CN1832922A

CN1832922A - Sulfonyl substituted n-(biarylmethyl) aminocyclopropanecarboxamides

Info

Publication number: CN1832922A
Application number: CN 200480022661
Authority: CN
Inventors: N·J·安东尼; R·戈麦斯; S·M·乔利; J·J·林; 苏达世
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 2003-08-07
Filing date: 2004-08-03
Publication date: 2006-09-13

Abstract

N-(Sulfonyloxybiarylmethyl)aminocyclopropanecarboxamide derivatives are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.

Description

Sulfonyl-substituted N- (biarylmethyl) aminocyclopropanecarboxamides

Background

The present invention relates to aminocyclopropanecarboxamide compounds. In particular, the invention relates to aminocyclopropanecarboxamide compounds which are bradykinin antagonists or inverse agonists.

Bradykinin ("BK") is a kinin which plays an important role in pathophysiological processes associated with acute and chronic pain and inflammation. Bradykinin (BK), like other kinins, is an autoreactive (auto-id) peptide produced by the catalytic action of kallikrein, a precursor to plasma and tissue of kininogen. The biological effects of BK are mediated by at least two major G-protein-coupled BK receptors, designated B1 and B2. It is believed that the B2 receptor, but not the B1 receptor, is expressed in normal tissues, whereas inflammation, tissue injury or bacterial infection can rapidly induce Bl receptor expression. This results in the B1 receptor being a particularly attractive drug target. The well-recognized role of kinins, in particular BK, in the control of pain and inflammation has provided a motivation for the development of potent and selective BK antagonists. In recent years, this effort has been increasing to expect that useful therapeutic agents with analgesic and anti-inflammatory properties can provide for the mitigation of BK receptor pathway-mediated diseases (see, e.g., m.g. bock and j.longmore, Current Opinion in chem.biol., 4: 401-406 (2000)). Therefore, there is a need for novel compounds that effectively block or reverse the activation of bradykinin receptors. Such compounds may be useful in the control of pain and inflammation, and in the treatment or prevention of bradykinin-mediated diseases and conditions; furthermore, such compounds are also suitable as research tools (in vivo and in vitro).

Canadian patent application publication No. 2,050,769 discloses compounds of the formula:

it is an intermediate in the preparation of angiotensin II antagonists.

Summary of The Invention

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

Detailed Description

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

Wherein,

R¹and R²Independently selected from hydrogen and C_1-4An alkyl group;

R^3aand R^3bIndependently selected from hydrogen and C optionally substituted by 1-5 halogen atoms_1-4An alkyl group;

R^4aand R^4bIndependently selected from hydrogen, halogen, and C optionally substituted with 1-4 groups selected from_1-4Alkyl groups: halogen, OR^a，OC(O)R^a，S(O)_kR^d，OS(O)₂R^dAnd NR¹R²Or is or

R^4aAnd R^4bTogether with the carbon atoms to which they are both attached form an exo-cyclic methylene (exo-cyclic methyl) group optionally substituted with 1 to 2 groups selected from: c optionally substituted by 1-5 halogen_1-4Alkyl, and C_1-4An alkoxy group;

R⁵selected from (1) C_1-6Alkyl, optionally substituted with 1-5 groups independently selected from: halogen, nitro, cyano, OR^a，SR^a，COR^a，SO₂R^d，CO₂R^a，OC(O)R^a，NR^bR^c，NR^bC(O)R^a，NR^bC(O)₂R^a，C(O)NR^bR^c，C_3-8Cycloalkyl, (2) C_3-8Cycloalkyl optionally substituted with 1-5 groups independently selected from halogen, nitro, cyano and phenyl, (3) C_3-6Alkynyl, (4) C optionally substituted with hydroxyethyl_2-6Alkenyl, (5) (CH₂)_k-aryl, optionally substituted with 1 to 3 groups independently selected from: halogen, nitro, cyano, OR^a，SR^a，C(O)₂R^a，C_1-4Alkyl and C_1-3A haloalkyl group; (6) (CH)₂)_k-heterocycle, optionally substituted with 1-3 substituents independently selected from halogen, nitro, cyano, OR^a，SR^a，C_1-4Alkyl and C_1-3Haloalkyl, wherein the heterocycle is selected from (a) a 5-membered heteroaromatic ring containing a ring heteroatom selected from N, O and S, and optionally containing up to 3 additional ring nitrogen atoms, wherein the ring is optionally benzo-fused; (b) a 6-membered heteroaromatic ring containing 1-3 ring nitrogen atoms and N-oxides thereof, wherein the ring is optionally benzo-fused; and (c) a 5-or 6-membered non-aromatic heterocyclic ring selected from tetrahydrofuranyl, 5-oxo-tetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1, 6-dihydropyridazinyl, (7) C (O)₂R^aAnd (8) C (O) NR^bR^c；

R^6aSelected from (1) -OSO₂R⁸，(2)-NR^8aSO₂R⁹And (3) -C (R)^8b)(R^8c)SO₂R⁹；R^6b，R^6cAnd R^6dIndependently selected from (1) hydrogen, (2) halogen, (3) OSO₂R⁸(4) C optionally substituted by 1 to 5 halogen atoms_1-4Alkyl, (5) cyano, (6) nitro, (7) OR^aAnd (8) CO₂R^aOr is or

R when bound to an adjacent carbon atom^6cAnd R^6dTogether with the carbon atom to which they are attached form a 5-to 8-membered saturated or unsaturated ring;

R⁷selected from (1) hydrogen, (2) halogen, (3) cyano, (4) nitro, (5) OR^a，(6)CO₂R^a，(7)C(O)NR^bR^cAnd (8) C optionally substituted by 1 to 5 halogen atoms_1-4An alkyl group, a carboxyl group,

R⁸selected from (1) C optionally substituted by 1 to 5 halogen atoms_1-4Alkyl, (2) optionally substituted (CH) with 1-3 groups independently selected from₂)_k-aryl: halogen, nitro, cyano, NR^aC(O)R^a，OR^a，SR^a，CO₂R^a，C_1-4Alkyl radical, C_1-3Haloalkyl and NR^bR^c，(3)NR^bR^cAnd (4) hydrogen;

R^8aselected from hydrogen, C optionally substituted by 1-5 halogen atoms_1-4Alkyl, halogen, and CO₂R^aOr is or

When R is^6aAnd R^6bWhen bound to an adjacent atom, R^8aAnd R^6bTogether form a 5-or 6-membered ring;

R^8band R^8cIndependently selected from hydrogen, C optionally substituted by 1-5 halogen atoms_1-4Alkyl, halogen, cyano, nitro, CO₂R^aAnd OR^a；

R⁹Selected from (1) C optionally substituted by 1 to 5 halogen atoms_1-4Alkyl, (2) aryl optionally substituted with 1-3 groups independently selected from: halogen, nitro, cyano, NR^a(C)OR^a，OR^a，SR^a，CO₂R^a，C_1-4Alkyl and C_1-3Haloalkyl, and (3) optionally substituted with 1-3 groups independently selected from (CH)₂)_k-aryl: halogen, nitro, cyano, NR^a(COR^a)，OR^a，SR^a，CO₂R^a，C_1-4Alkyl and C_1-3Haloalkyl, or

R^8aAnd R⁹Together with the atoms to which they are attached form a 5-to 8-membered heterocyclic ring;

R^a，R^band R^cIndependently selected from (1) hydrogen, (2) C optionally substituted with 1-5 halogen atoms_1-4Alkyl, (3) phenyl optionally substituted with 1-3 groups selected from: halogen, cyano, nitro, OH, C_1-4Alkoxy radical, C_3-6Cycloalkyl and C_1-4Alkyl optionally substituted with 1 to 5 halogen atoms, and (4) C_3-6Cycloalkyl radicals, or

R^bAnd R^cTogether 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

R^bAnd R^cTogether with the nitrogen atom to which they are attached form a cyclic imide;

R^dselected from (1) C optionally substituted by 1 to 5 halogen atoms_1-4Alkyl group, (2) C_1-4Alkoxy, (3) phenyl optionally substituted with 1-3 groups selected from: halogen, cyano, nitro, OH, C_1-4Alkoxy radical, C_3-6Cycloalkyl and C_1-4Alkyl optionally substituted with 1-5 halogen atoms, and (4) hydrogen;

x is selected from CH and N;

y is selected from C and S ═ O; and

k is selected from 0, 1 and 2.

For compounds of formula I, R¹And R²Examples of (b) include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and sec-butyl. In one embodiment of formula I is wherein R¹And R²Each hydrogen.

For compounds of formula I, R^3aAnd R^3bExamples of (b) include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, chloromethyl, fluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 2, 2-difluoroethyl, 1, 1, 2, 2, 2-pentafluoroethyl and the like. In one embodiment of formula I is wherein R^3aAnd R^3bOne being hydrogen and the other being hydrogen or C_1-4Alkyl compounds. In a subset, R^3aAnd R^3bAre each hydrogen, in another subset, R^3aAnd R^3bOne is hydrogen and the other is methyl.

