature of less than -33"C to provide a nitronate that is then reacted under acidic condition to provide the compound of formula 16a-d where Y is

-NO

2 according to the procedure described in H. Feuer et al., J. Am. Chem. Soc. 25 91(7):1856-1857 (1969) and as described in scheme 1.11 below, where RI, R 2 , n and p are as defined above.

203 Scheme 1.11 -NN R2 N N R1

CH

3

CH

3

CH

3

CH

3 2a 2b 2c 2d 1) NaNH 2 /liquid NH 3 2) CH 3

CHICH

2 -ON0 2 , < -33 0 C 3) H* (R2)n (R2 (R 2 )p N (R2)p N N -N -N R1 R1 R1 N R 1

NO

2

NO

2

NO

2

NO

2 The compounds of fonnula 16a-d where Y is -halo are commercially available or 5 can be prepared by methods known in the art. Certain Piperidine Compounds can have one or more asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A Piperidine Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses Piperidine Compounds and their uses as described herein in the 10 form of their optical isomers, diastereomers, and mixtures thereof, including a racemic mixture. Optical isomers of the Piperidine Compounds can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base. In addition, one or more hydrogen, carbon or other atoms of a Piperidine 15 Compound can be replaced by an isotope of the hydrogen, carbon or other atoms. Such compounds, which are encompassed by the invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. 5.5.1.7 Methods for Installing R 2 Groups on Ar, When RZ is Q 20 The conversion of a halide, L to a vinyl group via a Suzuki cross-coupling reaction is exemplified in scheme 1.12 below, where R 1 , R 2 , R 4 and p are as defined 204 above, L is defined as -halo, and P is a nitrogen protecting group known in the art. While this example demonstrates the conversion when L is in the 5-position of the pyridyl ring of 20, the transformation can be carried out when L is in other positions on the aryl ring as well. Moreover, the same technique can be used when Ar, is another 5 pyridyl ring, pyrimidinyl, pyrazinyl or pyridazinyl ring. Scheme 1.12 L/ (R) N (R 2 )n-. N /R)n N R 4 \ 0 R4 R Pd(DPPF) 2 C1 2 , RR (R3)m DMF, 100 0 C, 14h N (R3) N N> NP NP 20 21 10 To a degassed DMF solution of compound 20 (1.6 mmol) in a 100 mL round bottom flask, is added CsF (3.2 mmol), di-n-butyl vinyl boronic ester (0.388 mL, 1.76 inmol) and palladium diphenylphosphinoferrocene dichloride (Pd(DPPF) 2 Cl 2 , 0.128 mmol). The resulting mixture is stirred at I 00"C for 14 hr, then cooled to a temperature 15 of about 25'C and diluted with 100 mL ethyl acetate, which was washed with brine (3 x 50 mL). The organic layer was isolated, dried, and concentrated under reduced pressure. Silica gel column chromatography gives the product, 21. Other techniques for the installation of the vinyl group are shown in schemes 1.13a and 1.13b. In scheme 1.13a, the first step involves the oxidation of a benzylic 20 alcohol to an aldehyde. This is followed by a Wittig olefination, to yield the vinyl group. Once again, while this example demonstrates the conversion when the starting benzylic alcohol is in the 5-position of a pyridyl ring, similar conversions can be carried out at other positions. Moreover, the same technique can be used when Ar, is another pyridyl ring, pyrimidinyl, pyrazinyl or pyridazinyl.

205 Scheme 1.13a

(R

2

CH

2 OH

(R

2 CHO MnO, ( -R2n N

CH

2 Cl2 R1 N L 22 23

(R

2 )n CHO PPh 3

CH

3 Br

(R

2 )n (t-BuO)K N Benzene/THF N R,-1 R,-1 L L 23 24 5 To a 500 mL round-bottom flask, manganese oxide (0.50 mol) is added to a solution of 22 (50.0 mmol) in anhydrous CH 2

C

2 (150 mL). The resulting mixture is stirred at a temperature of about 25*C for 48 h and then the reaction mixture is filtered through CELITE and concentrated. The resulting mixture is chromatographed by silica gel column chromatography eluting with a gradient of ethyl acetate (0%-40%)/hexanes 10 to provide aldehyde 23. To a cooled 0*C, stirred slurry of methyltriphenylphosphonium bromide (10.0 g) in toluene (200 mL) is added potassium t-butoxide (3.07 g) portionwise to produce a yellow slurry. After I hr, the reaction mixture is cooled to -200C, and 23 (22.72 mmol) dissolved in tetrahydrofuran (6 mL) is added dropwise to produce a purple colored 1 5 slurry. The reaction mixture is heated to 000 and stirred for additional I hr. Then the reaction mixture is treated with saturated aqueous brine (150 mL) and diluted with ethyl acetate (200 mL). The resulting organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting product is chromatographed by silica gel column chromatography column, eluting with a 20 gradient of ethyl acetate (0%-10%)/hexanes to provide product 24. In scheme 1.13b, the first step involves the reduction of a benzylic ketone to a hydroxyl. This is followed by a dehydration reaction to yield the vinyl group. Once again, while this example demonstrates the conversion when the starting benzylic ketone 206 is in the 5-position of a pyridyl ring, similar conversions can be carried out at other positions. Moreover, the same technique can be used when Ar, is another pyridyl ring, pyrimidinyl, pyrazinyl or pyridazinyl. Scheme 1.13b 5 0 HO N RN L L HO (R 2)n (R2- O=50O OH N RN R, LL 23a 24 To a well-stirred suspension of 23 (665 g, 3.5 mol) in methanol (3.5L) at 0*C is added sodium borohydride (66.21 g, 1.75 mol) portionwise at a rate such that the 10 reaction mixture temperature does not exceed 5'C. Afier the addition is complete, the reaction mixture is warmed to a temperature of about 25"C and stirred an additional 1 h. The reaction mixture is concentrated under reduced pressure and the residue mixed with 2L diethyl ether and 2L IN HCL. The layers are separated and the aqueous layer extracted twice with diethyl ether (250 mL for each extraction). The organic portions 15 are combined, dried (MgSO 4 ), and concentrated under reduced pressure to provide 23a. To a solution of 23a (311 g, 1.62 mol) in chlorobenzene (3 L) is added p-toluene sulfonic acid (431 g, 2.5 mol). The reaction mixture is heated to reflux, about 140*C, and water is removed concurrently. At the completion of the reaction, the mixture is concentrated under reduced pressure to about 500 mL, diluted with 2L of water, and 20 extracted three times with ethyl acetate (I L for each extraction). The organic portions are combined, dried (Na 2

SO

4 ), and concentrated under reduced pressure under mild 207 heating to provide a residue. The residue is added to 500 mL of methylene chloride and applied to the top of column packed with 2 kg silica eluted with a 0% to 10% gradient of ethyl acetate in hexane to provide 24. 5 Vinyl groups are highly versatile, because they are a synthetic handle that can be further modified. It is well known in synthetic organic chemistry that olefin hydrolysis yields a benzylic hydroxyl group, hydroboration gives a primary hydroxyl group, ozonolysis gives an aldehyde or ketone, oxidation gives a carboxylic acid, olefin metathesis extends the chain, and dihydroxylation gives a 1,2-diol. Many additional 10 olefin functionalization techniques are available to those skilled in organic synthesis. Once functionalized, the group can undergo further transformations. Exemplified in scheme 1.14 is the vinyl group of 21 undergoing an asymmetric dihydroxylation.

208 Scheme 1.14 / OH

HO

(R2 N

(R

2 N R4 AD-mix a R4 R1, t-BuOH/H20 R1

-(R

3 )m

-(R

3 )m N N NP NP 21 25a OH HO H

(R

2 N r)k N R4 AD-mix pR4 R1-N> i-BuOH/H 2 0 R1

R

3 )m -(R3)m N N NP NP 21 25b HOH (R2 N

(R

2 ) N

R

4 OsO, NMO R4 R1 R )m H 2 0/Acetone R1 -(R3)m -(3)m N N NP NP 21 25c 5 In a 100 mL round bottom flask, AD-mix a (0.5 g) is added to a mixture of i-butanol and water (2mL/2mL) and the mixture is stirred at a temperature of about 254C for 0.5 hr, and then cooled to 0*C. This solution is quickly poured into another ice chilled flask, which contains compound 21 (0.41 nmol). The mixture is stirred vigorously in an ice bath for 96 h, and then diluted with ethyl acetate (50 rnL) and 2 mL 10 saturated Na 2

S

2 0 5 . The ethyl acetate layer is isolated, dried, and concentrated under reduced pressure with a rotary evaporator to provide 25a. The other enantiomer, can be synthesized by the reaction of 21 with AD-mix P to yield 25b. As demonstrated in scheme 1.14, the stereochemistry (R or S) of the resulting diol, is dependent upon the 209 chirality of the ligand used in the AD mix as described in Sharpless et al., J. Org. Chem. 57:2768-2771 (1992). AD-mix is composed of the following components: potassium osmate (K 2 0sO 2

(OH)

4 ), potassium ferricyanide (K 3 Fe(CN) 6 ), potassium carbonate

(K

2 C0 3 ), and the chiral ligands are shown in.scheme 1.15, Scheme 1,15 Ligand for AD-mix a N N-N 'N 0 0 HH - H MeO OMe N N Ligand for AD-mix P: N-- N-N H . H H MeO OMe N N The racemic diol, 25c, can be synthesized by methods known in the art, using osmium tetroxide (Os04) and N-methyl morpholine N-oxide (NMO) in an aqueous acetone solution. 5.5.2 Methods for Mnking Compounds of Formula I where W is C and the Dashed Line is Present The compounds of formula I where W is C and the dashed line is present, i.e., "Tetrahydropyridyl Compounds," can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below.

210 5.5.2.1 Methods for Making the Tetrahydronyridyl Compounds Where X isO0 The Tetrahydropyridyl Compounds where X is 0 can be obtained by the following illustrative method shown below in Schemes 2.1 and 2.2, where R 3 , Ar 2 , and m are as defined above. Scheme 2.1 0 O-SO2CF 3 1. LiHMDS N. Ng (R3m 2- l N R 3 )m C N O--' N H O-" N H 1r2 2 N(SO 2

CF

3

)

2 I Ar 2 26 27Ar 2 1 27 Referring to scheme 2.1 above, compound 1 (about 3.6mmol) is dissolved in THF (OOrmL) and the resulting solution cooled to -78*C. To the cooled solution is added LiHMDS (8.75mmol) and the reaction mixture is stirred at -78*C for 2 h. Compound 26 (about 3.6mmol, Sigma-Aldrich) is then added to the reaction mixture and the reaction mixture is stirred at -78*C for 2 h. The reaction mixture is then allowed to warm to 25'C and concentrated under reduced pressure to provide a compound of formula 27, The compound of formula 27 is then reacted with a compound of formula 28a-d to provide the Tetrahydropyridyl Compound where X is 0 as shown below in scheme 2.2: 211 Scheme 2.2

(R

2 )n (-N 2 7 + N P d ( P P h 3 ) 4 R , R - N THF, reflux -( ZnBr N- -(R 3 )m 28a OLNH Ar 2 (R2)p N 27 + -N Pd(PPh 3

)

4 R R1 TH F, ref lux -(R)m Zn Br N 28b O NH Ar 2 NH (R2)p N (R2)p\-NR N 27 + Pd(PPh 3

)

4 27 + R N TH F, reflux ZnBr N 28c OLNH Ar 2 0 NH (R2)p ' (R2)pX Nr 27 + R1 N Pd(PPh 3

)

4 R1 N ZnBr THF, reflux 28d R 3 )m N O NH Ar 2 5 where RI, R 2 , R 3 , Art, n, n, and p are as defined above.

212 Pd(PPh 2

)

4 (0.1 Immol) is dissolved in THF (about 50mL) and the compound of formula 27 (about 2.2mmol) is added to the resulting solution followed by a compound of formula 28a-d (about 6.6mmol as a 0.5M solution in THF). The reaction mixture is then heated for I h at the reflux temperature of the solvent. The reaction mixture is allowed to cool to 25*C and concentrated under reduced pressure to provide the Tetrahydropyridyl Compound where X is 0. The Tetrahydropyridyl Compound where X is 0 can be further treated if desired. In one embodiment, the Tetrahydropyridyl Compound where X is 0 is chromatographed using silica gel column chromatography -followed by trituration with ethyl acetate. Where m= , R 3 is bonded to an sp3 carbon, and 27 is either racemic or a mixture of enantiomers, the resulting Tetrahydropyridyl Compound in scheme 2.2 will also be racemic or an enantiomeric mixture. If a single stereoisomer is desired, it is possible to use chiral separation techniques known in the art, such as chiral chromatography or chiral resolution, to isolate a single isomer. Another technique that can be used to couple the tetrahydropyridyl group and Ar, is the Suzuki cross-coupling reaction. This is accomplished by a catalyst mediated reaction of 2a with the tetrahydropyridyl borane, 29 as exemplified in scheme 2.3 below. While the reaction shown has Ar as a pyridyl group, the same technique can be used when Ar, is a pyrazinyl (2b), pyrimidinyl (2c), pyridazinyl (2d) or other pyrazinyl rings. Scheme 2.3

R

2 n B R,

R

2 n - Z + ~ Pd(PPh3)2Cl7-( N +-(R3)m

K

2 CO3 (3 R1 N DMFJEtOH/H 2 0 N L NP NP 2a 29 30 A 150 mL sealed vessel is charged with 2a (3.37 mmol), 29 (4.04 mmol), Pd(PPh 3

)

2 C1 2 (0.27 mmol), potassium carbonate (6.40 mmol), and a mixture of DME/EtOH/H2o (s mL/4 mL/8 mL). The resulting mixture is purged with nitrogen, 213 sealed, and heated at 90'C with a vigorous stirring. After 2 hrs, the reaction mixture is cooled to a temperature of about 25'C and diluted with EtOAc (50 mL). The organic layer is washed with brine, dried (Na-SO4), and concentrated under reduced pressure. The residue is chromatographed by silica gel column chromatography with a gradient of 5 ethyl acetate (0%-30%)/hexanes to provide product 30. The boronate ester, 29 can be synthesized by the method demonstrated below in scheme 2.4. Scheme 2.4 S0 2

(CF

2

)

3

CF

3 B-B B

-(R

3 ) DPPF (3mol%) N Pd(DPPF)2C 2 , KOAc, Dioxane NP 85CNP 10 85 0 C 29 Bis(pinacolato)diboron (333.6 mmol), diphenylphosphino ferrocene (9.1 mmol), palladium diphenylphosphinoferrocene dichloride (1:1 complex with dichloromethane) (9.1 mmol), and potassium acetate (909.9 mmol) are suspended in dry dioxane (900 mL) 15 under argon with mechanical stirring. 4-(Nonafluorobutane-I-sulfonyloxy)-3,6-dihydro 2H-pyridine-l -carboxylic acid tert-butyl ester (303.3 mmol) in dry dioxane (500 mL) is added and the mixture is heated to 85'C for 16 h. The mixture is cooled, filtered through CELITE, and the filter cake is washed with dichloromethane (2L). The filtrate is concentrated under reduced pressure to provide a black solid. This is adsorbed onto 20 silica gel (250g) and applied to the head of a 4" silica gel column, and it is then eluted with hexanes (5L) followed by 20:1 hexanes:ethyl acetate, and finally ethyl acetate (IOL) to yield 29.

214 5.5.2.2 Methods for Making the Tetrahydropyridyl Compounds Where X is S The Tetrahydropyridyl Compounds where X is S can be obtained by methods analogous to that described above in schemes 2.1 and 2.2 to provide the Tetrahydropyridyl Compounds where X is 0, except that an isothiocyanate of formula Ar 2 -NCS is used in place of the isocyanate Ar 2 -NCO. 5.5.2.3 Methods for Making the Tetrahydropyridvl Compounds Where X is N-CN The Tetrahydropyridyl Compounds where X is N-CN can be obtained as shown below in Schemes 2.5 and 2.6 where Ar 2 , R 3 , and m are as defined above. Scheme 2.5 .- (R3)m, O, N i (R 3 ), NC-N ArNH 2 N HClI/Acetic acid (m SN INC-N!

NH

Cr2 NC-N- NH

S

Ar 2 31 32 33 Ci

N(SO

2

CF

3

)

2 LiHMDS 26 0-SO 2

CF

3 7

(R

3 )m N NC-N- NH Ar 2 215 A ketal of formula 31 (about 14mnmol) is reacted with an amine of formula Ar

NH

2 (about 14mmol) in an aprotic organic solvent (about 7mL) such as diethyl ether, di n-propyl ether, THF, DCM, or toluene at a temperature of from about 25 0 C to about the reflux temperature of the solvent for a period of from about 0.5 h to about 24 h. The reaction mixture is then concentrated under reduced pressure to provide a compound of formula 32. In one embodiment, the aprotic organic solvent is di-n-propyl ether. In another embodiment, a reaction mixture of di-n-propyl ether, a compound of formula 31 and the amine of formula Ar-NH 2 is heated at a temperature of about 70* to about 80* C. The compound of formula 32 is then dissolved in THF (about 20mL). About IN HCI in acetic acid (about 30mL) is added to the THF solution of the compound of formula 32 and the resulting mixture is heated at the reflux temperature of the solvent. Typically, the reaction mixture is heated at the reflux temperature of the solvent for about 3 h. The reaction mixture is then cooled and concentrated under reduced pressure to provide a residue that is dissolved in DCM. The DCM solution is then extracted with aqueous Na 2

CO

3 . The aqueous and organic layers are separated and the aqueous layer is extracted three times with DCM. The organic portions are combined, dried (MgSO 4 ), and concentrated under reduced pressure to provide a compound of formula 33. The compound of formula 33 can be further treated if desired. In one embodiment, the compound of formula 33 is chromatographed using silica gel column chromatography. The compound of formula 33 (about 3.6mmol) is thcn dissolved in THF (about 1OOmL) and the resulting solution cooled to about -78*t. To the cooled solution is added LiHMDS (about 8.75mmol) and the reaction mixture is stirred at about -78 0 C for about 2 h. A compound of formula 26 (about 3.6mmol. Sigma-Aldrich) is then added to the reaction mixture and the reaction mixture stirred at about -78"C for about 2 h, The reaction mixture is then allowed to warm to about 25*C and concentrated under reduced pressure to provide a compound of formula 34. The compound of formula 34 is then reacted with a compound of formula 28a-d as shown below in scheme 2.6 below to provide the Tetrahydropyridyl Compound where X is N-CN.

216 Scheme 2.6 (R2)n (R2)n N 34 + Pd(PPh 3

)

4 -N R N THF, ref lux ;-(R3 )m. ZnBr N 28a NC, N N JNH Ar 2 (R2)p N\" (R2)p -N 34 + Pd(PPh 3

)

4 R THF, reflux -(R3)m Zn Br Ne N 28b NC\ N N JNH Ar 2 N (R2)p N r (R2)pN RA N 34 + NPd(PPh 3

)

4 R THF, reflux ZnBr N 28c NC, N NH N NH Ar 2 (R2) (2) NN 34 + | N R1 N Pd(PPh 3

)

4 R1 ZnBr THF, reflux 28d N -(R 3 )m NC\ N NH Ar 2 5 where Ar 2 , RI, R 2 , R 3 , n, m, and p are as defined above. Pd(PPh 3

)

4 is dissolved in THF (about 50rnL) and the compound of formula 34 (about 2.2mnol) is added to the resulting mixture followed by a compound of formula 217 28a-d (about 6.6mmol as a 0.5M solution in THF). The reaction mixture is then heated for about I h at the reflux temperature of the solvent. The reaction mixture is allowed to cool to about 25'C and concentrated under reduced pressure to provide the Tetrahydropyridyl Compound where X is N-CN. The Tetrahydropyridyl Compound where X is N-CN can be Further treated if desired. In one embodiment, the Tetrahydropyridyl Compound where X is N-CN is chromatographed by silica gel column chromatography. Where m =1, R 3 is bonded to an sp3 carbon, and 34 is either racemic or a mixture of enantiomers, the resulting Tetrahydropyridyl Compound in scheme 2.6 will also be racemic or an enantiomeric mixtures. If a single stereoisomer is desired, it is possible to use chiral separation techniques known in the art, such as chiral chromatography or chiral resolution, to isolate a single isomer. The compound of formula 31 can be obtained as shown below in scheme 2.7. Scheme 2.7 N-CN (R3)M OA NC=N~N 0 H 35 4 31 where R 3 , and m are as defined above, Compound 4 is reacted with diphenyl cyanocarbonimidate 35 (Sigma-Aldrich) in an aprotic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene to provide the compound of formula 31, In one embodiment, the aprotic solvent is DCM and the reaction mixture of compound 4 and diphenyl cyanocarbonimidate 35 is allowed to react at about 25*C. In another embodiment, the aprotic solvent is toluene and the reaction mixture of compound 4 and diphenyl cyanocarbonimidate 35 is allowed to react 218 at about I 10*C. Compound 4 and diphenyl cyanocarbonimidate 35 are typically allowed to react for a period of about 0.5 h to about 24 h. The compounds of formula 28a-d can be obtained as described above by methods known in the art, 5.5.2.4 Methods for Making the Tetrahvdropvridvl Compounds Where X is N-OH The Tetrahydropyridyl Compounds where X is N-OH can be obtained in a manner analogous to schemes 2.6 and 2.7 in section 5.4.2.3, which is shown in scheme 2.8. Scheme 2.8 I. Ar 2 -NHO N--(R/m 2. HCI/Acetic acid N -- (R 3 )m OP-O-NGP - N 0 Ar 2 37 36 0

O-SO

2

CF

3

-(R

3 )m LiH-MDS (R3)m N 01 N N N OP-O-N:: NH OP-O-N: :NH Ar 2 N(SO2CF3)2 37 26 38 A2 219 (R2)n (2, R, N R N 3 8_ _+_ _N_ d e p r o t e c t R, THF, reflux ZnBr N N 28a OP--O-NANH HO.N NH Ar 2 Ar 2 39a (R2)p (R2)P N 11NI (R2)p R N R R 1 38 + N Pd(PPh 3

)

4 deprotect R,-- THF, rnfIux -(R3)m ;(R3) nBr N N 28b OP--O-N<NH HO-N NH Ar 2 Ar 2 39b (R2)P N (R2)P N

(R

2 ) N R R N 38 + j i Pd(PPhl), , deprotect R THF, reflux N (R)m N (R,)M nBr N N; 2 8c OP-O-N NH HO-N" NH Ir 2 Ar 2 39c (R2)P (R 2)P (R)pN N 38 + R, R1 R -N Pd(PPh 3

)

4 deprotect ZnBr THF, reflux N (R)m N (R3)M 28d N OP-O-N NH HO-N NH Ar 2 Ar 2 39d where Ar 2 , RI, R 2 , R 3 , n, m. and p are as defined above and P is an oxygen/hydroxyl protecting group, The method for obtaining the Tetrahydropyridyl Compounds where X is N-OH as described above in scheme 2.8 is analogous to that described above in Schemes 2.5 220 and 2.6 to provide the Tetrahydropyridyl Compounds where X is N-CN except that a compound of formula 38 is used in place of the compound of formula 34. The compound of formula 36 can be obtained as described below in scheme 2.9. Scheme 2.9 (R3)m NH 2 H N (R)m H3C-S Ethanol, 80* C HON NH Ar 2

.

