UA103596C2 - Pyridine-containing heterocyclic compounds and use thereof as trpv1 antagonists - Google Patents

Abstract

The invention relates to compounds of formula (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.(I)

Description

Antagonists of STI and their use

Priority to this application is claimed in Provisional Application 05, Serial No. 60/926,661, filed Apr. 27, 2007, Provisional Application 05, Serial No. 60/930,036, filed May 11, 2007, Provisional Application 5, Serial No. 60/937,003, filed 21 Jun. 2007, and Pre-Application Serial No. 60/962,409, filed Jul. 27, 2007, the disclosures of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compounds of formula I and their pharmaceutically acceptable derivatives, compositions containing an effective amount of a compound of formula I, and methods of treating or preventing a condition such as pain, NS, ulcer, ZZ3K and SPK, comprising administering to an animal in need of it an effective amount compounds of formula I.

PREREQUISITES FOR THE CREATION OF THE INVENTION

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute and chronic. While acute pain is usually short-term, chronic pain lasts up to 3 months or longer and can lead to significant changes in the patient's personality, quality of life, functional capacity, and overall quality of life (K.M. Eoieu, Raip, et al. Sessions

Tehirook of Medisipe 100-107 (U. S. Veppei apa RK. Risht edv., 201N ey. 1996)).

Additionally, chronic pain can be classified as either nociceptive or neuropathic.

Nociceptive pain includes pain due to tissue damage and inflammatory pain, such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and persists due to abnormalities in somatosensory processing.

There is a wide list of signs of the relative activity of vanilloid receptors (M. biMag2o ei a!., Siggepi

Oriop ip Meshigobiodiodu 12: 372-379 (2002)) to the development of pain.

Nociceptive pain is traditionally controlled by administration of nonopioid analgesics such as acetylsalicylic acid, magnesium choline trisalicylate, acetaminophen, ibuprofen, fenoprofen, difluzinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, leforphanol, fentanyl, oxycodone, and oxymorphone. 4. In addition to the above list of medications, intractable neuropathic pain can also be treated with antiepileptics (eg, gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), MMA antagonists (eg, ketamine, dextromethorphan), topical lidocaine ( with postherpetic neuralgia) and tricyclic antidepressants (for example, fluoxetine, sertraline and amitriptyline).

Urinary incontinence (UI) is uncontrolled urination, which is usually caused by instability of the bladder sphincter muscle. Urinary incontinence affects people of all ages and levels of physical health, both in health care facilities and in the family as a whole. Physiological contraction of the bladder in is largely a consequence of acetylcholine-induced stimulation of post-ganglionic muscarinic receptor sites on bladder smooth muscle Treatment of NS includes administration of drugs that relax the bladder and help control sphincter overactivity.

None of the existing commercial drugs for the treatment of NS are completely successful in treating all classes of NS patients, and the treatment has significant side effects.

Ulcer treatment usually involves reducing or inhibiting aggressive factors.

For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. However, antacids can cause alkalosis, which leads to nausea, headache and weakness. Antacids can also interfere with the absorption of other medicines into the blood and cause diarrhea.

Ng antagonists such as cimetidine, ranitidine, famotidine, and nizatidine are also used to treat ulcers. But antagonists promote ulcer healing by reducing the secretion of gastric acid and digestive enzymes, which is regulated by histamine and other Ne agonists in the stomach and duodenum. However, Ng antagonists can cause breast swelling and impotence in men, mental changes (especially in adults), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.

Inhibitors of He, K"-ATPase, such as omeprazole and lansoprazole, are also used to treat ulcers. Inhibitors of He, K"-ATPase inhibit the production of enzymes used to secrete acid by the stomach. Side effects caused by inhibitors of Ne, K--ATPase are nausea, diarrhea, abdominal colic, headache, dizziness, drowsiness, rashes on the skin and a short-term increase in the activity of aminotransferases in the plasma.

Inflammatory bowel disease ("IBD") is a chronic disorder in which inflammation of the intestines occurs, often resulting in periodic abnormal cramping and diarrhea. The two types of CKD are Crohn's disease and ulcerative colitis.

Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal walls. Crohn's disease occurs in people of both sexes and is

Antagonists of SARS and their use are more common in the ancestors of the Jews of Eastern Europe. In most cases, Crohn's disease occurs in people before the age of 30 and mostly begins between the ages of 14 and 24. The disease typically affects the overall thickness of the intestinal walls. The disease usually affects the lower part of the small intestine (ileum) and large intestine, but it can occur in any part of the digestive tract.

Cramps and diarrhea, side effects associated with Crohn's disease, can be managed with anticholinergic drugs, diphenoxylate, loperamide, deodorized tincture of opium, or codeine.

When Crohn's disease causes intestinal obstruction, or when abscesses or fistulas that do not heal, surgery may be necessary to remove diseased areas of the intestine. However, surgery does not cure the disease and the inflammation tends to recur when the bowel is sutured. In more than half of the cases, a second operation is necessary. Tpe MagsK Mapaiai oi Medisai! Iptogttaynop 528-530 (V. Ve Kom ea., 1997).

Ulcerative colitis is a chronic disease in which ulcers in the colon become inflamed or develop, leading to episodic bloody diarrhea, abdominal cramps, and fever.

Ulcerative colitis usually develops between the ages of 15 and 30; however, a small group of people have their first attacks of the disease between the ages of 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the overall thickness of the intestine. The disease usually develops in the rectum and sigmoid colon and eventually spreads partially or completely throughout the colon. The causes of ulcerative colitis are unknown.

Ulcerative colitis treatment is aimed at controlling inflammation, reducing symptoms, and restoring lost fluids and nutrients. In the treatment of moderate diarrhea, anticholinergic drugs and low doses of diphenoxylate or loperamide are administered. For more intense diarrhea, high doses of diphenoxylate or loperamide, or deodorized tincture of opium or codeine are administered.

Irritable bowel syndrome (IBS) is a motility disorder of a full gastrointestinal tract that causes abdominal pain, constipation, and/or diarrhea. PCOS occurs three times more often in women than in men. In PCOS, triggering factors such as stress, diet, medications, hormones, or irritants can cause abnormal contractions of the gastrointestinal tract.

During cases of PCOS, contractions of the gastrointestinal tract become longer and more frequent, resulting in rapid transit of food and feces through the small intestine, often leading to diarrhea.

Cramps are the result of strong contractions of the colon and increased sensitivity of pain receptors in the colon.

Treatment of PCOS usually involves modifying the PCOS patient's diet. It is often recommended that a patient with PCOS consume beans, cabbage, sorbitol and fructose. A low-fat, high-fiber diet may also help some patients with PCOS. Regular physical activity can also help keep the gastrointestinal tract functioning properly. Medicines such as propantheline, which slow down the functioning of the gastrointestinal tract, are usually ineffective in the treatment of PCOS. Antidiarrheals such as diphenoxylate and loperamide help with diarrhea. Tpe MagsK Mapiai oi Meaisai! Iptogtaiyop 525-526 (VA. VeKom ed., 1997).

Mo International Publication UMO 98/31677 describes a class of aromatic amines that are derivatives of cyclic amines that are useful as antidepressants.

Mo UMO International Publication 01/027107 describes a class of heterocyclic compounds that are inhibitors of sodium/proton exchange.

Mo UMO International Publication 99/37304 describes substituted oxoazaheterocyclyls useful for inhibiting factor Xa.

Patent 05 6,248,756, Apipopu eyi ai. and international publication MO MO 97/38665 describe a class of piperidine-containing compounds that inhibit farnesyltransferase (Riaze).

Mo UMO International Publication 98/31669 describes a class of aromatic amines that are derivatives of cyclic amines that are useful as antidepressants.

Mo international publication MO 97/28140 describes a class of piperidines which are derivatives of 1-(piperazin-1-yl)yauaryl(oxy/amino)carbonyl-4-aryl-piperidine, which are useful as 5-HT:α receptor antagonists.

Mo UMO International Publication 97/38665 describes a class of piperidine-containing compounds useful as farnesyltransferase inhibitors.

Patent 05 4,797,419, Moo5 ei aiI., describes a class of ureas for stimulating the release of acetylcholine and useful for treating symptoms of cognitive decline in the elderly.

Patent 05 5,891,889 describes a class of substituted piperidines useful as inhibitors of farnesyltransferase and farnesylation of the Kav oncogene.

Patent 05 6,150,129, Sook et al., describes a class of diazotized heterocycles useful as antibiotics.

Patent 5,529,998, Narbisp et al., describes a class of benzoxazolyl and benzothiazolyl oxazolidones

Antagonists of SARS and their use are useful as antibacterial agents.

Mo UMO International Publication 01/57008 describes a class of 2-benzothiazolylureas useful as inhibitors of serine/greonine and tyrosine kinases.

Mo UMO International Publication 02/08221 describes aryl piperazines useful in the treatment of chronic and acute pain conditions, pruritus and urinary incontinence.

International Publication Mo MUO 00/59510 describes aminopyrimidines useful as sorbitol dehydrogenase inhibitors.

Japanese patent application Mo 11-199573, Kiuov5pi ei aiI., describes benzothiazole derivatives, which are agonists of the neuronal 5NTZ receptor of the nervous system of the intestine and are useful for the treatment of digestive disorders and pancreatic insufficiency.

German patent application No. 199 34 799, Kaipeg et al., describes a chiral-smectic liquid crystalline mixture containing compounds with 2-linked (hetero)aromatic rings or compounds with 3-linked (hetero)aromatic rings.

M. Spy-Mouyeeg sei ai., U. May. Snpet. 45:511-528 (2002) describes heterocycle-substituted piperazinopyrimidines useful as sorbitol dehydrogenase inhibitors.

V.S. Kpnaibze oei a. Ex. Most. Ip5N. 1(3)27-32 (1975) describes 2-(M'-substituted-M'-piperazinyl)pyrido(3,2-4)thiazoles and 5-nitro-2-(M'-substituted-M'-piperazinyl )benzthiazoles are useful as anthelmintic agents.

Publication of the patent application 05 2004/0186111 A! and international publication Me UMO 2004/058754

A1 describes compounds useful in the treatment of pain.

Publication of patent application 5 2006/0199824-A1 and international publication Me M/O 2005/009987

A1 describes compounds useful in the treatment of pain.

Publication of patent application 05 2006/0128717 A1 and international publication Me UMO 2005/009988

A1 describes compounds useful in the treatment of pain.

However, there is still a need for new drugs useful for the treatment or prevention of pain, NS, ulcers, CKD, and PCOS.

The citation of any references in Section 2 of this application should not be construed as suggesting that such reference is prior art to the disclosed invention.

BRIEF DESCRIPTION OF THE INVENTION

The invention covers compounds of formula I:

Anya -V,

Also (S Dzit

M and

Ago (I) or their pharmaceutically acceptable derivative, where

X is O, 5, M-CM, M-OH, or M-OB o;

UM is M or C; dotted line means the presence or absence of a bond, and when the dotted line means the presence of a bond or UM is M, then Ka is absent, otherwise Ka is -Н, -ОН, -ОСЕ:», -halo, -(С1-Св )alkyl, -

СНгОН, -СНоСИ, -СНеВг, -СНеЙ, -СНоЕ, -СН(halo)», -SEz, -ОВио, -5Вио, -«СОН, -СООН о, -С(О)В:о, -С( О)Н, -ОС(О)Бо, -ОС(О)МНВА то, -МНО(О)Виз, -СОМ(Вз)2, -530)2Нио, or -MO";

Vo is -(C1-Ca)alkyl; each Kis is, independently, -H, -(C1-Ca)alkyl, -(C1-Ca)alkenyl, -(C1-Ca)alkynyl, or -phenyl;

Oh, there is

Antagonists of STI and their use

In V (Ro), V

X Y X y Y cha

IN; . IN; with B; . I . (In). (Nor (Nor a Mt Mt

PRESS well, M,

IN; A, B; same (Vodr, (Nory

Mtyakh di tkh Nor, ko Y or k Y.

V.V.; V.;

Аг» There are MA sts in UA and -(From) , ? , U

AND

AND

Mo 1 ha

V V n Mi Agg 8 No 8 No 8 No Uv8)s -(Vi4) Her With i

Mi » Mi ! And from SIM

Uv)s Uv)s

AND SCHI , I , SU , Z or

M mikh x X (Via) (Nia)a (Nidda (Niodv (No. s) is an integer 0, 1, or 2;

M, Me, z is, independently, C, M, or 0; where no more than one of U, M2, or Uz can be O, and for each U, U2, and Mz that is M, M is connected to one Co: group, and for each U, MU2, and Mz that is C, C is connected to two Cogho groups, provided that there are no more than two (C1-C8)alkyl groups replacing all of M, M", and Mz;

Vig and Vig are, independently, -H or -(C1-C8)alkyl;

E is 20, "5, "CH(C1-C8)alkyl, "CH(C:-C8)alkenyl, -MH(C:-C8)alkyl, or "M-ORb2o;

They are -H, -halo, -(C1-Cdalkyl, -MO», -SM, -OH, -OSH»z, -MH», -C(halo)z, -CH(halo)», -СНа( halo), -OS(halo)z, -OSH(halo)»g, or -OSH»(halo); each E2g is, independently: (a) -halo, -OH, -O(C1-Ca)alkyl, -CM, -MO", -MH", -(C1-C0)alkyl, -(C2-C0)alkenyl, -(C2-C0)alkynyl, -phenyl, or (5) group of formula C); deo is

Antagonists of STI and their use, in i) in 23 23 2 73 (Ф) ud 2 74 (c) 7 yo ; b 23, | in 5, 23 (c); o o Ngo nm7b2o OY Vo dl 3 ln dr 73 МН 75 73 73 -КИЖТтГ , 25 o. with ; o N no oh M. another 7 M Ngo Ngo M ZV2o 1 73 u 73 7 743 23 ; and 73 or, 73 7 is-H, -ОВ7, -587, -СН»-ОНВ?7, -СНо-587, -СНо-М(Вго)», or -halo; 72 6-H, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, -"СН2-ОВ"?, -phenyl, or -halo; each 2z is, independently, -H, -(C1-C8)alkyl, -(C2-C8)alkenyl, -(C2-C8)alkynyl, or -phenyl; 74 6-H, -OH, -OB2o, -(C1-Cv)alkyl, or -M(Bho)";

In is -ОВ2о, -5В2о, -М(Вго)г, or -СМ; provided that at least one KE" group is a group of formula OS), and provided that when 71 is -OB; or -

FOR, then 2" is not a -halo; each Ez is, independently: (a) -H, CHgO, or (C:1-C8)alkyl; or (B) two Ez groups together form a (C2-Cv) bridge that is unsubstituted or substituted by 1, 2 or C independently selected Ca" groups, and each bridge optionally contains -HC-CH- within (Co-

Saint Bridge; or (c) two Ez groups together form a -СН2-М(Ва)-СНе- bridge,

HER

TI 5 - snNA- M .ASNa 3 mistokvabo --СН»-М--СНо--- 2 2 bridge,

Ba is chosen from -H, -(C:1-Cv)alkyl, -(C3-Cv)ucycloalkyl, -"CH2-C(O)-Ae, -"CHn)-C(0)-OBc, -"" "SNeg)-С(0)-

M(Be)2, -««CHn)2-O-Be, -««CHn)2-5(0)2-M(Ae)2, or -««"CHn)2-M(Be)5 (0)2-Be;

B is chosen from: (a) -H, -(C1-C8)alkyl, -(C3-C8)ucycloalkyl, -(3-7-ene)heterocycle, -M(Hc)2, -M(Be) -(Sz-

C)cycloalkyl, or -M(Pce)-(3-7--lene)heterocycle; or (p) -phenyl, -(5- or b-membered)heteroaryl, -M(He)-phenyl, or -M(He)-(5-10-membered)heteroaryl, each of which is unsubstituted or substituted by 1, 2 or With independently selected K»7 groups; each Ks, independently, is selected from -H or -(C1-Cdalkyl; each K;7 is, independently, -H, -(C1-C8)alkyl, -(C8-C8)alkenyl, -(C2-C8)alkynyl , -(C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, -(C1-C8) haloalkyl, -(C1-C8) hydroxyalkyl, -(C1-C8) alkoxy(C:-C8) alkyl , - (C1-Cv)alkyl-M(HAgo)g, or -COM(Rho)2; each Kz and Ke are independently: (a) -(C1-Cv)alkyl, -(Cg-Cv)alkenyl, - (C2-Cv)alkynyl, -(C3-Cv)ucycloalkyl, -(C5-Cv)ucycloalkenyl, or - phenyl, each of which is unsubstituted or substituted by 1 or 2 -OH groups; or (5) -H, -СНеС( halo)z, -С(halo)z, -СН(halo)», -СНа(halo), -ОС(halo)з, -ОСН(halo)г6, -ОСНе»(halo), -ЗС(halo) з, -ЗСН(halo)», -ЗСНа(halo), -СМ, -ОО-СМ, -ОН, -halo, -Мз, -МО», -СН-АМА?, -М(А?7) г2, -MA?OH, -О87, -Ч«О)87, -YФЧ(ОЙУВ, -ОС(О)В87, -ОС(ООВ?, -587, -(0)НВ7, or -5(0) 287; each Kii is, independently, -CM, -OH, -(C1-Cv)alkyl, -(Co-Cv)alkenyl, -halo, -Mz, -MO», -M(ВН7)2, -

Sn-mMA?, -MA?OH, -OB?7, -C(O)8?7, -F(0)OH87, -OC(O)B?7, or -OC(OOHB; each Kia is, independently, -H, -(C1-Cv)alkyl, -(Cg-Cv)alkenyl, -(Cg-Cv)alkynyl, -(C3-Cv)ucycloalkyl, - (C5-Cv)cycloalkenyl, -(C1-Cv) (C1-Cv)alkyl , -(C2-Cv)haloalkenyl, -(C2-Cv)haloalkynyl, -(C2-

Antagonists of STI and their use

Св)hydroxyalkenyl, /-(С2-Св)hydroxyalkynyl, /-(С1-Св) alkoxy(С2-Св) alkyl, /-(С1-Св) alkoxy(Се2-

C1-C8) alkenyl, /-(C1-C8) alkoxy(C2-C8) alkynyl, /-(C1-C8) alkoxy(C3-C8) cycloalkyl, ASM, -OH, -halo, -OC(halo)z, - Mz, -MO», -CH-AMA;, -M(H7)2, -MA;OH, -O8;, -587, -O(СНаХОВ;, -О(СНа)ъЕА?, -

О(СНаМ(А?)2, -«ЖА;ХСНа ОВ», -М(А;ХСНг)я?, -М(87ХСНазмМ(А?)2, -«М(А7СОВ?, -«С(0) 87, -Ч(ООВ?, -0ОС(0)87, -ОС(00)ОН;, -5(0)87, or -5(0)287, -5(0)2М(Н7)", - 5О2С(halo)z, 5О2(3-7-membered)heterocycle, -СОМ(НА7)2, -(С1-Св)alkyl-С-MONВ?, -(С1-Св)alkyl-С(О)- M(H7)2, -(C1-Cv)alkyl-

MNHZO»M(А?)»g, or -(С1-Св)alkyl-С(-МН)-М(А?7)»2; each E is, independently, -H, -(C1-C6)alkyl, or -(C3-C6)cycloalkyl; each Co: is, independently, -H, -(C1-Cv)alkyl, cyt and MON 3) | АЖ і, і, 7 ав -і шах х or "7" г С лю each halo is, independently, -Е, -СИ, -Вг, or -Й; n is an integer 1, 2, or 3; p is an integer 1 or 2; each b is, independently, an integer 1 or 2; d is an integer 0, 1, 2, 3, or 4; r is an integer 0, 1, 2, 3, 4, 5, or 6; is an integer 0, 1, 2, 3, 4, or 5;

Y is an integer 0, 1, 2, or Z; and t is an integer of 0, 1, or 2.

The compounds of formula I are potent against TRTI receptors, and are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2.

A compound of formula I or a pharmaceutically acceptable derivative thereof is useful for the treatment or prevention of pain, NS, ulceration, CKD, or SPC (each a "Condition") in an animal.

The invention also relates to compositions containing an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.

The compositions are useful for treating or preventing a condition in an animal.

The invention also relates to methods of 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.

The invention also relates to the use of the compound of formula I in the manufacture of a medicament for the treatment and/or prevention of the condition.

The invention also relates to a method of preventing the condition, comprising administering to an animal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof.

The invention also relates to methods of inhibiting the Transient Receptor Potential

Vanilloid receptor 1 (TRVVI, formerly known as Vanilloid Receptor 1 or VR) functions in a cell, which involves contacting a cell capable of expressing VTRVI with an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof.

The invention also relates to a method of obtaining a composition that includes the stage of mixing a compound of formula I or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier or excipient.

The invention also relates to a kit comprising a container containing an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof.

Preferred compounds of formula I are compounds of formula II:

Ankh -V,

Also (S with

M and

Ago (1) or a pharmaceutically acceptable derivative thereof, where the dashed line, MU, X, Ag, Ag, Vz, Va, No, etc. are

7IZ

Antagonists of TRPVI and their use as defined above for the compound of formula I, deo is

M) in 73 23 21 is -OH, -5H, -M(Hho)г6, -СНо-ОН, -СНо-5Н, or -СНе2-М(Рхо)»2; 72 is -H, -CH3, or -СНо-ОВ;; each 7z is, independently, -H or -CH"; and

In is -OH, -5H, or -M(HgO)".

Compounds of formula I are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2, are very potent against the TRPVI1 receptor, have good bioavailability, and have a good therapeutic index.

Preferred compounds of formula II are compounds of formula PI:

Ag -V zhk A (C vit

M

Zh N

Kh M

Ago (I) or a pharmaceutically acceptable derivative thereof, where the dashed line, MU, X, Ag, Agg, Bz, Ba, and t are as defined above for a compound of formula I, wherein Ag is: but

HE eh

AM

IN,

You are -SI, -E, or -SEz; where Ag" is: and her r y

SEz Ag Vi

On 0 Vi, 0 SEZ , In ov , you" in SEz or

Z No B"5

Via is -H, -CI, -E, -Hg, -OCE»z, -(C1-Cv)alkyl, -502Ce3, -502(C1-Cv)alkyl, -OSH3, -OSNoCH», or -

ОСН(СН)», and mostly it is -СЕз, -ОСЕ:», -СИ, or -Е;

Vig is -Н, -СИ, -Е, -Вг, -СН3, -СНеСН3, -ОСН», -ОСЕ», or -ОСНеСН»; and each Kv and Co is, independently, -H, -Si, -Hg, -E, -CH3, -OSH»z, -OSNeCH»z, -SEz, -OSE:», iso-propyl, or tert-butyl .

The compounds of formula I are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2, are exceptionally potent against the SARS-CoV-1 receptor, have excellent bioavailability, have a high therapeutic index, and are believed to be highly effective in animals for the treatment pain

The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to illustrate non-limiting embodiments of the invention.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1. 96-well tablet with different agonist solutions (Agonist tablet). Seven different sulfuric acid solutions or agonist solutions, with varying concentrations of sulfuric acid (Na 25 O y ) (from 15.0 mM to 18 mM as indicated) were used for the pH study as indicated. For wells in row A, only measurement buffer was used. The final concentration is also shown

TPRVI antagonists and their use of sulfuric acid in the wells for each row, after a 1:4 dilution of the agonist solution, in each row in round brackets.

Fig. 2. pH-dependent Ca-: responses in TRPV1/CHO cells. Sa tributary? in TRPV1/CHO cells, as measured by ERiga-2 AM fluorescence, is shown by the curve within each rectangular box. The curve shows the fluorescence intensity over time starting from the addition of the agonist solution. Each rectangular area represents one experiment performed in one well of a 96-well plate. Each row represents six experiments performed with the same final concentration of sulfuric acid; the final concentration of sulfuric acid is shown on the left. Actual pH values were measured after the experiment and are indicated above the curve. No antagonist was added to the cell culture. Final sulfuric acid concentrations of 3.2 and 3.3 mM, giving an acceptable Ca? response, were selected for subsequent studies. These final sulfuric acid concentrations can be obtained by 1:4 dilutions of the agonist solution with sulfuric acid 16.0

MM or 16.5 mM, respectively (see Fig. 1).

Fig 3. (A) 96-well plate with two different concentrations of sulfuric acid. Wells in columns 1 - 6 had one final concentration of sulfuric acid; wells from columns 7 - 12 had different final concentrations of sulfuric acid. The final concentration of sulfuric acid was obtained by 1:4 dilution of two different agonist solutions with sulfuric acid X mM and (X t 0.5) mM, respectively. In the experiment described in Section 2 of Protocol 2, X was 16 mM. (B) 96-well plate with different concentrations of test compound or antagonist indicated in nM. Only one type of tested compound was used in a 96b-well plate. Since two different concentrations of sulfuric acid were used (columns 1-6 to columns 7-12), seven wells were tested for each combination of the concentration of the tested compound and the agonist solution (for example, wells AT, B1, C1, ET, E1,

CI1 and NI were tests of the tested compound with a concentration of 0.977 nM and of the agonist solution with a sulfuric acid solution of X mM). Wells in row O did not include antagonist in order to measure the maximum

Sag: the answer.

DETAILED DESCRIPTION OF THE INVENTION

COMPOUNDS OF FORMULA I

The invention covers compounds of formula I: ro (C z

M and

Ago (I) or a pharmaceutically acceptable derivative thereof, where MU, X, Ag", Ag", Bz, Ba, Vgo, etc. are as defined above for the compound of formula I.

Some embodiments of formula I are presented below.

In one embodiment, the compound of formula I is a pharmaceutically acceptable derivative of the compound of formula

AND.

In another embodiment, the compound of formula I is a compound of formula I, wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, the compound of formula I is a pharmaceutically acceptable salt of the compound of formula I.

In another embodiment, Ag: is a pyridyl group.

In another embodiment, Ag: is a pyrimidinyl group.

In another incarnation, Ah! is a pyrazinyl group.

In another embodiment, Ag: is a pyridazinyl group.

In another embodiment, UM is S.

In another embodiment, UM is M.

In another embodiment, X is o.

In another embodiment, X is 5.

In another embodiment, X is M-CM.

In another embodiment, X is M-OH.

In another embodiment, X is M-OVo.

In another embodiment, Ag is a benzoimidazolyl group.

In another embodiment, Ag is a benzothiazolyl group.

In another embodiment, Ag is a benzoxazolyl group.

In another embodiment, Ag" is

Antagonists of STI and their use

Mo

; yet (Sun).

In another embodiment, Ag" is )"

Me (Nida.

In another embodiment, Ag" is -x o (Kchadv

In another embodiment, Ag" is a bellows (Sun.

In another embodiment, Ag" is 7 (Vi),

In another embodiment, Ag" is "V c, I

In another embodiment, Ag is

b 1.

On

In another embodiment, Ag" is

Antagonists of STI and their use

AND

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, t is 2.

In another embodiment, each Kz is, independently, -H, or (C 1 -C 6 )alkyl.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted with 1, 2, or 3 independently selected Kα" groups, and each bridge optionally contains -HO-CH- within (C2-Cv ) bridge.

In another embodiment, two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted by a Kz group, and each bridge optionally contains -HC-CH- within the (C2-Cv) bridge.

In another embodiment, two Kz groups together form a (C2-C3) bridge that is unsubstituted or substituted by a Kz group, and each bridge optionally contains -HC-CH- within the (C2-C3) bridge.

In another embodiment, two Kz groups together form a (C2-C3) bridge that is unsubstituted and each bridge does not necessarily contain -HC-CH- within the (C2-C3) bridge.

In another embodiment, the two Kz groups together form a (Cg) bridge, -HC-CH- bridge, or (C3) bridge, each of which is unsubstituted.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted with 1, 2, or C independently selected Ka" groups, each bridge optionally containing -HC-CnH- within (C2-Cv) bridge, and the bridge connects position 2 and b of piperidine, 1,2,3,6- tetrahydropyridine or piperazine.

In another embodiment, the two Az groups together form a (C2-Cv) bridge that is unsubstituted or substituted by a Kz group, each bridge optionally containing -HC-CH- within the (Cg2-Cv) bridge, and the bridge connecting the positions 2 and 6 piperidine, 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-C3) bridge that is unsubstituted or substituted by a Kz group, each bridge optionally contains -HC-CH- within the (C2-C3) bridge, and the bridge connects the positions 2 and 6 piperidine, 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-C3) bridge that is unsubstituted, each bridge optionally contains -HC-CH- within the (C2-C3) bridge, and the bridge connects the 2 and 6 positions of the piperidine , 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (Cg)bridge, -HC-CH- bridge, or (C3)bridge, each of which is unsubstituted, and the bridge connects the 2 and 6 positions of the piperidine, 1,2,3, 6-tetrahydropyridine or piperazine.

In another embodiment, two Ez groups together form a -СН2-М(Ва)-СНе»- bridge (В1),

HER

ГГ ня -сн- 1 M 56082 - -- bridge (82), or --СН.--М- -СНО--tzhp bridge (B3); where Ka is chosen from -H, -(Ci-Cv)alkyl, -(C3-Cv)ucycloalkyl, -СНеа-С(О0)-ВНе, -(СНг)-С(0)-ОНсе, -(СНг)- C(0)-M(Be)"2, ""CHg)2-O-Be, ""CHg)"-5(0)2-M(Be)", or -"CHg)2-M(Ae )5(O0)2-Be;

B is selected from: (a) -H, -(C1-Cv)alkyl, -(C3-Cv)cycloalkyl, -(3-7-membered)heterocycle, -M(He)", /--M( No)-(Sz-

C)cycloalkyl, or -M(Pce)-(3-7--lene)heterocycle; or (p) -phenyl, -(5- or b-membered)heteroaryl, -M(He)-phenyl, or -M(He)-(5-10-membered)heteroaryl, each of which is unsubstituted or substituted by 1, 2 or With independently selected K»7 groups; and each Ks, independently, is selected from -H or -(C1-Sdalkyl;

In another embodiment, a B1, B2, or B3 bridge connects the 2 and b positions of piperidine, 1,2,3,6-tetrahydropyridine, or piperazine.

In another embodiment, two Ez groups form a bicyclo group of one of the following formulas,

Antagonists of STI and their use

Ag and in At. In 1zuu A 1 MU. 4 y y or y-y

M M

AJ "V AJ "V

X m 20 X Y 20

Aha Aha

In another embodiment, t is 1.

In another embodiment, t is 0.

In another embodiment, with both eeo.

In another embodiment, 5 or d is 1.

In another embodiment, 5 or d is 2.

In another embodiment, EK: is -N.

In another embodiment, KK. is a halo.

In another embodiment, Ki is -SI.

In another embodiment, Kch is -RE.

In another embodiment, EK: is -СНз.

In another embodiment, KE: is -MO".

In another embodiment, Ki is -SM.

In another embodiment, EC: is -OH.

In another embodiment, KE: is -OSN»V.

In another embodiment, EK: is -MN".

In another embodiment, Ki is -C(halo)z.

In another embodiment, EK: is -SEz.

In another embodiment, Ki is -CH(halo)".

In another embodiment, Ki is -CHNa(halo).

In another embodiment, Ag: is a pyridyl group and n is 1.

In another embodiment, Ag: is a pyrazinyl group and p is 1.

In another embodiment, Ag: is a pyrimidinyl group and p is 1.

In another embodiment, Ag: is a pyridazinyl group and p is 1.

In another embodiment, when n and p are 1, then Ko must be 0.

In another embodiment, C) is y y 7178 г 73 Ох и74 о 73 . 5 | with, | , 23 o (c) B in P ; 5 20; nm 2o; ош5--Но 3 А-МН З 3 А-МН 23 88 ОО. 23, (c); H (c); nem oh M. noya 2 V zvi 7 I) 20 M Vgo ! 23 g from 4 23 23 ,; 25 23 or7 ! mA 2 | WITH

In another embodiment, C) is n! oh n! o u 23 23 g 73 0 24 g 74 73 ha U 25 | 23; | at 23 7 7a7 ! - penya "pp ntya or vyv Z

In another embodiment, C) is

Antagonists of STI and their use

M. u

M. laruunnafak 77 (FO 73 i 25| 2, or 3

In another embodiment, C) is

M. gives you KA-78 or 25 more

In another embodiment, C) is

M. (Fi in 73

In another embodiment, C) is and is) in is) and and direct o ate and In , 25 ; 23 25 23 23 o'clock sun; Osy oo UM Vo Sho and 3 A-MN d 23 73, AMN 73 25 28 p (c); N

Ngo NM Zh. (F) M

NM" MOAgo Vgo 23 uh 73 u 73 23 o. 25 23 or 275 23

In another embodiment, C) is in (F) ud (c) 7 in z p N Z 7 Oskh5--Ngo M "Vo bort" 3 A-MN g 73 73, AMN 23 , 22 23 , t , (c) ; N

Well, ok

NM 20 Ngo 23 g 73 u 73 23 o. 25 23 or 275 23

In another embodiment, C) is

Antagonists of SARS and their use in this field; Wasps Noo MV sat

З -А-МН 2 23 23 МН 745 2 28 t , (c); N vyu 00 and oh M

NM MOAgo Vgo 23 uh 73 y 73 23 o. 25 23 or 275 23

In another embodiment, C) is ii n Z 7 Son MOVO 3 A-MN uya 73 g or 22 73

In another embodiment, C) is (c); But Oh. (F, B "In them m z w 20 z NM 20 M Ngo B2o 3 -MNOOOZ g 3 and 73 t , 23 o, 25 23 or 25 z

In another embodiment, C) is in

In another embodiment, O is in y 23 23

In another embodiment, O is

In

In another embodiment, O is

F) I have 24 2

In another embodiment, O is in (F) 23 23

In another embodiment, O is

Antagonists of STI and their use in) 2 in 723 23

In another embodiment, U is -OR2o, -5B2o or -M(Vgo)".

In another embodiment, U is -OVho.

In another embodiment, ) is -OH.

In another embodiment, y) is -SM.

In another embodiment, 21 is -H.

In another embodiment, 21 is -OH.

In another embodiment, 71 is -OSN»z.

In another embodiment, 21 is -"CHg2OH.

In another embodiment, 272 is -СН2-ОВ".

In another embodiment, 22 is -CH2OH.

In another embodiment, 2" is -H, -(C1-C8)alkyl, -(C2-C8)alkenyl, -(C2-C8)alkynyl, -phenyl, or -halo.

In another embodiment, 22 is -H.

In another embodiment, 22 is -CH»z.

In another embodiment, 2z is -Н.

In another embodiment, 7z is -CH»z.

In another embodiment, 274 is -N.

In another embodiment, 74 is -(C1-C1)alkyl.

In another embodiment, 24 is -M(Vgo)".

In another embodiment, 24 is -ОВ2о.

In another embodiment, 74 is -OH.

In another embodiment, C) is

SY p

On (Fin! (Fin! On on on

BUT, ish F) but BUT,

Ku. . ,

ON Sha ON on on

E BUT,,,,

E , , , ОН, (o) (c) 0-50 (o. ono o (FI by ra MN on 8) or |.

In another embodiment, C) is he on may MN M. ge" and " mA OA g , C or.

In another embodiment, C) is

Antagonists of STI and their use

Fin On On ON on on nO,,, no no NO,,,, ? and 5 2 B

ON ZD ON ON ON ON

E BUT,,,,

E or OH

In another embodiment, C) is he ОН ОН ОН ОН ОН ОН ОН

In another embodiment, C) is (Fin! On (Fin! (on! on on

BUT,, I but what) BUT,, "g. , m , or

In another embodiment, C) is (on! (on! (on! (on!

BUT,, but what, BUT,

IN M M p. or 7 |.

In another embodiment, C) is o o (o. ono (o; (FI (o,

I ren o

Kolya pray or

In another embodiment, C) is

That's it

In another embodiment, T is 1 and Ez is -(C 1 -C 1 )alkyl.

In another embodiment, t is 1 and Ez is -CH»z.

In another embodiment, t is 0.

In another embodiment, Ka is -OH.

In another embodiment, Ka is -OSEz

In another embodiment, Ka is a halo.

In another embodiment, Ka is -RE.

In another embodiment, Ka is -SI.

In another embodiment, Ka is -(C1-C1)alkyl.

In another embodiment, Ka is -CHz.

In another embodiment, Ka is -"CHgOH."

In another embodiment, Ka is -SNeSi.

In another embodiment, Ka is -СНе2ВГг.

In another embodiment, Va is -SNYEI.

In another incarnation, Ka is -SNYE.

In another embodiment, Ka is -CH(halo)".

In another embodiment, Ka is -SEz.

In another embodiment, Ka is -MO".

In another embodiment, Ka is -OV:o.

In another embodiment, Ka is -«5B0.

Antagonists of STI and their use

In another embodiment, Ka is -C(O)MAo.

In another embodiment, Ka is -COOH.

In another embodiment, Ka is -С(О)Н.

In another embodiment, Ka is -"SOOV o.

In another embodiment, Ka is -OS(O)A o.

In another embodiment, Ka is -502Н:0о.

In another embodiment, Ka is -OS(O)MNVA o.

In another embodiment, Ka is -МНОС(О)Вз.

In another embodiment, Ka is -SOM(Vz)".

In another embodiment, each K 0 is independently -H or -(C 1 -C 6 )alkyl.

In another embodiment, each Kogo is -N.

In another embodiment, each Ego is -(C 1 -C 1 )alkyl.

In another embodiment, Ar" is a benzothiazolyl, benzoimidazolyl or benzoxazolyl group; and at least one of Kz and P» is -H.

In another embodiment, Ar" is a benzothiazolyl, benzoimidazolyl or benzoxazolyl group; and at least one of Kz and K» is not -H.

In another embodiment, Ar" is a benzothiazolyl, benzoimidazolyl or benzoxazolyl group; and at least one of Kz and K» is a -halo.

In another embodiment, Ag" is

Хх с (АВча)5

Is 1 and Ka is -(C1-Cv)alkyl, -halo, -C(halo)z, -OS(halo)z, -OH?7, -M(H7)2, -«502H87, or -502C( halo)" with

In another embodiment, Ag" is ex p (Ka), 5 is 2, and each Ba is, independently, -(C1-Cv)alkyl, -halo, -C(halo)z, -OC(halo)z, - ОВ?7, -М(Н7)2, -«50287, or -50»C(halo)»z.

In another embodiment, Ka is -halo, paborye1, Kg is, deovye in t de) is -OVA.

In another embodiment, Ka is -halo, paborye1, P2 60, deovye in / and 23 with where / is -OV"o and 71 is "OVU.

In another embodiment, Ka is -halo, paborye1, Kg is, deovye in / and 23 25 with where / is -OVoo and 71 is -SNOVU.

In another embodiment, Ka is -halo, paborye1, Kg is, deovye where 74 is -OR»oy.

In another embodiment, Ka is -halo, paborye1, Kg is, deovye

Antagonists of SARS and their use in t where there is -on.

In another embodiment, Ka is -halo, paborye1, Kg is, deovye in / and 23 23 where is-OH and 21 6-OH.

In another embodiment, Ka is -halo, paborye1, Kg is, deovye y / y 23 25 23 where y is -OH and 71 is -STON.

In another embodiment, Ka is -P, paborye1, 26, des) is in / and 23 25 23 where there are OH and 21 6-OH.

In another embodiment, Ka is -P, paborye1, 26, des) is y / and 23 25 23 where y is -OH and 71 is -STON.

In another embodiment, KK: there is -halo, Ka is -alo, paborye1, 26, deo is in tr where there is -OV»o.

In another embodiment, KK: is -halo, Ka is -alo, paborye1, 26, deo is y y 23 25 23 where U is -OVgo and 2 is OK.

In another embodiment, KK: there is -halo, Ka is -alo,paborye1, 26, deo is in 23 25 23 where in is -ОВоо and 71 is -СНгОВУ.

In another embodiment, KK: is -halo, Ka is -alo, paborye1, 26, deo is

In and where 74 is -ОВ2о.

In another embodiment, KK. is -SI, Va is -P paboree1, Kgye OO, deo is

Antagonists of SARS and their use in t | and where there is -OV»o.

In another embodiment, KK. is -SI, Va is -P paboree1, Kgye OO, deo is y / y 23 23 where y is -ООоо and 71 is "ОВ".

In another embodiment, KK. is -SI, Va is -P paboree1, Kgye OO, deo is in / and 23 25 23 where / is -ОВоо and 71 is -SNgOVU.

In another embodiment, KK. is -SI, Va is -P paboree1, Kgye OO, deo is

In and where 24 is -OV»o.

In another embodiment, KK. is -SI, Va is -R paboreye1, Kgye OO, deo is in tr where is -on.

In another embodiment, KK. is -SI, Va is -P paboree1, Kgye OO, deo is in / and 23 25 23 where there are OH and 271 6-OH.

In another embodiment, KK. is -SI, Va is -P paboree1, Kgye OO, deo is y / y 23 25 23 where y is -OH and 71 is -STON.

In another embodiment, Ag: is a pyridyl group, dep is 1, and Kg is 0.

In another embodiment, Аг: is a pyridyl group, which is 1, КгеО, и1 0 is in t where is -on.

In another embodiment, Ag: is a pyridyl group, depy1, Kg is, is y / and 23 25 23 where / is -OV»o, and 71 is "OVU".

In another embodiment, Ag: is a pyridyl group, it is 1, KgeO, i1 0 is

Antagonists of STI and their use in / and 23 23 where / is -OH, and 7: is -OH.

In another embodiment, Ag: is a pyridyl group, depays 1, Kg is, 0 is y / and 23 25 23 where y is -ОВоо, and 71 is -СНгОВУ.

In another embodiment, Ag: is a pyridyl group, which is 1, KgeO, y1 0 is y / y 23 25 23 where y is -OH, and 71 is -CHON.

In another embodiment, Ag: is a pyridyl group, it is 1, KgeO, i1 0 is

In and where 24 is -OV»o.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, which is 1, Kge 00,10 is y y 23 25 23 where / is -OH, 71 is "ОВ".

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / and 23 25 23 where U is -OH, y2 is -OH.

In another embodiment, K is a -halo, Ka is a -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / y 23 25 23 where U is -OVgo, 21 is -"СН2ОВ".

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / and 23 25 23 where U is -OH, y2 is -CHg2OH.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / and 23 25 23 where y is -OH, 21 is -OH, Ag" is benzothiazolyl , where at least one of Kz or K» is not -H.

In another embodiment, K is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kg is 0.10 is

Antagonists of TRPVI and their use in / and 23 23 where U is -OH, 7 is -CHngOH, Ag" is benzothiazolyl, where at least one of Kz or Kz" is not -H.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depe 1, Kge 00,10 is y / y 23 25 23 where U is -OH, y2 is -OH, Ag: is benzoxazolyl , where at least one of Ez or Kz is not -H.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / y 23 25 23 where U is -OH, y2 is -CHnOH, Ag" is benzoxazolyl , where at least one of Kv or K» is not -H.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depe 1, Kge 00,10 is y / y 23 25 23 where U is -OH, y2 is -OH, Ag: is benzoimidazolyl , where at least one of Kz or Kz" is not -H.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depe 1, Kgye 00,10 is y / y 23 25 23 where U is -OH, y2 is -CHnOH, Ag" is benzoimidazolyl , where at least one of Kz or Kz is not -H.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / y 23 25 23 where U is -OH, y2 is -OH, Ag: is phenyl , where 5 is either 0 or 1.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Vgye 0.10 is y / and 23 25 23 where U is -OH, y2 is -CHnOH, Ag" is phenyl , where 5 is either 0 or 1.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / y 23 25 23 where U is -OH, y2 is -OH, Ag: is phenyl , where 5 is 2.

In another embodiment, K. is -halo, Ka is -halo, and Ag is a pyridyl group, depays 1, Kge 00,10 is y / and 23 25 z where U is -OH, y2 is -CHg2OH, Ag" is phenyl , where 5 is 2.

Antagonists of STI and their use

In another embodiment, the dashed line is a double bond, n or p is 1, KgeO, deo is in tr where is -OV»o.

In another embodiment, the dashed line is a double bond, paborye1, Kg is, deovye y y 23 23 where U is -OVgo and 2 is OK.

In another embodiment, the dashed line is a double bond, paborye1,K2eo,deovye y y 23 25 23 where y is -OVoo and 71 is -SNgOVU.

In another embodiment, the dotted line is a double bond, paborye1, Kg is, deovye

In and where 74 is -ОВ2о.

In another embodiment, the dotted line is a double bond, paborye1, Kg is, deovye in tr where is -on.

In another embodiment, the dotted line is a double bond, paborye1, Kg is, deovye y y 23 25 23 where OH and 271 6-OH are.

In another embodiment, the dotted line is a double bond, paborye1, Kg is, deovye y y 23 25 23 where y is -OH and 71 is -STON.

In another embodiment, the dashed line is a double bond, B: is -halo, pabore1, K2e6O, deos is u t where U is -OH.

In another embodiment, the dotted line is a double bond, EK: there is -halo, paborye1, K2 60, deose y / y 23 25 23 where there are OH and 21 6-OH.

In another embodiment, the dotted line is a double bond, EC: is -halo, paborye1, K2 60, deose

Antagonists of TPRVI and their use in / and 23 23 where U is -OH and 71 is -CHngOH.

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where n is 1,B2eb,iO is y / and 23 25 z where U is -OH, 71 is -OH .

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where p is 1,B2eb,iO is y / and 23 25 23 where U is -«OH, 71 is - SNgOH.

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where n is 1,B2eb,iO is y / and 23 25 z where y is -OH, 71 is -OH Ag" is benzothiazolyl, where at least one of Kv or Ke" is not a -H.

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where p is 1,B2eb,iO is y y 23 25 23 where y is -OH, 71 is -CHnOH, Ag" is benzothiazolyl, where at least one of Kv or K" is not a -H.

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, and 0 is y / and 23 25 23 where y is -OH, 21 is -OH Ag" is benzoxazolyl, where at least one of Kv or K» is not a -H.

In another embodiment, the dashed line is a double bond, Ki is -halo, and Ag: is a pyridyl group, where n is 1,10 is y / and 23 25 z where y is -OH, 21 is -"CHgOH, Ag » is benzoxazolyl, where at least one of Kz or K» is not a -H.

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where p is 1, B2eb, and O is y y 23 25 23 where y is -OH, 21 is -"OH , Ag" is benzoimidazolyl, where at least one of Kv or KE" is not a -H.

In another embodiment, the dashed line is a double bond, K is a -halo, and Ag: is a pyridyl group, where p is

Antagonists of TRPVI and their use 1, Bg26 sb, are y / y 23 z where U is -OH, y2 is -CHngOH, Ag" is benzoimidazolyl, where at least one of Ez or KE" is not a -H.

In another embodiment, the dotted line is a double bond, K. is -halo, and Ag: is a pyridyl group, where p is 1, Bg26 sb, is y y 23 25 23 where U is -OH, y2 is -OH Ag » is phenyl, where 5 is 0 or 1 and Ka is -(C1-C8)alkyl, -halo, -C(halo)z, -OC(halo)»z, -

ОВ, -М(А7)2, -502Н?7, or -50"2С(halo)", and preferably -Е, -СИ, -СЕз, or -ОСЕ".

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where n is 1, Bg26 sb, is y / y 23 25 23 where is -OH, 7 is -SNeOH, Ag: is phenyl, where 5 is 0 or 1 and Ka is -(C1-C8)alkyl, -halo, -C(halo)»z, -

ОС(halo)z, -ОНБ7, -М(Б7)2, -502Н7, or -502С(halo)»z, and preferably -Е, -СИ, -СЕз, or -ОСЕ».

In another embodiment, the dotted line is a double bond, K. is -halo, and Ag: is a pyridyl group, where p is 1, Bg26 sb, is y y 23 25 23 where" is -OH, 71 is -OH Ag »: is phenyl, where 5 is 2, and each K:4 is, independently, -(C1-Cv)alkyl, -halo, -

С(halo)з, -ОС(halo)з, -ОВ?7, -М(В7)», -50287, or -50»С(halo)», and mostly there are -Е, -СИ, -СЕз, or -OSE with.

In another embodiment, the dashed line is a double bond, K. is -halo, and Ag: is a pyridyl group, where p is 1, Bg26 sb, is y / y 23 25 23 where y is -OH, y2 is -CH2OH , Ag: is phenyl, where 5 is 2, and each K'a4 is, independently, -(C1-Cv)alkyl, -halo, -

С(halo)з, -ОС(halo)з, -ОВ?7, -М(В7)», -50287, or -50»С(halo)», and mostly there are -Е, -СИ, -СЕз, or -OSE with.

In another embodiment, O is

IF) where the compound of formula I is racemic.

In another embodiment, O is

IF) NO,, throne tone chlAa I chl ; where 95 6e There is more than 60 95 in the enantiomer.

In another embodiment, O is

IF) NO,, throne tone chllAA I chlAA ; where 95 6e is more than 70 95 in the enantiomer.

In another embodiment, O is

Antagonists of TRPVI and their use no NO,, tron ton chl I chlAA ; where 95 6e is more than 80 95 in the enantiomer.

In another embodiment, O is no NO,, throne tone chl I chlAA; where 95 6e is more than 90 95 in the enantiomer.

In another embodiment, O is no NO,, tron ton chl I chl ; where 95 6e is more than 99 95 in the enantiomer.

In another embodiment, О is no NO, tron ton chl I chlAA; where 95 6e 5 of the enantiomer is greater than 60 95.

In another embodiment, О is no NO, tron ton chl I chlAA; where 95 6e 5 of the enantiomer is greater than 70 95.

In another embodiment, O is no NO,, throne tone "ply I chl ; where 95 6e 5 of the enantiomer is greater than 80 95.

In another incarnation, O is no NO,, throne tone chlAA and chlAM; where 95 6e 5 of the enantiomer is greater than 90 95.

In another embodiment, O is no NO,, chllA and chl; where 95 of the 5 enantiomer is greater than 99 95.