For compounds of formula I, R^4aAnd R^4bExamples of (b) include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, chloro, fluoro, bromo, chloromethyl, 1-chloroethyl, hydroxymethyl, 2-methoxyethyl, ethoxymethyl, acetoxymethyl, methylthiomethyl, aminomethyl, methylaminomethyl, (dimethylamino) methyl, (methylsulfonyl) oxymethyl and the like. In one embodiment of formula I is wherein R^4aAnd R^4bOne is hydrogen and the other is selected from hydrogen, halogen and C_1-4Compounds of alkyl radicals, C_1-4Alkyl is optionally selected from halogen, OR^a，OC(O)R^a，S(O)_kR^d，OS(O)₂R^dAnd NR¹R²Is substituted by a group of (A), or R^4aAnd R^4bTogether with the carbon atoms to which they are both attached, form an exocyclic methylene group. In a subset, R^4aAnd R^4bAre each hydrogen; in another subset, R^4aIs hydrogen and R^4bIs selected from CH₂-halogen, CH₂-OR^a，CH₂-OC(O)R^a，CH₂-S(O)_kR^d，CH₂-OS(O)₂R^dAnd CH₂-NR¹R²(ii) a In another subset, R^4aIs hydrogen and R^4bSelected from the group consisting of hydroxymethyl, acetoxymethyl, chloromethyl, (methylsulfonyl) oxymethyl, (methylthio) methyl and (dimethylamino) methyl.

For compounds of formula I, R⁵Examples of (B) include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, chloromethyl, 1-chloroethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, cyanomethyl, 1-hydroxypropyl, isopropyl, methoxymethyl, 3-methoxy-3-oxo-propyl, isobutyl, 2-phenyl-ethyl, 1-ethylpropyl, phenylthiomethyl, phenoxymethyl, 2, 2-dimethylpropyl, 2-cyclopentylethyl, 2-methoxy-2-oxoethyl, 2-methoxyethyl, ethoxymethyl, 2-nitroethyl, 1-cyanocyclopropyl, cyclopropyl, cyclopentyl, 2-phenylcyclopropyl, allyl, 3-butynyl, propargyl, phenyl, benzyl, 3, 5-bis (trifluoromethyl) -phenyl, 2, 4-difluorophenyl, 4-methylphenyl, 3, 4-dimethoxybenzyl, 3, 4-dimethoxyphenyl, 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, 3-hydroxyphenyl, 3-nitro-5- (trifluoromethyl) phenyl, 5-isoxazolyl, 2-benzothienyl, 2-thienylmethyl, 3-pyridyl, 4-pyridyl, 2-furyl, 2-thienyl, 5-methyl-3-isoxazolyl, 3-tetrahydrofuryl, 4-methyl-1, 2, 5-oxadiazol-3-yl, 6-hydroxy-2-pyridyl, 6-chloro-2-pyridyl, 1-methyl-4-pyrazolyl, 1-pyrazolyl methyl, 1-methyl-2-imidazolyl, 1, 2, 4-triazol-1-ylmethyl, 4-thiazolyl, 5-oxo-tetrahydrofuran-2-yl, 2-oxo-5-pyranyl, 3-isoxazolyl3-pyridazinyl, 5-pyrimidinyl, 4-pyrimidinyl, 1-imidazolylmethyl, 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, 5-methyl-3-pyridyl, 2-quinoxalinyl, 2-chloro-3-pyridyl, 5-bromo-3-pyridyl, and 5-hydroxy-3-pyridyl.

In one embodiment of formula I are the following compounds, wherein R is⁵Is optionally substituted by 1-5 substituents independently selected from halogen, nitro, cyano, OR^a，SR^a，COR^a，SO₂R^d，CO₂R^a，OC(O)R^a，NR^bR^c，NR^bC(O)R^a，C(O)NR^bR^c，C_3-8C substituted by radicals of cycloalkyl groups_1-6An alkyl group. Within a subset are compounds wherein R is⁵Is optionally substituted with 1-5 substituents independently selected from halogen, nitro, cyano, OR^a，SR^a，CO₂R^aAnd C_3-8C substituted by radicals of cycloalkyl groups_1-5An alkyl group. In another subset are compounds wherein R is⁵Is selected from C_1-5Alkyl and C_1-3Alkyl substituted by 1 to 3 substituents selected from halogen, cyano, hydroxy, C_1-4-alkoxy and C_1-4Alkoxy carbonyl groups.

In another embodiment of formula I are wherein R⁵Is C optionally substituted with 1-3 groups independently selected from halogen, nitro, cyano and phenyl_3-6A compound of a cycloalkyl group. In a subset, R⁵Is C optionally substituted by a group selected from cyano and phenyl_3-6A cycloalkyl group.

In another embodiment of formula I are wherein R⁵Is optionally substituted by 1-2 substituents independently selected from halogen, nitro, cyano, OR^a，SR^a，C_1-4Alkyl and C_1-3Substituted by haloalkyl radicals (CH)₂)_k-a heterocyclic compound, wherein the heterocyclic ring is selected from the group consisting of isoxazolyl, thienyl, pyridyl,benzothienyl, furyl, tetrahydrofuryl, oxadiazolyl, 1-oxopyridyl, pyrazolyl, imidazolyl, 1, 2, 4-triazolyl, thiazolyl, 5-oxotetrahydrofuryl, 2-oxo-2H-pyranyl, 6-oxo-1, 6-dihydropyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl. In a subset, R⁵Selected from optionally substituted by 1 or 2C_1-4Alkyl-substituted isoxazolyl, thienyl, pyridyl optionally substituted with hydroxy or halogen, benzothienyl, furyl, tetrahydrofuryl, optionally substituted with C_1-4Oxadiazolyl substituted by alkyl, optionally substituted by C_1-4Alkyl-substituted 1-oxo-pyridyl, optionally substituted by C_1-4Alkyl-substituted pyrazolyl optionally substituted by C_1-4Imidazolyl substituted by alkyl, optionally C_1-41, 2, 4-triazolyl substituted by alkyl, optionally with C_1-4Alkyl-substituted thiazolyl, 5-oxotetrahydrofuryl, 2-oxo-2H-pyranyl, 6-oxo-1, 6-dihydropyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl.

For compounds of formula I, R^6aExamples of (b) include trifluoromethanesulfonyloxy, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, isopropylsulfonyloxy, benzenesulfonyloxy, phenylmethanesulfonyloxy, dimethylsulfamoyloxy, methylsulfonylamino, N- (methyl) -trifluoromethanesulfonylmethyl, methylsulfonylamino, trifluoromethylsulfonylamino, and

wherein R is^6aAnd R^6bTo adjacent atoms and R^6aIs R^8aSO₂R⁹Then R is^6aAnd R^6bTogether with the phenyl ring to which it is attached may represent N-sulfonyl-8-tetrahydro-quinolinyl. R^6bExamples of (A) include hydrogen, chlorine, fluorine, methyl, methoxy, methoxycarbonyl and OSO₂CF₃；R^6cAnd R^6dExamples of (A) include hydrogen, chlorine, fluorine, methyl, methoxy and methoxyA carbonyl group; wherein R is^6cAnd R^6dOne example of a ring formed with the carbon to which it is attached is benzene; r⁷Examples of (b) include hydrogen, fluoro, chloro, methoxy and methoxycarbonyl.

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

wherein X, Y, R¹，R²，R^3a，R^3b，R^4a，R^4b，R⁵，R^6a，R^6b，R^6cAnd R⁷Have the same definitions as provided for formula I.

In a subset of formula I (1), is wherein R^6bSelected from hydrogen, halogen and OSO₂R⁸The compound of (1). In a subgroup, R^6bIs fluorine or chlorine.

In another subset of formula I (1), R^6cIs hydrogen or halogen.

In another subset of formula I (1), R^6aIs OSO₂R⁸Or NHSO₂R⁹. In a subgroup, R^6aIs NHSO₂R⁹，R⁹Is C optionally substituted by 1 to 5 halogen atoms_1-4-an alkyl group.

In another subset of formula I (1), R⁷Is hydrogen or halogen. In a subgroup, R⁷Is hydrogen. In another subgroup, R⁷Is fluorine. In another subgroup, R⁷Is chlorine.

In a further subset of formula I (1) are the compounds wherein R is^6aIs OSO₂R⁸And R⁸Selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, benzyl, dimethylamino, 2, 2, 2-trifluoroethyl, and phenyl.

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

wherein X is N or CH, R^3aIs H or C_1-4Alkyl radical, R⁷Is hydrogen or halogen, R⁵，R^6a，R^6bAnd R^6cHave the same definitions as provided for formula I.

