ZA200208741B - Beta3 adrenergic agonists. - Google Patents

Description

BETA3 ADRENERGIC AGONISTS

This application claims the benefit of U.S. Serial

No.’'s 60/217,965; 60/241,614; and 60/292,988. \

Field of Invention

The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to PB3 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.

Background of the Invention

The current preferred treatment for Type II, non- insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity.

One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglvcemic effects.

Compounds that act as B3 receptor agonists have been shown to exhibit a marked effect. on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non- insulin dependent) diabetes.

The B3 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the P35 and f5 receptor subtypes yet is considerably less abundant. Stimulation of the Bj and Bg

-J- receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors. An agonist that is selective for the B3 receptor over the Bq and 7 receptors is, therefore, more desirable for treating Type II diabetes or obesity relative to a non-selective agonist.

However, recent studies have suggested the presence of an atypical beta receptor associated with atrial tachycardia in rats (Br. J. of Pharmacol., 118:2085-2098, 1996). In other words, compounds that are not agonists of the Bq and By receptors can still modulate tachycardia through activation of a yet to be discovered B4 or through some other unknown pathway.

A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the P3 receptor. Despite these recent developments, there remains a need to develop a selective fj receptor agonist which has minimal agonist activity against the B1 and Py receptors.

Summary of Invention

The present invention relates to a compound of formula I: la 2] 3 H R 4 0 \ LA 2S Re

NARS 2¢; 2_ 3

Het” Y—/ "Rr! RR xX (I); wherein: al, a2 and A3 are carbon or nitrogen provided that only one of Al, A2 and A3 can be nitrogen;

Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring;

Rl, rla and R1P are independently H, halo, hydroxy, C1-Cg alkyl, C3-Cg alkoxy, C1-C4 haloalkyl, or 803(C1-Cg alkyl);

R2 is H or C1-Cg alkyl;

R3 is H or C1-Cg alkyl;

R4 is H or C1-Cg alkyl; or R3 and R% combine with the carbon to which both are attached to form a C3-Cg cyclic ring; or R4 and X1 combine with the carbon to which both are attached to form a C3-Cg cyclic ring; or R4 combines with X1, the carbon to which both are attached, and the phenyl group to which x1 is attached to form: : RP

R® Mm wherein: : n and m are independently 0, 1, 2, or 3 provided that the sum of n + m is £ 4 and that R3 is H;

X is OCHp, SCHy or a bond; xl is a bond or a C1-Cg divalent hydrocarbon moiety; }

X2 is 0, S, NH, NHSO,, SO;NH, CHy or a bond; and x3 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring; or a pharmaceutical salt thereof.

: The present invention also relates to processes for preparing, as well as novel pharmaceutical formulations containing, a compound of formula I. In another embodiment, the pharmaceutical formulations of the present invention may be adapted for use in treating Type II diabetes and obesity and for agonizing the P3 receptor.

The present invention also relates to methods for treating Type II diabetes and obesity, as well as a method for agonizing the B3 receptor employing a compound of formula I.

In addition, the present invention relates to a : compound of formula I for use in treating Type II diabetes and obesity as well as a compound of formula I for use in agonizing the B3 receptor. The present invention is further related to the use of a compound of formula I for the manufacture of a medicament for treating Type II diabetes and obesity as a well as for agonizing the B3 receptor.

The present invention is also related to a compound of formula II:

RA p- 3 A get” 7 EK

IT; which is useful as an intermediate to prepare a compound of formula I.

Detailed Description

For the purposes of the present invention, as disclosed and claimed herein, the following terms are defined below.

The term “halo” represents fluoro, chloro, bromo, or iodo.

The terms “C1-Cg alkyl” and “C1-Cy alkyl” represent a straight, branched or cyclic hydrocarbon moiety having from one to six and one to four carbon atoms, respectively. C3-C4 alkyl groups include methyl, ethyl, n- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec- butyl, t-butyl and cyclobutyl. A “Cq1-Cg4 haloalkyl” group is a C1-C4 alkyl moiety substituted with up to six halo atoms, preferably one to three halo atoms. 2An example of a haloalkyl group is trifluoromethyl. A “C1-Cg alkoxy” group is a C1-Cg alkyl moiety connected through an oxy linkage.

The term “divalent hydrocarbon moiety” refers to a straight or branched chain of carbon atoms that may optionally have one or more points of unsaturation. Thus, a hydrocarbon diradical according to the present invention i includes alkylene, alkenylene and alkylidene moieties.

Examples include but are not intended to be limited to methylene, ethylene, propylene, butylene, -CH(CH3)CHp- ~CH (CoH )CHy-, -CH(CH3)CH(CH3)-, -CH2C(CH3)2-, -CH2CH(CH3)CH2-, -C(CH3)3CHp-, -CH=CHCH2-, -CH=CH-, -C=CCH2-, and the like.

The term “optionally substituted” as used herein means an optional substitution of one to three, preferably one or two groups independently selected from oxo, nitro, cyano, phenyl, benzyl, halo, C1-Cg alkyl, C3-Cg haloalkyl,

CORRS, NROR®, NROCORS, NR6SO,R7, ORS, OCOR>, 0S09R7, SRO, sor’, SOyR7 or SO,NROR6 ; wherein

R® is H, C1-Cg alkyl, phenyl, benzyl, C1-C4 haloalkyl,

NR6@R6E or OR6a;

R6® and rf2 are independently H, C1-Cg alkyl or phenyl; or when two R® or rfa groups are attached to the same nitrogen atom, said R® or R62 groups, together with the nitrogen to which they are attached, may combine to form a piperidine, .pyrrolidine, hexamethyleneimine or morpholine ring; and

R7 is C1-Cg alkyl or phenyl.

