ZA200405697B - N-biphenylmethyl aminocycloalkanecarboxamide derivatives with a substituent on the methyl useful as bradykininantagonists - Google Patents

Description

N-BIPHENYLMETHYL AMINOCYCLOALKANECARBOXAMIDE

DERIVATES WITH A SUBSTITUENT ON

. THE METHYL USEFUL AS BRADYKININ ANTAGONISTS ’ 5 BACKGROUND OF THE INVENTION

This invention is directed to aminocycloalkanecarboxamide compounds. In particular, this invention is directed to aminocycloalkanecarboxamide compounds that are bradykinin antagonists or inverse agonists.

Bradykinin (“BK”) is a kinin which plays an important role in the pathophysiological processes accompanying acute and chronic pain and inflammation.

Bradykinin (BK), like other kinins, is an autacoid peptide produced by the catalytic action of kallikrein enzymes on plasma and tissue precursors termed kininogens. The biological actions of BK are mediated by at least two major G-protein-coupled BK receptors termed B1 and B2. It is generally believed that B2 receptors, but not B1 receptors, are expressed in normal tissues and that inflammation, tissue damage or bacterial infection can rapidly induce B1 receptor expression. This makes the Bl receptor a particularly attractive drug target. The putative role of kinins, and specifically BK, in the management of pain and inflammation has provided the impetus for developing potent and selective BK antagonists. In recent years, this effort has been heightened with the expectation that useful therapeutic agents with analgesic and anti-inflammatory properties would provide relief from maladies mediated through a BK receptor pathway (see e.g., M.G. Bock and J. Longmore,

Current Opinion in Chem. Biol., 4:401-406(2000)). Accordingly, there is a need for novel compounds that are effective in blocking or reversing activation of bradykinin receptors. Such compounds would be useful in the management of pain and inflammation, as well as in the treatment or prevention of diseases and disorders mediated by bradykinin; further, such compounds are also useful as research tools (in vivo and in vitro).

Canadian Published Application No. 2,050,769 discloses compounds of the formula: °

Un EG

H HN ~~ ANS which are intermediates in the preparation of angiotensin II antagonists.

SUMMARY OF THE INVENTION

The present invention provides biphenyl cycloalkanecarboxamide derivatives which are bradykinin antagonists or inverse agonists, pharmaceutical compositions containing such compounds, and methods of using them as therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof:

Os R°

R42 . m 2 0” ~N-R 7b

Reb }

Rd » Rca

HANA ge

Roe

I wherein

R! and R2 are independently selected from @)) hydrogen and (2) Ciaalkyl

R3a is selected from @)) hydrogen and (2) Cj-4 alkyl optionally substituted with 1 to 5 halogen atoms;

R3b is Cj-4 alkyl optionally substituted with 1 to 5 halogen atoms;

R4a and R4D are independently selected form (D hydrogen, (2) halogen, and

3) C1-4 alkyl optionally substituted with 1 to 4 groups selected from halogen, ORa, OC(O)R2, S(O)kRd, OS(O)2Rd, and NRIR2, or

R4a and R4b together with the carbon atom to which they are both attached form an exo-cyclic methylene optionally substituted with 1 to 2 groups selected from C14 alkyl optionally substituted with 1-5 halogens and Cj_4 alkyloxy;

RS is selected from (1) C1-6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano, OR2, SRa, CORa, SO2Rd,

CO2R2, OC(O)Ra, NRbR¢, NRPC(O)Ra, NRbC(0)2R2, C(O)NRbRC, C3.8 cycloalkyl, 2) C3.8 cycloalkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano and phenyl, 3) C3.6 alkynyl, 4) C2-6 alkenyl optionally substituted with hydroxyethyl, 4) (CH2)k-aryl optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano, ORa, SR3, C(O)2R2, Cj_4 alkyl and C]-3 haloalkyl, wherein aryl is selected from phenyl, 3,4-methylenedioxyphenyl and naphthyl; 6) (CH2)k-heterocycle optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano, OR3, SR23, C1_4 alkyl and C}.3 haloalkyl wherein said heterocycle is selected from (a) a 5-membered heteroaromatic ring having a ring heteroatom selected from N, O and S, and optionally having up to 3 additional ring nitrogen atoms wherein said ring is optionally benzo-fused; (b) a 6- membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms and N- oxides thereof, wherein said ring is optionally benzo-fused; and (c) a 5- or 6- membered non-aromatic heterocyclic ring selected from tetrahydrofuranyl, S-oxo- tetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo0-1,6-dihydropyridazinyl, @)) C(O)2Ra3, and (8) C(O)NRbRe;

Rais selected from ) (1) C]-8 alkyl optionally substituted with 1-5 groups independently selected from halogen, nitro, cyano, COR, CO2R3, C(O)NRbREC, ORa, OC(O)Ra,

SR2, SO2R4, S(O)Rd, NRbRc, NRbC(O)Ra, NRbSO2Rd, NRbCO2R2, 2) C3.8 cycloalkyl,

3) C2.g alkenyl optionally substituted with CO2Ra, . 4) halogen, (5) cyano, . (6) nitro, (7) NRbRe, (8) NRbC(O)Ra, (9) NRbCOjRa, (10) NRbC(O)NRbRe, (11) NRbC(O)NRbCO7Ra, (12) NRbSO2Rd, (13) CO2Rg, (14) CORa3, (15) C(O)NRbRe, (16) C(O)NHORA3, (17) C(=NOR2)Ra, (18) C(=NORa)NRbRc, (19) ORa3, (20) OC(O)R3, (21) S(O)RA, (22) SONRbRC, and (23) optionally substituted heterocycle where the heterocycle is a 5- membered heteroaromatic ring having a ring heteroatom selected from N, O and S, and optionally having up to 3 additional ring nitrogen atoms, 4,5-dihydro-oxazolyl and 4,5-dihydro-1,2,4-oxadiazolyl, and wherein said substituent is 1 to 3 groups independently selected from Cj_4 alkyl optionally substituted with 1 to 5 halogen atoms, OR2 or OC(O)R3,

R6b and ROC are independently selected from 9) hydrogen, and 2) a group from R6a; with the proviso that not more than one of

R6a R6b, and ROC is a heterocycle; . R72 and R7b are independently selected from (1) hydrogen, . 2) halogen, 3) cyano,

4) nitro, (5) ORa, : (6) COR, ©) C(O)NRbRe¢, (8) C|1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (9) NRbRC, and (10) S(O)kRd,

Ra is selected from 1) hydrogen, 2) C1-4 alkyl optionally substituted with 1 to 5 halogen atoms, 3) phenyl optionally substituted with 1 to 3 groups independently selected from halogen, cyano, nitro, OH, C]-4 alkyloxy, C3-¢ cycloalkyl and Ci.4 alkyl optionally substituted with 1 to 5 halogen atoms, 4) C3.6 cycloalkyl, and 5) pyridyl optionally substituted with 1 to 3 groups independently selected from halogen and C4 alkyl;

Rb and R¢ are independently selected from 1) hydrogen, 2) C1-4 alkyl optionally substituted with 1 to 5 groups independently selected from halogen , amino, mono-C]-4alkylamino, di-

C1-4alkylamino, and SO2Rd, 3) (CH2)k-phenyl optionally substituted with 1 to 3 groups selected from halogen, cyano, nitro, OH, C)-4 alkyloxy, C3-¢ cycloalkyl and C14 alkyl optionally substituted with 1 to 5 halogen atoms, and -@ C3_6 cycloalkyl, or

Rb and RC together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered ring optionally containing an additional heteroatom selected from N, O, and S;or

RD and R¢ together with the nitrogen atom to which they are attached form a cyclic imide;

Rd is selected from ¢)) C1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (2) C1-4 alkyloxy, and

3) phenyl optionally substituted with 1 to 3 groups selected from halogen, cyano, nitro, OH, C]_4 alkyloxy, C3.¢ cycloalkyl and C].4 alkyl optionally substituted with 1 to 5 halogen atoms; kis 0, 1 or 2; and ) 5S misOorl.

For compounds of formula I, examples of R! and R2 include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and sec-butyl.

In one embodiment of formula I are compounds wherein R1 and R2 are each hydrogen.

Examples of R3a and R3b for compounds of formula I include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, chloromethyl, fluromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1,1,2,2,2-pentafluoroethyl, and the like. In one embodiment of formula I are compounds wherein one of R32 is hydrogen and R3b is C4 alkyl. In one subset thereof R3b is methyl.

Examples R42 and R4D for compounds of formula I include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, chlorine, fluorine, bromine, chloromethyl, 1-chloroethyl, hydroxymethyl, 2-methoxyethyl, ethoxymethyl, acetyloxymethyl, methylthiomethyl, aminomethyl, methylamino- methyl, (dimethylamino)methyl, (methylsulfonyl)oxymethyl, and the like; or R4a and

R4b on the same carbon atom taken together represent methylene. In one embodiment of formula I are compounds wherein one of R42 and R4b is hydrogen and the other is selected from hydrogen, halogen and C]_4 alkyl optionally substituted with a group selected from halogen, ORa, OC(O)R2, S(O)kRd, OS(0O)2R4, and

NRIR2, or R4a and R4b together with the carbon atom to which they are both attached form an exo-cyclic methylene. In one subset thereof R42 and R4b are each hydrogen; in another subset R42 is hydrogen and R4D is selected from CH2-halogen,

CH2-OR2, CH2-OC(O)R3a, CH2-S(0O)kRd, CH2-0OS(0)2Rd, and CH2-NRIR2: in a further subset R44 is hydrogen and R4b is selected from hydroxymethyl, : acetyloxymethyl, chloromethyl, (methanesulfonyl)oxymethyl, (methylthio)methy! and } (dimethylamino)methyl.

Examples of RS for compounds of formula I include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 1-ethylpropyl, 2,2-dimethyl- propyl, bromomethyl, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, cyanomethyl, aminomethyl, acetylaminomethyl, dimethyl-

aminomethyl, hydroxymethyl, methoxymethyl, ethox ymethyl, methylsulfonylmethyl, phenylthiomethyl, phenoxymethyl, 1-aminoethyl, 1-acetylaminomethyl, 1-imidazolyl- methyl, t-butoxycarbonylaminomethyl, 3-pyridylcarbonylmethyl, I-chloroethyl, 1,1- dichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-methoxyethyl, 2-phenylethyl, 2-cyclopentylethyl, 2-carboxyethyl, 2-methoxy-2-oxoethyl, 2-nitroethyl, 1,1-difluoro- 1-hydroxypropyl, 1-hydroxypropyl, 2-oxopropyl, 3-methoxy-3-oxopropyl, 1-cyano- cyclopropyl, cyclopropyl, cyclopentyl, 2-phenylcyclopropyl, allyl, ethenyl, 1-(1- hydroxyethyl)vinyl, 3-butynyl, propargyl, phenyl, benzyl, 3,5-bis(trifluoromethyl)- phenyl, 2,4-difluorophenyl, 4-methylphenyl, 3,4-dimethoxybenzyl, 3.4-dimethoxy- phenyl, 4-cyanophenyl, 3-nitrophenyl, 2-naphthyl, 3,4-methylenedioxyphenyl, 3- cyanophenyl, 2-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-chlorophenyl, 3,4- dichlorophenyl, 3,5-dimethoxyphenyl, 3-trifluoromethylphenyl, 3-methylphenyl, 3,5- dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-nitro-5-(trifluoromethyl)- phenyl, 5-isoxazolyl, 2-benzothienyl, 2-thienylmethyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 5-methyl-3-isoxazolyl, 3-tetrahydrofuranyl, 4-methyl-1,2,5- oxadiazol-3-yl, 5-carboxy-3-pyridyl, 6-hydroxy-2-pyridyl, 5-hydroxy-3-pyridyl, 2- hydroxy-3-pyridyl, 2-methyoxy-3-pyridyl, 6-chloro-2-pyridyl, 2-chloro-3-pyridyl, 5- chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-methyl-3-pyridyl, 3- (trifluoromethyl)-4-pyridyl, 5-(trifluoromethyl)-3-pyridyil, 1-methyl-4-pyrazolyl, 1- pyrazolylmethyl, 1-methyl-2-imidazolyl, 1,2,4-triazol-1-ylmethyl, 4-thiazolyl, 5-0xo- tetrahydrofuran-2-yl, 2-oxo-5-pyranyl, 3-isoxazolyl, 3-pyridazinyl, 5-pyrimidinyl, 4- pyrimidinyl, 1-methyl-5-pyrazolyl, 1-methyl-3-pyrazolyl, 5-thiazolyl, 5-methyl-1- pyrazolylmethyl, (3-methyl-1,2,4-triazol-5-yl)methyl, 2-(1,2,4-triazol-1-yl)ethyl, 5- methyl-4-thiazolyl, 2-quinoxalinyl, methoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, 2-(dimethylamino)ethylaminocarbonyl, benzyl- aminocarbonyl, 2-phenethylaminocarbonyl.