In a subset of formula I (2), R^6aIs NHSO₂R⁹. In a subgroup, R⁹Is C optionally substituted by 1 to 5 halogen atoms_1-4Alkyl radical, R^6bIs halogen, R^6cIs hydrogen or halogen. In another subgroup, R⁹Is methyl or trifluoromethyl, R^6bIs halogen, R^6cIs hydrogen.

In another subset of formula I (2), R^6aIs OSO₂R⁸. In a subgroup, R⁸Selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, benzyl, dimethylamino, 2, 2, 2-trifluoroethyl, and phenyl; r^6bIs hydrogen or halogen, R^6cIs hydrogen or halogen.

Some representative compounds of the invention are:

3, 3 ' -difluoro-4 ' - { [ ({1- [ (pyrimidin-5-ylcarbonyl) amino ] cyclopropyl } carbonyl) amino ] methyl } -1, 1 ' -biphenyl-2-yl trifluoromethanesulfonate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl trifluoromethanesulfonate,

3, 3 ' -difluoro-4 ' - ((1R) -1- { [ (1- { [ (trifluoromethyl) sulfonyl ] amino } cyclopropyl) carbonyl ] amino } ethyl) -1, 1 ' -biphenyl-2-yl trifluoromethanesulfonate,

1- ({ [ (1R) -1- (3, 3 ' -difluoro-2 ' - { [ (trifluoromethyl) sulfonyl ] oxy } -1, 1 ' -biphenyl-4-yl) ethyl ] amino } carbonyl) -cyclopropanaminium (cyclopropanaminium) trifluoroacetate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl methanesulfonate,

5-chloro-3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl trifluoromethanesulfonate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl ethanesulfonate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-ylpropane-1-sulfonate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-ylpropane-2-sulfonic acid ester,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl benzenesulfonate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-ylphenylmethanesulfonate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl dimethylsulfamate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl 2, 2, 2-trifluoroethanesulfonate,

3-chloro-3 ' -fluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-yl trifluoromethanesulfonate,

3 ' -fluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -2- { [ (trifluoro-methyl) sulfonyl ] oxy } -1, 1 ' -biphenyl-3-yl trifluoromethanesulfonate,

n- (1- { [ ((1R) -1- {3, 3 ' -difluoro-2 ' - [ methyl (methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-yl } ethyl) amino ] -carbonyl } cyclopropyl) pyrimidine-5-carboxamide,

n- (1- { [ ({3, 3 ' -difluoro-2 ' - [ (methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-yl } methyl) amino ] carbonyl } -cyclopropyl) pyrimidine-5-carboxamide,

n- {1- [ ({ [2 ' - (1, 1-dioxabridge-1, 2-thiazinan) -2-yl) -3, 3 ' -difluoro-1, 1 ' -biphenyl-4-yl ] methyl } amino) carbonyl ] -cyclopropyl } pyrimidine-5-carboxamide,

n- [ (1R) -1- (3, 3 ' -difluoro-2 ' - { [ (trifluoromethyl) sulfonyl ] methyl } -1, 1 ' -biphenyl-4-yl) ethyl ] -1- [ (trifluoro-acetyl) amino ] cyclopropanecarboxamide,

n- [ (1R) -1- (3, 3 ' -difluoro-2 ' - { [ (trifluoromethyl) sulfonyl ] amino } -1, 1 ' -biphenyl-4-yl) ethyl ] -1- [ (trifluoro-acetyl) amino ] cyclopropanecarboxamide, and

n- (1- { [ ((1R) -1- {3, 3 ' -difluoro-2 ' - [ (methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-yl } ethyl) amino ] carbonyl } -cyclopropyl) pyrimidine-5-carboxamide.

Unless otherwise indicated, the following terms have the following meanings:

"alkyl" and other groups having the prefix "alkane," such as alkoxy, alkanoyl, alkenyl, alkynyl and the like, refer to carbon chains which may be straight 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 straight or branched carbon chain containing at least one C ═ C bond. Examples of alkenyl groups include allyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, and the like.

"alkynyl" refers to a straight or branched carbon chain containing at least one C.ident.C bond. Examples of alkynyl groups include propargyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, and the like.

"aryl" refers to a carbocyclic aromatic ring system. Examples of aryl groups include phenyl and naphthyl.

"Cyclic imide" includes succinimide, maleimide, phthalimide, and the like.

"cycloalkyl" refers to carbocyclic rings that do not contain heteroatoms, including mono-, di-, and tricyclic saturated carbocyclic rings, as well as fused ring systems. Such fused ring systems may include a partially or fully unsaturated ring such as a benzene ring forming a fused ring system, e.g., a benzofused carbocyclic ring. Cycloalkyl includes such fused ring systems as spiro fused ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1, 2, 3, 4-tetrahydronaphthalene, and the like.

"haloalkyl" refers to an alkyl group as defined above wherein at least one and up to all hydrogen atoms are replaced with a halogen. Examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, and the like.

"halogen" refers to fluorine, chlorine, bromine and iodine.

"optionally substituted" includes both substituted and unsubstituted. Thus, for example, optionally substituted aryl may represent a perfluorophenyl or phenyl ring.

Optical isomer-diastereoisomer-geometric isomer-tautomer

The compounds described herein may contain asymmetric centers, whereby enantiomers may exist. When the compounds of the present invention have two or more asymmetric centers, they may additionally exist as diastereomers. The present invention includes all such possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. Formula I above does not show a defined stereochemistry at certain positions. The present invention includes all stereoisomers of formula I and pharmaceutically acceptable salts thereof. Diastereomeric pairs of enantiomers may be separated, for example, by fractional crystallization from an appropriate solvent, and the enantiomeric pairs thus obtained may be separated into the individual stereoisomers by conventional means, for example, using an optically active acid or base as a resolving agent or on a chiral HPLC column. Furthermore, enantiomers or diastereomers of the compounds of formula I can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

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

Certain of the compounds described herein may have different points of attachment for hydrogen, referred to as tautomers. Such examples may be the known keto group and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof belong to the compounds of formula I.

Salt (salt)

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, cuprous, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like salts. Ammonium, calcium, magnesium, potassium and sodium salts are preferred. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, which amines are derived from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N, N' -dibenzylethylenediamine, 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 compounds of the present invention are basic, their corresponding salts can be readily 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

Within the scope of the present invention includes prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds of the present invention which are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" shall include treating the various conditions with a compound specifically disclosed or treating the various conditions with a compound that may not be specifically disclosed but which converts to the specific compound in vivo after administration to a patient. Conventional methods for selecting and preparing appropriate prodrug derivatives are disclosed, for example, in "Design of produgs," ed.h. bundgaard, Elsevier, 1985. Metabolites of these compounds include the active species produced upon introduction of the compounds of the present invention into a biological environment.

Pharmaceutical composition

Another aspect of the invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. In pharmaceutical compositions, the term "composition" is intended to encompass a product comprising the active ingredient 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 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. Thus, the pharmaceutical compositions of the present invention include any composition made by mixing together a compound of formula I, other active ingredients, and pharmaceutically acceptable excipients.

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

In particular, the compounds of formula I of the present invention or pharmaceutically acceptable salts thereof may be combined in intimate admixture with a pharmaceutically acceptable carrier in accordance with 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 may be presented as discrete units suitable for oral administration, for example as capsules, caplets or tablets, each containing a predetermined amount of the active ingredient. In addition, the composition may be presented as a powder, granule, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion. In addition to the conventional dosage forms described above, the compound of formula I or a pharmaceutically acceptable salt thereof may also be administered by a controlled release means and/or by an administration device. The compositions may be prepared by any of the methods of pharmacy. Generally, the method comprises the step of bringing into association the active ingredient with the carrier which constitutes one or more required ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then generally be shaped into the desired form.

Accordingly, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of formula I. The compound of formula I or a pharmaceutically acceptable salt thereof may also be present in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier for administration may 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 syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any of the conventional 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; and carriers such as starch, sucrose, 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 in which a solid pharmaceutical carrier may be employed. Optionally, the tablets may be coated using standard aqueous or non-aqueous techniques.

Tablets containing the composition of the invention may be prepared by compression or moulding, 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 fluid flow form such as a 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 apparatus 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 caplet or capsule preferably contains from about 0.1mg to about 500mg of the active ingredient.

The pharmaceutical compositions of the invention suitable for enteral administration can be prepared as solutions or suspensions of the active compounds in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, preservatives may be added to prevent the unwanted growth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the composition may be in the form of a sterile powder for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be an effective fluid to facilitate injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; thus, the contaminating influence of microorganisms such as bacteria and fungi should preferably be prevented. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, for example, aerosols, creams, ointments, lotions, dusting powders and the like. In addition, the composition may be in a form suitable for use in a transdermal device. These formulations may be prepared by conventional procedures using a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof. For example, creams and ointments are prepared by mixing together a hydrophilic material and water, and from about 5% to about 10% by weight of the compound shown, to give a cream or ointment of the desired consistency.