The term “heterocyclic ring” represents a stable, saturated, partially unsaturated, fully unsaturated or aromatic ring, said ring having from one to four heteroatoms that are independently selected from the group consisting of sulfur, oxygen, and nitrogen. The heterocycle may be attached at any point which affords a stable structure.

Representative heterocyclic rings include 1,3-dioxolane, 4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole, imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole. Representative “benzofused” heterocyclic rings include benzoxazole, benzimidazole, benzofuran, benzothiophene, benzothiazole, azaindole, and indole.

Further specific examples of benzofused and non-benzofused heterocycles are described below in the Preparations and

Examples sections.

The term “suitable solvent” refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.

The term “patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. Ruminants or “cud-chewing” animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock. Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese.

Yet other examples of livestock include fish, shellfish and crustaceans raised in aquaculture. Also included are exotic animals used in food production such as alligators, water buffalo and ratites (e.g., emu, rheas or ostriches).

The preferred patient of treatment is a human.

The terms “treating” and “treat”, as used herein, include their generally accepted meanings, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of a pathological condition, or sequela thereof, described herein.

The terms “preventing”, “prevention of”, “prophylaxis”, “prophylactic” and “prevent” are used herein interchangeably and refer to reducing the likelihood that : the recipient of a compound of formula I will incur or develop any of the pathological conditions, or sequela thereof, described herein.

As used herein, the term “effective amount” means an amount of a compound of formula I that is capable of treating conditions, or detrimental effects thereof, described herein or that is capable of agonizing the Bj receptor.

The term “selective B3 receptor agonist” means a compound that displays preferential agonism of the f3 - receptor over agonism of the PB; or Bj receptor. Thus, Bi selective compounds behave as agonists for the P3 receptor at lower concentrations than that required for similar agonism at the PB; and By receptors. A P3 selective compound also includes compounds that behave as agonists for the B3 receptor and as antagonists for the fi; and By receptors.

The term “pharmaceutical” when used herein as an adjective means substantially non-deleterious to the recipient patient. : The term “formulation”, as in pharmaceutical formulation, is intended to encompass a product comprising the active ingredient (s) (compound of formula I), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.

The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other non-human animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

Because certain compounds of the invention contain an acidic moiety (e.g., carboxy), the compound of formula I may exist as a pharmaceutical base addition salt thereof.

Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like.

Because certain compounds of the invention contain a basic moiety (e.g., amino), the compound of formula I can also exist as a pharmaceutical acid addition salt. Such v WO 02/06276 PCT/US01/16519 salts include the salicylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono- hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne- 1,4 dioate, 3-hexyne-2, 5-diocate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, B- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene~-2-gulfonate, mandelate and like salts.

Preferred acid addition salts include the hemi-fumarate, benzoate, salicylate, R-mandelate, hydrochloride and glycolate salts.

It is recognized that various stereoisomeric forms of a compound of formula I exist. The compounds may be prepared as racemates and can be conveniently used as such.

Therefore, the racemates, individual enantiomers, diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.

It is also recognized that various tautomeric forms of a compound of formula I may exist, and all tautomeric forms are part of the present invention. Unless J otherwise specified, whenever a compound is described or referenced in this specification all tautomeric forms, or mixtures thereof, are included in said reference or description.

Preferred Compounds of the Invention

Certain compounds of the invention are particularly interesting and are preferred. The following listing sets out several groups of preferred compounds. It will be understood that each of the listings may be combined with other listings to create additional groups of preferred compounds. a) Al, AZ and a3 are carbon; b) Het is at the ortho-position relative to X; c) Het is optionally substituted one to three times independently with halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C31-C4 alkyl, C3-C4 haloalkyl, Cq1-C4 alkoxy, CORB, CO,R8, CONRBRS, NRBRS, NHCO(C;-Cg4 alkyl), NHCO (phenyl), NHCO(benzyl), SR8, S0(Ci-C4 alkyl), SO02(C1-C4 alkyl), SO, (NR8R8), oco(ci-C4 alkyl), OCO,R8 or OCONRSBR8 where R8 is independently at each occurrence H or C1-C4 alkyl; d) Het is an optionally substituted S5-membered, non- benzofused ring containing one or two heteroatoms i that are independently selected from the group consisting of sulfur, oxygen, and nitrogen; e) Het is selected from furan; isothiazole; isoxazole; oxazole; and thiophene; wherein said Het moieties are optionally substituted once with fluorine, methyl, cyano, SOgNH; or COCHj3; f) Het is selected from thien-2-yl; thien-3-yl; thiazol-2-yl; isoxazol-3-yl; isoxazol-5-yl; and isothiazol-5-y1; g) Het is thien-2-yl1 optionally substituted once with fluorine, methyl, cyano, SOgNHy or COCH3;

h) Het is thien-2-vyl; i) Rl, R12 and RIP are independently H, halo, Cq1-Cy alkyl, C1-Cgp alkoxy, C1-C4 haloalkyl, or SO; (C1-Ca alkyl); 3) rl is H, methyl, ethyl, CF3, chloro or fluoro; k) rl is H, methyl, chloro or fluoro; 1) Rl is H or fluoro; m) RL is H; n) rRla is H, methyl, ethyl, CF3, chloro or fluoro; 0) Rla is H, methyl, chloro or fluoro; -