In one embodiment of formula I are compounds wherein RS is C1.¢ alkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano, ORa, SRa, COR3, SO2Rd, CO2Ra, OC(O)Ra, NRbR¢, NRbC(O)R2,

NRbPCO2R2, C(O)NRbRC, and C3-g cycloalkyl. In one subset thereof are compounds wherein R3 is C]-5 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano, OR2, SRa, CO2R2 and C3-§ cycloalkyl. In a further subset are compounds wherein RS is selected from C]_5 alkyl and C3 alkyl substituted with 1 to 5 groups selected from halogen, cyano, hydroxy, C].4 alkoxy and C)-4 alkoxycarbonyl. In another further subset R5 is selected from Cj_3 alkyl substituted with 1 to 5 halogen atoms, or a group selected from cyano, hydroxy, C1-4 alkoxy and C] 4 alkoxycarbonyl.

In another embodiment of formula I are compounds wherein RS is

C3-6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano and phenyl. In one subset RS is C3. cycloalkyl optionally substituted with a group selected from cyano and phenyl.

In another embodiment of formula I are compounds wherein R3 is (CH2)k-aryl optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano, OR2, SR, C}_4 alkyl and C].3 haloalkyl, wherein aryl is selected from phenyl, 3,4-methylenedioxyphenyl and naphthyl. In one subset thereof,

RS3 is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, trifluoromethyl, nitro, cyano, C4 alkoxy and C1-4 alkyl; in a further subset

R35 is phenyl optionally substituted with 1 to 2 groups selected from methyl, trifluoromethyl, halogen, cyano, nitro and methoxy.

In another embodiment of formula I are compounds wherein RS is (CH2)k-heterocycle optionally substituted with 1 to 2 groups independently selected from halogen, nitro, cyano, OR&, SR3, C}_4 alkyl and C}]-3 haloalkyl wherein said heterocycle is selected from isoxazolyl, thienyl, pyridinyl, benzothienyl, furyl, tetrahydrofuranyl, oxadiazolyl, 1-oxidopyridinyl, pyrazolyl, imidazolyl, 1,2,4- triazolyl, thiazolyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6-dihydro- pyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl. In one subset thereof R5 is selected from isoxazolyl optionally substituted with 1 or 2 C14 alkyl, thienyl, pyridinyl optionally substituted with hydroxy, trifluoromethyl or halogen, benzothienyl, furyl, tetrahydrofuranyl, oxadiazolyl optionally substituted with C]_4 alkyl, 1-oxidopyridinyl optionally substituted with halogen or C]-4 alkyl, pyrazolyl optionally substituted with C1_4 alkyl, imidazolyl optionally substituted with C].4 : alkyl, 1,2,4-triazolyl optionally substituted with C1.4 alkyl, thiazolyl optionally substituted with C1-4 alkyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6- dihydropyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl. In another subset RS is selected from 5-isoxazolyl, S-pyrimidinyl, 5-bromo-3-pyridyl and N- oxide thereof, and 53-trifluoromethyl-3-pyridyl.

For compounds of formula I examples of R62 include 1-methylethyl, 1-hydroxyethyl, methoxymethyl, 2-oxo-2-methoxyethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, cyclopentoxycarbonyl, cyclo-

butoxycarbonyl, cyclopropoxycarbonyl, 2,2,2-trifluoroethox ycarbonyl, 4-trifluoro- methylphenoxycarbonyl, methoxyaminocarbonyl, methoxycarbonylmethyl, formyl, hydroxy, 3-methyl-1,2,4-oxadiazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 1-methyl-5- tetrazolyl, 2-methyl-5-tetrazolyl, cyano, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl, chloro, fluoro, methylaminosulfonyl, dimethyl- aminosulfonyl, methoxycarbonylamino, ethoxycarbonylamino, 2-fluoroethoxy- carbonylamino, isopropoxycarbonylamino, methylaminocarbonylamino, dimethyl- amino, methylaminocarbonyl, isopropylaminocarbonyl, ethylaminocarbonyl, cyclo- propylaminocarbonyl, cyclobutylaminocarbonyl, dimethylaminocarbonyl and amino- carbonyl; examples for Rb for compounds of formula I include hydrogen, chloro, fluoro, methyl and methoxycarbonyl; example of R6¢ include hydrogen, chloro, fluoro and methyl; and examples of R7a and R7b include hydrogen, hydroxy, methoxy, methylamino, methylsulfonyl, chloro and fluoro.

In another embodiment of formula I are compounds wherein m is 0.

In another embodiment of formula I are compounds represented by formula I(1):

Ra Ny R®

R4° fy m 0) NH rR x Re

R3a l P Hob

R’2 | N \Z ee

I(1) wherein m, R1, R2, R3a, R3b, R4a, R4b, RS, R62, R6D, R6C and R72 have the same definitions as provided under formula I.

In a subset of formula I(1) are compounds wherein R6a is selected : from (1) CO2R3, (2) C(O)NHORA, (3) cyano, (4) halogen, (5) OR2, (6) C}.8 alkyl optionally substituted with 1-5 halogen atoms, or a group selected from CO2Ra2, : 25 C(O)NRbRC and OR, (7) C(O)NRDRC, (8) NRbC(O)NRDRC, (9) NRbC(0)OR4, and (10) optionally substituted heterocycle where the heterocycle is selected from oxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groups independently selected from Cj_4 alkyl optionally substituted with 1 to 5 halogen atoms, ORa or : OC(O)Ra. In a further subset are compounds wherein R62 is selected from CO2Ra,

C(O)NHOR?, methyltetrazolyl, methyloxadiazolyl, NRbC(O)NRbRc, and : 5 NRbC(O)ORa,

In another subset of formula I(1) are compounds wherein ROD is selected from hydrogen, halogen and CO2R2. In a further subset ROD is hydrogen or halogen.

In another subset of formula I(1) are compounds where R62 js selected from (1) CO2R3, (2) C(O)NHORA2, (3) cyano, (4) halogen, (5) OR, (6) C1.g alkyl optionally substituted with 1-5 halogen atoms, or a group selected from CO2Ra,

C(O)NRbRe and OR, (7) C(O)NRDRC, (8) NRPC(O)NRDRC, (9) NRBC(0)OR2, and (10) optionally substituted heterocycle where the heterocycle is selected from oxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groups independently selected from Cj-4 alkyl optionally substituted with 1 to 5 halogen atoms, OR or

OC(O)R3; ROD is selected from hydrogen and halogen; and R6¢ is hydrogen.

In another subset of formula I(1) are compounds wherein RS is selected from Cj-4 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, C3.6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen.

In another embodiment of formula I are compounds represented by formula I(2):

Oy _R® re m oO NH

RSP Ro

A

Roe ® 12) : wherein m, R3b, R5, R6a, R6b, R6C and R72 have the same definitions as provided under formula I.

In one embodiment of formula I(2), R3b is methyl.

In another embodiment of formula I(2), R6b is hydrogen or halogen.

In one subset R6b is hydrogen; in another subset R6b is fluorine or chlorine.

In another embodiment of formula I(2), R64 is selected from 1) : 5 CO2R3, (2) C(O)NHORA, (3) cyano, (4) halogen, (5) OR, (6) C]-8 alkyl optionally substituted with 1-5 halogen atoms, or a group selected from CO2R2, C(O)NRbR¢ and ORa, (7) C(O)NRbRC, (8) NRbC(O)NRDRC, (9) NRbC(O)OR®, and (10) optionally substituted heterocycle where the heterocycle is selected from oxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groups independently selected from Cj_4 alkyl optionally substituted with 1 to 5 halogen atoms, OR2 or OC(O)Ra.

In one subset R6a is selected from CO2Ra, C(O)NHORA, methyltetrazolyl, methyloxadiazolyl, NRDC(O)NRDRC, and NRPC(O)ORA2, In a further subset R62 is selected from CO2R2, methyltetrazolyl and methyloxadiazolyl,

In another embodiment of formula I(2), R6¢ is hydgrogen or halogen.

In one subset R6C is hydgrogen.

In another embodiment R72 is hydrogen or halogen. In one subset R72 is hydrogen. In another subset R72 is fluorine. In yet another subset R6b is hydrogen, fluorine or chlorine, and R72 is hydrogen or fluorine.

In another embodiment of formula I(2) RS is selected from Cj 4 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, C3-6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen.

In another embodiment of formula I are compounds of formula I(3):

Ov R®

NH bay

Oo NH

R3P Roa

Ra ® ® R® 1(3)

wherein mis 0 or 1, R6a is 2-methyl-2H-tetrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,

CO2R2 or C(O)NHORA wherein R2 is C1-4 alkyl, particularly methyl; R6b is hydrogen, fluorine or chlorine; R3b is C1_4 alkyl, particularly methyl; RS is selected from C14 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, : 5 C3.6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen or trifluoromethyl, particularly trifluoromethyl, difluoromethyl, chlorodifluromethyl, 2,2,2-trifluoroethyl, pentafluoromethyl, cyanomethyl, 5-pyrimidinyl, 5-isoxazolyl and 5-bromo-3-pyridinyl and N-oxide thereof; and R72 is hydrogen or fluorine.

Some representative compounds are: nel

NH

(5 0) NH

HC 2 Roa

Rd 2 gob

R’a | Xn 3 ye = m| RS | = Rméa [Reb | Rée [Ra [| «

R3a is H unless otherwise specified 0 | CHyCF3 COCH3 | Fr |v | H [Rr 0 | CHyCR3 CONHOCH3 | F | H | H [R o| oF | COCH3 | F | BH | # 0 | or [romsizdondmorsy r | 5 | F |x o| cm | COCH3 a |v | F [Rr] 0] om | 2cmwmosy |r | wn |r |x [0 | CHN COCH3 FF | BH |b [Rr] 0 | CHyCN COCH3 a | HH [ H [rR] 0 | CHyCF3 COCH3 | a | #5 [85 [Rr] 0 | CHyCFs3 COCH3 [0 | isoxazol 5-y1 | COCH3 mw [me ne [we [ma] 0] amex | coms [rm |r le "0 | pyomiansal| _ Cosoms | r | wm | wu |x

[0] amor | coms |r | wr [5

Co cmors | coe |v | nr |x]

Co | pmisns | cones | © | mw |r |) "0 | sosaols | Coroms |r | wm |r |r 0] os | com |v |u| r [x

Co | pmmisns | cones |r | mw |r |x "0 | sono 5 | Cones |v | mw |r [5 0] os | com |r wm | rs] "0 [pyomiansi | Coscms |r | mn | rs] 0] om | com |r |u| r |x] ramen kiln : 1

BE Ia a Rl pyridin-3-yl

EN Ew "0 [pyamigins | coos | mw | wn | 5 x] cars | com |r [mw |r [w i Ici i RA 3.yl corm | comem a wr [x om | com |r [wr [x] omen | cosem |r |u| |x] om | com [or [mw |r [x] om [romsiasomamorsy] r | 5 |B | ®

Co | cmon [rorsiasoamorsy] | 5 | uw

Co | amor [cus adomdsmorsy] r | 5 | nr 0 | tsonsol 30 [CHs La doxatismorsy] 7 |B | 1 "0 cnacry [Cus 2aoxsdmorsy] F | wu | rs (0 | cmry [sortadonsamors| 5 | 1 | © x

Co | cmon [cusiadomsmorsy] Fw | Fe]

ml wm | me we [mee [wn] v] “0 | oir [pcm insondmorsy] | wn |r |e 0 | puimidins 1 [Cex L2donsainaor sy 5 | 10] cor [rorstasomanosy] Fu | Fn] 0 | puimidin 1 [>Cy 1 24oxaszorsy] | i | | 1

Co om [roms tasomamorsy F | uw |r |x “0 cmen | aCisemasy | | w | uw |x

Co | omer; | aches |r | uw | uw | x] “0 cmon | rememosy | | iw | uw |x “0 cmon | romeo | © | nw | uw |x om | rcmpemosy | © | uw | uw |x] "0 | ionazol5 | 2 Chistes |p | 5 |r |e]

Co | cmcrs | acmywmrsn |r |u| Fw] 0 [ims s1]_2-Ciptermorsy | | 5 | © |]

Co] cr | ocHywmosy |p | uw | © |s]

Co] car | acuyemosy |r | w |r |x] "0 om | acmemsy |r | w | © |x] 0] oor | ome |v | w | uw |r]

Co | oiors | aivorometony | 1 | 5 | 5 |x "0 | omors | uuoromenory | 5 | 5 | 5 | x]

Co | omer | wivoromenn |r | wm | 5 |xomen | a [ola wr] 0 | fsonarol 531 | itor | 0 | uw | wm [x] 0] CMON | witwoomeny | | 5 | 5

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* stereoconfiguration at the indicated carbon, § R3ais CH3

Unless otherwise stated, the following terms have the meanings indicated below: “Alkyl” as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. : “Alkenyl” means a linear or branched carbon chain containing at least one C=C bond. Examples of alkenyl include allyl, 2-butenyl, 3-butenyl, 1-methyl-2- propenyl, and the like. “Alkynyl” means a linear or branched carbon chain containing at least one C=C bond. Examples of alkynyl include propargyl, 2-butynyl, 3-butynyl, 1- methyl-2-propynyl, and the like. “Cyclic imide” includes succinimide, maleimide, phthalimide and the like. “Cycloalkyl” means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems.

Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles.

Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydro- naphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like. “Haloalkyl” means an alkyl radical as defined above wherein at least one and up to all of the hydrogen atoms are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like. “Halogen” means fluorine, chlorine, bromine and iodine. : "Optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.

Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.

The present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.

The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active ~ acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula L

Salts

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, . ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the : ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary,

secondary, and tertiary amines derived from both naturally occurring and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N -dibenzyl- } ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

Prodrugs

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of

Prodrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention : into the biological milieu. . Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) 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 compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, : as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carmiers or both. The product can then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1mg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about 0.1mg to about 500mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.

The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a : compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds. . In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservati ves (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation . isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL

Compound of Formula 1 10

Methylcellulose 5.0

Tween 80 0.5

Benzyl alcohol 9.0 Benzalkonium chloride 1.0

Water for injection to a total volume of 1 mL

Tablet mg/tablet

Compound of Formula [ 25

Microcrystalline Cellulose 415

Povidone 14.0

Pregelatinized Starch 43.5

Magnesium Stearate 2.5 500

Capsule mg/capsule

Compound of Formula I 25

Lactose Powder 573.5

Magnesium Stearate 1.5 600

Utilities : Compounds of this invention are antagonists or inverse agonists of bradykinin receptor, in particular the bradykinin B1 receptor, and as such are useful in the treatment and prevention of diseases and conditions mediated through the bradykinin receptor pathway such as pain and inflammation. The compounds would } be effective in the treatment or prevention of pain including, for example, visceral pain (such as pancreatitis, interstitial cystitis, renal colic), neuropathic pain (such as postherpetic neuralgia, nerve injury, the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful traumatic mononeuropathy, painful polyneuropathy), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system), and postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout). :

Further, the compounds of this invention can also be used to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and “wheezy-infant syndrome”.

Compounds of the present invention may also be used to treat chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), and vasomotor rhinitis. They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

Compounds of the present invention may also be used for the treatment of inflammatory bowel disease including Crohn’s disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders such as psoriasis and eczema, theumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema. They may be used to treat diabetic vasculopathy, diabetic : neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite : and kallikrein urinary excretion). They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus. Additionally, they may be effective against liver disease, multiple sclerosis, cardiovascular disease, e.g.

atherosclerosis, congestive heart failure, myocardial infarct; neurodegenerative diseases, eg. Parkinson's and Alzheimers disease, epilepsy, septic shock e.g. as anti- hypovolemic and/or anti-hypotensive agents, headache including cluster headache, migraine including prophylactic and acute use, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia and hyperactive bladder. Animal models of these diseases and conditions are generally well known in the art, and may be suitable for evaluating compounds of the present invention for their potential : utilities. Finally, compounds of the present invention are also useful as research tools (in vivo and in vitro).

The compounds of this invention are useful in the treatment of pain and inflammation by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, Img, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

The compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, Img, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

In particular, inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by the compounds of this invention by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

Further, the compounds of this invention can additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial . cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture by the administration of atablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, Img, 3mg,

Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

They may be used subsequent to surgical intervention (e.g. as post- operative analgesics) and to treat inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout) as well as for the treatment of pain associated with angina, menstruation or cancer by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, Img, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

They may be used to treat diabetic vasculopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion) by the

I5 administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

They may be used to treat inflammatory skin disorders such as psoriasis and eczema by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, Img, 3mg, Smg, 10mg, 25mg, S0mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn’s disease, ulcerative colitis or pancreatitis by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) . once, twice or three times a week.

Such compounds may be used therapeutically to treat hyperreactive : airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg,

0.5mg, Img, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a . compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week. : They may be used to treat intrinsic and extrinsic asthma including : allergic asthma (atopic or non-atopic) as well as exercise-induced broncho- constriction, occupational asthma, viral or bacterial exacerbated asthma, other non- allergic asthmas and “wheezy-infant syndrome” by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, Img, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis by : the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

Additionally, they may be effective against liver disease, multiple sclerosis, atherosclerosis, Alzheimer’s disease, septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache including cluster headache, migraine including prophylactic and acute use, closed head trauma, irritable bowel syndrome and nephritis by the administration of a tablet, cachet, or capsule each containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, Smg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or S00mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.

Combination Therapy : Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.

Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients,

in addition to a compound of Formula I.

Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:

(1) morphine and other opiate receptor agonists including propoxyphene (Darvon); (2)

non-steroidal antiinflammatory drugs (NSAIDs) including COX-2 inhibitors such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,

isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone,

mofebutazone, oxyphenbutazone, phenylbutazone), and the coxibs (celecoxib, valecoxib, rofecoxib and etoricoxib); (3) corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone; (4) histamine H1 receptor antagonists such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine,

clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine; (5) histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine; (6) proton pump inhibitors such as omeprazole,

pantoprazole and esomeprazole; (7) leukotriene antagonists and S-lipoxygenase inhibitors such as zafirlukast, montelukast, praniukast and zileuton; (8) drugs used for angina, myocardial ischemia including nitrates such as nitroglycerin and isosorbide nitrates, beta blockers such as atenolol, metoprolol, propranolol, acebutolol ,betaxolol, bisoprolol, carteolol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol and timolol, and calcium channel blockers such as diltiazam, verapamil, nifedipine,

bepridil, felodipine, flunarizine, isradipine, nicardipine and nimodipine; (9) . incontinence medications such as antimuscarinics, e.g., tolterodine and oxybutinin); (10) gastrointestinal antispasmodics (such as atropine, scopolamine, dicyclomine, : antimuscarinics, as well as diphenoxylate); skeletal muscle relaxants (cyclobenzaprine, carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol, baclofen, dantrolene, diazepam, or orphenadrine); (11) gout medications such as allopurinol, probenicid and colchicine; (12) drugs for rheumatoid arthritis such as methotrexate, auranofin, aurothioglucose and gold sodium thiomalate; (13) drugs for osteoporosis such as alendronate and raloxifene; decongestants such as pseudoephedrine and phenylpropanolamine; (14) local anesthetics; (15) anti-herpes drugs such as acyclovir, valacyclovir and famcyclovir; and (15) anti-emetics such as ondansetron and granisetron.

Biological Evaluation

Assessing the Affinity of Selected Compounds to Bind to the Bradykinin B1 or B2

Receptor

Radioligand binding assays are performed using membranes from

CHO cells that stably express the human, rabbit, rat, or dog B1 receptors or CHO cells that express the human B2 receptor. For all receptor types, cells are harvested from culture flasks in PBS/ImM EDTA and centrifuged at 1000xg for 10 minutes. The cell pellets are homogenized with a polytron in ice cold 20mM HEPES, 1mM EDTA, pH 7.4 (lysis buffer) and centrifuged at 20,000xg for 20 minutes. The membrane pellets are rehomogenized in lysis buffer, centrifuged again at 20,000xg and the final pellets are resuspended at Smg protein/ml in assay buffer (120mM NaCl, SmM KCl, 20mM

HEPES, pH 7.4) supplemented with 1% BSA and frozen at —-800C.

On the day of assay, membranes are centrifuged at 14,000xg for 5 minutes and resuspended to the desired protein concentration in assay buffer containing 100nM enaliprilat, 140pug/mL bacitracin and 0.1% BSA. 3H-des-arg10, leu9 kallidin is the radioligand used for the human and rabbit B1 receptors, 3H-des- arglO kallidin is used for the rat and dog B1 receptors, and 3H-bradykinin is used to label the human B2 receptor.

For all assays, compounds are diluted from DMSO stock solutions : with 4p added to assay tubes for a final DMSO concentration of 2%. This is followed by the addition of 100uL radioligand and 100uL of the membrane suspension. Nonspecific binding for the B1 receptor binding assays is determined using 14M des-argl0 kallidin and nonspecific binding for the B2 receptor is : determined with 1uM bradykinin. Tubes are incubated at room temperature (220C) for 60 minutes followed by filtration using a Tomtec 96-well harvesting system.

X Radioactivity retained by the filter is counted using a Wallac Beta-plate scintillation counter.

The compounds of this invention have affinity for the Bl receptor in the above assay as demonstrated by results of less than SuM. It is advantageous that the assay results be less than 1uM, even more advantageous for the results be less than 0.5uM. It is further advantageous that compounds of this invention have affinity for the bradykinin B1 receptor over the bradykinin B2 receptor; more advantageously, the affinity for the B1 receptor is at least 10 fold, and preferably over 100 fold, over that for the B2 receptor.

Assay for Bradykinin B1 Antagonists

B1 agonist-induced calcium mobilization was monitored using a

Fluorescence Imaging Plate Reader (FLIPR). CHO cells expressing the Bl receptor were plated in 96 or 384 well plates and allowed to incubate in Iscove’s modified

DMEM overnight. Wells were washed two times with a physiological buffered salt solution and then incubated with 4uM Fluo-3 for one hour at 370C. The plates were then washed two times with buffered salt solution and 100uL of buffer was added to each well. Plates were placed in the FLIPR unit and allowed to equilibrate for two minutes. The test compound was then added in 50ul volumes followed five minutes later by 50ul of agonist (des-arg10 kallidin). Relative fluorescence peak heights in the absence and presence of antagonist were used to calculate the degree of inhibition of the BI receptor agonist response by the test compound. Eight to ten concentrations of test compound were typically evaluated to construct an inhibition curve and determine

IC50 values using a four-parameter nonlinear regression curve fitting routine.

Assay for Bradykinin Inverse Agonists

Inverse agonist activity at the human B1 receptor was evaluated using : transiently transfected HEK293 cells. One day following transfection cell flasks were labeled overnight with 6uCi/ml [3H]myo-inositol. On the day of assay, the media was removed and the attached cells were gently rinsed with 2x20ml of phosphate-buffered saline. Assay buffer (HEPES buffered physiological salts, pH 7.4) was added and the cells were detached by tapping of the flask. The cells were centrifuged at 800xg for five minutes and resuspended at 1x106 cells/ml in assay buffer supplemented with 10mM lithium chloride. After 10 minutes at room temperature, one-half ml aliquots were distributed to tubes containing test compound or vehicle. After an additional 10 minutes the tubes were transferred to a 370C water bath for 30 minutes. The incubation was terminated by the addition of a 12% perchloric acid solution and the tubes were placed on ice for 30 minutes. The acid was then neutralized with KOH and the tubes centrifuged to pellet precipitated material. [3H]Inositol monophosphate formed was recovered by standard ion exchange chromatographic techniques and quantitated by liquid scintillation counting. Inverse agonist activity was determined by the degree to which a test compound reduced basal (cells incubated with vehicle) levels of [3H)inositol monophosphate accumulation.