The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture is formed into unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories are usually obtained by first mixing the composition with the softened or melted carrier, followed by freezing and shaping in moulds.

In addition to the above-mentioned carrier ingredients, the above-mentioned pharmaceutical preparations may, if appropriate, include one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the recipient. Compositions containing a compound of formula I or a pharmaceutically-acceptable salt thereof, may also be formulated as a powder or liquid concentrate.

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

injection suspension (I.M.) mg/mL	Tablet mg/tablet	Capsule mg/capsule
injection suspension (I.M.) mg/mL	Tablet mg/tablet	Capsule mg/capsule	Compound of formula I10 methylcellulose 5.0 Tween 800.5 benzyl alcohol 9.0 benzalkonium chloride 1.0 Water for injection to Total volume 1mL	Compound 25 microcrystalline cellulose 415 Povidone 14.0 pregelatinized starch 43.5 magnesium stearate 2.5500 of formula I	Compound 25 lactose powder 573.5 magnesium stearate 1.5600 of formula I

Practicality of use

The compounds of the invention are antagonists or inverse agonists of bradykinin receptors, particularly the bradykinin B1 receptor, and are useful in the treatment and prevention of diseases and conditions mediated by the bradykinin receptor pathway, such as pain and inflammation. The compounds are useful in the treatment or prevention of pain, including, for example, visceral pain (e.g., pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (e.g., postherpetic neuralgia, acute herpes zoster pain, nerve injury, "tonias," etc., vulvodynia, phantom limb pain, heel avulsion, radiculopathy, pain-traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndrome (which may be caused by injury to virtually any level of the nervous system, including but not limited to stroke, multiple sclerosis, spinal injury), and post-operative pain syndromes (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), spinal pain (e.g., acute and chronic low back pain, neck pain, spinal stenosis), shoulder pain, repetitive motion pain, dental pain, throat pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), post-operative, inter-operative pain and preferential analgesia (including but not limited to general surgery, orthopedic surgery, and gynecology), chronic pain, dysmenorrhea (primary and secondary), and pain associated with angina, and inflammatory pain of various origins (e.g., osteoarthritis, rheumatoid arthritis, rheumatic diseases, tendon-synovitis and gout, ankylosing spondylitis, bursitis).

In addition, the compounds of the invention may also be useful in the treatment of hyperreactive airways and in the treatment of inflammatory events associated with airways diseases such as asthma, including allergic asthma (atopic or non-atopic) and exercise-induced bronchoconstriction, occupational asthma, exacerbation of viral or bacterial asthma, other non-allergic asthma and "infantile asthmatic syndrome". The compounds of the invention may also be useful in the treatment of chronic obstructive pulmonary disease, including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and chronic), and vasomotor rhinitis. They are also effective against pneumoconiosis including aluminosis, silicosis, asbestos lung, chalicosis, avicularia, siderosis, silicosis, pneumoconiosis and byssinosis.

The compounds of the invention may also be useful in the treatment of inflammatory bowel disease, including crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin diseases such as psoriasis and eczema, rheumatoid arthritis and oedema resulting from wounds associated with burns, sprain or fracture, cerebral oedema and vascular oedema. They may be used to treat diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post-capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, polyuria, proteinuria and increased nitrite and kallikrein urine excretion). They may be used as smooth muscle relaxants for the treatment of spasticity of the gastrointestinal tract or uterus. In addition, they are effective against liver diseases, multiple sclerosis, cardiovascular diseases, such as atherosclerosis, congestive heart failure, myocardial infarction; neurodegenerative diseases such as parkinson's disease and alzheimer's disease, epilepsy, septic shock such as anti-hypovolemic and/or anti-hypotensive drugs, headaches including cluster headaches, migraine including prophylactic and emergency use, stroke, closed heart trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hypertrophy and overactive bladder. Animal models of these diseases and conditions are generally well known in the art and may be suitable for use in assessing the potential uses of the compounds of the present invention. Finally, the compounds of the invention are also useful as research tools (in vivo and in vitro).

The compounds of the invention are also useful as research tools (in vivo, in vitro and ex vivo). In one aspect, radionuclides for the compounds of the invention (preferably³⁵S) and used in a brain receptor occupancy assay to assess the ability of test compounds to cross the blood brain barrier and to distribute into tissues and bind to receptors. One such receptor occupancy assay is described below, in which transgenic animals expressing the human bradykinin B1 receptor are used.

The compounds of the invention are useful in the treatment of pain and inflammation by administration of tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, administered 1 time every 3-4 hours, 1, 2 or 3 times per day, or 1, 2 or 3 times per week (in a delayed release formulation).

The compounds are useful for the treatment or prevention of pain, including for example bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), intraoperative pain (systemic surgery, oral surgery, gynecology), neuropathic pain (postherpetic neuralgia) and chronic pain, by administering tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, 1 time every 3-4 hours, 1, 2 or 3 times daily, or (in a delayed release formulation) 1, 2 or 3 times weekly.

In particular, inflammatory pain, such as inflammatory airway disease (chronic obstructive pulmonary disease), can be effectively treated by administering tablets, caplets or capsules of a compound of the invention, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, administered 1 time every 3-4 hours, 1, 2 or 3 times daily, or (in a delayed release formulation) 1, 2 or 3 times weekly.

In addition, the compounds of the present invention can also be used for the treatment of asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disease, rheumatoid arthritis and edema resulting from trauma associated with burns, sprain or fracture by administering tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the present invention, 1 time every 3-4 hours, 1, 2 or 3 times per day, or (in a delayed release formulation) 1, 2 or 3 times per week.

They can be used after surgical intervention (e.g. as postoperative analgesia) and for the treatment of inflammatory pain of different origin (e.g. osteoarthritis, rheumatoid arthritis, rheumatic diseases, tendon-synovitis and gout) and for the treatment of pain associated with angina pectoris, menstruation or cancer by administering tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, 1 time every 3-4 hours, 1, 2 or 3 times daily, or 1, 2 or 3 times weekly (in a delayed release formulation).

They can be used for the treatment of diabetic vascular disease, post-capillary resistance or insulitis-related diabetic symptoms (e.g. hyperglycemia, polyuria, proteinuria and increased nitrite and kallikrein urine excretion) by administering tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, 1 time every 3-4 hours, 1, 2 or 3 times per day, or 1, 2 or 3 times per week (in a delayed release formulation).

They can be used for the treatment of inflammatory skin diseases, such as psoriasis and eczema, by administration of tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, administered 1 time every 3-4 hours, 1, 2 or 3 times per day, or 1, 2 or 3 times per week (in a delayed release formulation).

They can be used as smooth muscle relaxants for the treatment of spasticity of the gastrointestinal tract or of the uterus or for the treatment of crohn's disease, ulcerative colitis or pancreatitis by administering tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, 1 time every 3-4 hours, 1, 2 or 3 times daily, or 1, 2 or 3 times weekly (in a delayed release formulation).

Such compounds may be used therapeutically to treat the hyper-reactive airways and to treat inflammatory activity associated with airways disease, such as asthma, and to control, limit or reverse airway hyper-reactivity in asthma by administration of tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, administered 1 time per 3-4 hours, 1, 2 or 3 times per day, or (in a delayed release formulation) 1, 2 or 3 times per week.

They can be used for the treatment of intrinsic and extrinsic asthma by administration of tablets, caplets or capsules, including allergic asthma (atopic or non-specific) as well as exercise-induced bronchoconstriction, occupational asthma, asthma with viral or bacterial exacerbations, other non-allergic asthma and "infant asthma syndrome", each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, administered 1 time every 3-4 hours, 1, 2 or 3 times daily, or (in a delayed release formulation) 1, 2 or 3 times weekly.

They may also be used effectively against pneumoconiosis including aluminosis, silicosis, asbestosis, chalicosis, avicularis, siderosis, silicosis, pneumoconiosis and byssinosis as well as adult respiratory distress syndrome, chronic obstructive pulmonary or airway diseases, bronchitis, allergic rhinitis and vasomotor rhinitis by administering tablets, caplets or capsules, each dosage form containing, for example, 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, 1 time every 3-4 hours, 1, 2 or 3 times daily or (in a delayed release formulation) 1, 2 or 3 times weekly.

In addition, they can be used effectively against liver diseases, multiple sclerosis, atherosclerosis, alzheimer's disease, septic shock, e.g. against drugs acting as antianemia and/or hypotension, cerebral edema, headache including cluster headache, migraine including prophylactic or emergency use, closed head trauma, irritable bowel syndrome and nephritis, by administering tablets, caplets or capsules, each dosage form containing, e.g., 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg of a compound of the invention, 1 time every 3-4 hours, 1, 2 or 3 times daily, or 1, 2 or 3 times weekly (in a delayed release formulation).