Pp) Rla is H; a) rR1b is =m, methyl, ethyl, CF3, chloro or fluoro; r) RIP is H, methyl, chloro or fluoro; s) Rb is wu; t) RZ is H or C1-Cg alkyl; u) R? is H;

Vv) R3 and R% are independently H or C1-Cy4 alkyl; w) R3 is H or methyl; x) R4 is H or methyl;

Vv) R3 and RZ are both methyl; z) R8 is independently at each occurrence H or C1-Cyg alkyl; aa) X is OCHjy; bb) x! is a bond, methylene or ethylene; ce) x1 is methylene; dd) X2 is at the para-position relative to Xi; ee) X2 is a bond or O; ff) X2 is O or CHy; gg) X2 is 0;

hh) X3 is optionally substituted one to three times independently with halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C1-Cq4 alkyl, Cq-C4 haloalkyl, C1-Cy4 alkoxy, CORB, CcO,R8, cONRBR8, NRBR8, NHCO(C1-Cg alkyl), NHCO (phenyl), NHCO (benzyl), SR8, s0(C;-C4 alkyl), SOp(C1-C4 alkyl), SO2 (NRSR8), 0CO(C1-C4 alkyl), OCOoR8 or OCONR8RS; ii) x3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted one to three times with fluoro, chloro, cyano, hydroxy, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, amino, CO,CH3,

CO,CHoCH3, CONRSR8, SCH3, SCHoCH3, SOCH3, SOCH,CH3,

S0pCH3 or SO0pCHpCH3; " jj) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted one to three times with fluoro, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, amino, CO9CH3, CO,CHpCH3, CONHp, SCH3,

SCHpCH3, SOCH3, SOCHCH3, SO2CH3 or SOpCHZCH3; kk) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted one to three times . with fluoro, amino, COyCH3, CO2CH,CH3, cyano, CONHjp,

SO02CH3 or SO09CHZCH3; 11) x3 is phenyl, pyridyl or pyridazinyl wherein said x3 moieties are substituted once or twice with chloro, cyano, CONHy or SO2CHj3; mm) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted once with cyano or

CONH3 ;

nn) X3 is phenyl or pyridyl wherein said X3 moieties are substituted once with cyano or CONHy ; oo) X3 is pyridyl substituted once with cyano or CONHj; pp) X3 is 5-cyano or 5-carboxamido-pyrid-2-yl; aq) x3 is 4-cyano or 4-carboxamido-phenyl; rr) X3 is 3-cyano or 3-carboxamido-pyrid-2-y1; ss) X3 is 2-cyano or 2-carboxamido-phenyl; tt) the compound of formula I is an acid addition salt; uu) the compound of formula I is the hydrochloride salt; vv) the compound of formula I is the glycolate salt; ww) the compound of formula I is the hemi-fumarate salt.

Synthesis

The compound of formula I may be prepared as described in the following Schemes and Examples.

Scheme 1 la poi : A

SANS

Het” “=—/"R'

IT Compound of ) Formula I i ’ 1b 1 R

N X

Ve

H

IIT

The reaction of Scheme 1 may be carried out under conditions appreciated in the art for the amination of epoxides. For example, the epoxide of formula IT may be combined with an amine of formula III in a lower alcohol,

~14- dimethylformamide, dimethylsulfoxide, or acetone, preferably ethanol, isopropanol, n-butanol or t-butanal, at room temperature to the reflux temperature of the reaction mixture, preferably between 40°C - 90°C. The reaction may also be carried out under conditions generally described in

Atkins, et al., Tet. Let., 27:2451, 1986. These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or other polar aprotic solvents in which the reagents are soluble.

The compound of formula I may also be prepared via a Suzuki coupling as shown in Scheme 2.

Scheme 2 1a

JES A Compound

WL Nx + of _— halo \=/"g! Formula III

Iv , r:2 ; BP 2 RP

Be im oe halo rR: Formula I

Vv

A compound of formula IV may be reacted with a compound of formula IIT as described above in Scheme 1. The compound of formula V (an aryl halide) may then be reacted with a heteroaryl boronic acid, an aryl boronic ester, or an aryl boronic cyclic ester, preferably an aryl boronic acid, under conditions appreciated in the art for the coupling of aromatic halides with aryl boronic acids and their derivatives. This coupling is known in the art generally as a Suzuki coupling. The skilled artisan will recognize that an aryl triflate may also be employed in the present Suzuki coupling as an alternative to employing an aryl halide.

The epoxide starting materials employed in Schemes 1l and 2 may be prepared by techniques recognized and appreciated by one skilled in the art. See, e.g., U.S.

Patent No. 4,663,334; European Patent Application 171209;

Korn, et al., J. Pharm. Sci., 69(9):1010-13, 1980 and references cited below in the Preparations section for representative and/or analogous procedures for preparing the epoxides of formula II and IV. To illustrate, epoxides of formula II, where X is OCHp or SCHj, may be prepared according to the procedure detailed in Scheme 3 wherein R° is OH or SH and X' is OCHy or SCHj.

Scheme 3

A 2] 3

SUAS (28) = (+) -glycidyl- LA

Het" \—=/"R" 3_njitrobenzenesulfonate Het” \— "Rr"

VI I1(a)

Equimolar amounts of a compound of formula VI and (28) - (+) ~glycidyl 3-nitrobenzenesulfonate may be dissolved in an inert solvent such as acetone and treated with a slight excess of a weak base, such as potassium carbonate.

The suspension may then be heated at reflux for 16-20 hours with stirring to provide a compound of formula II(a).