Abbreviations Used :

The following abbreviations have the meanings indicated, unless stated otherwise in the specification:

BOC (boc) t-butyloxycarbonyl

DCM dichloromethane

DMEF dimethylformamide

DMSO Dimethyl sulfoxide

EDC or EDCI 1-(3-dimethylaminopropyl)3-ethylcarbodiimide HCl eq. equivalent(s)

ES (or ESI) - MS electron spray ionization - mass spectroscopy

Et ethyl

EtOAc ethyl acetate

EtOH ethanol

FAB-MS fast atom bombardment-mass spectroscopy

HOBt 1-hydroxybenzotriazole hydrate

HPLC high pressure liquid chromatography

LCMS Liquid chromatography/mass spectroscopy

LHMDS lithium bis(trimethylsilyl)amide

Me methyl

MeOH Methanol : MHz megahertz

MsCl Mesyl chloride

NEt3 Triethylamine

NMR nuclear magnetic resonance

TFA trifluoroacetic acid

THF tetrahydrofuran

Compounds of formula I may be prepared according to the following illustrative schemes.

SCHEME 1

NH, g7 R__R®

R32 / NHBoc

RY > RO: _@

R72” | A REP _O” OH OH 1 & EDCI, HOBt

Mo

R

Ra R42 \ \

Rib_< NHBoc R4b_< NH, m (1) HClg) m 0” "NH 7 (2) base 0” "NH 7b

RE R R3® R 6a 6a

R3a » vi R3a » vi 7a” Dp 7a” pe @ R % (4) R %

Roc 0) Roe

RR — R®

Rib_< NH

R°CO,H m

EDCI, HOBt _ 0) NH RTS or R3P )

RCOCI mda C0) R®

A

X

(Ia) Roe

In Scheme 1, compound (1a) is assembled by coupling the biarylmethanamine derivative (1) to the protected aminocycloalkanoic acid (2) using standard peptide coupling reagent combinations, such as EDCI/HOBY, in an appropriate solvent, such as THF, to provide (3). The Boc protecting group is then removed by the action of an acid, like HC, in an appropriate solvent, like MeOH, to : 10 yield an ammonium salt from which the free-base derivative (4) may be obtained using an appropriate base, such as ammonia, and an appropriate solvent, such as chloroform. This amine derivative (4) is then reacted with a carboxylic acid or carboxylic acid equivalent to yield title compound (Ia). Alternatively, the acid-salt of (4) can be used in the final reaction to yield title compound (Ia) provided an : appropriate base such as triethylamine is added.

Alternatively, compound (Ia) may be assembled by coupling the biarylmethanamine derivative (1), with the acylated aminocycloalkanoic acid (5) as shown in Scheme la.

SCHEME la

Ra R®

NH, RP 5

R% y, NHC(O)R m / ) ~ _—_——

R" |/Lr® EDCIHOBt =

Re’ 1) o)

R4a —r’

R% 2D NH m 0) NH b

RA R’

Sy

R3a (

R7a” | 2g

X’

Roe (Ia)

A number of synthetic strategies may be employed to assemble the intermediate biarylmethanamine derivative (1) as shown in Schemes 2a-2c.

SCHEME 2a 7b 6a

NC § Bra ve 15 OH REE

Rrra TB” «7 (7) on © Roo

Pd cat.

NC FH We gm » . a Raney Ni » R®

R72” | , peo H, gra” | A cw

Rec’ = 60 FZ

CG) | (1a) R

In Scheme 2a, the cyanobiaryl derivative (8) is assembled using a

Suzuki reaction between an aromatic boronic acid derivative (6), or an appropriate boronic ester derivative, and an aromatic halide (7) in the presence of a triarylphosphine, like triphenylphosphine, and a metal catalyst, like palladium acetate.

The resultant cyano biaryl intermediate (8) is then catalytically reduced to the corresponding amine biaryl derivative (1a) using hydrogen and a metal, such as Raney

Ni, in an appropriate solvent.

Alternatively, as illustrated in Scheme 2b, a methanamine derivative (9), after primary amine protection with an appropriate protecting group such as Boc, is elaborated to the pinacol boron ester (11) using a palladium catalyst in an appropriate solvent, like dimethyl sulfoxide. This boron ester (11) is coupled to an aryl halide derivative (7) employing Suzuki reaction conditions to yield (1).

SCHEME 2b \ NH, Rb NHBoc _., o 0

R 2 B O R32 a TX B-B, xr

R30 0Co 53 I] o © / Pd cat.

RT Br re’ Br DMSO (9) (10)

VB il We gm r X

Fda NHBoc R70 ~~ A4 o R32 6c _—7 —R 3b 6a

R3P R A 7 R R lgo PD soc wr A a

R’® Pd cat. A oO Ree (11) (1)

A third method for the preparation of biarylmethanamine derivatives is depicted in Scheme 2c. The biaryl moiety (14) is first assembled using a palladium catalyzed coupling of (12) with an aryl zinc compound (13) as shown. The methyl group of biaryl (14) is then elaborated according to the three step sequence of halogenation, nucleophilic displacement of the halogen with azide, and reduction to provide the corresponding amine intermediate (1a). Alternatively, the biarylmethanamine (1a) can also be prepared starting from the arylcarbonitrile (16) and aryl zinc compuond (13) as previously discussed. The resulting biarylcarbonitrile (8) is then reduced using hydrogen to provide (1a).

SCHEME 2c

R7? R 7b NBS

HiC “N RA 6a HC R EE—— : -I-R CCl

TL / (HF > C NS Rea ‘

R72” Br/OTil Rec (13) R72’ | 7 rm ~~ Reb

Pd cat. (FF (12) d (14) Red

Br HoN

Rea 1-NaN4 . Rsa 7a” PS 2-PhgP 7a” 73

R | rm R |, JR , 6b , 6b

R / Va R / = (1 5) 6c (1 a) 6c "

NC Zn | A NC -|-R

TL R / = % Rea

R72 7 Br/OTH/I 6c R72” VS (13) y J Re (1 6) —_— Rec” b

Pd cat. (8)

It will be appreciated by persons skilled in the art that functional group interconversion can be used to provide various compounds of formulal. As illustrated in Scheme 3, derivative (3a) is bis-deprotected first by the action of a strong acid, like TFA, and second by alkaline hydrolysis in a suitable mixture of water and an organic solvent, like methanol, at a temperature between 25 and 100 °C to yield the amino acid derivative (17). Prior activation of a carboxylic acid (RSCOOH) with an appropriate set of peptide coupling reagents, like EDCI/HOBt, forms the ‘active ester’ which then reacts with the amino acid derivative (17) to yield (18). The latter compound can either react with amines (HNRBRC) or alkyloxy amines (H2NORB2) under the action of an appropriate set of peptide coupling reagents, like

EDCIHOBt, to form the claimed compounds (Ib) and (Ic), respectively.

SCHEME 3 4a R42 iN D\_NH : R¥_< NHBoc 1-TFA, DCM Réb_< 5 m 2-NaOH, MeOH/water m 0) NH 0) NH

R R™ R%® R™ sa » CO,CHj sa » CO,H

AS J X

(3a) R’a 7 JR” R’® _

X 6b eX

R42 pY NHCOR® 1 i) EDCI, HOBt R*-<

DMF

HO R® _— J ii) (17) a NH R™ » CO.H

Ria

EDCI, HOBt R72” [ge

HNRPR® (18) 3 .

R>°

RA i EDCI, HOBt m

RS oO, NH gm éb_<"\_NHCOR®

R ! bme » CONRPR m

R32

AS OO” "NH

R7a / J RoP R3> R™

XX 2a CONHOR?® (Ib) R®° R N

R72” | JR ~~ (Ic) ee

N-alkylation is illustrated in Scheme 4. The amine (4) is alkylated with excess alkyl iodide (I-R1) in an appropriate solvent, like THF, in the presence of an acid scavenger, like triethylamine, at elevated temperatures to provide (19), along with bis-alkylated material. Secondary amine (19) is then converted to the title compound by reacting with a carboxylic acid or carboxylic acid equivalent to provide (Id).

SCHEME 4

R42 R4a

D\_NH >

Réb_< 2 Rr¥—< \ NHR m I-R', NEt, m © NH om THF, reflux 0” “NH 7b

R30 , } R3b R

Rl » il B® » Rea

J i A

R® | 5—R® R72” Len Ik x HEN 6c (19) X 4) R Ré¢

R42 R! 2\__N-COR®

Re_<

R°CO,H El : ” 0) NH

EDCI, HOBt Ra R™ or 6a 3a R

R°COCI R » A x 6c (Id) R

The preparation of compounds of formula I having a 1,2-cis- or 1,2- trans-cyclopropyl moiety is illustrated in Schemes 5 and 6. According to known procedures (K. Burgess et al., J. Org. Chem., 57:5931-5936(1992)), di-tert-butyl malonate is elaborated to derivative (20). The N-Boc group is removed using methane } sulfonic acid according to L. S. Lin et al. Tetrahedron Lett., 41:7013-7016(2000) to give amine (21). This amine is allowed to react with a carboxylic acid or carboxylic } acid equivalent under appropriate peptide coupling conditions to yield (22). The tert- butyl ester is then cleaved with an acid, like TFA, in an appropriate solvent, like

DCM, to provide acid (23). Biarylmethanamine (1) is then coupled with the acid (23)

using an appropriate set of peptide coupling reagents, like EDCI/HOBE, to produce the title compound (Ie). Further elaboration of (Ie) to additional compounds of formula I may be accomplished using procedures well known to those skilled in the art. For example, the acetyl group may be removed by hydrolysis to provide the corresponding alcohol; the alcohol may be converted to the corresponding sulfonate by treatment with sulfonyl chloride, and the sulfonate may be converted to the corresponding halide by treatment with a source of the halide. These and other functional transformations to provide compounds of formula I are described in typical organic chemistry textbooks such as March’s Advanced Organic Chemistry: Reactions,

Mechanisms, and Structure, 5th Ed., John Wiley & Sons, 2000.

SCHEME 5 0 -BuO NHBoc MeSOzH NH : — VAY 7 VAY 2 - A +-BUOAC/DCM aN 0” "OtBu 0 Ot-Bu 0) (20) (21) 0] 0)

YR Nal

R°CO,H NH TFA NH me IVAW a BRVAV

EDCI, HOBt P DCM P 0” Ot-Bu 0” “OH (22) (23)

Q 5

EDCI, HOBt MR

NH, IVAW

Rr » R 07 NH 7b 7a” A 6b R3v R

R | JR 6a 6c Xx (1) R R72 4 Deb

XX

6c (Ie) R

In Scheme 6, according to known procedures (K. Burgess et al., J. Org.

Chem., 57:5931-5936(1992)), di-fert-butyl malonate is elaborated to derivative (24).

The N-Boc group is removed using an acid, like TFA, in an appropriate solvent, like

DCM. This amine is allowed to react with a carboxylic acid or carboxylic acid equivalent under appropriate peptide coupling conditions, like EDCI/HOBUNEL3 to ] 10 yield (25). Biarylmethanamine (1), is then allowed to open the lactone (25) in an appropriate aprotic solvent, like DMF, at a temperature between 20 and 100 °C, to produce the title compound (If). Further elaboration of (If) to additional title compounds may be accomplished using procedures well known to those skilled in the art as previously discussed.

SCHEME 6 oO

M 0) HR _ LN NHBos TFA RCO.H /\_NH

Ae EDCI, HOBt § = tBuO No 0 NEty Ng SO

Oo (24) (25) 5

DMF /\NHCOR © HOS

NH ~~ 3 3b ° RP" 0” NH

R { R7°

Raa » Roa Rep ‘

S 6

R72” | Ne R32 » “% 2

Z 7a” SN 6b

X 6 R | J R (11a) R po (If) 5

The following examples are provided to illustrate the invention without limiting the invention to the particulars of these examples. Compounds were named using: ACD/Name version 4.53 (Advanced Chemistry Development Inc. © 1994- 2000). Address: 90 Adelaide Street West, Toronto, Ontario, MSH 3V9, Canada.