Ar 2 40 41 N'(Rm) Protecting Group -(R 3 )m HO-N NH OP-O-N NH 41k r 2 ONr2 43 36 where Ar 2 , R 3 , and m are as defined above and P is an oxygen/hydroxyl protecting group. A compound of formula 40 (about 0.3mmol) is reacted with hydroxylamine (50 weight percent in water, about 5.8mmol) in about 1.5mL of ethanol with stirring at a temperature of about 80*C for about 2 h. The mixture is then concentrated under reduced pressure to provide a compound of formula 41. The hydroxyl group of the compound of formula 41 is then protected using an hydroxyl protecting group to provide the compound of formula 36. Any hydroxyl protecting group known in the art can be used to protect the hydroxyl group in the compound of formula 41. Suitable hydroxyl protecting groups and methods for their removal are disclosed in T.W. Greene et al, Protective Groups in Organic Synthesis 17-200 (3d ed, 1999).

221 Where m =1, R3 is bonded to an sp3 carbon, and 38 is either racemic or a mixture of enantiomers, the resulting Tetrahydropyridyl Compound in scheme 2.8 will also be racemic or enantiomeric mixtures. If a single stereoisomer is desired, it is possible to use chiral separation techniques known in the art, such as chiral chromatography or chiral resolution, to isolate a single isomer. The compound of formula 40 can be obtained as shown below in scheme 2.10. Scheme 2.10 00 -- (R3)m N CH 3 I -(R 3 )m S NH TEA N NH Ethyl acetate

H

3 C-S N N 2k 42 40 where Ar2, R 3 , and m are as defined above. A solution of a compound of formula 42 (about 0.6mmol), obtained as described above in section 4.4.2.2, in DCM is reacted with iodomethane (about 0.9mmol) in about 3mL of tetrahydrofuran with stirring at about 25'C for about 12 h. Excess iodomethane is removed from the mixture under reduced pressure. A solution of triethylamine (about 1.74mmol) in about 2.5mL of ethyl acetate is then added to the mixture and the mixture is allowed to stir for about 2 h. The mixture is then concentrated under reduced pressure to provide the compound of formula 40 which can then be further treated if desired. In one embodiment,,the compound of formula 40 is chromatographed using column chromatography or recrystallized.

222 5.5.2.5 Methods for Making the Tetrahydropyridvi Compounds Where X is N-ORIO The Tetrahydropyridyl Compounds where X is N-ORio can be obtained by reacting a Tetrahydropyridyl Compounds where X is N-OH, obtained as described above in Scheme 2.8, with L-(Ci-C 4 )alkyl, where L is -I, -Br, -Cl, or -F, in the presence of about 3 eq. of triethylamine in THF, with stirring at about 25*C for about 12 h or at about 50*C for about 3 h. The reaction mixture is concentrated under reduced pressure to provide a residue. The residue is then chromatographed using silica gel column chromatography eluted with a gradient elution of from 100:0 hexane:ethyl acetate to 25:75 hexane:ethyl acetate to provide the Tetrahydropyridyl Compounds where X is N ORIO. In one embodiment, L is -I or -Br. 5.5.3 Methods for Maldng Compounds of Formula I where W Is N and the Dashed Line is Absent The compounds of formula I where W is N and the dashed line is absent, i.e., "Piperazine Compounds," can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below. 5.5.3.1 Methods for Making Finerazine Compounds where X is 0 and Ar, is a Benzothiazolyl Group Piperazine Compounds where X is 0., Ar 2 is a benzothiazolyl group, and R 20 is -H, can be obtained by the following illustrative method shown in scheme 3.1: 223 Scheme 3.1 Ar 1 N 2 N (R 3 )m Ar, HNLO N NHN R2, O N ~~(R3)m + N S N H 43 R R8 Re. 44 R9 Piperazine Compounds 5 where Arl, R 3 , R 8 , R 9 and m are as defined above. A compound of formula 44 (about 2mmol) is dissolved in an aprotic organic solvent (about 3mL). To the resulting solution is added a compound of formula 43 (about 2mmol) and the reaction mixture allowed to stir for about 10 min. The reaction mixture is concentrated under reduced pressure to provide the Piperazine Compounds 10 where X is 0, Ar 2 is a benzothiazolyl group, and R 20 is -H. Such Piperazine Compounds can be chromatographed on a silica column eluted with 5:95 ethyl acetate:hexane. The compound of formula 44 can be obtained as shown below in scheme 3.2: Scheme 3.2

NO

2

NH

2 N O C +N HN O 0 2 N S{N 4546 R qo4 15 45 where R 8 and R 9 are as defined above.

224 A compound of formula 45 (about 0.75mmol) in an aprotic organic solvent (about 0.04M) is cooled to about 0*C. To the cooled solution is slowly added a solution of a compound of formula 46 (about 0.75mmol) in an aprotic organic solvent (about O.4M). The reaction mixture is stirred at 0 0 C for about 5 min. and about 0.75mmol of 5 triethylamine are added to the reaction mixture. The reaction mixture is then allowed to warm to a temperature of about 25*C and concentrated under reduced pressure to provide the compound of formula 44. The compound of formula 45 is commercially available, e.g., from Sigma-Aldrich. Compounds of formula 46 are commercially available or can be prepared by the following illustrative method shown below in 10 scheme 3.3: Scheme 3.3 NH2

NH

2 S 'N + KSCN I. Bromine, Acetic acid \ /2. NH 4 0H

R

9

R

8

R

9

R

8 47 46 15 where R 8 and R 9 are as defined above. To a stirred solution of aniline 47 (about 74mmol) and potassium thiocyanate (about 148mmol) in about IOOmL of glacial acetic acid is added dropwise a solution of bromine (about 74mmol) in about 25mL of glacial acetic acid. The flask containing the bromine in acetic acid is then rinsed with about 15mL of acetic acid which is combined 20 with the solution of aniline 47. The reaction mixture is vigorously stirred at a temperature of about 25 0 C for between about 2 h and about 24 h. The reaction mixture is then poured over crushed ice (about 500mL) and the pH of the resulting mixture adjusted to a value of about 10 using ammonium hydroxide to provide a precipitate. The resulting precipitate is collected by filtration and recrystallized from toluene to provide 25 the compound of formula 46. Compounds of formula 47 are commercially available or can be prepared by methods known in the art. The compound of formula 50a-d can be obtained as shown below in scheme 3.4: 225 Scheme 3.4 (R2)n H (A N -rN -T(R3)m R N N + -ij NN H L (R3)m 48 49a N H 50a

(R

2 )p N (R2)pI N 48 + N N R , L N - (R3)m, LN 49b H 50b

(R

2 )p -NN (R2)pN 48 + N R1 - N N[ -(R 3 )m L N 49c H 50c

(R

2 )p N (R2)p N . R1 48 + N R1

-(R

3 )m L N 49d H 50d 5 where RI, R 2 , R 3 , in, n, and p are as defined above and L is a halogen. A compound of fonnula 49a-d (about 20mnol) is reacted with a compound of fonnula 48 (about 27.5mmol) in about 15mL of DMSO in the presence of triethylamine (about 30mnol), optionally with heating, for about 24 h to provide a compound of 226 formula 50a-d. The compound of formula 50a-d is isolated from the reaction mixture and further treated if desired. In one embodiment, the compound of formula 50a-d is chromatographed using column chromatography or recrystallized. Compounds of formula 48 and 49a-d are commercially available or can be 5 prepared by methods known in the art. The compound of fonnula 48 where m is 0 and the compound of fonnula 48 where in is I and R 3 is (R) -CH 3 or (S) -CH 3 are commercially available, e.g., from Sigma-Aldrich. In one embodiment, L is bromide, chloride, or iodide. Piperazine Compounds where X is 0, Ar is a benzothiazolyl group, and Rio is 10 -(Ci-C 4 )alkyl can be obtained by the following illustrative method shown below in scheme 3.5: Scheme 3.5 Ar 1 I Ar1 (N N

((R

3 ) NN HN O NaH R N S \ R20-L S~N

R

8

R

9 15 where Ari, R 3 , R 8 , R 9 , R 2 0 , and m are as defined above and L is a halogen. To a solution of a Piperazine Compound where X is 0, Ar 2 is a benzothiazolyl group, and R 2 0 is -H (about leq.), obtained as described above in Scheme 3.1, in DMF at 04C, is added a DMF solution of NaH (about 2 eq.). The reaction mixture is allowed to 20 warm to a temperature of about 25*C over about I I. To the resulting mixture is added about 1.2eq. of an alkyl halide, R 20 -L, and the reaction mixture allowed to stir until the Piperazine Compounds where X is 0, Ar 2 is a benzothiazolyl group, and R 20 is -(Ci

C

4 )alkyl form. The progress of the reaction can be monitored using conventional analytical techniques including, but not limited to, high pressure liquid chromatography 227 (HPLC), column chromatography, thin-layer chromatography (TLC), column chromatography, gas chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy such as 'H and ' 3 C NMR. Piperazine Compounds can be isolated and further treated if desired. In one embodiment, the Piperazine Compound is 5 isolated by removing the solvent under reduced pressure. In another embodiment, the Piperazine Compound is isolated by extraction. Piperazine Compounds can be further treated, for example, by column chromatography or recrystallization. 5.5.3.2 Methods for Making Piperazine Compounds where X is S and Ar 2 is 10 a Benzothiazolyl Group Piperazine Compounds where X is S, Ar 2 is a benzothiazolyl group, and R 20 is H can be obtained by the following illustrative method in scheme 3.6.

228 Scheme 3.6 NH2 S-- N N N N N HIN + N N DMAP HN S/DMSO SoO 0 C N

R

8 46

R

8 Ar, -- (R 3 )m DMSO 100*C N H 43 Ar 1

-(R

3 )m N HN S S- N R8a R9 Piperazine Compounds 5 where Ari, R 3 , R 8 , R<> and m are as defined above. A compound of formula 46 (about 2mmol), 1,1 '-thiocarbonyldiimidazole (about 2mmol) (Sigma-Aldrich), and 4-dimethylaminopyridine (DMAP) (Sigma-Aldrich) are suspended in DMSO (about 3mL) at a temperature of about 25*C and the resulting mixture is heated at about I 00"C for about 6 h. The reaction mixture is then cooled to a 10 temperature of about 25'C and a compound of formula 43 (about 2rnmol) is added to the 229 reaction mixture and the reaction mixture is heated to about 100*C for about 16 h. The reaction mixture is concentrated under reduced pressure to provide Piperazine Compounds where X is S, Ar 2 is a benzothiazolyl group, and R 20 is -H. Piperazine Compounds can be chromatographed on a silica column eluted with 5:95 ethyl 5 acetate:hexane. Piperazine Compounds where X is S, Ar 2 is a benzothiazolyl group, and R 20 is -(Ci-C 4 )alkyl can be obtained by a method analogous to the method used to obtain Piperazine Compounds where X is 0, Ar 2 is a benzothiazolyl group, and R 2 0 is -(Ci

C

4 )alkyl as described above in Scheme 3.5 except that a Piperazine Compound where X 10 is S, Ar 2 is a benzothiazolyl group, and R 20 is -H, obtained as described above in Scheme 3.6, is used in place of the Piperazine Compound where X is 0, Ar 2 is a benzothiazolyl group, and R 20 is -H. 5.5.3.3 Methods for Making Piperazine Compounds Where X is 0 and Ar, 15 is a Benzooxazolyl Group Piperazine Compounds where X is 0, Ar 2 is a benzooxazolyl group, and R 20 is -H can be obtained by a method analogous to that used to obtain the Piperazine Compounds where X is 0, Ar 2 is a benzothiazolyl, and R 20 is -H as described in section 20 5.4.3.1, scheme 3.1, except that a compound of formula 51, shown below:

NO

2 ' HN 0 4 N Rg~ Ra 51 where R 8 and R 9 are as defined above, is used in place of the compound of formula 44.

230 The compound of formula 51 can be obtained by a method analogous to that used to obtain the compound of formula 44 as described above in Scheme 3.2 except that a compound of formula 52, shown below,

NH

2 0-XN

R

8 5 52 where R 8 and R 9 are as defined above, is used in place of compound 46. 5.5.3.4 Methods for Making Piperazine Compounds Where X is S and Ar 2 is 10 a Benzooxazolyl Group Piperazine Compounds where X is S, Ar 2 is a benzooxazolyl group, and R 2 o is -H can be obtained by a method analogous to that used to obtain the Piperazine Compounds described above in Scheme 3.6 except that a compound of formula 53 is used in place of 15 the compound of formula 44. The compound of Formula 53 can be obtained as described above.

NO

2 HN ON R9O R8 53 20 Piperazine Compounds where X is S, Ar 2 is a benzooxazolyl group, and R 20 is

-(CI-C

4 )alkyl can be obtained by a method analogous to the method used to obtain the 231 Piperazine Compounds described above in Scheme 3.5 except that a Piperazine Compound where X is S, Ar2 is a benzooxazolyl group, and R2 0 is -H, obtained as described above, is used in place of the Piperazine Compound where X is 0, Ar is a benzothiazolyl group, and R? 0 is -H. 5 5.5.3.5 Methods for Making Piperazine Compounds Where X is 0 and Ar; is a Benzoimidiazolyl Group Piperazine Compounds where X is 0, Ar 2 is a benzoimidiazolyl group, the amide 10 R 2 0 is -H, and the benzoimidiazolyl group R2 0 is -H can be obtained by a method analogous to that used to obtain the Piperazine Compounds described above in Scheme 3.1 except that a compound of formula 54, shown below,

NO

2 0 HN 0 HN RR 54 15 where R8 and R 9 are as defined above, is used in place of the compound of formula 44. The Compound of fonnula 54 can be obtained by a method analogous to that used to obtain the compound of formula 44 as described in section 5.4.3.1, Scheme 3.2, except that a compound of formula 55, shown below, 20

NH

2 HN Rg R8 55 232 where R 8 and R 9 are as defined above, is used in place of the compound of formula 46. Compounds of formula 55 are commercially available or can be prepared by procedures known in the art. An illustrative procedure for obtaining compound 55 is shown below 5 in Scheme 3.7: Scheme 3.7 RI) C C1 Aqueous NH 3 xI)>NH 2 HN R N H 9 H 56 55 10 where R 8 and R 9 are as defined above. A compound of formula 56 (about I mmol), prepared as described below in Scheme 3.11, is dissolved in excess aqueous ammonia in a sealed tube and heated at a temperature of between about 140'C and 150'C for about 72 h. The mixture is cooled to a temperature of about 25*C and concentrated under reduced pressure to provide a 15 residue. In another embodiment, the mixture is cooled to a temperature of about 25*C, extracted with an organic solvent, the organic phase separated from the aqueous phase, and the organic phase is concentrated under reduced pressure to provide a residue. If desired, the residue is then further treated to provide the compound of formula 55. In one embodiment, the residue is recrystallized. In another embodiment, the residue is 20 chromatographed using flash chromatography. Compounds of formula 56 are commercially available or can be prepared by procedures known in the art. An illustrative method for preparing the compound of formula 56 is shown below in scheme 3.8: 233 Scheme 3.8 H

R

8 .a

NH

2 CDI O > N R9NH 2 RN 57 58 H POCla R N 9 H 56 5 where R 8 and R 9 are as defined above. A compound of formula 57 (about 5 mmol to about IOmmol) and di(1H imidazol-I-yl)methanone (CDI, about 2 eq) is dissolved in THF (about 50mL to about 70mL) and the reaction mixture is heated at reflux temperature for about 4 hours. The reaction mixture is then concentrated under reduced pressure to provide a residue. Ethyl 10 acetate (about 50mL) is added to the residue and the resulting insoluble material is collected by filtration and washed with ethyl acetate to provide a compound of formula 58. The compound of formula 58 is then reacted with POC13 according to the procedure described in J. Med. Chem. 40:586-593 (1997) to provide the compound of formula 56. The compounds of formula 57 are commercially available or can be prepared by 15 procedures known in the art. An illustrative procedure for obtaining a compound of formula 57 is shown below in scheme 3.9: Scheme 3.9 R NH 2 C 0 HSO a N NH 2 HN NH 2 9Rg

NO

2 10% Pd/C R NH 2 20 59 60 57 234 where R 8 and R 9 are as defined above, Aniline hydrochloride 59 (about I 2mmol) is dissolved in concentrated sulfuric acid (about 1 OmL) at 0*C and the resulting solution cooled to a temperature of about -13'C to about -15 0 C. About I mL of 70% nitric acid is added to the resulting solution 5 over a time period of about 30 min. and the reaction mixture allowed to stir for about 2 h at a temperature of from about -13*C to about -15*C. The reaction mixture is then poured into ice water (about I00mL), neutralized with 5% to 10% aqueous sodium hydroxide, and extracted with about 50mL of chloroform. The chloroform layer is separated from the aqueous layer. Concentration under reduced pressure provides a 10 residue that is chronatographed using flash chromatography (silica column and chloroform eluent) to provide a compound of formula 60. The compound of formula 60 is dissolved in ethanol (about 50mL) and hydrogenated for about 12 h at a temperature of about 25"C using 10% palladium on carbon as a catalyst. The catalyst is removed by filtration and the ethanol is removed under reduced pressure to provide a residue that is 15 chromatographed using flash chromatography (silica gel eluted with 20:1 dichloromethane:methanol) to provide the compound of formula 57. The compounds of formula 59 are commercially available or can be prepared by procedures known in the art. Piperazine Compounds where X is 0, Ar 2 is a benzoimidiazolyl group, the amide 20 R 20 is -H, and the benzoimidiazolyl group R 2 o is -(CI-C 4 )alkyl can be obtained by a method analogous to that used to obtain the Piperazine Compounds where X is 0, Ar 2 is a benzoimidiazolyl group, the amide R 20 is -H, and the benzoimidiazolyl group R 2 0 is -H except that a compound of formula 61, shown below,

NO

2 0/ HN R20s-,N4 N R256 R8 25 61 235 where R 8 , RO, and R 20 are as defined above, is used in place of the compound of formula 54. The compound of formula 61 can be obtained by a method analogous to that used to obtain the compound of formula 54 except that a compound of formula 62, shown below, 5

NH

2 R20 -sN4 Rg~ Rs 62 where R 8 , R 9 , and R 2 0 are as defined above, is used in place of the compound of formula 55. The compound of formula 62 can be obtained as shown below in scheme 3.10. 10 Scheme 3.10

NH

2

NH

2

NHR

20 HN R20 N H HN+N NaH N 4 N 1 N N + DMF RO-L Rg -L Rg Rg Rs~ RR Rs

R

8 9 R 8 8 55 62 63 15 where R 8 , R 9 , and R 2 0 are as defined above and L is a halogen. NaH (about 2 eq) is added to a solution of a compound of formula 55 in DMF at 0C and the resulting mixture is allowed to stir and to warm to a temperature of about 25*C over a period of about one hour. An alkyl halide, R 20 -L, (about I eq.) is then added to the solution and the reaction mixture allowed to stir until a mixture of a compound of 20 formula 62 and a compound of formula 63 is produced. In one embodiment, the alkyl halide is an alkyl iodide. The formation of the compound of formula 62 and the compound of formula 63 can be monitored by analytical methods known in the art 236 including, but not limited to, those described above. Water is then added to the reaction mixture to produce a precipitate of the compound of fonrmula 62 and the compound of formula 63, which are collected by filtration. The compound of formula 62 and the compound of formula 63 are then separated to provide the compound of formula 62. 5 The compound of formula 62 and the compound of formula 63 can be separated by methods known in the art including, but not limited to, column chromatography, preparative TLC, preparative HPLC, and preparative GC. 5.5.3.6 Methods for Making Piperazine Compounds Where X is S and Ar2 is 10 a Benzoimidiazollyl Group Piperazine Compounds where X is S, Ar 2 is a benzoimidiazolyl group, the thioamide R 20 is -H, and the benzoimidiazolyl group R 20 is -H can be obtained by a method analogous to that used to obtain the Piperazine Compounds described above in 15 scheme 3.6 except that a compound of formula 55 is used in place of the compound of formula 46. The compound of formula 55 can be obtained as described above. Piperazine Compounds where X is S, Ar 2 is a benzoimidiazolyl group, the thioamide R 2 0 is -H, and the benzoimidiazolyl group R 20 is -(CI-C 4 )alkyl can be obtained by a method analogous to that used to obtain Piperazine Compounds as described in 20 section 5.4.3.2, scheme 3.6, except that a compound of formula 62 is used in place of the compound of formula 46. The compound of formula 62 can be obtained as described above. Piperazine Compounds where X is S, Ar 2 is a benzoimidiazolyl group, the thioamide R 20 is -(CI-C 4 )alkyl, and the benzoimidiazolyl group R 20 is -H can be obtained 25 by a method analogous to that used to obtain the Piperazine Compounds as described above in scheme 3.5 except that a Piperazine Compound where X is S and each R 20 is -H, prepared as described above, is used in place of the Piperazine Compounds where X is 0 and the amide R 2 0 is -H. Piperazine Compounds where X is S, Ar 2 is a benzoimidiazolyl group, the 30 thioamide R 2 0 is -(CI-C 4 )alkyl, and the benzoimidiazolyl group R 20 is -(Ci-C 4 )alkyl can be obtained by a method analogous to that used to obtain the Piperazine Compounds where X is 0 and R 20 is -(Ci-C 4 )alkyl as described above in scheme 3.5 except that the Piperazine Compound where X is S, the thioamide R 20 is -H, and the benzoimidiazolyl 237 group R 20 is -(C 1

-C

4 )alkyl, prepared as described above, is used in place of the Piperazine Compound where X is 0 and R 20 is -H. Suitable aprotic organic solvents for use in the illustrative methods include, but are not limited to, DCM, DMSO, chloroform, toluene, benzene, acetonitrile, carbon 5 tetrachloride, pentane, hexane, ligroin, and diethyl ether. In one embodiment, the aprotic organic solvent is DCM. Certain Piperazine Compounds can have one or more asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A Piperazine Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the 10 invention encompasses Piperazine Compounds and their uses as described herein in the fonr of their optical isomers, diastereomers, and mixtures thereof, including a racemic mixture. In addition, one or more hydrogen, carbon or other atoms of a Piperazine Compound can be replaced by an isotope of the hydrogen, carbon or other atoms. Such 15 compounds, which are encompassed by the invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. 5.6 THERAPEUTIC USES OF COMPOUNDS OF FORMULA I 20 In accordance with the invention, the compounds of formula I are administered to an animal in need of treatment or prevention of a Condition. In one embodiment, an effective amount of a compound of formula I can be used to treat or prevent any condition treatable or preventable by inhibiting TRPV. Examples of Conditions that are treatable or preventable by inhibiting TRPV1 include, 25 but are not limited to, pain, UI, an ulcer, IBD, and IBS. The compounds of formula I, or a pharmaceutically acceptable derivative thereof, can be used to treat or prevent acute or chronic pain. Examples of pain treatable or preventable using the compounds of formula I include, but are not limited to, cancer pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative 30 pain, headache pain, muscle pain, arthritic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis. The compounds of fonnula 1, or a pharmaceutically acceptable derivative thereof, can also be used for treating or preventing pain associated with inflammation or 238 with an inflammatory disease in an animal. Such pain can arise where there is an inflammation of the body tissue which can be a local inflammatory response and/or a systemic inflammation. For example, the compounds of formula 1 can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to: 5 organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., J Mol. Cell Cardiol. 31:297-303 (1999)) including, but not limited to, transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases, such as ileitis, 10 ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; 15 leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer s disease, infectious 20 meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type Il diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic 25 neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar cora, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of the heart, 30 such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The compounds of formula I can also be used for inhibiting, treating, or preventing pain associated with inflammatory disease that can, for example, be a 239 systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is 5 adminstered as a treatment for cancer. The compounds of formula I, or a pharmaceutically acceptable derivative thereof, can be used to treat or prevent UI. Examples of UI treatable or preventable using the compounds of formula I include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total 10 incontinence. The compounds of formula I, or a pharmaceutically acceptable derivative thereof, can be used to treat or prevent an ulcer. Examples of ulcers treatable or preventable using the compounds of formula I include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or a stress ulcer. 15 The compounds of formula 1, or a pharmaceutically acceptable derivative thereof, can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis. The compounds of formula 1, or a pharmaceutically acceptable derivative thereof, can be used to treat or prevent IBS. Examples of IBS treatable or preventable 20 using the compounds of formula I include, but are not limited to, spastic-colon-type IBS and constipation-predominant 1BS. Applicants believe that the compounds of formula I, or a pharmaceutically acceptable derivative thereof, are antagonists for TRPV1. The invention also relates to methods for inhibiting TRPV I function in a cell comprising contacting a cell capable of 25 expressing TRPV I with an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof. This method can be used in vitro, for example, as an assay to select cells that express TRPV I and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an ulcer, IBD, or lBS. The method is also useful for inhibiting TRPV I function in a cell in vivo, 30 in an animal, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a compound of fonnula 1, or a pharmaceutically acceptable derivative thereof. In one embodiment, the method is useful for treating or preventing pain in an animal. In another embodiment, the method is useful for treating or preventing UI in an animal. In another embodiment, the method is useful for treating or 240 preventing an ulcer in an animal. In another embodiment, the method is useful for treating or preventing IBD in an animal. In another embodiment, the method is useful for treating or preventing IBS in an animal. Examples of tissue comprising cells capable of expressing TRPVI include, but 5 are not limited to, neuronal, brain, kidney, urothelium, and bladder tissue. Methods for assaying cells that express TRPVI are known in the art. 5.7 THERAPEUTIC/PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS OF THE INVENTION 10 Due to their activity, compounds of formula I, or a pharmaceutically acceptable derivative thereof, are advantageously useful in veterinary and human medicine. As described above, compounds of formula I, or a phannaceutically acceptable derivative thereof, are useful for treating or preventing a Condition. 15 When administered to an animal, compounds of fonnula I, or a phannaceutically acceptable derivative thereof, are typically administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient. The present compositions, which comprise a compound of formula I, or a pharmaceutically acceptable derivative thereof, can be administered orally. Compounds of formula 1, or a 20 pharmaceutically acceptable derivative thereof, can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with another therapeutically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in 25 liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the compound of formula 1, or a pharmaceutically acceptable derivative thereof. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, 30 particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of compounds of formula I, or a pharmaceutically acceptable derivative thereof, into the bloodstream.