In another embodiment, the invention covers compounds of formula 1.4:

Anya -V,

Also (S Dzit

M

Ago (I.4) or its pharmaceutically acceptable salt, where

X is O, 5, M-CM, M-OH, or M-OB o;

UM is M or C; dotted line means the presence or absence of a bond, and when the dotted line means the presence of a bond or UM is M, then Ka is absent, otherwise Ka is -Н, -ОН, -ОСЕ:», -halo, -(С1-Св )alkyl, -

СНгОН, -СНоСИ, -СНеВг, -СНеЙ, -СНоЕ, -СН(halo)», -SEz, -ОВио, -5Вио, -«СОН, -СООН о, -С(О)В:о, -С( О)Н, -ОС(О)Бо, -ОС(О)МНВА то, -МНО(О)Виз, -СОМ(Вз)2, -530)2Нио, or -MO";

Vo is -(C1-Ca)alkyl; each Kis is independently: -H, -(C1-Ca)alkyl, -(C1-Alkenyl, -(C1-Ca)alkynyl, or -phenyl;

Antagonists of STI and their use

But not

Vo)p Ve)p (Rod, Ne)p ( re ( kr DM " ny 2) hm U ne xx (B2)r. (Nar (Nor,

At Mt Mt

ZHIM, M,

VA; IN; the same (Wo), (Water

M Ta Z rt

Central Committee A2)r | or And still and tk "Ffy

AND; IN; In, ;

Agg is about -(Via , ? , U

AND

In u. 1 ha in the same Nuig 8 Vo 8 No Av Vo Uz)s

Her With Her Zo

At 9 o'clock! AND

Uz)s Uz)s

хххх Uh opomonone

XX Mo M X X (Aga (Nadya (Nidda (At4)5 (Age c is an integer 0, 1, or 2;

U, MU2, Uz are, independently, C, M, or 0; where no more than one of U, M2, or Uz can be O, and for each U, U2, and Mz that is M, M is connected to one Co: group, and for each U, MU2, and Mz that is C, C is connected to two Cogho groups, provided that there are no more than two (C1-C8)alkyl groups replacing all of M, M", and Mz;

Vig and Vig are, independently, -H or -(C1-C8)alkyl;

E is 50, -5, "O(C1-C5)alkyl, -C(C1-C5)alkenyl, -MH(C:1-C5)alkyl, or -M-ORho;

They are -H, -halo, -(C1-Cdalkyl, -MO», -SM, -OH, -OSH»z, -MH», -C(halo)z, -CH(halo)», -СНа( halo), -OS(halo)z, -OSH(halo)»g, or -OSH»(halo); each E2g is, independently: (a) -halo, -OH, -O(C1-Ca)alkyl, -CM, -MO", -MH", -(C1-C0)alkyl, -(C2-C0)alkenyl, -(C2-C0)alkynyl, -phenyl, or (5) group of formula C);

Antagonists of TRPVI and their application deo are n) n) n) 23 23 g iz o 2a o 73 (c) (c) in AV P 7 x 20 7 NM 20 Osev--B20 3, AN Z 23 MN eV ; 78 o, -eIB53K , (c) N nd o M. ts Okh

Z 7 20 Ngo M "Vo 7 1 az u 7 7 743 m . Z . 25 23 or 73 7 is-H, -ОВ7, -587, -СН»-ОНВ?7, -СНо-587, -СНо -M(Hbo)", or -halo; 72 is -H, -(C1-C8)alkyl, -(C8-C8)alkenyl, -(C2-C8)alkynyl, -phenyl, or -halo; each 2z is , independently, -H, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, or -phenyl; 74 6-H, -OH, -OB2o, -(C1-Cv )alkyl, or -MAgo;

U is -OB2o, -5B2o, or -M(Pho)2; provided that at least one KE" group is a group of formula OS), and provided that when 71 is -OB; or -

FOR, then 2" is not a -halo; each Ez is, independently: (a) -H, (C1-Cv)alkyl, or two Ez groups form a bicyclo group of one of the following formulas,

Ag. IN

Aphuu Na 1 M. 4 y y or y-y ;

M M

And in

X2e Neo X M 20 each K;7 is, independently, -H, -(C1-Cv)alkyl, -(Cg-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)cycloalkyl, - ( C5-Cv)cycloalkenyl, -phenyl, -(C1-Cv)haloalkyl, -(C1-Cv)hydroxyalkyl, -(C1-Cv)alkyl(C:-Cv)alkyl, - (C1-Cv)alkyl-M( NAho)r, or -SOM(Rho)2; each Kz and K» is, independently, -H, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)ucycloalkyl, -(C5-Cv) cycloalkenyl, -phenyl, -СНеС(halo)з, -С(halo)з, -СН(halo)», -СНе(halo), -ОС(halo)»з, -ОСНi(halo)з, -ОСНа( halo), -0O-CM, -OH, -halo, -Mz, -MO", -"СН-MA?, -М(В7)2, -"MA?OH, -ONB?7, -С(О )НВ?, -ФКО)ОвВ87, -ОС(О)В87, -ОС(ООН?, -587, -«5(0)Н87, or -5(0)2Н87; each Kii is, independently, -СМ, -OH, -(C1-Cv)alkyl, -(Co-Cv)alkenyl, -halo, -Mz, -MO», -M(ВН7)2, -

Sn-mMA?, -MA?OH, -OB?7, -С(О)8?7, -Ф(0)ОН87, -ОС(О)В?7, or -ОС(ООНВ; each P:4 are, independently, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(Cg-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(Cv5-

C1-cycloalkenyl, -(C1-C8) alkoxy-(C1-C8) alkyl, -phenyl, C(halo)z, CNi(halo)", CNae(halo), -(3-7- membered) heterocycle, - (C1-Cv)haloalkyl, -(C2-Cv)haloalkenyl, -(C2-Cv)haloalkynyl, -(C2-

Cn)hydroxyalkenyl, -(Cn-Cn)hydroxyalkynyl, (C1-Cn) alkoxy(C2-Cn) alkyl, (C1-Cn) alkoxy(C2-

C1-C8)alkenyl, (C1-C8)alkoxy(C2-C8)alkynyl, -CM, -OH, -halo, OS(halo)z, -Mz, -MO", -"CH-MA?, -M(B ?7)", -MA?ON, -ОВ8?7, -587, -"О(СНа)нОвВ?, -О(СНа)нз А", -О(СНАММ(А7)2, -"ЖМ(В87СНаїovВ ?, -М(В7)СНа)н А, -

М(А7ХСНаБМ(А7)», -М(А7)СОВ?, -С(0)87, -С(О)О87, -ОС(О)87, -ОС(О)ОВ7, -50)87, or -5(0)28;7, -5(0)2M(А7)2", 5О2С(halo)z, -"СОМ(Н7)2, -(С1-Св)alkyl-С-MONВ?, -( C1-Cv)alkyl-C(O)-M(НА7)", -(C1-Cv)alkyl-

MNHZO»M(А?)»g, or -(С1-Св)alkyl-С(-МН)-М(А?7)»2; each K 0 is, independently, -H or -(C:-C 1 )alkyl; each P»: is, independently, -H, -(Ci-Cv)alkyl,

27I/Z

Antagonists of TPRVI and their use cite Men 3)2, AJ

And in? he sends his hand to HIM or

So each halo is, independently, -Е, -СИ, -Вг, or -Й; n is an integer 1, 2, or 3; p is an integer 1 or 2; each br is, independently, an integer 1 or 2; d is an integer 0, 1, 2, 3, or 4; r is an integer 0, 1, 2, 3, 4, 5, or 6; is an integer 0, 1, 2, 3, 4, or 5;

Y is an integer 0, 1, 2, or Z; and t is an integer of 0, 1, or 2.

In another embodiment in relation to formula 1.4, E is 50, 5, "CH(C1i-Cv)alkyl, "CH(C:-Cv)alkenyl, or -M-ОВН2о.

In another embodiment, with respect to formula 1.4, E is 20, 5, or -M-OVho.

In another embodiment, the invention covers compounds of formula 1.3:

Anya -V,

Also (S Dzit

M

And in

X M 20

Ago (I.3) or its pharmaceutically acceptable salt, where

X is 0.5, M-CM, M-OH, or M-OHM o;

UM is M or C; dotted line means the presence or absence of a bond, and when the dotted line means the presence of a bond or UM is M, then Ka is absent, otherwise Ka is -Н, -ОН, -ОСЕ:», -halo, -(С1-Св )alkyl, -

СНгОН, -СНоСИ, -СНеВг, -СНеЙ, -СНоЕ, -СН(halo)», -SEz, -ОВио, -5Вио, -«СОН, -СООН о, -С(О)В:о, -С( О)Н, -ОС(О)Бо, -ОС(О)МНВА то, -МНО(О)Виз, -СОМ(Вз)2, -530)2Нио, or -MO";

Vo is -(C1-Ca)alkyl; each Kis is independently: -H, -(C1-Ca)alkyl, -(C1-Alkenyl, -(C1-Ca)alkynyl, or -phenyl;

But not

Antagonists of STI and their use

Vo)p Vo)p (Ao)p, Vo)p

M, but Kh what , (B2)r. (Nr (Nor ssha "fi she Kh , "fi

VA; IN; 2M (H2)d, (No)

M? Um um

Nor Y or P he i cha M

AND; IN; IN; ;

Agg is «st i H o (No) , ? , U

AND

V in 1ga t Nig in V in ( 8 No 8 No 8 No Uz)s

Her With Her Zo

In » In ! AND

Also E K heh

Uz)s Uz)s xx ЗХ -x -x

And | ; I ; Z E Z or x Mo mih 2 o (Aga (Nadya (Nidda (Ag4)5 (Viks) is an integer 0, 1, or 2;

M, Me, z is, independently, C or M; where for each U, U2, and Uz schoO is M, M is connected to one Kogo group, and for each U, M», and Uz CHO is C, C is connected to two Kogo groups, provided that no more than two (Ci-Cv)alkyl groups are present, replacing all of M, Mg, and Mz;

Vig and Vig are, independently, -H or -(C1-C8)alkyl;

E is 50, -5, "O(C1-C5)alkyl, -C(C1-C5)alkenyl, -MH(C:1-C5)alkyl, or -M-ORho;

They are -H, -halo, -(C1-Cdalkyl, -MO», -SM, -OH, -OSH»z, -MH», -C(halo)z, -CH(halo)», -СНа( halo), -OS(halo)z, -OSH(halo)»g, or -OSH»(halo); each E2g is, independently: (a) -halo, -OH, -O(C1-Ca)alkyl, -CM, -MO", -MH", -(C1-C0)alkyl, -(C2-C0)alkenyl, -(C2-C0)alkynyl, -phenyl, or (5) group of formula C); deo is

Antagonists of SARS and their use in 2341723

At 5 | with, | ; 23 (c); (c) in VP; the same 20; nm7 29 Oshes--В2о 3 МН С 73 МН -еИ53КГ 78 о, 5 (in); Sun Sun Oh Н З 7 20 Нго М ЗВ2о 7 у з г 73 у4 73 и ШХ З , 25 23 or 73 7 е-Н, -ОВ7, -587, -СН»-ОНВ?7, -"СНо-587, -"СНо -M(Vgo)", or -halo; 72 is-H, -(C1-C8)alkyl, -(C8-C8)alkenyl, -(C2-C8)alkynyl, -phenyl, or -halo; each 2z is, independently, -H, -(C1-C8)alkyl, -(C2-C8)alkenyl, -(C2-C8)alkynyl, or -phenyl; 74 6-H, -OH, -OB2o, -(C1-Cv)alkyl, or -MAho;

In is -ОВ2о, -5В2о, or -М(Рго)»; provided that at least one KE" group is a group of formula OS), and provided that when 71 is -OB; or -

FOR, then 2" is not a -halo; each Ez is, independently: (a) -H, (C1-Cv)alkyl, or two Ez groups form a bicyclo group of one of the following formulas,

Ag V

Aphuu Na 1 M. A

M M

And in heck X M 20

Ago Ago each K;7 is, independently, -H, -(C1-Cv)alkyl, -(Cg-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)cycloalkyl, - (C5-Cv) )cycloalkenyl, -phenyl, -(C1-Cv)haloalkyl, -(C1-Cv)hydroxyalkyl, -(C1-Cv)alkyl (C:-Cv)alkyl, - (C1-Cv)alkyl-M(HAgo)g , or -SOM(Rho)2; each Kz and K» is, independently, -H, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)ucycloalkyl, -(C5-Cv) cycloalkenyl, -phenyl, -СНеС(halo)з, -С(halo)з, -СН(halo)», -СНе(halo), -ОС(halo)»з, -ОСНi(halo)з, -ОСНа( halo), -0O-CM, -OH, -halo, -Mz, -MO", -"СН-MA?, -М(В7)2, -"MA?OH, -ONB?7, -С(О )НВ?, -ФКО)ОвВ87, -ОС(О)В87, -ОС(ООН?, -587, -«5(0)Н87, or -5(0)2Н87; each Kii is, independently, -СМ, -OH, -(C1-Cv)alkyl, -(Co-Cv)alkenyl, -halo, -Mz, -MO», -M(ВН7)2, -

Sn-mMA?, -MA?OH, -OB?7, -С(О)8?7, -Ф(0)ОН87, -ОС(О)В?7, or -ОС(ООНВ; each P:4 are, independently, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(Cg-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(Cv5-

C1-cycloalkenyl, -(C1-C8) alkoxy-(C1-C8) alkyl, -phenyl, C(halo)z, CNi(halo)", CNae(halo), -(3-7- membered) heterocycle, - (C1-Cv)haloalkyl, -(C2-Cv)haloalkenyl, -(C2-Cv)haloalkynyl, -(C2-

Cn)hydroxyalkenyl, -(Cn-Cn)hydroxyalkynyl, (C1-Cn) alkoxy(C2-Cn) alkyl, (C1-Cn) alkoxy(C2-

C1-C8)alkenyl, (C1-C8)alkoxy(C2-C8)alkynyl, -CM, -OH, -halo, OS(halo)z, -Mz, -MO", -"CH-MA?, -M(B ?7)", -MA?ON, -ОВ8?7, -587, -"О(СНа)нОвВ?, -О(СНа)нз А", -О(СНАММ(А7)2, -"ЖМ(В87СНаїovВ ?, -М(В7)СНа)н А, -

М(А7ХСНаБМ(А7)», -М(А7)СОВ?, -С(0)87, -С(О)О87, -ОС(О)87, -ОС(О)ОВ7, -50)87, or -5(0)28;7, -5(0)2M(А7)2", 5О2С(halo)z, -"СОМ(Н7)2, -(С1-Св)alkyl-С-MONВ?, -( C1-Cv)alkyl-C(O)-M(НА7)", -(C1-Cv)alkyl-

MNHZO»M(А?)»g, or -(С1-Св)alkyl-С(-МН)-М(А?7)»2; each K 0 is, independently, -H or -(C:-C 1 )alkyl; each halo is, independently, -Е, -СИ, -Вг, or -Й; n is an integer 1, 2, or 3; p is an integer 1 or 2; each br is, independently, an integer 1 or 2;

Z30/3

Antagonists of TRVVI and their application d is an integer 0, 1, 2, 3, or 4; r is an integer 0, 1, 2, 3, 4, 5, or 6; is an integer 0, 1, 2, 3, 4, or 5;

Y is an integer 0, 1, 2, or Z; and t is an integer of 0, 1, or 2.

In another embodiment in relation to formula 1.3, E is 50, 5, "CH(C1i-Cv)alkyl, "CH(C:-Cv)alkenyl, or -M-Ovo2o.

In another embodiment, with respect to formula 1.3, E is 20, 5, or -M-OVho.

In another embodiment, the invention covers compounds of formula 1.2:

Ag -B,

Also (S Dzit

M

IN

Ago (I.2) or its pharmaceutically acceptable salt, where

X is 0.5, M-CM, M-OH, or M-OB:o;

MU is M or C; dotted line means the presence or absence of a bond, and when the dotted line means the presence of a bond or UM is M, then Ka is absent, otherwise Ka is -Н, -ОН, -ОСЕ:», -halo, -(С1-Св )alkyl, -

СНгОН, -СНоСИ, -СНеВг, -СНеЙ, -СНоЕ, -СН(halo)», -SEz, -ОВио, -5Вио, -«СОН, -СООН о, -С(О)В:о, -С( О)Н, -ОС(О)Бо, -ОС(О)МНВА то, -МНО(О)Виз, -СОМ(Вз)2, -530)2Нио, or -MO";

Vo is -(C1-Ca)alkyl; each Kis is independently: -H, -(C1-Ca)alkyl, -(C1-Alkenyl, -(C1-Ca)alkynyl, or -phenyl;

Ach is (Vo)p (No)p (Nop, m (No)p

X years X | we «fi o xx y , (Vo)r. (Over oh, (Nor,

Kt M m Mt "fi she shkh ? M,

IN; AND; IN;

M (Nor, (ngdA

MU TA railway Hm pu A2)r | or I he and t "Ffy

IN; V.V.;

Ah" there is

Antagonists of SARS and their use "A vi A A o -(From) , , , U

AND

IN

In 1 ha in the north of Nig 8 8

No No 8 No Ua)s i Z i Zo

In? In 'I

U. U. vla: and M

Uz)s Uz)s ех хх -х -х опомононе

Х М М Ж Х

(B) (Ada (Nigda (Nia)v (Nv s) is an integer 0, 1, or 2;

U, Mg, Mz are, independently, C or M; where for each U, U2, and Uz schoO is M, M is connected to one Kogo group, and for each Uch, M", and Uz sCHO is C, C is connected to two Kogo groups, provided that that no more than two (Ci-Cv)alkyl groups are present, replacing all of Mch, Mg, and Mz;

Vig and Vig are, independently, -H or -(C1-C8)alkyl;

E is 50, -5, "O(C1-C5)alkyl, -C(C1-C5)alkenyl, -MH(C:1-C5)alkyl, or -M-ORho;

They are -H, -halo, -(C1-Cdalkyl, -MO», -SM, -OH, -OSH»z, -MH», -C(halo)z, -CH(halo)», -СНа( halo), -OS(halo)z, -OSH(halo)»g, or -OSH»(halo); each E2g is, independently: (a) -halo, -OH, -O(C1-Ca)alkyl, -CM, -MO", -MH", -(C1-C0)alkyl, -(C2-C0)alkenyl, -(C2-C0)alkynyl, -phenyl, or (5) group of formula C); deo is n) n) n) ar nniaa 73 Oh o 73 I same | with, | , shk (c) (c) in V P 7 sh that with. chu 70 Osh5--No 3 MN Z 23 Mn eV 78 o, 5 (c) H them oh. N Z 7 M Ngo Ngo M ZV2o and 23 in and 7z or; 73

C2/3

Antagonists of TRPVI and their application 7 are-H, -ОВ7, -587, -СН»-ОНВ?7, -"СНо-587, -"СНо-М(Вго)», or -halo; 72 is-H, -(C1-C8)alkyl, -(C8-C8)alkenyl, -(C2-C8)alkynyl, -phenyl, or -halo; each 2z is, independently, -H, -(C1-C8)alkyl, -(C2-C8)alkenyl, -(C2-C8)alkynyl, or -phenyl; 74 6-H, -OH, -OB2o, -(C1-Cv)alkyl, or -MAho;

U is -OB2o, -5B2o, or -M(Pho)2; provided that at least one KE" group is a group of formula OS), and provided that when 71 is -OB; or -

FOR, then 2" is not a -halo; each Ez is, independently: (a) -H, (C1-Cv)alkyl, or two Ez groups form a bicyclo group of one of the following formulas,

Ap uu Va pu 2- or y- ;

M M ul No ul yo

Ago Ag each K;7 is, independently, -H, -(C1-Cv)alkyl, -(Cg-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)cycloalkyl, - (C5-Cv) )cycloalkenyl, -phenyl, -(C1-Cv)haloalkyl, -(C1-Cv)hydroxyalkyl, -(C1-Cv)alkyl (C:-Cv)alkyl, - (C1-Cv)alkyl-M(HAgo)g , or -SOM(Rho)2; each Kz and K» is, independently, -H, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)ucycloalkyl, -(C5-Cv) cycloalkenyl, -phenyl, -СНеС(halo)з, -С(halo)з, -СН(halo)», -СНе(halo), -ОС(halo)»з, -ОСНi(halo)з, -ОСНа( halo), -0O-CM, -OH, -halo, -Mz, -MO", -"СН-MA?, -М(В7)2, -"MA?OH, -ONB?7, -С(О )НВ?, -Ф(Ф)onВ87, -ОС(О)В87, -ОС(ООН?, -587, -«5(0)НВ7, or -5(0)287; each Kii is, independently, - CM, -OH, -(C1-Cv)alkyl, -(Co-Cv)alkenyl, -halo, -Mz, -MO», -M(ВН7)2, -

Sn-mMA?, -MA?OH, -OB?7, -С(О)8?7, -Ф(0)ОН87, -ОС(О)В?7, or -ОС(ООНВ; each P:4 are, independently, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(Cg-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(Cv5-

C1-cycloalkenyl, -(C1-C8) alkoxy-(C1-C8) alkyl, -phenyl, C(halo)z, CNi(halo)", CNae(halo), -(3-7- membered) heterocycle, - (C1-Cv)haloalkyl, -(C2-Cv)haloalkenyl, -(C2-Cv)haloalkynyl, -(C2-

Cn)hydroxyalkenyl, -(Cn-Cn)hydroxyalkynyl, (C1-Cn) alkoxy(C2-Cn) alkyl, (C1-Cn) alkoxy(C2-

C1-C8)alkenyl, (C1-C8)alkoxy(C2-C8)alkynyl, -CM, -OH, -halo, OS(halo)z, -Mz, -MO", -"CH-MA?, -M(B ?7)", -MA?ON, -ОВ8?7, -587, -"О(СНа)нОвВ?, -О(СНа)нз А", -О(СНАММ(А7)2, -"ЖМ(В87СНаїovВ ?, -М(В7)СНа)н А, -

М(А7ХСНаБМ(А7)», -М(А7)СОВ?, -С(0)87, -С(О)О87, -ОС(О)87, -ОС(О)ОВ7, -50)87, or -5(0)28;7, -5(0)2M(А7)2", 5О2С(halo)z, -"СОМ(Н7)2, -(С1-Св)alkyl-С-MONВ?, -( C1-Cv)alkyl-C(O)-M(НА7)", -(C1-Cv)alkyl-

MNHZO»M(А?)»g, or -(С1-Св)alkyl-С(-МН)-М(А?7)»2; each K 0 is, independently, -H or -(C:-C 1 )alkyl; each halo is, independently, -Е, -СИ, -Вг, or -Й; n is an integer 1, 2, or 3; p is an integer 1 or 2; each br is, independently, an integer 1 or 2; d is an integer 0, 1, 2, 3, or 4; r is an integer 0, 1, 2, 3, 4, 5, or 6; is an integer 0, 1, 2, 3, 4, or 5;

Y is an integer 0, 1, 2, or Z; and t is an integer of 0, 1, or 2.

In another embodiment in relation to formula 1.2, E is 50, 5, "CH(C1i-Cv)alkyl, "CH(C:-Cv)alkenyl, or -M-Ovo2o.

In another embodiment, with respect to formula 1.2, E is 50, 5, or -M-OVho.

In another embodiment, the invention covers compounds of formula 1.1:

Anya -V,

Also (S Dzit

M and

Ago (1.1) or its pharmaceutically acceptable salt, where

X is 0.5, M-CM, M-OH, or M-OHM o;

C3/3

Antagonists of STI and their use

UM is M or C; dotted line means the presence or absence of a bond, and when the dotted line means the presence of a bond or UM is M, then Ka is absent, otherwise Ka is -Н, -ОН, -ОСЕ:», -halo, -(С1-Св )alkyl, -

СНгОН, -СНоСИ, -СНеВг, -СНеЙ, -СНоЕ, -СН(halo)», -SEz, -ОВио, -5Вио, -«СОН, -СООН о, -С(О)В:о, -С( О)Н, -ОС(О)Бо, -ОС(О)МНВА то, -МНО(О)Виз, -СОМ(Вз)2, -530)2Нио, or -MO";

Vo is -(C1-Ca)alkyl; each Kis is independently: -H, -(C1-Ca)alkyl, -(C1-Alkenyl, -(C1-Ca)alkynyl, or -phenyl;

An is (P2) V (P2)r M (P2) z NI pet ah de "fi M fII "fi

IN; "in "B, or B; ;

Agg there is

Anyu tstwo ho (Va . ? . M

AND

AND

Ugo 1ha v v n yo Ag 8 8

No On 8 No Uz)s

Her Zo Yi Zo

In » In ! AND

U. U. also E and M

Uv)s Uv)s s | with | | | From about F

XX M M XX X

(Aga)a (Aga)a (Nidda (Aia)5 (Vch), c is an integer 0, 1, or 2;

M, Me, z is, independently, C or M; where for each U, U2, and Uz schoO is M, M is connected to one Ego group, and for each U, M», and Uz sCHO is C, C is connected to two Kogo groups, provided that no more than two (Ci-Cv)alkyl groups are present, replacing all of Mch, Mg, and Mz;

Vig and Vig are, independently, -H or -(C1-C8)alkyl;

E is 50, -5, "C(C1-Cv)alkyl, -C(C1-Cv)alkenyl, -MH(C:-Cv)alkyl, or "M-OB2o;

They are -H, -halo, -(C1-Cdalkyl, -MO», -SM, -OH, -OSH»z, -MH», -C(halo)z, -CH(halo)», -СНа( halo), -OS(halo)z, -OSH(halo)»g, or -OSH»(halo); each E2g is, independently: (a) -halo, -OH, -O(C1-Ca)alkyl, -CM, -MO", -MH", -(C1-C0)alkyl, -(C2-C0)alkenyl, -(C2-C0)alkynyl, -phenyl, or (5) group of formula C); deo is

ЗА4/З

Antagonists of TRPVI and their application n) n) n) ar nniaa 73 Okh o 73 or i (c) (c) in V P ; the same 20; nm7 29 Oshes--В2о 3 МН З 23 МН -еИ53КГ 78 о, 5 (c) H nd ох. ts Zx 7 20 Ngo ZM "Vo and ShZ . 25 23 , 75 73 7 e-H, -ОВ7, -587, -СН»-ОНВ?7, -"СНо-587, -"СНо-М(Вго) ", or -halo; 72 is -H, -(C1-C8)alkyl, -(C8-C8)alkenyl, -(C2-C8)alkynyl, -phenyl, or -halo; each 2z is, independently, -H , -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, or -phenyl; 74 6-H, -OH, -OB2o, -(C1-Cv)alkyl, or - MAgo;

U is -OB2o, -5B2o, or -M(Pho)2; provided that at least one KE" group is a group of formula OS), and provided that when 21 is -OB; or - 57, 22 is not -halo; each Ez is, independently: (a) -H, (Ci-Cv)alkyl, or two Kz groups can form a bicyclogroup, which has the following structure, A in

G - -«

Aphuu Na 1 M. A and y or y-y ;

M M

Av

X2e Neo X M 20

Ago Ago each K7 is, independently, -H, -(C1-C8)alkyl, -(C2-C8)alkenyl, -(C8-C8)alkynyl, -(C3-C8)ucycloalkyl, - (C8-C8)cycloalkenyl . -SOM(Rho)2; each Kz and K» is, independently, -H, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)ucycloalkyl, -(C5-Cv) cycloalkenyl, -phenyl, -СНеС(halo)з, -С(halo)з, -СН(halo)», -СНе(halo), -ОС(halo)»з, -ОСНi(halo)з, -ОСНа( halo), -0O-CM, -OH, -halo, -Mz, -MO", -"СН-MA?, -М(В7)2, -"MA?OH, -ONB?7, -С(О )НВ?, -ФКО)ОвВ87, -ОС(О)В87, -ОС(ООН?, -587, -«5(0)Н87, or -5(0)2Н87; each Kii is, independently, -СМ, -OH, -(C1-Cv)alkyl, -(Co-Cv)alkenyl, -halo, -Mz, -MO», -M(ВН7)2, -

Sn-mMA?, -MA?OH, -OB?7, -С(О)8?7, -Ф(0)ОН87, -ОС(О)В?7, or -ОС(ООНВ; each P:4 are, independently, -(C1-Cv)alkyl, -(C2-Cv)alkenyl, -(Cg-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(Cv5-

C1-cycloalkenyl, -(C1-C8) alkoxy-(C1-C8) alkyl, -phenyl, C(halo)z, CNi(halo)", CNae(halo), -(3-7- membered) heterocycle, - (C1-Cv)haloalkyl, -(C2-Cv)haloalkenyl, -(C2-Cv)haloalkynyl, -(C2-

Св)hydroxyalkenyl, /-(С2-Св)hydroxyalkynyl, /-(С1-Св) alkoxy(С2-Св) alkyl, /-(С1-Св) alkoxy(Се2-

C1-Cv)alkenyl, -(C1-Cv)alkoxy(C2-Cv)alkynyl, -CM, -OH, -halo, OS(halo)z, -Mz, -MO», -CH-MA», -M(B ?7)", -MA?ON, -ОВ8?7, -587, -"О(СНа)нОвВ?, -О(СНа)нз А", -О(СНАММ(А7)2, -"ЖМ(В87СНаїovВ ?, -М(В7)СНа)н А, -

М(А7ХСНаБМ(А7)», -М(А7)СОВ?, -С(0)87, -С(О)О87, -ОС(О)87, -ОС(О)ОВ7, -50)87, or -5(0)28;7, -ЧО)2М(А?7)2, 5О2С(halo)z, -"СОМ(Н7)", -(С1-Св)alkyl-"С-MONВ?7, - (C1-Cv)alkyl-C(O)-M(B7)2, -(C1-Cv)alkyl-

MNHZO»M(А?)»g, or -(С1-Св)alkyl-С(-МН)-М(А?7)»2; each K 0 is, independently, -H or -(C:-C 1 )alkyl; each halo is, independently, -Е, -СИ, -Вг, or -Й; n is an integer 1, 2, or 3; p is an integer 1 or 2;

Z35/3

Antagonists of SARS and their application each br is, independently, an integer 1 or 2; d is an integer 0, 1, 2, 3, or 4; r is an integer 0, 1, 2, 3, 4, 5, or 6; is an integer 0, 1, 2, 3, 4, or 5;

Y is an integer 0, 1, 2, or Z; and t is an integer of 0, 1, or 2.

In another embodiment in relation to formula 1.1, E is 50, 5, "CH(C1i-Cv)alkyl, "CH(C:-Cv)alkenyl, or -M-Ovo2o.

In another embodiment, with respect to formula 1.1, E is 50, 5, or -M-OVho.

In other embodiments, the compound of formula I is on no on no no NO, b, r u k i i | SHI

M

E J SI -

M. E. H

M

XX

Y G A. A (c) MN (o) MN i

IS

E from OSEz from SEZ from 05 55 kb

Antagonists of SARS and their use

MN"

SM

M M M

SI -F S F F SI 4

M M M ra MN Zh ra MN

SEZ SEZ or OSRz 56 tb Ob

Other interesting compounds are

M | M M r si -4 si Ж E o х M х ШЕ

M M M re

Z cha cha (c) MN

E | "SI z z 9 z

SEZ OSEz SEz SEZ 213 214 208 215

Z7/Z

Antagonists of STI and their use

M M M M | M

E and c and a 4 c 4 E 4

E E E E E

M M M M M

A, Z Z ra Hu and "E | E

SEZ; SEZ, nn? OSEz hundred SE with 212 209

SE 21 207 210

Water solubility of compounds is often a desirable feature. For example, the water solubility of the compound makes it easier to formulate the compound into various dosage forms that can be administered to the animal. When the compound is not completely soluble in the blood, it can settle in the blood, and the effect of the drug on the animal will not correspond to the administered dose. Water solubility increases the likelihood that the compound will not be deposited in the animal's blood and increases the ability to predict the effect of the target compound.

The compounds of formula I are highly soluble in aqueous solution. For example, at either pH 6.8 or pH 1.2, compound 200 is insoluble in aqueous solution, i.e., has a solubility in water of 0.1 μM. On the contrary, the solubility in water at pH 6.8, in μM, of compounds of formula I E2, Eb, Eb, and 52 are 3.0, 9.0, 9.2, and 38.2, respectively. Solubility in water at a pH of 1.2, in µM, of compounds of formula I E2, Eb, Ebi 2 is 1.0, 27.2, »50 and »50, respectively. In addition, solubility in water at or pH 6.8. or pH 1.2 of each of the compounds of the formula

Ob, Nb, 92, and 71 are »50 µM. The following compounds are insoluble in water at pH 6.8: 203, 207, 200, and 208.

The following compounds have very low solubility in water at pH 6.8: 209, 210, 211, 212, 213, 214, and 215 have water solubilities, in µM, of 1.0, 0.4, 0.4, 1, 9, 0.8, 1.8, and 0.6, respectively. Solubility in water, v

MKM, at pH 1.2 of compounds 209, 210, 211, 212, 213, 2141215 are 9.3, 2.0, 1.3, 10.3, 39.6, »50 and 9.6, respectively. On the contrary, the solubility in water at pH 6.8, in µM, of compounds of formula I M1, E1, C1, 3, and OZ are 28.0, 22.6, 15.7, 17.4, and 26.4, respectively . At pH 1.2, the compounds of formula I M1, E1, C1, UZ and OZ all have a solubility in water of 250 µM. The solubility in water, at either pH 6.8 or pH 1.2, is »50 µM for each of the following compounds of formula !: NI, Mb, 21, 51, E2, and 01.

COMPOUNDS OF FORMULA II

Preferred compounds of formula I are compounds of formula II:

Anya "V,

Also (S with

M

And "V

X m 20

Ago (1) or a pharmaceutically acceptable derivative thereof, where the dashed line, MU, X, Ag, Ag, Bz, Ba, No, and t are as defined above for the compound of formula Y, where

Antagonists of STI and their use

M) in 23 23 71 there is -OH, -5H, -M(Vho)g2, -"CH"-OH, -СНо-ЗН, or -СНег-М(Вho)"; 72 is -H, -CH3, or -СНо-ОВ;; each 7z is, independently, -H or -CH"; and

In is -OH, -5H, or -M(HgO)".

In addition to high solubility in aqueous solution, compounds of formula II are preferred because side effects are less severe (eg, reduced or eliminated central nervous system side effects) in animals when a compound of formula II is administered. For example, muscle relaxation is less or absent in animals when a compound of formula I is administered. The sedative effect is less or absent in animals when the compound of formula II is administered. Ataxia is less or absent in animals when a compound of formula I is administered. Flattened body syndrome is less or absent in animals when a compound of formula II is administered. Tremor is less or absent in animals when a compound of formula II is administered. When a compound causes fewer severe side effects, the therapeutic index, which is the difference between the effective dose and the dose that causes unwanted effects, increases.

The therapeutic index is a measure of the safety of a compound when administered to an animal. The higher the therapeutic index, the safer the compound.

Compounds of formula II also have excellent pharmacokinetic properties. In particular, the plasma level of the compound of formula II in the animal is dose-proportional. In addition, the amount of compound in the animal's plasma can be more easily controlled according to the dose of the compound administered to the animal. In addition, for a given administered dose, the concentration in the plasma of the animal is higher and is reached more quickly for the compound of formula II. For example, compound 200 reaches its maximum plasma concentration 3.1 g after administration. In comparison, the compound of formula II 71 reaches its maximum plasma concentration 2.5 g after administration and the maximum plasma concentration is 2.5 times greater than the maximum for compound 200. In addition, the compound of formula II KE reaches its maximum concentration in plasma 1.85 g after administration and the maximum plasma concentration is 5.3 times greater than the maximum for compound 200. For each of the compounds of formula II 21 and Kb, the plasma concentration up to 24 g is agreed higher for each compared to the compound 200.

The KE compound has the following structure:

Antagonists of TBVI and their application

But - M

SI

M

J

SEZ

Compounds of formula II are also preferred because they have a high therapeutic index.

The Therapeutic Index is the difference between the amount of a compound that is effective in treating a Condition and the amount of the same compound that causes unwanted effects.

Other embodiments of formula II are presented below.

In one embodiment, the compound of formula II is a pharmaceutically acceptable derivative of the compound of formula II.

In another embodiment, the compound of formula II is a compound of formula II, wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, the compound of formula II is a pharmaceutically acceptable salt of the compound of formula II.

In another embodiment, Ag: is a pyridyl group.

In another embodiment, Ag: is a pyrimidinyl group.

In another incarnation, Ah! is a pyrazinyl group.

In another embodiment, Ag: is a pyridazinyl group.

In another embodiment, UM is S.

In another embodiment, UM is M.

In another embodiment, X is o.

In another embodiment, X is 5.

In another embodiment, X is M-CM.

In another embodiment, X is M-OH.

In another embodiment, X is M-OVo.

In another embodiment, Ag is a benzoimidazolyl group.

In another embodiment, Ag is a benzothiazolyl group.

In another embodiment, Ag is a benzoxazolyl group.

In another embodiment, Ag" is

M » eat (Ata)a

In another embodiment, Ag" is

Antagonists of STI and their use; h

M. (Ata) d

In another embodiment, Ag" is with

J

(Kcha)v

In another embodiment, Ag" is -,

МХ

(Aa)a

In another embodiment, Ag" is about (Vch)

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, t is 2.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted with 1, 2 or Z independently selected Kα groups, and each bridge optionally contains -HO-CH- within (C2-Cv) bridge

In another embodiment, two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted by a Kz group, and each bridge optionally contains -HC-CH- within the (C2-Cv) bridge.

In another embodiment, two Kz groups together form a (C2-C3) bridge that is unsubstituted or substituted by a Kz group, and each bridge optionally contains -HC-CH- within the (C2-C3) bridge.

In another embodiment, two Kz groups together form a (C2-C3) bridge that is unsubstituted and each bridge does not necessarily contain -HC-CH- within the (C2-C3) bridge.

In another embodiment, the two Kz groups together form a (Cg) bridge, -HC-CH- bridge, or (C3) bridge, each of which is unsubstituted.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted with 1, 2, or C independently selected Ka" groups, each bridge optionally containing -HC-CnH- within (C2-Cv) bridge, and the bridge connects position 2 and b of piperidine, 1,2,3,6- tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted by a Kz group, each bridge optionally containing -HC-CH- within the (Cg2-Cv) bridge, and the bridge connects the positions 2 and 6 piperidine, 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-C3) bridge that is unsubstituted or substituted by a Kz group, each bridge optionally contains -HC-CH- within the (C2-C3) bridge, and the bridge connects the positions 2 and 6 piperidine, 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-C3) bridge that is unsubstituted, each bridge optionally contains -HC-CH- within the (C2-C3) bridge, and the bridge connects the 2 and 6 positions of the piperidine , 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (Cg)bridge, -HC-CH- bridge, or (C3)bridge, each of which is unsubstituted, and the bridge connects the 2 and 6 positions of the piperidine, 1,2,3, 6-tetrahydropyridine or piperazine.

In another embodiment, two Ez groups together form a -СН2-М(Ва)-СНе»- bridge (В1),

Antagonists of STI and their use

HER

GG nn -sn- M 50682 - - bridge (B2), or - -СсН.--М- -СНО--with bridge (83); where Ka is chosen from -H, -(Ci-Cv)alkyl, -(C3-Cv)ucycloalkyl, -СНеа-С(О0)-ВНе, -(СНг)-С(0)-ОНсе, -(СНг)- C(0)-M(Be)"2, ""CHg)2-O-Be, ""CHg)"-5(0)2-M(Be)", or -"CHg)2-M(Ae )5(O0)2-Be;

B is selected from: (a) -H, -(C1-Cv)alkyl, -(C3-Cv)cycloalkyl, -(3-7-membered)heterocycle, -M(He)", /--M( No)-(Sz-

C)cycloalkyl, or -M(Pce)-(3-7--lene)heterocycle; or (p) -phenyl, -(5- or b-membered)heteroaryl, -M(He)-phenyl, or -M(He)-(5-10-membered)heteroaryl, each of which is unsubstituted or substituted by 1, 2 or With independently selected K»7 groups; and each Ks, independently, is selected from -H or -(C1-Sdalkyl;

In another embodiment, a B1, B2, or B3 bridge connects the 2 and b positions of piperidine, 1,2,3,6-tetrahydropyridine, or piperazine.

In another embodiment, two Ez groups form a bicyclo group of one of the following formulas,

Apeuu On the blade

SU oyu S

M M he sut ke sciv

Aha Aha

In another embodiment, t is 1.

In another embodiment, t is 0.

In another embodiment, with both eeo.

In another embodiment, 5 or d is 1.

In another embodiment, 5 or d is 2.

In another embodiment, EC: is -N.

In another embodiment, KK. is a halo.

In another embodiment, Ki is -SI.

In another embodiment, Kch is -RE.

In another embodiment, EK: is -СНз.

In another embodiment, KE: is -MO".

In another embodiment, Ki is -SM.

In another embodiment, EC: is -OH.

In another embodiment, KE: is -OSN»V.

In another embodiment, EK: is -MN".

In another embodiment, Ki is -C(halo)z.

In another embodiment, MK: is SEz.

In another embodiment, Ki is -CH(halo)".

In another embodiment, Ki is -CHNa(halo).

In another embodiment, Ag: is a pyridyl group and n is 1.

In another embodiment, Ag: is a pyrazinyl group and p is 1.

In another embodiment, Ag: is a pyrimidinyl group and p is 1.

In another embodiment, Ag: is a pyridazinyl group and p is 1.

In another embodiment, C) is

Antagonists of STI and their use

On On ОН on on shk y and Ir. and I and he a he ono he

Well, but

E NI MO or | ON

In another embodiment, U is -OVho.

In another embodiment, ) is -OH.

In another embodiment, 271 is -OH."

In another embodiment, 21 is -OH.

In another embodiment, 21 is - CH»-OH».

In another embodiment, 271 is -CH2OH.

In another embodiment, 272 is -СН2-ОВ".

In another embodiment, 22 is -CH2OH.

In another embodiment, 22 is -H or -CH.z.

In another embodiment, 22 is -H.

In another embodiment, 22 is -CH»z.

In another embodiment, 2z is -Н.

In another embodiment, 7z is -CH»z.

In another embodiment, t is 1 and R 3 is -(C 1 -C 1 )alkyl.

In another embodiment, t is 1 and Ez is -CH»z.

In another embodiment, Ka is -OH.

In another embodiment, Ka is -OSEz

In another embodiment, Ka is a halo.

In another embodiment, Ka is -RE.

In another embodiment, Ka is -SI.

In another embodiment, Ka is -(C1-C1)alkyl.

In another embodiment, Ka is -CHz.

In another embodiment, Ka is -"CHgOH."

In another embodiment, Ka is -SNegSi.

In another embodiment, Ka is -СНе2ВГг.

In another embodiment, Ka is -SNYEI.

In another incarnation, Ka is -SNYE.

In another embodiment, Ka is -CH(halo)".

In another embodiment, Ka is -SEz.

In another embodiment, Ka is -MO".

In another embodiment, Ka is -OV:o.

In another embodiment, Ka is -5НА0.

In another embodiment, Ka is -C(O)MAo.

In another embodiment, Ka is -COOH.

In another embodiment, Ka is -С(О)Н.

In another embodiment, Ka is -"SOOV o.

In another embodiment, Ka is -ОС(О)В o.

In another embodiment, Ka is -502Н:0о.

In another embodiment, Ka is -OS(O)MNVA o.

In another embodiment, Ka is -МНОС(О)Вз.

In another embodiment, Ka is -SOM(B3z)".

In another embodiment, each K 0 is independently -H or -(C 1 -C 6 )alkyl.

In another embodiment, each Ego is, independently, -H or -(C3-C6)cycloalkyl.

In another embodiment, each Ego is, independently, -(C 1 -C 6 )alkyl or -(C 3 -C 6 )cycloalkyl.

In another embodiment, each Kogo is -N.

In another embodiment, each Ego is -(C 1 -C 1 )alkyl.

In another embodiment, each C 60 is -(C 3 -C 6 )cycloalkyl.

In another embodiment, Ar" is a benzothiazolyl, benzoimidazolyl or benzoxazolyl group; and at least one of Kv and K»e is -H.

Antagonists of STI and their use

In another embodiment, Ar" is a benzothiazolyl, benzoimidazolyl or benzoxazolyl group; and at least one of Kz and K» is not -H.

In another embodiment, Ar" is a benzothiazolyl, benzoimidazolyl or benzoxazolyl group; and at least one of Kz and K» is a -halo.

In another embodiment, Ag" is eh (Kia),

Is 1 and Ka is -(C1-Cv)alkyl, -halo, -C(halo)z, -OS(halo)z, -OH?7, -M(H7)2, -«502H87, or -502C( halo)" with

In another embodiment, Ag" is ex p (Kchadv 5 is 2, and each Ba is, independently, -(C1-C8)alkyl, -halo, -C(halo)z, -OS(halo)z, -OB? 7, -M(H7)2, -"50287, or -50"C(halo)"z.

In another embodiment, y) is -OH and 21 is -"OH.

In another embodiment, Y is -OH and 71 is -CH2OH.

In another embodiment, Y) is -OH, 21 is -OH, 2" is -H, and 2z is -H.

In another embodiment, ) is -OH, 21 is -CH2OH, 22 is -H, and 2z is -H.

In another embodiment, Ka is -halo, U is -OH, 71 is -OH, 2" is -H, and 2z is -H.

In another embodiment, Ka is -halo, U is -OH, 71 is -CH2OH, 2" is -H, and 2z is -H.

In another embodiment, Ka is -E, U is -OH, 21 is -OH, 22 is -H, and 2z is -H.

In another embodiment, Ka is -E, U is -OH, 21 is -CH2OH, 22 is -H, and 2z is -H.

In another embodiment, KK. is -halo, Ka is -halo, y) is -OH, 21 is -OH, 22 is -H, and 2z is -H.

In another embodiment, EC: is -halo, Ka is -halo, y) is -OH, 271 is -СНоOH, 22 is -H, and 2z is -H.

In another embodiment, EC: is -SI, Ba is -E, U is -OH, 21 is -OH, 22 is -H, and 2z is -H.

In another embodiment, MK. is -Si, Ba is -E, U is -«OH, 71 is -CHnOH, 22 is -H, and 2z is -H.

In another embodiment of Ag: there is (F)

Wow

M

IN;

In another embodiment, GE is a -halo, Ka is a -halo, Ag is (F)

Wow

M

IN; in 6-OH, 716 OH, 72 6-H, and 7z 6-H.

In another embodiment, K. is -halo, Ka is -halo, Ag! is (F)

ХХ

A-M

IN;

In is-OH, 71 is 6-STON, 72 is 6-H, and 7z is 6-H.

In another embodiment, K. is -halo, Ka is -halo, Ag! is

Antagonists of SARS and their use (F) ex

A-M

IN;

U is -OH, and is -Hon, 72 6-H, 2z is -H, Ag is benzoxazolyl, where at least one of Kz or Kz is not -H.

In another incarnation, Ki. there is a halo, Ka there is a halo, Ah! is (F) x

AM

IN;

U is -OH, and is -stone, 72 6-H, 2z is -H, Ag is benzoxazolyl, where at least one of Kz or Kz is not -H.

In another embodiment, K. is -halo, Ka is -halo, Ag! is (F) ex

A-M

IN;

U is -OH, and is -on, 72 6-H, 2z is -H, Agg is benzothiazolyl, where at least one of Kz or K» is not -H.

In another embodiment, K. is -halo, Ka is -halo, Ag! is (F) x

AM

IN;

U is -OH, 71 is -CH2OH, 22 is -H, 23 is -H, Ar» is benzothiazolyl, where at least one of Kz or K» is not -H.

In another embodiment, K. is -halo, Ka is -halo, Ag! is (F) x

M

IN;

Y is -OH, 21 is -OH, 2" is -H, 2z is -H, Ag is benzoimidazolyl, wherein at least one of Kz or K" is not -H.

In another embodiment, K. is -halo, Ka is -halo, Ag! is (F) ex

M

IN;

In is -OH, and is -stTON, 72 6 -H, 23 is -H, Ag" is benzoimidazolyl, where at least one of Kz or Kz is not -

N.

In another embodiment, K. is -halo, Ka is -halo, Ag" is,

Antagonists of SARS and their use (F) ex

A-M

IN;

In 6-OH, 71 is -OH, 7" is 6-H, 7z is -H, Ag" is phenyl, where 5 is 1.

In another embodiment, K. is -halo, Ka is -halo, Ag! is (F)

Hh

AM

IN;

6-OH, 71 is-STON, 7" 6-H, 73 6-H, Ag" has phenyl, where 5 is 2.

In another embodiment, the dashed line is a double bond, K: is -halo, Ag: is (F) ex

A-M

IN;

In 6-OH, 71 6 OH, 72 6-H, and 7z 6-H.

In another embodiment, the dotted line is a double bond, K: is -halo, Ag: is (F)

Hh

AM

IN;

In is-OH, 71 is 6-STON, 72 is 6-H, and 7z is 6-H.

In another embodiment, the dotted line is a double bond, K.: is -halo, Ag: is (F) -Ch-x

M

IN;

U is -OH, 21 is -OH, 2" is -H, 2z is -H, Ag is benzoxazolyl, where at least one of Kv or KE" is not -H.

In another embodiment, the dashed line is a double bond, K: is -halo, Ag: is (F) ex

M

IN;

U is -OH, and is -stOH, 72 6-H, 2z is -H, Ag is benzoxazolyl, where at least one of Kz or Kz is not -H.

In another embodiment, the dotted line is a double bond, K.: is -halo, Ag: is (F) -Ch-x

M

IN;

Antagonists of STI and their use

Y is -OH, 21 is -OH, 2" is -H, 2z is -H, Ag is benzothiazolyl, wherein at least one of Ka or K" is not -H.

In another embodiment, the dotted line is a double bond, K.: is -halo, Ag: is (F) -Ch-x

A-M

IN;

U is -OH, 71 is -CHnOH, 22 is -H, 23 is -H, Ar" is benzothiazolyl, where at least one of Kz or K" is not -H.

In another embodiment, the dotted line is a double bond, K.: is -halo, Ag: is (F) ex

M

IN;

Y is -OH, 21 is -OH, 2" is -H, 2z is -H, Ag is benzoimidazolyl, wherein at least one of Kz or K" is not -H.

In another embodiment, the dotted line is a double bond, K: is -halo, Ag: is (F)

Ex

M

IN;

In is -OH, and is -stTON, 72 6 -H, 23 is -H, Ag" is benzoimidazolyl, where at least one of Kz or Kz is not -

N.

In another embodiment, the dotted line is a double bond, K: is -halo, Ag: is (F)

Wow

A-M

IN;

U is -OH, 21 is -OH, 2" is -H, 2z is -H, Agg is phenyl, where 5 is 1.

In another embodiment, the dotted line is a double bond, K: is -halo, Ag: is (F)

ХХ

AM

IN;

U is -OH, 21 is -OH, 2" is -H, 2z is -H, Agg is phenyl, where 5 is 2.

In another embodiment, the dotted line is a double bond, K.: is -halo, Ag: is (F) x

A-M

IN;

U is -OH, 21 is -SNeOH, 2" is -H, 7z is -H, Ag: is phenyl, where 5 is 1.

In another embodiment, the dotted line is a double bond, K.: is -halo, Ag: is

47/Z

Antagonists of SARS and their use (F) ex

M

IN;

In 6-OH, 716-CHON, 7" is -H, 7z 6 -H, Ag" is phenyl, where 5 is 2.

In another embodiment, the dashed line is a double bond, K: is -halo, Ag: is (F)

Hh

A-M

IN;

U is -OH, 2 is OH, 72 6 is -H, 7z is -H, Ag: is phenyl, where 5 is 1, and Ba is -(Ci-Cv)alkyl, -halo, -C(halo)»z , -

OS(halo)z, -O87, -M(А?7)2, -502Н7, or -502C(halo)z.

In another embodiment, the dashed line is a double bond, K: is -halo, Ag: is (F) ex

M

IN;

U is -OH, A is -stone, 72 6 -H, 7z is -H, Ag" is phenyl, where 5 is 1, and Ka is -(C1-Cv)alkyl, -halo, -C(halo)" with, -

OS(halo)z, -O87, -M(А?7)2, -502Н7, or -502С(halo)z.