EXAMPLE 1

Methyl 3-fluoro-4'-{ (IR)-1-{({ 1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl }- ~ carbonyl)amino]ethyl}-1,1 -biphenyl-2-carboxylate

0] )—CHzCFs ’ 0” “NH

H3C CO,CHj3

Commercially available (1R)-1-(4-bromophenyl)ethanamine was Boc protected, using standard procedures known to those skilled in the art, to produce tert- butyl (1R)-1-(4-bromophenyl)ethylcarbamate.

To a solution of tert-butyl (1R)-1-(4-bromophenyl)ethylcarbamate (7.6 g, 25.3 mmol) in DMSO (20 mL) was added bis(pinacolato)diboron (7.07 g, 27.9 mmol), dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloro- methane adduct (2.06 g, 2.53 mmol), and potassium acetate (7.45 g, 76.0 mmol) at room temperature under N2. The resulting mixture was heated at 80 °C for 1 hour.

The reaction was quenched by addition of EtOAc and filtered through celite. The organic extract was washed with water three times, saturated NaCl, dried over

MgSO4, filtered and concentrated under vacuum. The residue was purified on silica gel eluted with 0-20% ethyl acetate in hexane to provide tert-butyl (1R)-1-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyljethylcarbamate as a clear light yellow oil with a mass ion (ES+) of 333.

To a stirred solution of tert-butyl (1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]jethylcarbamate (1.0 g, 2.9 mmol) and methyl 2-fluoro-6- iodobenzoate (1.2 g, 4.32 mmol) in 25 mL of a 5:1 THF:water mixture was added potassium carbonate (1.2 g, 8.64 mmol), tri-o-tolylphosphine (350 mg, 1.15 mmol) and lastly palladium acetate (65 mg, 0.29 mmol). The reaction vessel was then sealed and placed into a 90 °C oil bath for overnight stirring and heating. After about 18 hours the reaction mixture was cooled to ambient temperature and then diluted with

EtOAc. The organics were washed with brine (x4), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an oil. This oil was subject \ 25 to silica gel chromatography eluting with 10-60% EtOAc in hexanes to provide methyl 4'-{ (1R)-1-[(terr-butoxycarbonyl)amino}ethyl}-3-fluoro-1,1'-biphenyl-2- carboxylate (205 mg), found to be pure by LC/MS and proton NMR.

Methyl 4>-{(1R)-1-[(zert-butox ycarbonyl)amino]ethyl}-3-fluoro-1,1*- biphenyl-2-carboxylate (205 mg, 0.60 mmol) dissolved in MeOH (15 mL) was cooled to 0 °C. This homogenous solution was saturated with anhydrous hydrogen chloride and allowed to sit for 20 minutes. Dry nitrogen was then bubbled through the solution for about 30 minutes. Solvent was then removed under reduced pressure to yield an oily residue. The oil was then dissolved in DCM and the solvent removed. This process was repeated until a solid amine hydrochloride was obtained.

The above amine hydrochloride (85 mg, 0.27 mmol) along with 1- [(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (55 mg, 0.27 mmol), HOBt*H>O (8.4 mg, 0.05 mmol) and triethylamine (33 mg, 0.33 mmol) were dissolved in 4.5 mL of THF. To this room-temperature solution was added EDCI (74 mg, 0.38 mmol). After overnight stirring (ca. 16.5 h) the reaction mixture was diluted with water and EtOAc. The organic layer was washed successively with 1N HCI, 5% sodium bicarbonate, half-brine (x3) and then brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue which was subjected to silica gel chromatography eluting with 1-6% MeOH in DCM.

Collection of product containing fractions and removal of solvent yielded 108 mg (86%) of methyl 4'-{(1R)-1-[({ 1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)- aminojethyl}-3-fluoro-1,1'-biphenyl-2-carboxylate.

Methyl 4'-{(1R)-1-[({ 1-[(tert-butoxycarbonyl)amino]cyclopropyl }- carbonyl)amino]ethyl}-3-fluoro-1,1'-biphenyl-2-carboxylate (108 mg, 0.24 mmol) dissolved in MeOH (5.0 mL) was cooled to 0 °C. This homogenous solution was saturated with anhydrous hydrogen chloride and allowed to sit for 30 minutes. Dry nitrogen was then bubbled through the solution for about 50 min. Solvent was then removed under reduced pressure to yield an oily residue. The oil was then dissolved in DCM and the solvent removed. This process being repeated until a solid amine hydrochloride was obtained.

The above amine hydrochloride (46 mg, 0.12 mmol) along with trifluoropropionic acid (15 mg, 0.12 mmol), HOBt*H20 (3.6 mg, 0.02 mmol) and triethylamine (14 mg, 0.14 mmol) were dissolved in 1.6 mL of THF plus 1.6 mL. of . DMF. To this room-temperature solution was added EDCI (31 mg, 0.16 mmol).

After overnight stirring (ca. 18 h) the reaction mixture was diluted with water and . EtOAc. The organic layer was washed successively with IN HCI, 5% sodium bicarbonate, half-brine (x3) and then brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue which was subjected to silica gel chromatography eluting with 1-12% MeOH in DCM.

Collection of product containing fractions and removal of solvent yielded 36 mg (67%) of the title compound as a foaming solid. Purity was determined by LCMS (ES

MS, M+H+ found:467) and proton NMR (400 MHz, CD30D : & 7.555, 7.540, 7.535, ’ 5 7.520,7.515, 7.500, 7.393, 7.373, 7.319, 7.302, 7.298, 7.240, 7.222, 7.221, 7.211, 7. : 188,7.167,7.165, 5.116, 5.099, 5.081, 5.064, 3.659, 3.268, 3.241, 3.214, 3.187, 1.508, 1.490, 1.483, 1.477, 1.474, 1.470, 1.465, 1.454, 1.444, 1.056, 1.049, 1.036, 1.031, 1.023, 1.007, 0.999, 0.995, 0.982, 0.974).

EXAMPLE 2 3-Fluoro-N-methoxy-4-{ (1R)-1-[({ 1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl } - carbonyl)amino]ethyl }-1,1-biphenyl-2-carboxamide @)

W—CHzCFy pe 0) NH H

HaC ©) N_ o Cs $ ® F

A solution of methyl 4*-{(1R)-1-[({ 1-[(tert-butoxycarbonyl)amino]- cyclopropyl }carbonyl)amino]ethyl }-3-fluoro-1,1-biphenyl-2-carboxylate (466 mg, 1.0 mmol) in DCM (15 mL) and TFA (15 mL) was stirred under N2 for 20 minutes at ambient temperature, then the organic solvent was removed under vacuum. The residue was dissolved in MeOH (20 mL), 4N NaOH (10 mL) and water (10 mL).

This mixture was heated at reflux for 4 hours and then neutralized with 6N HCI.

Purification was achieved by preparative HPLC on a delta-pack Cg column, 300 A, pore size 15 uM with 0.05% HCI acid -aqueous acetonitrile solvent systems using various linear gradients. Fractions containing product of 99% purity as measured by ’ HPLC were combined and lyophilized to give 4'-((1R)-1-{[(1-aminocyclopropyl)- carbonylJamino}ethyl)-3-fluoro-1,1'-biphenyl-2-carboxylic acid as a white solid. : To a solution of trifluoropropionic acid (128 mg, 1.0 mmol) in DCM (1 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (229 mg, 1.2 mmol) and 1-hydroxy-7-azabenzotriazole (136 mg, 1.0 mmol) were added. The } resulting solution was stirred at room temperature for 20 minutes, then 4-((1R)-1- {{(1-aminocyclopropyl)carbonyl]amino }ethyl)-3-fluoro-1,1-biphenyl-2-carbox ylic ] acid (171 mg, 0.5 mmol) in mL DCM was added, followed by N,N-diisopropylethyl- amine until pH = 10 was achieved. The reaction mixture was stirred at ambient temperature under N7 for 2 hours, concentrated under vacuum and then partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 40%

MeOH in CHCI3. Collection and concentration of appropriate fractions provided 3- fluoro-4-{ (1R)-1-[({ 1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl }carbonyl)- aminoethyl }-1,1-biphenyl-2-carboxylic acid as a white powder.

To a solution of the above acid (226 mg, 0.50 mmol) in DCM (1 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1- hydroxy-7-azabenzotriazole (68mg, 0.50 mmol) and methox yamine hydrochloride (167 mg, 1.0 mmol) were added, followed by N,N-diisopropylethylamine until pH = 10 was achieved. The resulting solution was stirred at room temperature for 2 hours, and then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Purification was achieved by preparative HPLC on a delta-pack C18 column with 0.05% HCI acid -aqueous acetonitrile solvent systems using various linear gradients. Fractions containing product of 99% purity as measured by HPLC were combined and lyophilized to give the title compound as a white solid. . Purity was determined by LCMS (ES MS, M+H+ found:482) and proton NMR (400 MHz,

DMSO0-dg) 6 1.40 (d, J = 7.1 Hz, 3H), 0.60-0.80 (m, 2H), 1.27 (m, 2H), 3.23 (m, J = 11.2 Hz, 2H). 3.44 (s, 3H), 5.02 (q, J = 8 Hz, 1H), 7.25-7.39 (m, 6H), 7.52 (m, 1H), 7.93 (d, J = 8.2Hz, 1H), 8.89 (s, 1H).

EXAMPLE 3

Methyl 3-fluoro-4’-{ 1-methyl-1-[({ 1-[(trifluoroacetyl)amino]cyclopropyl }- . carbonyl)amino]ethyl}-1,1-biphenyl-2-carboxylate

0)

MCF, ’ 0) NH

HC ® F

Methyl 2-(4-bromophenyl)-2-methylpropanoate (3.75 g, 14.6 mmol, prepared according to J. Org. Chem., 59:2620-2622(1994)) in 150 mL of THF was allowed to react with potassium trimethylsilanolate (2.62 g, 20.4 mmol) at ambient temperature, for 60 hours, with continuous stirring. The reaction was then diluted with water and DCM. The pH of the aqueous phase was then adjusted to ca. 4, using

IM HCI. The aqueous layer was then extracted three times with additional DCM.

The organic layers were pooled, dried over sodium sulfate, filtered and then concentrated to obtain 3.59 g of 2-(4-bromophenyl)-2-methylpropanoic acid, as a white solid, which gave LC/MS and proton NMR spectra consistent with theory.

To 82 mL of toluene was added the above acid (2.00 g, 8.23 mmol), triethylamine (1.20 mL, 8.64 mmol) and diphenylphosphoryl azide (1.86 mL, 8.64 mmol). After refluxing this mixture under nitrogen for 1 hour, benzyl alcohol (1.70 mL, 16.5 mmol) was added and the reaction mixture was allowed to reflux overnight.

Solvent was removed under reduced pressure and the resulting oil was diluted with ethyl acetate. The ethyl acetate solution was washed twice with 5% sodium bicarbonate and once with brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue which was subject to silica gel chromatography eluting with 0-2% MeOH in DCM. Collection of product containing fractions and removal of solvent yielded 2.26 grams of benzyl N-[1-(4- bromophenyl)-1-methylethyl]carbamate, which gave LC/MS and proton NMR spectra consistent with theory.

The above bromide (1.00 g, 2.87 mmol) was added to 25 mL of DMF, followed by bis(pinacolato)boron (0.875 g, 3.45 mmol), potassium acetate (0.846 g, 8.62 mmol) and PdClI2(dppf)2°CH2Cl2 (.063 g, 0.090 mmol). This mixture was heated to 80 °C, under nitrogen, for 3 hours. After cooling to ambient temperature, methyl 2-fluoro-6-iodobenzoate (0.965 g, 3.45 mmol), PdCI2(dppf)2°CH2Cl2 (.063 g,

0.090 mmol) and aqueous sodium carbonate (7.18 mL, 2M, 14.4 mmol) were added.

This mixture was then heated to 80 °C overnight. After cooling to ambient temperature, most of the DMF was removed under reduced pressure and the biphasic mixture was diluted with ethyl acetate. The pH of the aqueous layer was made neutral with IM HC], prior to extraction with two additional volumes of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue which was subject to silica gel chromatography eluting with 0-2% MeOH in DCM. Collection of product containing fractions and removal of solvent yielded 0.25 grams of methyl 4'-(1- {[(benzyloxy)carbonyl]amino}-1-methylethyl)-3-fluoro-1,1'-biphenyl-2-carboxylate, which gave LC/MS and proton NMR spectra consistent with theory.