241 In specific embodiments, it can be desirable to administer the compounds of formula I, or a pharmaceutically acceptable derivative thereof, locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by 5 injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In certain embodiments, it can be desirable to introduce the compounds of formula 1, or a phannaceutically acceptable derivative thereof, into the central nervous 10 system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or 15 nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the compounds of formula I can be formulated as a suppository, with traditional binders and excipients such as triglycerides. In another embodiment, the compounds of formula 1, or a pharmaceutically 20 acceptable derivative thereof, can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)). In yet another embodiment, the compounds of formula 1, or a pharmaceutically acceptable derivative thereof, can be delivered in a controlled-release system or 25 sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled- or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used. In one embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 4:201 (1987); Buchwald et al., Surgerv 88:507 30 (1980); and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release (Langer-and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et a!., Science 228:190 (1985); During et a., 242 Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 7L:105 (1989)). In yet another embodiment, a controlled- or sustained-release system can be placed in proximity of a target of the compounds of formula I, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose. 5 The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal. Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean 10 oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to an animal. Water is a particularly useful excipient when the compound 15 of formula I is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, 20 ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or can contain pH buffering agents. The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, multiparti culates, capsules, capsules containing liquids, powders, multiparticulates, sustained-release formulations, suppositories, emulsions, aerosols, 25 sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference. 30 In one embodiment, the compounds of formula I, or a pharmaceutically acceptable derivative thereof, are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered 243 compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the 5 compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells 10 to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium 15 saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. The compounds of formula I, or a pharmaceutically acceptable derivative thereof, can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art. Examples include, 20 but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, 25 ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the 30 invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release. Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or 244 non-sustained release counterparts. In one embodiment, a controlled- or sustained release composition comprises a minimal amount of a compound of formula I to cure or control the condition in a minimum amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage 5 frequency, and increased patient compliance. In addition, controlled- or sustained release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compound of formula I, and can thus reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can be designed to immediately 10 release an amount of a compound of formula 1, or a pharmaceutically acceptable derivative thereof, that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the compound of formula I to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the compound of formula I in the body, the compound of 15 formula I can be released from the dosage form at a rate that will replace the amount of compound of formula I being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological 20 conditions or compounds. In another embodiment, the compounds of formula I, or a pharmaceutically acceptable derivative thereof, can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. 25 Compositions for intravenous administration can optionally include a local anaesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the compounds 30 of formula I are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compounds of formula 1, or a pharmaceutically acceptable derivative thereof, are administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

245 The amount of the compound of formula 1, or a pharmaceutically acceptable derivative thereof, that is effective in the treatment or prevention of a Condition can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be 5 employed will also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of a practitioner and/or each animal's circumstances. Suitable effective dosage amounts, however, will typically range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although they are typically about 100 mg/kg of body weight or less. In one 10 embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a compound of formula I; in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight; and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, an effective dosage amount is administered about every 24 h 15 until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 12 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 8 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 6 h until the Condition is abated. In another embodiment, an effective dosage amount is 20 administered about every 4h until the Condition is abated. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound of formula I, or a pharmaceutically acceptable derivative thereof, is administered, the effective dosage amounts correspond to the total amount administered. 25 Where a cell capable of expressing TRPVI is contacted with a compound of formula I in vitro, the amount effective for inhibiting the TRPVI receptor function in a cell will typically range from about 0.01 pg/L to about 5 mg/L; in one embodiment, from about 0.01 ipg/L to about 2.5 mg/L; in another embodiment, from about 0.01 pg/L to about 0.5 mg/L; and in another embodiment, from about 0.01 pg/L to about 0.25 30 mg/L, of a solution or suspension of a phanrmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension comprising the compound of formula 1, or a pharmaceutically acceptable derivative thereof, is from about 0.01 pL to about I mL. In another embodiment, the volume of solution or suspension is about 200 pL.

246 The compounds of formula 1, or a pharmaceutically acceptable derivative thereof, can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy. 5 The present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering to the animal being administered a compound of fonnula 1, or a phannaceutically acceptable derivative thereof, another therapeutic agent. In one embodiment, the other therapeutic agent is administered in an effective amount. 10 The present methods for inhibiting TRPV 1 function in a cell capable of expressing TRPVI can further comprise contacting the cell with an effective amount of another therapeutic agent. Effective amounts of the other therapeutic agents are known in the art. However, it is within the skilled artisan's purview to determine the other therapeutic agent's 15 optimal effective-amount range. In one embodiment of the invention, where another therapeutic agent is administered to an animal, the effective amount of the compound of formula I is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the compounds of formula I and the other therapeutic agent act synergistically to treat or 20 prevent a Condition. The other therapeutic agent can be, but is not limited to, an opioid agonist, a non opioid analgesic, a non-steroid anti-inflammatory agent, an antimigraine agent, a Cox-Il inhibitor, an antiemetic, a D-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca c hannel blocker, an anticancer agent, an agent for treating or preventing UI, an 25 agent for treating or preventing an ulcer, an agent for treating or preventing IBD, an agent for treating or preventing IBS, an agent for treating addictive disorder, an agent for treating Parkinson's disease and parkinsonism, an agent for treating anxiety, an agent for treating epilepsy, an agent for treating a stroke, an agent for treating a seizure, an agent for treating a pruritic condition, an agent for treating psychosis, an agent for treating 30 Huntington's chorea, an agent for treating ALS, an agent for treating a cognitive disorder, an agent for treating a migraine, an agent for treating vomiting, an agent for treating dyskinesia, or an agent for treating depression, and mixtures thereof. Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, 247 butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, 5 hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, 10 phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable derivatives thereof, and mixtures thereof. In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, 15 morphine, tramadol, oxymorphone, pharmaceutically acceptable derivatives thereof, and mixtures thereof. Examples of useful non-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, 20 carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and phannaceutically acceptable derivatives thereof, 25 and mixtures thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophennol derivatives including acetaminophen and phenacetin; 30 indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolimetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicarn, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed 248 description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilnan's The Pharmacological Basis of Therapeutics 6 17-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9 1h ed. 1996) and Glen R. Hanson, Analgesic, Antipyretic and 5 Anti-Inflammatoiy Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (A.R. Gennaro ed., 19th ed. 1995) which are hereby incorporated by reference in their entireties. Examples of useful Cox-Il inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Patent No. 6,136,839, which is hereby 10 incorporated by reference in its entirety. Examples of useful Cox-Il inhibitors include, but are not limited to, rofecoxib and celecoxib. Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocomine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, 15 lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratniptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof. The other therapeutic agent can also be an agent useful for reducing any potential side effects of a compound of formula I. For example, the other therapeutic agent can be 20 an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, 25 methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. Examples of useful P-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, 30 bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, 249 oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol. Examples of useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric 5 acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 10 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, 15 tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide. Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, 20 thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, 25 melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, 30 piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine. Examples of useful Ca c hannel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, 250 semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and 5 perhexiline. Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, 10 benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, 15 decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, 20 etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n , interferon 25 alpha-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, 30 mitindomide, rnitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, 251 purornycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, sirntrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, 5 temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine 10 sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride. Examples of other anti-cancer drugs include, but are not limited to, 20-epi-l ,25 dihydroxyvitamin D3; 5-ethynyluracil, abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; 15 amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal i zing morphogenetic protein-]; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine 20 deaminase; asulacrine; atamestane; atrimustine; axinastatin I; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin Ill derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; 25 budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; 30 collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; 252 didox; diethylnorspennine; dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edel fosine; edrecolornab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen 5 agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; fornestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene 10 bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidaloacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-I receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; 15 lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyarnine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; 20 lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; 25 mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted 30 benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; 253 oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauarnine; palmitoylrhizoxin; parnidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase 5 inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-tri amine complex; porfimer sodium; porfirornycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein 10 tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RIl retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone 15 BI; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi I mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; 20 splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; 25 temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoralime; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; 30 turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

254 Examples of useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine. Examples of useful therapeutic agents for treating or preventing an ulcer include, 5 antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuth compounds such as bismuth subsalicylate and bismuth subcitrate; H? antagonists such as cimetidine, ranitidine, famotidine, and nizatidine; H*, K+ - ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as tetracycline, 10 metronidazole, timidazole, clarithromycin, and amoxicillin. Examples of useful therapeutic agents for treating or preventing IBD include, but are not limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized opium tincture; codeine; broad-spectrum antibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate. 15 Examples of useful therapeutic agents for treating or preventing lBS include, but are not limited to, propantheline; muscarine receptor antogonists such as pirenzapine, methoctranine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methylbromide, and methantheline; and antidiarrheal drugs such as diphenoxylate and loperamide. 20 Examples of useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists. Examples of useful therapeutic agents for treating or preventing Parkinson's 25 disease and parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride. Examples of useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolain, 30 chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non benzodiazepine agents, such as buspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, 255 aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; and propanediol carbamates, such as meprobamate and tybamate. Examples of useful therapeutic agents for treating or preventing epilepsy include, 5 but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, y-vinyl GABA, acetazolamide, and felbamate. Examples of useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, agents that break up clots such as 10 streptokinase or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid. Examples of useful therapeutic agents for treating or preventing a seizure include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, 15 gabapentin, lamotrigine, y-vinyl GABA, acetazolamide, and felbamate. Examples of useful therapeutic agents for treating or preventing a pruritic condition include, but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those given below, menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids; and antihistamines. 20 Examples of useful therapeutic agents for treating or preventing psychosis include, but are not limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; 25 molindone hydrochloride; pimozide; and ziprasidone. Examples of useful therapeutic agents for treating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide. Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, neurotrophic factors, riluzole, tizanidine, 30 benzodiazepines such as clonazepan and dantrolene. Examples of useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressant drugs such as those given below.

256 Examples of useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolol, verapamil, and divalproex. Examples of useful therapeutic agents for treating or preventing vomiting 5 include, but are not limited to, 5-HT 3 receptor antagonists such as ondansetron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine, chlorpromazin, metoclopramide, and domperidone; glucocorticoids such as dexamethasone; and benzodiazepines such as lorazepam and alprazolam. 10 Examples of useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, reserpine and tetrabenazine. Examples of useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amitryptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotilinr, 15 nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlaflaxine; selective serotonin reuptake inhibitors such as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimul ants such as dextroamphetamine and methylphenidate. 20 A compound of fonnula 1, or a pharmaceutically acceptable derivative thereof, and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, a compound of formula I is administered concurrently with another therapeutic agent; for example, a composition comprising an effective amount of a compound of formula I and an effective amount of another therapeutic agent can be 25 administered. Alternatively, a composition comprising an effective amount of a compound of formula I and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a compound of formula I is administered prior or subsequent to administration of an effective amount of another therapeutic agent. In this embodiment, 30 the compound of formula I is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the compound of formula I exerts its therapeutic effect for treating or preventing a Condition. A composition of the invention is prepared by a method comprising admixing a compound of fonnula I or a pharmaceutically acceptable derivative and a 257 pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the compound of formula I is present in the composition in an effective amount. 5 5.8 KITS The invention further encompasses kits that can simplify the administration of a compound of formula I, or a pharmaceutically acceptable derivative thereof, to an 10 animal. A typical kit of the invention comprises a unit dosage form of a compound of formula 1. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a compound of formula I and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed 15 instructions instructing the use of the compound of formula I to treat a Condition. The kit can also further comprise a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of the other therapeutic agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the kit comprises a container containing an effective amount of a compound of formula 20 1, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier or excipient. Examples of other therapeutic agents include, but are not limited to, those listed above. Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not 25 limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag. The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in 30 the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.

258 6. EXAMPLES 6.1 EXAMPLES 1-9, 10A AND 1OB: SYNTHESES OF COMPOUNDS OF FORMULA I 5 Example 1: The Syntheses of Compounds ZI, 11, D2, S, 16, Y1, J6 2,3-Dichloro-5-formylpyridine

CH

2 OH CHO MnO, C, CI CI Cl 10 64 65 To a 500 mL round-bottom flask, manganese oxide (43.5 g, 0.50 mol) was added to a solution of 2,3-dichloro-5-hydroxylnethylpyridine (64, 8.10 g, 50.0 mmol) in anhydrous CH 2 Cl 2 (150 mL). The reaction mixture was stirred at a temperature of about 15 25'C for 48 h, filtered through CELITE, and concentrated under reduced pressure. The mixture was chromatographed by a silica gel chromatography column eluting with a gradient of ethyl acetate (0%-40%)/hexanes to provide 7.2 g of 65 (90% yield). 'H NMR (400 MHz, CDCl 3 ) 5 10.08 (1 H, s), 8.77 (1 H, d, J=1 .97 Hz), 8.25 (1 H, d, J=l .97 Hz). LC/MS (M+]): 176. 20 2,3-Dichloro-5-vinylpyridine CHO PPh 3

CH

3 Br Ci N (t-BuO)K CI N Cl Cl 65 66 To a stirred slurry of methyltriphenylphosphonium bromide (10.0 g) in toluene 25 (200 mL) at 0"C was added potassium t-butoxide (3.07 g) portionwise to produce a 259 yellow slurry. After 1 hr, the reaction mixture was cooled to -20*C and 65 (4.0 grams, 22.72 mmol) dissolved in tetrahydrofuran (6 mL) was added dropwise to produce a purple colored slurry. The reaction mixture was heated to 0*C and stirred for additional I hr. Then the reaction mixture was treated with saturated aqueous brine (150 mL) and 5 diluted with ethyl acetate (200 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting product was chromatographed by silica gel chromatography column eluting with a gradient of ethyl acetate (0%-10%)/hexanes to provide 2.77 g of 66 (70% yield). 'H NMR (400 MHz, CDCl 3 ) 8 8.30 (1 H, d, J=2.19Hz), 7.80 (1 H, d, J=2.19Hz), 6.63 10 (I H, dd, J=10.96, 17.80Hz), 5.86 (1 H, d, J=17.80Hz), 5.45 (1 H, d, J=10.96Hz). LC/MS (M+1): 174. (S)- I -(5,6-dichloropyridin-3-yl)ethane- 1,2-diol and (R)- 1 -(5,6-dichloropyridin-3 yl)ethane- 1,2-diol OH OH AD-mix a. C - t-BuOH Cl N Cl CI 66 67a OH OH N. A D-mix D3 N. C1 i-BuOH CI N C1 C 15 66 67b To a stirred slurry of AD-mix a (8.95 g) or AD-mix p (8.95 g) in water (32 mL) and I-butanol (27 mL) at 0 0 C was added a solution of 66 (0.909 g, 5.25mmol) in t butanol (5 mL). After 24 hrs, solid sodium sulfite (9.57 g) was added and the resulting 20 slurry was allowed to stir at a temperature of about 25"C for 30 min. The mixture was extracted three times with ethyl acetate (50 mL for each extraction). The organic portions were combined, washed with brine, dried (Na 2

SO

4 ), and concentrated under reduced pressure. The mixture was chromatographed by a silica gel chromatography 260 column eluting with ethyl acetate(50%-100%)/hexanes to provide 0.75 g of product (67a for AD-mix a or 67b for AD-mix P) as a white solid (70% yield). 'H NMR (400 MHz, CDCl 3 ) 6 8.29 (I H, dd, J=0.44, 1.97Hz), 7.87 (1 H, dd, J=0.66, 2.19Hz), 4.87 (1 H, m), 3.84 (1 H, m), 3.66 (1 H, m), 2.83 (1 H, d, J=5.92Hz), 2.11 (1 H, t, J=5.92Hz). LC/MS 5 (M+1): 208. (S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3',6'-dihydro-2'H-[2,4'lbipyridinyl '-carboxylic acid tert-butyl ester HO,. OH HO.. O, ,~O N OH B Pd(PPh 3

)

2 Cl 2 C1 N K,C0 3 | + CI N N 67a 68 69 10 A 150 mL vessel was charged with 67a (0.70 g, 3.37 mmol), (N-tert butoxycarbonyl)- 1,2,3,6-tetrahrdropyridine-4-boronic acid pinacol ester (68, 1.25 g, 4.04 mmol), Pd(PPh 3

)

2 C1 2 (0.189 g, 0.27 mmol), potassium carbonate (0.883 g, 6.40 mmol), and a mixture of DME/EtOH/H 2 0 (8 mL/4 mL/8 mL). The reaction mixture was purged 15 with nitrogen, the vessel sealed, and the reaction mixture heated at 90'C with vigorous stirring. After 2 hrs, the reaction mixture was cooled to a temperature of about 25*C and diluted with EtOAc (50 mL). The organic layer was washed with brine, dried (Na 2

SO

4 ), and concentrated under reduced pressure. The residue was chromatographed by silica gel column chromatography with a gradient of ethyl acetate (50%-100%)/hexanes to 20 provide 0.96 g of 69 (80% yield). 'H NMR (400 MHz, CD 3 0D) S 8.47 (IH, s), 7.93 (I H, s), 6.06 (1 H, in), 4.74 (1 H, t, J=5.92Hz), 4.12 (2H, in), 3.67 (4H, mn), 2.54 (2H, m), 1.52 (9H, s). LC/MS (M+I): 355.

261 (S)- I -(3-Chloro- l',2',3',6'-tetrahydro-[2,4'lbipyridinyl-5-yl)-ethane- 1,2-diol O HH OHOOH OH N CN N O H 70 69 5 A vessel (50 mL) was charged with 69 (0.90 g, mmol) and 2M HCI in Et 2 O (10 mL) and sealed. The reaction mixture was stirred at 40*C for 20 hrs. The reaction mixture was cooled to a temperature of about 25'C and the solid precipitated was filtered, washed with Et20 (20 mL), and dried under reduced pressure to provide 0.65 g of 70 (>99% yield). 'H NMR (400 MHz, CD 3 0D) S 8.74 (IH, s), 8.52 (lH, s), 6.38 10 (1 H, m), 4.91 (1 H, m), 4.00 (2H, m), 3.75 (4H, m), 3.54 (2H, t, J=5.92Hz), 2.89 (2H, m). LC/MS (M+I): 255.

262 (S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3',6'-dihydro-2 H-f2,4'lbipyridinyl l'-carboxylic acid (4-trifluoromethyl-phenyl)anide OH OH O H -. OH OH N 11-O I N N H CF 3 70 DIEA

CF

3 Z I 5 To a suspension of 70 (800 mg, 2.45 mmol) in anhydrous dichloromethane (20 rnL), diisopropylethylamine (DIEA, 2 mL) was added dropwise and the reaction mixture was stirred at a temperature of about 25 0 C for 10 min. The mixture was cooled to -10"C and I-isocyanato-4-(trifluoromethyl)benzene (462 mg, 2.45 mol) which was diluted 10 with anhydrous dichloromethane (5 mL) was slowly added over 5 min. After stirring at -10*C for 10 additional minutes, the mixture was chromatographed by a silica gel chromatography column with a gradient of methanol (0%-5%)/ethyl acetate to provide 0.60 g of ZI (56% yield). 'H NMR (400 MHz, CD 3 0D) 8 8.49 (1 H, dd, J=0.44, 1.75Hz), 7.94 (1 H, dd, J=0.44, 1.75Hz), 7.72 (4H, m), 6.14 (1 H, m), 4.78 (1 H, t, 15 J=5.7OHz), 4.27 (2H, in), 3.82 (2H, t, 1=5.70Hz), 3.70 (2H, m), 2.66 (2H, in). MS: m/z = 441.

263 (S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3',6'-dihydro-2H-2.4'lbipyridinyl l'-carboxylic acid (4-tert-butyl-phenyl)amide HO, HO,. /O OH OH C N -NCI N NN HN~N H DIEA O NH 70 Il 5 The title compound 11 was obtained using a procedure similar to that described for obtaining ZI except that I -tert-butyl-4-isocyanatobenzene was used in place of I isocyanato-4-(trifluoromethyl)benzene (59% yield). 'H NMR (400 MHz, CD 3 OD) 8 8.48 (1 H, dd, J=0.66, 1.97Hz), 7.94 (1 H, dd, J=0.66, 1.75Hz), 7.36 (3H, m), 6.14 (1 H, 10 m), 4.79 (1 H, t, J=5.26Hz), 4.27 (2H, m), 3.78 (2H, t, J=5.48Hz), 3.71 (2H, m), 2.64 (2H,m). LC/MS(M+l): 430.

264 (S)-3-Chloro-5-( 1,2 -dihydroxy-ethyl)-3',6'-dihydro-2'H-[2,4'1bipyridinyl l'-carboxylic acid (3-chloro-4-tri fluorornethyl-phenyl)amide OH OH OH OH HN O J NO2 -C1 N N HN Cl Cl N N CF 3 H O NH DIEA 70 CI

CF

3 D2 5 To a suspension of 70 (95 mg, 0.29 mmol) in anhydrous dichloromethane (4 mL), DIEA (0.5 rnL) was added dropwise, and the reaction mixture was stirred at a temperature of about 25 0 C for 10 min. Then the mixture was cooled to -10C and 3 chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (104 mg, 0.29 mmol, 10 prepared in situ from 2-chloro-4-nitrobenzotrifluoride (Sigma-Aldrich)) in anhydrous dichloromethane (5 mL) was slowly added over 5 min. After stirring at -I "C for 10 additional minutes, the mixture was chromatographed by a silica gel chromatography column with a gradient of methanol (0%-5%)/ethyl acetate to provide 30 mg of D2 (23% yield). ' H NMR (400 MHz, CD 3 0D) 8 8.50 (I H, m), 7.95 (1 H, dd, J=0.44, 1.75Hz), 15 7.82 (1 H, d, J=1.97Hz), 7.66 (l H, d, J=8.77Hz), 7.53 (1 H, m), 6.15 (1 H, m), 4.78 (1 H, t, J=5.48Hz), 4.27 (2H, m), 3.81 (2H, t, J=5.7OHz), 3.69 (2H, m), 2.65 (2H, m). MS: m/z = 475.