Combination therapy

The compounds of formula I may be used in combination with other drugs employed in the treatment/prevention/inhibition or amelioration of diseases or conditions for which the compounds of formula I are useful. The other agents may be administered by a route and in an amount commonly used therefor, either simultaneously or sequentially with the compound of formula I. When a compound of formula I is administered concurrently with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compound of formula I are preferred. Accordingly, the pharmaceutical compositions of the present invention include those compositions that contain one or more additional active ingredients in addition to the compound of formula I. Examples of other active ingredients that may be combined with the compounds of formula I, either administered alone or together in the same pharmaceutical composition, include, but are not limited to: (1) morphine and other opioid receptor agonists, including propoxyphene (Darvon) and tramadol; (2) non-steroidal anti-inflammatory 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, fencloc acid, fentiazac acid, rofen, ibufenac, isoxofenac, oxpinac, sulindac, thiafenamic acid, tolmetin, azidoindac, and fenpicric acid), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and sarcinacalc) (oxicams), piroxicam, thiazoxib and tenoxicam), salicylates (acetylsalicylic acid, azosulfapyridine salicylate) and pyrazolones (azapropazone, bezpiperylon, feprazone, mofibazone, oxyphenbutazone, phenylbutazone), and coxibs (coxibss) (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 bronopolamine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenhydraline, tripelennamine, hydroxyzine, methdilazine, promethazine, isoethazine, azatadine, cyproheptadine, antazoline, pheniramine, 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 5-lipoxygenase inhibitors, such as zafirlukast, montelukast, pranlukast and zileuton; (8) drugs for angina, myocardial ischemia, including nitrates such as nitroglycerin and isosorbide dinitrate, 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 diltiazem, verapamil, nifedipine, bepridil, felodipine, cinnarizine, isradipine, nicardipine and nimodipine; (9) incontinence agents, such as antimuscarinic agents, e.g., tolterodine and oxybutynin); (10) gastrointestinal spasmolytics (e.g., atropine, scopolamine, bicyclic amines, antimuscarinic agents, and diphenoxylate); skeletal muscle relaxants (cyclobenzaprine, carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol, baclofen, dantrolene, diazepam or o-diphenhydramine); (11) gout drugs such as allopurinol, probenecid, and colchicine; (12) drugs for rheumatoid arthritis, such as methotrexate, meglumine acetate sulfate, gold thioglucoside, and disodium aurothioate; (13) drugs for osteoporosis such as alendronate and raloxifene; decongestants such as pseudoephedrine and phenylpropanolamine; (14) a local anesthetic; (15) anti-herpes drugs such as acyclovir, famciclovir and famciclovir; (16) antiemetics, such as ondansetron and gresulfuron; (17) migraine drugs, such as triptans (e.g., rizatriptan, sulfomotriptan), ergotamine, dihydroergotamine, CGRP antagonists, antidepressant drugs (e.g., tricyclic antidepressants, 5-hydroxytryptamine selective reuptake inhibitors, beta-adrenergic blockers); (18) a VR1 antagonist; (19) anticonvulsants (e.g., gabapentin, pregabalin, lamotrigine, topiramate, carbamazepine, oxcarbazepine, phenytoin); (20) glutamate antagonists (e.g., ketamine and other NMDA antagonists, NR2B antagonists); (21) acetaminophen; (22) CCR2 antagonists; (23) a PDE4 antagonist.

Biological evaluation

Assessing the affinity of selected compounds for binding to bradykinin B1 or B2 receptors

Radioligand binding assays were performed using membranes obtained from CHO cells stably expressing the human, rabbit, rat or dog B1 receptor or CHO cells expressing the human B2 receptor. For all receptor types, cells were harvested from culture flasks in PBS/1mM EDTA and centrifuged at 1000Xg for 10 minutes. The cell pellet was homogenized with polytron in ice-cold 20mM HEPES, 1mM EDTA, pH 7.4 (lysis buffer) and centrifuged at 20,000Xg for 20 minutes. The membrane pellet was re-homogenized in lysis buffer, centrifuged again at 20,000Xg, and the final pellet was resuspended at 5mg protein/ml in assay buffer (120mM NaCl, 5mM KCl, 20mM HEPES, pH 7.4) supplemented with 1% BSA and frozen at-80 ℃.

On the day of the assay, the membranes were centrifuged at 14,000Xg for 5 minutes and resuspended to the desired protein concentration in assay buffer containing 100nM enaliprilat, 140. mu.g/mL bacitracin and 0.1% BSA. 3H-des-arg10, leu9 pancreatic kinins are radioligands for the human and rabbit B1 receptor, 3H-des-arg10 pancreatic kinins for the rat and dog B1 receptor, 3H-bradykinin for the labeling of the human B2 receptor.

For all experiments, compounds were diluted from DMSO stock solutions by adding 4 μ Ι into the tube to reach a final DMSO concentration of 2%. Then 100. mu.L of radioligand and 100. mu.L of membrane suspension were added. Nonspecific binding for the B1 receptor binding assay was determined using 1 μ M des-arg10 kallidin and 1 μ M bradykinin for the B2 receptor. The tubes were incubated at room temperature (22 ℃) for 60 minutes and then filtered using a Tomtec 96 well harvest system. The radioactivity remaining on the filter was measured using a Wallac Beta plate scintillation counter.

The affinity of the compounds of the invention for the B1 receptor in the above assay was confirmed by results of less than 5 μ M. Suitably the assay results are less than 1. mu.M, more suitably the results are less than 0.5. mu.M. Advantageously, the compounds of the invention have a greater affinity for the bradykinin B1 receptor than for the bradykinin B2 receptor; more preferably, the affinity for the B1 receptor is at least 10 times greater than the affinity for the B2 receptor, preferably greater than 100 times greater than the affinity for the B2 receptor.

Testing of bradykinin B1 antagonists

Calcium mobilization by B1 agonists was monitored using a fluorescence imaging plate reader (FLIPR). CHO cells expressing the B1 receptor were plated in 96 or 384 well plates and allowed to culture overnight in Iscove's modified DMEM. The wells were washed 2 times with physiological buffered saline and then incubated with 4uMFluo-3 at 37 ℃ for 1 hour. The plate was then washed 2 times with buffered saline solution and 100uL of buffer was added to each well. The plate was placed in a FLIPR unit and allowed to equilibrate for 2 minutes. Subsequently 50ul volume of test compound was added and after 5 minutes 50ul of agonist (des-arg) was added¹⁰Pancreatic kinin). The degree of inhibition of the test compound on the B1 receptor agonist response was calculated using the relative fluorescence peak heights in the absence and presence of the antagonist. Typically, 8-10 concentrations of test compound are evaluated to construct an inhibition curve, and IC50 values are determined using a four parameter non-linear regression curve fitting method.

Testing of bradykinin inverse agonists

Inverse agonist activity of the human B1 receptor was assessed using transiently transfected HEK293 cells. On the day after transfection, the cell flask was filled with 6uCi/ml³H]myo-inositol labeling was performed overnight. On the day of the experiment, the medium was removed and the attached cells were gently rinsed with 2X 20ml of phosphate buffered saline. Add assay buffer (HEPES buffered saline)pH 7.4) were added to the flask to separate the cells by tapping the flask. The cells were centrifuged at 800Xg for 5 minutes at 1X 10⁶The individual cells/ml were resuspended in assay buffer supplemented with 10mM lithium chloride. After 10 minutes at room temperature, half ml aliquots were dispensed into tubes containing the test compounds or carriers. After an additional 10 minutes, the tubes were transferred to a 37 ℃ water bath for 30 minutes. The culture was stopped by adding 12% perchloric acid solution, and the tube was placed on ice for 30 minutes. The acid was then neutralized with KOH, and the tube was centrifuged to precipitate the material. Formed monophosphate [ alpha ]³H]Inositol was recovered by standard ion exchange chromatography techniques and quantified by liquid scintillation counting. The inverse agonist activity is a decrease in monophosphate [ alpha ]³H]The extent of basal (cell culture with vector) levels of inositol accumulation.

NSE_hB₁Ex vivo receptor occupancy assay in transgenic rats

Transgenic rats of both sexes were placed in induction cages and anesthetized with isoflurane under a FlowSciences hood. Once anesthetized, rats were placed in a circulating water heated basket (GaymarT-pump) and maintained anesthesia by nose cone with 2% isoflurane. The tail vein was cannulated with a 25G high speed maceration device connected to a syringe containing the test compound or carrier. The desired dose of test compound is administered. Blood samples were taken at the end of the experiment, rats were sacrificed and tissues (usually brain and spine) were removed for later testing.