In another embodiment, the dashed line is a double bond, K: is -halo, Ag: is (F) x

A-M

IN;

U is -OH, 71 is hen, 72 is 6-H, 7z is -H, Age is phenyl, where 5 is 2, and each Ka is, independently, -(C1-Cv)alkyl, -halo, -C(halo )z, -ОС(halo)z, -ОВ7, -М(В7)2, -50287, or -5020(halo)z.

In another embodiment, the dotted line is a double bond, K: is -halo, Ag: is (F)

ХХ

AM

IN;

U is -OH, and is -CHOH, 72" is -H, 7z is -H, Ag" is phenyl, where 5 is 2, and each Kia is, independently, -(C1-

C)alkyl, -halo, -C(halo)z, -OS(halo)z, -ОВ?7, -М(ВН7)», -50287, or -502С(halo)z.

In another embodiment, O is

IF) wherein the compound of formula II is racemic.

In another embodiment, O is

IF) NO,, throne tone chllAA I chlAA ; where 95 6e There is more than 60 95 in the enantiomer.

In another embodiment, O is

Antagonists of TRPVI and their use no NO,, tron ton chl I chlAA ; where 95 6e is more than 70 95 in the enantiomer.

In another embodiment, O is no NO,, throne tone chl I chlAA; where 95 6e is more than 80 95 in the enantiomer.

In another embodiment, O is no NO,, tron ton chl I chl ; where 95 6e is more than 90 95 in the enantiomer.

In another embodiment, О is no NO, tron ton chl I chlAA; where 95 6e is more than 99 95 in the enantiomer.

In another embodiment, О is no NO, tron ton chl I chlAA; where 95 6e 5 of the enantiomer is greater than 60 95.

In another embodiment, O is no NO,, throne tone "ply I chl ; where 95 6e 5 of the enantiomer is greater than 70 95.

In another incarnation, O is no NO,, throne tone chlAA and chlAM; where 95 6e 5 of the enantiomer is greater than 80 95.

In another embodiment, O is no NO,, chllA and chl; where 95 6e 5 of the enantiomer is greater than 90 95.

In another embodiment, O is no NO,, chllA and chl; where 95 6e 5 of the enantiomer is greater than 99 95.

In another embodiment, O is a neutron

In another embodiment, o is

BUT,, tone

In another embodiment, the invention covers compounds of formula 1.4:

Antagonists of STI and their use

Ag B 1 m (S Dzit

M

Hu

X M 20

Ago (1.4) or a pharmaceutically acceptable salt thereof, where the dashed line, MU, X, Ag, Ag2, Bz, Ba, Vgo, and t are as defined above for the compound of formula 1.4, where

M) in 23 73 71 there is -OH, -5H, M(Hho)2, -"CH2-OH, -CH2-5H, or -"СНо-М(Hho)"; 72 is -H or -CH3; each 7z is, independently, -H or -CH"; and

In is -OH, -5H, or -M(HgO)".

In another embodiment, the invention encompasses compounds of formula 11.3:

Anya "V,

Also (S with

M

Hu

X M 20

Ago (1.3) or a pharmaceutically acceptable salt thereof, where the dashed line, MU, X, Ag, Ag»g, Bz, Ba, Vgo, and t are as defined above for the compound of formula 1.3, where

M) in 73 25 73 71 there is -ОН, -5Н, М(Вхо)2, -"СН2-ОН, -СН2-5Н, or -"СНо-М(Вхо)"; 72 is -H or -CH3; each 7z is, independently, -H or -CH"; and

In is -OH, -5H, or -M(HgO)".

In another embodiment, the invention encompasses compounds of formula 11.2:

Ag -B,

Also (S Dzit

M

Hu

X M 20

Ago (I.2) or a pharmaceutically acceptable salt thereof, where the dashed line, MU, X, Ag, Ag2, Bz, Ba, Vgo, and t are as defined above for the compound of formula 1.2, where

Antagonists of TRPVI and their use in 23 23 71 6-OH, -ZH, M(Voo)», -CH»-OH, -CH»-5H, or -СНо-М(Воо)»; 72 is -H or -CH3; each 7z is, independently, -H or -CH"; and

In is -OH, -5H, or -M(HgO)".

In another embodiment, the invention covers compounds of formula 11.1:

Ag -B,

Also (S Dzit

M

And in

X M 20

Ago (1) or its pharmaceutically acceptable salt, where the dashed line, MU, X, Ag, Ag2, Bz, Ba, Vgo, and t are as defined above for the compound of formula 1.1, where is y y 73 25 73 71 is - OH, -5H, M(Hho)2, -"CH2-OH, -CH2-5H, or -"CHno-M(Hho)"; 72 is -H or -CH3; each 7z is, independently, -H or -CH"; and

In is -OH, -5H, or -M(HgO)".

COMPOUNDS OF FORMULA PI

Preferred compounds of formula II are compounds of formula PI:

Аг -В жк 4 (C vit

M

And he

Kh M

Ago (I) or a pharmaceutically acceptable derivative thereof, where the dashed line, MM, X, Kz, Ba, etc. are as defined above for a compound of formula Y, where Ag is:

Inf) (Fin

ХХ

AM

IN;

You are -SI, -P, or -SEz; where Ag" is:

Antagonists of TBVI and their application

SEz Ag Vi

No 00 Ag in SEz , 9 ov , you? » Oz or

Z No B"5

Via is -H, -CI, -E, -Hg, -OCE»z, -(C1-Cv)alkyl, -502Ce3, -502(C1-Cv)alkyl, -OSH3, -OSNoCH», or -

ОСН(СН)», and mostly it is -СЕз, -ОСЕ:», -СИ, or -Е;

Via is -Н, -СИ, -Е, Ви, -СН3, -СНегСН3, -ОСН», -ОСЕ», or -ОСНСН:.; and each Kv and Co is, independently, -H, -Si, -Hg, -E, -CH3, -OSH»z, -OSNeCH»z, -SEz, -OSE:», iso-propyl, or tert-butyl .

In addition to high solubility in aqueous solution at pH 6.8 and pH 1.2, a very high therapeutic index and excellent pharmacokinetic parameters, as described for the formulas | and Her, the compounds of formula I are preferred because they are also highly bioavailable and are believed to be highly effective in animals for the treatment of pain. Bioavailability is a measure of how much of a compound from an administered dose reaches the systemic circulation after oral administration.

For example, compounds of formula I Kb and 31 have 68.9 95 and 70.7 95 bioavailability after oral administration, respectively. The compound of formula I 02 provides 78.7 95 of the maximum reversible ESA-induced hyperalgesia within 5 hours after administration, with an EUHO of 1.63 mg/kg.

Some implementations of the HER formula are presented below.

In one embodiment, the compound of formula PP is a pharmaceutically acceptable derivative of the compound of formula PI.

In another embodiment, the compound of formula I is a compound of formula PI, wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, the compound of formula I is a pharmaceutically acceptable salt of the compound of formula PP.

In another incarnation, Ah! are: and F) he ex

V. M

In the predominant embodiment, Ah! is:

BUT, he eh

V. M

In another embodiment, t is 2.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted with 1, 2 or Z independently selected Kα groups, and each bridge optionally contains -HO-CH- within (C2-Cv) bridge

In another embodiment, two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted by a Kz group, and each bridge optionally contains -HC-CH- within the (C2-Cv) bridge.

In another embodiment, two Kz groups together form a (C2-C3) bridge that is unsubstituted or substituted by a Kz group, and each bridge optionally contains -HC-CH- within the (C2-C3) bridge.

In another embodiment, two Kz groups together form a (C2-C3) bridge that is unsubstituted and each bridge does not necessarily contain -HC-CH- within the (C2-C3) bridge.

In another embodiment, the two Kz groups together form a (Cg) bridge, -HC-CH- bridge, or (C3) bridge, each of which is unsubstituted.

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted with 1, 2, or C independently selected Ka" groups, each bridge optionally containing -HC-CnH- within (C2-Cv) bridge, and the bridge connects position 2 and b of piperidine, 1,2,3,6- tetrahydropyridine or piperazine.

Antagonists of STI and their use

In another embodiment, the two Kz groups together form a (C2-Cv) bridge that is unsubstituted or substituted by a Kz group, each bridge optionally containing -HC-CH- within the (Cg2-Cv) bridge, and the bridge connects the positions 2 and 6 piperidine, 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-C3) bridge that is unsubstituted or substituted by a Kz group, each bridge optionally contains -HC-CH- within the (C2-C3) bridge, and the bridge connects the positions 2 and 6 piperidine, 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (C2-C3) bridge that is unsubstituted, each bridge optionally contains -HC-CH- within the (C2-C3) bridge, and the bridge connects the 2 and 6 positions of the piperidine , 1,2,3,6-tetrahydropyridine or piperazine.

In another embodiment, the two Kz groups together form a (Cg)bridge, -HC-CH- bridge, or (C3)bridge, each of which is unsubstituted, and the bridge connects the 2 and 6 positions of the piperidine, 1,2,3, 6-tetrahydropyridine or piperazine.

In another embodiment, two Ez groups together form a -СН2-М(Ва)-СНе»- bridge (В1),

HER

Go shk -bnN-M -A60H2-- bridge (B2), or --СсСН.-- MA СНо-- bridge (83); where Ka is chosen from -H, -(Ci-Cv)alkyl, -(C3-Cv)ucycloalkyl, -СНеа-С(О0)-ВНе, -(СНг)-С(0)-ОНсе, -(СНг)- C(0)-M(Be)"2, ""CHg)2-O-Be, ""CHg)"-5(0)2-M(Be)", or -"CHg)2-M(Ae )5(O0)2-Be;

B is selected from: (a) -H, -(C1-Cv)alkyl, -(C3-Cv)cycloalkyl, -(3-7-membered)heterocycle, -M(He)", /--M( No)-(Sz-

C)cycloalkyl, or -M(Pce)-(3-7--lene)heterocycle; or (p) -phenyl, -(5- or b-membered)heteroaryl, -M(He)-phenyl, or -M(He)-(5-10-membered)heteroaryl, each of which is unsubstituted or substituted by 1, 2 or With independently selected K»7 groups; and each Ks, independently, is selected from -H or -(C1-Sdalkyl;

In another embodiment, a B1, B2, or B3 bridge connects the 2 and b positions of piperidine, 1,2,3,6-tetrahydropyridine, or piperazine.

In another embodiment, two Ez groups form a bicyclo group of one of the following formulas,

Ag -V Ag V 1zuu 4 1 MU; 4th in or th-

M M

Ж -Н ХК Н ho Х МИ

Aha Aha

In another embodiment, t is 1.

In another embodiment, t is 0.

In another incarnation of X there is o.

In another embodiment, the dashed line means the presence of a connection and the absence of Ka.

In another embodiment, MU has M and Ka is absent.

In another embodiment, Ka is -H, -OH, -SI, or B.

In another embodiment, each K 0 is independently -H or -(C 1 -C 6 )alkyl.

In another embodiment, each Kogo is -N.

In another embodiment, each Ego is -(C 1 -C 1 )alkyl.

In another embodiment, Ag is chosen from

In her r

Co

You: Ah

Via4 SEz that, you», SEz or "E

From Nv Av.

In another incarnation of Ag: there is

Antagonists of SARS and their use no

HE with

AM

AND; wherein the compound of formula I is racemic.

In another incarnation Ag: there is shF) BUT,, (Fin 7 (Fin. di di

M M

AND; AND; lAA I chl ; where 95 6e There is more than 60 95 in the enantiomer.

In another incarnation of Ag: there is no NO,, (Fin 7 (Fin. di di

M M

AND; AND; lAA I chl ; where 95 6e is more than 70 95 in the enantiomer.

In another embodiment Ag: there is shF) NO,, (Fin and (Fin. di di

M M

AND; AND; lAd I chl ; where 95 6e is more than 80 95 in the enantiomer.

In another embodiment Ag: there is shF) NO,, (Fin and (Fin. di di

M M

AND; AND; chlAA I chl ; where 95 6e is more than 90 95 in the enantiomer.

In another incarnation of Ag: there is no NO,, (Fin and (Fin. and V

M AM

IN; IN; la I sllA ; where 95 6e is more than 99 95 in the enantiomer.

In another incarnation of Ag: there is

Antagonists of TRPVI and their application shF) NO,, (Fin and (Fin. and V

M AM

IN; IN; la I slAA ; where 95 6e 5 of the enantiomer is greater than 60 95.

In another incarnation Ag: there is shF) BUT,, (Fin 7 (Fin. di di

M M

AND; AND; lAA I chl ; where 95 6e 5 of the enantiomer is greater than 70 95.

In another incarnation of Ag: there is no NO,, (Fin 7 (Fin. di di

M M

AND; AND; lAA I chl ; where 95 6e 5 of the enantiomer is greater than 80 95.

In another embodiment Ag: there is shF) NO,, (Fin and (Fin. di di

M M

AND; AND; lAd I chl ; where 95 6e 5 of the enantiomer is greater than 90 95.

In another embodiment Ag: there is shF) NO,, (Fin and (Fin. di di

M M

AND; AND; chlAA I chl ; where 95 6e 5 of the enantiomer is greater than 99 95.

In another incarnation of Ag: there is no (Fin -kh

M

IN;

In another embodiment, Ag Ye

Antagonists of STI and their use

BUT,, "hoOton ez

AM

IN;

In another embodiment, the compound of formula PI is heno

M r

SI

M

A, 9

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

But

M

NN

IS

M

Huh

WITH

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on ke

Mr. Si

M

Huh

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their application

IS

M

KU

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

But

M

-

Si

M

CA

To her

SEZ

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use in medicine

M

-

IS

M

Huh

To her

SEZ

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their application

M

-

SI

M

CA

SEz

Kia or a pharmaceutically acceptable derivative thereof, wherein K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is b2/3

Antagonists of SARS and their use in medicine

Mr

IS

M

Hu "SEZ

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use, Ono, Ya

M

-

SI

M

CA

To her

Ka

CEz or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is b4/3

Antagonists of TBVI and their application, O

M

-IS

IS

M

AND.

To her

Ka

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TPRVI and their application are here

M

AND.

Ka

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

6b/3

Antagonists of TBVI and their use on Shk

M

-

IS

M

CA

Ka

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

6b7/3

Antagonists of TPRVI and their use on shk schi p

M

AND.

To her

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is b8/3

Antagonists of TBVI and their application

But

M

-

IS

M

Huh

To her

Kia

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on

M

NOT

SI

M

Huh

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use in medicine

M r

IS

M

CA.

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

M

WELL

Si

IS

M

CA

9

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application, O

M

NV

IS

IS

M

Ku 8

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

7 3/3

Antagonists of TBVI and their application

But

M

WELL

(at

IS

M

Huh

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TPRVI and their use in medicine

IS

IS

M

Huh

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

But,

M

Sun Sat

IS

M

CA

To her

SEZ

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on Ya

M

NN

IS

IS

M

CA

To her

SEZ

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

7T7IZ

Antagonists of TBVI and their application

Mo

M

- Si

IS

M

CA

SEz

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application, O

M

NV

IS

IS

M

KU

"SEz

Kia or a pharmaceutically acceptable derivative thereof, wherein K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on Ya

M

- Si

IS

M

CA

TO Y a

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on Ya

M r

IS

IS

M

Huh

To her

Ka

CE»z or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

But

M

NV si

IS

M

Huh

Ka

CEz or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use at night

IS

IS

M

Hu

Ka

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

Mo

M

-

SI

IS

M

CA,

To her

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on co

M

-

IS

IS

M

AND

To her

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application, O

M

- (Fi

IS

M

CA

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application, O

M r

IS

IS

M

AND.

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their use on Shk

M r

SI

F

M

CA

WITH

Kia or a pharmaceutically acceptable derivative thereof, wherein K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

Mo

M

-

IS

F

M

Huh

8

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on Ya

M

-

SI

F

M

CA

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

But

M

NV

IS

F

M

Life

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use, Ono, Ya

M

- Si

F

M

Huh

TO Y i: SEZ a or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of the PI formula is also Y

M

-

IS

F

M

CA

TO Х сх SEZ

Ka

Antagonists of TBRI and their use or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is he o

M

- Si

F

M

CA

SEZ

Kia or a pharmaceutically acceptable derivative thereof, wherein K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on

M

-

IS

F

M

CA

"SEz

Ka or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for a compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

M

-

SI

WITH

M

CA

To her

Kia

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their application

IS

F

M

Huh

To her

Ka

SEZ or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TBVI and their application

But,

M

-

SI

F

M

CA

Ka

CE" or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is heno

M

E Zh

WITH

M

CA

Ka

SEZ

Antagonists of TBRI and their use or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is that

M

-

SI

WITH

M

CA

To her

Ka

OSEz or a pharmaceutically acceptable derivative thereof, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of TPRVI and their use on no, shchi

IS

F

M

CA

To her

Ka

ОСЕ»z or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is heno

M si 4

WITH

M

HU a

ОСЕ»z or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the compound of formula PI is

Antagonists of SARS and their use on Ya

M

And

F

M

CA

Ka

ОСЕ»z or its pharmaceutically acceptable derivative, where K.4 is as defined for the compound of formula I.

In another embodiment, the invention covers compounds of formula PPI.4:

Ag -V zhk A (C vit

M

Zh N

Kh M

Ago (Ш.4) or a pharmaceutically acceptable salt thereof, where the dashed line, MU, X, Ag, Ag, Bz, Ba, and t are as defined above for the compound of formula 1.4, where Ag is: but

HE xx

M

IN,

You are -SI, -E, or -SEz; where Ag" is:

Antagonists of SARS and their use 7 of her ra

IS -

Ag Nig

Ag E EE o ZO" , , ; , or

Re E SEz RE E Ezb B 9,

Vig is -Н, -СИ, -Е, -Вг, -СН3, -СН»СН3, -ОСН», or -ОСНеСН»;

B" is -SI, E, or CH".

In another embodiment, the invention covers compounds of formula PPI.3:

Ag -V zhk A (C vit

M

N

-is

Ago (I.Z) or a pharmaceutically acceptable salt thereof, where the dashed line, UM, X, Ag, Ag, Bz, Ba, and t are as defined above for the compound of formula 1.3, where Ag is: but

ON

Eh

M

IN,

You are -SI,-P, or "SE"; where Ag" is: and her M" St

Aa Aa 5O , ; , 5-52 or

RE E 7 svz Re ES Bo

Not

Va is -СИ, -Е, -СН3, -СН»СН3, -ОСН», or -ОСНеСН»;

B" is -SI, E, or CH".

Illustrative compounds of formula III are shown below in Tables 1-30:

Table 1

Antagonists of STI and their use

On, 1. ON ex

And M

IN

IS

M. Va

Ag

RE E

(Sha) and its pharmaceutically acceptable derivatives, where: -"ОСнеСН3 -"ОСНеСН3 -"ОСНеСН3

Table 2 on te ON a

OM, oh, oh

M o kn

Whig

GE E

(full name) and its pharmaceutically acceptable derivatives, where:

Antagonists of TPRVI and their use - "OSNeSN" - "OSNeSN" - "OSNeSN"z

Table Z on t On re yo

You

WITH

M o pl

Ag copper (Shs) and its pharmaceutically acceptable derivatives, where: "ОСНеСН"

OSSNSN

-"OSNeSN" with

Table 4

Antagonists of TBVI and their application

He is

OHM

Va

IS

M on

Whig

Re E (pa) and its pharmaceutically acceptable derivatives, where: -"ОСнеСН3 -"ОСНеСН3 -"ОСНеСН»з

Table 5 on on xx - M

No

Eh

Mo en

Not

Re E (She) and its pharmaceutically acceptable derivatives, where:

Antagonists of TPRVI and their use - "OSNeSN" - "OSNeSN" - "OSNeSN"

Table 6 on on

Eh

YAM

In the village

M o pl

Whig

Re E (PO and its pharmaceutically acceptable derivatives, where: "ОСНеСН»

OSSNSN

- "OSNeSNz".

Table 7

Antagonists of SARS and their use on t On

Wow

M

IN,

IS

M on

Ag o) "SEZ (Sho) and its pharmaceutically acceptable derivatives, where: -СнНеСНз -СнНеСНз -СнНеСНз

Table 8 on, te ОН сх

M

In school

M. a

Ae o "SEZ (SHY) and its pharmaceutically acceptable derivatives, where: -"СНеСНз

Antagonists of TPRVI and their use -СнНеСНз -СнНеСНз

Table 9

ON, t on

Wow

M

VI Fr

M on

Ag (6) "Sez (II) and its pharmaceutically acceptable derivatives, where: -СнНеСНз -СнНеСНз -СнНеСНз

Table 10 on

ON

Ex

M

IN; 4

IS

Section (6) "SEZ (II) and its pharmaceutically acceptable derivatives, where:

Antagonists of TPRVI and their application -СнНеСНз «СНеСНз-СнНеСНз

Table 11 (Fin)

ON

Wow

YAM

In, east

M oin

Ве (c) "SEv (PC) and its pharmaceutically acceptable derivatives, where: - СнНеСНз - СнНеСНз - СнНеСНз

Table 12

Antagonists of TBVI and their use

IS

M

You

WITH

M on

Ag

IF) "SEZ (I) and its pharmaceutically acceptable derivatives, where: -СнНеСНз -СнНеСНз -СнНеСНз

In other embodiments, the Kg substituent of Tables 1-12 can be N.

Table 13 on troOton

Eh

M

IN,

IS

M on

M

RE E

(pc) and its pharmaceutically acceptable derivatives, where:

Antagonists of STI and their use

Table 14 on with. HE is E

MIND

VI xx

M on

SM x me (Sha) and its pharmaceutically acceptable derivatives, where:

Table 15 on, t ON ex

OHM

IN,

F

M on

M

RI

(Shaw) and its pharmaceutically acceptable derivatives, where:

Table 16

Antagonists of SARS and their use on on ek

A-M

You

IS

M on

M. H

Goethe

(Shr) and its pharmaceutically acceptable derivatives, where:

Table 17 on on az

M

No

Oh

M on

M k

He E (Sha) and its pharmaceutically acceptable derivatives, where:

Table 18

Antagonists of TPRVI and their application (v/n -kh

KM

You are 3

M o ek

OM k

He E (He and its pharmaceutically acceptable derivatives, where:

Table 19 on te On -x

OHM

IN,

IS

M o ek 5O all? (P5) and its pharmaceutically acceptable derivatives, where:

Table 20

Antagonists of TPRVI and their application on t ON -th topics

V, xx

M on

What is it? (PO and its pharmaceutically acceptable derivatives, where:

Table 21 on t, ON ee

M

Va village

M on o) in? (Shy) and its pharmaceutically acceptable derivatives, where:

Table 22

Antagonists of SARS and their use on on -h

OHM

IN,

IS

M about 5O all (PM) and its pharmaceutically acceptable derivatives, where:

Table 23 on on

Me

M

IN

Eh

Mo en vast 2 (PM) and its pharmaceutically acceptable derivatives, where:

Table 24

Antagonists of TBVI and their application

He eh

YAM

Woo

WITH

M on Tue? (Px) and its pharmaceutically acceptable derivatives, where:

Table 25 on p, ON -x -M

IN,

IS

M. I

M 5

Ne (Shu) and its pharmaceutically acceptable derivatives, where: 111111bpolukai////// | 77777771 AS Я111111111вССсСсСсСсСшС

Antagonists of STI and their use

Table 26 on t ON xx

OHM

IN

TUH

M in

M7 8

Not (AI) and its pharmaceutically acceptable derivatives, where: 111111Compounds////// | 77777777 Av Ї1111111111вССсСсСсСсСшС

Table 27 on ОН, t, ОН on

Hey and

M dm i k

F xx

МХ СНз about kn about KE

And m" 78

M" Z / Ve Kv Ka or (Shaa) (Shab) and its pharmaceutically acceptable derivatives, where:

Antagonists of SARS and their use 11111 bpolukai//////// | 7 In HER 777777 vv HER Sun

Antagonists of SARS and their use 11111 bpolukai///////// | 7 In HER 7777777 vv HER SUN

Antagonists of SARS and their use 11111 bpolukai///////// | 7 In HER 7777777 vv HER SUN

Antagonists of SARS and their use 11111 Compounds//////// | 7 In HER 7777777 vv HER SUN

Antagonists of SARS and their use 11111 bpoluka./////// | 7 In HER 777777 vv HER Sun

Antagonists of SARS and their use 11111 bpolukai//////// | 7 In HER 7777777 vv HER SUN

Antagonists of SARS and their use 11111 bpolukai//////// | 7 In HER 7777777 vv HER SUN

Antagonists of SARS and their use 11111 bpolukai/////// | 7 In HER 7777777 vv HER SUN

Antagonists of SARS and their use 111111 bpoluka.й//////// | 7 V | 777777 V | vsSsS

EAM102 aa or ar

EAM103 aa or ar

EAM104 aa or ar

EAM105 aa or ar

EAM106 aa or ar - "OSNeSNz".

EAM107 aa or ar

EAM108 aa or ar

EAM109 aa or ar

EAM'1110 aa or ar

EAM111 aa or ar

EAM'112 aa or ar

EAM'113 aa or ar

EAM'114 aa or ar

EAM'1115 aa or ar

EAM'1116 aa or ar

EAM117 aa or ar -OSNeCHz

EAM'1118 aa or ar

EAM'1119 aa or ar

EAM120 aa or ar

EAM121 aa or ar

Table 28 on on x

M

You

IS

M o k n scha

On (AI) and its pharmaceutically acceptable derivatives, where: 111111bpolukai////// | 77777777 Av Ї1111111111вССсСсСсСсСшС

Table 29

Antagonists of TPRVI and their use (in/n ee

M

And xx

M. I

M7 75

Not (Shss) and its pharmaceutically acceptable derivatives, where: 111111bpolukai////// | 77777777 Av Ї1111111111вССсСсСсСсСшС

Table 30 on on

TX

A-M

VI village

M in

M7 78

But (pa) and its pharmaceutically acceptable derivatives, where: 111111bpolukai////// | 77777777 Av Ї1111111111вССсСсСсСсСшС

Antagonists of STI and their use

Table 31

ON, t, ON

Tech

M

VI

IS

M o en and SEZ

Ve (Sheye) and its pharmaceutically acceptable derivatives, where: -"ОСнеСН3 -"ОСНеСН3 -"ОСНеСН3

Table 32

Antagonists of STI and their use

HE, that HE a

OM thank you

M o chn / SEZ

Ag (EU and its pharmaceutically acceptable derivatives, where: -"ОСнеСН3 -"ОСНеСН3 -"ОСНеСН3

Table 33 he still he sch

M

You

WITH

M on / "SEz

Vig (99) and its pharmaceutically acceptable derivatives, where:

Antagonists of STI and their use

Sunday

Sunday

- "OSNeSN:z

Table 34 on on x

MIND

You

IS

M o nn / SEZ

Ag (SHYN) and its pharmaceutically acceptable derivatives, where: -"ОСнеСН3 -"ОСНеСН3 -"ОСНеСН3

Table 35

Antagonists of SARS and their use on on ek

KM

VI xx

M on and SEZ

No (AI) and its pharmaceutically acceptable derivatives, where: - "ОСНеСНз

Sunday

- "OSNeSNz

Table 36 on on east -M

Wu about

M o en / "SEz

Via (in and its pharmaceutically acceptable derivatives, where:

Antagonists of STI and their use

DEFINITION

As used herein, the terms used above have the following meanings: "-(C 1 -C 10 )alkyl" means a straight or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Characteristic unbranched -(C1-Cio)alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl , and -n-decyl. Typical branched -(C1-Cio)alkyls are -iso-propyl, -tert-butyl, -iso-butyl, -tert-butyl, -io-pentyl, -neo-pentyl, 1-methylbutyl, 2-methylbutyl, C- methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,

3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, З- methylhexyl, 4-methylhexyl,

B-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3 -dimethylheptyl. "-(C1-C1)alkyl" means a straight or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Characteristic unbranched -(C1-C8)alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Characteristic branched -(C:1-C) alkyls are -iso-propyl, -ter-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbutyl. "-(C1-C8)haloalkyl" means a straight or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms as defined above for -(C1-C8)alkyl substituted with 1, 2 or C of independently selected halogens. -(C1-C8)hydroxyalkyl" means a straight or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms as defined above for -(C1-C8)alkyl substituted with 1, 2 or 3 hydroxy groups. "-(C 1 -C 4 )alkyl" means a straight or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms. Typical unbranched -(C 1 -C 4 )alkyl are -methyl, -ethyl, -n-propyl, and -i- butyl. Typical unbranched -(C 1 -C 4 )alkyls are -iso-propyl, -t-butyl, -iso-butyl, and -tert-butyl. "-(C 1 -C 10 )dalkenyl" means a straight or branched acyclic hydrocarbon having has from 2 to 10 carbon atoms and includes at least one carbon-carbon double bond.

Typical unbranched or branched -(C2-Si)alkenyls are -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1- butenyl, -2-methyl-2-butenyl, -2,3- dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3- heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like. "-(Cg-Cv)alkenyl" means a straight or branched non-cyclic hydrocarbon having from 2 to b carbon atoms and including at least one carbon-carbon double bond.

Characteristic unbranched or branched -(C2-C)alkenyls are -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1- butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl and the like. "-(C 2 -C 2 )haloalkenyl" means a straight or branched acyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond as defined for -(C 2 -C 2 )alkenyl, which is substituted 1, 2 or C with independently selected halogens. "-(C2-C8)hydroxyalkenyl" means a straight or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond,

Antagonists of TRPVI and their use as defined for -(С2-Св)alkenyl, which is substituted by 1, 2 or 3 hydroxy groups. "-(C2-Cio)dalquinyl" means a straight or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon triple bond.

Characteristic unbranched or branched -(C2-Cio)dalkynyls are -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4- pentinyl, -1-hexynyl, -2- hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -b-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1- noninyl, -2-noninyl, -8-noninyl, -1-decynyl, -2-decynyl, -9-decynyl and the like. "-(C 2 -C 2 )alkynyl" means a straight or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond.

Characteristic unbranched or branched -(C2-C)alkynyl are -acetylenyl, -propynyl, -1- butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4- pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like. "-(C2-C8)haloalkynyl" means a straight or branched acyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond as defined for -(C2-C8)alkynyl, which is substituted 1, 2, or C with independently selected halogens. "-(C 2 -C 2 )hydroxyalkynyl" means a straight or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond, as determined for -(С2-Св)alkynyl, which is substituted by 1, 2 or 3 hydroxy groups. "-(C1-C8)Alkoxy" means a straight or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 2 carbon atoms. Characteristic unbranched or branched -(Ci-Cv)alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, methoxymethyl, 2-methoxyethyl, 5-methoxypentyl, 3-ethoxybutyl and the like. "-(C 1 -C 1 )Alkoxy(C 2 -C 2 )Alkyl" means a straight or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms, as defined above for -(C 1 -C 2 )Alkoxy, which is substituted by a -(C 2 -C 1 )alkyl group. "-(C 1 -C 2 ) alkoxy(C 2 -C 2 )alkenyl" means a straight or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms, as defined above for the -(C1-Cv)alkyl group, which is a substituted -(C2-Cv)alkenyl group. "-(C1-Cv)Alkoxy(C2-Cv)alkynyl" means a straight or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms, which is a substituted - (C2-Cv)alkynyl group. " -(C 1 -C )Alkoxy(C 3 -C )ucycloalkyl" means a straight or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms, as defined above for a -(C 1 -C )alkyl group, which is a substituted -(C3-C8)ucycloalkyl group. "-(C3-C10)ucycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Typical (C3-C10)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl and -diclodecyl. "-(C3-C8)ucycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Typical (C3-C8)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -dichlorooctyl. "-(C5-Cv)ucycloalkenyl" 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. Typical -(C5-Cv)cycloalkenyls are -cyclopentenyl, -cyclopentadienyl , -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, and the like. "-(3-7--leney)heterocycle" or "-(3-7 --lene)heterocycle" means a 3-7-lene monocyclic heterocyclic ring that is either saturated, unsaturated non-aromatic, or aromatic. A 3-membered heterocycle may contain up to 1 heteroatom, a 4-membered heterocycle may contain up to 2 heteroatoms, A 5-membered heterocycle may contain up to 4 heteroatoms, a b-membered heterocycle may contain up to 4 heteroatoms, and a 7-membered heterocycle may contain up to 5 heteroatoms. Each heteroatom is independently selected from nitrogen, which may be quaternized; oxygen and sulfur, including sulfoxide and sulfone. -(3-7--lene)heterocycle can be attached via nitrogen or carbon. Typical -(3-7--lene)heterocycles are pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxyranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like. "-(5- to 10-membered) heteroaryl" means an aromatic heterocyclic ring with 5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon atom of one or both rings is replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur, or at least two carbon atoms of one or both rings are replaced by a hetero atom selected from nitrogen, oxygen and

Antagonists of SARS and their use of sulfur. In one embodiment, one of the -(5-10-membered)heteroaryl rings contains at least one carbon atom. In another embodiment, both -(5-10-membered)heteroaryl rings contain at least one carbon atom. Typical (5-10-lene)heteroaryls are pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl , thiadiazolyl, triazinyl, cinolinyl, phthalazinyl and quinazolinyl. "-(5- or b-membered)heteroaryl" means a 5- or b-membered monocyclic aromatic heterocyclic ring wherein at least one carbon atom is replaced by a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of -( 5- or β-membered)heteroaryl rings contain at least one carbon atom. Typical -(5- or β-membered)heteroaryls are 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, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl and thiophenyl "-CHNa(halogen)" means a methyl group where one of the hydrogens of the methyl group is replaced by a halogen.

Characteristic -СНа(halogen) groups are -СНеЕ, -СНеСИ, -СНеВг and -СНИ. "-CH(halogen)g" means a methyl group where two hydrogens of the methyl group are replaced by halogens.

Characteristic -CH(halogen)" groups are -СНЕ", -СНСЙ2, -СНВИ:, СНВгГСИ, СНИ and "СНИ". "-C(halogen)z" means a methyl group where each of the hydrogens of the methyl group is replaced by a halogen.

Characteristic -C(halogen)z groups are -Сез, -СОіз, -СВіз and -С1з. "-Halogen" or "-halo" means -E, -CI, -Hg or -I. "(С2о-Св)bridge" as used herein means a hydrocarbon containing from 2 to 6 carbon atoms connected to two piperidine, 1,2,3,6-tetrahydropyridine or piperazine atoms of the compounds of formulas I, II and /or HER forming a condensed bicyclic system. The positions of piperidine, 1,2,3,6- tetrahydropyridine or piperazine are indicated as follows:

Auu m Agedia Agov zi r zri zri zr ? Tue C 75 Kaya C 75 Kaya

X m7? m7?

X m7 go, hmm oo; come on

Aha Aha Aha (0) (1) (p

For example, the compounds of the invention may include a (C2-Cv) bridge connecting positions 2 and 6 of piperidine, 1,2,3,6-tetrahydropyridine or piperazine (two Kz groups can together form (Cg-

Saint) town). Examples of compounds where two Kz groups can together form a (С2-Св) bridge are compounds containing the following cyclic systems: 8-aza-bicycloЇ3.2.1|octane; 8-azabicycloi|3.2.1|oct-3-ene; 3,8- diazabicycloY3.2. Tsoktan; 8-azabicycloi3.2.1|oct-6-ene; 8-azabicyclo/3.2.1|octa-3,6-diene; 3,8-diazabicyclo/3.2. Zoct-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/3.3.1|nona-3,b-diene; 9-azabicycloY3.3.1|nona-3,7-diene; 3,9-diazabicyclo|3.3.1|nonane; 3,9-diazabicycloI3.3.1|non-b-ene; 3,9-diazabicyclo|3.3.1|non-7-ene; 10-aza-bicyclo|4.3.1|decane; 10-azabicycloi|4.3.1|dec-8-ene; 8,10-diazabicyclo(|4.3.1|decane; 8,10-diazabicyclo|4.3.1|dec-3-ene; 8,10-diazabicyclo|4.3.1|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(10)-diene; b8-azabicyclo|4.3.1| deca-3,6(10)-diene; 8-azabicyclo(|4.3.1|deca-4,6(10)-diene;. 11-aza-bicyclo|5.3.1)undecane; 11-azabicyclo(|5.3 .PChundec-8-ene; 9,11-diazabicyclo|5.3.1)undecane; 12-aza-bicyclo|6.3.1|dodecane; 12-azabicyclo|b.3.1|dodec-9-ene; and 10,12- diazabicycloi|6b.3.1|dodecane.

In connection with the Agg group

IZ in r (Kakh t

Mo XX ze E when E is -MH(C:i-Cv)alkyl, it is clear that the dashed line in the above-mentioned Ag: group is absent, i.e., the Ag2 group is

Antagonists of STI and their use (On) chi

AND

IN.

In MH(C 4-Cv)alkyl

Uz)c where M, M2, Uz, Via, si are as defined above for the compound of formula I. When E is -0, -5, -6(C01-C8)alkyl, -C(C1-C8)alkenyl , or -M-ОВго, it is clear that the dotted line in the above-mentioned Ag" group is present, that is, the Ag group is (Nau Her Zo -(Vid) and that in 2 Mo also ( o and Z also SN(С 1-Св )alkyl

Uz)s MUz)s Uz)s (Aa and Zo

Huh? or.

AND

Uh what ( CH(С 1-Св)alkenyl and MOV go

У3)с МУз)с, respectively, where У, У2, Уз, Ва, Вго, сии are as defined above for the compound of formula I.

The phrase "pyridyl group" means in A (Av, A ( et ( Re phiM my 2)n "fi o xx z ! o , A . B, abod; where Ki, P", and n are as defined above for the compound of formula I, and where the numbers indicate the position of each atom in the cycle.

The phrase "pyrazinyl group" means (Ng)r

M de Ki, 2, ir are as defined above for the compound of formula Y.

The phrase "pyrimidinyl group" means (Vodr, (Nory, with M her

M or --

You are B; where Ki, H", and p are as defined above for the compound of formula I.

The phrase "pyridazinyl group" means

Antagonists of STI and their use

M (Ne)r, (Nor

M? o R m td 7) Nor | or ! - ? and "fi

IN; IN; IN; where Ki, H", and p are as defined above for the compound of formula I.

The phrase "benzoimidazolyl group" means

H

MU SM B2o

Be 8 Vo where Kv, Na", and Kgo are as defined above for the compound of formula I.

The phrase "benzothiazolyl group" means aa a

Be 8 Vo where Kv and Ke are as defined above for the compound of formula I.

The phrase "benzoxazolyl group" means chldlAg o

Be 8 Vo where Kv and Ke are as defined above for the compound of formula I.

The phrase phenyl group means

I x (Kchadv de Kia and 5 as defined for the compound of formula I.

The phrase "tetrahydropyridyl" means chllA zy 5 - (8 2 lo Z)t

The numbers denote the position of each atom of the tetrahydropyridyl ring.

The term "animal" includes, but is not limited to, cows, monkeys, chimpanzees, baboons, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, guinea pigs, and humans.

The phrase "pharmaceutically acceptable derivative" as used herein includes any pharmaceutically acceptable salt, solvate, radiolabeled derivative, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric isomer and/or tautomer,

Antagonists of SARS and their use, for example, compounds of formula I of the invention. In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, solvate, radiolabeled derivative, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer and/or tautomer, for example, compounds of formula I of the invention. In another embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, for example, of a compound of formula I of the invention.

The phrase "pharmaceutically acceptable salt" as used herein refers to any pharmaceutically acceptable salt obtainable from a compound of formula I, including a salt formed using an acidic and basic functional group, such as a nitrogen-containing group, of a compound of formula I. Illustrative salts are , but not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrophosphate, isonicotinate, lactate, salicylate, hydrocitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate , gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (ie, 1,1'-methylene-bis(2-hydroxy-3-naphthoate)). The term "pharmaceutically acceptable salt" also refers to a salt obtained from a compound of formula I having an acidic functional group, such as a carboxyl functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium and lithium; hydroxides of alkaline earth metals, 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; tributylamine; pyridine; M-methyl, M-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxy-lower alkylamines), such as mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris-(hydroxymethyl)methylamine, M ,M-di-lower alkyl-M-(hydroxy lower alkyl)amines, such as M,M-dimethyl-M-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; M-methyl-O-glucamine; and amino acids such as arginine, lysine and the like. A person skilled in the art should understand that, for example, acid addition salts of compounds of formula I can be prepared by reacting the compounds with an acceptable acid using various known methods.

Compounds of Formula I include all solvates of a compound of Formula I. "Solvates" are known in the art and are intended to mean the 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 solvent molecule to compound molecule ratio of formula I are 2:1, 1:1 or 1:2, respectively. This physical combination involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline substance. Thus, "solvate" as used herein encompasses both liquid-phase and isolated solvates. A compound of the invention may exist in solvate form with a pharmaceutically acceptable solvent such as water, methanol, ethanol, etc., and it is intended that the invention includes both solvated and unsolvated forms of the compound of formula 1. "Hydrate" refers to a separate subgroup of solvates, i.e., where the solvent molecule is water, hydrates are included within the limits of solvates of the invention. The preparation of solvates is known in the art. For example, M. Saiga et al., , U. РНаптасеци. оси., 93(3):601-611 (2004), describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar methods for the preparation of solvates, hemisolves, hydrates, etc. are described by E. S. Topaeg ei ai., AAR5 RNapt. 5si. Tesn., 5(1), article 12 (2004), and A.G. Vipopyat ei aI., Snpet. Sottyp., 603-604 (2001). Typically, without limitation, method includes dissolving the compound of formula I in the desired amount of the desired solvent (organic, water or their mixture) at temperatures in from about 20 "C to about 25 "C, cooling the solution at a rate sufficient for the formation of crystals and isolating the crystals by known methods, for example, filtration. Analytical techniques, such as infrared spectroscopy, can be used to show the presence of solvent in the solvate crystal.

The invention described herein also encompasses all prodrug forms of the compounds of the invention. "Prodrug forms" are known in the art and, while not necessarily exhibiting any pharmaceutical activity per se, are considered to be compounds with any covalently bound carrier(s) that release the active compound ip mimo. In general, such prodrug forms will be a functional derivative of a compound of formula !, ! and/or Ш, which are easily converted by passing, for example, metabolized, into the necessary compound of the formula I!, I and/or PS. Conventional methods for the selection and preparation of suitable derivative prodrug forms are described in, for example,

N. Vypadaaga eea., Eizemieg (1985); "Abomination apa Eplute Tagdeiipo, Ragi A," K. Uaaeg ei ai. edv., My. 112 in Meipod5 in Ep7utoiYodu, Asadetis Rge55 (1985); Vypadaaga, "Oezidp apa Arriisainop oi Rgoagidv,"

SNarieg 5 (year 113-191) in A Tehirook oi Ogid Oezidp apa Oemeiortepi, R. Ktodzdaaga-I agzep apa N.

Vypadaaga ed., Naglosa Asadetis Rybiizpegt5 (1991); Vypddaagoa eyi ai., Adm. Ota Oveiimegu Nem5. 8:11-38 (1992); Vypadaaga eyi ai., U. Rnaptaseshi. si. 77:285 (1988); and KaKeua ei aI., Spet. Riapt. howl 32:692 (1984).

In addition, one or more atoms of hydrogen, carbon or other atoms of the compound of the formula | may

Antagonists of SARS and their use be replaced by an isotope of hydrogen, carbon or another atom. Compounds of the formula | include all radiolabeled forms of a compound of formula I. Such "radiolabeled", "radiolabeled form" and similar compounds of formula I, each of which is encompassed by the invention, are useful as research and/or diagnostic tools in the study of pharmacokinetics of metabolism and study of binding. Examples of isotopes that can be included in the compound of formula I of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2Н, ЗН, 790, 140, 15М, 7180, 170, ЗР, З2рР, 355, 8E, and z60, respectively. Radiolabeled compounds of the invention can be prepared by methods known in the art.

For example, tritiated compounds of formula I can be obtained by introducing tritium into a certain compound of formula I, for example, by catalytic dehalogenation using tritium.

This method may include the interaction of a suitably halogen-substituted precursor compound of the formula

And with gaseous tritium in the presence of a suitable catalyst, for example, Pa/cS, in the presence or absence of a base. Other suitable methods of obtaining tritiated compounds can be found in

Hey, Isotorez in pe RPuzisai! apa Vioteais! Zsiepsev5, Moi. 1, Gabreiva Sotroypavz (Ragi A), Sparieg 6 (1987). "b-labeled compounds can be obtained using starting materials that have "b carbon.

A compound of formula I may contain one or more asymmetric centers and thus may exist as enantiomers, diastereomers, and other stereoisomeric forms. The compounds of the formula include all such possible forms, as well as their racemic and resolved forms or any mixtures thereof.

When a compound of formula I contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise indicated, it is intended to include all "geometric isomers," eg, both E and 2 geometric isomers. All "tautomers, for example keto-enol, amide-imidine, lactam-lactim, enamine-imine, amine-imine and enamine-eneimine tautomers, are also encompassed by this invention.

As used herein, the terms "stereoisomer", "stereoisomeric form", etc. are general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. Included are enantiomers and isomers of compounds with more than one choral center that not mirror images of each other ("diastereomers").

The term "chiral center" refers to a carbon atom to which four different groups are attached.

The term "enantiomer" or "enantiomeric" refers to a molecule that does not superimpose its mirror image and is therefore optically active, where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarization of light in the opposite direction.

The term "racemic" refers to a mixture of equivalent parts of enantiomers that are optically active.

The term "separation" refers to separating, or concentrating, or reducing the amount of one of the two enantiomeric forms of a molecule.

Optical isomers of the compound of the formula | can be obtained by known methods, such as chiral chromatography or the formation of diastereomeric salts with an optically active acid or base.

The optical purity can be determined by the values of the enantiomeric excess (95 eV), which is expressed by the formula: drev - | major enantiomer (mol) - minor enantiomer (mol) pe major enantiomer (mol) -i- minor enantiomer (mol) x 10076

The phrase "effective amount" when used in relation to a compound of formula | means an amount effective to: (a) treat or prevent a Condition; or (b) inhibit the function of SARS in a cell.

The phrase "effective amount" when used in connection with another therapeutic agent means an amount that provides a therapeutic effect of the therapeutic agent.

The phrase "therapeutic index" describes the interval between the dose that is effective and the dose that causes side effects.

When the first group is "substituted by one or more" second groups, one or more hydrogen atoms of the first group are replaced by a corresponding number of second groups. When the number of second groups is two or more, the second groups may be the same or different. In one embodiment, the number of second groups is one or two. In another embodiment, one second group is present.

The term "Meon" means methanol, that is, methyl alcohol.

The term "EN" means ethanol, that is, ethyl alcohol.

The term "t-VION" means tert-butyl alcohol, that is, 2-methylpropan-2-ol.

The term "THF" means tetrahydrofuran.

The term "DMF" means M,M-dimethylformamide.

The term "DHM" means methylene chloride, that is, dichloromethane.

The term "OCE" means dichloroethane.

Antagonists of STI and their use

The term "OME" means 1,2-dimethoxyethane, that is, dim ethyl ether of ethylene glycol.

The term "E(Ac)" means ethyl acetate.

The term "MNAOH" means ammonium hydroxide.

The term "TEA" stands for triethylamine.

The term "MesCM" means acetonitrile.

The term "Mann" means sodium hydride.

The term "AcSON" means acetic acid.

The term "OIEA" means M,M-diisopropylethylamine or M-ethyldiisopropylamine, ie, M-ethyl-M-isopropylpropan-2-amine.

The term "DMSO" means dimethylsulfoxide, that is, methylsulfinylmethane.

The term "SAT" means sulfur (diethylamino)trifluoride.

The term "INMO5" means lithium hexamethyldisilazide.

The term "You and" means butyllithium.

The term "ORPP" means 1,3-bisidiphenylphosphino)propane.

The term "BOC" means tert-butyloxycarbonyl:

O not r y

There is

Sz

The term "TV5" means tert-butyldimethylsilyl:

Y" SN

Cohen

AND.

The term "T5OH" means p-toluenesulfonic acid or toluene-4-sulfonic acid.

The term "TM5Hg" means trimethylsilyl bromide or (CH3)3Hg.

The term "TM5Cl3" means trimethylsilyl chloride or (CH3)3Cl3.

The term "CKD" means inflammatory bowel disease.

The term "IBS" means irritable bowel syndrome.

The term "ALLO" means amyotrophic lateral sclerosis.

The phrase "treatment", "therapy" and the like includes ameliorating or stopping a Condition or a symptom thereof.

In one embodiment, the treatment includes inhibition, eg, reducing the total number of episodes of the Condition or its symptoms.

The phrase "prophylaxis" and the like includes the reversal of the occurrence of the Condition or its symptom.

METHODS OF OBTAINING COMPOUNDS OF FORMULA I

Compounds of formula I can be prepared using well-known organic syntheses or using the illustrative methods shown in the schemes below.

Methods of preparation of compounds of formula I, where MU is C and the dashed line is absent

Compounds of formula I, where MU is C and the dashed line is absent, i.e., "Piperidine Compounds," can be prepared using conventional organic syntheses or using the illustrative methods shown in the schemes below.

Methods of obtaining Piperidine Compounds, where X is o and Ka is -OH or -E

Compounds of formula I, where X is O and K is -OH, can be obtained according to the illustrative method shown below in scheme 1.1:

Scheme 1.1

Antagonists of TPRVI and their use (Von tm on is) A, in (Vo)pu, in (Rz)t tu | and t-butyllithium/-787С A

M

MIN; tГгФ (c) МН 97 МН n , more

Piperidine compound Za

Ago 2a 1 (under m 5 on

V. in (Norm -y we ( Z)t and t-butyllithium/-787С A

M ak tgF on 1 ni

And Ago

Piperidine compound 35 -t-- (Vo 5 on (P2)r. m A, its Z dv dm t-butyllithium/-787С t y V. slbutllvstv s, |. i i tgF o MH 2s Ag

Piperidine compound Zs

M

(Von M 5 on (P2)r, V.

M two

M

Vu 2 t-butyllithium/-787C A 1 y tgF o MN

Ag 2a PShperidine compound Za where Ag», Ni, RH», B», n, t, and p are as defined for the compound of the formula | and I. is a halogen.

To a solution of ha-4y in the presence of tert-butyllithium (1.7M in heptane, 6.45 ml, 11.12 mmol) in THF (20 ml) at -78"C, add compound Her in anhydrous THF (10 ml) dropwise . The reaction mixture is stirred at -78 "C for about 3h and quenched with aqueous MNACI at about 0 "C, and then the organic and aqueous layers are separated. The aqueous layer is extracted with THF, the organic parts are combined, and dried (Mag2504). The resulting solution is concentrated under reduced pressure to obtain a residue.

The residue is chromatographed using column chromatography on silica gel, eluting with ethyl acetate/hexane (elution gradient 30:70 - 70:30) to give the Piperidine Compound, which is O and

Wa is -ON (Za-a).

Antagonists of STI and their use

Compounds of the formula g2a-4j are commercially available or can be obtained by methods known from the literature.

Compound 1 can be obtained by the reaction of 4 with isocyanate as shown below in Scheme 1.2:

Scheme 1.2 (c) "1 o zt

LV 00) AtuMsO AH t 2) 4AM NSI b chn

N

4 1.7 where Kz and t are as defined above and K is Ag".