265 (S)-3-Chloro-5-(1,2 -dihydroxy-ethyl)-3',6'-dihydro-2H-[2,4']bipyridinyl l'-carboxylic acid (3-fluoro-4-trifluoromethyl-phenyl)anide OH OH O H NO 2 OH OH H N H 0 I CI CI F

CF

3 N H DIEA O NH 70 F

CF

3 SI 5 The title compound S1 was obtained using a procedure similar to that described for obtaining D2 except that 4-nitrophenyl 3-fluoro-4-(trifluoromethyl)phenylcarbamate was used in place of 3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (38% yield). 'H NMR (400 MHz, CD 3 0D) S 8.48 (IH, dd, J=0.44, 1.75Hz), 7.95 (1H, 10 dd, J=0.66, 1.97Hz), 7.57 (2H, m), 7.36 (1 H, m), 6.14 (I H, m), 4.77 (I H, t, J=5.48Hz), 4.23 (2H, m), 3.81 (2H, (, J=5.48Hz), 3.69 (2H, m), 2.65 (2H, m). MS: n/z = 459.

266 (5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3',6'-dihydro-2'H-[2,4'1bipyridinyl I'-carboxylic acid (3-ethyl-4-tri fluoromethyl-phenyl)amide OH OH OH OH H O HN ' O ~ Cl

CF

3 NN N~N H DIFA 5 NH 70

CF

3 16 5 The title compound 16 was obtained using a procedure similar to that described for obtaining D2 except that 4-nitrophenyl 3-ethoxy-4-(trifluoromethyl)phenylcarbamnate was used in place of 3-chloro-4-rifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (25% yield). ' H NMR (400 MHz, CD 3 0D) S 8.27 (1 H, dd, J=0.66, 1.97Hz), 7.72 (1 H, dd, J=0.66, 1.97Hz), 7.25 (2H, m), 6.88 (1 H, d, J=8.55Hz), 5.94 (1 H, n), 4.57 (I H, t, 10 J=5.48Hz), 4.08 (2H, m), 3.96 (2H, q, J=7.02Hz), 3.64 (2H, m), 3.52 (2H, m), 2.44 (2H, in), 1.23 (3H, t, J=7.02Hz). LC/MS (M+l): 486.

267 (S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3',6'-dihydro-2H-[2,4'1bipyridinyl l'-carboxylic acid (3-chloro-4-trifluoromethoxy-phenyl)amide OH S NO 2 OH OH2 HN 0 N C1 Cl N C I'

F

3 CO N N * O "NH H DIEA 70 C1

OCF

3 YI 5 The title compound YI was obtained using a procedure similar to that described for obtaining D2 except that 4-nitrophenyl 3-chloro-4 (trifluoromethoxy)phenylcarbanate was used in place of 3-chloro-4 trifluoromethylphenyl)carbainic acid 4-nitrophenyl ester (20% yield). 'H NMR (400 10 MHz, CD 3 0D) 8 8.30 (1 H, dd, J=0.44, 1.75Hz), 7.74 (1 H, dd, J=0.66, 1.75Hz), 7.57 (I H, d, J=2.4l Hz), 7.25 (1 H, dd, J=2.63, 8.99Hz), 7.14 (1 H, n), 5.94 (I H, m), 4.57 (1 H, t, J=5.70Hz), 4.06 (2H, in), 3.59 (2H, t, J=5.70Hz), 3.50 (2H, m), 2.46 (2H, m). LC/MS (M+]): 492.

268 (S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3',6'-dihydro-2'H -[2 4']bipyridinyl I'-carboxylic acid (3-ethyl-4-trifluoromethoxy-phenyl)amide OH OH HN O NO 2 OH HN CCI F3CO N N H DIEA 0 NH 70

OCF

3 J6 5 The title compound J6 was obtained using a procedure similar to that described for obtaining D2 except that 4-nitrophenyl 3-ethyl -4-(tri fluoromethoxy)phenylcarbamate was used in place of 3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (30% yield). 'H NMR (400 MHz, CD 3 0D) 8 8.49 (IH, d, J=l.97Hz), 7.94 (lH, d, 10 J=1.75Hz), 7.42 (IH, d, J=2.63Hz), 7.33 (11H, dd, J=2.85, 8.99Hz), 7.17(1 H. in), 6.16 (I H, in), 4.77 (l H, t, J=5.48Hz), 4.25 (2H, m), 3.80 (2H, t, J=5.48Hz), 3.70 (2H, m), 2.68 (2H, m), l.25 (3H, t, J=7.67Hz). LC/MS (M+l): 486.

269 Example 2: The Synthesis of Cornound NI 2-bromo-3,5-dichloropyridine Cl CI TMSBr -N N CI CI CI Br 5 71 72 A 100 mL round-bottom flask equipped with a condenser was charged with 1.82 g of compound 71 (10.0 mmol) and propiononitrile (20 mL), 3.06 g TMSBr (20.0 mmol) was slowly added to the above solution. The reaction mixture was stirred at 100*C 10 under nitrogen for 14 hrs, then cooled to a temperature of about 25'C and diluted with EtOAc (100 mL). The EtOAc layer was isolated, dried, and concentrated under reduced pressure to provide 72 as a yellowish solid (>99% yield). tert-butyl 4-(3,5-dichloropyridin-2-yl)-4-hydroxypiperidine- I -carboxylate Cl CI ) t-BuLi C1 N ________OH Cl N Br 2)N N BOC 72 BOC 15 74 Under nitrogen atmosphere, to a 200 mL diethyl ether solution of 72 (2.27 g, 10 mmol) at -78 0 C was dropwise added an ice-cold 1.7M t-BuLi in pentane solution (6 mL, 10.5 mmol) via a syringe while maintaining the mixture below -75*C. After completion 20 of the addition, the reaction mixture was stirred at -78*C for 2 hrs. Then 20 mL of an anhydrous diethyl ether solution of 4-BOC-piperridone ( 1.99 g, 10 mmol) was slowly added via a syringe. The reaction mixture was stirred at -78"C for 2 hrs and slowly 270 heated to a temperature of about 25"C. Saturated aqueous NH 4 Cl was added to the mixture and the diethyl ether layer was isolated, dried, and concentrated under reduced pressure with a rotary evaporator. Silica gel column chromatography of the residue with ethyl acetate/hexanes as eluent provided 2.1 g of 74 as a yellowish oil (61% yield over 2 5 steps). tert-butyl 4-(3,5-dichloropyridin-2-yl)-4-fluoropiperidine-I -carboxylate CI CI N N Cl DAST Cl N OH F N N BOC BOC 74 75 10 To a 100 mL DCM solution of 74 (6.0 g, 17.3 mmol) at -78*C was slowly added DAST (2.5 mL, 18.8 mmol) and the resulting mixture was allowed to warm to a temperature of about 25"C for 16 h, then washed with saturated NaHCO 3 , dried (MgSO 4 ), and concentrated under reduced pressure. Silica gel column chromatography of the residue with EtOAc/hexanes provided 2.5 g of 75 as yellowish solid (42% yield). 15 tert-butyl 4-(3-chloro-5-vinylpyridin-2-yl)-4-fluoropiperidine-1-carboxylate CI N -N CI N ' CI F a F CsF N Pd(DPPF) 2 Cl 2 N BOC BOC 75 76 To a degassed DMF solution of 75 (0.558g, 1.6 mol) in a 100 mL round 20 bottom flask, was added CsF (0.486 g, 3.2 mmol), di-n-butyl vinyl boronic ester (0.388 271 mL, 1.76 mmol) and Pd(DPPF) 2 Cl 2 (0.105 g, 0.128 mmol). The reaction mixture was stirred at 100"C for 14 hr, then cooled to a temperature of about 25'C, diluted with 100 mL ethyl acetate, and washed three times with brine (50 mL for each wash). The organic layer was isolated, dried, and concentrated under reduced pressure. Silica gel 5 column chromatography of the residue provided 0.33 g of 76 as a yellowish oil (60% yield). (S)-iert-butyl 4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl) 4-fluoropiperidine- I -carboxylate OH HO,. Ad-mix-O N C1 N Cl F t-BuOH F N N BOC BOC 10 76 77 In a 100 mL round bottom flask, AD-mix-ct (0.5 g) was added to a mixture of t butanol and water (2mL/2mL) and the mixture was stirred at a temperature of about 25"C for 0.5 hr, then cooled to 0"C. This solution was quickly poured into another ice 15 chilled flask which contained 76 (140 mg, 0.41 mmol). The mixture was stirred vigorously in an ice bath for 96 h and then diluted with ethyl acetate (50 mL) and 2 mL saturated Na 2

S

2 0 5 . The ethyl acetate layer was isolated, dried, and concentrated under reduced pressure with a rotary evaporator to provide 77.

272 (S)- I -(5-chloro-6-(4-fluoropiperidin-4-yl)pyridin-3-yl)ethane- 1,2-diol OH OH HO,,,. HO, HCI - ' I -N F F N N BOG H 77 78 5 A 200 mL round bottom flask was charged with 0.15 g 77 (0.36 mmol) dissolved in about 1 mL dichloromethane. Then 10 rnL of 4M HCI in dioxane was slowly added with vigorous stirring. The flask was sealed with a rubber septum and stirred at a temperature of about 25"C for 16 h. The reaction mixture was filtered and the solid was washed twice with diethyl ether (20 mL for each wash) and dried under reduced pressure 10 to provide 112 mg of 78 as a white solid (>99% yield). MS (M+H): m/z= 312. (S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoro N-(4-(trifluoromethyl)phenyl)piperidine-l-carboxamide OH OH OH OH I N F NN CIF F N N CF 3 , O- NH H DIEA 78

CF

3

NI

273 A 100 mL round bottom flask was charged with 90 mg 78 (0.26 mmol) suspended in dichloromethane. DIEA (0.1 mL, 0.72 mmol) and 4-trifluoromethyl phenylisocyanate (48 mg, 0.26 mmol) were added, and the reaction mixture was stirred 5 for 10 minutes. The mixture was chromatographed using a silica flash column with a gradient of 0% to 5% methanol in dichloromethane to provide 50 mg of NI as a white solid (60% yield). 'H NMR (CD 3 0D) 8 8.49 (d, J=2 Hz, I H), 7.90 (m, I H), 7.60 (m, 4H), 4.76 (t, J=6 Hz, I H), 4.17 (m, 2H), 3.68 (n, 2H), 3.45 (m, 2H), 2.50-2.34 (m, 4H). MS(M+l): n/z=462.l. 10 Example 3: Syntheses of Piperazine Compounds K6, L6, M6, V6 and W6 2,3-dichloro-5-vinylpyridine CHO PPh 3

CH

3 Br C 1 N K(N(TMS) 2 ) ci C1 C1 65 66 15 To a suspension of methyltriphenylphosphonium bromide (PPh3CH3Br, 7.08 g, 19.8 mmol, Sigma-Aldrich) in THF (40 mL) at 0*C was added dropwise a 0.5N solution of potassium bis(triinethylsilyl)amide {K(N(TMS) 2 )]in toluene (39.6 mL, 19.8 mmol, Sigma-Aldrich). Then the resultant mixture was stirred at 0"C for Ihour. To the mixture 20 was added a solution of 65 (3.1 7 g, 18.0 mmol) in THF (20 mL) at 0"C. The reaction mixture was stirred for 2 h at 0*C. The reaction was quenched with water, and the mixture was extracted three times with EtOAc (150 mL for each extraction). The organic portions were combined, washed with brine, and concentrated to dryness. Compound 66 was obtained as a slight yellowish oil via flash chromatography using 25 ethyl acetate/hexane gradient as an eluent (64% yield). 'H NMR: (CDCl 3 )S 8.28 (d, J=2.1 Hz, I H), 7.82 (d, J=2.2 Hz, I H), 6.65 (dd, J=l 1.0, 17.5 Hz, I H), 5.85 (d, J=17.5 Hz, I H), 5.48 (d, J=11.0 Hz, I H) ppm.

274 tert-butyl 4-(3-chloro-5-vinylpyridin-2-yl)piperazine-I -carboxylate H N N BOC N O Cl N (t-BuO)Na N C1 Pd(OAc) 2 DPPP N 66 BOC 81 5 To a solution of 66 (1.74 g, 10.0 mmol) in toluene (15 mL) was added tert-butyl 1-pipeiazine-carboxylate (1.86 g, 10.0 mmol, Sigma-Aldrich), palladium acetate (0.113 g, 0.5 mmol, Sigma-Aldrich), 1,3-bis(diphenylphosphino)propane (DPPP, 0.220 g, 0.5 nmol, Sigma-Aldrich), and sodium tert-butoxide (1.05 g, 11.0 mmol, Sigma-Aldrich) at a temperature of about 25"C. The reaction mixture was stirred at 75*C for 16 h. After 10 cooling to a temperature of about 25'C, water was added to quench the reaction. Then the mixture was extracted three times with diethyl ether (150 mL for each extraction). The organic portions were combined, washed with brine, and concentrated to dryness. Compound 81 was obtained as a white solid via silica gel column chromatography using an ethyl acetate/hexane gradient as an eluent (88% yield). 'H NMR: (CDCIb) 8.14 (m, 15 IH), 7.69(d,J=1.5 Hz, IH), 6.60(dd,J=11.0, 17.5 Hz, IH), 5.68 (d,J=17.5 Hz, IH), 5.28 (d, J=1 1.0 Hz, I H), 3.58 (m, 4H), 3.32 (m, 4H), 1.49 (s, 9H) ppm. MS (M+Na): n/z = 346.1.

275 (S)-tert-butyl 4-(3-chloro-5-(1,2-dihydroxyethyl )pyridin-2-yl)piperazine I -carboxylate HO,... OH N CI AD-mix a CI N t-BuOH ') N N BOC BOC 81 82 5 To a suspension of 81 (2.84 g, 8.77 mnol) in tert-butanol (60 mL) and water (60 mL) was added AD-mix-a (11.93 g, 8.77 mmol, Sigma-Aldrich) at 0"C. The reaction mixture was stirred at 0*C for 8 hours then extracted three times with diethyl ether (150 mL for each extraction). The organic portions were combined, washed with brine, and 10 concentrated to dryness under reduced pressure. Compound 82 was obtained as a white solid via flash chromatography using an ethyl acetate/hexane gradient as an eluent (90% yield). 'H NMR: (CDCI) 8 8.14 (d, J=2.0 Hz, I H), 7.67 (d, J=2.2 Hz, I H), 4.79 (m, I H ), 3.77 (m, I H), 3.64 (m, I H), 3.56 (m, 4H), 3.28 (m, 4H), 2.87 (d, J=3.2 H z, I H), 2.27 (in, I H), 1.48 (s, 9H) ppm. MS (M+1): m/z = 358. 1. 15 (S)- I -(5-chloro-6-(piperazin- I -y1)pyridin-3 -yl)ethane- 1 ,2-diol HO,... OH HO,.. OH -l N -l N CI CI HCI N N N N Q HO BOC H 82 83 276 A suspension of 82 (2.81 g, 7.85 mmol) and 4M HCI in dioxane (60 mL) was stirred at a temperature of about 25*C for 1 hour. The reaction mixture was concentrated under reduced pressure to provide 83 as a white solid. (S)-N-(4-tert-butylphenyl)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin 5 2-yl)piperazine- I -carboxanide OH HO,.. HO.. OH NK0 N Cl NN N CI N( N | N N NH H TEA 83 K6. To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL) was added 10 dropwise a solution of 4-tert-butylphenyl isocyanate (0.5 mmol, Sigma-Aldrich) in DCM (1.0 mL) at 0"C. The reaction mixture was stirred at a temperature of about 25*C for 4 hours. Thereafter, silica gel column chromatography using an ethyl acetate/methanol gradient as an eluent provided K6 as a white solid. 'H NMR:

(CD

3 0D) 6 8.18 (d, J=2.0 Hz, I H), 7.78 (d, J=2.0 Hz, I H), 7.30 (m, 4H), 4.66 (t, J=5.5 15 Hz, I H), 3.68 (m, 4H), 3.62 (m, 2H), 3.34 (in, 4H), 1.30 (s, 9H) ppm. MS (M+]): m/z = 433.2.

277 (S)-4-(3-chloro-5-( 1,2 -dihydroxyethyl)pyridin-2-yl) N-(4-(trifluoromethoxy)phenyl)piperazine- I -carboxarnide OH HO,.... HO... OH --C (NN C N Cl -N N N NOCF3 NH H 83 TEA

OCF

3 L6 5 To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL), was added dropwise a solution of 4-trifluoromethoxyphenyl isocyanate (0.5 mmol, Sigma-Aldrich) in DCM (1.0 mL) at 0*C. The reaction mixture was stirred at a temperature of about 25*C for 4 hours. Thereafter, silica gel column chromatography using an ethyl 10 acetate/methanol gradient as an eluent provided L6 as a white solid. 'H NMR:

(CD

3 0D) 8 8.18 (d, 1=1.6 Hz, I H), 7.78 (d, J=1 .7 Hz, I H), 7.47 (m, 2H), 7.18 (m, 2H), 4.66 (t, 1=5.9 Hz, IH), 3.69 (m, 4H), 3.63 (m, 2H), 3.35 (m, 4H) ppm. MS (M+l): n/z =461.1.

278 S)-4-(3-chloro-5-(1,2 -dihydroxyethyl)pyridin-2-yl) N-(4-(tri fluoromethyl)phenyl)piperazine-I -carboxamide OH HOE.. HO,.. OH -0 N N TACF3 NH N am O H TEA 83

CF

3 M6 5 To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL) was added dropwise a solution of 4-trifluoromethylphenyl isocyanate (0.5 mmol, Sigma-Aldrich) in DCM (1.0 mL) at 0*C. The mixture reaction was stirred at a temperature of about 25'C for 4 hours. Thereafter, direct flash chromatography using an ethyl acetate/methanol 10 gradient as an eluent provided M6 as a white solid. 'H NMR: (CD 3 0D) 8 8.18 (m, I H), 7.78 (m, I H), 7.58 (m, 4H), 4.66 (t, J=5.5 Hz, I H), 3.71 (m, 4H), 3.63 (in, 2H), 3.36 (m, 4H) ppm. MS (M+1): n/z = 445.0. N-(6-fluorobenzo[dlthiazol-2-yl)- 1 H-imidazole- I -carboxamide

NH

2 0 HN N N + / N \ N10 INN N N F 122 123 F 15 124 279 To a solution of 6-fluorobenzo[d]thiazol-2-amine (122, 336 mg, 2 mmol, Sigma Aldrich) in DMF (5 mL) was added CDI (123, 357 mg, 2.2 mmol, Sigma-Aldrich) at 0*C. Under vigorous stirring, the reaction mixture was slowly allowed to warm to a temperature of about 25"C over 14 h. A white precipitate formed. The precipitate was 5 collected by vacuum filtration, washed twice with EtOAc (10 mL for each wash), and dried under reduced pressure to provide 124 (yield >99%). (S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-N-(6-fluorobcnzo[dlthiazol 2-yl)piperazine-I -carboxamide OH HO.. HO''' OH 0 1 HN N -'\\ Cl C1 N N N) N) +

--

TEA N NH N O HF N 83 124 F 10 To a mixture of 83 (0.3 mmol) in DCM (2.0 mL) and TEA (0.2 mL) was added dropwise a suspension of 124 (0.3 mmol) in DMF (1.0 mL) at 0*C. The reaction mixture was stirred a( a temperature of about 25 0 C for 4 hours. Thereafter, direct flash 15 chromatography using an ethyl acetate/methanol gradient as an eluent provided V6 as a slightly yellowish solid. 'H NMR: (CD 3

SOCD

3 ) 8 8.19 (m, IH), 7.76 (m, 3H), 7.22 (m, 1 H), 5.41 (d, J=4.6 Hz, I H), 4.79 (t, J=6.0 Hz, I H), 4.53 (m, I H), 3.71 (m, 4H), 3.50 (m, 2H), 3.26 (m, 4H) ppm. MS (M+I): m/z = 452.1.

280 (S)-N-(4-chIoro-3-(trifluoromethyllphenyl)-4-(3chloro-5( 1,2 dihydroxyethyl)pyridin-2-yl)piperazine- I -carboxamide OH HO,,.. HO, OH C-0 C1 N N ClI (N) CF3 N CH NH N am O' H TEA 83 CF3 W6 5 To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL) was added dropwise a solution of I-chloro- 4 -isocyanato-2-(trifluoromethyl)benzene (0.3 mmol, Sigma-Aldrich) in DCM (1.0 mL) at 0*C. The reaction mixture was stirred at a temperature of about 25"C for 4 hours. Thereafter, direct flash chromatography using an ethyl acetate/methanol gradient as an eluent provided W6 as a white solid. 'H NMR: 10 (CD 3 0D) 8 8.18 (m, I H), 7.91 (d, J=2.4 Hz, I H), 7.78 (d, J=2.6 Hz, I H), 7.64 (dd, 1=2.6, 8.8 Hz, I H), 7.47 (d, J=9.2 Hz, I H), 4.66 (m, I H), 3.70 (m, 4H), 3.63 (m, 2H), 3.35 (m, 4H) ppm. MS (M+1): m/z = 479.1.

281 Example 4: Synthesis of Compound F4 5,6-dichloro-N-methoxy-N-methylnicotinanide COOH 0 N H 1 N EDCI, HOBt, TEA N C1 CI CA C1 5 87 88 To a stirred solution of 5,6-dichloronicotinic acid ( 87, 7 g, 36.5 rnmol) in dichloromethane (100 mL) at a temperature of about 25'C was added N,O dimethyihydroxylamine hydrochloride (3.56 g, 36.5 mmol), ]-(3-dimethylaminopropyl) 10 3-ethylcarbodiimide hydrochloride (EDCI, 7.69 g, 40.1 nmol), I -hydroxybenzotniazole (HOBt, 5.42 g, 40.1 mmol), and TEA (7.6 mL, 54.7 mmol). After being stirred for 4.5 h at a temperature of about 25*C, the reaction mixture was diluted with ethyl acetate. The mixture was washed with water, IN aqueous hydrogen chloride, saturated aqueous sodium hydrogen carbonate and brine, dried (Na 2

SO

4 ), filtered, and concentrated under 15 reduced pressure to provide 88. I-(5,6-dichlioropyridin-3-yl)ethanone 0 N 0

CH

3 MgCI N CI N Cl Cl 88 89 20 To a stirred solution of 88 in tetrahydrofuran (100 mL) was added dropwise a 3M solution of methylmagnesium chloride in THF (18 mL, 54.7 mmol) at 0*C under nitrogen. After being stirred for I h at 0*C, the reaction mixture was partitioned between 282 ether and saturated aqueous ammoniurn chloride at 0"C. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with a gradient of from 90:10 to 5 70:30 hexane:ethyl acetate to provide 5.92 g of 89 as a white solid (85% yield for 2 steps). 2-bromo- 1 -(5,6-dichloropyridin-3-yl)ethanone Br 0 O Br 2 C N AcOH -N CI CI C1 CI 89 90 10 To a stirred solution of 89 (3 g, 15.8 mmol) in glacial acetic acid (25 mL) was added dropwise a solution of bromine (0.81 mL, 15.8 mmol) in glacial acetic acid (5 mL) at a temperature of about 25*C. After being stirred for 24 h at about 25*C, the reaction mixture was precipitated. The precipitate was filtered off and washed with 15 diethyl ether to provide 3.89 g of 90 as a pale yellow solid (92% yield). 2-(5,6-dichloropyridin-3-yi)-2-oxoethyl acetate Br O0 0 .0 NaOAc N -N CI C 1 Cl Cl 90 91 20 To a stirred solution of 90 (1 g, 3.72 mmol) in DMF (15 mL) at a temperature of about 25*C was added sodium acetate (457.6 mg, 5.58 mmol). The reaction mixture was heated to 70"C. After being stirred for I h at 70"C, the reaction mixture was cooled to a 283 temperature of about 25'C and diluted with diethyl ether. The mixture was washed with water, washed with brine, dried (Na-SO 4 ). filtered, and concentrated under reduced pressure. The residue was chrornatographed using flash chromatography eluting with a gradient of from 90:10 to 65:35 hexane:ethyl acetate to provide 563 mg of 91 as a 5 yellow solid (61% yield). 2-(5,6-dichloropyridin-3-yl)-2,2-difluoroethy acetate OAQ H 3 CO OJo 0 N-SF 3 F

H

3 COF N-N CI Cl 91 92 10 To a stirred solution of 91 (257 ing, 1.04 mmol) in dichloromethane (10 mL) at a temperature of about 25*C was added bis(2-methoxyethyl)aminosulfur trifluoride (0.57 iL, 3.11 mmol). The reaction mixture was heated to 65*C and stirred for 18 h. Thereafter, the reaction mixture was cooled to a temperature of about 0*C and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. 1 5 The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with 90:10 hexane:ethyl acetate to provide 201.3 mg of 92 as a yellow oil (75% yield).