Compounds of formula IV, where X is OCHy or SCHj, may be prepared in an analogous fashion.

The amino starting materials employed in Schemes 1 and 2 (formula III compound) may also be prepared by techniques recognized and appreciated by one skilled in the

-16~- art. For example, an amine of formula III, where X2 is 0, may be prepared according to the procedure detailed in

Scheme 4.

Scheme 4

B®

HO

OH ib

CF O,N »

H,N. vii — a» RY WR OH —>" , XN_s OH , R R +

IX xX

ON

2

Na

R R

VIII »

HN. ,

Rr rR? O0—X

III (a)

A compound of formula IX may be prepared by reacting an arylalkyl alcohol of formula VII with excess (5 mol/equivalent) formula VIII compound by methods well known in the art (see, e.g., Sh. Prikl. Kin., 45:1573-77, 1972).

The reaction may also be carried out by mixing the reagents in an aprotic solvent, preferably diglyme, and adding potassium t-butoxide (0.5 mol/equivalent). The reaction is typically heated at reflux until water present in the reaction mixture is removed (generally 2-8 hours). A compound of formula X may then be prepared by hydrogenation of the corresponding compound of formula IX over a precious metal catalyst. The hydrogenation can be affected at

Dbetween 20 and 60 psi of hydrogen (preferably 50 psi), and with a variety of solvents (preferably methanol/acetic ‘ acid), temperatures (preferably 50°C), and catalysts

(preferably 5% palladium on carbon wetted with ethanol denatured with toluene) well known in the art.

A skilled artisan will appreciate that a compound of formula X could be coupled with a wide variety of halides to yield the claimed ethers. The coupling can be carried out according to procedures well known in the art and is preferably performed by mixing the starting materials in

N,N-dimethylacetamide and toluene in the presence of potassium carbonate. The reaction is typically then heated to reflux for 5 to 24 hours to effect the reaction and to remove water present in the reaction mixture.

Compounds of formula VI, VII and VIII are either commercially available, known in the art, or can be prepared by methods known in the art or described herein.

The following Preparations, Examples and

Formulations are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way.

Preparations

Epoxides of Formula II and IV

Epoxides 1-21, 23-54 and 56-74 are prepared for use as described in Scheme 1. Epoxides 22 and 55 are prepared for use as described in Scheme 2. These epoxides are pictured in Tables 1 and 2 below.

Table 1 0

Cr A

Het = “my he

N= N-N 57

Me Me 3 Nn 1 2 — ’ — /

S 7 ] TY 9g N- N 4 5 ® -, 6

X_ h® MN 0] 8 9 7

NTN TN INT

(_o Ln 11 12

Ne Ks N°

N N N

13 14 15

Le Pd fF XO oD | OD =~ N~y 16 17 18 pa x p Nx NH, lap) - ; | SN

N—q ZN 22 21 23 x xX S X N

N= Nr / W\ he I) Ay ~N ~N S 27 28 29

HK fas Tr od a Ny 32 33 34

AN “NA * = pu LN

N x o) 0) H : 36 38 - N , H 0 Le ive [S N 0) 41 40 - 43

Se { e rd N N XN AN ~ ~ / \

N

CN 0 J

H

45 47

-2 0-

XN Nes <

I > hs, iy \} 0 NN 58 54 62 , H L_S 0 {

X_N ; NS 4 4 CN

Nr aS Or

N- © os 64 65 . a 8 | - \ - .

O- = = x5 LS 66 CN 67 68

X xX >< a

J S J S H— = = O-N

CN 71 ; / S O / “A sw, he! / ] - 7

O-nN Oo N 73 72 74

Table 2

O

© LA

JN a Q

N .

Z x OY . ™ Boc

C1 20 24 hd WO 02/06276 PCT/US01/163519 /4 72 x — AY

X x x F = s-/ 30 26 \ X 7 “

FS 0 \ 5 31 37 39 = AN —

BUN s—7 S S~7 48 49 50 ¥ pe AY S \ /

F O. I.

S

52 51 53 ' S s ’ F 55 56 57

Ne ) Sc

NZS (s = F ZN. / = —_ — 59 60 61

Epoxide 1

A mixture of 2-(l-methylpyrazol-5-yl)phenol (4.65 mmol, 810 mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.58 mmol, 1.45 g), potassium carbonate (5.58 mmol, 771 mg) and acetone (40 ml) are refluxed for 16 hours, cooled to room temperature and the solids removed via filtration. The filtrate is concentrated and the crude product purified on silica gel (40% ethyl acetate/hexane) to give 956 mg of the title epoxide.

Epoxide 2

Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution of 2-(3-hydroxy-2-propen-l-on-lyl)phenol (J. Am.

Chem. Soc., 72:3396, 1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the mixture is heated at 100°C for one hour.

After cooling, the reaction mixture is diluted with water (100 ml) and stirred for one hour. The precipitate is collected via filtration and purified on silica gel (30% ethyl acetate/hexane) to give 811 mg of 2- (l-methylpyrazol- 3-yl)phenol.