Compound 4 (20 mmol) in chloroform is added to a solution of isocyanate of the formula K-MSO in chloroform (30 ml) at approximately 25 °C. The resulting reaction mixture is stirred for approximately 3 g at approximately 25 °C, then concentrated under reduced pressure to obtain a residue.

The residue is suspended in THF (50 ml) and 4M NOI (50 ml) is added to the resulting solution. The reaction mixture is left to stir for about 12 hours. The reaction mixture was then poured into water (200 mL) and the pH was adjusted to 10 or greater using aqueous potassium carbonate. The resulting solution is extracted with ethyl acetate and the ethyl acetate layers are combined, dried (Moa5O»4) and concentrated under reduced pressure to give a residue that can be chromatographed using flash chromatography on a silica gel column eluted with ethyl acetate/hexane (elution gradient 30:70 - 70: 30) obtaining compound 1.

Isocyanates of the formula Ago-MSO are commercially available or can be prepared by amine reaction

Ag2Mng with phosgene according to known methods (See, for example, N. EsKep apa V. Eozvivg,

Apdem/. Spent Yippee Ed. Epao!i., 26, 894 (1987); N. Eskep, Seg. OMep. OE Z 440 141; Spent Abvig. 106, 42944 (1987); and I. Sopiagsa ei aiI., 5upipeziv, 553-576 (1996). For example, the amine AggMNeg can react with triphosgene as shown below.

Triphosgene

SM

K-MB

Typically, a solution of triphosgene (about 0.3 equivalents or 0.3 eq;) in DCM (about 0.3 M) is slowly added to a stirred solution of the amine (about 1.0 eq) in DCM (about 0.3 M) at about 25 "C. The reaction mixture is then stirred at about 25 "C for about min. and the temperature is raised to approximately 70 "C. After stirring at 70 "C for 3 h, the reaction mixture is cooled to 25 "C, filtered, and the filtrate is concentrated to give isocyanate.

Cyclic acetals of formula 4 are commercially available or can be obtained by methods known from the literature.

Piperidine compounds, where X is o and Ka is -OH, can also be obtained by the illustrative method shown below in schemes 1.3 and 1.4:

Scheme 1.3

Antagonists of SARS and their use - (vok 9); x on (No) su R -|- | What is t-butyllithium / -787C 1 --(Vz) (Vz)t 4 ro - yati PE Auth

M V, tГгФ them

I MR for ba (VodvnYa

M Chu (No. ON

Ka Shk o v

Y t-butyllithium / -78C 1 --(B3) 5 yah Am - | | ЯИ Я- -- in vol

IN; tГгФ M

And MR

26 br

M

(No)rd--- I" (Vodvum 5-X on di 5 nya | NYA o B,

In ADM t-butyllithium / -78 C To Hv)t i -- t 5 5 5 5 3 3-- tHgF M

AND

MR

M

(Water /y m 5 on (Nor y | | NYA o -U«(B3)t v M t-butyllithium / -78 С m ! " y tГgF MR 24 va de Ki, V», Vz, p, t, and p are as defined above, Y is a halogen, and MR is a nitrogen-protecting group (see, for example, T.MU. Sgeepe ei ai., Rgoiesiime Sgoir5 ip Ogdapis Zupipeziz 494-653 (Za ed. 1999).

To a solution of t-Via (1.7M in heptane, 18.4 ml, 31.3 mmol) or n-Via (1.6M in heptane, 19.5 ml, 31.3 mmol) in ether (30 ml) a solution of compounds of formula 2a-4a (31.3 mmol) in ether (20 ml) is added dropwise at -78 "C in a nitrogen atmosphere. The resulting solution is stirred at -78 "C for about 1 hour. A compound of formula 5 (25.0 mmol) dissolved in ether (20 ml) at -78 °C is added dropwise to the resulting solution, and the resulting mixture is left to stir at approximately -50 °C for 3 h. The reaction mixture is then quenched with aqueous MNACI at 0 °C. The reaction mixture is extracted with ether. The organics are combined, dried (Ma»5O4), and concentrated under reduced pressure to give a residue which can be chromatographed using flash chromatography on a silica gel column eluting with ethyl acetate/hexane (elution gradient 30/70 - 70/30) to give the compound formulas ba-0y. The nitrogen protecting group is then removed to give a compound of formula 7a-j, respectively. The compound of the formula 7a-4 then reacts with the isocyanate of the formula К-МСО to give the compound of the formula За-и, as shown below in scheme 1.4:

Scheme 1.4

Antagonists of SARS and their use (cf

ON AB-MSO these

В -- --- - --- Ж -- Shperidynova 1 dv) Compound Za i

N things (Nav / M chu

ON ABMSO these

In -- -- 2--- --- Shperidynova 1 st. Compound 30

She

N

75

M

(New in; xx

ON Ab-MSO.

В -- ж ( жщ763А3 5 53- Shperidynova ! od Vodt Spoluka Zs

She

N

7s

M

(In Zh. on AgMSO

YAZ-----77 Piperidinova

B. - -(B5)t Compound for

her

N

7a where Ag», Ni, RN», B», n, t, and p are as defined above.

A solution of the compound of the formula 7a-i (1 mmol) in DCM (1 ml) is added dropwise to a solution of Ag-MSO isocyanate (1 mmol) in DCM (1 ml) at approximately 25 °C. The resulting mixture is left to stir at 25 °C g and concentrated under reduced pressure to obtain a residue that can be chromatographed using a silica gel column eluted with ethyl acetate/hexane (elution gradient 10/90 - 70/30) to obtain the compound of the formula Za-a.

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: o

For her

N

8

Compounds of formula 8 are commercially available or can be obtained by methods known from the literature.

Antagonists of STI and their use

Any nitrogen protecting group known in the art can be used to protect the nitrogen atom of a compound of formula 8. Suitable protecting groups are described in T.M. Sgeepe ei ai., Rgoiesiime Stoimrz ip Ogdapis

Zupipeziz, 494-653 (Za ey. 1999). Isocyanates of the formula Ago-MSO are commercially available or can be prepared as described above.

Methods of obtaining Piperidine Compounds, where X is 5 and Ka is -OH

A Piperidine Compound, where X is 5 and K is -OH, can be prepared by a method similar to that described above in Scheme 1.1 to obtain Piperidine Compounds, where X is O and Ka is -OH (Za-a), except that the compound of the formula 9, shown below, (6)

By

University of M

Ago 9 where Kz and t are as defined above is used instead of compound 1.

The compound of formula 9 can be obtained by a method similar to that described above in Scheme 1.2, obtaining 1, except that the isothiocyanate of the formula Ag-MOSZ5 is used instead of the isocyanate Ag-MSO.

Isothiocyanates are commercially available or can be prepared by reacting an amine of formula Аг2гМН" with thiophosgene as shown in the scheme below (see, for example, Tei. Iei., 41(37), 7207-7209 (2000);

Oh9. Roger Rgosed., Ipi., 23(6), 729-734 (1991); 9. Neiegosusie Speth., 28(4), 1091-1097 (1991); 9.

Ninotipe Snet., 41(3), 303-310 (1988); and Tay. I ey, 42(32), 5414-5416 (2001).

Atgo-MNo - s, Ato-MS5

Alternatively, isothiocyanates of the formula Ag2-MO5 can be obtained by the reaction of the amine of the formula

AggMNeg with carbon disulfide in the presence of triethylamine (TEA) in THF, followed by reaction with hydrogen peroxide and hydrochloric acid in water as shown in the scheme below (see, for example, 4. Ogu. Speth., 62(13), 4539-4540 ( 1997)). 1. TEA, TNE, C", 2. NO, 3. NOI, water

AB-MN - 20 years. And Ms8

Piperidine Compound, where X is 5 and K is -OH, can be obtained by a method similar to that described above in Schemes 1.3 and 1.4, obtaining Piperidine Compounds, where X is c and Ka is -OH (Za-a) except that the isothiocyanate the formula Ag»-MO5 is used instead of the isocyanate of the formula Ag»e-

MSO.

Methods of obtaining Piperidine Compounds, where X is M-CM and Ka is -OH

The Piperidine Compound, where X is M-CM and Ka is -OH, can be obtained as shown below in Scheme 1.5:

Scheme 1.5

An ON

Ag ON to Nvt

That ARMN, A|-«Av)t

J. M

MO --M (c);

J

MO--M MN

Aha

PShperidynova

Spo luka de Ag", Agg, Vz Y t are as defined above.

The compound of the formula 10 reacts with the amine of the formula Ago-MH»e in an aprotic organic solvent,

TPRVI antagonists and their uses such as diethyl ether, di-n-propyl ether, THF, DCM or toluene at a temperature of from about 25 "C to about the boiling point of the solvent for from about 0.5 g to about 24 g to give a Piperidine Compound where X is M-CM and Ka 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 an amine of formula Ag2-MH" e is heated at a temperature of from about 70" to about 80 "C. In another embodiment, the reaction mixture of di-n-propyl ether, a compound of formula 10 and an amine of the formula Ag-MHn2 is heated at a temperature of about 75" for about 12 g.

The compound of formula 10 can be prepared as shown below in scheme 1.6:

Scheme 1.6

Yes, he is

SM

-

X TU (K3)t 7a- o o ---- - where Ag: is as defined above for Piperidine Compounds.

The compound of formula 7a-a reacts with diphenylcyanocarbonimidate 35 (commercially available from Zidt-

Aiagis, 5. Gotsi5, MO) in an aprotic solvent, such as diethyl ether, di-n-propyl ether,

THF, DCM, or toluene to give a compound of formula 10. In one embodiment, the aprotic solvent is

DCM and the reaction mixture of the compound of formula 7a-a and diphenylcyanocarbonimidate 35 are left to react at approximately 25 °C. In another embodiment, the aprotic solvent is toluene and the reaction mixture of the compound of formula 7a-a and diphenylcyanocarbonimidate 35 is left to react at approximately 110 °C.

The compound of formula 7a-a and diphenylcyanocarbonimidate 35 are typically reacted for from about 0.5 g to about 24 g. Typically, the compound of formula 10 is used without further purification.

Compounds of formula 7a-4 can be prepared as described above in section 5.5.1.1.

Methods of obtaining Piperidine Compounds, where X is M-OH and Ka is -OH

A Piperidine Compound, where X is M-OH and Ka is -"OH, can be obtained by a method similar to that described above in Scheme 1.1, obtaining Piperidine Compounds, where X is O and Ka is -OH (Za-a), except that a compound of formula 11, shown below, (b)

WITH

Mr

RO-M MN

IN

11 where Kz and t are as defined above, K is Ag, and P is an oxygen/hydroxy protecting group, is used in place of compound 1 followed by removal of the oxygen/hydroxy protecting group.

The compound of formula 11 can be prepared as shown below in scheme 1.7:

Scheme 1.7

Antagonists of SARS and their use 9 o 9)

Protective group --(8

F (АЯz)ut mMnOon - SU, - 5 - -k -|«Az)t

M Ethanol 80 C M M still in Zh zovno-kechn oR-0-M7 "MH in He) in 12 13 In de Ez and t are as defined above, K is Ag", and OR is an oxygen/hydroxy protecting group .

A compound of formula 12 (about 0.3 mmol) is reacted with hydroxylamine (50 wt.9o in water, about 5.8 mmol) in about 1.5 mL of ethanol with stirring at a temperature of about 80°C for about 2 h. The mixture is then concentrated under reduced pressure to give a compound of formula 13. The hydroxyl group of a compound of formula 13 is then protected using an oxygen/hydroxy protecting group to give a compound of formula 11. An oxygen/hydroxy protecting group is known in the art and can be used to protect the oxygen atom in a compound of formula 13. Suitable oxygen/hydroxy protecting groups groups are described in T.M. sgepe eii ai., Rgoiesiime Stoyrz5 ip Ogdapis Z5upipeviv 17-200 (per e. 1999).In one embodiment, the compound of formula 11 is also processed using column chromatography or recrystallization.

The compound of formula 12 can be prepared as shown below in Scheme 1.8:

Scheme 1.68 (6) (e); (From eoch SN Zach - 3 6 sh|- : :«.-A»

M TEA M vn nyu-v7 sk

Kk Kk 9 12 where Kz and t are as defined above and K is Ag".

A solution of the compound of formula 9 (about 0.6 mmol) prepared as described above in DCM is reacted with iodomethane (about 0.9 mmol) in about 3 mL of tetrahydrofuran with stirring at about 25 C for about 12 g. Excess iodomethane is removed from the mixture at reduced pressure. A solution of triethylamine (about 1.74 mmol) in about 2.5 mL of ethyl acetate is added to the mixture and the mixture is allowed to stir for about 2 g. The mixture is then concentrated under reduced pressure to give the compound of formula 12, which can be further worked up if desired. In one embodiment, the compound of formula 12 is further processed using column chromatography or recrystallized.

Methods of obtaining Piperidine Compounds, where X is M-OV'o and Ka is -OH

A Piperidine Compound, where X is M-OH:o and Ka is -OH, can be obtained by a method similar to that described above in Scheme 1.1 to obtain Piperidine Compounds, where X is O and Ka is -OH (Za-a), except that that the compound of formula 14, shown below,

Antagonists of STI and their use (c);

WITH

M

UNTIL

Vi0O-M MN

AND

14 where Kz, Nio and t are as defined above and K is Ag", is used instead of compound 1.

The compound of formula 14 can be obtained by the reaction of the compound of formula 13, obtained as described above in Scheme 1.7, with I-(C1-Ca)alkyl, where H is -I, -Bg, -CI, or -E, in the presence of sodium hydride in DMF at approximately 25 "C. In one of the embodiments, H. is -I or -Vg.

Methods of obtaining Piperidine Compounds, where Ka is a group other than -OH

Piperidine Compounds, where Ka is -halo, -OSEz, -"SiSv)alkyl, -CHnOH, -SNeSi, -SNeHg, -SNy, -SNYe, -CH(halo)g, -SEz, -OVio, -5A1o, - "СООН, -СООВ:о, -С(О)Аио, -С(О)Н, -ОС(О)Во, -ОС(О)МНВ о, -

MHC(co)Vz, -502Nio, -SOM(Viz)2" or -MO" can be obtained from Piperidine Compounds, where Ka is -OH.

Piperidine Compounds, where Ka is -E, can be obtained by the reaction of Piperidine Compounds, where Ka is -

OH, with fluorine reagents such as CA5BT, Deoxo-Fluorine, ZE, HE, KE, С5E, reagent

Yakovenko, Ishikawa's reagent, according to the method described in M. ZsPiIo55eg eyi ai., Hemaneadgop 52(24):8257-8262 (1996).

Piperidine Compounds, where Ka is -SI, can be obtained by the reaction of Piperidine Compounds, where Ka is -

ON, with OSI" or RSI5 according to the method described in .). Ateg. Spent boss. 120(4):673-679 (1998) or from SNISOSI according to the method described in Thea!. And hey. 41(47):9037-9042 (2000).

Piperidine Compounds, where Ka is -Vg, can be obtained by the reaction of Piperidine Compounds, where Ka is -

OH, with pyridine and 5OVHg" according to the method described in .). Ophthalmology of Spetiwig 627(2):179-88 (2001) or by the reaction of Piperidine Compound, where Ka is -OH, with pyridine and PRPz/Vgg2 according to the method described in /). Ateg. Spent boss. 112 (9):3607-14 (1990).

Piperidine Compounds, where Ka is -I, can be obtained by the reaction of Piperidine Compounds, where Ka is -

OH, with NO in acetic anhydride according to the method described in ). Ateg. Spent boss. 87(3):539-542 (1965).

Piperidine Compounds, where Ka is -CH3, can be obtained by the reaction of Piperidine Compounds, where Ka is -

ON, with RSI5 and SNITiSiz according to the method described in Apdeul"apaie Spetiee, 92(11), 933-4 (1980).

Piperidine Compounds, where Ka is -(C1-Cv)alkyl, can be obtained by reacting a Piperidine Compound, where Ka is -OH, with p-toluenesulfonic acid in toluene and then with n-butyllithium and X-(C1-Cv)alkyl, where X is a halogen, according to the method described in SGapez U. Vagpei, Yei Ai, U. Oh Spet., 54(20) 4795-4800 (1989) with subsequent hydrogenation of the product according to the method described in Tpotaz E. O'Atrga ei ai, U. Ogu. Spet., 54(23) 5632-5 (1989) as described below. dm I) p-I(HON/Toluol, kip. 4 ra/n, ay on OШЩШШЩ8О ТЛ ЗБ. zl in 2) n-ВШ/THF, VХ " a

Her and her

MR MR MR

Piperidine Compounds, where Ka is -CH2OH, can be obtained by the reaction of a Piperidine Compound, where

Va is -SOON, with GAIN"a according to methods known in this field. Piperidine Compounds, where Ka is -

CHgOH can be obtained by the reaction of the Piperidine Compound, where K4 is -C(O)H, with MavBna according to techniques known in this field.

Piperidine Compounds where Ka is -COOH can be prepared by reacting Piperidine Compounds where Ka is -CM with KOH according to techniques known in the art.

Piperidine Compounds, where Ka is -CM, can be obtained by the reaction of Piperidine Compounds, where Ka is -

ON, with KSM and BOSI" according to the method described in AgptuapsvkKia KpitisnezkKia 2pigpai. 30(9):723-727 (1977).

Piperidine Compounds, where Ka is -C(O)H, can be obtained by the reaction of Piperidine Compounds, where Ka

Antagonists of TRPVI and their use are -SM, with di-iso-butylaluminum hydride (OIVAIH-N) according to methods known in this field.

Piperidine Compounds, where Ka is -OSEz, can be obtained by the reaction of Piperidine Compounds, where Ka is -OH, with C52; methyl iodide; and bromosuccinimide and pyridine/HE in DCM according to the method described in

Spetis! Sottipisayop5 (Satgidde) 3:309-310 (1997) or VyPeiyyp oi yipe Spetisai! 5osiveiyu oi darap, 73(2):471-484 (2000).

Piperidine Compounds, where Ka is -CHNOCl, can be obtained by the reaction of the Piperidine Compound, where Ka is -CH2OH, obtained as described above, with PCi5 according to the method described in .). Ateg. Spent 5os., 120(4):673-679 (1998).

Piperidine Compounds, where Ka is -CHNaHg, can be obtained by the reaction of the Piperidine Compound, where Ka is -CH2OH, obtained as described above, with 5OVg2 according to the method described in .). Ogdapotei

Spet., 627(2):179-188 (2001) or with RRAZ/Vi" according to the method described in ). Ateg. Spent 50os., 112(9):3607-3614 (1990).

Piperidine Compounds, where Ka is -CHnoE, can be obtained by the reaction of Piperidine Compounds, where Ka is -CHnOH, obtained as described above, with Tech. OA5T according to the method described in M. ZspiIoz5eg eyii a!., Teiganedgop 52(24):8257-8262 (1996) and Ogdapis I eTsegv. 3(17):2713-2715 (2001).

Piperidine Compounds, where Ka is -CH2O, can be obtained by reacting the Piperidine Compound, where Ka is -CH»OH, obtained as described above, with PP3/I2 according to the method described in Ogdapis Rgose55

Vezeagsi apa Oemeiortenpi 6(2):190-191 (2002).

Piperidine Compounds, where Ka is -CH(halo)", can be obtained by the reaction of the Piperidine Compound, where

Ba is -C(O)H prepared as described above from (EzC50O2)20 and then from Ma(halo)" to C3" according to the method described in bZupipevz5 12:1076-1078 (1986).

Piperidine Compounds, where Ka is -СНЕ", can also be obtained by the reaction of Piperidine Compounds, where Ka is -С(О)Н, obtained as described above, with 2 eq. OA5T according to the method described in M. zZepioz5eg ei a)., Temapeagop 52(24):8257-8262 (1996) and Ogdapis I enegv. 3(17):2713-2715 (2001).

Piperidine Compounds, where Ka is -SEz, can be obtained by the reaction of Piperidine Compounds, where Ka is -

C(O)H, obtained as described above, with copper iodide (I) and sodium trifluoroacetate according to the method described in patent 5 4,866,197, Vashtap.

Piperidine Compounds, where Ka is -OH:o, can be prepared by reacting a Piperidine Compound, where Ka is -OH, obtained as described above, with K:o-X, where X is halogen, in the presence of Mahon according to the procedure described in Epigoreap oh Medisippa! Spetiwig 24(4):391-396 (1989).

Piperidine Compounds, where Ka is -5Biz, can be obtained by the reaction of Piperidine Compounds, where Ka is -OH, obtained as described above, with Kis-ZN according to the method described in patent O5 4,409,229,

Op ei a., or mahtpai oi Medisipa! Spetiwig 24(1):74-79 (1981).

Piperidine Compounds, where Ka. is -СООН:о, can be obtained by esterification of Piperidinova

Compounds where Ka is -COOH, obtained as described above, with Kio-OH. Methods of esterification of carboxylic acids are known in this field.

Piperidine Compounds, where Ka is -OC(O)NVio, can be obtained by the reaction of the Piperidine Compound, where

Ba is -OH, obtained as described above, from KioC(O)CI according to the method described in Eigoreap doitai! oh Medisippa! Spetiwig 24(4):391-396 (1989). Acid chlorides, KiC(O)CI, can be prepared from the corresponding carboxylic acid, KisCOOH, using techniques known in the art.

Piperidine Compounds where Ka is -MNO(O)Viz can be prepared by reacting a Piperidine Compound where Ka is -OH with KioSM in the presence of Nag5O" and then with CaSbOz in DCM as described in Viogdapis apa

Meadisipa! Spetivigh I eygz 10(17):2001-2014 (2000).

Piperidine Compounds, where Ka is -OC(O)MH», can be obtained by reacting a Piperidine Compound, where Ka is -OH, with SiSSO in DCM at 0 "C with stirring for about 2 g and then adding to the resulting mixture CaSbOz in methanol -water and stirring the resulting mixture for about 4 g at 0"C and about 2 g at about 25 "C according to the method described in

Spgiziorneg" R. Noi/tez evy ai, U. Ogu. Spet., 54(1):98-108 (1989).

Piperidine Compounds, where Ka is -OS(O)MNV o, can be obtained by reacting a Piperidine Compound, where Ka is -OH, with an isocyanate of the formula K:oMSO in boiling THF for about 24 g at about 25 "C according to the procedure described in Apage Naoi et al., U. Med. Snet., 29(3):369-375 (1986).

Piperidine Compounds where Ka is -502Nio, -MO", -SM, -SOV:o, -SOOV:o, and COM(Kiz)g2 can be prepared by the illustrative methods described below.

A compound of formula 15 is reacted with a compound of formula 16ba-i in the presence of a base according to the method described in Washtpai oi Neiegosusie Spetivigu, 23(1):73-75 (1986) or Ogdapis Spetivigu apa Rgosedigev Ipiegpaiopa! 28(4):478-480 (1996) yielding the compound of formula 17a-y as described below in Scheme 1.9:

Scheme 1.9

Antagonists of TRPVI and their use (Vo), (Vo)p "CHI si si he 7 yo G | ts base Wu

M voVI SY --Щ -)«Вv)t

MR In her 1st MR 17a (North (ov U

M I base -- 5 -Щ- - шя В, -Й. in A-M (Nz)t 15 - 1 TI

In MR

166 175 (pom (ode, m V

M basis ---I V dy cha -)«Av)t 15 nya 1 st

IN

16s MR 17s

M

(Von o in /

Its basis is in battle od SIM 0553557 Z -)kVv)t in its 16a MR 17a where En, V», V», p, t, and p are as defined above; ХУ is -502Н1о, -МО", -СМ, -СОВ:о, -СООНВ:о, or

SOMI(VI3)2; and MR is a nitrogen protecting group.

The nitrogen protecting group is then removed from the compound of formula 17a-y to obtain the compound of formula 18a-y. Any nitrogen protecting group known in the art can be used to protect the nitrogen in the compound of formula 15.

To obtain piperidine compounds of the formula Y, where X is c and Ka is -5О2Н:о, -МО», -СМ, -СОВо, -

СООВ:о, or СОМ(Киз)г, the compound of the formula 18а-а is then reacted with the isocyanate of the formula К-МСО according to a procedure similar to that described above in Scheme 1.4 and described below in Scheme 1.10:

Scheme 1.10

Antagonists of TPRVI and their use (Water in the volume of 5 meals

Kk

Ki 1 -- in

ЛЮ) about the Navy -- M 2 ve them

H o7 pl

AND

18a IB (Vadvnia (Voden tm m MD y x X y g 1 -(B3)t K-МСО --zkv- y (Kz)t

And M them

H o7eKmN 1865 c

M--k (Vodv Me, (Koru p hu x H

Kk

Kk 1 - "b - (Vu) VMO ---- Kvt

And M her re

N o OTMN 18s R m (Vodyani (Wadi Kui

M 1 y x U e t -i (v 1 --(Vz)t - В-МСО --z:x- y ( З)t

And M and

N o7ekN 18a Kk de Ki, R», V», n, t, and r are as defined above; X is -502B:o, -MO", -SOV o, or -SOM(B z)"; and

K is Ag".

The compound of the formula 18a-4 reacts with the compound of the formula K-МСО according to a method similar to that described above in scheme 1.4.

For obtaining Piperidine Compounds, where X is 5 and Ka is -"502Н1о, -МО", -СМ, -СОВ:о, -СООВо, or

COM(B13)g, the compound of the formula 18а-y reacts with the isothiocyanate of the formula К-МОС5 according to a method similar to that described above in section 5.5.1.2.

To obtain Piperidine Compounds, where X is M-SM and Ka is -502Vcho, -MO», -SM, -SOOV o, -SOOV o, or СОМ(Киз)г, the compound of the formula 18a2-4 reacts with diphenylcyanocarbonimidate 35 and then amine of the formula К-МНе according to a method similar to that described above in section 5.5.1.3.

For the preparation of Piperidine Compounds, where X is M-OH and Ka is -502H10o, -MO», -SM, -СОВо, -СООВо, or СОМ(К:з)г2, Piperidine Compound, where X is 5 and Ka are -5028Vch10, -MO», -SM, -SOV:o, -SOOV o, and

COM(B13)2 reacts with methyl iodide according to a method similar to that described above in scheme 1.8, giving the compound of formula 19,

Antagonists of STI and their use

Ag M

WITH,

H

NUS-55 tm

IN

19 where Ag, Bz, t, and U are as defined above and EK is Ag".

The compound of formula 19 is then reacted with hydroxylamine in ethanol according to a procedure similar to that described above in Scheme 1.8 to give Piperidine Compounds, where X is M-OH and Ka is -502H:10, -MO", -СМ, -СОВ'o, -СООВ o, or SOM(K z)".

For the preparation of Piperidine Compounds, where X is M-OVto and Ka is -502Н10, -МО", -СМ, -СОВо, -

СООВ:о, or СОМ(Киз)г2, Piperidine Compound, where X is MON and Ka is -502Н:0о, -MO", -СМ, -СОВо, -

СООВ о, and СОМ(Е з)2, reacts with X-(C1-C1)alkyl, where X is -1, -Bg, -CI, or -E in the presence of triethylamine according to a method similar to that described above in section 5.5. 1.6.

The compound of formula 15 is commercially available or can be obtained by methods known from the literature.

Compounds of formula 1ba-y, where M is -502Nio, can be obtained by the reaction of compounds of formula 16ba-y, where

In is a halogen, with К1о5О2Н according to the method described in U. Ogu. Spent 67(13):4387-4391 (2002) or

International publication Me M/O 02/48098.

Compounds of formula 16ba-y, where U is -CM, can be obtained by reacting compounds of formula 1ba-a, where M is halogen, with potassium cyanide according to the method described in Ragtaso 45(9):945-953 (1990).

Compounds of the formula 1ba-y, where XM is -"СООВ:о, can be obtained by the reaction of compounds of the formula 16ba-y, where

U is a halogen, with (a) potassium cyanide, (b) water, and (c) K:ioOH and 5O2CI, according to the method described in

ERaptaso 45(9):945-953 (1990).

Compounds of the formula 16a-4j, where M is -СОВ:о, can be obtained by the reaction of the compound of the formula 16ba-j, where U is a halogen, with KioС(О)Н and trimethylsilylcyanide according to the method described in the International publication Me UUO 01/81333.

Compounds of the formula 1ba-y, where M is -COM(Vis)g, can be obtained by reacting the compounds of the formula 1ba-a, where U is a halogen, with (a) potassium cyanide, (b) water, and (c) MH(Kz) 2 and 5O»SI, according to the method described in

ERaptaso 45(9):945-953 (1990).

Compounds of formula 16ba-y, where M is -MO" can be obtained by the reaction of compounds of formula 2a-y, where X is -

CHz, with MamMmNo in liquid MHz and then with СНаСН».СНаз-ОМО»: at a temperature less than -33 С, obtaining a nitronate, which then reacts in an acidic environment, with the formation of a compound of the formula 16ba-4, where M is -MO». according to the method described in N. Retseg eyi ai., ). At. Set. boss. 91(7):1856-1857 (1969) and as described in Scheme 1.11 below, where Ki, B", n and p are as defined above.

Scheme 1.11 in A Vo)r. in ( beer, ( where ( "I am ( "p

AM - M M M

СНз СНз СНз СНз 2а 2 2с 24 1) MamMnН,», / liquid. MNu ») SUSNISNO-OMO», « -337C - z) H in (R») in Vo)r. ( write, LE ( such, ( "their v

AM AM -M M is "7 is B;

MO about MO MO MO about

Antagonists of STI and their use

Compounds of the formula 1ba-d, where M is -halo, are commercially available or can be obtained by methods known from the literature.

Some Piperidine Compounds can have one or more asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The Piperidine Compound may be in the form of an optical isomer or a diastereomer. Accordingly, the invention covers Piperidine Compounds and their use as described herein in the form of their optical isomers, diastereomers and mixtures thereof, including racemic mixtures. Optical isomers of Piperidine Compounds can be obtained by known techniques, such as chiral chromatography or the formation of diastereomeric salts with an optically active acid or base.

In addition, one or more hydrogen, carbon or other atoms of the Piperidine Compound may be replaced by an isotope of hydrogen, carbon or another atom. Such compounds, which are covered by the invention, are useful as research and diagnostic tools for the study of the pharmacokinetics of metabolism and the study of binding.

Methods of introducing E: groups on Ag, when Kg is present

Halide conversion, GI. into the vinyl group via the Suzuki condensation reaction is shown in Scheme 1.12 below, where Ki, AN, Na. and p are as defined above, Y as defined as -halo, and P is a nitrogen protecting group known in the art. While this example demonstrates the transformation when Y is in the 5-position of the pyridyl ring 20, the transformation can also be performed when G is in other positions of the aryl ring. In addition, the same technique can be used when Ag is a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.

Scheme 1.12 y l ra ok (vo same aa (vo

Vu RYAOYURRE'SI,, V. Z (Va) tu 00 OME, os, 14 h At i i

MR MR

2

To a degassed DMF solution of compound 20 (1.6 mmol) in a 100 ml round-bottom flask, add

С5Е (3.2 mmol), di-n-butylvinyl ester of boric acid (0.388 ml, 1.76 mmol) and diphenylphosphinoferrocenepalladium dichloride (OR(ОРПРЕ)2Сиі», 0.128 mmol). The resulting mixture is stirred at 100 "С 14 g, then cooled to a temperature of approximately 25 "С and diluted with 100 ml of ethyl acetate, which is washed with brine (3 x 50 ml). The organic layer is removed, dried and concentrated under reduced pressure. Column chromatography on silica gel gave the product, 21.

Other techniques for introducing a vinyl group are shown in diagrams 1.13Za and 1.13r. In scheme 1.1Za, the first stage involves the oxidation of benzyl alcohol to an aldehyde. After that, olefination takes place

Wittig giving the vinyl group. Again, while this example demonstrates a transformation where the parent benzyl alcohol is in the 5-position of the pyridyl ring, a similar transformation can be performed in other positions. In addition, the same technique can be used when Ag is a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.

Scheme 1.1Za

Antagonists of TRPVI and their application snoOn vl 0 (Vo)p ( ok p» MpO» | In:

M SNSI, M that A;

And I

22 23 sno 7 (No) RRIZSNUVg (Vo)p p (t-VoОЖ he:

AM Benzol/ITG F | AM

And I

23 24

In a 500 mL round-bottom flask, manganese oxide (0.50 mol) was added to a solution of 22 (50.0 mmol) in anhydrous SNCl (150 mL). The resulting mixture is stirred at a temperature of approximately 25 °C to 48 g, then the reaction mixture is filtered through Celite and concentrated. The resulting mixture is chromatographed using column chromatography on silica gel, eluting with a gradient of ethyl acetate (0 95-

U5)u/hexanes, obtaining aldehyde 23.

Potassium t-butoxide (3.07 g) is added in portions to a stirred suspension of methyltriphenylphosphonium bromide (10.0 g) in toluene (200 ml) cooled to 0 "С, obtaining a yellow suspension. After 1 g, the reaction mixture is cooled to -20 "С , and dropwise add 23 (22.72 mmol) dissolved in tetrahydrofuran (b ml) to obtain a clear suspension. The reaction mixture is heated to 0 °C and stirred for another 1 g. 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 product is chromatographed using column chromatography on silica gel, eluting with a gradient of ethyl acetate (0 95-10 9o)/hexanes, obtaining product 24.

In Scheme 1.130, the first step involves the reduction of the benzyl ketone to the hydroxyl. Then a dehydration reaction gives a vinyl group. Again, while this example demonstrates the transformation when the parent benzyl ketone is in the 5-position of the pyridyl ring, a similar transformation can be performed in other positions. In addition, the same technique can be used when Ag; is an opiridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.

Scheme 1.136

Antagonists of SARS and their use (e) no (Ka)dp (Ko)p

LJ Mavn, Kh. Zh

M

DYB- EY

You V

And I

23 23a no TO (ge) (vod o-y-o (y

H

X kh on | and straight

M

-

EE" in; o

AND

AND

23 and 24

To a well-stirred suspension of 23 (665 g, 3.5 mol) in methanol (3.5 L) at 0 "C, sodium borohydride (66.21 g, 1.75 mol) is added in portions at such a rate that the temperature of the reaction mixture does not exceeds 5 "C. After the addition is complete, the reaction mixture is heated to a temperature of approximately 25"C and stirred for another 1 g. The reaction mixture is concentrated under reduced pressure and the residue is mixed with 2 L of diethyl ether and 2 L of 1M HCl. The layers are separated and the aqueous layer is extracted twice with diethyl ether (250 ml for each extraction.) The organics were combined, dried (M9505), and concentrated under reduced pressure to give 23a.

To a solution of 2Za (311 g, 1.62 mol) in chlorobenzene (3 l) p-toluenesulfonic acid (431 g, 2.5 mol) is added. The reaction mixture is heated to reflux, approximately 140 "C, and simultaneously removed water. After the reaction is complete, the mixture is concentrated under reduced pressure to about 500 mL, diluted with 2 L of water, and extracted three times with ethyl acetate (1 L for each extraction). The organics are combined, dried (Mg50O»4), and concentrated under reduced pressure under moderate heating, yielding a residue. The residue is added to 500 mL of methylene chloride and applied to the top of a column packed with 2 kg of silica, eluting with a gradient of 0 95 - 10 95 ethyl acetate in hexane, yielding 24.

Vinyl groups are highly reactive because they are a synthetic fragment that can be further modified. It is well known in organic chemistry that hydrolysis of an olefin gives a benzylic hydroxyl group, hydroboration gives a primary hydroxyl group, ozonolysis gives an aldehyde or ketone, oxidation gives a carboxylic acid, an olefin exchange reaction lengthens the chain and dihydroxylation gives a 1,2-diol. Many techniques for additional olefin functionalization are available to the average organic synthesis expert. Once modified, the group can be subjected to additional transformations. Scheme 1.14 shows how vinyl group 21 is subjected to asymmetric dihydroxylation.

Scheme 1.14

Antagonists of SARS and their use / on

NOn. (Nad /m (Nadam x VA Art-tikh a U V,

TO v)t Two

And M

MR MR

2 2za / on (Vodan /y (Vo) M

In AO-tikh B 5 in,

V. t-VyOnN/NYO Wu two two) her M

MR PR

2 250 / on 5 (Vo) /p (Water M x Va O503, MMO ZA v,

B. NoO/Acetone and

Dt dz) her M

MR MR

2 25s

In a 100 ml round-bottomed flask, AYU-tych a (0.5 g) is added to a mixture of t-butanol and water (2 ml/2 ml) and the mixture is stirred at a temperature of about 25 °C for 0.5 g and then cooled to 0 "with.

This solution was quickly poured into another ice-cooled flask containing compound 21 (0.41 mmol). The mixture is intensively stirred in an ice bath with 96 g and then diluted with ethyl acetate (50 ml) and 2 ml of saturated Mag252O5. The ethyl acetate layer is separated, dried and concentrated under reduced pressure on a rotary evaporator to give 25a. Another enantiomer can be synthesized by the reaction of 21 with АЯ-thіch B, obtaining 25Yur. As shown in Scheme 1.14, the stereochemistry (K or 5) of the resulting diol depends on the chirality of the used ligand in the AYU of those described in

ZPagriev5 sei a!., U. Oga. Spent 57:2768-2771 (1992). AO-thich consists of the following components: potassium osmate (КгО5О2(ОН)»«), potassium ferricyanide (КзРе(СМ)в), potassium carbonate (КСО), and chiral ligands are shown in scheme 1.15.

Scheme 1.15

Antagonists of STI and their use

Ligand for AYU-tikh a

Shan M--Mm -m oi-0-i U-- nt - is H meO zh d | OMe - che

M M

Ligand for AYU-tikh D:

M M-A-M watt. t H o / H o -

N Y N N meO | xx d OMe r Ya

M M

The racemic diol, 25c, can be synthesized by methods known in the art, using osmium tetroxide (05054) and M-methylmorpholine M-oxide (MMO) in aqueous acetone.

Methods of preparation of compounds of formula I, where UM is C and the dashed line is present

Compounds of formula 1, where UM is C and a dashed line is present, i.e., "Tetrahydropyridyl

"Compounds" can be prepared using conventional organic synthesis or by the illustrative methods shown in the schemes below.

Methods of obtaining Tetrahydropyridyl Compounds, some of which are o

Tetrahydropyridyl Compounds where X is O can be prepared by the following illustrative procedure shown below in Schemes 2.1 and 2.2, where BH", Agg, and t are as defined above.

Scheme 2.1

TF) O-505SEz

Ф 1. l1НМО5 З - -- В ---------- -- m ( З)t 9. si ch ba З/t

M

Ago 26 M(ZO»SE 3)» Ag 1 2

With reference to Scheme 2.1 above, compound 1 (approximately 3.6 mmol) is dissolved in THF (100 mL) and the resulting solution is cooled to -78 °C. GINMO5 (8.75 mmol) is added to the cooled solution and the reaction mixture is stirred at - 78 "C for 2 h. Compound 26 (approximately 3.6 mmol,

Zidta-Algisp) is added to the reaction mixture and the reaction mixture is stirred at -78 "С for 2 h.

The reaction mixture is then allowed to warm to 25 °C and concentrated under reduced pressure to obtain the compound of formula 27.

The compound of formula 27 then reacts with the compound of formula 28a-4 to give tetrahydropyridyl

A compound where X is 0, as shown below in Scheme 2.2:

Scheme 2.2

Antagonists of TRPVI and their use (Not) even with -M mch 5 RI(RRIV)A and tent

V. dl TIF, boil. M:

U7Az)t 2pVg M 28a opening

Ag (Nor

M

(Vr I ek

M V. 27 M | І РІ(РРІІ) 4 p

AND; TI F, boiling.

ZT7«Nz)t 2pVg M 285 ot-kn

Ag. (In the city

Shchi (No) M same V. 27 | RY(RRIV)4 ni -------

Wu dm TI F, boiling. Ve

UNN) 2pVg M 28s opening

Ag in (P2)r ek ( guest M 27 i | I M

VO R(RRIV)d V; ------ 7 AUG TI F, boiling. In the call (Ent

M ot-vn

Ag de Ki, NE", B", An, n, t, and p are as defined above.

RY(PP:z)4 (0.11 mmol) is dissolved in THF (approximately 50 ml) and the compound of formula 27 (approximately 2.2 mmol) is added to the resulting solution, after which the compound of formula 28a-j (approximately 6.6 mmol as a 0.5M solution in TIGF).

The reaction mixture was then heated for 1 g at the boiling temperature of the solvent. The reaction mixture was allowed to cool to 25"C and concentrated under reduced pressure to give

Tetrahydropyridyl Compound where X is O. Tetrahydropyridyl Compound where X is O can also be purified if desired. In one embodiment, the Tetrahydropyridyl Compound where X is o is chromatographed using silica gel column chromatography followed by trituration with ethyl acetate.

When m -1, Ez is bonded to the 5p3 carbon, and 27 is either a racemate or a mixture of enantiomers, the resulting Tetrahydropyridyl Compound in Scheme 2.2 will also be racemate or enantiomeric.

Antagonists of SARS and their use as a mixture. If an individual stereoisomer is desired, chiral separation techniques known in the art, such as chiral chromatography or chiral separation, can be used to isolate the individual isomer.

Another technique that can be used to condense the tetrahydropyridyl group and Ag is the Suzuki condensation reaction. It is a reaction in which a catalyst is used and in which H reacts with tetrahydropyridylborane, 29 as shown in Scheme 2.3 below. While the reaction shown has a pyridyl group as Ag, the same technique can be used when Ag is pyrazinyl (25), pyrimidinyl (2c), pyridazinyl (24), or another pyrazinyl.

Scheme 2.3

Capt

Shchi (F) o zv' dich"

Kap ota xx RA(RRZ)5SI Same with P(Vaya 0030 Nad» di cha m RME/EUN/NO M 1

And MR MR

2a 29 30

A 150 ml vessel with a lid is charged with ha (3.37 mmol), 29 (4.04 mmol), RYAD(PPH3)2Si" (0.27 mmol), potassium carbonate (6.40 mmol) and a mixture of OME/EUN/ NgO (8 ml/4 ml/8 ml). The resulting mixture is washed with nitrogen, closed and heated at 90 "С with intensive stirring. After 2 g, the reaction mixture is cooled to a temperature of about 25С and diluted with EtOAc (50 ml).

The organic layer was washed with brine, dried (Mag5054), and concentrated under reduced pressure.

The residue is chromatographed using column chromatography on silica gel with a gradient of ethyl acetate (0 95-30 9)/hexanes to obtain product 30.

Boronate ester 29 can be synthesized according to the method shown below in scheme 2.4.

Scheme 2.4 0, ,0 5О5(СЕ2)ЗСЕ more than 2 239473 v-V with those where

Y nn Gen m (Vz)t ORRE (3 moloo) M (No) is RYAI(ORRE) SI", KOAs, Dioxan PR 857 29

Bis(pinacolate diboron (333.6 mmol), diphenylphosphinoferrocene (9.1 mmol), diphenylphosphinoferrocenepalladium dichloride (111 complex with dichloromethane) (9.1 mmol), and potassium acetate (909.9 mmol) are suspended in dry dioxane (900 mL) under argon with mechanical stirring.

Add 4-(Nonafluorobutane-1-sulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (303.3 mmol) in dry dioxane (500 ml) and heat the mixture at 85 "С 16 g. The mixture is cooled, filtered through CELIT and the residue on the filter is washed with dichloromethane (2 L).

The filtrate is concentrated under reduced pressure to give a black solid. It is adsorbed onto silica gel (250 g) and loaded onto the top of a 4" silica gel column, then eluted with hexanes (5 L) followed by 20:1 hexanes:ethyl acetate, and finally with ethyl acetate (10 L) to give 29.

Methods of obtaining Tetrahydropyridyl Compounds, where X is 5

Tetrahydropyridyl Compounds, where X is 5, can be obtained by methods similar to those described above in schemes 2.1 and 2.2, obtaining Tetrahydropyridyl Compounds, where X is O, except that the isothiocyanate of the formula Ago-MO5 is used instead of the isocyanate Ago-MSO.

Methods of obtaining Tetrahydropyridyl Compounds, where X is M-CM

Tetrahydropyridyl Compounds where X is M-CM can be prepared as shown below in Schemes 2.5 and 2.6, where Ag", Hz, and t are as defined above.

Antagonists of STI and their use

Scheme 2.5 chu lt-

AT

Sya g me dv F -Mi- ABMN M 7 Nz)t

MO--M o 7 A HCsI/Acetic acid m - - zh 'chsh73Z2723

MO--M

Oh yeah

Ago 31 32 33 -M a-44 /--mvogogz» pНnMO5 26

О-50oСЕз

ZE tu ve

MO--M MN

Oh yes

A ketal of formula 31 (approximately 14 mmol) is reacted with an amine of formula Ag-MNe (approximately 14 mmol) in an aprotic organic solvent (approximately 7 mL) such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene at a temperature from about 25 °C to about the boiling point of the solvent for about 0.5 g to about 24 g. The reaction mixture is then concentrated under reduced pressure to give the compound of formula 32. In one embodiment, the aprotic organic solvent is di-n-propyl ether. in another embodiment, the reaction mixture of di-n-propyl ether, compound of formula 31 and amine of formula Ag-MH»e is heated at a temperature of from about 70" to about 80 "C.

The compound of formula 32 is then dissolved in THF (approximately 20 mL). Approximately 1M HCl in acetic acid (approximately 30 mL) is added to a THF solution of the compound of formula 32 and the resulting mixture is heated at the boiling point of the solvent. Typically, the reaction mixture is heated at the boiling temperature of the solvent for approximately 3 g. The reaction mixture is then cooled and concentrated under reduced pressure to give a residue that is dissolved in DCM. The DCM solution is then extracted with aqueous Mag2bOz. The aqueous and organic layers are separated and the aqueous layer is extracted three times with DCM. The organic parts are combined, dried (Md5O3) and concentrated under reduced pressure to give the compound of formula 33. The compound of formula 33 can, if desired, be purified. In one embodiment, the compound of formula 33 is chromatographed using silica gel column chromatography.

The compound of formula 33 (about 3.6 mmol) is then dissolved in THF (about 100 mL) and the resulting solution is cooled to about -78 °C. To the cooled solution is added GINMO5 (about 8.75 mmol) and the reaction mixture is stirred at about -78 "C for about 2 h. The compound of formula 26 (about 3.6 mmol, 5bidta-AlHydhys") is added to the reaction mixture and the reaction mixture is stirred at about -78 °C for about 2 h. The reaction mixture is allowed to warm to about 25 C and concentrate under reduced pressure to obtain

Antagonists of TPRVI and their use of the compound of formula 34.

A compound of formula 34 is then reacted with a compound of formula 28a-y as shown below in Scheme 2.6 below to give a Tetrahydropyridyl Compound where X is M-CM.

Scheme 2.6 (No) p (А хх В M 34 M, Ра(РРИВ)Я ' --- -Ж - 2 Ь6Ьттфё я - 2-25 - т н.

V. dm TIF, boiling. M:

U7Az)t 2pVg M 28a MO - ext

Ah (No)

Me (Vo)r schy;

M V. z4 and | АЙ РЯ(РРИЙ) 4 h

A. TI F, boiling.

T7Nv)t 2pVg M 285 MS. ec

Ag. (In the city

SHI

(Not) M z4 | РІ(РРІІ)4 ni -------

Wu dm TI F, boiling. and:

U7Nz)t 2pVg M 28s Mo ze vn

Ag in "Arkhst ( axis and i --- -3rd---- 7 AVG TI F, boiling. s zva t (Intro

M

Mo vn

Ag where Ag», Ni, RN», B», n, t, and p are as defined above.

RA(PP3)4 is dissolved in THF (approximately 50 mL) and the compound of formula 34 (approximately 2.2 mmol) is added to the resulting mixture and then the compound of formula 28a-j (approximately 6.6 mmol as a 0.5 M solution in THF) is added ). The reaction mixture is then heated for about 1 g at the boiling point of the solvent. The reaction mixture is allowed to cool to about 25°C and concentrated under reduced pressure to give the Tetrahydropyridyl Compound, where X is M-CM.

The Tetrahydropyridyl Compound, where X is M-CM, can be further purified if desired. In one of

Antagonists of TPRVI and their application embodiments, Tetrahydropyridyl Compound, where X is M-CM, is chromatographed using column chromatography on silica gel.

When m -1, Ez is bonded to the 5p3 carbon, and 34 is either a racemate or a mixture of enantiomers, the resulting Tetrahydropyridyl Compound in Scheme 2.6 will also be a racemate or an enantiomeric mixture. If an individual stereoisomer is desired, chiral separation techniques known in the art, such as chiral chromatography or chiral separation, can be used to isolate the individual isomer.

The compound of formula 31 can be prepared as shown below in scheme 2.7.

Scheme 2.7

Oh oh

SM no sh

M g F (Kz)t

AH 052 st

LKvz)t Mom to

M

N

4 31 where Kz, and t are as defined above.

Compound 4 reacts with diphenylcyanocarbonimidate 35 (Zidta-Aiagist) in an aprotic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene to give a compound of formula 31. In one embodiment, the aprotic solvent is DCM and the reaction mixture compound 4 and diphenylcyanocarbonimidate 35 are left to react at about 25 "C. In another embodiment, the aprotic solvent is toluene and the reaction mixture of compound 4 and diphenylcyanocarbonimidate 35 is left to react at about 110 "C. Compound 4 and diphenylcyanocarbonimidate 35 are typically left to react for about 0.5 g to about 24 g.

The compound of formula 28a-y can be prepared as described above by techniques known in the art.

Methods of obtaining Tetrahydropyridyl Compounds, where X is M-OH

Tetrahydropyridyl Compounds, where X is M-OH, can be obtained by a method similar to that outlined in schemes 2.6 and 2.7 in section 5.4.2.3, which is shown in scheme 2.8.

Scheme 2.68

Antagonists of STI and their use

I U o

With (ud 1 Ao-MN,

A /to2, Neu/Acetic acid

A Vo) - I nn ny

ОР-О-М7 МН

Ago 37 36 o O-805SEz

From in nMO5 of them to 2 -« 2 - from (Aq

M (about with M - M ovo ve oye--o-ke

A M5O»oCE 8)»

Ge Ago 37 26 38 (Ro) (Ag) xxx eh

SCHI SCHI s B; IN; zv DM RatRm 000 removal of protection OK vd 4 TIF, boiling. 4 (V MV--6Й6 - (В 1 ru ( 3)t r ( Z)t 29Vg Ж Й 2Va ОР--О-М7 un nom вn

Ago Ago 3Zda (B2) in 2 la (re

M M ov vh y B; and 38 SCHI RO(RRIV)4 sk withdrawal of protection p

V. typhus, boil. d(Vz)t -I-(Vvz)t 7pVg Zh M r 285 oR-O7 "In nom vn

Ah Ah

Antagonists of STI and their use (B") (Ag)

AM | M poh V. V. 38 in | r RA(RRIV)X with removal of protection of the same

Wu TI F, boiling. --(B3) --(Az) ro t r t 7pVg Zh X - 28s oR-O7 VN No-m VN

Ago Ago 39s c

I I in M zv ( gr B; M B; -- in ХА RA(РРИ)А сх removal of protection сх and pishna ---37-

TI F, boiling. -- -- (B 7 Vy m (Kz)t F, (Nz)t 25a - oR---o-me vn no-ke kn

Ago Ago c9a where Ag", Ni, RH", HB", n, t, and p are as defined above and P is an oxygen/hydroxy protecting group.