284 tert-butyl 4-(3-chloro-5-(1, I -difluoro-2-hydroxyethyl)pyridin-2-yl) 5,6-dihydropyridine- I (2H)-carboxylate F OH O O B'O F F F -N N Cl BOC C1 -N CI Pd(DPPF) 2

C

7 N

K

2 C0 3 BOC 92 93 5 To stirred solution of 92 (326.2 mg, 1.41 mmol) in dimethoxyethane:ethanol (6 mL, 2:1) at a temperature of about 25'C was added Pd(DPPF) 2

C

2 (230.3 mg, 0.282 nimol), boron pinacol ester (436.0 mg, 1.41 mmol), potassium carbonate (389.8 mg, 2.82 mmol), and water (4 mL). The reaction mixture was heated to 70*C and stirred for 10 1.5 h. Thereafter, the reaction mixture was cooled to a temperature of about 0C and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with brine, dried (N-a 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with a gradient of 15 from 70:30 to 60:40 hexane:ethyl acetate to provide 506.9 mg of 93 as yellow oil (96% yield).

285 2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)-2,2-difluoroethanol hydrochloride OH OH F F F F Cl -N H Cl N N HCI BOC 93 94 5 To a stirred solution of 93 (506.9 mg, 1.35 mmol) in dichloromethane (2 mL) at 0 0 C was added an excess amount of 4N HCI in dioxane (4 mL). After heating to a temperature of about 25*C and stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether to provide 10 292.2 mg of the hydrochloride salt of 94 as a pale yellow solid (70% yield). 4-(3-chloro-5-(1,1 -difluoro-2-hydroxyethyl)pyridin-2-yI) N-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1 (2H')-carboxamide OH F OH F F 0 2 N FN Cl NNH Cl -N N N CF 3 O NH H HCI 95 94 DIEA

CF

3 F4 286 To a stirred solution of 4-trifluoroaniline (26 nL, 0.289 mmol) in dichloromethane (3 mL) at 0*C was added 4-nitrophenyl chloroformate (58.3 mg, 0.289 mmol) and pyridine (28 mL, 0.347 mmol). After heating to a temperature of about 254C and stirring for 2 h, the reaction mixture was cooled to 0 0 C and 94 (90 mg, 0.289 mmol) 5 and DIEA (0.13 nL, 0.723 mnol) were added. After I h at 0 0 C, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with a gradient of from 70:30 to 65:35 hexane:ethyl acetate. The resulting solid was recrystallized from hexane:ethyl acetate to provide 82.3 mg of F4 as a white solid (62% yield). 10 Example 5: Synthesis of Compound 04 2-(tert-butyldimethylsilyloxy)-l -(5,6-dichloropyridin-3-yl)ethanone OH OTBS HO,,. 0 TBSCI - N Imidazole - N Cl Cl C, C1 15 67a 97 To a stirred solution of 67a (19.2 g, 81.4 mmol) in dichloromethane (250 mL) at 0 0 C under nitrogen was added imidazole (11.1 g, 162 mmol) and tert-butyldimethylsilyl chloride (TBSCI, 12.3 g, 81.4 mmol). After heating to a temperature of about 25 0 C and 20 stirring for 2.5 h, the reaction mixture was cooled to 0C and partitioned between diethyl ether and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with a gradient of from 90:10 to 80:20 hexane:ethyl 25 acetate to provide 24.1 g of 97 as pale yellow oil (92% yield).

287 2-(tert-butyldimethylsilyloxy)- I -(5,6-dichloropyridin-3-yl)ethanone OTBS OTBS HO.. 102 OH -N CI Cl CI 97 98 5 To a stirred solution of silyl ether 97 (8 g, 24.8 mmol) in tetrahydrofuran/methyl sulfoxide (100 mL, 1:1) at a temperature of about 25'C was added o-iodoxybenzoic acid (20.9 g, 74.5 mmol). The reaction mixture was stirred for 5 h at about 25*C. Thereafter, the reaction mixture was cooled to a temperature of about 0C and partitioned between diethyl ether and saturated aqueous sodium hydrogen carbonate. The aqueous layer was 10 extracted with diethyl ether. The organic portions were combined, washed with saturated aqueous sodium hydrogen carbonate, washed with brine, dried (Na 2

SO.

4 ), filtered, and concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with 90:10 hexane:ethyl acetate to provide 8.0 g of 98 as a yellow oil (99% yield). 15 5-(3-(tert-butyldimethylsilyloxy)prop- I -en-2-yl)-2,3-dichloropyridine OTBS OTBS 0 PPh 3

CH

3 Br N (t-BuO)K N CN Cl CI CI 98 99 To a stirred suspension of methyltriphenylphosphonium bromide (11.8 g, 33.0 20 rnmol) in toluene (100 mL) at 0*C under nitrogen was added potassium tert-butoxide (3.70 g, 33.0 mmol). After being stirred for I h at 0*C, a solution of 98 (8.8 g, 27.5 mnol) in toluene (60 mL) was added dropwise to the reaction mixture over I h at 0 0

C.

288 After an additional 2 h at 0 0 C, the reaction mixture was partitioned between diethyl ether and saturated aqueous ammonium chloride. The aqueous layer was extracted with diethyl ether. The organic portions were combined, washed with water, washed with brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue 5 was chromatographed using flash chromatography eluting with 90:10 hexane:ethyl acetate to provide 7.6 g of 99 as a yellow oil (87% yield). 3-(tert-butyldinethylsilyloxy)-2-(5,6-dichloropyridin-3-yl)propan- 1 -ol OTBS OH OTBS 1) BH 3

S(CH

3

)

2 -N 2) NaOH, H 2 02 N C, C CI CI 99 100 10 To a stirred solution of 99 (7.6 g, 23.9 mmol) in tetrahydrofuran (120 mL) at 0*C under nitrogen was added borane-methyl sulfide complex (2.3 mL, 23.9 mmol). The reaction mixture was heated to a temperature of about 25'C and stirred for 5 h. Thereafter, the reaction mixture was cooled to 0"C and to the reaction mixture was 15 added IN sodium hydroxide (48 mL) dropwise followed by the addition of hydrogen peroxide (17 mL, 35 wt% solution in water). After 2 h more at 0C, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with water, aqueous sodium sulfite and brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. 20 Compound 100 was isolated by silica gel column chromatography as a yellow oil (42% yield).

289 tert-butyl 4-(5-(1-(,ert-butyldimethylsilyloxy)-3-hydroxypropan-2-yl) 3-chloropyridin-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate OH OTBS OB OH OTBS N N BOC - N Pd(DPPF) 2 Cl.

K

2 C0 3 N 100 BOG 101 5 To stirred solution of 100 (1 g, 2.97 mmol) in dimethoxyethane:ethanol (18 mL, 2:1) at a temperature of about 25"C was added Pd(DPPF) 2

C

2 (485.6 mg, 0.595 mmol), pinacol ester (919.4 mg, 2.97 mmol), potassium carbonate (821.9 mg, 5.95 mnol), and water (12 mL). The reaction mixture was heated to 60'C and stirred for 1.5 h. 10 Thereafter, the reaction mixture was cooled to a temperature of about 0"C and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue was chromatographed using flash chromatography eluting with a gradient of 15 from 70:30 to 40:60 hexane:ethyl acetate to provide 1.49 g of 101 as a yellow oil (>99% yield).

290 2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)propane- ,3-diol hydrochloride OH OTBS OH OH | HCI -N ,N N HCI BOC 101 102 S To a stirred solution of 101 (1.49 g, 2.97 mmol) in dichloromethane (7 mL) and methanol (2 mL) at 25*C was added excess amount of 4N HCI in dioxane (7.5 mL). After being stirred for 2 h at a temperature of about 25"C, the reaction mixture was concentrated under reduced pressure. The residue was crystallized from diethyl 10 ether to provide 606.3 mg of the hydrochloride salt of 102 as a pale brown solid (70% yield).

291 4-(3-chloro-5-( 1,3-dihydroxypropan-2-yl)pyridin-2-yl) N-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxamide OH OH 0 2 N OH OH 0 0 NH -N CI N C CF 3 N 103 O NH N HCI DIEA H 102

CF

3 04 5 To a stirred solution of 4-trifluoroaniline (29 mL, 0.328 mmol) in dichloromethane (3.5 mL) at 0 0 C was added 4-nitrophemyl chloroformate (66.0 mg, 0.328 mmol) and pyridine (32 mL, 0.393 mmol). After heating to a temperature of about 25'C, the reaction mixture was stirred for 2 h. Thereafter, the reaction mixture 10 was cooled to 0*C and the hydrochloride salt of 102 (100 mg, 0.328 mmol) and DIEA (0.14 mL, 0.819 mmol) were added. After I h more at 0*C, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with saturated aqueous sodium hydrogen carbonate and brine, dried (Na 2

SO

4 ), filtered, and concentrated under reduced 15 pressure. The residue was chromatographed using flash chromatography eluting with a gradient of from 95:5 to 90:10 chlorofonn:methanol. The resulting solid was recrystallized from isopropyl ether:ethyl acetate to provide 97.2 mg of 04 as a white solid (65% yield).

292 Example 6: Determination of the Optical Purity for BI and NI: The % ee was determined for compounds BI and NI as shown below: OH OH OH HO HO,... HO -N -N N C1 Cl CI F F F N N N OA NH O NH O NH

CF

3 CF 3 CF 3 Al NI BI 0% ee 99.4% ee by 'H NMR 99.4% ee by 'H NMR 5 99.3% ee by HPLC 99.2% ee by HPLC 'H NMR and chiral HPLC were used to determine the % ee for both NI and B1. For the HPLC assay, a CHIRALPAK I A column was used, the peak areas for the major and minor enantiomers were determined, and % ee was calculated from the equation in 10 section 5.3. For 'H NMR, bis-Mosher's ester derivatives were synthesized for Al, BI, and NI by a technique known in the art. The % ee determinations were done by adding an excess of Mosher's acid chloride to Al, B1, or NI (about 0.6 mg) in pyridine-d 5 (0.530 mL) at a temperature of about 25 0 C in an NMR tube. A 'H NMR was taken 20 h after the addition of Mosher's acid chloride. The peak chosen for the bis-Mosher's ester 15 of N1 is at approximately 8 6.90, and for BI at 6 6.78. It is important to note the 3 C satellites were observed at 5 (7.02 and 6.78) for NI and 8 (6.90 and 6.65) for B1. The H NMR peaks for the minor and major enantiomer in each case were integrated, the 1 3 C satellites were subtracted out, and the % ee was calculated.

293 Example 7: Synthesis of Compound M4 2,3-dichloro-5-rnethylsulfonamidylmethyl pyridine 0 H 0 H1 N- S 0

CH

3

SO

3

NH

2

N

CI CI C1 Cl 79 105 5 To a suspension of methyl sulfonamnide (1.08 g, 11.3 5 mrnol), 2,3-dichioropyridinyl aldehyde, (79, 3.0 g, 17.03 mmol), AcOH (1.35 mL), and NaBH(OAc) 3 in dry dichloromethane (70 mL) at 0 0 C, TEA (3.1 8 mnL, 22.7 mmnol) was added. The reaction mixture was heated to a temperature of about 25'C and stirred for 10 15 hi. Thereafter, saturated NaHCO 3 (2 mL) was added. The mixture was extracted twice with ethyl acetate (8OmL for each extraction). The organic portions were combined, washed twice with brine (5Oml- for each wash), dried over anhydrous Na 2

SO

4 , and concentrated under reduced pressure. The oily residue was chromatographed using a COMBIFLASH apparatus with a 40 g REDISEP column with 15 eluent of 40% ethyl acetate in hexanes to provide 2.8 g of 105 (65% yield) and 20% recovered starting material. 'H- NMR (CDCI 3 ): 6 8.38 (s, I H), 8.27 (s, I H), 5.03 (bs, NH), 4.35 (d, J=l 7Hz, 2H), 3.0 (s, 3H).

294 lert-butyl 4-(3-chloro-5-(miiethylsulfonanidonethyl)pyridin-2-yl) 5,6-dihydropyridine- 1(2H)-carboxylate 0 H 11 O N-S ,\ 0 11 B 0 0 H 1

N-S-

II / O1 NNC N BOC Pd(PPh 3

)

2

CI

2 N Cl BOC 105 106 5 To a suspension of 105 (3.86g, 15.1mnol), boronate (4.78, 15.1 mnol), and Pd(PPh3) 2

CI

2 in ethylene glycol dimethyl ether (38 mL) and EtOH (19 mL) at a temperature of about 25 0 C was added 2M K 2

CO

3 (15 mL). The reaction mixture was heated 40'C for 9hr. Thereafter, the reaction mixture was cooled to a temperature of 10 about 25"C, IN HCl (10 mL) was added. The mixture was extracted twice with ethyl acetate (60 mL for each extraction). The organic portions were combined, washed with water, dried over anhydrous Na 2

SO

4 , and concentrated under reduced pressure to provide the oily residue which was then chromatographed using a COMBIFLASH apparatus with a 80 g REDISEP column with 30% EtOAc in hexanes to provide 5.Og of 15 106 (83% yield). 'H NMR (CDCl 3 ): & 8.35(s, I H), 7.70 (s, I H), 6.03 (bs, I H), 5.34 (bs, t, NH), 4.26 (d, J=6.3Hz, 2H), 4. 10 (m, 2H), 3.55 (t, J=5.6Hz, 2H), 2.89 (s, 3H), 1.42 (s, 9H).

295 N-((5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)methyl)methane sulfonamide hydrochloride o 0 H i1 H it N-S- N- S I I I I 0 0 C1 N HC, Cl N HHCI N N I H HOI BOG 106 107 5 Compound 106 (1.0g, 2.5mmol) was dissolved in dry dichloromethane (10 mL) and cooled to 0 0 C. 4N HCI in dioxane (10 mL, 25mmol) was added. The reaction mixture was heated a temperature of about 25*C and stirred for 16 h. The resulting white slurry was filtered and, after drying under reduced pressure, 790 mg of the 10 hydrochloride of 107 was collected as an off-white solid (94% yield). 4-(3-chloro-5-(methylsulfonamidomethyl)pyridin-2-y) N-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine- 1 (21-f)-carboxanide 0 H 1

N-S

I1 0 O ' H P- "C 0 N N-1 N C1 -N 0 N 11N 'N

'NCF

3 -l DI EA N H HCl 107

CF

3 M4 296 To a suspension of salt (4, 790mg, 2.34mmol) in dichloromethane at 0*C was added DIEA (1.21 mL, 7.03 mmol). The reaction mixture was stirred until it became homogenous. a,c,a-trifluoro-p-tolyl isocyanate (0.3 mL, 2.22nmmol) was added thereto and the reaction mixture stirred for 10 min, until the reaction was complete. The 5 reaction mixture was concentrated under reduced pressure. The oily residue was chromatographed using a COMBIFLASH apparatus with a 12 g REDISEP column with 50% EtOAc in hexanes to provide 812 mg of M4 as a white solid (71% yield). 'H NMR (CDCl 3 ): 8 8.98 (s, 1 H), 8.49 (s, I H), 7.89-7.54 (m, 4H), 6.2 (bs, NH), 4.20-4.24 (m, 4H), 3.70 (t, J=5.5Hz, 2H), 2.96 (s, 3H), 2.51-2.33 (bs, 2H). 10 Example 8: Synthesis of Compound N3 OH HO OH C HO N

NH

2 C1 N O ODIEA + O- - 0 + HNN C1 N | HN

CF

3 O N 108 109 0 NH N N

CF

3 H HCI 110 111

CF

3 N3 297 Phenyl 5-(trifluoromethyl)pyridin-2-ylcarbamate To a stirred solution of 5-(trifluoronethyl)pyridin-2-amine 108 (20 g, 123.5 mmol) in dichloromethane (85 mL) at -5*C was slowly added phenyl carbonochloridate 5 109 (21.2 g, 136 mmol) over 10 mini. At -5"C, pyridine (11.1 mL, 136 mmol) was then added drop wise to the reaction mixture. After heating the reaction mixture to a temperature of about 254C and stirring for I h, a precipitate gradually formed. The precipitate was filtered and washed with dichloromethane and ethyl acetate to provide 24.1 g of 110 as a white solid (69.2% yield). 'H NMR (400 MHz, DMSO-d 6 ) 5 11.3 (br 10 s, I H), 8.75-8.70 (m, 1 H), 8.24-8.17 (m, I H), 8.05-7.98 (m, I H), 7.50-7.40 (m, 2H), 7.33-7.22 (m, 2H). (R)- I -(5-chloro-6-(1.2,3,6-tetrahydropyridin-4-yI)pyridin-3-yI)ethane-1.2-diol The title compound 111 was obtained using a procedure similar to that described in Example I for obtaining 70 except that 67b was used in place of 67a. 15 (R)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-N-(5 (trifluoroimethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxamide To a stirred suspension of the hydrochloride salt of 111 (9.36 g, 32.26 mmol) in dichloromethane (30 nL) at -20"C was added 110 (8.19 g, 29 nmol) in one portion. Then at -20'C, DIEA (14 mL, 80.65 mmol) was added drop wise to the reaction mixture 20 over 15 min. After being stirred for 2 h at -20*C, the reaction mixture was diluted with 200 mL of dichloromethane, washed twice with IN aqueous sodium hydroxide (200 mL for each wash), dried (Na 2

SO

4 ), filtered, and concentrated under reduced pressure. The residue (12 g) was dissolved in 25 mL hot ethyl acetate and allowed to cool slowly. The precipitate was collected by vacuum filtration and washed twice with a solution of 50% 25 ethyl acetate in hexane (100 mL for each wash) to provide 10.15 g of N3 as a white solid (71% yield). 'H NMR (400 MHz, DMSO-d 6 ) 8 9.88 (s, I H), 8.66-8.60 (m, I H), 8.49 8.44 (im, I H), 8.10-8.03 (m, I H), 8.03-7.96 (m, I H), 7.85-7.81 (m, I H), 6.21-6.14 (n, I H), 5.57-5.51 (m I H), 4.89-4.82 (m, I H), 4.64-4.57 (m, I H), 4.25-4.19 (m, 2H), 3.76 3.67 (n, 2H), 3.60-3.43 (n, 21-1), 2.62-2.52 (m, 2H). 30 Example 9: Synthesis of Compounds of Formula I Using procedures similar to those described above, the following compounds of fonnula I were prepared.

298 OH OH OH HN04, HNO4 HOH * N N F N Fl F F F F NN N 0 NH 0 NH 0 N H IN

CF

3

CF

3

CF

3 N6 06 P6 N6: 'H NMR (CD 3 OD) 8 8.41 (s, I H), 7.59 (in, 5H), 4.80 (t, J=6 Hz, I H), 4.15 (m, 2H), 3.69 (m, 2H), 3.45 (m, 2H), 2.45-2.26 (m, 4H). MS (M+1): mn/z = 446.1. 5 06: H NMR (CD 3 0D) 8 8.38 (in, I H), 7.79 (in, I H), 7.68 (in, I H), 7.52 (d, J=8 Hz, IH), 7.38 (m, IH), 4.65 (t, J=6 Hz, IH), 4.04 (m, 2H), 3.57 (m, 2H), 3.33 (m, 2H), 2.39-2.21 (in, 41H). MS (M+1): n/z = 496.0. P6: ' H NMR (CD 3 0D) 8 8.55 (in, I H), 8.41 (s, I H), 7.98 (in, 2H), 7.67 (m, I H), 4.80 (t, J=6 Hz, I H), 4.18 (in, 2H), 3.70 (in, 2H), 3.48 (in, 2H), 2.46-2.26 (In, 4H). MS 10 (M+I): m/z=447.1.

299 OH OH OH OH HO /,,, ,HO,, OH XNN Cl NCl N N F F F N N N 0 NH 0 NH O NH N F

CF

3

CF

3

CF

3 Fl G, T5 Fl: 'H NMR (CD 3 OD) 8 8.38 (m, I H), 7.79 (in, I H), 7.44 (m, 2H), 7.21 (i, I H), 4.65 (t, J=5.6 H z, I H), 4.05 (m, 2H), 3.56 (m, 2H), 3.33 (m, 2 H), 2.38-2.2.21 (m, 5 4H). MS (M+1): ni/z = 480.0. GI: 'H NMR (CD 3 0D) 8 8.43 (m, I H), 8.37 (d, J=2 Hz, I H), 7.87 (m, 2H), 7.79 (I, IH), 4.65 (t, J=6 Hz, I H), 4.08 (m, 2H), 3.57 (m, 2H), 3.35 (m, 2H), 2.38-2.22 (m, 4H). MS (M+]): n/z = 463.1. T5: 'H NMR (CDOD) 88.64 (dd, J=1.8, 0.6 Hz, IH), 8.04 (d, J=2.1, 0.3 Hz, 10 I H), 7.59 (dd, J=1 4.4, 8.9 Hz, 4H), 4.19-4.15 (br d, J=13.8 Hz, 2H), 3.78 (dd, J=24.8, 11.3 Hz, 4H), 3.49-3.42 (m, 2H), 2.49-2.34 (m, 4H). MS (M+1): m/z = 492.

300 oH OH OH HO0,, HO,, HOO N F F F NN 0 H= 0 CH F

CF

3

CF

3 LI HI Q3 LI: 'H NMR (CD 3 OD) 8 8.37 (s, I H), 7.79 (s, I H), 7.42 (in, 2H), 7.02 (in, I H), 4.64 (t, J=6 Hz, I H), 4.21 (in, 2H), 3.56 (in, 2H), 3.35 (in, 2H), 2.35-2.20 (m, 4H). MS 5 (M+1): m/z = 469.0. HI: 'H NMR (CD 3 0D) 8 8.38 (in, IH), 7.82 (in, 3H), 7.70 (in, 2H), 4.64 (t, J=6 Hz, I H), 4.06 (in, 2H), 3.57 (in, 2H), 3.36 (in, 2H), 2.40-2.23 (in, 4H). MS (M+1): ni/z = 526.0. Q3: 'H NMR (CD 3 0D) 8 8.39 (s, I H), 7.78 (in, I H), 7.63 (m, 2H), 7.48 (in, 10 1 H), 4.78 (t, J=6 Hz, I H), 4.13 (in, 2H), 3.67 (in, 2H), 3.43 (m, 2H), 2.43-2.23 (in, 4H). MS (M+1): m/z = 480.5.