Methyl 4'-(1-{[(benzyloxy)carbonyl]amino }-1-methylethyl)-3-fluoro- 1,1'-biphenyl-2-carboxylate (0.25 g, 0.59 mmol) was dissolved in 6.0 mL of anhydrous ethanol. Pd/C (90 mg) was then added and the nitrogen atmosphere was exchanged for hydrogen. The reaction mixture was allowed to stir for 72 hours. After filtration though celite, the ethanol was removed under reduced pressure to yield 0.15 grams of methyl 4'-(1-amino-1-methylethyl)-3-fluoro-1,1'-biphenyl-2-carboxylate which was of sufficient purity to use directly in the next reaction.

The above-mentioned amine (80 mg, 0.28 mmol), was dissolved in anhydrous DCM (4 mL). To this stirred solution was added 1-[(terz-butoxycarbonyl)- amino]cyclopropanecarboxylic acid (67 mg, 0.33 mmol), HOBt*H20 (8 mg, 0.08 mmol) and lastly EDCI (69 g, 0.36 mmol). This mixture was allowed to stir overnight. Solvent was then removed under reduced pressure and the residue was subjected to silica gel chromatography eluting with a 1-3% MeOH in DCM gradient to provide methyl 4'-{1-[({ I-[(tert-butoxycarbonyl)amino]cyclopropyl }carbonyl)- amino)-1-methylethyl }-3-fluoro-1,1'-biphenyl-2-carboxylate(82 mg), giving LC/MS and proton NMR spectra consistent with theory.

The above material (82 mg, 0.17 mmol) dissolved in ethyl acetate (4 mL) was cooled to 0 °C. This homogenous solution was saturated with anhydrous hydrogen chloride and allowed to sit for 30 minutes. Dry nitrogen was then bubbled . through the solution for about 30 minutes. Solvent was then removed under reduced pressure to yield an oily residue, which was used directly in the next reaction. ] To a 0 °C, stirred solution of the above mentioned amine (32 mg, 0.09 mmol) in DCM (2.0 mL) was added triethylamine (20 uL, 0.13 mmol) and lastly trifluoroacetic anhydride (20 uL, 0.11 mmol). After 10 minutes the ice bath was remove and stirring was continued for a total of 30 minutes The reaction mixture was } subject to silica gel chromatography eluting with 0.5-2% MeOH in DCM. Collection of product containing fractions and removal of solvent yielded 34 mg (84%) of the . title compound as a foaming solid. Purity was determined by LCMS (ES MS, M +

Ht found:467) and proton NMR (400 MHz, CD30D : § 7.552, 7.537, 7.531, 7.517, 7.512,7.497, 7.442, 7.425, 7.420, 7.302, 7.297, 7.280, 7.250, 7.231, 7.203, 7.181, 7.159, 3.644, 1.664, 1.444, 1.432, 1.424, 1.412, 1.080, 1.068, 1.060, 1.048).

EXAMPLE 4 N-{(IR)-1-[3,3-difluoro-2’-(3-methyl-1,2,4-oxadiazol-5-yl)-1,1-biphenyl-4-yl]ethyl } - 1-[(trifluoroacetyl)amino]cyclopropanecarboxamide oO .

Aire 3 0” “NH N=(

HsC ON

E J C F

To a solution of 2-fluoro-6-iodobenzoic acid (15.00g, 56.39 mmol) in 150 mL CH2Cl containing 0.1 mL DMF was added oxalyl chloride (9.30g, 73.3 mmol) dropwise. The solution was stirred at room temperature for 75 minutes, then concentrated in vacuo. The residue was re-dissolved in 150 mL CH2CI?2, and the solution was saturated three times with ammonia gas. The solution was concentrated in vacuo and dried under vacuum overnight. The residue was dissolved in N,N- dimethylacetamide dimethyl acetal (24.7 mL, 0.169 mol) and heated to 120 °C for 5 hours. Additional N,N-dimethylacetamide dimethyl acetal (25 mL, 0.17 mol) was added over the course of the reaction to drive it to completion. The solution was . cooled to room temperature, concentrated in vacuo, and dried under vacuum overnight. To a solution of the intermediate in 57 mL dioxane was added . hydroxylamine hydrochloride (4.704g, 67.69 mmol), SN NaOH (13.5 mL, 67.7 mmol), and 70% acetic acid (57 mL). The mixture was stirred at 60 °C for 2 hours, then at 90 °C for 3 hours. The resulting solution was cooled to room temperature,

diluted with ethyl acetate, and neutralized with aqueous sodium bicarbonate. The organic extract was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was filtered through silica gel eluted with 10% ethyl acetate in hexanes to provide 5-(2-fluoro-6- iodophenyl)-3-methyl-1,2,4-oxadiazole as orange yellow crystals that gave proton

NMR spectra consistent with theory and a mass ion (ES+) of 305.06 for M+H+.

To a solution of (S)-(-)-2-methyl-2-propanesulfinamide (20.20 g, 0.167 mol) in 350 mL CH2Cl2 were added 4-bromo-2-fluorobenzaldehyde (35.53g, 0.1750 mol), pyridinium-p-toluenesulfonate (2.09g, 8.33 mmol), and magnesium sulfate (200.6 g, 1.667 mol). The reaction mixture was stirred at room temperature for 48 hours. Additional magnesium sulfate (100.3g , 0.833 mol) was added, and the reaction was stirred 24 hours. The mixture was filtered through celite, washing with

CHCl, and concentrated in vacuo. The resulting residue was subjected to column chromatography on silica gel eluted with 0-10% ethyl acetate in hexanes to afford N- [(1E)-(4-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide as a white solid that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 308.09 for M+H+(81Br).

To a solution of N-[(1E)-(4-bromo-2-fluorophenyl)methylidene}-2- methylpropane-2-sulfinamide (32.65g, 0.1066 mol) in 550 mL CH2Cl) at —48 °C was added methylmagnesium chloride (3.0 M solution is ether, 53.31 mL, 0.1599 mol) dropwise. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted with methylene chloride. The combined organics were dried over Na2S04, filtered and concentrated under vacuum. The resulting residue was subjected to column chromatography on silica gel eluted with 10-50% ethyl acetate in hexanes to afford N-[(1R)-1-(4-bromo-2-fluorophenyl)ethyl]-2-methyl- propane-2-sulfinamide as a white solid that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 324.14 for M+H+(81Br).

To a solution of N-[(1R)-1-(4-bromo-2-fluorophenyl)ethyl]-2-methyl- propane-2-sulfinamide (26.29g, 81.58 mmol) in 40 mL methanol was added HCI/ dioxane (4M, 40.8 mL, 0.163 mol) solution. The reaction mixture was concentrated . in vacuo, and ether was added. The white solid was collected, washing with cold ether, and dried under vacuum to yield (1R)-1-(4-bromo-2-fluorophenyl)ethan- aminium chloride that gave proton NMR spectra consistent with theory.

To a solution of the above (1R)-1-(4-bromo-2-fluorophenyl)-ethan- aminium chloride (14.24g, 55.95 mmol) in 300 mL CH2CI at 0 °C was added di-tert-

butyl dicarbonate (17.98g, 82.40 mmol) and triethylamine (8.256 g, 81.58 mmol).

The solution was washed with water and brine, dried over Na2S0Oy4, filtered and concentrated under vacuum to provide crude (1R)-1-(4-bromo-2-fluorophenyl)ethan- ) aminium chloride as a white solid that gave proton NMR spectra consistent with theory.

A mixture of (1R)-1-(4-bromo-2-fluorophenyl)ethanaminium chloride (26.42g, 83.03 mmol), bis(pinacolato)diboron (31.63g, 0.1246 mol), potassium acetate (24.45 g, 0.2491 mol), and [1,1 -bis(diphenylphosphino)ferrocene]- palladium(II) dichloride (0.265 g, 0.362 mmol) in 80 mL DMSO was heated to 90 °C under N2 for 3 hours. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried over NapSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide tert-butyl (1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa- borolan-2-yl)phenyl]ethylcarbonate as a beige solid that gave proton NMR spectra consistent with theory.

A mixture of 5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole (1.50g, 4.93 mmol), tert-butyl (1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa- borolan-2-yl)phenyl]ethylcarbonate (1.80 g, 4.93 mmol), potassium carbonate (1.70 g, 12.3 mmol), tri-o-tolylphosphine (0.060 g, 0.20 mmol), and palladium acetate (0.011 g, 0.05 mmol) in 25 mL of THF and 4 mL of water was heated in a sealed flask at 100°C overnight. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over NapS0y4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate and hexane to provide tert- butyl (1R)-1-[3,3'-difluoro-2'-(3-methyl-1,2,4-oxadiazol-5-yl)-1,1'-biphenyl-4-yl]- ethylcarbamate as a yellow oil that gave proton NMR spectra consistent with theory.

The product was dissolved in ethyl acetate and saturated with HCI gas. The solution was concentrated in vacuo and azeotroped 3 times with toluene to provide (1R)-1- [3,3-difluoro-2'-(3-methyl-1,2,4-oxadiazol-5-yl)-1,1'-biphenyl-4-yl]Jethanaminium . chloride.

A solution of (1R)-1-[3,3'-difluoro-2'-(3-methyl-1,2,4-oxadiazol-5-y1)- 1,1'-biphenyi-4-ylJethanaminium chloride (0.500g, 1.42 mmol), Boc-1-aminocyclo- propane-1-carboxylic acid (0.300g, 1.49 mmol), 1-ethyl-(3-dimethylaminopropy!)- carbodiimide hydrochloride (0.545 g, 2.84 mmol), 1-hydroxy-7-azabenzotriazole

(0.010 g, 0.15 mmol), and triethylamine (0.863 g, 8.53 mmol) in 10 mL CHCl was stirred at room temperature overnight. The solution was washed with aqueous sodium bicarbonate and brine, dried over NapSO4, filtered and concentrated. The residue was . subjected to silica gel chromatography eluted with 10-40% ethyl acetate in hexanes to provide tert-butyl 1-[({(1R)-1-[3,3"difluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1,1"- biphenyl-4-yl]ethyl }amino)carbonyl]cyclopropylcarbamate as a white solid that gave proton NMR spectra consistent with theory. The product was dissolved in ethyl acetate and saturated with HCI gas. The solution was concentrated in vacuo and azeotroped 3 times with toluene to provide 1-[({(1R)-1-[3,3™difluoro-2-(3-methyl- 1,2,4-oxadiazol-5-yl)-1,1-biphenyl-4-yljethyl }amino)carbonyl}-cyclopropanaminium chloride that gave a mass ion (ES+) of 399.21 for M+H+.

To a solution of the above compound (0.290 g, 0.667 mmol) in 5 mL

CH2Cl2 at 0 °C was added triethylamine (0.135 g, 1.33 mmol) and trifluoroacetic anhydride (0.14 g, 0.67 mmol). The solution was diluted with addition CH2Cl2 and washed with aqueous sodium bicarbonate and brine, dried over Na2SO¢4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 10- 40% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 495.22 for M+H+: 1H NMR (300 MHz, MeOH-d4) 6 9.71 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.77-7.70 (m, 1H), 7.41-7.30 (m, 3H), 6.95 (s, 1H), 6.93-6.91 (m, 1H), 5.32-5.22 (m, 1H), 2.36 (s, 3H), 1.51-1.45 (m, 5H), 1.15-1.01 (m, 2H)."

EXAMPLE 5

Methyl 3-chloro-3'-fluoro-4'-{ (1R)-1-{({ 1-{(trifluoroacetyl)amino]cyclopropyl }- carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate °ycFs xX 0) NH

Cl

TTC

To a solution of n-BuLi (2.5M in hexanes, 41.8mL, 0.104 mol) in 400 mL THF at —78 °C was added 2,2,6,6-tetramethylpiperidine (14.76 g, 0.1045 mol) dropwise followed by 3-bromochlorobenzene (20.00g, 0.1045 mol) dropwise. The mixture was stirred at —78 °C for 2h, then quenched with dry ice and warmed to room temperature. The solution was concentrated in vacuo and the resulting residue was dissolved in water and washed with ether. To the aqueous fraction was added IN HCl to pH = 2, and the product was extracted with CH2Cl2, The combined organics were dried over Na2SOy4, filtered and concentrated under vacuum to provide 2-bromo-6- chlorobenzoic acid that gave proton NMR spectra consistent with theory.