For autoradiographic analysis of human B1 receptor expression, tissues removed from transgenic rats were frozen in dry ice powder and stored at-70 ℃. Coronal sections and transverse sections of the spine were prepared using a cryostat (Leica, CM3050) at 20TM, respectively. The frozen sections were stored at-70 ℃. For analysis, the frozen sections were heated at Room Temperature (RT) for 15 minutes and pre-incubated in a buffer without radioligand at room temperature for 15 minutes. After pre-incubation, the sections were transferred into culture buffer and incubated for 90 minutes at RT. Total binding, non-specific and specific, was achieved by binding in a solution containing 0.3nM [ H-3 ]]And DALK was cultured in buffer.Adjacent sections were used to determine non-specific binding in the presence of 0.3nM [ H-3 ]]DALK and 200nM in buffer of a non-peptide receptor antagonist with high affinity and specificity for the human B1 bradykinin receptor. After 90 minutes of incubation, the sections were washed 3 times in buffer for 3 minutes each in DIH₂Rinsed in O at 4 ℃ for 30 seconds and then dried with a blower at RT. Sections were placed on fuji imaging plates and exposed for 1 week at RT. The plates were scanned with fujiphoshor imager BAS 5000 and the images were analyzed with MCID M5 software.

For the homogenate-based binding assay, 35mg of frozen brain (cerebral cortex or cerebellum) or spine was homogenized with Polytron in a large volume of ice-cold assay buffer (20mM HEPES, 120mM NaCl, 5mM KCl, pH 7.4) and transferred into two refrigerated centrifuge tubes. To precipitate the membrane, the tube was centrifuged at 75,000Xg for 10 minutes in a drum pre-cooled to 4 ℃. The supernatant was discarded and each tube was rinsed with 20ml of ice-cold buffer, followed by homogenization of the above pellet in ice-cold assay buffer. Mixing the homogenates, adding to a mixture containing a radiotracer and 20pM³⁵S-labeled non-peptide human B₁The tubes for the receptor antagonist contained 0.5ml of room temperature assay buffer in each tube. Non-specific binding was achieved by adding homogenate to human B containing radiotracer and 100nM unlabeled non-peptide₁Receptor antagonists in-tube. At the set time points (1, 2, 4, 6, 8, 10 minutes), the contents of the three tubes were each filtered through a 25mm GF/B filter, which was pre-impregnated with 0.05% Triton X-100. The filtration step was performed by adding 4ml of ice-cold test buffer to each of three equal sample tubes, pouring the contents onto the filters, and washing each filter 2 times with 4ml of ice-cold buffer. Filtration was carried out using a Hoefer FH 225V filtration header. Non-specific binding tubes were similarly filtered after completion of 6 time points. The filters were transferred to 5ml scintillation vials and counted after 10 hours immersion in 3ml Beckman Ready Safe scintillation fluid.

Specific binding (total cpm-non-specific cpm) was calculated for each time point and the slope of association was determined by linear regression. Receptor occupancy in drug-treated animals was determined by the following formula:

% occupancy ═ 1- (slope)_MedicineSlope of_Carrier))×100

Slope of_MedicineIs the slope of the association rate line for drug treated animals;

slope of_CarrierIs the slope measured for the carrier treated animals.

Expression of human bradykinin B₁Transgenic rats for receptors are disclosed in PCT application publication WO 03/016495.

Abbreviations used

Unless otherwise indicated, the following abbreviations have the meaning indicated in the specification: boc (boc) tert-butyloxycarbonyl; DCM ═ dichloromethane; DMF ═ dimethylformamide; DMSO ═ dimethyl sulfoxide; EDC or EDCI ═ 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide HCl; eq. ═ equivalent; ES (or ESI) -MS ═ electron spray ionization-mass spectrometry; et ═ ethyl; EtOAc ═ ethyl acetate; EtOH ═ ethanol; FAB-MS is fast atom bombardment-mass spectrometry; HOAT ═ 1-hydroxy-7-azabenzotriazole; HOBt ═ 1-hydroxybenzotriazole hydrate; HPLC ═ high pressure liquid chromatography; LCMS ═ liquid chromatography/mass spectrometry; LHMDS ═ lithium bis (trimethylsilyl) amide; me ═ methyl; MeOH ═ methanol; MHz-MHz; NEt₃Triethylamine; NMR ═ nuclear magnetic resonance; ph ═ phenyl; TFA ═ trifluoroacetic acid; THF ═ tetrahydrofuran;

the compounds of formula I can be prepared according to the following exemplified routes. In scheme 1, the biphenyl derivative (3) is synthesized using a Suzuki reaction between an aromatic boronic acid derivative (1) or an appropriate boronic ester derivative and an aromatic halide (2) in the presence of a triarylphosphine such as triphenylphosphine and a metal catalyst such as palladium acetate. The resulting cyanobiphenyl intermediate (3) is then catalytically reduced to the benzylamine derivative (4) with hydrogen and a metal such as raney nickel in a suitable solvent. The amine derivative (4) is then coupled with an acid (5) in a suitable solvent such as THF using a standard peptide coupling reagent combination such as EDCI/HOBt to give (6). The Boc protecting group is thereafter removed under the action of an acid such as HCl in a suitable solvent such as MeOH to give the ammonium salt, from which the free base derivative (7) can then be obtained using a suitable base such as ammonia and a suitable solvent such as chloroform. This amine derivative (7) is then reacted with a carboxylic acid or carboxylic acid equivalent to give the title compound (Ia). Alternatively, the acid-salt of (7) may be used in the final reaction to give the title compound (Ia) with the proviso that an appropriate base, such as triethylamine, is added.

Route 1

And

route 1 (continuation)

Alternatively, as exemplified in scheme 2, after protection of the primary amine with an appropriate protecting group such as Boc, the benzylamine derivative (8) is treated with a palladium catalyst in an appropriate solvent such as dimethyl sulfoxide to afford the pinacolboronic ester (10). The boron ester (10) is coupled with the aryl halide derivative (2) by adopting Suzuki reaction conditions to obtain (11). Biphenyl (11) was reacted with cyclopropylcarboxylic acid (5) to give compound (12) via standard procedures for Boc removal and peptide coupling. Subsequent removal of the N-terminal Boc group with hydrogen chloride and reaction of the amine hydrochloride with a carboxylic acid or carboxylic acid equivalent in the presence of a suitable base such as triethylamine affords the title compound (Ib).

Route 2

Route 2 (continuation)

Alternatively, as illustrated in scheme 3, the N-Boc protected compound (12) prepared according to scheme 2 is deprotected with a strong acid such as HC1 and the resulting salt is converted to the corresponding free base with aqueous ammonia in a suitable solvent such as chloroform to give the amine (15). The amine is then treated with an excess of alkyl iodide (I-R)¹) Alkylation in a suitable solvent such as THF in the presence of an acid scavenger such as triethylamine at elevated temperatures gives (16), as well as the di-alkylated species. The secondary amine (16) is then converted to the title compound by reaction with a carboxylic acid or carboxylic acid equivalent to afford (Ie).

Route 3

Alternatively, di-tert-butyl malonate can be made into the derivative (17) according to known methods (K.Burgess et al, J.org.chem., 57: 5931-. The N-Boc group was substituted with methanesulfonic acid according to L.S.Lin et al Tetrahedron Lett., 41: 7013-7016(2000) to give the amine (18). Reacting the amine with a carboxylic acid or carboxylic acid equivalent under suitable peptide coupling conditions to form (19). The tert-butyl ester is then cleaved with an acid such as TFA in an appropriate solvent such as DCM to afford the acid (20). Benzylamine (11a) prepared according to scheme 2 is then coupled with acid (20) using an appropriate series of peptide coupling reagents such as EDCI/HOBt to yield the title compound (If). (If) further reaction to give further compounds of formula I may be carried out using methods well known to those skilled in the art. For example, the acetyl group can be removed by hydrolysis to give the corresponding alcohol; the alcohol may be converted to the corresponding sulfonate ester by treatment with a sulfonyl chloride, which sulfonate ester may be converted to the corresponding halide by treatment with a halide source. The transformation of these and other functions to give compounds of formula I is disclosed in typical organic chemistry textbooks, such as March's higher organic chemistry: reactions, Mechanisms, and Structure, 5^th Ed.，John Wiley&Sons，2000。

Route 4

Alternatively, di-tert-butyl malonate can be reacted to the derivative (21) according to known methods (K.Burgess et al, J.org.chem., 57: 5931- & 5936(1992)), as illustrated in scheme 5. The N-Boc group is removed with an acid such as TFA in a suitable solvent such as DCM. Reacting the amine with a carboxylic acid or carboxylic acid equivalent under suitable peptide coupling conditions such as EDCI/HOBt/NEt₃The next reaction produces (22). Benzylamine (11a) prepared according to scheme 2 followed by opening of lactone (22) in a suitable aprotic solvent such as DMF at a temperature of 20-100 ℃ gives the title compound (Ig). Further reactions to produce other title compounds (Ig) can be accomplished using methods well known to those skilled in the art as described above.