301 OH OH OH HO, HO,,, HO, F NF F N F F N NN N NH 0 NH NH S N NCN NH F

CF

3 Y3 F5 Q6 Y3: 'H NMR (CD 3 OD) 8 8.41 (m, 1 H), 7.67 (m, 1 H), 7.55 (m, 2H), 7.34 (n, 1 H), 4.79 (t, J=6 H z, I H), 4.14 (m, 2H), 3.69 (m, 2H), 3.46 (in, 2H), 2.43-2.26 (m, 4H). 5 MS(M+1): m/z=464.1. F5: 'H NMR (CD 3 0D) 68.41 (s, IH), 7.65 (d, J=12 Hz, IH), 7.53 (m, 2H), 7.14 (I, 1 H), 4.79 (t, J=6 Hz, 1 H), 4.28 (m, 2H), 3.69 (m, 2H), 3.48 (in, 2H), 2.45-2.26 (m, 4H). MS (M+1): m/z = 453. 1. Q6: 'H NMR (CD 3 0D) 8 8.41 (s, I H), 7.66 (m, 1 H), 7.41 (m, 2H), 7.10 (m, 10 2H), 4.80 (t, J=6 Hz, I H), 4.08 (m, 2H), 3.69 (m, 2H), 3.50 (m, 2H), 2.49-2.23 (m, 4H), 1.33 (s, 9H). MS (M+1): m/z = 458.5.

302 OH OH OH NN N N 0 NH 0 NH 0 NH =-0 F CF, CF 3

CF

3 UI Ij U1: 'H NMR (MeOD) 8 8.44-8.38 (1 H, m), 7.68-7.54 (5H, m), 6.60-6.53 (1 H, m), 4.82-4.74 (1 H, m), 4.34-4.25 (2H, m), 3.84-3.75 (2H, m), 3.74-3.66 (2H, m), 2.82 5 2.72 (2 H, m). MS: m/z = 425. Q1: 'H NMR (MeOD) 88.51-8.46 (IH, m), 7.99-7.92 (3H, m), 7.89-7.82 (2H, in), 6.17-6.12 (1 H, m), 4.80-4.73 (1 H, m), 4.33-4.25 (2H, m), 3.87-3.76 (2H, m), 3.75 3.64 (2H, m), 2.70-2.61 (2H, m). MS: ni/z = 505. JI: 'H NMR (MeOD) 6 8.44-8.37 (1 H, m), 7.96-7.89 (1 H, m), 7.69-7.51 (3H, 10 m), 7.41-7.34 (1 H, m), 6.60-6.53 (1 H, m), 4.83-4.75 (1 H, m), 4.34-4.26 (2H, n), 3.83 3.75 (2H, m), 3.74-3.65 (2H, m), 2.82-2.73 (2H, m). MS: m/z = 443.

303 OH OH OH HO,,, HO. F N N N Cl N N N 0 NH O NH O NH N O vO

CF

3

CF

3 F P1 KI RI P1: H NMR (MeOD) 8 8.47-8.37 (I H, m), 8.05-7.83 (SH, m), 7.71-7.59 (1 H, in), 6.66-6.53 (1H, m), 4.85-4.74 (1 H, m), 4.42-4.28 (2H, in), 3.91-3.64 (4H, m), 2.89 5 2.74 (2H, m). MS: rm/z = 489. K1: 'H NMR (CDC 3 ) 8 8.51-8.43 (2H, in), 8.25-8.18 (I H, m), 7.92-7.85 (1 H, in), 7.83-7.78 (1 H, n), 7.53 (1 H, br s), 6.22-6.15 (1 H, m), 4.95-4.84 (1 H, m), 4.31-4.19 (2H, m), 3.93-3.64 (4H, m), 3.08-2.97 (1 H, m), 2.77-2.63 (2H, m), 2.24-2.14 (1 H, in). MS: m/z = 442. 10 R: 'H NMR (DMSO) 5 8.50-8.44 (1H, in), 7.87-7.82 (1H, m), 7.82-7.75 (IH, m), 7.70 (1 H, br s), 7.26-7.17 (1 H, m), 6.23-6.17 (1 H, m), 5.58-5.51 (1 H, m), 4.89-4.82 (I H, m), 4.64-4.57 (1 H, in), 4.31-4.21 (2H, m), 3.85-3.73 (2H, m), 3.60-3.42 (2H, m), 2.61-2.5 1 (2H, m). MS: m/z = 448.

304 OH OOH HOH HO,,," HO,,, HOt,, F F N N N 0 NH N NH S N NH CI F CF, CF, L4 U3 K4 U3: 'H NMR (MeOD) 68.42-8.36 (1 H, m), 7.92 (1 H, s), 7.83-7.77 (IH, in), 7.67-7.58 (2H, n), 7.55-7.48 (1 H, m), 6.58-6.52 (l H, m), 4.80-4.72 (1 H, m), 4.31-4.24 5 (2H, m), 3.81-3.74 (2H, m), 3.72-3.63 (2H, m), 2.80-2.71 (2H, m). MS: m/z = 459. L4: 'H NMR (DMSO) 8 8.45-8.33 (1 H, m), 7.85-7.73 (1 H, m), 7.69-7.51 (2H, m), 7.29-7.51 (1 H, m), 6.63-6.49 (1 H, m), 5.62-5.49 (1 H, m), 4.91-4.79 (1 H, m), 4.70 4.56 (1 H, m), 4.37-4.23 (2H, im), 3.87-3.71 (2H, m), 3.59-3.41 (2H, m), 2.73-2.59 (2H, m). MS: m/z = 432. 10 K4: 'H NMR (MeOD) S8.61-8.49 (IH, m), 8.46-8.34 (IH, in), 8.09-7.87 (2H, m), 7.70-7.56 (1 H, m), 6.63-6.51 (1 H, m), 4.82-4.72 (1 H, in), 4.38-4.26 (2H, m), 3.89 3.75 (2H, m), 3.74-3.62 (2H, m), 2.84-2.70 (2H, m). MS: mn/z = 426.

305 Example 10: Alternate Synthesis of Compound 67a 5,6-dichloronicotinoyl chloride COOH COC SOC11 N DMF N CI C1 C1 C1 112 113 To a well stirred suspension of 5,6-dichloronicotinic acid 112 (600g. 3.125 mol) and N.N-dimethylformamide (20.0 mL) in dichloroethane (1.2 L) a temperature of about 25 0 C was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mol). In a 10 reflux apparatus fitted with a gas trap filled with saturated aqueous sodium bicarbonate, the reaction mixture was heated and refluxed, at about to 75'C, until the reaction mixture became a clear solution, after about 3 h. LC/MS analysis of a sample quenched in methanol showed only the presence of the methyl ester, The reaction mixture was cooled to a temperature of about 25'C and concentrated under reduced pressure to 15 provide 113 as a thick slurry. I-(5,6-dichloropyridin-3-yl)ethanone COGl HCi 0 N

CH

3 MgC1 i N TEA N N ,~N C1 C1 C1 CI C1 113 114 115 306 In a dry ice/acetone bath, a suspension of N.O-dimethylhydroxylamine hydrochloride (350.53 g, 3.59 mol) in methylene chloride was cooled to 0C and TEA (711.5 g, 7.03 mol) was added. Compound 113 was dissolved in methylene chloride (2.4 L) and added to the mixture at a rate such that the reaction mixture temperature did 5 not exceed 15 0 C. After the addition of 113 was complete, the reaction mixture was allowed to warm slowly to a temperature of about 25*C over 16 h. Then the reaction mixture was poured into 2L of water, the layers were separated, and the aqueous portion was extracted twice with methylene chloride (500 mL for each extraction). The organic portions were combined, dried (MgSO 4 ), and concentrated under reduced pressure to 10 yield a brown solid. The solid was treated with IL of boiling hexanes and heated at reflux for about 10 minutes. The resulting pale orange solution was decanted from the dark yellow-brown tar and allowed to cool. This boiling hexanes treatment was repeated twice on the tar (500 mL for each treatment). The hexane mixtures were combined, allowed to cool to a temperature of about 25 0 C, then cooled in an icc/water bath. The 15 resulting yellow needles were collected by vacuum filtration and dried in air to provide 730 g of 5,6-dichloro-N-methoxy-N-methylnicotinamide 114 (99% yield). 'H NMR (400 MHz, CDC 3 )S 8.68 (m, I H), 8.18 (m, I H), 3.59 (OCHH, 3H), 3.40, (NCH 3 , 3H). 431 g of 115 was obtained using a procedure similar to that described in Example 4 for obtaining 89 except that 114 was used in place of 88 (97% yield). 'H 20 NMR (400 MHz, CDCl 3 ) 8 8.82 (m, IH), 8.29 (m, 1 H), 2.62 (COCH 3 , 3H). 1-(5,6-dichloropyridin-3-yl)ethanol 0 HO NaBH 4 CI C N C1 CI 115 116 25 To a well-stirred suspension of 115 (665 g, 3.5 mol) in methanol (3.5L) at 0"C was added sodium borohydride (66.21 g, 1.75 mol) portionwise at a rate such that the WO 2008/132600 PCT/IB2008/001069 307 reaction mixture temperature did not exceed 5*C. After the addition was complete, the reaction mixture was warmed to a temperature of about 25*C and stirred an additional I h. LC/MS analysis of an aliquot showed that the reaction was essentially complete. The reaction mixture was concentrated under reduced pressure. The residue was mixed with 5 2L diethyl ether and 2L IN HCI. The layers were separated and the aqueous layer was extracted twice with diethyl ether (250 mL for each extraction). The organic portions were combined, dried (MgSO4), and concentrated under reduced pressure to provide 670g of 116 as a pale yellow oil (99% yield). 'H NMR (400 MHz, CDCl 3 ) 6 8.20 (n, I H), 4.96 (m, I H), 3.57 (s, I H), 1.51 (d, J=6.5Hz, 3H). 10 2,3-dichloro-5-vinylpyridine HO O=S=0 OH NN C1 C1 CI CI 116 66 To a solution of 116 (311 g, 1.62 mol) in chlorobenzenc (3 L) was added p 15 toluene sulfonic acid (431 g, 2.5 mol). The reaction mixture was heated to reflux, about 140 0 C, and water was removed concurrently. At the completion of the reaction, the mixture was concentrated under reduced pressure to about 500 mL, diluted with 2L of water, and extracted three times with ethyl acetate (I L for each extraction). The organic portions were combined, dried (Na 2

SO

4 ), and concentrated under reduced pressure under 20 mild heating to provide a residue. The residue was added to 500 mL of methylene chloride and applied to the top of column packed with 2 kg silica eluted with a 0% to 10% gradient of ethyl acetate in hexane to provide 178.55 g of>99% pure 2,3-dichloro 5-vinylpyridine 66 as a clear oil, which solidified upon cooling to 4"C (63% yield). 'H NMR (400 MHz, CDCl 3 ) 8 8.32 (m, I H), 7.85 (m, I H), 5.72 (m, I H), 4.88 (n, I H), 4.37 25 (n, I H).

308 (S)- I -(5,6-dichloropyridin-3-yl)ethane- 1,2-diol OH HO AD-mix x N 1:1 i-BuOH:H,O Cl N C1 C1 C1 Cl 66 67a 5 In a 5 L three neck round bottom flask fitted with an overhead mechanical stirrer and a thermocouple, a stirred mixture of 66 (150 g, 0.861 mol), t-butanol (2.15L), and water (2.15L) was cooled with an ice/water bath until the temperature of the mixture was below I 0 0 C. AD-mix a (729 g, 1.15 eq.) was added all at once; an endothermic heat of solution lowered the temperature of the reaction mixture to 7"C. The bath was packed 10 with ice and the reaction mixture was allowed to stir for 16 h while its temperature gradually increased to about 25 0 C. Thereafter, an aliquot of the reaction mixture was removed, diluted with methanol, filtered, and analyzed by LC/MS; the LC/MS results showed that the reaction was essentially complete. To promote clumping of the solids and aid filtration, the reaction mixture was 15 diluted with 2L ethyl acetate and filtered under reduced pressure to remove the solids. The resulting clear mixture was phase separated. The aqueous portion was extracted twice with ethyl acetate (250mL for each extraction). The organic portions were combined, dried (MgSO 4 ) and concentrated under reduced pressure to provide a dark gray solid. The solid was added to 500 mL of methanol, treated with decolorizing 20 carbon, boiled, filtered warm through a pad of CELITE, and concentrated under reduced pressure to provide a gray solid. The solid was recrystallized from chloroform to provide 115 g of 67a as a white solid. A second crop of 67a, 12.3 g, was obtained by concentrating the supernatant (71% total yield). 'H NMR (400 MHz, CD 3 0D) 6 8.32 (m, I H), 8.0 (m, I H), 4.75 (t, J=6H z, I H), 3.65 (m, 2H).

309 Example 1OA: Synthesis of Compound E6 (5,6-dichloropyridin-3-yl)methyl methanesulfonate OH 0 0

O-S-CH

3 6

'CH

3 |0 1 0 1 N Cl -N a DIEA l 5 117 118 To a solution of (5,6-dichloropyridin-3-yl)melhanol (117, 5000 mg, 28.1 mmol, Tokyo Chemical Industry Co., Tokyo, Japan) in CH 2

C

2 (150 mL) at a temperature of about 25"C was added DIEA (30.9 mmol). The mixture was cooled to OC and 10 methansulfonyl chloride (MsCl, 30.9 mmol) was added dropwise over 15 min. Thereafter, the reaction mixture was stirred at 0*C for I h. After quenching with water, the mixture was extracted three times with CHC3/H 2 O (100 mL for each extraction), dried (MgSO 4 ), and concentrated under reduced pressure to provide a yellow oil. The oil was chromatographed by silica gel column chromatography (Yamazen) with a 15 gradient of ethyl acetate (20%-50%)/n-hexane to provide 6360 mg of 118 as a yellow oil (88% yield). 'H NMR (400MHz, DMSO) 8: 8.51 (I H, s), 8.26 (1 H, s), 5.35 (2H, s), 3.32 (3H, s). 2-(5,6-dichloropyridin-3-yl)acetonitrile 0 CN 4'CH3 NaCN | N Cl 'N -- , a a 3 20 118 119 To a solution of 118 (6360 mg, 24.8 mmol) in ethanol (75 mL) at a temperature of about 25 0 C was added a solution of NaCN (32.3 mmol) in water (25 mL). The reaction mixture was heated to 80*C and stirred for 1h. After concentration under 310 reduced pressure, the mixture was extracted three times with EtOAc/H 2 0 (100 mL for each extraction), dried (Na 2

SO

4 ), and concentrated under reduced pressure to provide an orange oil. The oil was chromatographed by silica gel column chromatography (Yamazen) with a gradient of ethyl acetate (30%-50%)/n-hexane to provide 2648 mg of 5 119 as a colorless solid (57% yield). H NMR (400MHz, DMSO) S:8.42 (IH, s), 8.18 (I H, s), 4.15 (2H, s). lert-butyl 4-(3-chloro-5-(cyanonethyl)pyridin-2-yl)-5,6-dihydropyridine- 1 (2f) carboxylate CN Pd(PPh 3

)

2 Cl 2 + N N | -N + N2CO3 ,C1 'N (03 N 119 11 0 0 68 120 10 To a mixture of 119 (187 mg, I mmol), 68 (1 mmol), and Na 2

CO

3 (1.5 mnol) in 2/l/2 DME/EtOH/H 2 0 (10 mL) at a temperature of about 25'C was added Pd(PPh 3

)

2 Cl 2 (0.1 mmol). The reaction mixture was heated to 120*C and stirred for 30 min. After cooling to a temperature of about 25 0 C, the mixture was diluted with water, extracted 15 three times with CHCI 3

/H

2 0 (30 nL for each extraction), dried (Na 2

SO

4 ), and concentrated under reduced pressure to provide a yellow oil. The oil was chromatographed by silica gel column chromatography (Yamazen) with a gradient of ethyl acetate (20%-50%)/n-hexane to provide 287 mg of 120 as a pale yellow oil (86% yield). 'H NMR (400MHz, DMSO) 5: 8.50 (1 H, s), 7.95 (I H, s), 6.17 (I H, s), 4.11 (2H, 20 s), 4.02 (2H, s), 3.54 (2H, n), 2.47 (2H, in), 1.43 (9H, s).

311 2-(5-chloro-6-( 1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yllacetonitrile CN CN C1 N TFA, Cl N N N 120 121 5 To a solution of 120 (287 mg, 0.86 rnmol) in CH 2

CI

2 (3 mL) at 0*C was added trifluoroacetic acid (TFA, 8.6 mnmol). The reaction mixture was heated to a temperature of about 25'C and stirred for 45 min. After concentration under reduced pressure, the mixture was neutralized with 28% aqueous ammonia, extracted three times with CHCl3/H-,O (50 mnL for each extraction), dried (Na-,SO4), and concentrated under 10 reduced pressure to provide 200 mg of 121 as a yellow oil (>99% yield). 'H NMR (400MHz, DMSO) 8. 8.53 (1 H, s), 7.98 (I H, s), 6.12 (1 H, s), 4.11 (2H, s), 3.40 (2H, s), 3.19 (1 H, br), 2.90 (2H-, s), 2.24 (2H, s). 4-(3-chloro-5-(cyanomethyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6 dihydropyridine- I (2H)-carboxamide 15 CN O a 'N CN NC N C1 'N O-, N H

CF

3 N H

CF

3 121 E6 312 To a solution of 121 (200 mg, 0.86 mmol) in CH 2 Cl 2 (7 mL) at a temperature of about 25 0 C was added I-isocyanato-4-(trifluoromethyl)benzene (0.86 mmol, Acros Organics, Geel, Belgium). The reaction mixture was stirred at a temperature of about 25*C for 1.5h. After concentration under reduced pressure, the mixture was 5 chrornatographed by silica gel column chromatography (Yamazen) with a gradient of

CHC

3 (99%-20%)/MeOH to provide 64 mg of E6 as a colorless solid (18% yield). 'H NMR (400MHz, DMSO) 5: 8.96 (IH, s), 8.52(IH, s), 7.97 (IH, s), 7.73 (IH, d, J=8Hz), 7.60 (1 H, d, J=8H z), 6.25 (1 H, s), 4.2 1 (2H, s), 4.12 (2H, s), 3.70 (2H, t, J=8H z), 2.58 (I H, s), 2.50 (1 H, s). LC/MS (100%, tr = 6.72 min) [M + H]*, n/z = 420.8 (Calc: 10 420.1). Example lOB: Synthesis of Compound LI (S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoro-N-(6 15 fluorobenzo[d]thiazol-2-yl)piperidine- I -carboxamide OH N H O,,,, N OH c1 N HO',. HN O F N S DIEA N c N + F 0 NH N N S H F 78 124 F L1 A 100 mL round bottom flask was charged with 78 (800 mg, 2.56 mmol) 20 suspended in DMF (2 mL). DIEA (0.87 mL, 5.12 mmol) and 124 (672 mg, 2.56 mmol) were added. The resulting reaction mixture was stirred at a temperature of about 25'C until all the solids dissolved, about 2 h. The reaction mixture diluted with water; an off- 313 white precipitate formed. The precipitate was collected by vacuum filtration. The precipitate was washed with water, washed twice with DCM (10 mL for each wash), and dried under reduced pressure to provide 1.0 g of Li (yield 90%) which was then recrystalized from EtOAc/MeOH. 'H NMR: 8 8.35 (s, I H), 7.80 (s, I H), 7.35(m, 2H), 5 6.98(m, I H), 4.70 (t, I H), 4.2(m, 2H), 3.6 (m, 2H), 3.3 (m, 2H), 2.25(m, 4H) ppm. MS (M+ ): m/z -= 468. 6.2 EXAMPLE 11: IN VIVO ASSAYS FOR PREVENTION OR TREATMENT OF PAIN 10 Test Animals: Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a compound of formula I when food is removed for 16 hours before dosing. A control group acts as a comparison to 15 rats treated with a compound of formula 1. The control group is administered the carrier for the compound of formula I. The volume of carrier administered to the control group is the same as the volume of carrier and compound of formula I administered to the test group. 20 Acute Pain: To assess the actions of the compounds of formula I on the treatment or prevention of acute pain the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are as defined as the interval between the onset of the 25 thermal stimulus and the flick of the tail. Animals not responding within 20 seconds are removed from the tail flick unit and assigned a withdrawal latency of 20 seconds. Tail flick latencies are measured immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a compound of formula 1. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 20 seconds, 30 is calculated as follows: I (post administration latency) - (pre-administration latency) I %MPE= x 100 (20 s pre-administration latency) 314 The rat tail flick test is described in F.E. D'Amour et al., "A Method for Determining Loss of Pain Sensation," J. Pharinacol. Exp. Ther. 72:74-79 (1941). Acute pain can also be assessed by measuring the animal's response to noxious 5 mechanical stimuli by detennining the paw withdrawal threshold ("PWT"), as described below. Inflammatory Pain: To assess the actions of the compounds of formula I on the treatment or prevention of inflammatory pain the Freund's complete adjuvant ("FCA") 10 model of inflammatory pain is used. FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical and thermal hyperalgesia and provides reliable prediction of the anti-hyperalgesic action of clinically useful analgesic drugs (L. Bartho et al., "Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and Enhanced Opioid Antinociception in Inflammation," Naunyn 15 Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). The left hind paw of each animal is administered a 50 pL intraplantar injection of 50% FCA. 24 hour post injection, the animal is assessed for response to noxious mechanical stimuli by determining the PWT, or to noxious thermal stimuli by detennining the PWL, as described below. Rats are then administered a single injection of 1, 3, 10 or 30 mg/Kg 20 of either a compound of formula 1; 30 mg/Kg of a control selected from Celebrex, indomethacin or naproxen; or carrier. Responses to noxious mechanical or thermal stimuli are then determined I, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal is defined as: I (post administration PWT or PWL) - (pre-administration PWT or PWL) I % Reversal x 100 {(baseline PWT or PWL) - (pre-administration PWT or PWL)] 25 Assessments of the actions of the compounds of formula 111 that were tested revealed these compounds were surprisingly efficacious, e.g., compounds of formula III significantly reduced FCA-induced thermal hyperalgesia, with ED 5 0 values of from about 0.1 mg/kg to about 10 mg/kg and maximum % reversal values of from about 50% 30 to about 100%. For example, for compound D2 the EDso value for reversal of thermal hyperalgesia was 0.95 mg/kg at 3 hours after administration and 1.63 mg/kg at 5 hours 315 after administration of D2. Additionally, the maximum % reversal of thennal hyperalgesia was 78.7% at 5 hours after administration of D2. Neuropathic Pain: To assess the actions of the compounds of formula I for the 5 treatment or prevention of neuropathic pain either the Seltzer model or the Chung model can be used. In the Seltzer model, the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al., "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic 10 Nerve Injury," Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/0 2 inhalation anaesthesia. Following induction of anaesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps 15 semitendinosus nerve branches off of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1/3 to 2 of the nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue. Following surgery, the wound area is dusted with antibiotic powder. Sham-treated 20 rats undergo an identical surgical procedure except that the sciatic nerve is not manipulated. Following surgery, animals are weighed and placed on a warm pad until they recover from anaesthesia. Animals are then retired to their home cages until behavioral testing begins. The animal is assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then 25 immediately prior to and 1, 3, and 5 hours after drug administration for rear paw of the animal. Percentage reversal of neuropathic hyperalgesia is defined as: [ (post administration PWT) - (pre-administration PWT) ] % Reversal = x 100 [(baseline PWT) - (pre-administration PWT) In the Chung model, the spinal nerve ligation model of neuropathic pain is used 30 to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. Surgery is performed under isoflurane/0 2 inhalation anaesthesia. Following induction of 316 anaesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L 4 - S2 levels. The L 6 transverse process is carefully removed with a pair of small rongeurs to identify visually the L 4 - L 6 spinal nerves. The left L 5 (or L 5 and L) spinal nerve(s) is isolated and tightly ligated with silk thread. A complete 5 hemostasis is confirmed and the wound is sutured using non-absorbable sutures, such as nylon sutures or stainless steel staples. Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they 10 recover from the anaesthesia. Animals are then be returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after being administered a compound of formula I for the left rear paw of the animal. The animal can also be assessed for 15 response to noxious thermal stimuli or for tactile allodynia, as described below. The Chung model for neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992). 20 Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia: The paw pressure assay can be used to assess mechanical hyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C. Stein, "Unilateral Inflammation of the Hindpaw in 25 Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacol. Biochem. and Behavior 31:451-455 (1988). The maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw. PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested. 30 Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, hind paw withdrawal latencies (PWL) to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the 317 technique described by K. Hargreaves et a., "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(1):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point. Three latencies 5 are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested. Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear, Plexiglas compartments with a wire mesh floor and allowed to habituate for a 10 period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 15 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses. Capsaicin-Induced Eye Wipe Test: To assess the effect of compounds of formula I on TRPVI receptor-mediated pain, the capsaicin-induced eye wipe test is used 20 (N.R. Gavva et al., "AMG 9810 [(E)-3-(4-+-Butylphenyl)-N-(2,3 dihydrobenzo[b][ I,4]dioxin-6-yl)acrylamide], a Novel Vanilloid Receptor I (TRPV 1) Antagonist with Antihyperalgesic Properties", J. Pharmacol. Exp. Ther. 313:474-484 (2005)). The eye wipe test is a reliable high-throughput test of the effect of TRPVI antagonists. Rats are given a single injection of 1, 3, 10 or 30 mg/kg of either a 25 compound of formula 1; 30 mg/kg of a control selected from Celebrex, indomethacin or naproxen; or carrier. At 1, 3 or 5 hours after drug administration, 3 PL of a 100 IlM capsaicin solution (in 10% EtOH/PBS) is instilled in one eye of each animal with a pipette. The number of forelimb movements (touching or wiping of the capsaicin treated eye) are counted during a 2 minute period following instillation of capsaicin into 30 the eye. Assessments of the actions of the compounds of formula III revealed these compounds were surprisingly efficacious, e.g., compounds of formula Ill dose dependently reduced (he number of capsaicin-induced eye wipes by from about 25% to about 100% after their administration relative to the pre-administration eye wipe value.