To a solution of 2-bromo-6-chlorobenzoic acid (17.7g, 75.2 mmol) in methanol (200 mL) at 0 °C was added (trimethylsilyl)diazomethane (2M in hexanes, 100 mL, 0.200 mol). The solution was stirred at 0 °C for 1.5 hours, then warmed to room temperature and washed with aqueous sodium bicarbonate and brine, dried over

Na2S04, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 0-5% ethyl acetate in hexanes to provide methyl 2- bromo-6-chlorobenzoate as a pale yellow oil that gave proton NMR spectra consistent with theory.

A mixture of methyl 2-bromo-6-chlorobenzoate (2.25g, 9.03 mmol), tert-butyl (1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- ethylcarbonate (see Example 11, 3.00 g, 8.21 mmol), potassium carbonate (2.84 g, 20.5 mmol), tri-o-tolylphosphine (0.10 g, 0.33 mmol), and palladium acetate (0.018 g, 0.08 mmol) in 40 mL of THF and 4 mL of water was heated in a sealed flask at 100°C for 4h. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over

NapSO0g4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate and hexane to provide methyl 4'- { (1R)-1-[(tert-butoxycarbonyl)amino]ethyl } -3-chloro-3'-fluoro-1,1'-biphenyl-2- carboxylate that gave proton NMR spectra consistent with theory. The product was dissolved in ethyl acetate and saturated with HCI gas. The solution was concentrated in vacuo and azeotroped 3x with toluene to provide (1R)-1-[3"-chloro-3-fluoro-2'- : (methoxycarbonyl)-1,1'-biphenyl-4-ylJethanaminium chloride.

A solution of the above compound (1.00g, 2.91 mmol), boc-1-amino- : cyclopropane-1-carboxylic acid (0.614g, 3.05 mmol), 1-ethyl-(3-dimethylamino- propyl)carbodiimide hydrochloride (1.11g, 5.81 mmol), 1-hydroxy-7-azabenzotriazole (0.010 g, 0.15 mmol), and triethylamine (1.76 g, 17.4 mmol) in 20 mL CH2Cl2 was stirred at room temperature overnight. The solution was washed with aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 10-40% ethyl acetate in hexanes to provide methyl 4’-{ (1R)-1-[({ 1-[(tert-butoxycarbonyl)amino]cyclopropy! }carbonyl)- aminolethyl }-3-chloro-3*-fluoro-1,1-biphenyl-2-carboxylate as a white solid that gave proton NMR spectra consistent with theory. The product was dissolved in ethyl acetate and saturated with HCI gas. The solution was concentrated in vacuo and azeotroped three times with toluene to provide 1-[({(1R)-1-[3-chloro-3-fluoro-2’- (methoxycarbonyl)-1,1"-biphenyl-4-ylJethyl Jamino)carbonyl]cyclopropanaminium chloride that gave a mass ion (ES+) of 391.21 for M+H+.

To a solution of the above compound (0.300 g, 0.702 mmol) in 5 mL

CH2Cl3 at 0 °C was added triethylamine (0.142 g, 1.40 mmol) and trifluoroacetic anhydride (0.147 g, 0.70 mmol). The solution was diluted with addition CH2CI2 and washed with aqueous sodium bicarbonate and brine, dried over Na2S04, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 10- 40% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 487.22 for M+H+: IH NMR (300 MHz, MeOH-d4) 8 7.51-7.33 (m, 4H), 7.17-7.07 (m, 2H), 5.31 (q, J=7.1 Hz, 1H), 3.69 (s, 3H), 1.52-1.49 (m, 5H), 1.27-1.03 (m, 2H).

EXAMPLE 6

N-{(1R)-1-[3,3'-difluoro-2'-(2-methyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]ethyl }-1- [(trifluoroacetyl)amino]cyclopropanecarboxamide

Oo : en

CHs 0) NH N—=N

N___N pe ae

A solution of 2-fluoro-6-iodobenzonitrile (17.82g, 72.15 mmol) and } azidotrimethyltin (15.00g, 72.88 mmol) in 150 mL toluene was heated to 125 °C for 72 hours. The solution was cooled to room temperature and partitioned between ethyl acetate and 0.5 N HCI. The organic extract was washed with water and brine, dried over NapSOy, filtered and concentrated under vacuum to provide 5-(2-fluoro-6-iodo- phenyl)-1H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 291.01 for M+H+.

A mixture of 5-(2-fluoro-6-iodophenyl)-1H-tetrazole (23.48g, 80.97 mmol), potassium carbonate (16.79g, 0.121 mol), and iodomethane (16.09g, 0.113 mol) in 25 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over NapSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole that gave proton

NMR spectra consistent with theory and a mass ion (ES+) of 305.06 for M+H*.

To a solution of 2-fluoro-4-bromo-benzaldehyde (20.0 g, 98.5 mmol) in 500 mL of THF at 0 °C was added slowly a solution methyllithium (1.4 M in Et20, 70.3 mL). After one hour the reaction was carefully quenched with saturated aqueous ammonium chloride, extracted with diethyl ether, washed with saturated NaCl, dried over MgSO4 and concentrated. A solution of the crude alcohol in 200 mL of

CH2Cl2 and TEA (14.0 mL, 100 mmol) at 0 °C was added methanesulfonyl chloride (7.42 mL, 95.9 mmol) over a period of five minutes. After and overnight reaction period, the reaction was extracted with CH2Cl2 , washed with NaHCO3, saturated

NaCl, dried over MgSO4 , and concentrated. A solution of the crude mesylate in 50 mL of DMF was treated with sodium azide (12.5 g, 191 mmol) overnight. The reaction was extracted with EtOAc , washed with NaHCO3, saturated NaCl, dried over MgSO4 , and concentrated. To a solution of the crude azide in 100 mL of THF was triethylphosphine (1 M in THF, 90.1 mL) over a period of 30 minutes. After one hour, 100 mL of 1 N HCI was added and the mixture was heated overnight. The mixture was cooled and washed with Et20. The aqueous layer was made basic by the addition of potassium carbonate, extracted with Et0, dried over MgSO4 , and concentrated. A solution of the crude amine (9.0 g, 41.2 mmol) in 50 mL of CH2Cl2 : was treated with Boc anhydride (9.00 g, 41.2 mmol). After one hour the mixture was concentrated. A solution of the crude carbamate in 40 mL of DMSO was added potassium acetate (12.1 g, 123.1 mmol), bis(pinacolato)diboron (11.5 g, 45.4 mmol),

and dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane ] adduct (1.4 g, 1.8 mmol). The resulting mixture was heated at 80 °C for 16 hours.

After cooling to room temperature, the mixture was partitioned between water and

EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 20% ethyl acetate in hexanes to provide tert-butyl 1-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate as a tacky solid that gave a proton NMR consistent with theory.

A mixture of 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole (1.49g, 4.89 mmol), tert-butyl 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- phenyl]ethylcarbamate (1.70g, 4.65 mmol), potassium carbonate (1.61 g, 11.6 mmol), tri-o-tolylphosphine (0.057 g, 0.19 mmol), and palladium acetate (0.010 g, 0.05 mmol) in 20 mL of THF and 4 mL of water was heated in a sealed flask at 100 °C overnight. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over

NapSO0y4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-20% ethyl acetate and hexane to provide tert-butyl 1-[3,3'-difluoro-2'-(2-methyl-2H-tetrazol-5-yl)- 1,1'-biphenyl-4-yl]ethylcarbamate as a yellow oil that gave proton NMR spectra consistent with theory. The product was dissolved in ethyl acetate and saturated with HCI gas. The solution was concentrated in vacuo and azeotroped 3x with toluene to provide 1-[3,3"-difluoro-2'-(2-methyl-2H- tetrazol-5-yl)-1,1'-biphenyl-4-yl]Jethanaminium chloride.

A solution of 1-[3,3"-difluoro-2'-(2-methyl-2H-tetrazol-5-yl)-1,1'- biphenyl-4-yljethanaminium chloride (0.670g, 1.89 mmol), Boc-1-aminocyclo- propane-1-carboxylic acid (0.419g, 2.08 mmol), 1-ethyl-(3-dimethylaminopropyl)- carbodiimide carboxylic acid (0.726g, 3.79 mmol), 1-hydroxy-7-azabenzotriazole (0.010g, 0.15 mmol), and triethylamine (1.15g, 11.4 mmol) in 10 mL CHCl? was stirred at room temperature for 48 hours. The solution was washed with aqueous sodium bicarbonate and brine, dried over Na2SOy4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 10-50% ethyl acetate : in hexanes to provide tert-butyl 1-[({ 1-[3,3'-difluoro-2'-(2-methyl-2H-tetrazol-5-yl)- 1,1'-biphenyl-4-yl]ethyl }amino)carbonyl]cyclopropylcarbamate that gave proton

NMR spectra consistent with theory and a mass ion (ES+) of 499.7 for M+H+. The enantiomers were resolved at this point on a Chiralcel OD column 10% isopropanol/

hexane (containing 0.1% TFA). The R enantiomer eluted first and was used for the } remainder of the synthesis.

The above product was dissolved in ethyl acetate and saturated with

HCl gas. The solution was concentrated in vacuo and azeotroped 3x with toluene to provide (1R) 1-[({ 1-[3,3difluoro-2(2-methyl-2H-tetrazol-5-yl)-1,1-biphenyl-4-yl}- ethyl }amino)carbonyl]cyclopropanaminium chloride that gave a mass ion (ES+) of 399.6 for M+H+.

To a solution of the above compound (0.105g, 0.241 mmol) in 2 mL

CH2CI2 at 0 °C was added triethylamine (0.049g, 0.48 mmol) and trifluoroacetic anhydride (0.051g, 0.24 mmol). The solution was diluted with additional CHCl» and washed with aqueous sodium bicarbonate and brine, dried over Na3SQg, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 10-40% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 495.32 for M+H+: 1H NMR (300 MHz, MeOH-dg) 8 7.68-7.61 (m, 1H), 7.34-7.21 (m, 3H), 6.89-6.83 (m, 2H), 5.23 (d,J=7.1 Hz, 1H), 4.86 (s, 3H), 1.49 (d, J =3.7 Hz, 2H), 1.44 (d, J =7.1 Hz, 3H), 1.18-1.01 (m, 2H).

The following compounds in Table 1 were prepared by methods analogous to those described in Example 1.

Tablel

NT pe 0) NH

HiC * ® CO,CH3 6b

R72 $ R a a dl : M+H+ 7 lymomethy | F | BW [| R | 4a8 lymometny | a | uw [R | 40 9 [oouifuocethyt | co | mw | R [482 13 lpyimidinsyl | BF | WO | R | 463

Pootifluoroethyl | F | F | R | 485 17 lsoazolsyl | F | F | R | 410 18 eiflworomethyy | F | F | R | 411 19 lpyimidinsy | F | F | R | 481 23 lmey | FF | R | a7 24 |sbomopyidindyi | F | F | R | 558

Ce pyridin-3-yl 26 wifluoromeyl | H | F | R | 453 27 lpyimidnsy | mH | F | R | 463 28 |chlorodifluoromethyt | F | F | R [| 487

CE TE pyridin-3-yl chlorodifiuoromethy | ©) | F | R | 503 31 difuoromeyt | F | F | R | 453 32 Jpentafluoroethyl | BF | F | R | s21 33 laforometnyt | oo [| F | R | 460 * stereoconfiguration at designated chiral center; (+) = racemic mixture

The following compounds in Table 2 were prepared by methods analogous to those described in Example 1.

Table 2 ov R® nel

CHj, 0” “NH N= * O__N

HC

SSN Ee =F TEE]

M+H+ 34 lmetyt | F |u| R [| 43 35 Jymometyt | F | mw | R | ass 36 [222uifluoroethyl | F | BH [ R | 491 37 lisoxmolSyl | F | H | R | 476 39 220wiflorethyl | F | F | R | 500 43 |chlorodifluoromethyl| F | F | R | sii 44 lpyimidinsyt | F | F | R [ 505 45 ldifwometnyt | F | P| rR [ 477 * stereoconfiguration at designated chiral center; (+) = racemic mixture

The following compounds in Table 3 were prepared by methods analogous to those described in Example 1.