The method of obtaining Tetrahydropyridyl Compounds, where X is M-OH, as described above in Scheme 2.8 is similar to that described above in Schemes 2.5 and 2.6, obtaining Tetrahydropyridyl Compounds, where X is

M-CM, except that the compound of formula 38 is used instead of the compound of formula 34.

The compound of formula 36 can be prepared as described below in Scheme 2.9.

Scheme 2.9

With (Well) |. m 7 MON (Nv)t -- -- -ya- M

Ethanol, 807 C

H s-v- , -m-

Z i ish F) ko

Aha Aha a1

F o Ka

F) --(8

M (Nz)t Protective group (Z-i"

M no ek -

Ag I

Ag 41 36

HPV antagonists and their applications where Ag, Nz, and t are as defined above and P is an oxygen/hydroxy protecting group.

A compound of formula 40 (about 0.3 mmol) is reacted with hydroxylamine (50 wt.95 in water, about 5.8 mmol) in about 1.5 mL of ethanol with stirring at a temperature of about 80°C for about 2 h. The mixture is then concentrated under reduced pressure to give the compound of formula 41. The hydroxy group of the compound of formula 41 is then protected using a hydroxy protecting group to give the compound of formula 36. Any hydroxy protecting group known in the art can be used to protect the hydroxy group in the compound of formula 41. Suitable hydroxy protecting groups and methods of their removal are described in T.M.

Ogodapis Zupipeviv 17-200 (For unit 1999).

When m -1, Ez is bonded to the 5p3 carbon, and 38 is either a racemate or a mixture of enantiomers, the resulting Tetrahydropyridyl Compound in Scheme 2.8 will also be a racemate or an enantiomeric mixture. If an individual stereoisomer is desired, chiral separation techniques known in the art, such as chiral chromatography or chiral separation, can be used to isolate the individual isomer.

The compound of formula 40 can be prepared as shown below in Scheme 2.10.

Scheme 2.10

WITH

F about Z

O yu "Author

M SNI "| "Nut about TBA Her

Ethyl acetate Nas-57

Ag Y

Ag 42 40 where Ag", Nz, and t are as defined above.

A solution of the compound of formula 42 (about 0.6 mmol) prepared as described above in section 4.4.2.2. in DCM is reacted with iodomethane (about 0.9 mmol) in about 3 mL of tetrahydrofuran with stirring at about 25 °C for about 12 g. Excess iodomethane is removed from the mixture under reduced pressure. A solution of triethylamine (ca. 1.74 mmol) in ca. 2.5 mL of ethyl acetate is added to the mixture and the mixture is allowed to stir for ca. 2 g. The mixture is then concentrated under reduced pressure to give the compound of formula 40, which may, if desired, be further purified In one embodiment, the compound of formula 40 is chromatographed using column chromatography or recrystallization.

Methods of obtaining Tetrahydropyridyl Compounds, where X is M-ОВ:o

Tetrahydropyridyl Compounds, where X is M-ОВ:о, can be obtained by the reaction of Tetrahydropyridyl

Compounds where X is M-OH, prepared as described above in Scheme 2.8, with I -(C1-C4)alkyl, where I is -I, -Bg, -CI, or -E, in the presence of about 3 eq. of triethylamine in THF, with stirring at about 25 C for about 12 g or at about 50 C for about 3 g. The reaction mixture is concentrated under reduced pressure to give a residue. The residue is then chromatographed using column chromatography on silica gel eluting with an elution gradient from 100: 0 hexane-ethyl acetate to 25:75 hexane-ethyl acetate, obtaining Tetrahydropyridyl Compounds, where

X is M-OH:o. In one of the incarnations, I. has -I or -Vg.

Methods of preparation of compounds of formula I, where MU is M and the dashed line is absent

Compounds of formula I wherein MU is M and the dashed line is absent, i.e., "Piperazine Compounds," may be prepared using conventional organic synthesis or by the following illustrative methods shown in the schemes below.

Methods of obtaining Piperazine Compounds, where X is O and Ag" is a benzothiazolyl group

Piperazine Compounds where X is o, Aggo is a benzothiazolyl group, and Ego is -H can be prepared by the following illustrative procedure shown in Scheme 3.1:

Scheme 3.1

Antagonists of STI and their use and

MO M. a) sa

Ag DI M

M - (9) zi A Ngo M (Yaz)t in 0087 nn

A M 57

M M

N

43 In 9 d. in 44. From 5 c

Piperazine Compounds where Ag, INz, Iv, NVoz and t are as defined above.

The compound of formula 44 (approximately 2 mmol) is dissolved in an aprotic organic solvent (approximately 3 ml). The compound of formula 43 (approximately 2 mmol) was added to the resulting solution and the reaction mixture was allowed to stir for approximately 10 min. The reaction mixture is concentrated under reduced pressure to obtain Piperazine Compounds, where X is 0, Ag2 is a benzothiazolyl group, and Ego is -H. Such Piperazine Compounds can be chromatographed on a silica gel column eluting with 5:95 ethyl acetate:hexane.

The compound of formula 44 can be prepared as shown below in Scheme 3.2:

Scheme 3.2

MO"

MN

And Her Iv)

Ex

Axes M nm" about z and A bom about 5

IN

45 With Av 46 in 44 9 Ve where Kz and K»e are as defined above.

A compound of formula 45 (about 0.75 mmol) in an aprotic organic solvent (about 0.04 M) is cooled to about 0 °C. To the cooled solution is slowly added a solution of a compound of formula 46 (about 0.75 mmol) in an aprotic organic solvent (about 0 ,4M). The reaction mixture is stirred at 0 "C for about 5 min. and approximately 0.75 mmol of triethylamine is added to the reaction mixture. The reaction mixture is allowed to warm to a temperature of about 25°C and concentrated under reduced pressure to give the compound of formula 44. The compound of formula 45 is commercially available, for example, from Zidta-Agiagis. The compounds of formula 46 are commercially available or can be prepared by the following illustrative procedure shown below at scheme 3.3:

Scheme 3.3

Antagonists of STI and their use

МН» kn» that 1. Bromine, acetic acid - 2. MAON in B 9 8 Vo Va where Kz and K»e are as defined above.

To a stirred solution of aniline 47 (ca. 74 mmol) and potassium thiocyanate (ca. 148 mmol) in ca. 100 mL of glacial acetic acid was added dropwise a solution of bromine (ca. 74 mmol) in ca. 25 mL of glacial acetic acid. The flask containing bromine in acetic acid is then washed with about 15 mL of acetic acid, which is combined with the aniline solution 47. The reaction mixture is stirred vigorously at a temperature of about 25 "C from about 2 g to about 24 g. The reaction mixture is then poured onto crushed ice (about 500 mL) and the pH of the resulting mixture adjusted to about 10 using ammonium hydroxide to give a precipitate. .

The compound of formula 50a-4 can be obtained as shown below in scheme 3.4:

Scheme 3.4

Antagonists of STI and their use (No) and Gi" (No)

M M

You n VI (Nz)t - 4 --k

And in MM

MV; and

Number 48 492 M

N zba (Ne)r p (Ne)r

M AM

M d-- -ya- Vi 48 nya | ts M 4 y y (S ot y M 49r H (Ne)r M

Shchi (Vg)r

HM AM oo tya tt V; 48 ty | ts M 4 y y (S dya ts M 49s Нn 5b0s (Nor

He (Vo)r SCHO pe: Pi 48 i | n M 2 y

V. (S dov ts M doanzoa de Ki, NE", B", t, n, and p are as defined above and Y. is a halogen.

A compound of formula 49a-a (about 20 mmol) is reacted with a compound of formula 48 (about 27.5 mmol) in about 15 mL of DMSO in the presence of triethylamine (about 30 mmol), optionally with heating, for about 24 g to give a compound of formula 50a-d. The compound of formula 50a-ia is isolated from the reaction mixture and, if desired, purified. In one embodiment, the compound of formula 50a-a is chromatographed using column chromatography or recrystallization.

Compounds of formula 48 and 49a-4 are commercially available or can be obtained by methods known from the literature. A compound of formula 48, where t is 0, and a compound of formula 48, where t is 1 and Ez is (B) -

CH3 or (5) -CH»3, are commercially available, for example, from Zidta-Algisp. In one of the embodiments, Y. is bromide, chloride, or iodide.

Piperazine Compounds, where X is O, Ag2 is a benzothiazolyl group, and Ko is -(Ci1-C4)alkyl, can be prepared by the following illustrative procedure shown below in Scheme 3.5:

Scheme 3.5

Antagonists of STI and their use

Ah! Ag

She M (S -G(Nz)t y v we 7 zt r Man y a

Nm V To

A ----3- 20 UM

Whoah, the 5th

Not | in

On Nv

Not where Ag, Hz, Hv, Ho, H2go, and t are as defined above and H is a halogen.

To a solution of the Piperazine Compound, where X is 0, Agg is a benzothiazolyl group, and Ego is -H (approximately 1 eq.), obtained as described above in Scheme 3.1, in DMF at 0 "C, is added a solution of MaN in DMF (approximately 2 eq .). The reaction mixture is left to heat up to a temperature of about 25 "С for about 1 h. About 1.2 eq. is added to the resulting mixture. of an alkyl halide, CoO-Yi, and the reaction mixture is left to stir until the formation of Piperazine Compounds, where X is O, Agg is a benzothiazolyl group, and Ego is -(C1-Ca4)alkyl. The progress of the reaction is monitored using conventional analytical techniques including, but not limited to, high performance liquid chromatography (HPLC), column chromatography, thin layer chromatography (TLC), column chromatography, gas chromatography, mass spectroscopy, and nuclear magnetic resonance, such as H and 3C NMR.

Piperazine Compounds can be isolated and, if desired, further purified. In one of the embodiments,

The piperazine compound is isolated by removing the solvent under reduced pressure. In another embodiment,

The Piperazine Compound is isolated by extraction. Piperazine Compounds can also be purified, for example, by column chromatography or recrystallization.

Methods of obtaining piperazine compounds, where X is 5 and Agg is a benzothiazolyl group

Piperazine Compounds where X is 5, Ag" is a benzothiazolyl group, and Ego is -H can be prepared by the following illustrative procedure in Scheme 3.6.

Scheme 3.6

Antagonists of TPRVI and their use d 5 Ha 87 chu UM am ha NM in RMAR A

And in; Huh

Mi dmMsSO 100

Not

Nv 46 in 9 Av i

M gu(v ) o u 3Z/l| DMSO 100 C

M

N

43 and

M and Zoya

M

J

WE

5-X

SHU

IN

8 Va

PSperazine Compounds where Ag, INz, Iv, NVoz and t are as defined above.

The compound of formula 46 (about 2 mmol), 1,1'-thiocarbonylimidazole (about 2 mmol) (bBidalagis), and 4-dimethylaminopyridine (OMAR) (Zidita-AlIdgisp) are suspended in DMSO (about 3 mL) at a temperature of about 25 °C and the resulting mixture is heated at about 100 "C for about 6 g. The reaction mixture is then cooled to a temperature of about 25 "C and a compound of formula 43 (about 2 mmol) is added to the reaction mixture and the reaction mixture is heated to about 100 "C for about 16 g The reaction mixture is concentrated under reduced pressure to obtain Piperazine Compounds, where X is 5, Ag is a benzothiazolyl group, and K is -H. Piperazine

Compounds can be chromatographed on a silica column eluted with 5:95 ethyl acetate:hexane.

Piperazine Compounds, where X is 5, Ag" is a benzothiazolyl group, and K is -(Ci-C4)alkyl, can be obtained by a method similar to the method used for the preparation of Piperazine compounds

A compound where X is c, Ar" is a benzothiazolyl group and K is -(C1-C4)alkyl as described above in Scheme 3.5, except that a Piperazine Compound where X is 5, Ar" is a benzothiazolyl group, and Who is -H obtained as described above in Scheme 3.6 using instead of Piperazine Compound where X is

O, Ag: is a benzothiazolyl group, and P20 is -H.

Methods of obtaining piperazine compounds, where X is c and Ag" is a benzoxazolyl group

Piperazine Compounds where X is 0, Agg is a benzoxazolyl group, and Ego is -H can be obtained by

TRTI antagonists and their use in a manner similar to that used to prepare Piperazine Compounds where X is o, Agg is benzothiazolyl, and Cog is -H as described in Section 5.4.3.1, Scheme 3.1, except that the compound of formula 51 is shown below :

MO" her nm" at 075

Not

Hv 51 where Kv and Ke are as defined above is used instead of the compound of formula 44.

Compound of formula 51 can be prepared by a method similar to that used to prepare compound of formula 44 as described above in Scheme 3.2, except that compound of formula 52, shown below,

MN" 0-X

Not

Hb 52 where Kv and Ke are as defined above is used instead of compound 46.

Methods of obtaining piperazine compounds, where X is 5 and Ag" is a benzoxazolyl group

Piperazine Compounds, where X is 5, Ago is a benzoxazolyl group, and Kgo is -H can be obtained by a method similar to that used for the preparation of Piperazine Compounds described above on

Scheme 3.6, except that the compound of formula 53 is used instead of the compound of formula 44. The compound of formula 53 can be prepared as described above.

MO"

Her nm" at 0-5

Co

Square 53

Piperazine Compounds where X is 5, Ag" is a benzoxazolyl group, and Ego is -(Ci-C3alkyl) can be prepared by a method similar to that used to prepare the Piperazine Compounds described above in Scheme 3.5, except that the Piperazine Compound where X is 5, Ag2 is a benzoxazolyl group, and Kogo is -H obtained as described above is used instead of

Piperazine Compound, where X is OS, Ag" is a benzothiazolyl group, and K is -H.

Methods of obtaining piperazine compounds, where X is O and Ag" is a benzoimidazolyl group

Antagonists of STI and their use

Piperazine Compounds where X is 0, Ag" is a benzoimidazolyl group, the amide of Who is -H, and the benzoimidazolyl group Ego is -H can be prepared by a method similar to that used to prepare the Piperazine Compounds described above in Scheme 3.1, except that the compound of formula 54, shown below,

MO" i nm" o smell

She

Co

Kv 54 where Kv and Ke are as defined above is used instead of the compound of formula 44.

Compound of formula 54 can be prepared by a method similar to that used to prepare compound of formula 44 as described in Section 5.4.3.1, Scheme 3.2, except that compound of formula 55, shown below,

I have a sense of smell

She

Co

Kv 55 where Kz and K»e 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 techniques known in the art.

An illustrative procedure for the preparation of compound 55 is shown below in Scheme 3.7:

Scheme 3.7

Nv M Nv M -siyi Vodnyi MN" fi Z-MN"

M -6-Vy8yY33

Ne H No » 56 55 where Kv and Ke are as defined above.

A compound of formula 56 (approximately 1 mmol), prepared as described below in Scheme 3.11, is dissolved in excess aqueous ammonia in a sealed test tube and heated at a temperature of about 140 °C to 150 °C for about 72 g. The mixture is cooled to a temperature of about 2570 and concentrated under reduced pressure to give a residue. In another embodiment, the mixture is cooled to a temperature of about 25 °C, extracted with an organic solvent, the organic phase is separated from the aqueous phase, and the organic phase is concentrated under reduced pressure to obtain a residue. If desired, the residue is further purified to obtain a compound of formula 55.

In one embodiment, the residue is recrystallized. In another embodiment, the residue is chromatographed using flash chromatography.

Compounds of formula 56 are commercially available or can be prepared by techniques known in the art. An illustrative method of preparation of the compound of formula 56 is shown below in Scheme 3.8:

Scheme 3.8

Antagonists of STI and their use

N

Kb 51 MN" Ke of them 58 axes

Kv M to"

They are 56 where Kz and K»e are as defined above.

A compound of formula 57 (ca. 5 mmol - ca. 10 mmol) and di(1H-imidazol-1-ylumethanone (CO, ca. 2 eq) are dissolved in THF (ca. 50 mL - ca. 70 mL) and the reaction mixture is heated at reflux for ca. 4 hours. The reaction mixture is then concentrated under reduced pressure to give a residue. Ethyl acetate (about 50 mL) is added to the residue and the resulting insoluble material is collected by filtration and washed with ethyl acetate to give the compound of formula 58. The compound of formula 58 is then reacted with ROCI according to the procedure described in . ). Honey. Spent 40:586-593 (1997) giving a compound of formula 56.

Compounds of formula 57 are commercially available or can be prepared by techniques known in the art. An illustrative procedure for the preparation of the compound of formula 57 is shown below in Scheme 3.9:

Scheme 3.9 -- - - -- c. "NSI NMO"z 9 Kb MO" 1095 RO/S Rv Mne 59 60 57 where Kz and K"e are as defined above.

Aniline hydrochloride 59 (approximately 12 mmol) is dissolved in concentrated sulfuric acid (approximately 10 mL) at 0 °C and the resulting solution is cooled to a temperature of approximately -13 °C to approximately -15 °C. 1 ml of 70 95 nitric acid and the reaction mixture is left to stir for about 2 g at a temperature from about -13 "C to about -15 "C. The reaction mixture is then poured into ice water (about 100 ml), neutralized with 595 - 1095 aqueous sodium hydroxide and extracted with approximately 50 ml of chloroform.The chloroform layer was separated from the aqueous layer.

Concentration under reduced pressure gave a residue which was chromatographed using flash chromatography (silica and chloroform as eluent) to give the compound of formula 60. The compound of formula 60 was dissolved in ethanol (about 50 mL) and hydrogenated for about 12 g at a temperature of about 25 °C using 10 95 palladium on carbon as catalyst The catalyst is removed by filtration and the ethanol removed under reduced pressure to give a residue which is chromatographed using flash chromatography (silica gel eluting with 20:1 dichloromethane:methanol) to give the compound of formula 57. Compounds of formula 59 are commercially available or it can be obtained by techniques known in the field.

Piperazine Compounds, where X is OO, Ag" is a benzoimidazolyl group, the amide of Who is -H, and the benzoimidazolyl group of Who is -(C1-C1)alkyl, can be obtained by a method similar to that used for the preparation of Piperazine Compounds, where X is 0, Ago is a benzoimidazolyl group, the amide of Who is -H, and the benzoimidazolyl group of Ego is -H, except that the compound of formula 61, shown below,

Antagonists of STI and their use

MO,

Al nM7 o

Kooch A

M

She

Co

Kv 61 where Ka, B", and Kgo are as defined above is used instead of the compound of formula 54.

The compound of formula 61 can be prepared by a method similar to that used to prepare the compound of formula 54, except that the compound of formula 62, shown below,

MN"

Koch A

M tm

Co

Kv 62 where Kz, MN", and Ego are as defined above, is used instead of the compound of formula 55.

The compound of formula 62 can be prepared as shown below in Scheme 3.10.

Scheme 3.10

MN» MN» MNAA»o

B2oh A A nm M NIH

Mo man She M -- sh

OME

KKo-I.

Vv Vv Av 62 63 where Ka, No", and Ego are as defined above and Y. is a halogen.

Mann (about 2 eq) is added to a solution of the compound of formula 55 in DMF at 0 °C and the resulting mixture is allowed to stir and heated to a temperature of about 25 °C for about one hour. Alkyl halide, E20-Y, (approximately 1 eq.) is added to the solution and the reaction mixture is allowed to stir until a mixture of compound of formula 62 and compound of formula 63 is formed. In one embodiment, the alkyl halide is an alkyl iodide. The formation of compounds of formula 62 and compounds of formula 63 can be monitored by analytical methods known in the art including, but not limited to, those described above. Water is added to the reaction mixture to obtain a precipitate of compounds of formula 62 and compounds of formula 63, which are collected by filtration. The compound of formula 62 and the compound of formula 63 are then separated to give the compound of formula 62. The compound of formula 62 and the compound of formula 63 can be isolated by techniques known in the art including, but not limited to, column chromatography, preparative TLC, preparative HPLC, and preparative GC.

Methods of obtaining Piperazine compounds, where X is 5 and Ago is a benzoimidazolyl group

Piperazine Compounds where X is 5, Ag" is a benzoimidazolyl group, the Cog thioamide is -H, and the benzoimidazolyl group Ego is -H can be prepared by a method similar to that used to prepare the Piperazine Compounds described above in Scheme 3.6, except that the compound of the formula 55 is used instead of the compound of the formula 46. The compound of the formula 55 can be obtained

Antagonists of STI and their use as described above.

Piperazine Compounds, where X is 5, Ag" is a benzoimidazolyl group, the thioamide of Who is -H, and the benzoimidazolyl group of Who is -(C1-C1)alkyl can be obtained by a method similar to that used for the preparation of Piperazine Compounds as described in section 5.4.3.2 , Scheme 3.6, except that the compound of formula 62 is used instead of the compound of formula 46. The compound of formula 62 can be prepared as described above.

Piperazine Compounds, where X is 5, Ag" is a benzoimidazolyl group, the thioamide K0 is -(C1i-C alkyl, and the benzoimidazolyl group E0 is -H) can be prepared by a method similar to that used for the preparation of Piperazine Compounds as described above in Scheme 3.5, except that which

A Piperazine Compound where X is 5 and each Kogo is -H, prepared as described above, is used instead of a Piperazine Compound where X is C and the Kogo amide is -H.

Piperazine Compounds, where X is 5, Ag2 is a benzoimidazolyl group, thioamide K is -(C1-C alkyl, and the benzoimidazolyl group of Co is -(C1-C1)alkyl) can be prepared by a method similar to that used for the preparation of Piperazine Compounds, where X is c and Ego is -(C1-C6)alkyl as described above in Scheme 3.5, except that the Piperazine Compound where X is 5, the Cogo thioamide is -H, and the benzoimidazolyl group of Ego is -(C1-C4)alkyl, obtained as described above is used instead

Piperazine Compound, where X is O and Kogo 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 tetrachloride, pentane, hexane, naphtha, and diethyl ether. In one embodiment, the aprotic organic solvent is DCM.

Some Piperazine Compounds may have one or more asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The Piperazine Compound may be in the form of an optical isomer or a diastereomer. Accordingly, the invention covers Piperazine Compounds and their use as described herein in the form of their optical isomers, diastereomers and mixtures thereof, including racemic mixtures.

In addition, one or more hydrogen, carbon or other atoms of the Piperazine Compound may be replaced by an isotope of hydrogen, carbon or other atoms. Such compounds, which are covered by the present invention, are useful as diagnostic and research tools in the study of the pharmacokinetics of metabolism and the study of binding.

THERAPEUTIC APPLICATION OF COMPOUNDS OF FORMULA I

According to the invention, compounds of the formula !/ are administered to an animal in need of treatment or prevention of the condition.

In one embodiment, an effective amount of a compound of formula I can be used to treat or prevent any condition that is treated or prevented by inhibiting

TRPVI Examples of conditions treated or prevented by inhibition of SARS include, but are not limited to, pain, NS, ulcers, CKD, and PCOS.

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 treated or prevented using compounds of formula | include, but are not limited to, cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache, muscle pain, arthritic pain, and pain due to periodontal disease, including gingivitis and periodontitis.

Compounds of formula I or a pharmaceutically acceptable derivative thereof can also be used to treat or prevent pain associated with inflammation or inflammatory diseases in an animal. Such pain can occur due to inflammation of body tissue, and which can be a local inflammatory response and/or systemic inflammation. For example, compounds of the formula | may be used to treat or prevent pain associated with inflammatory disease including, but not limited to: rejection of a transplanted organ; reoxygenation injury as a result of organ transplantation (see Ogyrr ei ai., 9). My. Sow! Sagaiyo!i. 31:297-303 (1999)) including, but not limited to, heart, lung, liver, or kidney transplantation; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases due to increased bone resorption; inflammatory lung diseases such as asthma, adult respiratory distress syndrome and chronic obstructive airways disease; inflammatory eye diseases, including corneal dystrophy, trachoma, onchocerciasis, uveitis, metastatic ophthalmia and endophthalmitis; chronic inflammatory diseases of the gums, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidneys, including uremic complications, glomerulonephritis and nephrosis; inflammatory skin diseases, including scleroderma, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-induced neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis,

Antagonists of SARS and their use in Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including type I and type II diabetes; diabetic complications including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminaria and progressive diabetic nephropathy), polyneuropathy, mononeuropathy, autonomic neuropathy, leg gangrene, atherosclerotic coronary artery disease, peripheral artery disease, nonketotic hyperglycemic-hyperosmolar coma , leg ulcers, joint and skin problems, or mucosal complications (such as infection, spot on the shin, candidal infection, or necrobiosis Iroidis aiiabiiisogyt); immune complex vasculitis and systemic lupus erythematosus (SLE); inflammatory heart diseases such as cardiomyopathy, ischemic heart disease, hypercholesterolemia and atherosclerosis; as well as various other diseases with significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord injury, and cancer. The compounds of formula I may also be used to treat or prevent pain associated with an inflammatory disease, which may, for example, be systemic inflammation of the body, such as gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to proinflammatory cytokines, such as shock induced by proinflammatory cytokines. Such a shock can be induced, for example, by a chemotherapeutic agent administered in the treatment of cancer.

Compounds of formula I or a pharmaceutically acceptable derivative thereof can be used to treat or prevent NS. Examples of NCs that are treated or prevented using compounds of formula I include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and general incontinence.

Compounds of formula I or a pharmaceutically acceptable derivative thereof can be used to treat or prevent ulcers. Examples of ulcers treated or prevented using compounds of formula I include, but are not limited to, duodenal ulcers, gastric ulcers, marginal ulcers, esophageal ulcers, or stress ulcers.

The compounds of formula I or a pharmaceutically acceptable derivative thereof can be used to treat or prevent CKD, including Crohn's disease and ulcerative colitis.

A compound of formula I or a pharmaceutically acceptable derivative thereof can be used to treat or prevent PCOS. Examples of PCOS that are treated or prevented using compounds of formula I include, but are not limited to, PCOS spasticity colon and retrodominant PCOS.

Applicants believe that the compounds of formula I or a pharmaceutically acceptable derivative thereof are antagonists of TRPVI1. The invention also relates to methods of inhibiting the function of TRIPVI in a cell, which includes contacting a cell capable of expressing TRIPVI with an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof. This method can be used by others, for example, as a screening test for cells expressing TRPVUI and, accordingly, is useful as part of a screening test for compounds useful in the treatment or prevention of pain, NS, ulcers, CKD, or PCOS. The method is also useful for inhibiting the function of STI in an animal cell, in one embodiment in a human, by contacting the animal cell with an effective amount of a compound of formula I 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 NS in an animal. In another embodiment, the method is useful for treating or preventing ulcers in an animal. In another embodiment, the method is useful for treating or preventing CKD in an animal. In another embodiment, the method is useful for the treatment or prevention of PCOS in an animal.

Examples of tissues containing cells capable of expressing TRPRI include, but are not limited to, neuronal tissue, brain tissue, kidney, urothelium, and bladder. Methods for studying cells expressing TPRI are well known in the art.

THERAPEUTIC/PROphylactic ADMINISTRATION AND COMPOSITIONS OF THE INVENTION

Due to their activity, compounds of formula I or a pharmaceutically acceptable derivative thereof are preferably useful in veterinary medicine and in the treatment of humans. As described above, a compound of formula I or a pharmaceutically acceptable derivative thereof is useful for the treatment or prevention of a Condition.

When administered to an animal, compounds of formula I or a pharmaceutically acceptable derivative thereof are typically administered as a component of a composition containing a pharmaceutically acceptable carrier or excipient.

The compositions presented, which contain a compound of formula I or a pharmaceutically acceptable derivative thereof, can be administered orally. The compounds of formula I or a pharmaceutically acceptable derivative thereof of the invention may also be administered by any other acceptable route, for example, by infusion or bolus administration, by absorption through epithelium or mucocutaneous patches (e.g., orally, rectally and intestinally, etc.). i.) they can be administered together with another biologically active agent. Input can be system or local. Different systems are known

Antagonists of STI and their applications release, for example, encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to introduce a compound of formula I or a pharmaceutically acceptable derivative thereof.

Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topically, particularly to the eyes, nose, ears, or on the skin The route of administration remains at the discretion of the physician. In most cases, administration will result in the release of compounds of formula I or a pharmaceutically acceptable derivative thereof into the bloodstream.

In specific embodiments, it may be desirable to administer a compound of formula I or a pharmaceutically acceptable derivative thereof locally. This can be done, for example, and not by way of limitation, by local infusion during surgery, local application, for example, by dressing a wound after surgery, by injection, by catheter, by suppository or enema. or by means of an implant, said implant being a porous, non-porous or gelatinized material, including membranes such as sialastic membranes or fibers.

In some embodiments, it may be desirable to administer a compound of formula I or a pharmaceutically acceptable derivative thereof to the central nervous system or gastrointestinal tract using a suitable route, including intragastric, intrathecal, and epidural injection, and enema.

Intragastric injection can be performed using an intragastric catheter, for example, attached to a reservoir, such as an Ommay reservoir.

Pulmonary administration can also be performed, for example, by using an inhaler or nebulizer, and formulation with a nebulizing agent or by perfusion in a fluorocarbon or synthetic pulmonary surfactant. In some embodiments, compounds of formula I or a pharmaceutically acceptable derivative thereof may be formulated as suppositories, with conventional binding agents and excipients such as triglycerides.

In another embodiment, the compounds of formula I or a pharmaceutically acceptable carrier thereof can be released from a vesicle, particularly a liposome (see Iapdeg, zZsiepse 249:1527-1533 (1990) and Tgeai et al.,

Prosotez ip ilye Tnegaru oi IpTesioiv bizease apa Sapseg 317-327 and 353-365 (1989)).

In yet another embodiment, the compounds of formula I or a pharmaceutically acceptable equivalent thereof may be delivered in a controlled release or sustained release system (see, e.g., Sosazop, Meaisa! Arriisaiop5 oii SopigoPei Keivaze, zirga, moi. 2, pp. 115-138 ( 1984).

Other controlled or sustained release systems may be used, as discussed in IGapdeg Review, 5ciepse 249:1527-1533 (1990). In one embodiment, a pump can be used (Iapdeg, Zsiepse 249:1527-1533 (1990); Zeyop, SAS Stii. Vei. Vioteide. Epod. 14:201 (1987); Vyspu/aya ei aI., Zygdegu 88: 507 (1980); and Zatsaek et al., M. Epoi. U. May. 321:574 (1989)).

In another embodiment, polymeric materials can be used (see Medisa! Arriisaiope oi

Sopigoiyed Neivaze (I apdeg apa M/ize eadv., 1974); Sopigoii Ogyd Vioamaiiiarbiiiu, Ogyd Rhodisi Oevidp apa Repopgtapse (Ztoiep and Vai!Y ea5., 1984); Kapdeg apa Rerrach, In Masgotoi. si. Chem. Masgotoi

Spent 23:61 (1983); I emu ei aI., Zsiepse 228:190 (1985); bigipd ei ai., App. Meygoi. 25:351 (1989); and

Nomaga ei ai., 9. Meigozygod. 71:105 (1989)). In yet another embodiment, the controlled or sustained release system can be placed adjacent to the target of the compounds of formula I, for example in the spinal cord, brain or gastrointestinal tract, thus requiring only a fraction of the systemic dose.

The presented compositions may optionally contain a suitable amount of a pharmaceutically acceptable excipient, in order to obtain a form suitable for administration to an animal.

Such pharmaceutical excipients may be liquids such as water and oils, including petroleum, animal, vegetable or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical excipients can be saline, acacia, gelatin, starch paste, talc, keratin, colloidal silica gel, urea and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricating agents and dyes can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to the animal. Water is a particularly useful excipient when the compound of formula | administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid excipients, especially for injectable solutions. Suitable pharmaceutical excipients are also starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, ethanol and similar to them Presented compositions, if desired, may also contain small amounts of wetting or emulsifying agents or pH buffering agents.

The presented compositions can be in the form of solutions, suspensions, emulsions, tablets, pills, balls, capsules, capsules containing liquids, powders, formulations of sustained release, suppositories,

Antagonists of SARS and their use of emulsions, aerosols, sprays, suspensions or any other forms suitable for use. In one embodiment, the composition exists in the form of a capsule (see, for example, patent 05 5,698,155).

Other examples of suitable pharmaceutical excipients are described in Ketipdiopye Rpaptaseshisai!

Zsiepsez 1447-1676 (AMopzo V. Seppago ed., 191st Ey. 1995), incorporated herein by reference.

In one of the embodiments, compounds of formula I or their pharmaceutically acceptable derivative are formulated in accordance with 3 typical methods as compositions adapted for oral administration to humans. Compositions for oral administration may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs.

Oral compositions may contain one or more agents, for example, sweeteners such as fructose, aspartame or sugar; flavorings such as peppermint, evening primrose oil, or cherries; dyes; and preservatives, to ensure a pharmaceutically palatable formulation. However, in the case of tablets or pills, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract in order to provide sustained action over a long period of time. Selectively permeable membranes surrounding the osmotically active driving compound are also useful in orally administered compositions. In these latter platforms, fluid from the surrounding capsule medium saturates the propellant compound, which swells by stirring the agent or complex agent through the holes. These release systems may provide an essentially zero release profile in contrast to the immediate release formulation systems discussed. Inert materials such as glycerol monostearate or glycerol stearate can also be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharate, cellulose and magnesium carbonate. In one embodiment, the excipients are pharmaceutically pure.

The compounds of formula I or a pharmaceutically acceptable derivative thereof may be administered by means of controlled or sustained release or by means of release devices well known to one of ordinary skill in the art. Examples include, but are not limited to, devices described in patents 05 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, hydropropylmethylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof for providing the desired release profile in various proportions. Suitable controlled- or sustained-release formulations known to one of ordinary skill in the art, including the formulations described herein, may be readily selected for use with the active ingredients of the invention. Thus, the invention encompasses individual unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel caps and caplets adapted for controlled- or sustained-release.

The main purpose of controlled- or sustained-release pharmaceutical compositions is to improve treatment with the use of a drug compared to the effect achieved when using compositions with uncontrolled or short-term release. In one embodiment, the controlled- or sustained-release composition contains a minimal amount of a compound of formula I to treat or control the condition in a minimal amount of time.

The advantages of controlled- or sustained-release compositions are the long-term activity of the drug, reducing the frequency of dosing and increasing convenience for the patient. In addition, controlled- or sustained-release compositions may benefit the duration of action or other characteristics, such as blood levels of compounds of formula I, and may thus reduce the occurrence of undesirable side effects.

Controlled- or sustained-release compositions may initially release an amount of a compound of formula I or a pharmaceutically acceptable derivative thereof that immediately produces a desired therapeutic or prophylactic effect and gradually and continuously release other amounts of a compound of formula I to maintain that 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 formula | can be released from the dosage form at a rate that will replace the amount of the compound of formula I that is metabolized and extracted from the body. Controlled- or sustained- release of the active ingredient can be stimulated by various conditions, including, but not limited to, a change in pH, a change in temperature, concentration, or the presence of enzymes , concentration or availability of water or other physiological conditions or compounds.

In another embodiment, compounds of formula I or a pharmaceutically acceptable derivative thereof may be formulated for intravenous administration. Typically, formulations for intravenous administration contain a sterile isotonic aqueous buffer. When necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may be optional

Antagonists of STI and their uses include local anesthetics such as lignocaine to reduce pain at the injection site. Typically, the ingredients are supplied either separately or mixed together in a unit dosage form, for example as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or a small packet containing a specified amount of the active agent. When the compounds of formula I are administered by infusion, they can be divided, for example, into infusion bottles containing sterile pharmaceutical water or saline. When compounds of formula I are administered by injection, an ampoule of sterile water for injection or saline can be designed so that the ingredients can be mixed prior to administration.

The amount of a compound of formula I or a pharmaceutically acceptable derivative thereof that is effective in treating or preventing a condition can be determined using standard techniques.

In addition, ip migo or ip mimo studies may, optionally, be used to identify optimal dosing intervals. The exact dose to be used will also depend on the route of administration and the complexity of the condition being treated, and should be selected according to the judgment of the specialist and the conditions of each patient with reference to, for example, published clinical studies. However, suitable effective dosage amounts range from about 0.01 mg/kg body weight to about 2500 mg/kg body weight, although they are typically about 100 mg/kg body weight or less. In one embodiment, an effective dosage amount of a compound of Formula I is in the range of from about 0.01 mg/kg body weight to about 100 mg/kg body weight, in another embodiment, from about 0.02 mg/kg body weight to about 50 mg /kg body weight, and in another embodiment, about 0.025 mg/kg body weight to about 20 mg/kg body weight.

In one embodiment, an effective dosage amount is administered approximately every 24 g until the condition subsides. In another embodiment, an effective dosage amount is administered approximately every 12 g until the condition subsides. In another embodiment, an effective dosage amount is administered approximately every 8 g until the condition subsides. In another embodiment, an effective dosage amount is administered approximately every b g until the condition subsides. In another embodiment, an effective dosage amount is administered approximately every 4 g until the condition subsides.

Effective dosage amounts are described here for a total number of uses; that is, if more than one compound of formula I or a pharmaceutically acceptable derivative thereof is administered, in an effective dosage amount corresponding to the total amount administered.

When a cell capable of expressing TRIPVI1 is contacted with a compound of Formula I, the amount effective to inhibit the function of the TRIPVI receptor in the cell will typically be in the range of about 0.01 μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/L to about 2.5 mg/L, in another embodiment, from about 0.01 μg/L to about 0.5 μg/L, in another embodiment, from about 0.01 μg/L to about 0.25 μg/l of a solution or suspension of a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of the solution or suspension containing the compound of formula I or its pharmaceutically acceptable derivative is from about 0.01 μl to about 1 ml. In another embodiment, the volume of the solution or suspension is approximately 200 μl.

Compounds of formula I or a pharmaceutically acceptable derivative thereof may be tested ip migo or ip mimo for desired therapeutic or prophylactic activity prior to use in humans.

Animal model systems can be used to demonstrate safety and efficacy.

Presented methods of treating or preventing a Condition in an animal in need thereof may also include administering to the animal to which it is administered a compound of formula | or its pharmaceutically acceptable, other therapeutic agent. In one embodiment, another therapeutic agent is administered in an effective amount.

Presented methods of inhibiting the function of TRTI in a cell capable of expressing TRTI1 may also include contacting the cell with an effective amount of another therapeutic agent.

Effective amounts of other therapeutic agents are well known to those skilled in the art. However, it is within the skill of one skilled in the art to determine optimal effective amounts of other therapeutic agents. In one embodiment of the invention, where another therapeutic agent is administered to the animal, an effective amount of the compound of formula | is less than the effective amount when no other therapeutic agent is prescribed. In this case, without being bound by theory, it is understood that the compounds of formula I and the other therapeutic agent act synergistically in the treatment or prevention of the condition.

Other therapeutic agents include, but are not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an anti-migraine agent, a Soh-II inhibitor, an antiemetic agent, a β-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca blocker? -channels, anticancer agent, agent for the treatment or prevention of NS, agent for the treatment or prevention of ulcers, agent for the treatment or prevention of CKD, agent for the treatment or prevention of PCOS, agent for the treatment of habit, agent for the treatment of Parkinson's disease and parkinsonism, agent for the treatment

STI antagonists and their applications anxiety, agent for the treatment of epilepsy, agent for the treatment of stroke, agent for the treatment of seizure, agent for the treatment of pruritus, agent for the treatment of psychosis, agent for the treatment of Huntington's chorea, agent for the treatment of ALS, agent for the treatment of cognitive impairment, agent for the treatment of migraine, an agent for the treatment of emesis, an agent for the treatment of dyskinesia or an agent for the treatment of depression and mixtures thereof.

Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, dampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimeheptanol, dimethylthiambutene, dioxafetil butyrate, dipipanone, eptazocine, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocin, morone, metopone, methadfin, mirofine, nalbuphine , narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaverine, pentazocine, phenadoxone, phenomorphan, phenazocine, phenopyridine, piminodine, pyritramide, proheptazine, promedol, properdin, propyram, propoxyphene, sufentanil, tilidine , tramadol, their pharmaceutically acceptable salts and their mixtures.

In some embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.

Examples of useful non-opioid analgesics are non-steroidal anti-inflammatory agents such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxanic acid, indomethacin, sulindac, tolmetin, zomerirac, tiopinac, zidomethacin, acemethacin, phentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurizal, flufenizal, piroxicam, sidoxicam, isoxicam, and their pharmaceutically acceptable salts and their mixtures. Other suitable non-opioid analgesics include, but are not limited to, the following chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, magnesium choline trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indenoacetic acids, including indomethacin, sulindac, and etodolac; heteroarylacetic acids, including tolmetin, diclofenac and ketorolac; anthranilic acids (phenamates), including mefenamic acid and meclophenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam) and pyrazolidinediones (phenylbutazone, oxyfentartazone); and alkanones, including nabumetone. For a more detailed introduction to

NSPZLK, see Ratsi A. Ipzei, ApaiYidevzis-Apiirugeiis apa Apii-ipPattaiyugtu Adepiz apa Ogyd5

Etriouei ip iShie Tgeaitepi oi Soc, boodtap 4 Siitapye Te Rpaptasoiodisa! Vaziv oi Tegareshisv 617-57 (Reitu V. Moiippoi apa Nautopa MU. VKidaop edv., 9 ey 1996) and Siep K. Napsop, Apa!davis,

Apiirugeiis apa Apii-IpPattayogu Ogydz5 ip Ketipdiop: Te Zsiepse i Rgasiise oi Rpagtasu Mo! AND! 1196-1221 (A. V. Seppago ed. 1917 ey. 1995), which are incorporated herein by reference in their entirety.

Examples of useful Soh-II and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in US Pat. No. 6,136,839, which is incorporated herein by reference in its entirety. Examples of useful Cox-II 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, ergocornine, ergocominine, ergocriptine, ergonovine, ergot, ergotamine, flumedroxone acetate, phonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone , pizotilin, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan and their mixtures

Another therapeutic agent may also be useful in reducing any potential side effects of a compound of formula I. For example, another therapeutic agent may be an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromide, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol .

Examples of useful β-adrenergic blocking agents include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butydrine hydrochloride, butofilolol, carazolol, carteolol , carvedilol, celiprolol, ketamolol, cloranolol, dilevalol,

Antagonists of STIs and their use epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, niphenanol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronetalol, propranolol, sotalol, sulfinanol, talinolol , tertatolol, tilisolol, timolol, toliprolol and xibenolol.

Examples of useful anticonvulsants include, but are not limited to, acetylfeneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, zinromide, clomethiazole, clonazepam, decimide, dietadione, dimethadione, doxenitroine. . Z-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, fenetarbital, feneturide, phenobarbital, phensuccimid, phenylmethylbarbituric acid, phenytoin, sodium fetenylate, potassium bromide, pregabalin, primidone, progabid, sodium bromide, solanum, strontium bromide, suclofenide, sulthiam, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.

Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (5)-citalopram, dimetazane, phencamine, indalpine, indeloxasine hydrochloride, nefopam, nomiphenzine, oxytriptan, oxypertin, paroxetine, sertraline, thiazem, trazodone, benmoxine, iprocloside, iproniazid, isocarboxazid, nialamide, octamoxine, phenelzine, cotinine, roliciprin, rolipram, maprotiline, metrolindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptyline oxide, amoxapine, butryptyline, clomipramine, demeciptyline, desipramine, dibenzapine, dimethacrine, dothiepine, doxepin fluacizin, imipramine , imipramine M-oxide, iprindole, lofepramine, melitracene, metapramine, nortriptyline, noxyptyline, opipramol, pisotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactysine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levofacetoperan, medifoxamine, milnacipram, minaprine, moclobe copper, nefazodone, oxaflozan, piperaline, prolintane, pyrisuccidanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, tozalinone, tofenacin, toloxatone, tranylcypromine, I-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful Ca? channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, halopamil, mibefradil, prenilamine, semotiadil, terolidine, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine , lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencycline, etafenone, fentofaron and perhexyline.

Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelecin, aldesleukin, altretamine, ambomycin, amethantrone acetate, aminoglutethimide, amsacrine, anatsrosol, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisanthrene hydrochloride, bisnafide dimesylate, biselezine, bleomycin sulfate, brequinar sodium, bropyrimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelezine, sedefingol, chlorambucil, cirolemicin, cisplatin, cladribine, krysnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diazichone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflomisamine hydrochloride, endoplatin hydrochloride enpromate, epipropidine, epirubits inu hydrochloride, erbulozole, ezorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fasarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, foschidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea , idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin I! or gi/2), interferon alfa-2a, interferon alfa-2p, interferon alfa-p1, interferon alfa-p3, interferon beta-ia, interferon gamma-IiB, iproplatin, irinotecan hydrochloride, linreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometeroxol sodium, lomustine, lozoxantrone hydrochloride, mazoprocol, maintansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaryl, mercaptopurine, methotrexate, methotrexate sodium, methoprine, meturedep, mitindomide, mitocarcin, mitochromin, mitogiline, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxysuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perphosphamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestan, porfimer sodium, porfiromycin, prednimustine, procarbazine

Antagonists of SARS and their use hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazen, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, thalizomycin, tekogalan sodium, tegafur, tuloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprin, thioguanine, thiotepa, thiazofurin, tirapazamine, toramycin citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucoronate, triptorelin, tubulozole hydrochloride, nitrogen mustard, uredepa, vapreotide, verteporfin .

Examples of other anticancer drugs include, but are not limited to, 20-epi-1,25-dihydroxyvitamin 03; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecyphenol; adozeletin; aldesleukin; AGI/-TC antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrazole; andrographolide; angiogenesis inhibitors; antagonist O; antagonist with; Antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostate carcinoma; anti-estrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; modulators of the apoptosis gene; regulators of apoptosis; auric acid; aga-SOR-OI -RTVA; arginine deaminase; azulacrine; atamestan; atrimustine; Axinastatin 1; axinastatin 2; Axinastatin 3; azasetron; azatoxin; azatyrosine; derivatives of bacatin I; balanol; batimastat; VSK/AVI antagonists; benzochlorins; benzoylstaurosporine; betalactam derivatives; beta-alletin; betaclamycin B; betulinic acid; BEOE inhibitor; bicalutamide; bisanthrene; bisaziridinylspermine; bisnafid; Bistraten A; biselezin; breflat; bropyrimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; capmptothecin derivatives; canarypox 1-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; Sakkezi M3; SAM 700; cartilage modifier inhibitor; carzelestine; casein kinase inhibitors (ISO5); castanospermine; cecropin B; cetrorelix; chlorine; chlorquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; analogues of clomiphene; clotrimazole; colismycin A; colismycin B; combretastatin A4; analogue of combretastatin; conagenin; crambescidin 816; chrysnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentantraquinones; cycloplatam; Cypemcin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diazychone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; doconazole; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin ZA; ebselen; ecomustin; edelfosine; edrecolomab; eflomitin; element; emitefur; epirubicin; epristeride; analogue of estramustine; estrogen agonists; estrogen antagonism; etanidazole; etoposide phosphate; exemestane; fadrozole; fasarabine; fenretinide; filgrastim; finasteride; Fflavopiridol; flezelastin; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; hydramanton; ilmofosine; ilomostat; imidazoacridones; imiquimod; immunostimulating peptides; insulin-like growth factor-I receptor inhibitor; interferon agonists; interferons; interleukins; iobenguan; iododoxyrorubicin; 4- ipomeanol; iroplast; irsogladin; isobenzazole; isohomohalichondrin B; itasetron; jasplakinolide; kagalalide E; lamellarin-M triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolidtestosterone and progesterone; leuprorelin; levamisole; liarozol; analogue of linear polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lisoclinamide 7; lobaptalin; Lombricin; lometrexol; lonidamine; lozoxantrone; lovastatin; loxoribine; lurtotecan; texaphyrin lithium; lysophyllin; virulent peptides; maytansine; matostatin A; marimastat; mazoprokol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbaron; meterelin; methioninase; metoclopramide; MIR inhibitor; mifepristone; miltefosine; measurable; uncoordinated double-stranded RNA; mitohuason; mitolactol; mitomycin analogues; mitonafid; growth factor mitotoxin fibroblast-saporin; mitoxantrone; mofarotene; thunderous; human chorionic gonadotropin monoclonal antibody; monophosphoryloipide Myobacterial cell walls; mopidamol; multidrug resistance gene inhibitor; cancer suppressor; anticancer agent based on mustard; micaperoxide B; mycobacterial cell wall extract; myriaporon; M- acetyldinalin; M-substituted benzamides; nafarelin; nagrestype; naloxonepentazocine; Napavin naphtherpine; nartograstim; nedaplatin; Nemorubcin; neridronic acid; neutral endopeptidase; nilutamide; nizamycin; nitric oxide modulators; nitroxide antioxidants; nitrulin;

Ob-benzylguanine; octreotide; okiuenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin;

Antagonists of STI and their use pacltaxel; analogues of paclitaxel; paclitaxel derivatives; palauamine; palmitoyl rhizoxin; pamidronic acid; panoxytriol; panomifen; parabactin; pazeliptin; pegaspargase; peldesin; sodium pentosan polysulfate; pentostatin; Pentrozol; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; pizzabanil; pilocarpine hydrochloride; pirarubicin; pyritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complexes; platinum compounds; platinum-triamine complex; sodium orphimer; porfiromycin; prednisone; propyl bis-acridine; prostaglandin 2; proteasome inhibitors; protein A-based immunomodulator; protein kinase C inhibitor; inhibitors of protein kinase C, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugates; antagonists of the grove; raltitrexide; ramosetron; gah farnesyl protein transferase inhibitors; HA5 inhibitors; GAB5-SAP inhibitor; reteliptin demethylated; rhenium Ke!85 etidronate; rhizoxin; ribozymes; EYELASH retinamide; rogletimide; rohitukin; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; Cyintopin; orders; Sarcophytol A; sarliterate; Bayi 1 mimetics; semustine; inhibitor of aging modification 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding protein; Sizophyran; zobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; momatomedin binding protein; sonermin; sparphosic acid; spicamycin 0; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; antagonist of superactive vasoactive intestinal peptide; suradista; suramin; swainsonine; synthetic glycosaminoglycans; talismustine; tamoxifen methiodide; tauromustine; tazarotene; tekogalan sodium; tegafur; tellurapyryllium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetic; timalfazin; thymopoietin receptor agonist; timotrine; thyroid-stimulating hormone; tin ethylthiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; pluripotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosterid; tyrosine kinase inhibitor; tyrphostin; OBS inhibitors; ubenimex; urogenital sinus-aorhoid growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; erythrocyte gene system vector; velarezol; veramin; verdins; verteporfin; vinorelbine; Vinxaltine; vitaxin; vorozol; zanoterone; Zeniplatin; zilassorb and zinostatin stimalamer.

Examples of useful therapeutic agents for the treatment or prevention of NS include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for the treatment or prevention of ulcers are antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuth compounds such as bismuth subsalicylate and bismuth subcitrate; Neg antagonists such as cimetidine, ranitidine, famotidine, and nizaidine; NU, K"-ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as tetracycline, metronidazole, thimidazole, clarithromycin, and amoxicillin.