318 For example, for compound NI the number of eye wipes decreased to I to 3 after the administration of NI relative to the pre-administration eye wipe value of 24. Specifically, the eye wipe value was 3 at I hour after the administration of NI (87.5% decrease), I at 3 hours after the administration (96% decrease), and 2 at 5 hours after the 5 administration of NI (92% decrease). 6.3 EXAMPLE 12: BINDING OF COMPOUNDS OF FORMULA I TO TRPV1 10 Methods for assaying compounds capable of inhibiting TRPV I are known in the art, for example, those methods disclosed in U.S. Patent No. 6,239,267 to Duckworth et al.; U.S. Patent No. 6,406,908 to Mc Intyre et al.; or U.S. Patent No. 6,335,180 to Julius et al. The results of these assays will demonstrate that compounds of formula I bind to and modulate the activity of TRPV1. 15 PROTOCOL I Human TRPJV1 Clonin g: Human spinal cord RNA (commercially available from Clontech, Palo Alto, CA) 20 is used. Reverse transcription is conducted on 1.0 pg total RNA using Thermoscript Reverse Transcriptase (commercially available from Invitrogen, Carlsbad, CA) and oligo dT primers as detailed in its product description. Reverse transcription reactions are incubated at 55 0 C for I h, heat-inactivated at 85*C for 5 min, and RNase H-treated at 37*C for 20 min. 25 Human TRPV I cDNA sequence is obtained by comparison of the human genomic sequence, prior to annotation, to the published rat sequence. Intron sequences are removed and flanking exonic sequences are joined to generate the hypothetical human cDNA. Primers flanking the coding region of human TRPVI are designed as follows: forward primer, GAAGATCTTCGCTGGTTGCACACTGGGCCACA (SEQ 30 ID No: 1); and reverse primer, GAAGATCTTCGGGGACAGTGACGGTTGGATGT (SEQ ID No: 2). Using these primers, PCR of TRPV I is performed on one tenth of the Reverse transcription reaction mixture using Expand Long Template Polymerase and Expand Buffer 2 in a final volume of 50 pL according to the manufacturer's instructions (Roche 319 Applied Sciences, Indianapolis, IN). After denaturation at 94"C for 2 min PCR amplification is performed for 25 cycles at 94"C for 15 sec, 58*C for 30 sec, and 68*C for 3 min followed by a final incubation at 72"C for 7 min to complete the amplification. The PCR product of about 2.8 kb is gel-isolated using a 1.0% agarose, Tris-Acetate gel 5 containing 1.6 pg/mL of crystal violet and purified with a S.N.A.P. UV-Free Gel Purification Kit (commercially available from Invitrogen). The TRPV1 PCR product is cloned into the pIND/V5-His-TOPO vector (commercially available from Invitrogen) according to the manufacturer's instructions to result in the TRPV I -p[ND construct. DNA preparations, restriction enzyme digestions, and preliminary DNA sequencing are 10 performed according to standard protocols. Full-length sequencing confirms the identity of the human TRPV I. Generation of Inducible Cell Lines: Unless noted otherwise, cell culture reagents are purchased from Life 15 Technologies of Rockville, MD. HEK293-EcR cells expressing the ecdysone receptor (commercially available from Invitrogen) are cultured in Growth Medium (Dulbecco's Modified Eagles Medium containing 10% fetal bovine serum (commercially available from HYCLONE, Logan, UT), lx penicillin/streptomycin, lx glutamine, 1 mM sodium pyruvate and 400 pg/mL Zeocin (commercially available from Invitrogen)). The 20 TRPVI-pIND constructs are transfected into the HEK293-EcR cell line using Fugene transfection reagent (commercially available from Roche Applied Sciences, Basel, Switzerland). After 48 h, cells are transferred to Selection Medium (Growth Medium containing 300 pg/mL G418 (commercially available from Invitrogen)). Approximately 3 weeks later individual Zeocin/G41 8 resistant colonies are isolated and expanded. To 25 identify functional clones, multiple colonies are plated into 96-well plates and expression is induced for 48 h using Selection Medium supplemented with 5 tM ponasterone A ("PonA") (commercially available from Invitrogen). On the day of assay, cells are loaded with Fluo-4 (a calcium-sensitive dye that is commercially available from Molecular Probes, Eugene, OR) and CAP-mediated calcium influx is 30 measured using a Fluorescence Imaging Plate Reader ("FLIPR") as described below. Functional clones are re-assayed, expanded, and cryopreserved.

320 pH-Based Assay: Two days prior to performing this assay, cells are seeded on poly-D-lysine coated 96-well clear-bottom black plates (commercially available from Becton Dickinson) at 75,000 cells/well in growth media containing 5 PM PonA (commercially 5 available from Invitrogen) to induce expression of TRPV 1. On the day of the assay, the plates are washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1.6 mM CaC1 2 and 20 mM HEPES, pH 7.4 ("wash buffer"), and loaded using 0.1 mL of wash buffer containing Fluo-4 (3 pM final concentration, commercially available from Molecular Probes). After I h, the cells are 10 washed twice with 0.2 mL wash buffer and resuspended in 0.05 mL I x Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 3.5 mM CaCl 2 and 10 mM Citrate, pH 7.4 ("assay buffer"). Plates are then transferred to a FLIPR for assay. The test compound is diluted in assay buffer, and 50 pL of the resultant solution is added to the cell plates and the solution is monitored for two 15 minutes. The final concentration of the test compound is adjusted to range from about 50 picoM to about 3 pM. Agonist buffer (wash buffer titrated with IN HCI to provide a solution having a pH of 5.5 when mixed 1:1 with assay buffer) (0.1 mL) is then added to each well, and the plates are incubated for I additional minute. Data are collected over the entire time course and analyzed using Excel and Graph Pad Prism to determine the 20 IC5 0 . Capsaicin -Based Assay: Two days prior to performing this assay, cells are seeded in poly-D-lysine-coated 96-well clear-bottom black plates (50,000 cells/well) in growth media containing 5 gM 25 PonA (commercially available from Invitrogen) to induce expression of TRPV 1. On the day of the assay, the plates are washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing I mM CaC 2 and 20 mM H EPES, pH 7.4, and cells are loaded using 0.1 mL of wash buffer containing Fluo-4 (3 pM final). After one hour, the cells are washed twice with 0.2 mL of wash buffer and 30 resuspended in 0. 1 mL of wash buffer. The plates are transferred to a FLIPR for assay. 50 puL of test compound diluted with assay buffer (l x Hank's Balanced Salt Solution containing I mM CaCl 2 and 20 mM HEPES, pH 7.4) are added to the cell plates and incubated for 2 min. The final concentration of the compound is adjusted to range from about 50 picoM to about 3 pM. Human TRPVI is activated by the addition of 50 pL of 321 capsaicin (400 nM), and the plates are incubated for an additional 3 min. Data is collected over the entire time course and analyzed using Excel and GraphPad Prism to determine the IC 50 . 5 PROTOCOL2 For Protocol 2, a Chinese Hamster Ovary cell line (CHO) that has been engineered to constitutively express human recombinant TRPVI was used (TRPVI/CHO cells). The TRPVl/CHO cell line was generated as described below. 10 Human TRPVI Cloninme: A cDNA for the human TRPV I receptor (hTRPV1) was amplified by PCR (KOD-Plus DNA polymerase, ToYoBo, Japan) from a human brain cDNA library (BioChain) using primers designed surrounding the complete hTRPVI open reading frame (forward 5'-GGATCCAGCAAGGATGAAGAAATGG (SEQ ID NO:3), and 15 reverse 5'-TGTCTGCGTGACGTCCTCACTTCT (SEQ ID NO:4)). The resulting PCR products were purified from agarose gels using Gel Band Purification Kit (GE Healthcare Bioscience) and were subcloned into pCR-Blunt vector (Invitrogen). The cloned cDNA was fully sequenced using a fluorescent dye-terminator reagent (BigDye Terminator ver3.1 Cycle Sequencing Kit, Applied Biosystems) and ABI Prism 3100 20 genetic analyzer (Applied Biosystems). The pCR-Blunt vector containing the hTRPVI cDNA was subjected to restriction digestion with EcoRI. The restriction fragment was subcloned into expression vector pcDNA3.l(-) (Invitrogen) and named pcDNA3.1(-) hVR I plasmid. The sequence of the cDNA encoding TRPVI is available at GenBank accession number AJ277028. 25 Generation of the TRPVI/CHO Cell Line: CHO-KI cells were maintained in growth medium consisting of a-M EM, 10% FBS (Hyclone), and 100 IU/mL of penicillin - 100 pg/mL of streptomycin mixed solution (Nacalai Tesque, Japan) at 37 0 C in an environment of humidified 95% air and 30 5% CO 2 . The cells were transfected with the pcDNA3. I (-)-hVR I plasnid using FuGENE6 (Roche) according to the manufacturer's protocol. 24 hr after transfection, neomycin-resistant cells were selected using I mg/mL G41 8 (Nacalai Tesque). After 2 weeks, individual colonies were picked, expanded, and screened for the expression of 322 hTRPVI in the capsaicin-induced Ca 2 influx assay (see below) with a FLIPR (Molecular Devices). A clone with the largest Ca 2 , response to capsaicin was selected and re-cloned by the same procedure. The cells expressing hTRPVI were cultured in the growth medium supplemented with I mg/mL G418. Approximately I month later, 5 stable expression of functional TRPVI receptors in the selected cell line was confined by validating Ca 2 ' responses with or without capsazepine (Sigma, at I nM-10 pM) in capsaicin assay. Capsaicin-Iniduced Ca 2- Influx Assay For Cell Selection: 10 The following assay was performed to identify cells with hTRPVI expression. CHO-KI cells transfected with pcDNA3.I(-)-hVRI plasmid were seeded in 384-well black-wall clear-bottom plates (Corning) and cultivated in growth medium (see above) for I day. On the day of experiment, culture medium was exchanged to assay buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCI, 0.9 mM MgC 2 , 5.0 mM CaC 2 , 5.6 mM D 15 glucose, 2.5 mM probenecid, pH 7.4) containing 4 pM Fluo-3-AM (Dojin, Japan). After the incubation at 37"C for 1 hr, each well was washed 3 times with assay buffer using an EMBLA 384 plate washer (Molecular Devices) and refilled with assay buffer. The plates were incubated at a temperature of about 25'C for 10 min. Subsequently, the plates were inserted into a FLIPR, and 1.5 pM capsaicin (Sigma) solution prepared in 20 assay buffer was added to each well (final concentration was 500 nM). Cellular responses were monitored for 5 min. Cell Culture: 1. Cell Culture Media 25 1. Alpha-MEM (Gibco, CAT: 12561-056, LOT: 1285752): 450 mL. 2. Fetal Bovine Serum (FBS), heat inactivated (Gibco, CAT: 16140-071, LOT: 1276457): 50 mL. 3. HEPES Buffer Solution, I M stock (Gibco, CAT: 15630-080): 10 mL (final 20 mM). 4. Geneticin, 50mg/mL stock (Gibco, CAT: 10135-035): 10 mL (final I mg/mL). 30 5. Antimicotic Antibiotic Mixed Solution, I00x stock (Nacalai Tesque, Japan, CAT: 02892-54): 5 mL. Components 1-5 above were combined at the indicated amounts and stored at 4"C. The cell culture media were brought to about 37'C before use. Optionally, 323 component 5 can be replaced by penicillin-streptomycin solution (for example, Gibco 15140-122 or Sigma P-0781). 2. Thawing the cells TRPVl/CHO cells were frozen in CellbankerTM (Juji-Field [NC, Japan, CAT: 5 BLC-I) and stored at -80*C. Optimized cryopreservation solution containing dimethyl sulphoxide and FBS was used. Vials containing the TRPV I/CHO cells were stored at -80*C. After removal from -80'C, the vial was immediately transferred to a 37'C water bath to thaw for ca. I 2 minutes. Once completely thawed, the contents of the vial (I mL/vial) was transferred 10 to a sterile 15 mL test tube and 9 mL warm culture media were slowly added. The test tube was subsequently centrifuged at 1000 rpm for 4 min at a temperature of about 25"C. The supernatant was removed and the pellet resuspended in 10 mL of culture media. The cell suspension was transferred to a sterile 75 cm 2 plastic flask and incubated at humidified 5% C0 2 /95% air at 37"C. To monitor viability, the cells were visually 15 inspected and/or counted, beginning at approximately I hr after incubation. 3. Passaging the Cells The cells in a flask were close to confluence at the time of passaging. Cell culture media were removed from the culture flask and 10 mL of sterile PBS(-) added and the flask gently shaken. The PBS was removed from the flask and 2 mL of 20 trypsin/EDTA solution (0.05% trypsin with EDTA-4Na; Gibco, CAT: 25300-054) was added and the flask gently shaken. The flask was incubated at 37'C for about 2 min. 8 mL cell culture media were subsequently added to the flask and the flask shaken to ensure that all cells were in solution. The cell suspension was then transferred to a sterile 15 mL or 50 mL plastic tube, centrifuged at 1,000 rpm for 4 min at a temperature 25 of about 25*C. The supernatant was removed and the pellet resuspended in ca. 5 mL of culture media. The cell count was measured using the Burker-Turk hemocytometer. The cells were seeded into a sterile 75 cm 2 plastic flask in ca. 0.8 x 105 cells/mL for 72 hr and incubated in humidified 5% C02/95% air at 37*C. 4. Freezing the cells 30 The procedure up to the measurement of the cell count was the same as in the section Passaging the Cells above. Subsequently, the cell suspension was centrifuged at 1,000 rpm for 4 min at a temperature of about 25*C. The supernatant was removed and the pellet resuspended in CellbankerTM solution to get a final concentration of from 5 x 324 105 to 5 x 106 cells/mL. The cell suspension was transferred into appropriately labeled I mL cryovials and then placed into the -80"C freezer. pH-Based Assay: 5 The following assay was conducted to determine the concentration of sulfuric acid that would give rise to a pH that induces a Ca 2 + response optimal to test compounds for their effect on TRPVI. 1. Cells TRPVI/CHO cells were seeded in the 96-well clear-bottom black-wall plate 10 (Nunc) at densities of 1-2 x 104 cells/well and grown in 100 sL of culture medium (alpha-MEM supplemented with 10 % FBS, 20 mM HEPES, I mg/mL geneticin and I % antibiotic-antimycotic mixed stock solution) for 1-2 days before the experiment. 2. Determination of pH Sensitivity and Agonist Dose 2. 1. Agonist Solution 15 Different agonist solutions with sulfuric acid concentrations of from 15 mM to 18 mM (see Figure 1) were prepared by diluting I M sulfuric acid with measuring buffer. The different sulfuric acid concentrations in the agonist solutions were selected such that a 1:4 dilution would result in a final sulfuric acid concentration of between 3.0 mM to 3.6 mM, respectively, as indicated in Figure 1. 20 2.2. Assav pH dependent Ca 2 responses in TRPVI/CHO cells cultured in a 96-well plate are shown in Figure 2. In particular, Ca 2 influx into TRPVI/CHO cells in response to low pH as measured by Fura-2 AM fluorescence is indicated in Figure 2. The cells were stimulated using 3.0 mM (well number BI-6), 3.1 mM (CI-6), 3.2 mM (DI-6), 3.3 25 mM (El-6), 3.4 mM (F 1-6), 3.5 mM (G 1-6), or 3.6 mM (H 1-6) H 2

SO

4 or pH 7.2 measuring buffer without H 2 S0 4 (A]-6) (Figure 2). (1) Culture medium was removed using an 8-channel-pipette (Rainin, USA) from the 96-well plate and the wells were refilled with 100 PL of loading buffer (20 mM HEPES, 115 mM NaCl, 5.4 mM KCI, 0.8 mM MgCI 2 , 1.8 mM CaC 2 , 13.8 mM D 30 glucose, 2.5mM probenecid, pH 7.4) containing 5 pM Fura-2 AM (Dojin, Japan). (2) The 96-well plate was incubated at 37"C for 45 min. (3) The loading buffer was removed from each well. The cells were subsequently washed twice with 150 p L of measuring buffer (20 mM HEPES, 115 mM 325 NaCl, 5.4 mM KCl, 0.8 mM MgCl 2 , 5.0 mM CaCl 2 , 13.8 mM D-glucose, 0.1 % BSA, pH 7.4) (no probenecid). The wells were then refilled with 80 PL of measuring buffer. (4) After an incubation at 4'C for 15 min, the 96-well plate was transferred to FDSS-3000 (Hamamatsu Photonics, Japan). 5 (5) The Fura-2 fluorescent intensity was monitored at a wavelength of 340 nrn and at 380 nm, respectively, at a rate of 0.5 Hz for a total of 240 seconds. After 16 time points (32 sec) of baseline detection, 20 pL of agonist solution was added to each well. The final volume was 100 pL/well. (6) Fluorescence intensity ratio refers to the fluorescence intensity at 340 nm 10 over the fluorescence intensity at 380 nm at a particular time point. The baseline was set as the average of the fluorescent intensity ratios for the first 16 time points before the addition of agonist solution. The maximum response was the highest fluorescent intensity ratio during the 60 time points following addition of agonist solution. (7) Maximal signal ratios from each well were calculated as output data using the 15 FDSS-3000 analysis program. Data were analyzed using Excel (Microsoft) and XLfit (idbs) software. 2.3. pH Determination After the observation of Ca 2 4 responses, the buffer of each lane (50 piL/well, 8 20 wells/plate) was collected well by well and the pH values were measured using a 20 portable pH meter (Shindengen, Japan). As shown in Figure 2, the Ca 2 responses in lanes D and E were intermediate and therefore optimal for testing the effects of compounds on the TRPV I calcium channel. The final sulfuric acid concentrations in the wells of these lanes were 3.2 mM and 3.3 mM, respectively. These final sulfuric acid concentrations were obtained using 25 agonist solutions with 16.0 mM and 16.5 mM sulfuric acid concentrations, respectively (lanes D and E in Figure 1). The pH obtained using these sulfuric acid concentrations was ca. 5.0 -5.1. Thus, agonist solutions with 16.0 mM and 16.5 mM sulfuric acid concentrations, respectively, (lanes D and E in Figure 1) were selected for the experiments described 30 below in section 3. 3. pH Assav 3.1. Agonist Two different agonist solutions with different H 2

SO

4 concentrations were used for the pH assay (Figure 3A). For one half of a 96-well plate one agonist solution was 326 used, for the other half the other agonist solution. The agonist solutions were obtained by diluting sulfuric acid (H 2

SO

4 , IM) with measuring buffer. The concentrations for the two agonist solutions were determined as described above in Section 2 of Protocol 2. The sulfuric acid concentrations between the two agonist solutions differed by 5 0.5 mM. In the experiment described in Section 2 of Protocol 2, the sulfuric acid concentrations in the agonist solutions were determined to be 16 mM and 16.5 mM, respectively. After 1:4 dilution of the agonist solutions, the final sulfuric acid concentration was 3.2 mM and 3.3 mM, respectively. The resulting pH value for the pH assay was 5.0 to 5.1. 10 3.2. Test Compounds Test compounds were dissolved in DMSO to yield 1 mM stock solutions. The stock solutions were further diluted using DMSO in 1:3 serial dilution steps with 6 points (1000 pM, 250 pM, 62.5 pM, 15.625 j.M, 3.9062 pM and 0.977 pM). The thereby-obtained solutions were further diluted in measuring buffer (1:100) as I 0x stock 15 serial dilutions with a DMSO concentration of 1%. 10 pL of a I Ox stock was added into each well at step 3.3.(4) of Protocol 2. Thus, the final concentrations of antagonists ranged from 1000-0.977 nM containing 0.1% DMSO (Figure 3B). 3.3. Assav Steps (1) and (2) of this Assay were the same as steps 2.2.(1) and 2.2.(2) of 20 Protocol 2, respectively. (3) The cells were washed twice with 150 pL of measuring buffer (mentioned in 2.2.(3) of Protocol 2, no probenecid). The wells were subsequently refilled with 70 P L of measuring buffer. (4) Either 10 p L of measuring buffer or 10 p L of lOx stock serial dilution of test 25 compound (described in 3.2. above) were applied to each well. Usually, only one test compound was tested per 96-well plate. The number of replicates per 96-well plate for a particular antagonist at a particular concentration was 7 x 2 since two different sulfuric acid concentrations were used per 96-well plate (N = 7 x 2)(Figure 3). Step (5) was the same as 2.2.(4) above. 30 (6) Fura-2 fluorescent intensity was monitored as described in 2.2.(5) above. After 16 time points of baseline detection, 20 p L of agonist solution (measuring buffer titrated with H 2 S0 4 to yield pH 5.0 - 5.1 when mixed 1:4 with the measuring buffer containing test compound) was added to each well (final volume 100 pL/well). Steps (7) and (8) were as described in 2.2.(6) and 2.2.(7) above, respectively.