A mixture of 2-(l-methylpyrazol-3-yl)phenol (4.59 ] mmol, 800 mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.51 mmol, 1.42 g), potassium t-butoxide (5.51 mmol, 515 mg) and tetrahydrofuran (30 ml) are refluxed for 16 hours, cooled to room temperature and poured into saturated aqueous ammonium chloride. The aqueous layer is extracted with ethyl acetate (3x) and the extracts washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified on silica gel (40% ethyl acetate/hexane) to give 785 mg of the title epoxide.

i -23-

Epoxide 6

A mixture of 2-(pyrazol-5-yl)phenol (Catalan, et: al., J. Am. Chem. Soc., 114(13):5039-48, 1992, 10 mmol, 1.60 4g), triethylamine (40.0 mmol, 5.6 ml), and acetonitrile (55 ml) is cooled in an ice bath under N; and treated dropwise with chlorotrimethylsilane (12.0 mmol, 1.52 ml). After the addition is complete, the cold bath is removed and the reaction mixture stirred at ambient temperature for 1 hour.

The reaction mixture is then treated with trityl chloride (10.0 mmol, 2.78 g) and stirred at ambient temperature overnight, followed by refluxing for 1 hour. The reaction mixture is concentrated, treated with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 x 50 ml). The extracts are dried over magnesium sulfate and concentrated to a viscous oil. The oil is crystallized from 20% ethyl acetate/hexane to give 1.72 g of N-trityl-2- (pyrazol-5-vy1) phenol.

A solution of this intermediate phenol (4.27 mmol, 1.72 g) is reacted with (2S)-glycidyl 3- nitrobenzenesulfonate (4.27 mmol, 1.11 g) substantially as decribed for epoxide 2 except that the present reaction is refluxed for 48 hours and the crude product is purified via crystallization from ethyl acetate to give 860 mg of the title epoxide.

Epoxide 7

Phenylhydrazine (476 mmol, 51.5 g) and 2- hydroxyacetophenone (476 mmol, 64.8 g) are stirred under reflux in dry ethanol (280 ml) for 6 hours. After cooling, the crystals are filtered off, washed with cold ethanol and dried under vacuum at 50°C to yield 73 g (68%) of the hydrazone, which is then mixed with nickel chloride (7 g)

and heated under a nitrogen atmosphere to 240°C for 3 hours.

After cooling, the mixture is suspended in dichloromethane (800 ml), salt is removed by filtration and the filtrate is concentrated. The resulting crystals are filtered off, washed with dichloromethane (50 ml) and dried in vacuo at 40°C to give 16.1 g of 2-(2-indolyl)phenol (24%). This phenolic product is reacted with (28)-glycidyl 3- ’ nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 8 2-Hydroxyacetophenone (220 mmol, 30 g) is stirred in a mixture of dimethylformamide-dimethyl acetal for 5 hours at 70°C, cooled and recrystallised from diethylether.

The intermediate is dissolved in dry ethanol (200 ml) and : formamidine acetate (0.61 mmol, 63.5 g) is added. 2a solution of sodium (0.61 mol, 14 g) in ethanol (450 ml) is added in several portions and the mixture is refluxed for 18 hours and evaporated. Recrystallisation from diisopropylether yielded 3.6 g (10%) of 2-(pyrimidin-4- vl)phenol as a solid. This phenolic product is reacted with (28) -glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 19

A mixture of 4-chloro-2-hydroxybenzoic acid hydrazide (Chemical Abstracts, 93:7808, 475 mg, 2.55 mmol) and triethylorthoformate (3.6 ml) is heated at 130°C for 3.5 hours. After cooling, a precipitate formed and is collected by filtration. The filter cake is recrystallized from methanol to give 173 mg (35%) of S5-chloro-2-(1,3,4- oxadiazol-2-yl)phenol. This phenolic product is reacted

. ~25- with (2S) -glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield 170 mg (69%) of the title epoxide.

Epoxide 20

A mixture of methyl 3-hydroxybenzoate (5.48 g, 36.0 mmol) and 1,2-diaminoethane monotosylate (9.85 g, 42.4 mmol) is heated at 210°C for 7 hours. After cooling, the mixture is stirred with agueous 2N sodium hydroxide and extracted with ethyl acetate. The precipitate which formed and is present in the aqueous layer is collected by filtration and dried in vacuo to give 1.3 g (22%) of 2-(3- hydroxyphenyl) imidazoline.

To a solution of 2-(3-hydroxyphenyl)imidazoline (0.895 g, 5.52 mmol) in tetrahydrofuran (11 ml) is added water (11 ml), potassium carbonate (1.5 g, 10.8 mmol), then di-t-butyl-dicarbonate (1.2 g, 5.5 mmol). The resulting mixture is stirred over night before additional di-t-butyl- dicarbonate (120 mg) is added and the stirring is continued for several hours. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified via chromatography on silica gel with dichloromethane/ethanol (gradient up to 20:1) to give 615 mg of t-butyl (2-(3- hydroxyphenyl)imidazolin-1-yl) carboxylate (42%) . This Boc- protected product (610 mg, 2.33 mmol) is reacted with (28)- glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield 720 mg (97%) of the title epoxide.

h WO 02/06276 PCT/US01/16519 ~26-

Epoxide 22

A mixture of 2-iodophenol (5.00 g, 22.7 mmol), (2S) -glycidyl 3-nitrobenzenesulfonate (5.89 g, 22.7 mmol) and potassium carbonate (3.44 g, 24.9 mmol) in methylethylketone (150 ml) is refluxed for 18 hours. After cooling, the salts are removed by filtration. The filter cake is rinsed thoroughly with dichloromethane and the collected filtrates are evaporated. The residue is purified via flash chromatography on silica gel using a hexane- hexane/ethyl acetate gradient (100 to 90:10).