Examples of useful therapeutic agents for the treatment or prevention of CKD include, but are not limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized tincture of opium; codeine; broad-spectrum antibiotics, such as metronidazole; sulfasalazine; olsalazine; mesalamine; prednisone; azathioprine; mercaptopurine and methotrexate.

Examples of useful therapeutic agents for the treatment or prevention of PCOS include, but are not limited to, propantheline; muscarinic receptor antagonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methyl bromide, and methantheline; and antidiarrheal agents such as diphenoxylate and loperamide.

Examples of useful therapeutic agents for the treatment or prevention of addiction include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenoprine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists.

Examples of useful therapeutic agents for the treatment or prevention of disease

Parkinson's 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 the treatment or prevention of anxiety include, but are not limited to, benzodiazepines such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxepam, diazepam, estazolam, flumazenil, flurazepam, galazepam, lorazepam, midazolam, nitrazepam, nordazepam , oxazepam, prazepam, quazepam, temazepam and triazolam; nonbenzodiazepine agents such as buspirone, gepirone, ipsaprion, thiospiron, zolpicone, zolpidem, and zaleplon; tranquilizers such as barbiturates such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital and thiopental; and propanediol carbamates such as meprobamate and tibamate.

Antagonists of STI and their use

Examples of useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, y-vinyl SZAVA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, clot-dissolving agents such as streptokinase or tissue plasminogen activator, anti-edema agents such as mannitol or corticosteroids, and acetylsalicylic acid .

Examples of useful therapeutic agents for the treatment or prevention of epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, gabapentin, lamotrigine, y-vinyl

SAVA, acetazolamide and felbamate.

Examples of useful therapeutic agents for treating or preventing pruritus include, but are not limited to, naltrexone; nalmefene; danazol; tricyclic compounds such as amitriptyline, imipramine and doxepin; antidepressants, such as the compounds below, menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids and antihistamines.

Examples of useful therapeutic agents for the treatment or prevention of psychosis include, but are not limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and toridazine hydrochloride; thioxanthans such as chlorprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide and ziprasidone.

Examples of useful therapeutic agents for the treatment or prevention of chorea

Huntington's includes, but is not limited to, haloperidol and pimozide.

Examples of useful therapeutic agents for the treatment or prevention of ALS include, but are not limited to, baclofen, neutrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepane and dantrolene.

Examples of useful therapeutic agents for the treatment or prevention of cognitive disorders include, but are not limited to, agents for the treatment or prevention of dementia, such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressants such as the compounds below.

Examples of useful therapeutic agents for the treatment or prevention of 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 emesis include, but are not limited to, 5-HT3 receptor antagonists such as ondansetron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlorperazine, triethylperazine, chlorpromazine, metoclopramide, and domperidone; glucocorticoids such as dexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for the treatment or prevention of dyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for the treatment or prevention of depression include, but are not limited to, tricyclic antidepressants such as amitriptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlaflaxine; selective serotonin reuptake inhibitors such as citalopram, (5)-)ucitalopram, fluoxetine, fluvoxamine, paroxetine and cetraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate.

The compound of the formula | or a pharmaceutically acceptable derivative thereof and another therapeutic agent may act additively or, in one embodiment, synergistically. In one embodiment, a compound of the formula is administered simultaneously with another therapeutic agent. In one embodiment, a composition containing an effective amount of a compound of formula I and an effective amount of another therapeutic agent may be administered. Alternatively, a composition containing an effective amount of a compound of formula I and another composition containing an effective amount of another therapeutic agent may be administered simultaneously. In another embodiment, an effective amount of a compound of formula I is administered before or after administration of an effective amount of another therapeutic agent. In this embodiment, 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 !| exerts its preventive or therapeutic effect aimed at the treatment or prevention of the Condition.

The composition of the invention is obtained by a method that includes mixing a compound of formula I or a pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier or excipient.

Mixing can be done using methods well known for mixing compounds (or

Antagonists of TPRVI and their salt application) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition is prepared so that the compound of formula I is present in the composition in an effective amount.

SETS

The invention includes a set that can simplify the introduction of a compound of the formula ! or its pharmaceutically acceptable derivative to an animal.

Typically, a kit of the invention contains a unit dosage form of a compound of formula I. In one embodiment, the unit dosage form is a container, which may be sterile, and which contains an effective amount of a compound of formula I and a pharmaceutically acceptable carrier or excipient. The kit may also include a label or printed instructions for use of the compound of formula | to treat or prevent a Condition. The kit may also contain a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the kit includes a container containing an effective amount of a compound of formula I and 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, the compounds described above.

Kits of the invention may also include a device useful for administering unit dosage forms. Examples of such devices include, but are not limited to, a syringe, dropper bag, patch, inhaler, and enema.

The following examples are provided to facilitate an understanding of the invention and, of course, 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 discovered, which would be within the knowledge of a person skilled in the art and changes in the formulation or minor changes in the experimental plan, are considered within the scope of the invention presented herein.

EXAMPLES

EXAMPLES 1-9, 10A AND 108: SYNTHESIS OF COMPOUNDS OF FORMULA I

Example 1: Syntheses of compounds 21, 11, 02, 51, Ib, M1, 9Ub 2,3-dichloro-5-formylpyridine snoH sno si AM si AM

SI (about 64 65

In a 500-mL round-bottom flask, manganese oxide (43.5 g, 0.50 mol) was added to a solution of 2,3-dichloro-5-hydroxymethylpyridine (64, 8.10 g, 50.0 mmol) in anhydrous SN3S (150 mL ). The reaction mixture was stirred at a temperature of about 25 "C for 48 g, filtered through CELY and concentrated under reduced pressure. The mixture was chromatographed using column chromatography on silica gel, eluting with a gradient of ethyl acetate (0 95-40 95)/hexanes to give 7.2 g 65 ( 90 95 exit). "H NMR (400 MHz, SOSI") b 10.08 (1H, s), 8.77 (1H, d, 9U-1.97 Hz), 8.25 (1H, d, 9 -1.97

Hz). LC/MS (M): 176. 2,3-Dichloro-5-vinylpyridine sno -

Z/ RRIBSNZVg hSh pen si dm (t-VyO Zh s M a sa 65 06

To a stirred suspension of methyltriphenylphosphonium bromide (10.0 g) in toluene (200 ml) at 0 "C, potassium t-butoxide (3.07 g) was added in portions to obtain a yellow suspension. After 1 g, the reaction mixture was cooled to -20 "C and 65 (4.0 grams, 22.72 mmol) dissolved in tetrahydrofuran (b ml) was added dropwise to obtain a purple suspension. The reaction mixture was heated to 0 °C and stirred for another 1 h. The reaction mixture was then treated with a saturated aqueous solution of sodium chloride (150 mL) and 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 obtained product was chromatographed using column chromatography on silica gel, eluted with a gradient of ethyl acetate (0 95-10 uO)/hexanes, obtaining 2.77 g of 66 (70 Fo output).

Antagonists of STI and their use

IN NMR (400 MHz, SOSI") b 8.30 (1H, d, 9U-2.19Hz), 7.80 (1H, d, uU-2.19Hz), 6.63 (1H, dd, 9- 10.96, 17.680Hz), 5.86 (1H, d, U-17.80Hz), 5.45 (1H, d, 9U-10.96Hz). LC/MS (M1): 174. (5)-1-(5,6-dichloropyridin-3-yl)ethane-1,2-diol and (K)-1-(5,6-dichloropyridin-3-yl) )ethane-1,2-diol

ON y la, ON ek AR-thich o. ХУ -жн- - 35 aby" otvono dyna (o) s 66 67a on 7 On

Me AR-tih r - -- » t - - I al t-Voon wallah

С sa 66 67b

A solution of 66 (0.909 g, 5 .25 mmol) in t-butanol (5 mL). After 24 g, solid sodium sulfite (9.57 g) was added and the resulting suspension was allowed to stir at about 25 °C for 30 min. The mixture was extracted three times with ethyl acetate (50 ml for each extraction). The organic parts were combined, washed with brine, dried (Mag 5 O»x), and concentrated under reduced pressure. The mixture was chromatographed using column chromatography on silica gel, eluting with ethyl acetate (50 95-100 9do)/hexanes, obtaining 0.75 g of product (67a for АЯ-those sa or 676 for AO-those VD) as a white solid (70 95 yield ). "H NMR (400 MHz, SOSI»z) b 8.29 (IN, dd, 9-0.44, 1.97Hz), 7.87 (1H, dd, 9-0.66, 2.19Hz), 4.87 (1H, m), 3.84 (1H, m), 3.66 (1H, m), 2.83 (IN, d, 9-5.92Hz), 2.11 (1H, t, U-5.92Hz). LC/MS (M1): 208. (5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3,6'-dihydro-2'H-(2, 4bipyridinyl-1-carboxylic acid tert-butyl ester nO,, ' (Fin 3-4 More

BUT,,, (6) (c); M to Ton "V' RaO(RRB3)" SIYU SI

KSO, in: хх эх ны - 5 -

AM

SI M M s F F (c) (6) () o 67a - -- 68 69

B7a (0.70 g, 3.37 mmol), (M-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (68, 1.25 g, 4.04 mmol), RD(PPAz)2Si" (0.189 g, 0.27 mmol), potassium carbonate (0.883 g, 6.40 mmol), and a mixture of OME/EUN/HgO (8 ml/4 ml/8 ml ).

The reaction mixture was flushed with nitrogen, the flask was closed and the reaction mixture was heated at 90 °C with vigorous stirring. After 2 g, the reaction mixture was cooled to a temperature of approximately 25 °C and diluted with EtOAc (50 ml). The organic layer was washed with brine, dried (Mag5Oa4) and concentrated under reduced pressure. The residue was chromatographed by column chromatography on silica gel using a gradient of ethyl acetate (50 950-100 9 and hexanes to give 0.96 g of 69 (80 95 yield). "H NMR (400 MHz, CO3Ob) b 8.47 (1H, s), 7, 93 (1H, s), 6.06 (1H, m), 4.74 (1H, t, 9-5.92 Hz), 4.12 (2H, m), 3.67 (AN, m), 2 .54 (2H, m), 1.52 (9H, s). LC/MS (M-1): 355.

Antagonists of SARS and their use (5)-1-(3-Chloro-127,3,6'-tetrahydro-(2,4bipyridinyl-5-yl)-ethan-1,2-diol on peOtoN ov, te on

Uh 7

M

SI M

NSI SI

--zh3- xx

Wow

M

M

N

() (6) ra " 69

69 (0.90 g, mmol) and 2M NOSI in ESO (10 ml) were loaded into a flask (50 ml) and closed. The reaction mixture was stirred at 40 "C for 20 g. The reaction mixture was cooled to a temperature of about 25 "C and the solid precipitate was filtered, washed with ESO (20 ml) and dried under reduced pressure to obtain 0.65 g of 70 (299 95 yield). "H NMR (400 MHz, COzObB) b 8.74 (1H, s), 8.52 (1H, s), 6.38 (IN, m), 4.91 (1H, m), 4.00 ( 2H, m), 3.75 (4H, m), 3.54 (2H, t, 9U-5.92Hz), 2.89 (2H, m). LC/MS (M-1): 255. ( 5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3,6'-dihydro-2'H-(2,4bipyridinyl-1-carboxylic acid (4-trifluoromethyl-phenyl)amidon OH, ",, ON (Fin! 7 f -0o M

M with 2

In o r

M i SEz F -- I -F -t3- ) MN 70 PRIVA 8

SEZ

71

To a suspension of 70 (800 mg, 2.45 mmol) in anhydrous dichloromethane (20 mL), diisopropylethylamine (O1IEA, 2 mL) was added dropwise, and the reaction mixture was stirred at a temperature of approximately 25 °C for 10 min. The mixture was cooled to -10 °C. C and 1-isocyanato-4-(trifluoromethyl)benzene (462 mg, 2.45 mmol) was added slowly over 5 min, which was diluted with anhydrous dichloromethane (5 mL).

After stirring at -10 "C for 10 additional minutes, the mixture was chromatographed by silica gel column chromatography using a methanol (0 95-90)/ethyl acetate gradient to afford 0.60 g of 71 (56 95 yield). "H NMR (400 MHz, COzOb) b 8.49 (1H, dd, 9U-0.44, 1.75Hz), 7.94 (1H, dd, 9U-0.44, 1.75Hz), 7.72 (4H, m), 6.14 (1N, m), 4.78 (1TN, t, 9U-5.70Gu), 4.27 (2N, m), 3.82 (2N, t, U-5.70Hz), 3, 70 (2H, m), 2.66 (2H, m). MS: t/ - 441. (5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3,6'-dihydro-2'H-(2,4bipyridinyl-1-carboxylic acid (4- tert-butyl-phenyl)amide

Antagonists of STI and their use

BUT, but, in ron kak ol u sia

M | eh

TH and M

M

SI ee ee

M

Oh

BEER at MN 70 o

Pp

The title compound 1 was prepared using a procedure similar to that described for the preparation of 7271 except that 1-tert-butyl-4-isocyanatobenzene was used instead of 1-isocyanato-4-(trifluoromethyl)benzene (59 95 yield). "H NMR (400 MHz, COzOb) b 8.48 (1H, dd, 9U-0.66, 1.97 Hz), 7.94 (1H, dd, U-0.66, 1.75Hz), 7 .36 (ZH, m), 6.14 (1H, m), 4.79 (1H, t, U-5.26Hz), 4.27 (2H, m), 3.78 (2H, t, 9U -5.48Hz), 3.71 (2H, m), 2.64 (2H, m). LC/MS (M.-1): 430. (5)-3-Chloro-5-(1,2 -dihydroxy-ethyl)-3,6'-dihydro-2'H-(2,4bipyridinyl-1-carboxylic acid /(3- chloro-4-trifluoromethyl-phenyl)amidone (ene) t on t» on a

M

AK

UM ts neo si -

SI xx xx

SI M

SEz

M o ek -Z33nnnnnnNnNnNnNnNnNnNnNnNnNnNnNn33Н3Н33----

PVA

70

SI

SEZ

02

To a suspension of 70 (95 mg, 0.29 mmol) in anhydrous dichloromethane (4 mL) was added dropwise

RIEA (0.5 ml) and the reaction mixture were stirred at a temperature of approximately 25 °C for 10 min.

Then the mixture was cooled to -10°C and 3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (104 mg, 0.29 mmol, obtained in situ from 2-chloro-4-nitrobenzotrifluoride (bidtta -Aiyagis!)) in anhydrous dichloromethane (5 mL). After stirring at -10 "C for an additional 10 minutes, the mixture was chromatographed by silica gel column chromatography using a methanol (0 95-5 95)/ethyl acetate gradient to afford 30 mg of 02 ( 23 95 output). "H NMR (400 MHz, COzOb) b 8.50 (IN, m), 7.95 (1H, dd, 9-0.44, 1.75Hz), 7.82 (1H, d, 9U-1, 97Hz), 7.66 (1H, d, 9U-8.77Hz), 7.53 (1IN, m), 6.15 (1H, m), 4.78 (1H, t, y-5.48Hz) , 4.27 (2H, m), 3.81 (2H, t, 9U-5.70 Hz), 3.69 (2H, m), 2.65 (2H, m). MS: t/; - 475 (5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3,6'-dihydro-2'H-(2,Abipyridinyl-1-carboxylic acid) /(3-fluoro-4-trifluoromethyl -phenyl)amide

Antagonists of TBVI and their application

ON, o) en I on t on

Uh neo -h dm si

SI ay

E xx and SEZ

M

--------7 7

M PIBA Zh

H ) MH 70

IS

SEZ

51

The title compound 51 was prepared using a procedure similar to that described for the preparation of 02, except that 4-nitrophenyl 3-fluoro-4-(trifluoromethyl)phenylcarbamate was used instead of 3-chloro-4-(rifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (38 95 output). "H NMR (400 MHz, COzObB) b 8.48 (1H, dd, 9U-0.44, 1.75Hz), 7.95 (1H, dd, U-0.66, 1.97Hz), 7, 57 (2H, m), 7.36 (1H, m), 6.14 (1H, m), 4.77 (1IN, t, 9U-5.48Hz), 4.23 (2H, m), 3 .81 (2H, t, 3-5.48 Hz), 3.69 (2H, m), 2.65 (2H, m). MS: t/; - 459. (5)-3-Chloro-5- (1,2-dihydroxy-ethyl)-3,6'-dihydro-2'H-(2,4-bipyridinyl-1-carboxylic acid)/(3-ethyl-4-trifluoromethyl-phenyl)amidone

HE, oh oh hey! (Fin y N s no | ee aby" (7 ay o» eh x SEz -- -Ж lal hеya; and :0:':,A:B NN» M m Ж

Н PIBA o МН 70 o»

SEZ

16

The title compound IE was prepared using a procedure similar to that described for the preparation of 02, except that 4-nitrophenyl 3-ethoxy-4-(trifluoromethyl)phenylcarbamate was used instead of 3-chloro-4-(rifluoromethylphenyl)carbamic acid of the 4-nitrophenyl ester (25 95 output). "H NMR (400 MHz, COzOb) b 8.27 (1H, dd, 9U-0.66, 1.97Hz), 7.72 (1H, dd, U-0.66, 1.97Gu), 7, 25 (2H, m), 6.88 (1H, d, U-8.55Hz), 5.94 (1H, m), 4.57 (1H, t, U-5.48Gu), 4.08 ( 2H, m), 3.96 (2H, k, U9-7.02Gu), 3.64 (2H, m), 3.52 (2H, m), 2.44 (2H, m), 1.23 (ZH, t, U-7.02Hz). LC/MS (M--1): 486. (5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3,6'-dihydro -2'H-(2,4bipyridinyl-1-carboxylic acid /(3-

Antagonists of SARS and their use chloro-4-trifluoromethoxy-phenyl)amide

he

MTF) v. (Fin!

Also (en! a

NM (6);

MIND

A: SI

M

SI SI xx

EZSO

M: M nn

M (c) MN

N PRIVA

70

SI

OSE»z

U1

The title compound 71 was prepared using a procedure similar to that described for the preparation of 02, except that 4-nitrophenyl 3-chloro-4-(trifluoromethoxy)phenylcarbamate was used instead of 3-chloro-4-(rifluoromethylphenyl)carbamic acid of the 4-nitrophenyl ester (20 95 output). "H NMR (400 MHz, COzObB) b 8.30 (1H, dd, 9U-0.44, 1.75Hz), 7.74 (1H, dd, 9U-0.66, 1.75Hz), 7, 57 (1H, d, 9U-2.41Gu), 7.25 (1H, dd, 9U-2.63, 8.99Hz), 7.14 (1H, m), 5.94 (1H, m), 4.57 (1H, t, y-5.70Hz), 4.06 (2H, m), 3.59 (2H, t, 9U-5.70Hz), 3.50 (2H, m), 2, 46 (2H, m). LC/MS (M.-1): 492. (5)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3,6'-dihydro-2'H- (2,4bipyridinyl-1-carboxylic acid /(3-ethyl-4-trifluoromethoxy-phenyl)amid on on MO» and on tv, OH DT neo | te a ru M s

MIND

SI ee

EZSO v-k K)

M

M -:.-- ra (c) MN

N FISH

OSE" from 16

The title compound UbE was prepared using a technique similar to that described for the preparation of 02, except that 4-nitrophenyl 3-ethyl-4-(trifluoromethoxy)phenylcarbamate was used instead of 4-nitrophenyl 3-chloro-4-(rifluoromethylphenyl)carbamic acid ester (30 95 yield). "H NMR (400 MHz, COzObB) b 8.49 (1H, d, 9U-1.97Hz), 7.94 (1H, d, 9-1.75Hz), 7.42 (IN, d, U- 2.63Hz), 7.33 (1H, dd, U-2.85, 8.99Hz), 7.17 (1H, m), 6.16 (1H, m), 4.77 (1H, t, U-5.48Hz), 4.25 (2H, m), 3.80 (2H, t, U-5.48Hz), 3.70 (2H, m), 2.68 (2H, m), 1 ,25 (ZN, t, U-7.67Gu). LC/MS (M1): 486.

Antagonists of STI and their use

Example 2: Synthesis of compound M1 2-bromo-3,5-dichloropyridine (about SI

TM5VI

Eh

AM | DI (7 SI 2

C Vg 71 72

1.82 g of compound 71 (10.0 mmol) and propionitrile (20 ml) were charged into a 100 ml round-bottom flask equipped with a refrigerator, and 3.06 g of TM5Vg (20.0 mmol) was slowly added to the resulting solution. The reaction mixture was stirred at 100 "C under nitrogen 14 g, then cooled to a temperature of approximately 25 "C and diluted with EIOAc (100 ml). The EIOAc layer was separated, dried and concentrated under reduced pressure to give 72 as a yellowish solid (299 95 yield). tert-butyl 4-(3,5-dichloropyridin-2-yl)-4-hydroxypiperidine-1-carboxylate

IF; xx si

І) tvshi alYa" t-Vy 7 on

AM with o sh-o i

M Sov 72 os 74

Under nitrogen, to a solution of 72 (2.27 g, 10 mmol) in 200 ml of diethyl ether at -78 "C dropwise while cooling with ice through a syringe, maintaining the temperature below -75 "C, 1.7M t-

You! in pentane (6 mL, 10.5 mmol). After the addition was complete, the reaction mixture was stirred at -78 "C for 2 h. Then, a solution of 4-BOC-piperidone (1.99 g, 10 mmol) in 20 mL of anhydrous diethyl ether was slowly added via syringe. The reaction mixture was stirred at -78 " C for 2 g and slowly heated to a temperature of approximately 25 "C. Saturated aq. was added to the mixture

The second layer of diethyl ether was separated, dried and concentrated under reduced pressure on a rotary evaporator. Column chromatography of the residue on silica gel using ethyl acetate/hexanes as eluent afforded 2.1 g of 74 as a yellowish oil (61 95 yield after 2 steps). tert-butyl 4-(3,5-dichloropyridin-2-yl)-4-fluoropiperidine-1-carboxylate

SI SI ee | eh

M M si VABT STI

HE and E and and vos vos 74 75

VAZT (2.5 mL, 18.8 mmol) was slowly added to 100 mL of a DCM solution of 74 (6.0 g, 17.3 mmol) at -78 °C, and the resulting mixture was allowed to warm to a temperature of approximately 25 °C for 16 h , then washed with saturated MnHsCO3, dried (M95O5) and concentrated under reduced pressure.

Silica gel column chromatography of the residue using E(Ac/hexanes) afforded 2.5 g of 75 as a yellowish solid (42 95 yield).tert-butyl 4-(3-chloro-5-vinylpyridin-2-yl)-4-fluoropiperidin-1 -carboxylate

Antagonists of SARS and their use in XX

Also Shchi 2-M si M svo SI

E would E -- - yan --3zk

St. Vos os

To a degassed solution of DMF 75 (0.558 g, 1.6 mmol) in a 100 ml round-bottom flask was added

C5E (0.486 g, 3.2 mmol), di-n-butyl vinyl ester of boric acid (0.388 ml, 1.76 mmol) and

РА(ОРРРЕ)2СИ» (0.105 g, 0.128 mmol). The reaction mixture was stirred at 100 "C for 14 g, then cooled to a temperature of approximately 25 "C, diluted with 100 ml of ethyl acetate and washed three times with brine (50 ml for each wash). The organic layer was separated, dried and concentrated under reduced pressure. Column chromatography on silica gel of the residue gave 0.33 g of 76 as a yellowish oil (60 95 yield). (5)-tert-butyl 4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoropiperidine-1-carboxylate on de HO,,,

Aya-tih-oh

M M

SI E -- a i-VION y i Y vos vos 76 77

In a 100 mL round-bottom flask, AYU-teh-a (0.5 g) was added to a mixture of t-butanol and water (2 mL/2 mL) and the mixture was stirred at a temperature of approximately 25 °C for 0.5 g, then cooled to 0 "s.

This solution was quickly poured into another ice-cooled flask containing 76 (140 mg, 0.41 mmol).

The mixture was intensively stirred in an ice bath of 96 g and then diluted with ethyl acetate (50 ml) and 2 ml of saturated Mag52O5. The ethyl acetate layer was separated, dried and concentrated under reduced pressure on a rotary evaporator to obtain 77. (5)-1-(5-chloro-6-(4-fluororegialip-4-yl)pyridin-3-yl)ethane-1 2-diol he he

BUT,,, BUT,,,

And I

NSI

M M si 0 --b2e beat

E E

M M vos y

0.15 g of 77 (0.36 mmol) dissolved in about 1 ml of

Antagonists of SARS and their use of dichloromethane. Then 10 ml of 4M HCl in dioxane was slowly added with intensive stirring.

The flask was closed with a rubber membrane 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 to give 112 mg of 78 as a white solid (299 95 MS (MAN): m/2 - 312. (5)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoro-M-(4- (trifluoromethyl)phenyl)piperidine-1-carboxamide

ON, toton on t (Fin | - 7 S

ME

M

SI

IS

M

SE ra

M Z , o pl

N

PROBLEM

78

SEZ

E

90 mg of 78 (0.26 mmol) suspended in dichloromethane was charged into a 100 ml round-bottom flask. OIEA (0.1 mL, 0.72 mmol) and 4-trifluoromethylphenylisocyanate (48 mg, 0.26 mmol) were added and the reaction mixture was stirred for 10 minutes. The mixture was chromatographed using flash column chromatography on silica gel and using a gradient of 0 95 - 5906 methanol in dichloromethane to give 50 mg of M1 as a white solid (60 95 yield). "H NMR (SOzOB) b 8.49 (d, 7-2 Hz, 1H), 7.90 (m, 1H), 7.60 (m, 4H), 4.76 (t, U-6 Hz, 1H), 4.17 (m, 2H), 3.68 (m, 2H), 3.45 (m, 2H), 2.50-2.34 (m, 4H). MS (M--1) : t/: - 462.1.

Example 3: Syntheses of piperazine compounds Kb, I6, Mb, Mb and UUb 2,3-dichloro-5-vinylpyridine sno - -

M DM si 4 K(M(TM5)") si si s 65 66

To a suspension of methyltriphenylphosphonium bromide (РРИзЗСНзВГ, 7.08 g, 19.8 mmol, Zidta-Aiagisp) in

A 0.5 M solution of potassium bis(trimethylsilyl)amide (K(IM(TM5)»2) in toluene (39.6 ml, 19.8 mmol, Zidta-Alaigisp) was added dropwise to THF (40 ml) at 0 "C. The resulting mixture was then stirred at 0 °C for 1 hour. A solution of 65 (3.17 g, 18.0 mmol) in THF (20 mL) was added to the mixture at 0 °C.

The reaction mixture was stirred for 2 g at 0 "C. The reaction was quenched with water and the mixture was extracted three times

EtOAc (150 ml for each extraction). The organic parts were combined, washed with brine and concentrated to dryness. Compound 6b was obtained as a light yellowish oil after flash chromatography using an ethyl acetate/hexane gradient as eluent (64 95 yield). "H NMR: (SOS Iz) b 8.28 (d, 9-21 Hz, 1H), 7.82 (d, 9U-2.2 Hz, 1H), 6.65 (dd, U-11.0 , 17.5 Hz, 1H), 5.85 (d, 9U-17.5 Hz, 1H), 5.48 (d, 9U-11.0 Hz, 1H) m.p.. tert-butyl 4- (3-chloro-5-vinylpyridin-2-yl)piperazine-1-carboxylate

Antagonists of STI and their use

N

M ona 4 os r --- p

M

SY 00 (t-Select) Mma M

SI RIOAs)" (C )

ORRR M

AND

66 axis 81

To a solution of 66 (1.74 g, 10.0 mmol) in toluene (15 mL) was added tert-butyl-1-piperazine carboxylate (1.86 g, 10.0 mmol, Zidta-Hiaghisi), palladium acetate (0.113 g, 0.5 mmol, bZidta-Alagisn), 1,3-bisidiphenylphosphino)propane (ORPP, 0.220 g, 0.5 mmol, 5idta-Alagisp), and sodium tert-butoxide (1.05 g, 11.0 mmol . The organic parts were combined, washed with brine and concentrated to dryness.

Compound 81 was obtained as a white solid after column chromatography on silica gel using an ethyl acetate/hexane gradient as eluent (88 95 yield). "H NMR: (SOSI") b 8.14 (m, 1H), 7.69 (d, 9U-1.5 Hz, 1H), 6.60 (dd, 9U-11.0, 17.5 Hz , 1H), 5.68 (d, 9U-17.5 Hz, 1H), 5.28 (d, 9-11.0 Hz, 1H), 3.58 (m, 4H), 3.32 (m , 4H), 1.49 (c, 9H) mol. MS (Mae-Ma): t/2 - 346.1. ,2-dihydroxyethyl)pyridin-2-yl)piperazine-1-carboxylate and NO TON

Go I

M y AM a 2 Art-tikh y (S

M inn an M (C ) t-VyOoN (C ) i i os os 81 82

To a suspension of 81 (2.84 g, 8.77 mmol) in tert-butanol (60 ml) and water (60 ml) at 0 "C was added AO-tikh-a (11.93 g, 8.77 mmol, zZidta 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 parts were combined, washed with brine and concentrated to dryness under reduced pressure. Compound 82 was obtained as a white solid after flash chromatography using an ethyl acetate/hexane gradient as eluent (90 95 yield). "H NMR: (SOSI") b 8.14 (d, 952.0 Hz, 1H), 7.67 (d, 9-22

Hz, 1H), 4.79 (m, 1H), 3.77 (m, 1H), 3.64 (m, 1H), 3.56 (m, 4H), 3.28 (m, 4H), 2.87 (d, 9-3.2 Hz, 1H), 227 (m, 1H), 1.48 (s, 9H) m.ch.. MS (Ma-1): t/2 - 358.1 . (5)-1-(5-chloro-6-(piperazin-1-yl)pyridin-3-yl)ethane-1,2-diol

Antagonists of STI and their use

NoOn., Fin NoOn., ON di Shchi -M

SI SI AM

NSI

M M their M vos y 82 83

A suspension of 82 (2.81 g, 7.85 mmol) and 4M HCl 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 give 83 as a white solid. (5)- M-(4-tert-butylphenyl)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)piperazine-1-carboxamidone

But oh

NoO., ON 27 | eh

M M

M: SI

M

A-M s (C )

S. I

And many

M » (e,;

N

TEA

83

Ke

To a mixture of 83 (0.5 mmol) in DCM (2.0 ml) and TEA (0.3 ml) was added dropwise at 0 °C a solution of 4-tert-butylphenyl isocyanate (0.5 mmol, β-Bidta-Alydgis) in DCM (1.0 ml). The reaction mixture was stirred at a temperature of about 25"C for 4 hours. After that, column chromatography on silica gel using an ethyl acetate/methanol gradient as eluent gave Kb as a white solid. "H NMR: (COzOr) b 8.18 (d, 9U-2.0 Hz, 1), 7.78 (d, 9U-2.0 Hz, 1H), 7.30 (m,

AN), 4.66 (t, U-5.5 Hz, 1H), 3.68 (m, 4H), 3.62 (m, 2H), 3.34 (m, 4H), 1.30 ( s, 9H) m.ch. MS (Ma1): t/2 - 433.2. (5)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-M-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxamide

Antagonists of TBVI and their application

BUT",

BUT", ON | h -0

M y: m" SI 4

M M si (C )

M

C 3 Y

M

H -- -- -- at 83 TEA

OSEz 16

To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL), a solution of 4-trifluoromethoxyphenyl isocyanate (0.5 mmol, Zidta-AiYdgis in DCM (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at about 25 °C for 4 h. After that, column chromatography on silica gel using an ethyl acetate/methanol gradient as eluent afforded 1.6 as a white solid. H NMR: (CO3Ob) b 8 ,18 (d, 9U-1.6 Hz, 1H), 7.78 (d, 9U-1.7 Gu, 1H), 7.47 (m, 2H), 7.18 (m, 2H), 4 .66 (t, U-5.9 Hz, 1H), 3.69 (m, 4H), 3.63 (m, 2H), 3.35 (m, 4H) m.ch.. MS (Ma1) : m/2 - 461.1. (5)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-M-(4-(trifluoromethyl)phenyl)piperazine-1- carboxamide (Fin!

BUT", -

BUT", ON 02? | c

M lo hu SI

M

AM si (C )

M M

SE

M - n YaA--- c)

N

TEA

83

SEZ

Me

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-trifluoromethylphenylisocyanate (0.5 mmol, 5-ylta-Alagisp) in DCM (1.0 mL) at 0 "C. The reaction mixture was stirred at a temperature of approximately 25 "C for 4 hours. After that, direct flash chromatography using an ethyl acetate/methanol gradient as eluent afforded Mb as a white solid. "H NMR: (SOzOBr) b 8.18 (m, 1H), 7.78 (m, 1H), 7.58 (m, 4H), 4.66 (t, U-5.5 Hz, 1H) , 3.71 (m, 4H), 3.63 (m, 2H), 3.36 (m, 4H) m.p.. MS (M--1): t/2 - 445.0.

M-(6b-fluorobenzo|4|hiazol-2-yl)-1H-imidazole-1-carboxamide

Antagonists of STI and their use

MN" i

And about nm see

M. 5 years M

Ж I-/ y b U d-ya M me іs-m

IS

122 123 E 124

To a solution of b-fluorobenzo|d|hiazol-2-amine (122, 336 mg, 2 mmol, Bidta-AiYdgis"!) in DMF (5 ml) was added SOY (123, 357 mg, 2.2 mmol, zZidta-AiYdgis ) at 0 "С. With vigorous stirring, the reaction mixture was allowed to slowly warm to a temperature of approximately 25 °C for 14 h.

A white precipitate was formed. The precipitate was collected by vacuum filtration, washed twice with EAs (10 ml for each wash), and dried under reduced pressure to give 124 (yield 299 95). (5)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-M-(b-fluorobenzoyl|4|hiazol-2-yl)piperazine-1-carboxamidone

BUT

BUT, HE is about | - ZShC

M

7 nka, Si

DM Zh I-/ M

S M7 St. (S Z

M. Sh. TEA M

With us

M b MN

NE A

M" St. 83 124

IS

Killed

A suspension of 124 (0.3 mmol) in DMF (1.0 mL) was added dropwise to a mixture of 83 (0.3 mmol) in DCM (2.0 mL) and TEA (0.2 mL) at 0 °C. The reaction the mixture was stirred at about 25° C. for 4 h. After that, direct flash chromatography using an ethyl acetate/methanol gradient as eluent gave Mb as a pale yellowish solid. ), 7.76 (m, ЗН), 7.22 (m, 1Н), 5.41 (d, 9-46 Hz, 1Н), 4.79 (t, U-6.0 Hz, 1Н), 4.53 (m, 1H), 3.71 (m, 4H), 3.50 (m, 2H), 3.26 (m, 4H) m.h. MS (M--1): t/ 2 - 452.1. (5)-M-(4-chloro-3-(trifluoromethyl)phenyl)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)piperazine-1-carboxamide

Antagonists of TBVI and their application

But, with

BUT, FI! -0 -k SI

M

M si (S Z

M SEZ M

(9

S A v

M -- 5 -.7 k»za (,;

N

TEA

83 SEZ

SI

Mb

A solution of 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (0.3 mmol, Zidt -Aiagisp) in DCM (1.0 mL) at 0 °C. The reaction mixture was stirred at about 25 °C for 4 h. After that, direct flash chromatography using an ethyl acetate/methanol gradient as eluent gave UUb as a white solid. "H NMR: (COz3O0) b 8.18 (m, 1H), 7.91 (d, 9-24 Hz, 1H), 7.78 (d, 9-26 Hz, 1H), 7.64 (dd , U-2.6, 8.8 Hz, 1H), 7.47 (d, 9U-9.2 Gu, 1H), 4.66 (m, 1H), 3.70 (m, 4H), 3 .63 (m, 2H), 3.35 (m, 4H) m.p.h. MS (Man1): t/2 - 4791.

Example 4: Synthesis of compound E4 5,6-dichloro-M-methoxy-M-methylnicotinamide c) M soon - o

В (o - -Жж Z I; - I;ХЯЯЯft-- - -

M EOSI, NOVI, TEA M si i si J si SI 87 88

M,.O-dimethylhydroxylamine hydrochloride (3.56 g, 36.5 mmol) was added to a stirred solution of 5,6-dichloronicotinic acid (87.7 g, 36.5 mmol) in dichloromethane (100 ml) at a temperature of approximately 25 °C ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EOSI, 7.69 g, 40.1 mmol), 1-hydroxybenzotriazole (NEW, 5.42 g, 40.1 mmol) and TEA (7.6 ml, 54.7 mmol).After stirring for 4.5 g at a temperature of about 25 "C, the reaction mixture was diluted with ethyl acetate. The mixture was washed with water, 1M aqueous hydrogen chloride, saturated aqueous sodium bicarbonate and brine, dried (Mag5O4), filtered and concentrated under reduced pressure to obtain 88. 1-(5,6-dichloropyridin-3-yl)ethanone () M (6) -- ---

M M si si

SI SI

88 89

Antagonists of STI and their use

To a stirred solution of 88 in tetrahydrofuran (100 mL) was added dropwise at 0 "C under nitrogen a 3M solution of methylmagnesium chloride in THF (18 mL, 54.7 mmol). After stirring for 1 g at 0 "C, the reaction mixture was partitioned between ether and saturated aqueous ammonium chloride at 0"C. The aqueous layer was extracted with ethyl acetate. The organic parts were combined, washed with brine, dried (Mag25O4), filtered and concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluted with a gradient of 90:10 - 70:30 hexaneethyl acetate to give 5.92 g of 89 as a white solid (85 95 yield for 2 steps).2-Bromo-1-(5,6-dichloropyridin-3-yl)ethanone

Wg o o)

VI. -k 2 7M AsOon Y si si

SI SI

89 90

A solution of bromine (0.81 mL, 15.8 mmol) in glacial acetic acid (5 mL) was added dropwise to a stirred solution of 89 (3 g, 15.8 mmol) in glacial acetic acid (25 mL) ).After stirring for 24 g at about 25 "C, the reaction mixture gave a precipitate. The precipitate was filtered off and washed with diethyl ether to give 3.89 g of 90 as a pale yellow solid (92 95 yield). 2-(5,6-dichloropyridin-3-yl)-2-oxoethyl acetate

VG oh oh! at

MaOds -- D y

A-M si dl SI

SI SI

90 91

Sodium acetate (457.6 mg, 5.58 mmol) was added to a stirred solution of 90 (1 g, 3.72 mmol) in DMF (15 mL) at about 2570 °C. The reaction mixture was heated to 70 "C. After stirring for 1 g at 70 "C, the reaction mixture was cooled to a temperature of approximately 2570 and diluted with diethyl ether. The mixture was washed with water, washed with brine, dried (Mag2504), filtered and concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluting with a gradient of 90:10 - 65:35 hexane:ethyl acetate to give 563 mg of 91 as a yellow solid (61 95 yield). 2-(5,6-dichloropyridin-3-yl)-2,2-difluoroethyl acetate oo nzsO, oo

E about M-ZEz

A-- E

HU Co.) | huh -- ----

AM AM

SI SI

SI SI

91 92

To a stirred solution of 91 (257 mg, 1.04 mmol) in dichloromethane (10 mL) at a temperature of approximately 25°C was added bis(2-methoxyethyl)aminosulfur trifluoride (0.57 mL, 3.11 mmol).

Antagonists of STI and their use

The reaction mixture was heated to 65°C and stirred for 18 g. After that, the reaction mixture was cooled to a temperature of approximately 0°C and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The organic parts were combined, washed with brine, dried (Mag25O4), filtered, and concentrated under reduced pressure.

The residue was chromatographed using flash chromatography, eluting with 90:10 hexane-ethyl acetate to give 201.3 mg of 92 as a yellow oil (75 95 yield). tert-butyl 4-(3-chloro-5-(1,1-difluoro-2-hydroxyethyl)pyridin-2-yl)-5,6-dihydropyridin-1 (2H)-carboxylate ' IS

E with | eh

And you are me"

He ih m vos s

SI »

SI RA(YURRE)ІСІ, them

KSO, vos 92 93

To a stirred solution of 92 (326.2 mg, 1.41 mmol) in dimethoxyethane:ethanol (6 mL, 2:1) at a temperature of approximately 25 °C was added PaYAA(ORPRE)2CI2 (230.3 mg, 0.282 mmol), borpinacol 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 1.5 g. After that, the reaction mixture was cooled to a temperature of approximately 0 "C and partitioned between ethyl acetate and saturated aqueous ammonium chloride.

The aqueous layer was extracted with ethyl acetate. The organic parts were combined, washed with brine, dried (Mag505), filtered and concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluting with a gradient of 70:30 - 60:40 hexane:ethyl acetate to give 506.9 mg of 93 as a yellow oil (96 95 yield). 2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)-2,2-difluoroethanol hydrochloride on on

K E

E E

And you

NSI

-M A--M

SI -- s oh eh

M M NS

H vos 93 94

An excess of 4M NOSI in dioxane (4 mL) was added to a stirred solution of 93 (506.9 mg, 1.35 mmol) in dichloromethane (2 mL) at 0 °C. After heating to approximately 25 °C and stirring for 2 g , the reaction mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 292.2 mg of the hydrochloride salt of 94 as a pale yellow solid (70 95 yield). 4-(3-chloro-5-(1,1-difluoro-2-hydroxyethyl)pyridin-2-yl)-M-(4-trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H) -carboxamide

Antagonists of TBVI and their application

E he E

E OM

IF and

E (F) Am eh ra SI

Sh 97 Mn si Ve

ZH M

M SEZ on

N her 95 ---А--- 94 PIVEA

SEZ

E4

To a stirred solution of 4-trifluoroaniline (26 mL, 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 approximately 25 °C and stirring for 2 g, the reaction mixture was cooled to 0 °C and 94 (90 mg, 0.289 mmol) and OIEA (0.13 mL, 0.723 mmol) was added. After 1 g at 0 "C, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluted with a gradient of 70:30 - 65:35 hexane:ethyl acetate.

The resulting solid was recrystallized from hexaneethyl acetate to give 82.3 mg of Be as a solid (62 Fo yield).

Example 5: Synthesis of compound 04 2-(tert-butyldimethylsilyloxy)-1-(5,6-dichloropyridin-3-iluethanone)

ON OtTv5

BUT, oh

TV5SI zho - - -3k | and: imidazole M sa sa y (o si a 67a 97

To a stirred solution of 67a (19.2 g, 81.4 mmol) in dichloromethane (250 mL) at 0 C under nitrogen was added imidazole (11.1 g, 162 mmol) and tert-butyldimethylsilyl chloride (TVZSI, 12.3 g, 81 .4 mmol). After heating to a temperature of about 25 C and stirring for 2.5 g, the reaction mixture was cooled to 0 "C and partitioned between diethyl ether and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic parts were combined, washed with brine, dried (Mag25O04 ), filtered, and concentrated under reduced pressure.

The residue was chromatographed using flash chromatography, eluting with a gradient of 90:10 - 80:20 hexane:ethyl acetate to give 24.1 g of 97 as a pale yellow oil (92 95 yield). 2-(tert-butyldimethylsilyloxy)-1-(5,6-dichloropyridin-3-yluethanone)

Antagonists of TBVI and their use otv otv

BUT,,, IO" Fr

ON

Ge and (c) M

AM

-----7 5- 97 98

O-iodoxybenzoic acid (20.9 g, 74.5 mmol) was added 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 approximately 25 °C. The reaction mixture was stirred for 5 g at about 2576. After that, the reaction mixture was cooled to a temperature of about 0 "C and partitioned between diethyl ether and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with diethyl ether. The organic parts were combined, washed with saturated aqueous sodium bicarbonate, washed with brine, dried (Mag5O4), filtered and concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluting with 90:10 hexane-ethyl acetate to give 8.0 g of 98 as a yellow oil (99 95 yield). 5-(3-(tert-butyldimethylsilyloxy)prop-1-en-2-yl)-2,3-dichloropyridine

ОТв5 ОТв5 o

RRIZSNUZVg

In Vi

AM (t-VOO)K M (6; (6; a a 98 99

Potassium tert-butoxide (3.70 g, 33.0 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (11.8 g, 33.0 mmol) in toluene (100 mL) at 0C under nitrogen. After stirring for 1 g at 0 "C, a solution of 98 (8.8 g, 27.5 mmol) in toluene (60 ml) was added dropwise to the reaction mixture for 1 g at 0 "C. After 2 g at 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 parts were combined, washed with water, washed with brine, dried (Mag505), filtered and concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluting with 90:10 hexane-ethyl acetate to give 7.6 g of 99 as a yellow oil (87 95 yield).

3-(tert-butyldimethylsilyloxy)-2-(5,6-dichloropyridin-3-yl)upropan-1-ol

ОтВ5 on оОтв5

I) University (SNI) eh ----- | ex 2) Mahon, NO

M 7272 M

SI SI

SI (Fi 99 100

Borane-methyl sulfide complex (2.3 mL, 23.9 mmol) was added to a stirred solution of 99 (7.6 g, 23.9 mmol) in tetrahydrofuran (120 mL) at 0 "C under nitrogen. The reaction mixture was heated to a temperature of approx. 25 "C and stirred for 5 g. After that, the reaction mixture was cooled to 0 "C and 1 M sodium hydroxide (48 ml) was added dropwise to the reaction mixture, after which hydrogen peroxide (17 ml, 35 wt. 95 solution in water) was added. After more than 2 g at 0 "C, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic parts were combined, washed with water, aqueous sodium sulfite and brine, dried (Mg5Ox),

Antagonists of SARS and their applications were filtered and concentrated under reduced pressure. Compound 100 was isolated by silica gel column chromatography as a yellow oil (42 95 yield). tert-butyl 4-(5-(1-(tert-butyldimethylsilyloxy)-3-hydroxypropan-2-yl)-3-chloropyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Ов on оОтв5 сх | xx

M -M with axis -----l

SIM 0 RFORREUSI, 7

I.) 100 October 1901

To a stirred solution of 100 (1 g, 2.97 mmol) in dimethoxyethane:ethanol (18 mL, 2:1) at a temperature of approximately 25 °C was added RA(OYURPE)2CI» (485.6 mg, 0.595 mmol), pinacol ester (919.4 mg, 2.97 mmol), potassium carbonate (821.9 mg, 5.95 mmol) and water (12 mL). The reaction mixture was heated to 60" C and stirred for 1.5 g. After that, the reaction the mixture was cooled to a temperature of approximately 0 °C and partitioned between ethyl acetate and saturated aqueous ammonium chloride.

The aqueous layer was extracted with ethyl acetate. The organic parts were combined, washed with brine, dried (Mag505), filtered and concentrated under reduced pressure. The residue was chromatographed using flash chromatography, eluting with a gradient of 70:30 - 40:60 hexane-ethyl acetate to give 1.49 g of 101 as a yellow oil (299 95 yield). 2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)upropane-1,3-diol hydrochloride он оОтТв5 он

Whoah Whoah

Center of the NSI | m - ---j -

SI SI

-h heh

M M NS

N vos 1901 102

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 an excess of 4M HCl in dioxane (7.5 mL).

After stirring for 2 g at a temperature of approximately 25 °C, the reaction mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 606.3 mg of the hydrochloride salt 102 as a pale brown solid (70 95 yield). 4-(3-chloro) -5-(1,3-dihydroxypropan-2-yl)pyridin-2-yl)-M-(4-"-trifluoromethyl)phenyl)-5,6-dihydropyridin-1(2H)-carboxamide

Antagonists of SARS and their use on on on on X | About Mn M

SI eh eh -M

SI SEz M ----

PVA

Monet 102

SEz

O4

To a stirred solution of 4-trifluoroaniline (29 mL, 0.328 mmol) in dichloromethane (3.5 mL) at 0 C was added 4-nitrophenyl chloroformate (66.0 mg, 0.328 mmol) and pyridine (32 mL, 0.393 mmol).

After heating to a temperature of approximately 25 °C, the reaction mixture was stirred for 2 g. After that, the reaction mixture was cooled to 0 °C and the hydrochloride salt 102 (100 mg, 0.328 mmol) was added and

RIEA (0.14 ml, 0.819 mmol). After more than 1 g at 0 "C, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with saturated aqueous sodium bicarbonate and brine, dried (Ma250O4), filtered and concentrated under reduced pressure. The residue chromatographed using flash chromatography, eluting with a gradient of 95:5 - 90:10 chloroform:methanol.The resulting solid was recrystallized from isopropyl ether ethyl acetate to give 97.2 mg of 04 as a white solid (85% yield).

Example 6: Determination of the optical purity of VI and M1: this was determined for the compounds VI and M1 as shown below: ОН ОН ОН но шу НО! from. but

ADM AM M a a verses

E E E

- he about Mn kn

SEz SEz SEz

A1 M1 VI 005 ve 99.495 eeza NMR 99.496 ee by "H NMR 99.39 ee by HPLC 99.296 eeza HPLC -;

IN NMR and chiral HPLC were used to determine 95 e6e for both MI and VI. For HPLC

Antagonists of TRPVI and their research applications, using the SNIKAG RAK TA column, determined the peak planes for the major and minor enantiomers, and calculated 95 ee from the equation in section 5.3. For H NMR, bis-Mosher ester derivatives of At, VI, and M1 were synthesized according to techniques known in the art. Determination of 95 ee was performed by adding an excess of Mosher acid chloride to AT, VI, or M1 (approximately 0.6 mg) in pyridine -c" (0.530 ml) at a temperature of approximately 25 "C in an NMR tube. "H NMR was recorded 20 g after the addition of Mosher acid chloride. The selected peak for bis-Mosher ester M1 would be approximately 6.90, and for VI would be 6.78. It should be noted that "ZS satellites were observed at 6 (7.0216 .78) for Mi and b (6.90 and 6.65) for B1. "H NMR peaks for minor and major enantiomers in each case were integrated, "C satellites were subtracted and 95 ee were calculated.

Example 7: Synthesis of MA compound 2,3-dichloro-5-methylsulfonamidylmethylpyridine (6)

N p (6) and | SNZVOZMN, | "X "fi nia si sita

SI SI

79 105

To a suspension of methylsulfonamide (1.08 g, 11.35 mmol), 2,3-dichloropyridinylaldehyde, (79, 3.0 g, 17.03 mmol), ASON (1.35 ml) and Mavn(OAc)z in dry dichloromethane (70 ml) at 0 "C was added TEA (3.18 ml, 22.7 mmol). The reaction mixture was heated to a temperature of approximately 25 "C and stirred g. After that, saturated Mansoz (2 ml) was added. The mixture was extracted twice with ethyl acetate (80 ml for each extraction). The organic parts were combined, washed twice with brine (50 ml for each wash), dried over anhydrous Mag25O4 and concentrated under reduced pressure.