327 3.4. pH check (1) The pH values of the buffer in the wells of A l - H I and A7 -+ H7 (longitudinally; Figure 3) were measured one by one using a portable pH meter. (2) When a well was confirmed as pH 5.0 or 5.1, the next five wells to its right 5 were checked one after another. (3) For ICso calculation, only the data from wells with pH values of 5.0-5.1 were used. The number of wells tested for their pH varied among plates (about 16 - 60 wells/plate). The number depended on the results of 3.4.(1) above and the Ca 2 10 responses. Capsaicin-Based Assay: One day prior to assay, TRPVI/CHO cells were seeded in 96-well clear-bottom black plates (20,000 cells/well) in growth media. On the day of the experiment, the cells 15 were washed with 0.2 mL lx Hank's Balanced Salt Solution (Life Technologies) containing 1.6 mM CaC 2 and 20 mM HEPES, pH 7.4 ("wash buffer"). Subsequently, the cells were loaded by incubation in 0.1 mL of wash buffer containing Fluo-4 at 3 pM final concentration. After 1 hour, the cells were washed twice with 0.2 mL wash buffer and resuspended in 0.1 mL wash buffer. The plates were then transferred to a 20 Fluorescence Imaging Plate Reader (Molecular Devices). Fluorescence intensity was monitored for 15 seconds to establish a baseline. Subsequently, test compounds diluted in assay buffer (Ix Hank's Balanced Salt Solution containing 1 mM CaC 2 and 20 mM HEPES, pH 7.4) containing 1% DMSO were added to the cell plate and fluorescence was monitored for 2 minutes. The final concentration of the compound was adjusted to 25 range from 100 pM to 1.5625 pM. If the test compound was an especially potent antagonist, the final concentration of the compound was adjusted to range from 10 pM to 1.5625 nM. Human TRPVI was then activated by the addition of 50 piL capsaicin (100 nM final concentration) and plates incubated for an additional 3 min. Data were collected over the entire time course and analyzed using Excel and the curve-fitting 30 formula GraphPad Prism. The results of the assays of Protocol 2 are shown in Table I., which demonstrates that many compounds of formula I have superior potency. The IC 50 data 328 provided in Table I. are shown as mean ± standard error of the mean; the number of trials conducted for each assay is shown in parentheses. Table I: TRPV1 ICe 0 Potency Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) OH .C e F Al 7.0 1.8 (4) 0NH HC, BI 7.81 ± 1.2 (4) 7.40 0.3 (3) N O NN 329 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) o. Cl 15.3 6.9 (3) 11.3 0.8 (3) C 0o , E 1 18.5 *4.9 (3) N El 16.5 4.1 (3)0 330 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Fl 18.6 i 6.8 (3) 9.0 + 2.3 (3) G1 31.3 8.8 (3) 16.4 (2) N C', 0c HI 31.7 8.9 (3) N0 O O 331 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 0. 11 33.8 9.1 (3) 1.1 + 0.2 (3) SNM JI 34.5 + 17.5 (3) 18.0 (2) C3( 90 C, Ki 35.1 ± 8.8 (3) 39.5 (2) O N

N

332 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure "0, LI 35.3 12.0 (3) 27.5 + 3.4 (4) M1 37.5 9.0 (3) 5.7 0.3 (5) N CCF NI 38.7 5.3 (3) 6.3 t0.8 (5)

N

333 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 0 01 41.1 17.8 (3) C', N Ho P1 50.5 + 9.5 (3) 0=S=0 QI 51.0 16.4 (3) 8.1 0.7 (3) 0=C=0 334 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure o0 R1 51.0t 18.8 (3) 00 N SI 53.5 ±16.3 (3) 16.3 ±2.0 (3) T 1 60.3 i1l9.0 (3) 29.7 +2.3 (3) o C 335 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 09 Ul 61.3 + 22.5 (3) 14.7 + 3.3 (3) Cr, N 00 C3 VI 66.3 5.7 (3) 22.4 ±1.1 (3) oc F, 0.~ C, Wi 68.9± 18.4 (3) 9.3 +1.9 (3) 336 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) X1 74.4 11.5 (3) 18.8 1.6 (6) N 0~ M~CF, -N Yi 74.7* 18.4 (4) 13.5 1.2 (3) 0. C, Zi 75.8* 12.4 (4) 11.6 0.7 (3)

C,

337 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 0c A2 84.1 11.2 (3) CC, N 0.K B2 77.6*±12.0 (4) 40.5 (2) 00 Ce, N C2 98.7 t33.9 (5) 41l.8 3.8 (3) N

CFC

338 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) o. D2 85.3 20.7 (6) 10.8 + 0.9 (3) CF E2 107.4 18.8 (5) 20.3 ±1.7 (4) oN ocr, F2 108.0 ±24.3 (3) 62.9 ±8.8 (4)N O 4- 339 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure C Ho G2 112.4 22.3 (3) 84.8 8.8 (3) N cF3 0" 0-. C, H2 118.1 + 22.1 (3) 13.1 2.1 (3) N C. 0" 12 122.0± 7.1 (3) 18.0± 1.0 (5) c0 340 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) OH cl J2 128.6 26.0 (3) 41.7 4.4 (3)N 0 0N CF, N C1 L2 153.0 24.4 (3) 57.4 * 9.1 (5) C,

C'

341 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure 0. C. M2 156.3 5.6 (3) 42.0 9.1 (3) CFI ONH C, N2 161.4 16.6 (3) 27.3 2.6 (6) ONH 0I C. 02 161.8 + 29.5 (3) 18.8 4.0 (4) 0- N

O,

342 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) ON P2 172.9 40.3 (4) 44.4 (2) ONM Q2 194.4 27.1 (3) 85.9 21.8 (4) CF, 0" Q2 194.49 27.1 (3) 849 ± 2.4) Brr

CCF

343 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) OH II C, S2 205.3 i 35.4 (3) 31.9 + 2.5 (3) o N CF3 C, 'N C, U2 230.5 45.3 (4) 53.4 5.9 (3) ON H oN 344 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 0 V2 234.2 44.6 (3) 83.2 7.6 (3) 0NM C, W2 244.8 34.4 (3) 241.3 34.9 (5) 00 ONH C I X2 248.4 + 25.1 (3) 81.1 10.5 (3) N O NH 345 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure 0. C.. cN Y2 350.9 ± 69.8 (3) 59.9 ± 11.8 (3) 1< oN Z2 401.0 122.4 (3) 247.6 +45.3 (3) 0 O H N CF, A3 414.1 L 99.6 (3) 309.5 * 38.9 (3) crS 346 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) o3 B3 537.2 62.0 (3) 106.0 1 1.4 (5) o) N el C. C3 541.4 215.8 (3) 0=5=0 cC, D3 564.8 58.6 (3) 39.8 2.2 (3) N oCF, 347 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) C, 0~ c E3 670.7 + 133.1 (3) 141.0± 23.1 (3) ONH CF, O CC F3 915.7 305.6 (4) 584.8 (2) N 0 C, G3 1075.9*20 1.8 (3) ONH OCr, 348 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 0 CI H3 1114.9 134.0 (3) DNH 13 1363.7 337.4 (3) 0~. C, J3 2940.7+ 318.9 (3) N 0 NN 349 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) , N K3 > 10,000 (3) L3 37.1 14.8 (3) 38.3 4.0 (3) NO Ci M3 186.9 * 43.7 (3) 30.0 2.1 (3) NH c, 350 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) D. M0 C, N3 161.1 41.7 (3) 223.3 14.0(3) Cr, 0 03 4 6.0 11.3(3 P3 183.4 i38.1 (3) 28.5 (2)

'N

351 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) HOW, O ON F F Q3 14.3 1.3 (3) 5.3 1.0 (4) CF, ON F F R3 15.5 3.5 (3) N HN "LO OCF3 S3 17.7 2.0 (3) 9.2 (3) N O N

OCF,

352 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 00 .0 C, T3 23.8 6.8 (3) 12.9 (3) Cl 0. .0 N U3 27.9 + 9.9 (3) 13.5 (2) ONH 0 C, C, o~. OOH N C, V3 34.0 t 9.2 (3) N., N

CF,

353 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) ON W3 35.6 8.9 (3) 22.4 (2) Cl F Y3 43.9* 10.0 (3) HN 0 FF A4 55.1 8.6 (4) 0 354 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) 0 MD C, " B4 57.2 + 11.6 (3) 5.8 1.3 (4) CF, 0. C4 66.2 + 7.5 (3) 18.6 t 2.8 (3) 0H NO C, D4 69.6 6.9 (3) 54.8 (2) ' N 355 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure OH 00 ~0 N F, E4 75.7 + 12.8 (3) QNHA 0 CF, 0H F4 86.7 + 18.9 (3) 32.5 ±2.4 (3) CFG "o0 H4 175.8 28.4 (3) 97.0 9.9 (3) N S 356 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure OH K4 210.2 * 19.5 (3) N 0" L4 439.4 *139.8 (3) M4 471.3 127.3 (3) N N.

CF,

357 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) on N4 1312.9 220.5 (3) C 0 Cl 04 1517.2 338.6 (3) CC, P4 1809.9 302.1 (4) 358 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) c. Q4 2897.7 + 302.1 (3) R4 3278.6 760.6 (3) HN 0~ C, S4 7028.4 ±2059.0 (3) N 60 359 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) -0 H0 N X4 38.4 ±8.0 (3) Z4 62.8 t 11.4 (3) 16.5 ± 3.3 (3) B5 106.5 21.0 (3) 15.0 3.0 (3) cc, Br 360 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) F C5 107.7 + 38.4 (3) 39.9 7.9 (3) 0 .0 cF MO HO DS 1 32.7 ±29.1 (3) 0 N F E5 132.8 * 28.5 (3) 33.8 (2) HN 0 CF, Cl 361 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) "o F5 166.1 ±24.7 (3) G5 400.0 10.6 (3) 108.5(2) CF, Cd. O NN C, H5 520.0 88.6 (3) 515.6 99.2 (3) 0 362 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure .0 C, 15 709.1 94.1 (3) 117.6 27.5 (3) FN F T4 1330.7 + 334.3 (3) 1175.1 147.2 (3) J8 6N O 'N J5 1879.8 ± 633.8 (3) c- 363 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) K5 2753.2 541.9 (3) C L5 > 10,000 (3) ONH CF, o OH M5 > 25,000 (2) 0 NH

CF-

364 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) -0 "o N5 140.25 (2) NM 05 243.62 (2) MO 0 P5 49.51 (2)

CF,

365 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure Cr R5 346.05 (2) CN OCF 0. 0. C, TS 451.5 + 92.4 (3) 0 NH CF, 0 ~ OH .0 N CI U5 19.9 * 6.9 (3) NH

N

366 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) OH .0 C N V5 45.5i 2.1 (3) 10.1 1 .4 (6) HOC M0 c0 C W5 423.2 ±122.5 (3) 71.2 ± 10.5 (5) X5 229.8 ±65.5 (3) 00 367 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) "0 Ho F Y5 196.4 37.7 (3) 108.5 + 7.7 (3) -N CF, Z5 35.5 3.9(3) 16.4 1.9 (5) CO A6 49.8 1 2.1 (3) 9.0+ 0.8 (4) Cs 3 368 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) .0 e C, B6 922.2* 204.6 (3) 361.6 69.1 (3) N CF, NO HO, C, C6 > 25,000 (2) N 0 D6 620.5 *116.5 (3) 0 K N O N NN

CC'

369 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure E6 265 165 0 C', 0 F6 864 467 o r, OH G6 > 25,000

NH

370 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) c:N C' H6 924 N CF, OH HO,.. N Cl N K6 9.8 2.3 (4) 0.8 0.1 (3) CN) N NH OH HO.. N CI L6 14.2 1.4 (3) 5.8 (2) (N) N FNH OF3 371 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure OH HO... N Cl M6 7.0 1.0 (5) 3.5 1.0 (3) (N) N NH

CF

3 C I ClN V6 16.0 1.6 (3) 6.2 (2) OH HO N CI W6 32.9 11l.8 (3) 1 4.9 *2.2 (4) N N NH

CF

3 C1 372 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure ciN 200 136 31.8 ciN 201 131 185 N CF, 202 182 590 O NH F

CF

373 Comp Human Capsaicin CHO Human pH CHO Structure ound (hCAP-CHO) (nM) (hpH-CHO) (nM) CI F 203 90.2 51.2 o N F N CC F 204 167 154 0 NH CCF 205 > 25,000

OCF,

374 Comp Human Capsaicin CHO Human pH CHO ound (hCAP-CHO) (nM) (hpH-CHO) (nM) Structure CN N 206 508 1463 SXN F The invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. 5 Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. A number of references have been cited, the entire disclosures of which are incorporated herein by reference. 10

Claims

1. A compound of formula I: Arl, -R 4 -(R 3 )m N Xl N N'R20 5 Ar 2 (I) or a pharmaceutically acceptable derivatives thereof, where X is 0, S, N-CN, N-OH, or N-ORIO; 10 W is N or C; the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R4 is -H, -OH, -OCF 3 , -halo, -(Ci-C 6 )alkyl, -CH 2 OH, -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 F, -CH(halo) 2 , -CF 3 , -ORio, -SRio, -COOH, -COORio, -C(O)Rio, -C(O)H, -OC(O)Rio, -OC(O)NHRo, 15 -NHC(O)RI3, -CON(R 3 ) 2 , -S(0) 2 Ro, or -NO 2 ; Rio is -(Ci-C 4 )alkyl; each R 1 3 is independently -H, -(Ci-C 4 )alkyl, -(Ci-C 4 )alkenyl, -(Ci-C 4 )alkynyl, or -phenyl; 375 Arl is N NN "- N NN" " N R (R )P N l R) T(R2)p, or 1 5 Ar 2 is INN-2o N- S N~ - e 0I R1 ~~~ / 'F \/Ri 2 a R 8 R 9 R 8 R 9 R 8 R 9 ~ 3)C R~ ( R l 4 t ( 14 5 (y3)c (y3)C N"" T -15: N (R14)q (R14)q (R,4)q (R1 4 )s (Rll)r. c is the integer 0, 1, or 2; 376 YI, Y 2 , Y 3 are independently C, N, or 0; wherein no more than one of YI, Y 2 , or Y3 can be 0, and for each YI, Y 2 , and Y 3 that is N, the N is bonded to one R 2 1 group, and for each YI, Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (CI 5 C 6 )alkyl groups substituted on all of YI, Y 2 , and Y 3 ; R1 2 a and RI2b are independently -H or -(Ci-C 6 )alkyl; E is =0, =S, =CH(CI-Cs)alkyl, =CH(Ci-C 5 )alkenyl, -NH(CI-C 6 )alkyl, or =N-OR 20 ; R, is -H, -halo, -(Ci-C 4 )alkyl, -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , 10 -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , or -OCH 2 (halo); each R 2 is independently: (a) -halo, -OH, -O(Ci-C 4 )alkyl, -CN, -NO 2 , -NH 2 , -(Ci-Cio)alkyl, -(C 2 CI)alkenyl, -(C 2 -Cio)alkynyl, -phenyl, or (b) a group of formula Q; 15 wherein Q is J or Z each Z 3 is independently -H, -(Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, or -phenyl; Z 4 is -H, -OH, -OR 20 , -(C i-C 6 )alkyl, or -N(R 20 ) 2 , with the proviso that -OR 20 is 20 not -OCH 2 CH 3 ; J is -OR 20 , -SR 20 , -N(R 20 ) 2 , or -CN; provided that at least one R 2 group is a group of formula Q; each R 3 is independently: (a) (CI-C 6 )alkyl, or CH 2 OR 7 ; or 25 (b) two R 3 groups together form a (C 2 -C 6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains -HC=CH- within the (C 2 -C 6 )bridge; or (c) two R 3 groups together form a -CH 2 -N(Ra)-CH 2 - bridge, a Rb Rb 0 =0 -CH 2 -N--CH 2 - bridge, or a - CH 2 -- N-CH 2 -- bridge; 377 Ra is selected from -H, -(C-C 6 )alkyl, -(C 3 -C 8 )cycloalkyl, -CH 2 -C(O)-R, -(CH 2 )-C(O)-ORe, -(CH 2 )-C(O)-N(Re) 2 , -(CH 2 ) 2 -O-Re, -(CH 2 ) 2 -S(0) 2 -N(Re) 2 , or -(CH2)r-N(Rc)S(0)r-e; 5 Rb is selected from: (a) -H, -(C-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, -(3- to 7 membered)heterocycle, -N(Re) 2 , -N(Re)-(C 3 -C 8 )cycloalkyl, or -N(Re)-(3- to 7 membered)heterocycle; or (b) -phenyl, -(5- or 6-membered)heteroaryl, -N(Rc)-phenyl, or -N(Re)-(5 10 to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups; each R, is independently selected from -H or -(C-C 4 )alkyl; each R 7 is independently -H, -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -Cs)cycloalkyl, -(C 5 -Cs)cycloalkenyl, -phenyl, -(CrC 6 )haloalkyl, -(C 15 C 6 )hydroxyalkyl, -(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, -(CI-C 6 )alkyl-N(R 2 0 ) 2 , or -CON(R 2 0) 2 ; each R 8 and R 9 is independently: (a) -(C-C)alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -Cs)cycloalkyl, (C 5 -C 8 )cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with I or 2 -OH groups; or 20 (b) -H, -CH 2 C(halo) 3 , -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -OC(halo) 3 , -OCH(halo) 2 , -OCH 2 (halo), -SC(halo) 3 , -SCH(halo) 2 , -SCH 2 (halo), -CN, -O-CN, -OH, -halo, -N 3 , -NO 2 , -CH=NR 7 , -N(R 7 ) 2 , -NR 7 0H, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OC(O)OR7, -SR 7 , -S(O)R 7 , or -S(0)2R7; each R I is independently -CN, -OH, -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -halo, -N 3 , 25 -NO 2 , -N(R 7 ) 2 , -CH=NR 7 , -NR 7 0H, -OR 7 , -C(O)R 7 , -C(O)OR7, -OC(O)R 7 , or -OC(0)OR 7 ; each R 14 is independently -H, -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, -(C-C 8 )cycloalkenyl, -(C -C 6 )alkoxy-(C -C 6 )alkyl, -phenyl, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(3- to 7-membered)heterocycle, -(CI-C 6 )haloalkyl, 30 -(C 2 -C 6 )haloalkenyl, -(C 2 -C 6 )haloalkynyl, -(C 2 -C 6 )hydroxyalkenyl, -(C 2 C 6 )hydroxyalkynyl, -(CrC 6 )alkoxy(C 2 -C 6 )alkyl, -(CrC 6 )alkoxy(C 2 -C 6 )alkenyl, -(Cr C 6 )alkoxy(C 2 -C 6 )alkynyl, -(CI-C6)alkoxy(C 3 -C 8 )cycloalkyl, -CN, -OH, -halo, -OC(halo) 3 , -N 3 , -NO 2 , -CH=NR 7 , -N(R 7 ) 2 , -NR 7 0H, -OR 7 , -SR 7 , -O(CH 2 )bOR 7 , O(CH 2 )bSR 7 , -O(CH 2 )bN(R 7 ) 2 , -N(R 7 )(CH 2 )bOR 7 , -N(R 7 )(CH 2 )bSR 7 , 378 -N(R 7 )(CH 2 )bN(R 7 ) 2 , -N(R 7 )COR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R7, -OC(O)OR7, -S(0)R7, or -S(O) 2 R 7 , -S(O) 2 N(R 7 ) 2 , -SO 2 C(halo) 3 , -S0 2 (3- to 7-membered)heterocycle, -CON(R 7 ) 2 , -(CI-C 5 )alkyl-C=NOR 7 , -(CI-C 5 )alkyl-C(O)-N(R 7 ) 2 , -(CI-C 6 )alkyl NHSO 2 N(R 7 ) 2 , or -(CI-C 6 )alkyl-C(=NH)-N(R 7 ) 2 ; 5 each R 2 0 is independently -H, -(CI-C 6 )alkyl, or -(C 3 -C 8 )cycloalkyl; each R 2 1 is independently -H, -(C 1 -C 6 )alkyl, \ ,N(CH 3 ) 2 or 0 10 each halo is independently -F, -Cl, -Br, or -I; n is the integer 1, 2, or 3; p is the integer I or 2; each b is independently I or 2; q is the integer 0, 1, 2, 3 or 4; 15 r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2. 20

2. The compound of claim 1, wherein X = 0.

3. The compound according to any one of claims I to 2, wherein R 4 is halo. 25

4. The compound according to claim 3, wherein R 4 is F.

5. The compound according to any one of claims 1 to 4, wherein R, is halo.

6. The compound according to claim 5, wherein Ri is Cl or F. 379

7. The compound according to any one of claims I to 6, wherein W is C and the dashed line is absent. 5

8. The compound according to any one of claims 1 to 6, wherein W is C, and the dashed line is a double bond.

9. The compound according to any one of claims I to 6, wherein W is N, R4 is absent and the dashed line is absent. 10

10. A compound according to any one of claims I to 9, wherein Ar, is (R2)n R 1 N N 15

11. The compound according to any one of claims 1 to 10, wherein J is selected from OR 20 or -N(R 20 ) 2 .

12. The compound according to any one of claims I to 11, wherein J is OR 20 . 20

13. The compound of any one of claims I to 12, wherein R 2 0 is selected from H or -(C i-C 6 )alkyl.

14. The compound of any one of claims I to 13, wherein R 20 is H. 25

15. The compound according to any one of claims I to 14, wherein J is OH.

16. The compound according to any one of claims I to 14, wherein Z 3 is independently selected from H or (Ci-C 6 )alkyl. 30

17. The compound according to any one of claims I to 15, wherein Z 3 is H. 380

18. The compound according to any one of claims I to 17, wherein Ar 2 is (R 14 )s 5

19. The compound according to any one of claims 1 to 17, wherein Ar 2 is N (R14)q

20. The compound according to claim 19, wherein R 14 is independently 10 selected from halo, C(halo) 3 , -(CI-C 6 )alkyl, OR 7 , OC(halo) 3 , or SO 2 C(halo) 3 .

21. The compound according to any one of claims I to 20, wherein halo is F or Cl. 15

22. The compound according to any one of claims I to 21, wherein s or q is I or 2.

23. The compound according to any one of claims 1 to 17, wherein Ar 2 is N s R 8 R 9 20

24. The compound according to claim 23, wherein R 8 and R 9 are independently selected from H, halo and -(CI-C 6 )alkyl. 381

25. The compound according to claim 23, wherein R 8 and R 9 are H or halo, wherein halo is Cl or F. 5

26. The compound according to any one of claims I to 25, wherein Ar 2 is 2 pyridyl or phenyl, s or q is I and the R 14 substituent is in the 4-position of the Ar 2 substituent.

27. The compound according to any one of claims I to 25, wherein Ar 2 is 2 10 pyridyl or phenyl, s or q is 2 and the R 1 4 substituent is in the 3- and 4-position of the Ar 2 substituent.

28. The compound according to any one of the preceding claims, wherein m -0. 15

29. The compound according to any one of claims 1 to 27, wherein m = 1.

30. The compound according to claim 29, wherein R 3 is (CI-C 6 )alkyl. 20

31. The compound according to claim 29, wherein R 3 is -CH 3 or -CH 2 CH 3 .

32. A compound of any one of the preceding claims, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt. 25

33. A composition comprising a compound of any one of claims 1 to 31 or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.

34. A method of inhibiting TRPVI function in a cell comprising contacting a 30 cell capable of expressing TRPV 1 with an effective amount of a compound of any one of claims I to 31 or a pharmaceutically acceptable derivative thereof.

35. A method for treating or preventing pain, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective amount of a 382 compound of any one of claims I to 31 or a pharmaceutically acceptable derivative thereof.

36. Use of a compound according to any one of claims 1 to 31 as a 5 medicament. 383