Epoxide 23

Sodium (1.21 g, 52.6 mmol) is added to 200 ml methanol to prepare a solution of sodium methoxide. After addition of guanidine hydrochloride (12.41 g, 129.9 mmol) and 3- (dimethylamino)-1- (2-hydroxyphenyl)-2-propen-1l-one {5.0 g, 26.15 mmol; J. Heterocyclic Chem., 14:345, 1977) the mixture is heated at reflux over night. The reaction : solvent is removed under reduced pressure, and the residue treated with water. The resulting precipitate is collected by filtration and dried in vacuo to give 4.25 g of 2-amino- 4- (2-hydroxyphenyl) pyrimidine (87%). This pyrimidine pre- cursor is reacted with (28)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 2.05 g of the title epoxide (37.5%). : Epoxide 24

A mixture of 3-hydroxyacetophenone (20.0 g, 146.9 mmol) and N,N-dimethylformamide dimethyl acetal (26.26 ag, 220.4 mmol) is heated over night at 100°C. The excess of the acetal is removed under reduced pressure and 3-

(dimethylamino) -1- (3-hydroxyphenyl) -2-propen-1l-one (10.32 g, 37%) is obtained after chromatography on silica gel with dichloromethane/ethanol 9:1. This intermediate enone is ~ reacted with (28)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 5.02 g of the title epoxide (78%).

Epoxide 25

A solution of 3-{(dimethylamino)-1-(3- hydroxyphenyl)-2-propen-l-one (2.2 g, 11.5 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45 ml dioxane/water 1:1 is heated for 2 hours at 60°C. The reaction is poured into ice-water and the precipitate is collected by filtration, washed with water, and dried in vacuo to give 1.4 g of 3-(5-isoxazolyl)phenol (75.5%). This phenolic product is reacted with (2S)-glycidyl 3- nitrobenzenesulfonate substantially as described for Epoxide 1l to give 1.33 g of the title epoxide (70%).

Epoxide 26 2-Amino-4- (3-hydroxyphenyl)pyrimidine, prepared substantially as described for 2-amino-4-(2- hydroxyphenyl)pyrimidine, is reacted with (2S)-glycidyl 3- nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.

Epoxide 30 : To dioxane (113 ml) is added 2-methoxy-5- fluorophenylboronic acid (4.25 g, 24.9 mmol), 2- bromothiophene (3.65 g, 22.7 mmol, 0.9 eg.) and potassium carbonate (2M, 37 ml). Palladium (0)

-28~ tetrakistriphenylphoshine (.03 eq.) is then added and the resulting mixture is heated to 85°C for 3 hours. The reaction is cooled to room temperature and poured into ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, and dried over sodium sulfate, concentrated to a brown oil and the resulting residue is flash chromatographed in 20% toluene/hexanes to afford 11.5 g of 2-(thien-2-yl1)-4- fluoroanisole (90%).

The protected product from above (11.0 g, 52.8 mmol) is demethylated with 110 grams of pyridine hydrochloride neat at 200 degrees for 3 hours. The reaction is poured into ice/water and ethyl acetate is added. The layers are separated and the organic layer is washed with water, dried over sodium sulfate and concentrated to a brown solid. This is then flash chromatographed with 1:3 ethyl acetate/hexanes to afford 7.82 g of 2-(thien-2-yl)-4- fluorophenol (77% yield). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 31

Epoxide 31 is prepared from 2-methoxy-6- flourophenylboronic acid and 2-bromothiophene by a procedure substantially similar to that described for Epoxide 30.

Epoxide 33

A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol), tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate (10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours. The solvent is removed under reduced pressure and the residue poured into ice-water

(800 ml). The precipitate is collected by filtration, washed with water, and dried in vacuo to give 9.05 g of 5- (2-methoxyphenyl) oxazole (70 %).

Boron tribromide (1M in dichloromethane, 36 ml) is added slowly to a cold solution (0°C) of the above oxazole . (3.0 g, 17.1 mmol) in dichloromethane (215 ml). After stirring over night at room temperature, ice-water (50 ml) is added carefully. The aqueous layer is extracted with dichloromethane (50 ml), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The precipitate which formed after addition of dichloromethane (70 ml) is collected by filtration, heated with dichloromethane (15 ml), and filtered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 400 mg of the title epoxide (9.5%).

Epoxide 34 2-Methoxyphenylboronic acid (2 eq.) and pyrazole (1 eq.) are coupled with copper(II) acetate catalysis as described in Tetrahedron Lett. 39:2941-44, 1998 and the product is demethylated by treatment with boron tribromide in dichloromethane (see, for example, Synth. Commun. 27(20) :3581-90, 1997) to yield 2-(pyrazol-1l-yl)phenol. This phenolic product is reacted with (28)-glycidyl 3- nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.

Epoxide 35 2-(Imidazolidin-2-on-l1-yl)anisole (Ger. Offen. 1977, DE 2528079) is demethylated with boron tribromide and the resulting 2-(imidazolidin-2-on-1-yl)phenol is reacted with (28) ~glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 36 2-(Imidazol-l-yl)anisole (L.M. Sitkina, A.M.

Simonov, Khim. Geterotsikl. Soedin 1966, 143) is demethylated with boron tribromide and the resulting 2- (imidazol-1-yl)phenol is reacted with (28) -glycidyl 3- nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.