Route 5

Reference example 1: preparation of (1R) -1- (3, 3 ' -difluoro-2 ' -hydroxy-1, 1 ' -biphenyl-4-yl) ethylammonium (ethanaminium) bromide. To (1R) -1- (4-bromo-2-fluorophenyl) ethanaminium chloride (14.24g, 55.95mmol) in CH at 0 deg.C₂Cl₂To a solution in (300mL) was added di (tert-butyl) dicarbonate (17.98g, 82.40mmol) and triethylamine (8.256g, 81.58 mmol). The solution was washed with water and brine, washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave (1R) -tert-butyl 1- (4-bromo-2-fluorophenyl) ethylcarbamate as a white solid, giving a proton NMR spectrum consistent with theory.

The above compound (26.42g, 83.03mmol), bis (pinacolato) diboron (31.63g, 0.1246mol), potassium acetate (24.45g, 0.2491mol) and [1, 1' -bis (diphenylphosphino) -ferrocene]A mixture of palladium (II) dichloride (0.265g, 0.362mmol) in 80mL DMSO at 90 deg.C and N₂The mixture was heated for 3 hours. After which the mixture is cooled to room temperature and cooled atPartitioned between ethyl acetate and water. The organic extract was washed with water and brine, and Na₂SO₄Dried, filtered under reduced pressure and concentrated. The residue was subjected to silica gel chromatography and eluted with 0 to 10% ethyl acetate in hexane to give (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Tert-butyl ethyl carbamate, which is a beige solid, gives a proton NMR spectrum consistent with theory.

The above compound (7.00g, 19.164mmol), tris (dibenzylideneacetone) -dipalladium (0) (1.755g, 1.916mmol), tricyclohexylphosphine (1.344g, 4.791mmol) and cesium carbonate (7.493g, 22.997mmol) were charged to an oven dried flask under argon. To this was added dioxane (50mL) and then 1-bromo-3-fluoro-2-methoxybenzene (4.912g, 23.956 mmol). The suspension was heated at 85 ℃ for 12 hours. The reaction was filtered through celite and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography eluting with 10% ethyl acetate in hexane to give tert-butyl (1R) -1- (3, 3 ' -difluoro-2 ' -methoxy-1, 1 ' -biphenyl-4-yl) ethylcarbamate. Low resolution mass spectrum: (M + H)⁺)＝364.2。

The above compound (5.75g, 15.822mmol) was dissolved in CH₂Cl₂And cooled to-78 ℃. Adding boron tribromide to the solution to form a solution in CH₂Cl₂1M solution (31.645mL, 31.645mmol) and then allowed to rise to 25 ℃. After 16 h, the reaction was again cooled to-78 ℃ and quenched with methanol (500mL) and concentrated under reduced pressure to give the title compound. Low resolution mass spectrum: (M + H)⁺-NH₃)＝233.2。

Reference example 2: 1- [ (trifluoroacetyl) amino group]Preparation of cyclopropane carboxylic acid. 1-Carboxypropyleneammonium chloride (0.980g, 7.124mmol) was suspended in methanol (14mL), followed by triethylamine (1.514g, 14.960 mmol). Ethyl trifluoroacetate (1.113g, 7.836mmol) was added to the suspension and stirred at 25 ℃. After 16 h, the reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered under reduced pressure and concentrated to give the title compoundMaterial, which is a white solid.¹H NMR(400MHz，(CD₃)₂SO)δ12.76(s，1H)，9.94(s，1H)，1.38-1.44(m，2H)，1.08-1.14(m，2H)。

Reference example 3: 1- [ (pyrimidin-5-ylcarbonyl) amino]Preparation of cyclopropanecarboxylic acid compound with lithium chloride (1: 1). Triethylamine (7.026g, 69.44mmol) was added to 1- (ethoxycarbonyl) cyclopropaneammonium chloride (11.50g, 69.44mmol), pyrimidine-5-carboxylic acid (8.617g, 69.44mmol), EDC (13.312g, 69.44mmol) and HOAT (0.945g, 69.44mmol) in CH₂Cl₂(125mL) and stirred for 16 hours. The reaction was adsorbed on silica and purified by chromatography on silica gel eluting with ethyl acetate to give ethyl 1- [ (pyrimidin-5-ylcarbonyl) amino]Cyclopropane carboxy esters, which are white solids low resolution mass spectra: (M + H)⁺)＝236.2。

To in CH₃The above compound (13.50g, 57.39mmol) in CN/MeOH (1: 1, 200mL) was added to a 1N lithium hydroxide solution (60mL, 60mmol) and stirred for 16 h. The reaction was quenched by the addition of 1N hydrochloric acid (60mL, 60mmol) and concentrated under reduced pressure while heating to give the title compound as white. Low resolution mass spectrum: (M + H)⁺)＝208.1。

The following examples are provided to illustrate the invention, but the invention is not limited to the details of these examples. The compounds are named as follows: ACD/Name version 4.53(advanced chemistry Development Inc. * 1994-2000). Address: 90 Adelaide street West, Toronto, Ontario, M5H 3V9, Canada.

Example 1

3, 3 '-difluoro-4' - { [ ({1- [ (pyrimidin-5-ylcarbonyl) amino ] cyclopropyl } carbonyl) amino ] methyl } -

1, 1' -Biphenyl-2-yl triflate

Triethylamine (1.036g, 10.24mmol) was added to the compound of reference example 3 (2.556g, 10.24mmol), (4-bromo-2-fluorophenyl) methylammonium chloride (2.463g, 10.24mmol), EDC (1.963g, 10.24mmol) and HOAT (0.418g, 3.072mmol) in CH₂Cl₂(25mL) in a stirred solution. After 1 hour, the reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over sodium sulfate, filtered under reduced pressure and concentrated to give a yellow solid. The solid was purified by silica gel chromatography using 5% methanol/CH₂Cl₂Elution gave N- (1- { [ (4-bromo-2-fluorobenzyl) amino]Carbonyl } cyclopropyl) pyrimidine-5-carboxamide, which is a white solid. Low resolution MS: (M + H)⁺)＝393.03。

The above compound (0.050g, 0.127mmol), bis (pinacolato) diboron (0.039g, 0.153mmol), dichloro [1, 1' -bis (diphenylphosphino) ferrocene were added under argon]Palladium (II) dichloromethane adduct (0.009g, 0.013mmol) and potassium acetate were combined in an oven dried flask. DMSO (1mL) was added to the solids and the reaction was heated at 90 ℃. After 2 hours, the reaction was diluted with ethyl acetate, washed with water (3 ×), washed with brine (1 ×), washed with water (1 ×), dried over sodium sulfate, filtered under reduced pressure and concentrated to a solid. The solid was purified by chromatography on silica gel with 7% methanol/CH₂Cl₂Eluting to obtain N- [1- ({ [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl]Amino } carbonyl) cyclopropyl]Pyrimidine-5-carboxamide, which is a solid. Low resolution mass spectrum: (M + H)⁺)＝441.2。

The above compound (1.200g, 2.73mmol), tetrakis (triphenylphosphine) palladium (0) (0.315g, 0.273mmol) and potassium phosphate (0.382g, 1.80mmol) were mixed in an oven dried tube under argon. To these solids was added 1-bromo-3-fluoro-2-methoxybenzene (1.118g, 545 mmol). It was suspended in DMSO (20mL) and heated to 110 ℃. After 16 h, the reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water (3 ×), dried over sodium sulfate and concentrated to an oil. The oil was purified by silica gel chromatographyWith 5% methanol/CH₂Cl₂Eluting to obtain N- [1- ({ [ (3, 3 ' -difluoro-2 ' -methoxy-1, 1 ' -biphenyl-4-yl) methyl]Amino } -carbonyl) cyclopropyl]Pyrimidine-5-carboxamide, which is a solid. Low resolution MS: (M + H)⁺)＝439.2。

To the above compound (0.575g, 1.311mmol) in CH₂Cl₂(2mL) to a solution at-78 deg.C, boron tribromide in CH₂Cl₂(1.971g, 7.87mmol) and allowed to warm to room temperature. After 48 hours, the reaction was cooled to 0 ℃, quenched with methanol, and concentrated under reduced pressure to give a solid. The solid was purified by reverse phase chromatography using 95/5H₂O/CH₃CN-5/95H₂O/CH₃A gradient of CN was purified. The product was lyophilized to give N- [1- ({ [ (3, 3 ' -difluoro-2 ' -hydroxy-1, 1 ' -biphenyl-4-yl) methyl]Amino } carbonyl) cyclopropyl]Pyrimidine-5-carboxamide, which is a solid. Low resolution mass spectrum: (M + H)⁺)＝425.2。

To the above compound (0.090g, 0.212mmol) and triethylamine (0.164g, 1.272mmol) in CH₂Cl₂(2mL) Trifluoromethanesulfonic anhydride (0.120g, 0.424mmol) was added to a stirred solution at-78 ℃. It was allowed to warm to room temperature. After 2 hours the reaction was completed with CH₂Cl₂Diluting and pouring into water. The organic extract was separated, dried over sodium sulfate, filtered under reduced pressure and concentrated to give the title compound as a solid. Low resolution MS: (M + H)⁺)＝557.1。