The oily residue was chromatographed using a SOMVIEGAZN device with a 40 g column

KEOIBSER, eluted with 40 95 ethyl acetate in hexanes, obtaining 2.8 g of 105 (65 95 yield) and 20 95 reduced starting material. "H NMR (SOCI3): 5 8.38 (s, 1H), 8.27 (s, 1H), 5.03 (shs, MH), 4.35 (d,

U-17Hz, 2H), 3.0 (s, ЗН). tert-butyl 4-(3-chloro-5-"methylsulfonamidomethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6) nya o o Dt "B o e);

No. In:

M-8-

I si -M and voOos Oh si M ---.

РА(РРИЗ3)5СИ, IM her vos 105 106

To a suspension of 105 (3.86 g, 15.1 mmol), boronate (4.78, 15.1 mmol) and RD(PP3)2SiI" in ethylene glycol dimethyl ether (38 ml) and EN (19 ml) at a temperature of about 2M K»CO3 (15 ml) was added at 25 "C. The reaction mixture was heated at 40 "C for 9 h. After that, the reaction mixture was cooled to a temperature of about 25 "C, 1 M HCl (10 ml) was added. The mixture was extracted twice with ethyl acetate (60 ml for each extraction).The organic parts were combined, washed with water, dried over anhydrous Ma»50Ox and concentrated under reduced pressure to obtain an oily residue, which was then chromatographed using a SOMVINGABZN device with an 80 g KEOIZER column, 30 95

ECOAc in hexanes, obtaining 5.0 g of 106 (83 95 yield). "H NMR (SOSIv):! b 8.35 (s, 1H), 7.70 (s, 1H), 6.03 (shs, 1H), 5.34 (shs, t, MH), 4.26 (d, U-6.3Hz, 2H), 4.10 (m, 2H), 3.55 (t, U-5.6Hz, 2H), 2.89 (s, ЗН), 1.42 (s , 9H).

M-((5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)umethyl)methanesulfonamide hydrochloride

Antagonists of STI and their use 6); (is);

N Her N"

M m (; (c); phi phi

M NS AM

SIS o -- zh s xx eh

M

M But she was 106 107

Compound 106 (1.0 g, 2.5 mmol) was dissolved in dry dichloromethane (10 mL) and cooled to 0 C. 4M NCIII in dioxane (10 mL, 25 mmol) was added. The reaction mixture was heated to a temperature of approximately 25 °C and stirred for 16 g. The resulting white suspension was filtered and after drying under reduced pressure, 790 mg of hydrochloride 107 was obtained as an off-white solid (94 95 yield). 4-(Z-chloro-5 -(methylsulfonamidomethyl)pyridin-2-yl)-M-(4-trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxamide o

N

M o

Gee! ex i a -8-1 -

AND MU SI

(F)

G r)

AM

(Fee M

SEZ Ж ех - - ж -3- (e) МН

PVA

M

BUT she is 107

SEZ

MA

OIEA (1.21 mL, 7.03 mmol) was added to a suspension of the salt (4.790 mg, 2.34 mmol) in dichloromethane at 0 °C. The reaction mixture was stirred until it became homogeneous. trifluoro-p-tolylisocyanate (0.3 ml, 2.22 mmol) and the reaction mixture were stirred for 10 min until the reaction was complete. The reaction mixture was concentrated under reduced pressure. The oily residue was chromatographed using a SOMVIEGAZN device with a 12 g KEOIZER column, 50 95 EOAS in hexanes, yielding 812 mg of MA as a white solid (71 95 yield). "H NMR (SOCIv):" δ 8.98 (s, 1H), 8.49 (s, 1H), 7.89- 7.54 (m, 4H), 6.2 (shs, MH), 4.20-4.24 (m, 4H), 3.70 (t, U-5.5Hz, 2H), 2.96 ( s, ZN), 2.51-2.33 (shs, 2H).

Example 8: Synthesis of compound MZ

Antagonists of SARS and their use on no on | SHE si no M

MN" A. si Nd (in) (o) (o hom b RIVA eh that --3- o -- | ---

ZhySh- NM -d M si M

CE x A ' /

From у o МН 108 109

TO

SEZ M not Y 110 111 Zh

SEZ

M

Phenyl 5-(trifluoromethyl)pyridin-2-ylcarbamate

Phenylcarbonochloridate 109 (21.2 g, 136 mmol) was slowly added to a stirred solution of 5-(trifluoromethyl)pyridin-2-amine 108 (20 g, 123.5 mmol) in dichloromethane (85 ml) at -5 "C over 10 min. ). At -57C, pyridine (11.1 mL, 136 mmol) was added dropwise to the reaction mixture. After heating the reaction mixture to a temperature of approximately 25 "C and stirring for 1 g, a precipitate gradually formed. The precipitate was filtered and washed with dichloromethane and ethyl acetate to give 24.1 g of 110 as a white solid (69.2 95 yield). "H NMR (400 MHz,

DMSO-a5) b 11.3 (w s, 1H), 8.75-8.70 (m, 1H), 8.24-8.17 (m, 1H), 8.05-7.98 (m , 1H), 7.50-7.40 (m, 2H), 7.33-7.22 (m, 2H). (A)-1-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)ethane-1,2-diol

The title compound 111 was prepared using a technique similar to that described in

Example 1 to obtain 70, except that 670 was used instead of 67a. (8A)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-M-(5-trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridin-1 (2H)-carboxamide

To a stirred suspension of the hydrochloride salt 111 (9.36 g, 32.26 mmol) in dichloromethane (30 ml) at -20 "С, 110 (8.19 g, 29 mmol) was added in one portion. Then at -20 "С, to OIEA (14 mL, 80.65 mmol) was added dropwise to the reaction mixture over 15 min. After stirring for 2 g at -20 "C, the reaction mixture was diluted with 200 ml of dichloromethane, washed twice with 1M aqueous sodium hydroxide (200 ml for each wash), dried (Ma»5O4), filtered and concentrated under reduced pressure. The residue (12 d) was dissolved in 25 mL of hot ethyl acetate and allowed to cool slowly.The precipitate was collected by vacuum filtration and washed twice with a solution of 50 95 ethyl acetate in hexane (100 mL for each wash) to give 10.15 g of M3 as a white solid (71 95 yield). "H NMR (400 MHz, DMSO-ae) b 9.88 (s, 1H), 8.66-8.60 (m, 1H), 8.49-8.44 (m, 1H), 8.10 -8.03 (m, 1H), 8.03-7.96 (m, 1H), 7.85-7.81 (m, 1H), 6.21-6.14 (m, 1H), 5 .57-5.51 (m, 1H), 4.89-4.82 (m, 1H), 4.64-4.57 (m, 1H), 4.25-4.19 (m, 2H) , 3.76-3.67 (m, 2H), 3.60-3.43 (m, 2H), 2.62-2.52 (m, 2H).

Example 9: Synthesis of a compound of formula I

Using methods similar to those described above, the following compounds of formula I were obtained.

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M M r

E 4 Ge and E

Eh and

MMA

A A (in MN

To her

That's it

SEZ SEZ og

MB Ob Ro

Mb: H NMR (COzOB) b 8.41 (s, 1H), 7.59 (m, 5H), 4.80 (t, 9-6 Hz, 1H), 4.15 (m, 2H), 3 .69 (m, 2H), 3.45 (m, 2H), 2.45-2.26 (m, 4H). MS (Ma1): t/t - 446.1.

Ov: H NMR (СОЗ3О0О) b 8.38 (m, 1Н), 7.79 (m, 1Н), 7.68 (m, 1Н), 7.52 (d, 9-8 Hz, 1Н), 7 .38 (m, 1H), 4.65 (t, 9-6 Hz, 1H), 4.04 (m, 2H), 3.57 (m, 2H), 3.33 (m, 2H), 2 ,39-2,21 (m, 4H). MS (Ma-1): t/x - 496.0.

Rv: H NMR (СОЗ3О0) b 8.55 (m, 1Н), 8.41 (s, 1Н), 7.98 (m, 2Н), 7.67 (m, 1Н), 4.80 (t, 9-6 Hz, 1H), 4.18 (m, 2H), 3.70 (m, 2H), 3.48 (m, 2H), 2.46-2.26 (m, 4H). MS (Ma): t/h - 447 1.

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BUT, oh he

Ha | Seh c

M r si dDYd SI ra si

E E E m A M

Hu o Yin Zh

TO Y in

IS

SEZ SEZ SEZ

KI c1 te

E1: "H NMR (SOZZOB) b 8.38 (m, 1H), 7.79 (m, 1H), 7.44 (m, 2H), 7.21 (m, 1H), 4.65 (t , 9U-5.6 Hz, 1H), 4.05 (m, 2H), 3.56 (m, 2H), 3.33 (m, 2H), 2.38-2.2.21 (m, 4H). MS (M-1): t/; - 480.0.

C1: H NMR (COzO0B) b 8.43 (m, 1H), 8.37 (d, 9-2 Hz, 1H), 7.87 (m, 2H), 7.79 (m, 1H), 4 .65 (t, 9-6 Gu, 1H), 4.08 (m, 2H), 3.57 (m, 2H), 3.35 (m, 2H), 2.38-2.22 (m, 4H). MS (M1): t/2 - 463.1.

T5:H NMR (SOzOB) b 8.64 (dd, 9-1.8, 0.6 Hz, 1H), 8.04 (d, 9-21, 0.3 Hz, 1H), 7.59 ( dd, y-14,4, 8,9

Hz, 4H), 4.19-4.15 (w d, 9U-13.8 Hz, 2H), 3.78 (dd, 9-24.8, 11.3 Hz, 4H), 3.49- 3.42 (m, 2H), 2.49-2.34 (m,

Academy of Sciences). MS (M): t/y - 492.

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Ge

BUT, But

Well, yes and no:

M si 4 si -4 | M

E E E "4

IS

M M

And A. and

Gee! MN about MN

H i o 57 i o ut SI

R SEZ SEZ

11 NO

I: H NMR (SOzOB) b 8.37 (s, 1H), 7.79 (s, 1H), 7.42 (m, 2H), 7.02 (m, 1H), 4.64 (t, 9-6 Hz, 1H), 4.21 (m, 2H), 3.56 (m, 2H), 3.35 (m, 2H), 2.35-2.20 (m, 4H). MS (M1): t/x - 469.0.

NO: H NMR (SOZZOB) b 8.38 (m, 1H), 7.82 (m, ЗН), 7.70 (m, 2H), 4.64 (t, 9-6 Hz, 1H), 4.06 (m, 2H), 3.57 (m, 2H), 3.36 (m, 2H), 2.40-2.23 (m, 4H). MS (Mn1): t/x - 526.0.

О3:"H NMR (SOZZOB) 5 8.39 (s, 1H), 7.78 (m, 1H), 7.63 (m, 2H), 7.48 (m, 1H), 4.78 (t , 9-6 Hz, 1H), 4.13 (m, 2H), 3.67 (m, 2H), 3.43 (m, 2H), 2.43-2.23 (m, 4H). MS (M1): t/x - 480.5.

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But, t, SYA and

EE" ra

MEE

E - E E

IS

M

M t A A. c) MN

MSM MN

MN

9 57 and

SEZ and

UZ E5 vol

US: "H NMR (COzO0) b 8.41 (m, 1H), 7.67 (m, 1H), 7.55 (m, 2H), 7.34 (m, 1H), 4.79 (t , 9-6 Hz, 1H), 4.14 (m, 2H), 3.69 (m, 2H), 3.46 (m, 2H), 2.43-2.26 (m, 4H). MS (Ma1): p/z - 4641.

EB: "H NMR (SOZZOB) b 8.41 (s, 1H), 7.65 (d, 9-12 Hz, 1H), 7.53 (m, 2H), 7.14 (m, 1H), 4.79 (t, 9-6

HC, 1H), 4.28 (m, 2H), 3.69 (m, 2H), 3.48 (m, 2H), 2.45-2.26 (m, AN). MS (M--1): t/x - 4531.

О6: "H NMR (SOzOB) 5 8.41 (s, 1H), 7.66 (m, 1H), 7.41 (m, 2H), 7.10 (m, 2H), 4.80 (t , U-6 Hz, 1H), 4.08 (m, 2H), 3.69 (m, 2H), 3.50 (m, 2H), 2.49-2.23 (m, 4H), 1 .33 (s, 9H). MS (M1): t/lx - 458.5.

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Ho | x Zh

AND

-- and 4 EE"

E E b sx sx

M

M A M

A (o) MN A.

Gee! MN (in) MN nn E

SEZ SEZ SEz

Year 01 1

I: "H NMR (MeOb) b 8.44-8.38 (1Н, m), 7.68-7.54 (5Н, m), 6.60-6.53 (1Н, m), 4, 82-4.74 (1H, m), 4.34-4.25 (2H, m), 3.84-3.75 (2H, m), 3.74-3.66 (2H, m), 2.82-2.72 (2H, m). MS: t/g - 425.

О1: "H NMR (MeOb) b 8.51-8.46 (1Н, m), 7.99-7.92 (ЗН, m), 7.89-7.82 (2Н, m), 6, 17-6.12 (1H, m), 4.80-4.73 (1H, 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: t/» - 505.

U1: H NMR (Meob) b 8.44-8.37 (1H, m), 7.96-7.89 (1H, m), 7.69-7.51 (ZH, m), 7.41 -7.34 (1Н, m), 6.60-6.53 (1Н, m), 4.83-4.75 (1Н, m), 4.34-4.26 (2Н, m), 3 .83-3.75 (2H, m), 3.74-3.65 (2H, m), 2.82-2.73 (2H, m). MS: t/» - 443.

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E si sh y Zakh

M

M

A Y ry b MN A. (c) MN 67 vn XX

As

To her

J nn

SEZ SEz E

RI ki B1

RI: "H NMR (MeOb) b 8.47-8.37 (1Н, m), 8.05-7.83 (5Н, m), 7.71-7.59 (1Н, m), 6, 66-6.53 (1H, m), 4.85-4.74 (1H, m), 4.42-4.28 (2H, m), 3.91-3.64 (AN, m), 2.89-2.74 (2H, m). MS: t/; - 489.

KI: "H NMR (SOSIv) b 8.51-8.43 (2Н, m), 8.25-8.18 (1Н, m), 7.92-7.85 (1Н, m), 7, 83-7.78 (1H, m), 7.53 (IN, w s), 6.22-6.15 (1H, m), 4.95-4.84 (1H, m), 4.31 -4.19 (2H, m), 3.93-3.64 (AN, m), 3.08-2.97 (1H,

M), 2.77-2.63 (2H, m), 2.24-2.14 (AN, m). MS: t/» - 442.

B1:H NMR (DMSO) 5 8.50-8.44 (1H, m), 7.87-7.82 (1H, m), 7.82-7.75 (1H, m), 7.70 (1H, w s), 7.26-7.17 (IN, m), 6.23-6.17 (1H, m), 5.58-5.51 (1H, m), 4.89- 4.82 (1H, m), 4.64-4.57 (1H, m), 4.31-4.21 (2H, m), 3.85-3.73 (2H, m), 3, 60-3.42 (2H, m), 2.61-2.51 (2H, m). MS: t/l - 448.

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But,

VH

: | b"

M to tsi de" E 4

E p

G m y:

KK M

A paradise "7 rya b (o)

To her

J

SI E

SEZ SEZ

14

OZ kA

IZ:H NMR (Meob) 5 8.42-8.36 (1H, m), 7.92 (1H, s), 7.83-7.77 (1H, m), 7.67-7.58 (2Н, m), 7.55-7.48 (IN, m), 6.58-6.52 (1Н, m), 4.80-4.72 (1Н, m), 4.31-4 .24 (2H, m), 3.81-3.74 (2H, m), 3.72-3.63 (2H, m), 2.80-2.71 (2H, m). MS: tp/2 - 459.

I4:H NMR (DMSO) b 8.45-8.33 (1Н, m), 7.85-7.73 (1Н, m), 7.69-7.51 (2Н, m), 7.29 -7.51 (1H, m), 6.63-6.49 (1H, m), 5.62-5.49 (1H, m), 4.91-4.79 (1H, m), 4 .70-4.56 (1H, m), 4.37-4.23 (2H, m), 3.87-3.71 (2H, m), 3.59-3.41 (2H, m) , 2.73-2.59 (2H, m). MS: t/ - 432.

Ka: "H NMR (Meobr) b 8.61-8.49 (1Н, m), 8.46-8.34 (1Н, m), 8.09-7.87 (2Н, m), 7, 70-7.56 (1H, m), 6.63-6.51 (1H, m), 4.82-4.72 (1H, m), 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: t/ - 426.

Example 10: Alternative synthesis of compound 67a 5,b-dichloronicotinoyl chloride soon SOS 7 vosu, b naty

M OME M si Zh SI 4

SI si 112 113

To a well-stirred suspension of 5,6-dichloronicotinic acid 112 (600 g, 3.125 mol) and M,M-dimethylformamide (20.0 ml) in dichloroethane (1.2 L) at a temperature of approximately 25 "C, thionyl chloride was added dropwise with stirring (743.56 g, 6.25 mol). In a reflux apparatus equipped with a gas trap filled with saturated aqueous sodium bicarbonate, the reaction mixture was heated and boiled, at about 75 °C, until the reaction mixture became clear solution, after about 3 g. LC/MS analysis of the sample quenched with methanol showed the presence of only methyl ester. The reaction mixture was cooled to a temperature of approximately 25 °C and concentrated under reduced pressure to give 113 as a thick

Antagonists of SARS and their suspension application. 1-(5,6-dichloropyridin-3-yl)uethanone

F) M F) sosi yo

NSI o) y: y SNUMeSI Ж pu PO an

A r TE M M si si dY7 s dDYb-si CSI 113 114 115

In a dry ice/acetone bath, a suspension of M,O-dimethylhydroxylamine hydrochloride (350.53 g, 3.59 mol) in methylene chloride was cooled to 0 "С 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 such a rate that the temperature of the reaction mixture did not exceed 15 "С. After the addition of 113 was complete, the reaction mixture was allowed to slowly warm to a temperature of approximately 25 °C for 16 h. The reaction mixture was then poured into 2 L 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 (Md95O»4) and concentrated under reduced pressure to give a brown solid.The solid was treated with 1 L of boiling hexanes and heated at reflux for about 10 minutes.

The resulting pale orange solution was decanted from the dark yellow-brown resin and allowed to cool. The resin was treated twice (500 mL for each treatment) with these boiling hexanes.

The hexane mixtures were combined, allowed to cool to approximately 25 °C, then cooled in an ice/water bath. The resulting yellow needles were collected by vacuum filtration and air-dried to yield 730 g of 5,6-dichloro-M-methoxy-M-methylnicotinamide 114 (99 95 output). "H NMR (400 MHz, SOSIz") b 8.68 (m, 1H), 8.18 (m, 1H), 3.59 (OSN»z, ЗН), 3.40, (MES, ZN). 431 g of 115 was obtained using a procedure similar to that described in Example 4 for the preparation of 89, except that 114 was used instead of 88 (97 95 yield). "H NMR (400

MHz, SOSI") 6 8.82 (m, 1H), 8.29 (m, 1H), 2.62 (SOSN", ZN). 1-(5,6-dichloropyridin-3-yl)ethanol c) no. mavn, skh gl, | h

M M

SI 4 SI 4

SI SI

115 116

Sodium borohydride (66.21 g) was added to a well-stirred suspension of 115 (665 g, 3.5 mol) in methanol (3.5 L) at 0 °C in portions at such a rate that the temperature of the reaction mixture did not exceed 5 °C , 1.75 mol). After the addition was complete, the reaction mixture was heated to a temperature of approximately 25 °C and stirred for another 1 g. LC/MS analysis of an aliquot showed that the reaction was completely complete. The reaction mixture was concentrated under reduced pressure. The residue was mixed with 2 L of diethyl ether and 2 L of 1M HCl. . The layers were separated and the aqueous layer was extracted twice with diethyl ether (250 mL for each extraction). The organics were combined, dried (M950"), and concentrated under reduced pressure to give 670 g of 116 as a pale yellow oil (99 95 yield) . "N

NMR (400 MHz, SOSI") 6 8.20 (m, 1H), 4.96 (m, 1H), 3.57 (s, 1H), 1.51 (d, U-6.5Hz, ЗН) . 2,3-dichloro-5-vinylpyridine

Antagonists of SARS and their use o0-5-0 in z --|i

M M si F si F (o) SI 116 66

To a solution of 116 (311 g, 1.62 mol) in chlorobenzene (3 L) was added p-toluenesulfonic acid (431 g, 2.5 mol). The reaction mixture was heated to reflux, approximately 140 C, and water was simultaneously removed. After completion of the reaction, the mixture was concentrated under reduced pressure to approximately 500 ml, diluted with 2 L of water and extracted three times with ethyl acetate (1 L for each extraction). The organic parts were combined, dried (Mg50O4) and concentrated under reduced pressure and moderate heating to give a residue. The residue was added to 500 ml of methylene chloride and charged to the top of a column packed with 2 kg of silicon dioxide, eluted with a gradient of 0 95 - 95 ethyl acetate in hexane, obtaining 178.55 g, »99 95 purity, 2,3-dichloro-5-vinylpyridine 66, as a clear oil, which solidified on cooling to 4 "C (63 95 output). "H NMR (400 MHz, COcSi") 6 8.32 (m, 1H), 7.85 (m, 1H), 5.72 (m, 1H), 4.88 (m, 1H), 4.37 (m, 1H). (5)-1-(5,6-dichloropyridin-3-yl)ethane-1,2-diol

He dO she y: Art-tikh o; Ah --- -lultl l v

MO T1t-VyON Fr

M si XX -dYSH-

SI

SI with 66 bta

In a 5 L three-necked round-bottom flask equipped with an overhead mechanical stirrer and a thermocouple, a stirred mixture of 66 (150 g, 0.861 mol), t-butanol (2.15 L), and water (2.15 L) was cooled in an ice/water bath to a mixture temperature below 10 "C. AYUO-thich a (729 g, 1.15 eq.) was added in one portion; the endothermic reaction lowered the temperature of the reaction mixture to 7 "C. The bath was filled with ice and the reaction mixture was allowed to stir for 16 g and the temperature was gradually raised to about 25 °C. After that, an aliquot of the reaction mixture was removed, diluted with methanol, filtered and analyzed by LC/MS; the results of LC/MS showed that the reaction was completely complete .

To promote agglomeration of solids and facilitate filtration, the reaction mixture was diluted with 2 L of ethyl acetate and filtered under reduced pressure to remove solids.

The resulting transparent mixture was separated into phases. The aqueous part was extracted twice with ethyl acetate (250 ml for each extraction). The organic parts were combined, dried (Md5bOzh) and concentrated under reduced pressure to give a dark gray solid. The solid substance was added to 500 ml of methanol, treated with decolorized charcoal, boiled, filtered hot through a layer

CELIT was concentrated under reduced pressure to give a gray solid. The solid was recrystallized from chloroform to give 115 g of 67a as a white solid. The second portion of b7a, 12.3 g, was obtained by concentrating the supernatant (total yield 71 95). "H NMR (400

MHz, COzOb) 5 8.32 (m, 1H), 8.0 (m, 1H), 4.75 (t, U-6Hz, 1H), 3.65 (m, 2H).

Example 10A: Synthesis of Compound Eb (5,6-dichloropyridin-3-yl)umethyl methanesulfonate

Antagonists of SARS and their use on her o.3

СсИ-5--СНз ""СНз

F || more) om o

SI -eshshULLPTTNTNNNNNN C 2M si OIEA si 117 118

To a solution of (5,6-dichloropyridin-3-yl)methanol (117, 5000 mg, 28.1 mmol, ToKkuo Spetis! Ipaivigu

So., Tokuo, darap) in SNeSi" (150 ml) at a temperature of about 25 "C was added OIEA (30.9 mmol).

The mixture was cooled to 0 "C and methanesulfonyl chloride (M5CI, 30.9 mmol) was added dropwise over 15 minutes. After that, the reaction mixture was stirred at 0 "C for 1 h. After quenching with water, the mixture was extracted three times with CHCl3/HgO (100 ml for each extraction), dried (Mo50Ox5), and concentrated under reduced pressure to give a yellow oil. The oil was chromatographed by silica gel column chromatography (Uataep) using an ethyl acetate (20 U6-50 95)/n-hexane gradient to give 6360 mg of 118 as a yellow oil (8895 yield). "H NMR (400MHz,

DMSO) 6: 8.51 (1H, s), 8.26 (1H, s), 5.35 (2H, s), 3.32 (ZH, s). 2-(5,6-dichloropyridin-3-yl)acetonitrile

SI SI

118 119

To a solution of 118 (6360 mg, 24.8 mmol) in ethanol (75 mL) at a temperature of approximately 25 C was added a solution of MasMM (32.3 mmol) in water (25 mL). The reaction mixture was heated to 807°C and stirred for 1 g. After concentration under reduced pressure, the mixture was extracted three times

EtOAc/H2H0 (100 mL for each extraction), dried (Mag50") and concentrated under reduced pressure to give an orange oil. The oil was chromatographed by silica gel column chromatography (Uataep) using an ethyl acetate (30 95-50 9o)/n-hexane gradient to give 2648 mg of 119 as a colorless solid (57 95 yield). "H NMR (400MHz, DMSO) 5: 8.42 (1H, s), 8.18 (IN, s), 4.15 (2H, s). tert-butyl 4-(3Z-chloro-5-( Cyanomethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

SM

SM Ov and

Y Z RYAA(RRNZz)2СИо | M ni Ma»Soz -4

СИ 4 M ---я-ЬВНееЯ s (Fi y: oo

M

119 Zh oo 68 120

To a mixture of 119 (187 mg, 1 mmol), 68 (1 mmol) and MgCO3 (1.5 mmol) in 2/1/2 OME/EUN/H2O (10 ml) at a temperature of approximately 25"C was added Ra(PPi3) "Si" (0.1 mmol). The reaction mixture was heated to 120 "С and stirred for 30 min. After cooling to about 25 °C, the mixture was diluted with water, extracted three times with CHCl3/H2O (30 mL for each extraction), dried (Mg25O04), and concentrated under reduced pressure to give a yellow oil. The oil was chromatographed by column chromatography on silica gel ( Uata?ep) using a gradient of ethyl acetate (20 95-50 95)/n-hexane affording 287 mg of 120 as a pale yellow oil (86 95 yield). 1H NMR (400 MHz, DMSO) 5 : 8.50 (1H, s), 7.95 (1H, s), 6.17 (IN, s), 4.11 (2H, s), 4.02 (2H, s), 3.54 (2H, m), 2, 47 (2H, m), 1.43 (9H, s).

Antagonists of SARS and their use 2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)uacetonitrile

And I

--х 7 The same

AH and oo 120 121

Trifluoroacetic acid (TEA, 8.6 mmol) was added to a solution of 120 (287 mg, 0.86 mmol) in SNeoCl (3 mL) at 0 °C. The reaction mixture was heated to a temperature of approximately 25 °C and stirred for 45 min. After concentration under reduced pressure, the mixture was neutralized with 28 95 aqueous ammonia, extracted three times with CHCl3/H2H2O (50 mL for each extraction), dried (Mag5054) and concentrated under reduced pressure to give 200 mg of 121 as a yellow oil (299 95 yield). "H NMR (400 MHz, DMSO) 6: 8.53 (1H, s), 7.98 (1H, s), 6.12 (1H, s), 4.11 (2H, s), 3.40 ( 2H, c), 3.19 (1H, Bg), 2.90 (2H, c), 2.24 (2H, c). 4-(3-chloro-5-(cyanomethyl)pyridin-2-yl) -M-(4-trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxamide

SM

She

M so st -

SM M s fi o Y sie" va

SEZ

Chh

I nni m

SEZ

121 Eb

To a solution of 121 (200 mg, 0.86 mmol) in NaCl (7 mL) at a temperature of approximately 25 °C was added 1-isocyanato-4-(trifluoromethyl)benzene (0.86 mmol, Asgo5 Ogdapis5, seeii, VeIdiit). The reaction mixture was stirred at a temperature of about 25°C for 1.5 g. After concentration under reduced pressure, the mixture was chromatographed by column chromatography on silica gel (Utaep) using a gradient of CHCl3 (99 95-20 959/MeonH yielding 64 mg of Eb as a colorless solid substance (18 95 yield). "H NMR (400MHz, DMSO) 5: 8.96 (1H, s), 8.52(1H, s), 7.97 (1H, s), 7.73 (IN, d, 9U-8Hz), 7.60 (1H, d, U-8Hz), 6.25 (1H, s), 4.21 (2H, s), 4.12 (2H, s), 3.70 (2H, t, U-8Hz), 2.58 (IN, s), 2.50 (1H, s). LC/MS (100 95, chu - 6.72 min) |M z NI", t/ - 420.8 (Raz: 420.1).

Example 10B: Synthesis of compound 1 1 (5)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoro-M-(6-fluorobenzo|d|hiazole-2 - yl)upiperidine-1-carboxamide

Antagonists of TBVI and their application

M X NO, shchi

M still he J si r

NO, NM GF) E

AND

M Z M y | RIEA Y

E about Mn and Kh

M M 5

N E

IS

1

A 100 mL round-bottom flask was charged with 78 (800 mg, 2.56 mmol) suspended in DMF (2 mL). OIEA (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 approximately 25 °C until all solids dissolved, approximately 2 g. The reaction mixture was diluted with water; an almost white precipitate was 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 obtain 1.0 g of 1/1 (yield 90 95), which was then crystallized from

EUAs/Maeon. "H NMR: δ 8.35 (s, 1H), 7.80 (s, 1H), 7.35 (m, 2H), 6.98 (m, 1H), 4.70 (t, 1H), 4.2 (m, 2H), 3.6 (m, 2H), 3.3 (m, 2H), 2.25 (m, 4H) m.ch.. MS (M--1): t/ 2 - 468.

EXAMPLE 11: INVESTIGATION OF IM OVER THE PREVENTION OR TREATMENT OF PAIN

Research animals: Rats weighing 200-260 g at the beginning of the experiment were used in each experiment. Rats were divided into groups with free access to food and water at all times, except for the time preceding oral administration of a compound of formula I, when food was not provided for 16 hours prior to administration. A control group was used for comparison with rats treated with a compound of formula I. The control group was administered vehicle for the compound of formula I. The volume of vehicle administered to the control group is the same as the volume of vehicle and compound of formula I administered the group being tested.

Acute pain: The rat tail twitch test can be used to evaluate the effects of compounds of formula I for the treatment or prevention of acute pain. Rats are gently held by hand and the tail is exposed to focused heat irradiation 5 cm from the tip using a tail twitch device (Mode! 7360, commercially available from Odo Vaviier, Nau). Tail twitch latency is defined as the interval between thermal irritation and tail twitch. Animals that do not respond within 20 seconds are removed from the tail-flick device and marked as a 20-second twitch delay. Tail twitch latency is measured immediately before (pretreatment) and 1, 3, and 5 hours after administration of a compound of formula I.

Data are expressed as tail twitch latency(s) and percentage of maximum possible action (90 MMD), i.e., 20 seconds, calculated as follows: c; MMd- ((post-introduction delay) - (pre-introduction delay) | x100 (20 s pre-introduction delay)

The rat tail twitch test is described in E. E. F'Atoitg ei ai., "A Meipoa og Oeiegtipipud Go55 oi Raip Zepzaiijop," U. Rnaptasoi. Ex. Tag. 72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response to noxious mechanical stimulation, which determines the paw withdrawal threshold ("PVL"), as described below.

Inflammatory Pain: The Friends' Complete Adjuvant Inflammatory Pain Model ("PAF") is used to evaluate the effects of compounds of formula I for the treatment or prevention of inflammatory pain. PAF-induced inflammation of the hind paw of rats is associated with the development of persistent inflammatory mechanical hyperalgesia and provides a reliable prediction of the anti-hyperalgesic effect of clinically useful

Antagonists of SARS and their use of analgesic drugs (I. Vagyo ei ai., "Ipmoimetepi oi Sarzaisip-zepeyime Meshgopev ip

NuregaIdesia apa Epnapsed Orioia Apiiposiseriip ip IpyChattaiiop," Mashpup-5sNptivderega5 Agspime5 oi Rpaptasiodu 342:666-670 (1990)). 50 μl of 100 95 PAF is injected under the sole of the left hind paw of each animal. 24 hours after injection, the animals response to noxious mechanical stimulation by determining PVL or noxious thermal stimulation by determining ZVL is assessed as described below. Rats are then given a single injection of 1, 3, 10, or 30 mg/kg of a compound of formula I; 30 mg/kg of a control compound , chosen from Celebrex, indomethacin, or naproxen; or vehicle. The response to noxious mechanical or thermal stimulation is then determined at 1, 3, 5, and 24 hours post-injection. The percent resolution of hyperalgesia for each animal is determined as: vu, Elimination- (Pvl or ZVL post-injection) - (PVL or ZVL before introduction) x100 (initial without VlL or ZVL) - (PVL or ZVL before introduction)

The evaluation of the compounds of formula I, which were studied by disclosing these compounds, was surprisingly effective, for example, the compounds of formula II significantly reduce PAF-induced thermal hyperalgesia, with an EUSO value of about 0.1 mg/kg to about 10 mg/kg and a maximum percent elimination is from about 50 95 to about 100 95. For example, for compound 02, the Eb 50 value for the elimination of thermal hyperalgesia was 0.95 mg/kg at 3 hours after administration and 1.63 mg/kg at 5 hours after administration of 02. In addition , the maximum percentage of elimination of thermal hyperalgesia was 78.7 9o at 5 hours after the introduction of 02.

Neuropathic pain: The Seltzer model or the Chang model can be used to evaluate the effects of compounds of formula I in the treatment or prevention of neuropathic pain.

In the Seltzer model, a model of neuropathic pain is used with the help of a partial ligature of the sciatic nerve to produce neuropathic hyperalgesia in rats (7. Zeigeg et al. "A

Mother! Venamioga! Moadwei! ой Meshigorayis Raip Oizogayeg5 Rgodisea ip Vaiz Bu Rapia! bsiais Megue Ipishgu,"

Raiip 43:205-218 (1990)). Partial ligation of the left part of the sciatic nerve was performed using isoflurane/O inhalation anesthesia. After anesthesia, the left femur of the rats was cut off and the sciatic nerve was freed through a small incision and the surrounding connective tissue was gently pushed apart in the place of the nearest trochanter just peripheral to the point where the common sciatic nerve branches off of the semitendinosus nerve of the posterior biceps. The nerve was entangled with a 7-0 silk thread using a 3/8 bent inverted mini needle and compactly ligated so that 1/3 - 1/2 of the thickness of the spinal nerve was held by the ligature. The wound was closed with a single muscle suture (4-0 nylon (Misgui)) and Meibop surgical glue. After surgery, the wound surface was dusted with antibiotic powder. Sham-treated rats underwent an identical surgical procedure, except that the sciatic nerve was not manipulated. After surgery, the animals were weighed and placed on a warm pad until they recovered from anesthesia. The animals were then returned to their cages before behavioral analysis began. The animal was evaluated for response to noxious mechanical stimulation by determining the PVL as described below, before surgery (baseline), then immediately before and 1, 3, and 5 hours after the injection of the drug into the left hind paw of the animal. The percentage of elimination of neuropathic hyperalgesia was determined as follows: vu, Elimination- (PVL after administration) - (PVL before administration))| x100

KPVL basic) - (PVL pre-introduction))

Chang's model uses a model of neuropathic pain by applying a ligature to a spinal nerve to produce mechanical hyperalgesia, thermal hyperalgesia, and tactile allodynia in rats. The operation was performed using isoflurane/Og inhalation anesthesia. After the onset of anesthesia, a 3 cm incision was made and the left paraspinal muscles were separated from the spinous process of levels I 4-52. | the transverse process was carefully removed using a pair of small nippers for visual identification of the I14-Y spinal nerves.

The left I 5 (or | 5 and I 6) spinal nerve(s) was isolated and tightly ligated with a silk thread. Complete hemostasis was ensured and the wound was sutured using non-absorbable sutures such as nylon sutures or stainless steel sutures. Sham-treated rats underwent an identical surgical procedure, except that the spinal nerve was not manipulated. After surgery, the animals were weighed, saline or lactate was injected subcutaneously, the wound area was sprayed with an antibiotic, and they were kept on a warm pillow until they recovered from anesthesia. The animals were then returned to their cages before behavioral analysis began. Animals were evaluated for response to noxious mechanical stimulation by determining PVL as described below before surgery (baseline), then

Antagonists of TRPVI and their use immediately before and after 1, 3 and 5 hours after the introduction of the compound of formula I into the left hind paw of the animal. The animal can also be assessed for response to noxious thermal stimulation or tactile allodynia, as described below. Chang's model of neuropathic pain is described 5. N.

Cat, "Ap Ehregitepia! Modei! yog Reghirpega! Meshigorainu Rhodiseid Bu Zedtepia! Zripa! Megme I idayop ip

She Nai," RAIP 50(3):355-363 (1992).

Response to mechanical stimulation as an assessment of mechanical hyperalgesia: Paw pinching can be used to assess mechanical hyperalgesia. For this study, the hindpaw withdrawal threshold (HPV) to noxious mechanical stimulation was determined using an analgesimeter (Modei! 7200, commercially available from Odo Vavziie oi Nau) as described by S. zieip, "Opiiaiega! Ipiattaitsiiop oi uiPe Nipdram ip RNaiv az a Moadbei oi oi Rgoiopdei Mohoiiv Biitsiatsop: AMegaiop5 ip Vepamiog apa Mosiseriime TNgezpoid5," Rpaptasiodu Viospetivhigu apa Vepamiog 31:451-455 (1988).

The maximum weight that can be applied to the hind leg is 250 g and the end point is taken as a full extension of the leg. PVL is determined for each rat at each time point and only the affected (ipsilateral) paw is tested.

Response to thermal stimulation as an assessment of thermal hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, hindpaw withdrawal latency (HLL) is determined under noxious thermal stimulation using a plantar apparatus (commercially available from Odo Wabhiiye, Mamou) following the method described by K.

Nagageamev5 ei ai., "A Memzh/ apa bepeyime MeiStoi og Meazigipd Tnepta! Mosisseriyup ip Sschshapeoi5

NuregaiYidesia," Raip 32(1):77-88 (1988). The maximum time of action is 32 seconds to eliminate the possibility of tissue damage and any directional withdrawal of the paw from the heat source taken as an endpoint. Three withdrawals were determined for each time point and averaged

Only the affected (ipsilateral) paw was tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats were placed in clear Plexiglas compartments with mesh bottoms and allowed to habituate for at least 15 minutes.

After habituation, a row of von Frey monofibers was attached to the plantar surface of the left (operated) foot of each rat. The von Frey monofilament series includes six monofilaments of increasing diameter, with the smallest fiber diameter denoted by one. Five experiments were conducted with 3 DYNAMICAL FIBERS with each individual experiment after approximately 2 minutes. Each trial lasted for 4-8 seconds or until nociceptive withdrawal behavior. Twitching, withdrawal of the paw, or licking of the paw were considered as nociceptive behavioral responses.

Capsaicin-induced eye rubbing study: To assess the effect of compounds of formula I on TKRM1 receptor-mediated pain, capsaicin-induced eye rubbing studies (M.K. Samma ei a), "SAMO 9810 KE)-3-(4-4- Vshiuirpepu!)-M-(2,3-ainudgorep29IB111,Aliohip-6-u)asguiatide|, and Mome! Mapioidy Reseriog 1 (TARM1) Apiadopibi m/p Apiipuregaidesis Rgoregpiev", ").

Rpaptosai Ex. Tag. 313:474-484 (2005)). the capsaicin-induced eye rubbing study is a reliable, high-throughput study of the effects of TKRM1 antagonists. Rats were given a single injection of 1, 3, 10 or 30 mg/kg or compounds of formula I; 30 mg/kg control selected from Celebrex, indomethacin, or naproxen; or wear At 1, 3, or 5 hours after drug administration, 3 μl of a 100 μM capsaicin solution (in 10 96 EUN/RV5) was instilled dropwise into one eye of each animal using a pipette. The number of forepaw movements (touching or rubbing the eye treated with capsaicin) was counted within 2 minutes after capsaicin was instilled into the eye.

Evaluation of the compounds of formula I, which were tested by disclosing these compounds, was surprisingly effective, for example, compounds of formula II dose-dependently reduced the amount of capsaicin-induced eye touching from about 25 95 to about 100 95 after its administration compared to the value before administration. For example, for compound MI, the number of eye touches decreased from 1 to 3 after MI administration relative to the eye touch value before administration, which was 24.

Specifically, the eye touch value was 3 1 hour after M1 injection (87.5 95 reduction), 1 three hours after injection (9695 reduction), and 2 5 hours after M1 injection (92 95 reduction).

EXAMPLE 12: BONDING OF COMPOUNDS OF FORMULA I WITH TER1

Methods of researching compounds capable of inhibiting BRI1 are well known to the average person skilled in the art, for example, these methods are described in patent 5 6,239,267, YuisKmogii ei ai.; in patent O5 6,406,908, Msipiuge ei aiY.; or in patent O5 6,335,180, Oiiii5 ei ai. The results of these studies demonstrate that the compounds of formula I bind and modulate the activity of TKRM1.

PROTOCOL 1

Cloning of human TKRM1:

Human spinal cord RNA was used (commercially available from Siopiesp, Raiu AK,

CA.) Reverse transcription was performed on 1.0 μg of total RNA using Tpegtozsegiri Kemegze Tgapsgiriase reverse transcriptase (commercially available from Ipmigodep, Saghizrad, CA) and oligo aT primers, which are described in more detail in the product description. Reverse transcription reactions

Antagonists of TPRVI and their use were incubated at 55 "C for 1 h, inactivated by heating at 85 "C for 5 min. and RNase H- was treated at 37 "С for 20 min.

The human TKRM1 cDNA sequence was obtained by comparing the human genomic sequence, prior to annotation, with the known rat sequence. The intron sequences were removed and the flanking exon sequences were joined to the generated hypothetical human cDNA. The flanking primers of the human TCRMI coding region are designated as follows: direct primer,

SAASATSTTSOSTOSTTOSASASTOOOOSSASA (BO OO Mo: 1); and the reverse primer, vAADSATOTtToSsOS,aASAaa,ataAaSasttTacATaIt (5EO I Mo: 2).

TCRMI PCR was performed on one-tenth of the reverse transcription reaction mixture using template elongation polymerase and buffer 2 in a final volume of 50 μl according to the manufacturer's instructions (Kospe Arriii Zsiepsev, Ipaiaparoiii5, Ipa.). After denaturation at 94 C for 2 min, PCR amplification was performed with 25 cycles at 94 C for 15 sec, 587 for 30 sec, and 68 C for 3 min, followed by final incubation at 72 C for 7 min until complete amplification. The PCR product -2.8 KO was separated on a gel using 1.0 95 agarose,

Tris-acetate gel containing 1.6 μg/ml of crystal violet and purified using the 5.M.A.R. kit. UV-free cleansing gel (commercially available from Ipmigodep). The TERM PCR product was cloned into the rimMmo/L/5-NiZ-TORO vector (commercially available from Ipmigodep) according to the manufacturer's instructions to obtain TKRM1-RIMO. Obtaining DNA, degenerating with restriction enzymes and determining the sequence of the prepared DNA was carried out according to standard protocols. Determination of the raw sequence confirmed the identity of human TERMI.

Generation of inducible cell lines:

Unless otherwise indicated, cell culture reagents were obtained from I.e. Tesppoiiodiev,

VosKmiPe, Ma. NEK293-ESC cells expressing the ecdysone receptor (commercially available from

Ipmiygodep), cultivated in the medium for growing (Igla medium modified

Dulbecco's containing 10 95 fetal calf serum (commercially available from NUSI OME,

Godap, SHT), Ichpenicillin/Treptomycin, Ichglutamine, 1 mM sodium pyruvate and 400 μg/ml zeocin (commercially available from Ipmigodep))O. TKRM1-RIMO constructs were transfected into a cell line

NEK293-ESSK using Fugene transfection reagent (commercially available from Kospe

Arriei Zsiepse5, Vazei, Zm/ylegiapa). After 48 g, cells were transferred to selection medium (growth medium containing 300 μg/ml 5418 (commercially available from Ipmigodep)).

After approximately 3 weeks, colonies resistant to Zeocin/5418 were isolated and propagated. To identify functional clones, colonies were transferred to a 96-well plate and expression was induced for 48 h using selection medium supplemented with 5 μM ponasterone A (RopA") (commercially available from Ipmigodep). On the day of the study, cells were supplemented with RiIo-4 (calc -sensitive dye commercially available from Moiesciag Rgobe5, Eidepe, OK.) and measured CAP-mediated calcium influx using a fluorometric fingerprint plate reader ("RGIRK") as described below. Functional clones were re-examined, propagated, and frozen for storage. pH-based study:

Two days prior to this study, cells were plated on poly-O-lysine-coated 96-well black clear-bottom plates (commercially available from Vesiop-OisKipwop) at 75,000 cells/well in growth medium containing 5 μM RopA (commercially available from

Ipmigodep) to induce the expression of TKRM1. On the day of the study, the plates were washed with 0.2 ml of Hank's balanced salt solution (commercially available from I.e. Tesppoiodiyev) containing 1.6 mM Sassi" and 20 mM NEREZ, pH 7.4 (wash buffer") and supplemented using 0.1 ml of wash buffer containing RiIsho-4 (final concentration 3 μM, commercially available from

Moyesshiag Rgobevs). After 1 h, the cells were washed twice with 0.2 ml of wash buffer and resuspended in 0.05 ml of Hank's balanced salt solution (commercially available from Iie Thesppoiodiev) containing 3.5 mM Sassi and 10 mM citrate, pH 7, 4 (assay buffer"). The plates were then transferred to EGIRK for testing. The test compound was diluted in the assay buffer and 50 μl of the resulting solution was added to the cell plates and the solution was observed for two minutes. The final concentration of the test compound was in the range of approximately 50 pM to approximately 3 µM.Buffered agonist (wash buffer titrated with 1M HCl to a pH of 5.5 when mixed 1:11 with assay buffer) (0.1 mL) was then added to each well and the plates incubated for an additional 1 minute Data were collected throughout time and analyzed using Ehsei! and shari Rai Rgiht to determine ISbo.

A capsaicin-based study:

Two days before this study, cells were plated on poly-O-lysine-coated 96-well black clear-bottom plates (50,000 cells/well) in growth medium containing 5 μM RopA (commercially available from Ipmigodep) to induce expression TKRMI1. In the day

TRVVI antagonists and their research applications, the plates were washed with 0.2 ml of 1x Hank's balanced salt solution (commercially available from I She Tesppoiodie5) containing 1 mM Sasi» and 20 mM HERE5, pH 7.4, and the cells were supplemented using 0.1 ml of wash buffer containing RiIco-4 (final concentration

From MKM). After 1 g, the cells were washed twice with 0.2 ml of wash buffer and resuspended in 0.1 ml of wash buffer. The tablets were then transferred to BHIRKE for examination. 50 μl of the test compound diluted with the research buffer (1x Hank's balanced salt solution containing 1

MM Sasi" and 20 mM NEREF5B, pH 7.4) were added to the cells of the tablets and incubated for 2 minutes.

The final concentration of the compound ranged from about 50 pM to about 3 µM.

Human TCRMI was activated by adding 50 μl of capsaicin (400 nM) and the plates were incubated for another 3 min. Recorded data throughout time and analyzed using Ehsei and sharp Rai

Rgizt for determining ISvo.

PROTOCOL 2

For Protocol 2, a Chinese Hamster Ovary (CHO) cell line was used, which was constructed with significant expression of human recombinant THERMI (TKRM1/CHO cells).

The TKRM1/CHO cell line was obtained as described below.

Cloning of human TKRM1:

Human TKRMI1 (PTKRMI1) receptor cDNA was amplified by PCR (KOO-Plus DNA polymerase, ToMmoVo, Chdarap) from a human brain cDNA library (VioSpaip) using primers that flank the complete PTKRMI1 open reading frame (3 (5-

SOATSSASSAAADOSATOAASAAAATOS (ZEO IO MO:3), and vice versa 5-

TOTSTOSOTOASOTSSTSATSTST (5EO AND MO:4)). The resulting PCR products were purified from agarose gels using the Sei Vapa Ritgiysayop Kii purification kit (ZE Neaxage Viozsiepse) and subcloned into rSV-Winppi vector (Ipmygodep). The cloned cDNA was completely synthesized using a fluorescent dye-terminator reagent (VidObue Teptipafog meg3.1 Susieye zedcepsipo Kiyi, Arriey Viozuetv) and AVI Regist 3100 genetic analyzer (Arriey Viozuetv). The pOV-Viipi vector containing the NTERMI cDNA was cleaved by restriction with EsokK1.

The restriction fragment was subcloned into the expression vector rsrmAZ.1(-) (Ipuygodep) and called the rheoOMAZ.1(-)-pUK1 plasmid. The cDNA sequence encoding TERMI is available in the gene bank under the number A.)277028.

Generation of TKRM1/CHO in the cell line:

SHO-KI1 cells were maintained in a growth medium consisting of 0-MEM, 1095 EB5 (Nussiope), and a mixed solution of 100 IU/ml penicillin - 100 μg/ml streptomycin (Masaiai Tezdie,

Huarap), at 37 "С in an environment with air humidity of 9595 and 595 СО". Cells were transfected with the rheoMAZ.1(-)-LMAK1 plasmid using HySEMEb (Cospe) according to the manufacturing protocol.

Neomycin-resistant cells were selected 24 g after transfection using 1 mg/ml 418 (Masaiai Tezdieye). After 2 weeks, individual colonies were selected, grown, and tested for PTERMI1 expression in a capsaicin-induced Ca influx assay. (see below) from EGIRVE (MoIesshag YuOemise5). Was the clone selected with the greatest response? to capsaicin and re-cloned using the same procedure. Cells expressing pNTKRM1 were cultured in a growth medium supplemented with 1 mg/ml (53418. After approximately 1 month, the stable expression of functional TERMI receptors of selected cell lines was confirmed using the justification of the Ca response with or without capsazepine (bZidta, at 1 nM-10 µM) in the capsaicin study.

Assay of capsaicin-evoked Sag influx: For cell selection:

The next study was carried out to identify cells with PTKRM1 expression. SHO-K1 cells transfected with rsoMAZ.1(-)-pLMK1 plasmid were seeded on 384-well black plates with a clear bottom (Sogpipdu) and cultured in growth medium (see above) for 1 day.

One day after the experiment, the culture medium was replaced with the research buffer (20

MM NERE5, 137 mM Masi, 2.7 mM KSI, 0.9 mM Masig, 5.0 mM Sasig, 5.6 mM O-glucose, 2.5 mM probenecid, pH 7.4), which contained 4 µM RiIpo -3-AM (Soyip, darap). After incubation at 37°C for 1 hour, each well was washed three times with assay buffer using an EMVIA 384 plate washer (MoiIeschag Oemise5) and filled with assay buffer.

The plates were incubated at a temperature of approximately 25 °C for 10 min. After that, the plates were inserted into EGIRE, and 1.5 µM capsaicin (bZidta) solution prepared in assay buffer was added to each well (final concentration was 500 nM). the response was observed for 5 min.

Cell culture: 1. Medium for cell culture 1. Airna-MEM (Sibso, CATA: 12561-056, I OT: 1285752): 450 ml. 2. Calf embryo serum (EV5), other activated by heat (IRSO, SAT: 16140-071, 101: 1276457): ml.