Epoxide 37 3- (Dimethylamino)-1- (4-hydroxyphenyl) -2-propen-1- one is prepared from 4-hydroxyacetophenone substantially in the same manner as that described for 3-(dimethylamino)-1- (3-hydroxyphenyl) -2-propen-1-one (Epoxide 24). 4-(5-

Isoxazolyl)phenol is prepared from 3-(dimethylamino)-1-(4- hydroxyphenyl) -2-propen-1-one substantially in the same manner as that described for 3-(5-isoxazolyl)phenol (Epoxide 25). This phenolic product is reacted with (2S) -glycidyl 3- nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 45 2-(3-Formyl-1l-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6 mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g, 17.6 mmol) in acetic anhydride (7.7 ml) and the mixture is allowed to stir overnight at ambient temperature. The mixture is refluxed for 5 hours, concentrated, dissolved in 50 ml ethanol and stirred for 10 min with 50 ml 2 M aqueous sodium hydroxide.

After neutralisation with aqueous hydrochloric acid, and extraction with ethylacetate, the organic layer is dried and concentrated. The residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-cyano-1l-pyrrolyl)phenol (2.4 g, 92 %). This phenolic product is reacted with (28)- glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide. | Epoxide 47 :

To 2-(3-formyl-l-pyrrolyl)phenol (2.9 g, 15.5 mmol) in 50 ml dry tetrahydrofuran are added sodium cyanoborohydride (1.94 g, 31 mmol) and boron trifluoride diethyletherate (5.7 ml, 47 mmol). The resulting solution is stirred for 3 hours at ambient temperature. Saturated : sodium bicarbonate (100 ml) is added and the resulting mixture is stirred for 1 hour before extraction with t- butylmethylether. The organic layer is dried and concentrated and the residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-methyl-1l-pyrrolyl)phenol (300 mg, 11%). This phenolic product is reacted with (28) - glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 48 2-Bromo-5-fluoro-phenol (0.87 ml, 7.9 mmol) and 2- thiopheneboronic acid (2.02 g, 15.8 mmol) are dissolved in 100 ml dioxane. The resulting solution is flushed with argon before tetrakis (triphenylphosphine)palladium (456 ng, 0.395 mmol) and 2 ml of aqueous 2M sodium carbonate solution (20. mmol) are added. After flushing again with argon the mixture is refluxed for 15 hours at 100°C. The solution is py allowed to cool to room temperature and the mixture is filtered. The filtrate is evaporated and the residue is taken up in dichloromethane and extracted with water. The organic layer is dried with sodium sulfate then concentrated. The residue is purified by chromatography (CH2Clo /EtOH gradient 100:0 to 98:2) to yield 1.13 g of 2- (thien-2-yl1)-5-fluorophenol (74%). 2-(Thien-2-yl)-5-fluorophenol and (2S)-glycidyl 3- nitrobenzenesulfonate are reacted as described for the preparation of Epoxide 1 to give the title epoxide.

Epoxides 49-51 2-Bromo-5~-fluorophenol is coupled with thiophene- 3-boronic acid; 2-bromo-4,5-difluorophenol is coupled with thiophene-2-boronic acid; and 2-bromo-4,5-difluorophenol is coupled with thiophene-3-boronic acid in Suzuki reactions substantially as described for Epoxide 48, to yield 2- (thien-3-yl)-5-fluorophenol; 2-(thien-2-yl)-4,5- difluorophenol; and 2-(thien-3-yl)-4,5-difluorophenol, respectively. These phenolic products are reacted with (28) -glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.

Epoxides 52 and 61

To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in acetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a rate as to not raise the temperature above 25°C. After the addition is complete, the reaction is allowed to stir for 2 hours before pouring into 1 liter of ice. The resulting mixture is stirred over night. The precipitate which formed is filtered and placed in drying oven to produce 21 g of 3-bromo-6-fluorochroman-4-one.

The product from (14 g, 57 mmol) above is dissolved in triethylamine (100 ml) and is stirred at reflux for 2 hours. The reaction is cooled and concentrated, taken up in chloroform, washed with 2N aqueous hydrochloric acid and water. The organic layer is dried over sodium sulfate and concentrated. The product residue is crytallized from hot ethyl acetate.

The product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol) and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved in ethanol (180 ml) and the resulting mixture is heated to reflux. The reaction is allowed to stir for 18 hours before cooling and concentrating. The residue is is taken up in toluene and filtered to give 690 mg of 4-fluoro-2-(isoxazol-5-yl)phenol and from the filtrate 594 mg of 4-fluoro-2-(isoxazol-3- vl)phenol. These phenolic products are separately reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.

Epoxide 53 2-Fluoro-6-(thien-3-yl)anisole is prepared from 2- fluoro-6-iodoanisole (1.35 g, 5.36 mmol) by Suzuki coupling with thiophene-3-boronic acid according to the general procedure described in Representative Procedure 4(b) below; yield: 1.05 g (94 %). 2-Fluoro-6-(thien-3-yl)phenol is obtained from the anisole (1.0 g, 4.8 mmol) with an excess of boron tribromide in dichloromethane by stirring over night. The crude phenol (1.1 g) is used for the next step without further purification.

Sodium hydride (0.18 g, 4.5 mmol, 60 % in oil) is washed several times with hexane under argon and added to a solution of 2-fluoro-6-(thien-3-yl)phenol (0.44 g, 2.26

Claims (17)

We claim:

1. A compound of formula I: la 7 2] 3 H R t J 2S a SIN >< — rR “r* xx Het rR (I); wherein: al, a2 and a3 are carbon or nitrogen provided that only one of Al, A2 and a3 can be nitrogen; Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring; Rl, rla and RID are independently H, halo, hydroxy, Cq1-Cg alkyl, C1-Cg alkoxy, C1-C4 haloalkyl, or S505 (C1-Cg alkyl); R2 is H or C1-Cg alkyl; R3 is H or C31-Cg alkyl; RY is H or C1-Cg alkyl; or R3 and R%4 combine with the carbon to which both are attached to form a C3-Cg cyclic ring; or R% and Xl combine with the carbon to which both are attached to form a C3-Cg cyclic ring; } or R4 combines with X1, the carbon to which both are attached, and the phenyl group to which Xl is attached to form: RiP R® m wherein:

n and m are independently 0, 1, 2, or 3 provided that the sum of n + m is < 4 and that R3 is H; X is OCHy, SCHy or a bond; xl is a bond or a Cq1-Cg divalent hydrocarbon moiety; X2 is 0, S, NH, NHSO, SO,NH, CH; or a bond; and x3 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring; or a pharmaceutical salt thereof.