Table 3 as 07 “NH N-N CH,

NSN

“IC

R72 @ F

Example RS R7a |tetrazole | * ES MS,

M+H+ 46 |cymometnyl | mw | om | R | 448 222uifluoroethyl | H | om | R | 401 48 |oymometyl | mw | mm | R | 48 22uifluoroethyl | MH | mm | R | 401 50 [mehyl | ow | wm | rR [ 43 51 lisoxaolsyl | F | om | | a4 2.2.2 trfluoroethy] chloro(difluoro)methyl] F | 2H | R | 501 iflvoromethyl | F | on | R | 477 * stereoconfiguration at designated chiral center; (+) = racemic mixture

The following compounds in Table 4 were prepared by methods analogous to those described in Example 1.

Table 4 oy R® 0) NH 6a

HsC"R R ® Reb 3 .

Example RS ES MS,

M+H+ 57 122)-uifluoroethyl 58 [2.22 trifluoroethyl H 59 122)-wifluoroethyl H 60 |22,2-uifluoroethy! 61 222-uifluoroethyl 66 lcymometyt | FE |COMe 68 [2.2.2-trifluorocthyl | (dimethylamino)carbonyl| F__| 480 69 |pyrimidin5-y1 | (methoxycarbonyamino “170 pyrimidin-5-yl [(methylamino)carbonyl] F 477 : amino [71 trifluoromethyl (methylamino)carbonyl (methylamino)carbony! -6l -

The following compounds in Table 5 were prepared by methods analogous to those described in Example 2.

Table 5 as wll 0 NH (R)

Example RS ES MS,

M+H+ 2,2,2-trifluoroethyl (methylamino)carbonyl (methoxyamino)carbony} 2,2 2-trifluoroethyl | (cycloprop lamino)carbon ] 2,2,2-trifluoroethyl | (cyclobutylamino)carbonyl

The following compounds in Table 6 were prepared by methods analogous to those described in Example 1.

Table 6 oy R°

CH, 07 NH o—~(

R NaN

HsC ®

Roe a ll 3

M+H+ 50 lwifuoometyt | mw | uw | P| am 8 lwifluoomenyt | mw [ FP | P| 405

The following compounds in Table 7 were prepared by methods analogous to those described in Example 1.

Table 7 aa 0) NH

HsC(R) ® Ree

REP

TU

Ree

Ex. RS R6c |R7a| ES MS,

M+H+ 89 | pyrimidin-5-yl 2-methyl-2H-tetrazol-5-yl 90 |rifluoromethyl __|2-methyl-2H-tetrazol-5-yl 91 |iffuoromethyl |COaMe 92 |chlorodifluoromethyl [CO2Me 93 |ifluoromethyl [COM 94 |chlorodifluoromethyl [CO2Me 95 |cifluoromethyl ~~ |3-methyl-1,2,4-oxadiazol- F | 495 5-yl 96 (trifluoromethyl 3-methyl-1,2,4-oxadiazol- F 511 5-yl 97 |chlorodifluoromethyl 3-methyl-1,2,4-oxadiazol- 527 : 5-yl trifluoromethyl 3-methyl-1,2,4-oxadiazol- 491 : 5-yl 99 |chlorodifluorometh 1 |3-methyl-1,2,4-oxadiazol-

I I 4 : M+H+

I I "A amino carbonyl)amino

The following compounds in Table 8 were prepared by methods analogous to those described in Example 1.

Table 8

Oy R° 0) NH

R

HoC ® CO,Me “0

Example RS R6¢ ES MS,

M+H+ 118 |chloro(difluoro)methyl 121 [chloro(difluoro)methy!

The following compounds in Table 9 were prepared by methods analogous to those described in Example 3, using the commercially available 1-[(tert- butoxycarbonyl)amino]cyclobutanecarboxylic acid instead of 1-[(tert-butoxy- carbonyl)amino]cyclopropanecarboxylic acid.

Table 9

N

= 0 @) x_N gr 0” NH R™ 3b ne CO,Me

R R60

R32,R3b | R6b | R72 |ES MS, MH

The following compounds in Table 10 were prepared by methods analogous to those described in Example 1, using the commercially available 1-[(tert- butoxycarbonyl)amino]cyclobutanecarboxylic acid instead of 1-[(tert-butoxy- carbonyl)amino]cyclopropanecarboxylic acid.

Table 10 oy gr

Oo NH

R

Hy C ® Roa 6b aa

FI NO +4 ‘ M+H+* : 1 1 yl

Claims (16)

a WHAT IS CLAIMED IS:

1. A compound having the formula I(3) and pharmaceutically acceptable salts thereof: ol NH m 0} NH R30 ® R52 6 Jao 13) whereinmis 0 or 1, R6a is 2-methyl-2H-tetrazol-5-y], 3-methyl-1,2,4-oxadiazol-5-yl, CO2Ra or C(O)NHOR@ wherein Ra is C] 4 alkyl; R6b is hydrogen, fluorine or chlorine; R3b is C14 alkyl; RS is selected from C14 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, C3.6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen or trifluoromethyl; and R72 is hydrogen or fluorine.

2. A compound of Claim 1 selected from: a NH Om 0) NH H3C—~ R62 Ra 2 péb R72 | Xx 3 Ree” -69 - AwicNDED SHEET m| ® | Ré | meb | mec | m7 [+ jo] CHR | copes | r | uw | u | & o| CHXFs | coNHOCHS | F | mw | wu |g 0] CF |3CHylodowdmolSyl F | u | fF |g lo] on [| cols | a | um | F |r 0] Ch | oCHstewmzolSyl | pr | um | F |p (o| CHN | cocms | ¢ | um | u |g 0] CoN | cocHs | a | um | u | & lo cmors | cools | a | wm | um |r 0] CHCFs [| coCHs | ¢ | wm | rm] 0 |isoxazalbsyl | COCH3 | ¢ | uw | fF |] 0] CN | coms | F | uw | F 0 |pyimidinsyl| COCH3 | § | nm | wu |g [0 CHpoRs | cooms | Fr | uw | Fr (0) CHCFs [| COXHs | ¢ | uw | F |r 0 |pyimidinsyi| COXCHs | F | mW | F |) 0 |isoxazobsy | COCH3s | ® | mw | § |g

[0] Ch | copcHs | k | um | § |g 0 |pyimidinsyi| COoCHs | F | mw | F |r 0 |isoxasolsyi | COpCHs | F | m | 5 |. lo] cm | copoms | F | wm | F 0 |pyrimidinsyl| COCH3 | ¢ | wm | F |g of om | coms | F [wm | F |® lr ON EEA 1 Tem oe EE pyridin-3-yl of CO | coocHs | Ww | wm | F |& 0 [pyrimidinSyl| COCH3s | W | um | pF |g 0 Com [| cocHs | kr | wm | F |r Fr TT 3-yl -70- AMENDED SHEET m| RS | mea [eb | pec | pra |v] o| cor [ cols | oa | w |r |x] o] cw | coms |r | uw | § |g] [o| CFCs | cools | Fr | yw | |g] of CHR | com [| oa | wm | F |x o| CH [pCMyiptoudaolsy] Fr | B | uw |g |]

[0] CHIN [-CHylzdomdaotsy] F | 5 | u 0] CHCRy [sCHylatoxsdimlsyil F | 5 | uw |g 0 | isoxazol-5:y1 [3:CH3-124omadinzolsyl| F | 5 0 | CHR [3CHylpbowdimsobsyl Fr | m | p |g] [0 CHiCFs [3-CHylzdomdinsolsyl ¢ | 5 | 7 0 | CHON [3CHsiptoudisolsyl] F | 5 | p |] 0 | CHC; [3-CHyladoxadisosyl| F | 5 | ¢ 0 | pyrimidin-5-y1 [3-CH3-124omadiazol si] ¢ | 5 | F |g] o| CCF [sCHylztoxsdimaolsyl F | un | 5 | & 0 | pyrimidin:5-yi [3-CHy-L24onadinzol5yi] F | 5 | | g lo CHR [3CHylitoudsolsy] § | uw | F |r 0] CHON | oCHptemaolSyl | ¢ | 5 | uw |g 0| CHCFy | oCHytemaolSyl | § | py | 5 |g 0 | isoxazolsyl | 2CHatetmzolSyl | F | 5 | F |]

[0] CHR | 2CHytemsolsyl | ¢ | 5 | 5 |g] jo] Cf | 2CHytmmSy | F | mw | ps

[0] cop | oCHpamolsyl | F | up | § |r

[0] CHF | oCHytemmolSyl | § | ug | p |g 0 isoasolsyl | CONHOCHs | ¥ | uw | u |g of Cs | cols | a | uw | F |g] of CO | cocHs om | yw | fr | & 0) ccF2 | cocHy | ams | mw | F | &

[1] CB [sCHylzdoxdimsoSy| F | un | fF |g 1] COR [CHylztonadimoSy| F | uw | p 1 Tomita tomadimo si + | 5 | 3a” -71 - : AMENDED SHEET m| BS | ~~ Réa | méb | Réc | R7a | + [om [coms |r | m |r |® [com | coems |r |u| r [rn Tommie] cocms | | mw | |r 1 | pyrimidin-5-yt | 2-CHy-2Hetetrazol-5-yl | °F [ u | F | R 1] crs | coms [a lm | F [R]

[1] com | cocns [a [uw | F |R] cw | copes [a | wm | F [rR * stereoconfiguration at the indicated carbon, or a pharmaceutically acceptable salt thereof.

3. A compound of Claim 1 selected from: methyl 3-fluoro-4"-{(1R)-1-[({1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl}- carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate, 3-fluoro-N-methoxy-4'- {(1R)-1-[({1-{(3,3,3-trifluoropropanoyl)amino]cyclopropyl} - carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxamide, methyl 3-fluoro-4'- { 1-methyl-1-{({1-[(trifluoroacetyl)amino]cyclopropyl}- carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate, N-{(1R)-1-[3,3"-difluoro-2'-(3-methyl-1,2,4-oxadiazol-5-yl)-1,1"-biphenyl-4- yl]ethy!}- 1-[(trifluoroacetyl)amino]cyclopropanecarboxamide, methyl 3-chloro-3"-fluoro-4'- {(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}- carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate, and N-{(1R)-1-[3,3"-difluoro-2"-(2-methyl-2H-tetrazol-5-yI)-1,1'-biphenyl-4-yl]ethyl} -1- [(trifluoroacetyl)amino]cyclopropanecarboxamide; and pharmaceutically acceptable salts thereof.

4. The compound methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1- [(trifluoroacetyl)amino]cyclopropyl} carbonyl)amino]ethyl} -1,1'-biphenyl-2- carboxylate.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compuond of Claim 1 and pharmaceutically acceptable excipients. -72- AMENDED SHEET

6. Use of a compound of Claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of pain and inflammation.

7. Use of a compound of Claim 4 for the manufacture of a medicament for the treatment and prevention of pain and inflammation.

8. The use of Claim 6 wherein said pain is postherpetic neuralgia, osteoarthrititis pain, post- or perioperative pain or dental pain.

9. The use of Claim 7 wherein said pain is postherpetic neuralgia, osteoarthrititis pain, post- or perioperative pain or dental pain.

10. A compound of Claim 1 or a pharmaceutically acceptable salt thereof, for the use in the treatment of prevention of pain and inflammation.

11. A compound of Claim 4, for use in the treatment and prevention of pain and inflammation.

12. The compound of Claim 10 wherein said pain is postherpetic neuralgia, osteoarthrititis pain, post- or perioperative pain or dental pain.

13. The compound of Claim 11 wherein said pain is postherpetic neuralgia, osteoarthrititis pain, post- or perioperative pain or dental pain.

14. The compound of Claim 1 or 4, substantially as herein described and exemplified.

15. The pharmaceutical composition of Claim 5, substantially as herein described and exemplified.

16. Use of a compound according to Claim 6 or 7, substantially as herein described and exemplified. -73- AMENDED SHEET