Antagonists of TRPVI and their use 3. NERE5 buffered ready solution, 1M (bibso, CATA: 15630-080): 10 ml (final 20 mM). 4. Geneticin, ready-made 50 mg/ml (sirso, CATA: 10135-035): 10 ml (final 1 mg/ml). 5. Mixed antimiotic antibiotic solution, 100x ready (Masaiai Tezdieh, darap, CATA: 02892-54): 5 ml.

The above components 1-5 were mixed in the specified amounts and stored at 4h76s.

The medium for cell cultures was heated to approximately 37 °C before use.

Optionally, component 5 is replaced with a penicillin-streptomycin solution (for example, Sibso 15140-122 or Bidta P-0781). 2. Melting of cells

TARM1/СНО cells were frozen in SeiyrapkegM (Utsi-RieiI IMS, Ucharap, SAT: VI S-1) and stored at -80 "C. An optimized solution for cryopreservation was used, which contained dimethylsulfoxide and EV5.

Tubes containing TERM1/CHO cells were stored at -80 "C. After removal from -80 C, the tubes were immediately transferred to a water bath at 37 "C for thawing for 1-2 min. After complete thawing, the contents of the tubes (1 ml/tube) were transferred to sterile 15 ml test tubes and 9 ml of warm culture medium was slowly added. The test tubes were centrifuged at 1000 rpm. within 4 min. at a temperature of about 25 6.

The supernatant was removed and the pellet was resuspended in 10 ml of culture medium. The cell suspension was placed in sterile plastic flasks with a surface of 75 cm and incubated at air humidity

BU СО2/9595 at 37 "С. To assess viability, cells were visually inspected and/or counted starting approximately 1 hour after incubation. 3. Passivation of cells

The cells in the flask were close to confluency during passaging. The culture medium was removed from the culture flask and 10 ml of sterile PB5(-) was added and the flask was gently shaken. PB5 was removed from the flask and 2 ml of trypsin/EOTA solution (0.05 95 trypsin with

EOTA-4Ma; Sirso, CATE: 25300-054) and the flask was slowly shaken. The flask was incubated at 37 °C for approximately 2 min. After that, 8 ml of culture medium was slowly added and the flask was shaken to ensure that all cells were in the solution. The cell suspension was then transferred to a sterile 15 or 50 ml plastic tube, centrifuged at 1,000 rpm for 4 minutes at a temperature of approximately 25 "С. The supernatant was removed and the residue was resuspended in 5 ml of culture medium. Cells were counted using a Vigkeg-GI hemocytometer.

Cells were seeded in a sterile 75 cm plastic flask? in 0.8 x 105 cells/ml for 72 g and incubated at an air humidity of 5 95 С2О2/95 95 at 37 "С. 4. Freezing of cells

The procedure for cell quantification was the same as in the cell passivation section above.

After that, the cell suspension was centrifuged at 1,000 rpm for 4 minutes. at a temperature of approximately 25 "C. The supernatant was removed and the residue was resuspended in the SePrapKeg"M solution to reach a final concentration of 5 x 105 to 5 x 106 cells/ml. The cell suspension was transferred into appropriately marked cryotubes with a volume of 1 ml and then placed in a refrigerator at -80 "С.

Research based on pH:

The following study was conducted to determine the concentration of sulfuric acid that would increase the pH that would cause the Ca? response to be optimal for the test compounds for their effects on THERM. 1. Cells

ТКРМ1/СНО cells were seeded on 96-well black plates with a transparent bottom (Mips) at a density of 1-2 x 107 cells/well and grown in 100 μl of culture medium (alpha-MEM supplemented with 1095 ЕВ5, 20 MM HERE5, 1 mg/ml geneticin and 1 95 with a ready-made solution of an antibiotic-antimiotic mixture) within 1-2 days before the experiment. 2. Determination of sensitivity to pH and agonist dose 2.1. Agonist solution

Different agonist solutions were prepared with different concentrations of sulfuric acid from 15 mM to 18 mM (see Figure 1) by diluting 1 M sulfuric acid with buffer buffer. Different concentrations of sulfuric acid in the agonist solutions were chosen so that a 1:4 dilution would give a final concentration of sulfuric acid between 3.0 mM and 3.6 mM, respectively, as shown in Figure 1. 2.2. Are pH studies dependent on Ca? responses in TERM1/CHO cells grown in a 9b-well plate are shown in Figure 2. Specifically, Ca influx in TERM1/CHO cells in response to a decrease in pH, as measured by Eiga-2 AM fluorescence, is shown in Figure 2. Cells were stimulated using 3.0 mM (well number B1-6), 3.1 mM (C1-6), 3.2 mM (01-6), 3.3 mM (E1-6), 3.4 mM (E1- 6), 3.5 mM (1-6) or 3.6 mM (НИ1-6) Не5О" or pH 7.2 measured buffer without Н2г5О" (А1-6) (Figure 2). (1) The culture medium was removed using an 8-channel pipette (Kaipip, OBA) with 96-

Antagonists of TPRVI and their application well plate and wells were filled with 100 μl of loading buffer (20 mM NEREF5, 115 mM Mass, 5.4 mM KS, 0.8 mM Massi, 1.8 mM Sasi, 13.8 mM O-glucose, 2 .5 mM probenecid, pH 7.4), containing 5 μM Riga-2 AM (Roiip, Charap). (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 then washed twice with 150 μl of measurement buffer (20 mM NEREFZ, 115 mM Masi, 5.4 mM KSI, 0 .8 mm Masi", 5.0 mm Sasi", 13.8

MM O-glucose, 0.195 B5BA, pH 7.4) (without probenecid). The wells were then filled with 80 μl of measuring buffer. (4) After incubation at 4 "C for 15 h, the 96-well plate was transferred to EOZ5-3000 (Natataizi Rpoyuopisz, Charap). (5) Riga-2 fluorescence intensity was monitored at a wavelength of 340 nm and at 380 nm, respectively, at a frequency of 0.5 Hz for 240 seconds. After baseline readings were taken 16 times (32 seconds), 20 μL of agonist solution was added to each well. The final volume is 100 μL/well. (6) The fluorescence intensity ratio refers to the fluorescence intensity at 340 nm and fluorescence intensity at 380 nm at a certain time.The baseline reading was the average value of the fluorescence intensity taken 16 times before the addition of the agonist solution.

The maximum response was considered to be the greatest fluorescence intensity within 60 readings after adding the agonist solution. (7) Maximum signal ratios of each well were calculated as data obtained using the EOB55-3000 analysis program. Data were analyzed using Echsei (Mysgozoic) and XI Tia (1065) software. 2.3. Determination of pH

After observing the Ca? response, the buffer of each line (50 μl/well, 8-20 wells/plate) was collected and the pH value was measured using a portable pH meter (Zpipaepdep, darap).

As shown in Figure 2, the Ca response in lines Y and E had an average value and is therefore optimal for studying the effect of compounds on TKRM1 calcium channels. The final concentrations of sulfuric acid in the wells of these lines are 3.2 mM and 3.3 mM, respectively. This final sulfuric acid concentration was obtained using agonist solutions with 16.0 mM and 16.5 mM sulfuric acid concentrations, respectively (line O and E in Figure 1). The pH value obtained when using these concentrations of sulfuric acid was 5.0-5.1.

Thus, agonist solutions with 16.0 mM and 16.5 mM sulfuric acid concentrations, respectively (lines O and E in Figure 1) were selected in the experiments described below in Section 3. 3. pH Analysis 3.1. Agonist

Two different agonist solutions with different Na25O4 concentrations were used for pH analysis (Figure ZA). One agonist solution was used for half of the 96-well plate, and another agonist solution was used for the other half. Agonist solutions were obtained by diluting sulfuric acid (Hg5O»x, 1M) with buffer for measurement. Concentrations for the two agonist solutions were determined as described above in section 2 of Protocol 2.

The concentration of sulfuric acid between the two agonist solutions differed by 0.5 mM. In the experiment described in Section 2 of Protocol 2, the concentrations of sulfuric acid in the agonist solutions were 16 mM and 16.5 mM, respectively. After a 1:4 dilution of the agonist solutions, the final concentration of sulfuric acid was 3.2 mM and 3.3 mM, respectively. The obtained pH value was 5.0 - 5.1. 3.2. The studied compounds

The studied compounds were dissolved in OM5O to obtain ready 1 mM solutions. The prepared solutions were then diluted using UM5O in 1:3 serial dilutions 6 times (1000 µM, 250 µM, 62.5 µM, 15.625 µM, 3.9062 µM and 0.977 µM). The solutions obtained in this way were diluted with a buffer for measurement (1:100) as 10x ready serial dilutions of ЮМ5О 1 95. 10 μl of 10x was added to each well at stage 3.3.(4) of Protocol 2. Thus, the final concentrations of antagonists are in the range of 1000- 0.977 nM containing 0.1 96 OM50O (Figure 3B). 3.3. Research

Stages (1) and (2) of this study were the same as stages 2.2.(1) and 2.22) of Protocol 2, respectively. (3) Cells were washed twice with 150 μl of measurement buffer (described in 2.2.(3) of Protocol 2, without probenecid). The wells were then refilled with 70 μl of assay buffer. (4) Each 10 μl of measurement buffer or 10 μl of a 10x serial dilution of the test compound (described in 3.2. above) was applied to each well. Typically, only one test compound was tested in a 96-well plate. The number of replicates per 96-well plate for a certain antagonist at a certain concentration was 7 x 2, given the fact that two different concentrations of sulfuric acid were used per 96-well plate (M - 7 x 2U (Figure 3).

Antagonists of STI and their use

Stage (5) was the same as 2.2.(4) above. (6) Riga-2 fluorescence intensity was measured as described in 2.2.(5) above. After 16 baseline readings, 20 μl of the agonist solution (measurement buffer titrated with H25Ox to pH 5.0 - 5.1 when mixed 1:4 with the measurement buffer containing the test compound) was added to each well (final volume in a container of 100 μl/well).

Steps (7) and (8) are described in 2.2.(6) and 2.2.(7) above, respectively. 3.4. pH test (1) The pH values of the buffer in wells A1 -» NI and A7 -» H7 (along; Figure 3) were measured one by one using a portable pH meter. (2) When a well confirmed a pH value of 5.0 or 5.1, the next 5 wells to the right of it were measured one by one. (3) To calculate ISvo, only data from wells with a pH value of 5.0-5.1 were used.

The number of wells tested for their pH level varied among tablets (approximately 16 - 60 wells/tablet). The number depended on the results of 3.4.(1) above and Ca: responses.

A capsaicin-based study:

One day after the study, TCRM1/CHO cells were seeded in 96b-well black clear-bottom plates (20,000 cells/well) in growth medium. One day after the experiment, the cells were washed with 0.2 ml of Hank's balanced salt solution (I and Tespoiodiev5), which contained 1.6 mM Sasi" and 20 mM NEREB, pH 7.4 (washing buffer"). cells were supplemented by incubating using 0.1 ml of washing buffer containing Ritso-4 (final concentration Z

MKM). After 1 g, the cells were washed twice with 0.2 ml of wash buffer and resuspended in 0.1 ml of wash buffer. After that, the tablets were transferred to the tablet-reader Ripogezsepse Itadipd Riaie

Keadeg (MoiIesshag Oemise5). Fluorescence intensity was measured for 15 seconds. to establish a baseline. Thereafter, test compounds diluted in assay buffer (1x Hank's balanced salt solution containing 1 mM Sasig and 20 mM NEREZ, pH 7.4) containing 1 96 DMSO were added to the cell plate and fluorescence was measured for 2 minutes. The final concentration of the compound was set in the range from 100 µM to 1.5625 µM. In the case where the test compound was a particularly strong antagonist, the final concentration of the compound was set in the range from 10 μM to 1.5625 nM. After that, human TKRM1 was activated by adding 50 μl of capsaicin (100 nM final concentration) and the plates were incubated for an additional 3 min. Data were collected throughout the study and analyzed using Echsey and the curve fitting formula sharpRaa Rgizt.

The results of the study of Protocol 2 are shown in Table I, which demonstrates that many of the compounds of the formula show a significant effect. ISvo data are given in Table | shown as mean xz standard error of the mean; the number of samples for each study is given in the introduction.

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it (7

M si XX

Edi 7.0 - 1.8 (4)

M

Huh

SEZ on no

Sh

M si XX

EV 7.8112(4 7.40 with 0.3 (3)

M

CA,

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

But

G

M

SI g

EC 15.3 w 6.9 (3) 11.3 w 0.8 (3)

M

J

OSEz he is still 7

M is db and ri 16.5 z 4.1 (3) 0.9 (2)

M

J

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Go

M si Zh bach

IS! 18.5 x 4.9 (3)

Mr. On

BUT,

Go

M si 74

IS

Yes 18.6 with 6.8 (3) 9.0 with 2.3 (3)

M

Yes

AND

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Its structure 7 more

Ms. Zh

E st 31.3 - 8.8 (3) 16.4 (2)

M cha

To her

J

SEZ on

BUT, (7

Ms. Zh

E no 31.7 1 8.9 (3)

M

Yes, c

SEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Its structure 7 more

Masses 33.8 5 91 (3) 110.2 (3)

M ra on no, Fr

M

E XX and 1 34.5 and 17.5 (3) 18.0 (2)

M cha i

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure but what 7

Msi 4th

CI 35.1 and 8.8 (3) 39.5 (2)

M

J

To her

J

SEZ on that 7

Ms

IS

I 35.3 x 12.0 (3) 27.5 x 3.4 (4) M ra

AND

IS

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Sh

Ms

IS

MI 37.5 zhk 9.0 (3) 5.7 zh 0.3 (5)

M

J

SI

OSEz on

BUT, (7

ee"

SI

IS

M 38.7 w 5.3 (3) 6.3 w 0.8 (5)

M

Yes

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it

Go

M si 4

Ex pts 41.1 vs 17.8 (3)

M

Yes

S Y 7 i

SEZ on she 7

M

Eh eh

RI 50.5 and 9.5 (3)

M cha rt

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

But,

Go

M

SI 4 s her 51.0 z 16.4 (3) 81 0.7 (3)

M

CA,

AND"

SEZ on

BUT, 7 - M si tah

VI 51.0 w 18.8 (3)

Mr

AND

IS

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

But, (7

M

SI 74

Ch 51 53.5 w 16.3 (3) 16.3 w 2.0 (3)

M che and

SEZ on

BUT, oh

M si 4

These are 60.3 with 19.0 (3) 29.7 with 2.3 (3)

M chi

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

M

E 4 th

AI 61.3 out of 22.5 (3) 14.7 out of 3.3 (3)

M

J

SEZ

Gee,

Go

M

E Z bo mi 66.3 i 5.7 (3) 22.4 z 1.1 (3)

M

Well,

OSEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

But,

Go

M

SI and

VH

M 68.9 w 18.4 (3) 9.3 w 1.9 (3)

M

Ху ра

SI on

Go

M

SI 74 ah

Chi 74.4 w 11.5 (3) 18.8 w 1.6 (6) m

J.

SEZ paradise

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Its structure (7

M

E dDy eh

In 74.7 5 18.4 (4) 13.5 and 1.2 (3)

M

J.

SI

OSEz on no, (7

M si 4 xx 71 75.8 12.4 (4) 11.6 w 0.7 (3)

M

CA,

SEZ

237/Z

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Its structure 7 more

M

SI 4 and d2 84.1 11.2 (3)

M chi and cha

SEZ he still

Go

M

SI 4 bach weight 77.6:-12.0 (4) 40.5 (2)

M cha

OSEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no. 7

M si 4 ex

C2 98.7 - 33.9 (5) 41.8 with 3.8 (3) Ma

ZY

SEZ he still

Go

M

SI g "xx p2 85.3 w 20.7 (8) 10.8 w 0.9 (3)

M

J.

SI

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Go

M

SI Zh and

E2 107.4 with 18.8 (5) 20.3 with 1.7 (3)

M

J

ОСЕз 9) ше

Go

M si 4

IN:

E2 108.0 out of 24.3 (3) 62.9 out of 8.8 (4)

M cha

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure No. 7

M

SI 74 ah c2 112.4 with 22.3 (3) 84.8 with 8.8 (3)

M

Yes

SEZ is still 7

M si ha

Sh ng 118.1 22.1 (3) 13.1 2.1 (3)

M h

SI

OSEz

2A41/3

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Go

M

SI 74 ah

AND? 122.0 w 7.1 (3) 18.0 w 1.0 (5) АХ o МН "SEZ va on 7

M

SI and W 92 128.6 with 26.0 (3) A1.7 in A A (3)

M

CA.

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Go

M

E TO kh

Kg 140.8 with 41.9 (3) 47.2 6.7 (3)

Moscow and SEZ

SI on (7

M

SI and

VH

AND? 153.0 with 24.4 (3) 57.4 with 9.1 (5)

M

AND.

SI

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Go

M

SI 4 7

M2 156.3 x 5.6 (3) 42.0 with 9.1 (3)

M

KA and

SEZ on

Go

M

SI 4

SHE

M2 161.4 with 16.6 (3) 27.3 with 2.6 (6)

M

Ху ех

EzS

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Go

M si 74 bo

O2 161.8 w 29.5 (3) 18.8 w 4.0 (4) A (o) Mn

She

Yes and he no

Go

M s 4 ex r2 172.9 w 40.3 (4) 44.4 (2)

M

J. "SEZ

Hg

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

ON

7

Ms

Sh

O2 194.4 of 27 1 (3) 85.9 of 21.8 (4)

M

CA,

OSEz on 7

MS g

ВХ в2 199.9 out of 26.8 (3) 49.6 out of 3.4 (5)

M

AND,

Hg

OSEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Its structure (7

M

SI 4 and 52 205.3 z 35.4 (3) 31.9 2.5 (3)

M chi

SI

SEZ on no, 7

M si -

Ex t2 225.8 with 69.3 (5)

Mr

SEZ

SI

247/Z3

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no (o

M

SI -

Ch 2 230.5 with 45.3 (4) 53.4 with 5.9 (3)

M

KH

SEz on 7

ee"

SI ah

U2 234.2 with 44.6 (3) 83.2 with 7.6 (3) AH

H

M

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure No. 7

EE" si xx mg 244.8 z 34.4 (3) 241.3 z 34.9 (5) M 7 4 on 7

M si 4 kh

X2 248.4 of 25.1 (3) 81.1 10.5 (3)

M

CA

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Go

M

SI I

Tech

M

Ug2 350.9 with 69.8 (3) 59.9 with 11.8 (3) A (about MN

SEZ

AH on 7

Msi g sx 72 401.0 with 122.4 (3) 247.6 with 45.3 (3)

M. a

TO Y in

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

Go

M

SI 4 x

AZ 414.1 with 99.6 (3) 309.5 with 38.9 (3) k cha o-- -5- o i, on 7 de" si

Seh in 537.2 with 62.0 (3) 106.0 with 11.4 (5) m 7

M 4 Z

SI

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of 7

M

SI 4 ех сЗ 541.4 x 215.8 (3) ХХ (o; Mn o--8-o0 o on

Go

M

SI 74

Width 564.8 x 58.6 (3) 39.8 x 2.2 (3) m

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it 7

M si and tah

EZ 670.7 with 133.1 (3) 141.0 with 23.1 (3)

M. a

And and

Sh

Ms

Seh

EC 915.7 - 305.6 (4) 584.8 (2)

M

Well,

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure and (7

M

SI 74

H

OZ 1075.9 and 201.8 (3)

M

Huh

OSEz and 7

M si g s

NNZ 1114.9 out of 134.0 (3)

M

UNTIL

To her

J

SEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it 7

M si 4 b

IZ 1363.7 x 337.4 (3) A. (e) Mn and "SEZ

You are 7

M

SI -

VH

UZ 2940.7 x 318.9 (3)

M r i)

S ui Jie

EzS

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Go

M si g

H

KZ » 10,000 (3) A. o) MN

You are only 7

M

SI 4 Bach

IZ 37.1 w 14.8 (3) 38.3 w 4.0 (3)

M r

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

The compound PSAR-CHO) (NM) PrH-CHO) (nm) The structure of he no (o

M si Zh sch

M 186.9 with 43.7 (3) 30.0 with 2.1 (3)

M ra ke on no

Go

M si - bah

M 161.1 with 41.7 (3) 223.3 with 14.0 (3)

M r

DK Y

J

SEZ

257/Z3

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it no

Go

M si 4

Sh

OZ 46.0 out of 11.3 (3)

M ra ot

SEZ

N no o -6 M s y

RZ 183.4 with 38.1 (3) 28.5 (2)

Mr

And with

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no, t, on bach schi

IS

IS

OZ 14.3 w 1.3 (3) 5.3 w 1.0 (4)

M

Ah, ke

SEZ no, ", on

EX

More

IS

IS

VZ 15.5 x 3.5 (3)

M sha

OSEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Well, 7 cy

E b 53 17.7 2.0 (3) 9.2 (3)

M

Yes

OSEz he no,

Go

M

SI 74

IS

TK 23.8 out of 6.8 (3) 12.9 (3)

M. a

SI

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

BUT,

Go

M

E dDSh- x

OZ 27.9 w 9.9 (3) 13.5 (2)

M

Well,

SI

SEZ he no eh still

SI

IS

UZ 34.0 and 9.2 (3)

M

KA and

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

Well, he is

ВХ шчи

IS

IS

MIZ 35.6 of 8.9 (3) 22.4 (2) XX ni (e)

AND,

Yes, but he

EH still

IS

IS

UZ 43.9 and 10.0 (3)

M

And, and

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

Nopny,. xx shh

E b

Ada 55.1 w 8.6 (4)

M ra on no, (7

M si 74

E vi 57.2 w 11.6 (3) 5.8 w 1.3 (4) m a o--5--her10 in

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

But, come on

Wow

CA 66.2 x 7.5 (3) 18.6 x 2.8 (3) k

J

J

SI on no (fr

M si 4

Era 69.6 with 6.9 (3) 54.8 (2)

M. a

To her

J

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of 7

Ms

IS

E4 75.7 12.8 (3)

M

CA. and what

SEZ on

IS

IS

Go

M

SI 74 7,

E4 86.7 - 18.9 (3) 32.5 with 2.4 (3)

M. a

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Go

M

SI XX

E on 175.8 with 28.4 (3) 97.0 xz 9.9 (3) k

Ху ра

And he

But, (fr

WHERE"

And

KA 210.2 x 19.5 (3)

M

UNTIL,

To her

J

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

BUT, hey

E b

I4 439.4 from 139.8 (3)

M

Hu

AND

IS

H (9)

M i se (v

Go

M si 4 ex

MA 471.3 with 127.3 (3)

M

AND

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Go

M

SI -

IS

MA 1312.9 5 220.5 (3) m ra

AND,

SI on on 7

M si - in 04 1517.2 - 338.6 (3)

M

J

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

BUT, 7

M

SI - o

RA 1809.9 with 302.1 (4) M ra with, (9) on no 7

M

SI - x 4 2897.7 w 302.1 (3) k

Same with, si

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no, te on

What

M

IS -

IS

Va 3278.6 with 760.6 (3) M

AND,

Ah, he is still 7

М с 4 бе 54 7028.4 и- 20590 (3)

M

AND

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no no, 7

M

And

IS

XA 38.4 out of 8.0 (3)

M

Huh

SEZ on

Well, Mr

EE" si

IS

74 62.8 out of 11.4 (3) 16.5 out of 3.3 (3)

M

7 and

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Its structure will be

SI

E in 106.5 with 21.0 (3) 15.0 with 3.0 (3)

M i h

SEZ

Oh, that's Ge

Oh shit

IS

IS

Sat5 107.7 w 38.4 (3) 39.9 w 7.9 (3)

M

AND,

She

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

IS

E p5 132.7 w 29.1 (3)

M

Hu 57

SEZ

BUT, p. he and shchi

IS

IS

EB5 132.8 of 28.5 (3) 33.8 (2)

M

A, "SEZ p

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no

But, bang shchi

IS

IS

E5 166.1 of 24.7 (3)

M

KA ra

Well, but, with shchi

IS

E a5 400.0 with 10.6 (3) 108.5 (2)

M h

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

ON

BUT, 7

Where are you?

M n 520.0 with 88.6 (3) 515.6 with 99.2 (3) and I

Mr

Oh no

But 7

M si g y

IB 709.1 out of 941 (3) 117.6 27.5 (3)

M. a

SEZ

275/Z

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure about dk"

IS

IS

M t4 1330.7 w 334.3 (3) 1175.1 w 147.2 (3) A (Fe) MN y no no, sx schi

IS

IS

95 1879.8 5 633.8 (3)

M

AND

A, (fr

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

Go

M

E dЙ8

Sh

M

KB 2753.2 z 541.9 (3) A c) MN a

BUT, t, t o

M si 4 x

IS » 10,000 (3)

M

KH

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

F) he (7

M

SI 74 x

M5 » 25,000 (2)

M

J

SEZ no no

Go

M

E dDY

IS

MB 140.25 (2)

M

Yes

HA,

IS

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no

BUT, 7 thanks

Sh

O5 243.62 (2)

M

7

M and 5 no no

With shchi

IS

IS

RB 49.51 (2)

M

KU

SI

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no no, (7

M

SI 4 x v 346.05 (2)

M

Yes

OSEz on on on 7

M si -

E t 451.5 w 92.4 (3)

M

AND,

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it,

Go

M

SI 4

IS

OB 19.9 w 6.9 (3)

M

Yes

AND

SEZ on

BUT, (fr

Ms

IS

U5 45.5 521 (3) 10.1 of 1.4 (6)

Mr

OSEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no no,

Go

M

SI and

WITH

MI5 423.2 z 122.5 (3) 71.2 10.5 (5)

M. a

AND

SEZ no

BUT,

Go

M si y y: x5 229.8 w 65.5 (3)

M

J

: Kh.

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no

BUT,

Go

M

E dDyo

E y5 196.4 хз 37.7 (3) 108.5 with 7.7 (3)

M

CA,

To her

J

SEZ on no 7 j"

IS

IS

75 35.5 with 3.9 (3) 16.4 with 1.9 (5)

M

7 4

SI

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of it

IS

IS

Av 49.8 w 12.1 (3) 9.0 w 0.8 (4)

M

And

SEZ No. 7

M si g xx 922.2 w 204.6 (3) 361.6 z 69.1 (3)

M h

To her

J

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure no

BUT,

Sk schi

SI

Eh

Sat » 25,000 (2)

m ev)

CA. to Y

J

SEZ on (7

M with 4

Ex 620.5 with 116.5 (3)

M. Chi and Y

J

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of

Go

M si - y

Eb 265 165

M

J

SEZ

19)

She

Go

Ms. Zh

WITH

E6 864 467

Mr

SEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure o

Ge b shchi si xx ab » 25,000

M

Hu

SEZ yo

Go

Msi 4 and nb 924

M

CA,

SEZ

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of on

BUT, and

KAM

SI

M kb 9.8 with 2.3 (4) 0.8 with 0.1 (3) (С Z

M fin on

BUT, and

M

SI

M

I 6 14.2 with 1.4 (3) 5.6 (2) (S Z

M Fin

OSEz on

BUT,

M

(Fi

M

Mb 7.0 w 1.0 (5) 3.5 w 1.0 (3) (S Z

M Fin

SEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure of he no, o si and

M uv 16.0 w 1.6 (3) 6.2 (2) and y)

M r

And he

BUT", i

M

SI

M

MI 32.9 w 11.8 (3) 14.9 zhk 2.2 (4) (S Z

M Fin

SEZ

(Fi

G

M

SI 4 sch

M

200 136 31.8 AH (in) MH

CE"

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure o

M si 4 b

M

201 131 185 A. about MN

To her

J

SEZ

(7

M

E dDSh o

M

202 182 590 A about MN and

SEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure

Go

M

SI 4

IS

M

203 90.2 512 A (in) MN

SEZ

7

M

SI 4

IS

M

204 167 154 A (c) MN

HO Y

J

SEZ

(at

M

SI and y

M

205 » 25,000 A (e) MH

OSEz

Antagonists of STI and their use

Table I: ISvo activity of TRPVI1

Human capsaicin CHO Human RH CHO

Compound PSAR-CHO) (NM) PrH-CHO) (nm) Structure o

M si 4

IS

M

206 508 1463 A. (c) MN

AND

IS

The present invention is not limited to the specific embodiments described in the examples, which are intended to illustrate some aspects of the invention, and any embodiments that are functionally equivalent are within the scope of the present invention. In fact, various modifications of the invention, in addition to those shown and described herein, will be apparent to one skilled in the art and are intended to fall within the scope of the appended claims.

The description contains a number of references, the full description of which is incorporated herein by reference.

Antagonists of STI and their use

List of sequences of "1102 Perdyk" L.P. Famma.

Shshchisonogi Shf8NA CO., MED. "120z Antagrsists TVP) due to jamming "305 reVBRya and KA "150 PE BOG, VI "i515 20072504-97 -1505 Pa 6500/9530, 936 "1BIi" 3007-05-11 "i50z B 600937, "1515 2007-05 -24 "her" SHE vp/9va3, 09 "151 80075077 "zhh 4 "170" Rakepsip hehgyaiov 3.3 "105 1 "her" 3 "eye" WILD "213 Artificial "2" "skiae Direct primer ЖРНИ1 "-400z 41 hChaachayesees dstuchekosa sasruuaesa sa 38 "10" y "iiy khzhiy" DNA "yy fuUchna "00" "ee" bReverse primer TRIVI "300" 2 chaassasssks sadaasachka asodssachak de 32 "eh Z "Ki" 25 "vyih dNE "oi" Shtuzna "vai" "vyy" Direct pryweb of the full YATRIPV OVE "azh Z chchakssvatsyaa adtschayessavcha dabche 25 "K10z and "ih 6

Antagonists of TRPVI and their application ky DE "23" PrRUCHNE motto ch"eg3" Reverse primer of full vVITRIpVi OV "2800z 4 geEskdschsea aschisostsovs Ese 24

Tablet hinged 00003303 to

PC un vonnnnnyu contributed and and Mn and Z Z opnntennonnonununyunov I wholesale, - and Buffer! : | | ! juices 8 NOZOYA 150 MM fintseva 3.0 MM). 00004500 renia nn sonya 2-4. NEW 15.5 MM (FINAL WITH MMO 00000 nnnnifnnnnnn ny 8.1.. NEW 16.0 MM (crown Z.9.MIM). 000005 nn mn mon 2-8. .825ОZ 18.5.MIM (Final 3.9 MM) 300000035onnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

POV NEW4170 MM Final 34 MM).C0000000snnnnnn fenny ryn 02221248. 8250417.5.MM (final 3.5.MM) 00000 nen nanni

New 185.0 MM (final 3.6 MM, A ! ny nny M o Fig

Final Without agonist conc. Н2ЗО4 g voza and lym shshshshto 0.0 | and every day of the year 3.0 in | | and ! ego Guensfinnn. di i i ia z ii ' | !

Ziat ke 3.2 I and r. in the city of Ren These concentrations

KU write (M that give a pH of about 5.0 and - Я»»o 5.5! were selected and used 3.3 and и| va for the next research

For. whether or not

More | about in has more шЧ и Ж ж ше ок дыны мыш в а В г Кк И Г Иж

Zo M HCM chu yi I, tmsna vne kny 36 her A o . che KU EN ii x "r i. m. - K. M sh

ANA

Fig. 2

Antagonists of STI and their use

ODA) Tablet racer. (00000100 pn ia ni o NO NI I IN ION NE SHY: 10 kih R pn as ! still schi- schen I-i. . NVO X tii NO IH same 0.5) TM more

ЧВ) Tablet antagonist 000 final concentration of the antagonist | nM

SA, : : | : | | and | 4

SV ov (3.206 О15.63 652.5: 250 100010.977 3.906 and 15.63 62.5 250 1000| . 2000003.8 R 3... .Besantagonist. .. o... .Besantagonist. p. :

EE and N Y : N ! 1 : N N shi 0.977 :3.906 15.63 62.5 250 1000Щ0.977 3.90615.63 82.5 250 1000 1

Fig.Z

Claims (80)

1. A compound of the formula I: Ag «B, M Z (in (С A ( Z)t M a Az 0) or its pharmaceutically acceptable derivatives, where X is O, M-CM; M is M or C; the dotted line means the presence or absence of a bond, and when the dashed line means the presence of a bond or M is M, then Ka is absent, otherwise Ka is -H, -halo; At is re OM A; Ato is A, ; Y or Z s (Nidda (Ach 4)v Not v. . Ki is -H, -halo, -C(halo)z; Ko is a group of formula O; where O is -"СНХОНСНООН, -СЕСНоООН, -СВОН, -"СН(ИНООН )", -"СОНХСНоОН)", - СНСМ, -СНоМН-5ОСсН", "СОН, -СНХСОН, -СОу(Си-Св)alkyl or -СНХСОХСИ-Св)alkyl; each Kz is, independently, -H, -(C1-C8)alkyl; every Ku; are, independently, -H, -(Ci-Cv)alkyl, -(Co-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(C5-Cv)cycloalkenyl, -phenyl, -(C1-Cv)haloalkyl, -(C1-Cv)hydroxyalkyl, -(C1-Cv)alkyl(Ci-Cv)alkyl, -(C1-Cv)alkyl-M(Co2o)" or -COM(C2o)" ; each Cz and Co is, independently: (a) -Ci-Cv)alkyl, -(Co-Cv)alkenyl, -(Co-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(C5-Cv)cycloalkenyl or -phenyl, each of which is unsubstituted or substituted by 1 or 2 -OH groups; or (5) -H, -СНоС(halo)з, -С(halo)з, -СН(halo)», -СНо(halo), -ОС(halo)з, -ОСН(halo)», - OSnНз (halo), -5С(halo)z, -5СН(halo)", -5СНо(halo), -СМ, -ОО-СМ, -OH, -halo, -Mz, -MO", - СсН-МК, -М(К7)", -МК7ОН, -ОК7, -С(О)ЖК7, -С(О)ОК, -ОССТЖУ, -ОС(О)ОК", -5К7, -500)К7 or -Б(О OK; each Ki is, independently, -H, -(Ci-Cv)alkyl, -(Co-Cv)alkenyl, -(Co-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(C5-Cv)cycloalkenyl , -(Ci-Cv)alkyl (Ci-Cv)alkyl, -phenyl, -C(halo)z, - CH(halo)", -СНu(halo), -(3-7-membered) heterocycle, - (C1-Cv)haloalkyl, -(Co-Cv)haloalkenyl, - (Co-Cv)haloalkynyl, -(Co-Cv)hydroxyalkenyl, -(C2-Cv)hydroxyalkynyl, -(C1-Cv)alkoxy(Co-Cv) )alkyl, -(C1-Cv) alkoxy(Co-Cv) alkenyl, -(C1-Cv) alkoxy(Co-Cv) alkynyl, -(C1-Cv) alkoxy(C3-Cv) cycloalkyl, -CM, -OH , -halo, -OS(halo)z, -Mz, -MO", -"SNAMK", -M(К7)", -МК7ОН, -OK", - ZKU, -О(СНЙОК), -О(СНо)кО, -"О(СНо)М(КоИ)", -М(К7ХСНИОКУ, -М(К7)СНо)ёкК, - M(Е7ХСНМ(КИ)), -M(PIECE, -C(O)KU, -C(OHOK»U, -OS(K", -OS(OOK", -B(OK"; or - (OK, -540)22M(K7)" . -M(K7)". , -H, -(C1-C6)alkyl or -(C3-C6)cycloalkyl; each halo is, independently, -E, -CI, -Bg or -I; n is an integer 1; each B is, independently, 1 or 2; D is an integer 0, 1, 2, 3 or 4; is an integer 0, 1, 2, 3, 4 or 5; t is an integer 0, 1 or 2, where the pharmaceutically acceptable derivative is selected from acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 2. The compound according to item I, where X is 0. 3. The compound according to item 1 or 2, where Ka is a halo, preferably E. 4. The compound according to any of items 1-3, where Ki is a halo, preferably Si or E. 5. Compound according to any of items 1-4, where MU is C 1 dashed line is absent. b. The compound according to any of items 1-4, where M/ is C 1 is a double bond in a dotted line. 7. The compound according to any one of clauses 1-4, where MU is M, Kia is absent and the dashed line is absent. 8. The compound according to any of items 1-7, where Ag» is -х с (Ат5 9. The compound according to any of items 1-7, where Ag" is What (Niddd 10. The compound according to any of items 1-9, where Ki4 is independently selected from halo, C(halo)»z, -(Ci-Cv)alkyl, ОВ7, OS(halo)z or 502С(halo)» with 1 is preferably halo, C(halo)z or OS(halo)z. 11. The compound according to any of items 1-10, where halo is E or SI. 12. The compound according to any of items 1-11, where 5abod is 1 or 2. 13. The compound according to any of items 1-7, where Ag" is va Vv Va 14. The compound according to any of items 1-7 1 13, where Kz» 1 Ko, independently, is selected from H, halo 1 -(Ci-Cb)alkyl 1 is preferably H or halo, where halo is Si or E. 15. Compound according to any of the previous clauses, where t is 0. 16. The compound according to any of items 1-15, where t - 1 1 is preferably Bz is (Ci-Cv)alkyl and more preferably is -CH3 or -"SNOCH". 17. A compound according to any of the preceding items, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt. 18. A compound according to any of items 1-17 for use as a medicament. 19. A compound of the formula IP: Ag «B, Shche (C Dvit M min Az (1) or a pharmaceutically acceptable derivative thereof, where X is O, M-CM; M is M or C; the dashed line means the presence or absence of a bond , and when the dashed line means the presence of a bond or MU is M, then Ka is absent, otherwise Ka is -H, -halo; At is re M B; Ato is A, , Y or Zh c (Aga)a (Ni ) Not in. Ki is -H, -halo, -C(halo)z; Ko is a group of the formula O; where O is -"CH(IONISNOOH, "СССНООН, -СНООН, "СНИСН»ООН)", -" "YANnNHHSNoOH)"; each Kz is, independently, -H, -(C1-C8)alkyl; every Ku; are, independently, -H, -(Ci-Cv)alkyl, -(Co-Cv)alkenyl, -(C2-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(C5-Cv)cycloalkenyl, -phenyl, -(C1-Cv)haloalkyl, -(C1-Cv)hydroxyalkyl, -(C1-Cv)alkyl(Ci-Cv)alkyl, -(C1-Cv)alkyl-M(Co2o)" or -COM(C2o)" ; each Cz and Co is, independently: (a) -Ci-Cv)alkyl, -(Co-Cv)alkenyl, -(Co-Cv)alkynyl, -(C3-Cv)cycloalkyl, -(C5-Cv)cycloalkenyl or -phenyl, each of which is unsubstituted or substituted by 1 or 2 -OH groups; or (5) -H, -СНоС(halo)з, -С(halo)з, -СН(halo)», -СНо(halo), -ОС(halo)з, -ОСН(halo)», - OSnНз (halo), -5С(halo)z, -5СН(halo)", -5СНо(halo), -СМ, -ОО-СМ, -OH, -halo, -Mz, -MO", - СНА-МК» , -М(К7)", -МК7ОН, -OK, -С(О)К, -С(О)ОК, -ОС(ОЖ, -"ОС(О)ОК", -5К7, -6(О) K7 or -B(O OK; each Ki is, independently, -H, -(Ci-Cv)alkyl, -(Co-Cv)alkenyl, -(Co-Cv)alkynyl, -(C3-Cv)cycloalkyl, - (C5-Cv) cycloalkenyl, -(Ci-Cv) alkoxy(Ci-Cv) alkyl, -phenyl, -C(halo)z, - СН(halo)», -СНу(halo),. -(3-7-membered)heterocycle, -(C1-Cv)haloalkyl, -(Co-Cv)haloalkenyl, - (Co-Cv)haloalkynyl, -(Co-Cv)hydroxyalkenyl, -(C2-Cv)hydroxyalkynyl, -(C1-Cv)Alkoxy(Co-Cv)alkyl, -(C1-Cv)Alkoxy(Co-Cv)alkenyl, -(C1-Cv)Alkoxy(Co-Cv)alkynyl, -(C1-Cv)Alkoxy( C3-Cv)cycloalkyl, -CM, -OH, -halo, -OS(halo)z, -Mz, -MO", -"SNAMK", -M(K7)", -MK7OH, -OK", - ZKU , -О(СНЙОК), -О(СНо)кО, -"О(СНо)М(КоИ)", -М(К7ХСНИОКУ, -М(К7)СНо)ёкК, - М(Е7ХСНМ(КИ)), - M(PIECE, -С(О)КУ, -С(ОХОК»У, -ОС(К», -ОС(ООК», -Б(OK»; or - (OK, -540)22М(К7)») -502C(halo)z, -505(3-7-membered) heterocycle, -COM(K7)", -(Ci-Cv)alkyl-C-MOK, -(C1-C5)alkyl-C(O)- M(K7)", "("Ci-Cv)alkyl-MH5O"M(K7)" or -(C1i1-Cv)alkyl-C(-MH)- M(K7)"; each halo is, independently, -E, -CI, -Bg or -I; each Coo is, independently, -H, -(C1-C6)alkyl or -(C3-C6)cycloalkyl; n is an integer of 1; each B is, independently, 1 or 2; D is an integer of 0, 1, 2, 3, or 4; is an integer of 0, 1, 2, 3, 4, or 5; t is an integer of 0, 1, or 2, wherein the pharmaceutically acceptable derivative is selected from but an acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 20. The compound according to item 19, where X is 0. 21. The compound of any one of clauses 19 or 20, wherein Ka is halo, preferably E. 22. The compound of any one of items 19-21, wherein Ki is a halo, preferably Si or E. 23. The compound according to any of items 19-21, where MU is C 1 dashed line is absent. 24. The compound according to any of clauses 19-21, where M/ is C 1 dotted line is a double bond. 25. The compound according to any one of clauses 19-21, wherein M/ is M, Ka is absent and the dashed line is absent. 26. The compound according to any of items 19-25, where At" is xx s (Rd)v, 27. Compound according to any of items 19-25, where At" is What (Niddd 28. The compound according to any of items 19-27, where Ki4, independently, is selected from -H, halo, C(halo)z, -(C1-Cv)alkyl, OKU, OS(halo)z or 5О02С( halo)z and is mostly halo, C(halo)z or OsSsgalo)»z. 29. The compound according to any one of items 19-28, wherein the halo is, independently, E or Si. 30. The compound of any of items 19-29, wherein 5 or 4 is 1 or 2. 31. The compound according to any of clauses 19-30, where Ag" is 2-pyridyl or phenyl, because the 11 Ki4-substituent is in the 4-position of the Ago-substituent. 32. The compound according to any of clauses 19-31, where Ag" is 2-pyridyl or phenyl, because the 21 Ki4-substituent is in the 3-14-position of the Ag"-substituent. 33. The compound according to any of items 19-25, where Ag" is I Bv Va 34. The compound according to any of items 19-25 1 33, where Kz 1 Ko is independently selected from H, halo 1 -(C1-Cv)alkyl and is preferably H or halo, where halo is, independently, Si or IS. 35. The compound according to any of items 19-34, where t is 0. 36. The compound according to any of items 19-34, where t - 1 1 is preferably Kz is (Ci-Cv)alkyl 1 is more preferably -CH3 or -"СНоCH". 37. The compound according to point 1IO, dem is SIiX is 0. 38. The compound according to item 19, where MU is C, where the dotted line is a double bond, X is 0, 0) is -СНООНСНООН, Ki is -С1 1 Аг» is хх с (Кд)в, 39. The compound according to item 19, where MU is C, X is O, O is -SNIOONSNOON, Ki is -SI, Ka is -E 1 Ag" is ex s (Kia) 40. The compound according to item 19, where MU is C, where the dotted line is a double bond, X is O, 0) is -СНОНСНООН, Ki is -С1 1 Аг» is H. Ve and Z 41. The compound according to item 19, where MU is C, X is O, O is -CH(ОНИСНООН, Ki; is -СИ, Ka is -Е 1 Ag» is X Ve and Z 42. The compound according to any of items 19-41, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt. 43. A compound according to any of items 19-42 for use as a medicament. 44. A compound of the formula Ш: Agh «B, Che (C Dvit M a Ago (PP) or a pharmaceutically acceptable salt thereof, where X is O, M-CM; M is M or C; the dashed line means the presence or absence of a bond , and when a dashed line indicates the presence of a bond or MU is M, then Ka is absent, otherwise Ka is -H, -halo; each Kz is, independently, -H or (C1-C6)alkyl; or t is an integer 0, 1 or 2; where Agi is: no on xx "aley Ki is -SI, -E or -SEz; where Ag" is: od nu SEz Vi: Ag Ni 00 Vi 000.0 SEZ sho , vas "bo bz or Cyl is -H, -CI, -E, -Bg, -OCEb, -(Ci1-Cv)alkyl, -500Ce3, -50(C1-Cv)alkyl, -OCH», -OCNOCH» or -OCH(CH C)" 1 is mainly -SEz, -OSE", -SI or -E; Kig is -H, -SI, -E, -Bg, -CHz, -СНоCH», -ОСН»з, -ОСН(СН» )" or -OSNOCH"; 1 each Kz" and Co is, independently, -H, -Si, -Bg, -E, -CHz, -OSHz, -OSNoCH", -SEz, -OSI, isopropyl or tert-butyl . 45. The compound according to item 44, where X is 0. 46. The compound according to item 44 or 45, wherein Ka is halo and preferably E. 47. The compound according to any of items 44-46, wherein Ki is halo, preferably Si, E or CEz. 48. The compound according to any of items 44-47, where MU is C 1 dashed line is absent. 49. The compound according to any one of clauses 44-47, where M is C 1 is a double bond in a dotted line. 50. The compound according to any one of clauses 44-47, wherein M/ is M, Ba is absent and the dashed line is absent. 51. The compound according to any of items 44-50, where t is 0. 52. The compound according to any of items 44-51, where t - 1 1 is preferably Kz is (Ci-Cv)alkyl 1 is more preferably -CH3 or -"СНоCH". 53. The compound according to any of items 44-52, where Ag" is chosen from ХО their r o Vi A Vig Ni o 00 SEz ,; 9 ov , you in SEz or Z Nv V". 54. The compound according to any of items 44-53, where Ag" is OM and Ge is E 55. The compound according to any of clauses 44-54, where Ag" is Ka, where Ki4 is selected from -H, -SI, -E, -Bg, -OSE", -(C1-Cv)alkyl, -502SEz, -50(Ci1-Cbv)alkyl, -OCH», -OOCHOoCH», -OCH(CH5Z)» 1 is preferably -CE3, -OCE», -CI or -E. 56. A compound according to any of items 44-54, where Ag" is Kg HE CE " where Ki is -H, -SI, -E, -Bg, -СН3, -СНоСН», -ОСН»3, -« OSN(SNZ)" or -OSNoSN". 57. The compound according to any of items 44-54, where Ag" is Ka o "SEZ with where Ki is -Н, -СИ, -Е, -Вг, -СН3, -СНоСН», -ОСН»3, - "OSN(SNZ)" or -OSNoSN". 58. The compound according to any of items 44-54, where Ag" is io) vs? 59. A compound according to any of items 44-54, where Ag" is va Kv Ka where each Kz 1 Ko is, independently, -Н, -СИ, -Вг, -Е, -СНз, -ОСНЗз, -ОСНОСН ", -SEz, -OSE", isopropyl or tert-butyl. 60. The compound according to any of items 44-59, where the chiral carbon atom of the O-group has the (5)-configuration: HO, tone 61. The compound according to any of items 44-59, where the chiral carbon atom of the O-group has the (VK )- configuration: proton 62. The compound according to item 44, which has the formula ons t onschi I o s Zh M KU Va. or a pharmaceutically acceptable salt thereof; where Ki is-SI, -E or -SE"; Ez is -СН3 or -СНоОСН»; 1 Kz 1 Ko is, independently, -Н, -СИ, -Втг, -Е, -СН3, -"ОСН3", -"ОСНоСН", -СЕ», -ОСЕ, isopropyl or tert-butyl. 63. The compound according to item 62, where Kz 1 Ko is each, independently, -Н, -СИ, -Вг, -Е, -СНз, -ОСН», -ОСНоСН», -СЕз or -ОСЕ.. 64. Compound according to clauses 62 or 563, where Ki is -E 1 Kz is -SNU. 65. The compound according to item 44, which has the formula on o " on y schi E M ve v X, and 9 or its pharmaceutically acceptable salt. 66. The compound according to any of items 44-65, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt. 67. The compound of claim 66, wherein the pharmaceutically acceptable salt is fumarate. 68. A compound according to any of items 44-67 for use as a medicament. 69. A composition containing a compound according to any of items 1-18 or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier or excipient, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer and/or tautomer. 70. A composition containing a compound according to any of items 19-43 or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier or excipient, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 71. A composition containing a compound according to any of items 44-67 or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier or excipient, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 72. A method of treatment or prevention of pain, NS, ulcer, ZZK or SPK in an animal, in which the animal in need is administered an effective amount of the compound according to any of items 1-18 or its pharmaceutically acceptable derivative, where the pharmaceutically acceptable derivative is chosen from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 73. A method of treating or preventing pain, NS, ulcer, CKD or SPK in an animal, in which the animal in need is administered an effective amount of the compound according to any of items 19-43 or its pharmaceutically acceptable derivative, where the pharmaceutically acceptable derivative is chosen from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 74. A method of treating or preventing pain, NS, ulcers, CKD or SPK in an animal, in which an animal in need is administered an effective amount of a compound according to any of clauses 44-67 or a pharmaceutically acceptable derivative thereof, where a pharmaceutically acceptable derivative is chosen from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 75. A method of inhibiting the function of STI in a cell, in which cells capable of expressing STI are contacted with an effective amount of the compound according to any of items 1-19 or a pharmaceutically acceptable derivative thereof, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 76. A method of inhibiting the function of STI in a cell, in which cells capable of expressing STI are contacted with an effective amount of a compound according to any of items 19-43 or a pharmaceutically acceptable derivative thereof, wherein the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound, stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 77. A method of inhibiting the function of STI in a cell, wherein the cells capable of expressing STI are contacted with an effective amount of the compound of any one of items 44-67 or a pharmaceutically acceptable derivative thereof. 78. Use of the compound according to any of items 1-18 or its pharmaceutically acceptable derivative as a medication for the treatment or prevention of pain, NS, ulcers, CKD or SPK in animals, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound , stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer 1/or tautomer. 79. Use of the compound according to any of clauses 19-43 or its pharmaceutically acceptable derivative as a medication for the treatment or prevention of pain, NS, ulcers, CKD or SPK in animals, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound , stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer and/or tautomer. 80. Use of the compound according to any of items 44-67 or its pharmaceutically acceptable derivative as a medication for the treatment or prevention of pain, NS, ulcers, CKD or SPK in animals, where the pharmaceutically acceptable derivative is selected from a pharmaceutically acceptable salt, solvate, radiolabeled compound , stereoisomer, enantiomer, diastereomer, other stereoisomeric forms, racemic mixture, geometric isomer and/or tautomer.