2. The compound of Claim 1 wherein: al, a2 and a3 are carbon; Het is optionally substituted one to three times independently with halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C1-C4 alkyl, Cq1-C4 haloalkyl, C;-Cs alkoxy, CORS, CcooR8, CONRBRS, NRBR8, NHCO(C1-C4 alkyl), NHCO (phenyl), NHCO (benzyl), SR8, S0(C1-Cg4 alkyl), SO3(C1-C4 alkyl), S05 (NR8R8), 0CO(C31-Cy4 alkyl), OCOoR8 or OCONRSRS; Rl, rla and RID are independently H, halo, Cq1-Cg alkyl, C1-C4 alkoxy, C3-Cy4 haloalkyl, or SO5(C1-Cyz alkyl); R?2 is H or C1-C4 alkyl; R3 and R? are independently H or C1-Cy alkyl; or R3 and R4 combine with the carbon to which both are attached to form a C3-Cg cyclic ring; or R4 and X! combine with the carbon to which both are attached to form a C3-Cg cyclic ring;

—-85-~ or R4 combines with x1, the carbon to which both are attached, and the phenyl group to which xl is attached to form: Rj 3 R n ; and X3 is optionally substituted one to three times : independently with halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C3-Cg alkyl, C1-C4 haloalkyl, C3-C4 alkoxy, CORS, COoR8, CONRER8, NRSR8, NHCO(C;1-C4 alkyl), NHCO (phenyl), NHCO (benzyl), SR8, S0(C1-C4 alkyl), S05(C1-Cgq alkyl), S05 (NR8R8), 0CO(Cq1-C4 alkyl), OCOoR® or OCONRSR8; and R8 is independently at each occurrence H or C1-Cy alkyl; or a pharmaceutical salt thereof.

3. The compound of Claim 1 or 2 of the formula: OH I OA N 3 4 CX TL x’ Het 0 (I); wherein: Het is selected from furan; isothiazole; isoxazole; oxazole; and thiophene; wherein said Het moieties are optionally substituted once with fluorine, methyl, cyano, SOpNH, or COCH3; R3 and R4 are independently H or methyl; x3 is phenyl, pyridyl or pyridazinyl or wherein said X3 moieties are substituted once or twice with chloro, cyano, CONHy or SO2CH3; or a pharmaceutical salt thereof.

4. The compound of any one of Claims 1-3 wherein Het is thien-2-yl optionally substituted once with fluorine, methyl, cyano, SO9NHy or COCH3; R3 and RY are both methyl; and X3 is phenyl or pyridyl wherein said x3 moieties are substituted once with cyano or CONHj; or a pharmaceutical salt thereof.

5. The compound of any one of Claims 1-4 wherein x3 is pyridyl substituted once with cyano or CONHj; or a pharmaceutical salt thereof.

6. The compound of any one of Claims 1-5 which is selected from the group consisting of: H yg . H OL OL

S S. Ww, 4 WY 2 and ; or a pharmaceutical salt thereof.

7. The compound of any one of Claims 1-6 which is: H ug Rae! S \ 7 AN or a pharmaceutical salt thereof.

8. The compound of any one of Claims 1-7 which is the hydrochloride salt.

9. The compound of Claim 7 which is the hemi- fumarate, benzoate, salicylate or R-mandelate salt.

10. A method of agonizing the B3 receptor comprising administering to a patient in need thereof a compound of any one of Claims 1-9.

11. A method of treating obesity comprising administering to a patient in need thereof a compound of any one of Claims 1-9.

12. A method of treating Type II Diabetes comprising administering to a patient in need thereof a compound of any one of Claims 1-9.

13. A pharmaceutical formulation comprising a compound of any one of Claims 1-9 and a pharmaceutical carrier.

14. A compound of any one of Claims 1-9 for use in treating Type II diabetes, obesity or for use in agonizing the P3 receptor.

15. A compound of formula II: la - po ; JA SARC Het \—/"R' wherein:

al, AZ and A3 are carbon or nitrogen provided that only one of Al, a2 and A3 can be nitrogen; Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring; Rl and R12 are independently H, halo, hydroxy, C1- Cg alkyl, C1-Cg alkoxy, C1-Cjp haloalkyl, or S03 (Ci-Cg alkyl); or a salt thereof.

16. The compound of Claim 15 of the formula: 9] or oo Het ; wherein: Het is selected from benzothiophene; furan; isothiazole; isoxazole; oxazole; thiophene; and thiazole; wherein said Het moieties are optionally substituted once with fluorine, chlorine, methyl, cyano, SO9NHy, or COCH3; or a salt thereof.

17. A process for preparing a compound of any one of Claims 1-9 which comprises reacting a compound of formula II: la pel s 0 Sah : — N_1 Het R IT; with a compound of formula III:

x’ 1 1b Fe ITY; in the presence of a suitable solvent.