Example 2

3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethane

1, 1' -Biphenyl-2-yl trifluoromethanesulfonate radical

The compound of reference example 1 (0.838g, 2.537mmol), 1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxylic acid (0.500g, 2.537mmol), EDC (0.486g, 2.537mmol) and HOAT (0.345g, 2.537mmol) were combined. To which CH was added in a ratio of 1: 1₃CN/CH₂Cl₂(25mL) followed by triethylamine (0.257g, 2.537 mmol). After 16 h, the reaction was concentrated in vacuo to give a solid. It was purified by chromatography on silica gel with 7% methanol/CH₂Cl₂Eluting and separating out N- [ (1R) -1- (3, 3 ' -difluoro-2 ' -hydroxy-1, 1 ' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide. High resolution mass spectrometry: c₂₀H₁₇F₅N₂Theoretical value of O3: 429.1232, found: 429.1187.

the above compound (0.100g, 0.233mmol) and triethylamine (0.060g, 0.466mmol) were dissolved in CH₂Cl₂(2mL) and cooled to-78C. To this solution was added trifluoromethanesulfonic anhydride (0.072g, 0.257 mmol). After 30 minutes, the reaction was quenched with saturated bicarbonate solution and warmed to 25 ℃. By CH₂Cl₂Extracting with Na₂SO₄The extract was dried, filtered under reduced pressure and concentrated to give a solid. The solid was purified by silica gel chromatography using 5% methanol/CH₂Cl₂Elution afforded the title compound. High resolution mass spectrometry: c₂₁H₁₆F₈N₂O₅Theoretical value of S: 561.0725, found: 561.0729.¹H NMR(400MHz，(CD₃)₂SO)δ9.80(s，1H)，8.30(d，J＝7.4Hz，1H)，7.58-7.68(m，2H)，7.44-7.55(m，2H)，7.32-7.42(m，2H)，5.24(qn，J＝7.4Hz，1H)，1.41(d，J＝7.4Hz，3H)，1.30-1.38(m，2H)，0.92-1.08(m，2H)

example 3

3, 3 '-difluoro-4' - ((1R) -1- { [ (1- { [ (trifluoromethyl) sulfonyl ] amino } cyclopropyl) carbonyl ] amino

Ethyl-1, 1' -biphenyl-2-yl trifluoromethanesulfonate

Reacting N- [ (1R) -1- (3, 3 ' -difluoro-2 ' -hydroxy-1, 1 ' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) amino group]-Cyclopropanecarboxamide (1.930g, 4.51mmol) and triethylamine (2.912g, 22.53mmol) were dissolved in CH₂Cl₂(20mL) and cooled to-78C. To the solution was added trifluoromethanesulfonic anhydride (2.225g, 7.885 mmol). After 30 minutes, the reaction was quenched with saturated bicarbonate solution and heated at 25 ℃. By CH₂Cl₂Extracting with Na₂SO₄The extract was dried, filtered under reduced pressure and concentrated to give a solid. The solid was suspended in 6N hydrochloric acid (10mL) and heated to 90 ℃. After 1.5 hours the reaction was poured into saturated aqueous bicarbonate solution and subsequently extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered under reduced pressure and concentrated to give a solid. The solid was then chromatographed on reverse phase using 95/5H₂O/CH₃CN-5/95H₂O/CH₃A gradient of CN was purified. The product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: c₂₀H₁₆F₈N₂O₆S₂Theoretical value: 597.0395, found: 597.0392.¹HNMR(400MHz，(CD₃)₂SO)δ10.10(s，1H)，7.81(d，J＝7.3Hz，1H)，7.58-7.68(m，2H)，7.40-7.52(m，2H)，7.33-7.43(m，2H)，5.21(qn，J＝7.3Hz，1H)，1.44-1.49(m，2H)，1.41(d，J＝7.3Hz，3H)，1.17-1.24(m，2H)。

example 4

1, 1' -Biphenyl-2-yl methanesulfonate

Reacting N- [ (1R) -1- (3, 3 ' -difluoro-2 ' -hydroxy-1, 1 ' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) -amino]Cyclopropanecarboxamide (0.040g, -0.093mmol) and triethylamine (0.019g, 0.187mmol) were dissolved in CH₂Cl₂(2mL) and cooled to-78 ℃. To the solution was added methanesulfonylchloride (0.012g, 0.103mmol) and the reaction was stirred for 16 hours. The reaction was concentrated under reduced pressure, diluted with methanol and chromatographed on reverse phase using 95/5H₂O/CH₃CN-5/95 H₂O/CH₃A gradient of CN was purified. The product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: c₂₁H₁₉F₅N₂O₅Theoretical value of S: 507.1076, found: 507.1002.¹H NMR(400MHz，(CD₃)₂SO)δ9.79(s，1H)，8.30(d，J＝7.5Hz，1H)，7.44-7.54(m，3H)，7.30-7.39(m，3H)，5.23(qn，J＝7.5Hz，1H)，2.99(s，1H)，1.42(d，J＝7.5Hz，3H)，1.32-1.38(m，2H)，0.92-1.06(m，2H)。

example 5

5-chloro-3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino

Yl ] ethyl } -1, 1' -biphenyl-2-yl trifluoromethanesulfonate

To N- [ (1R) -1- (3, 3 ' -difluoro-2 ' -hydroxy-1, 1 ' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) amino group]To a solution of cyclopropanecarboxamide (125mg, 0.292mmol) in acetic acid (1ml) was added N-chlorosuccinimide (39mg, 0.292mmol) and the solution was heated to 90 ℃ for 2 hours. Thereafter, the mixture was evacuatedConcentrating, purifying by column chromatography with 0-10% EtOAc/CH₂Cl₂To obtain N- [ (1R) -1- (5 '-chloro-3, 3' -difluoro-2 '-hydroxy-1, 1' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide. Low resolution mass spectrum: (M + H)⁺)＝462.9。¹H NMR(400MHz，CDCl₃) δ 7.26-7.34(m, 3H), 7.12(dd, 1H, J ═ 9.9 and 2.4Hz), 7.08(s, 1H), 6.98(s, 1H), 6.59(d, 1H, J ═ 8.6Hz), 5.38-5.51(br, 1H), 5.23(quin, 1H, J ═ 7.2Hz), 1.55-1.70(m, 2H), 1.52(d, 3H, 7.2Hz), and 1.08-1.21(m, 2H) ppm.

In a similar manner to example 2, N- [ (1R) -1- (5 '-chloro-3, 3' -difluoro-2 '-hydroxy-1, 1' -biphenyl-4-yl) ethyl is used]-1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide to give the title compound as a solid. High resolution mass spectrometry:¹H NMR(400MHz，CD₃CN) δ 8.10(brs, 1H), 7.52(dd, 1H, J ═ 2.5 and 9.7Hz), 7.46(dd, 1H, J ═ 5 and 9.7Hz), 7.46(s, 1H), 7.31(dd, 1H, J ═ 1.7 and 8.0Hz), 7.26(dd, 1H, J ═ 1.7 and 11.3Hz), 7.18(d, 1H, J ═ 9.2Hz), 5.26(quin, 1H, J ═ 7.0Hz), 1.46(d, 3H, J ═ 7.0Hz), 1.34-1.45(m, 2H) and 1.01-1.16(m, 2H) ppm.

The following compounds were prepared in a similar manner to that described in example 4.

Examples	R⁸(reagent)	The name of the compound; MS;¹H NMR(400MHz，(CD₃)₂SO)
Examples	R⁸(reagent)	The name of the compound; MS;¹H NMR(400MHz，(CD₃)₂SO)	6	ethyl (ethanesulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-yl ethanesulfonate. HRMS521.1161 δ 10.12(s, 0.28H), 9.79(s, 0.72H), 8.96(s, 0.28H), 8.30(d, J ═ 7Hz, 0.72H)7.43-7.54(m, 3H), 7.26-7.37(m, 3H), 5.14-5.26(m, 1H), 2.96-3.08(m2H), 1.42(d, J ═ 7Hz, 3H), 1.20-1.38(m, 2H), 0.84-1.10(m, 5H)
7	N-propyl (propanesulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-yl propane-1-sulfonate. HRMS 535.1299	6	ethyl (ethanesulfonyl chloride)

Examples	R⁸(reagent)	The name of the compound; MS;¹H NMR(400MHz，(CD₃)₂SO)
Examples	R⁸(reagent)	The name of the compound; MS;¹H NMR(400MHz，(CD₃)₂SO)			δ10.14(s，0.23H)，9.80(s，0.77H)，8.98(s，0.24H)，8.32(d，J＝7.8Hz，0.76H)，7.45-7.55(m，3H)，7.27-7.38(m，3H)，5.16-5.30(m，1H)，2.90-3.02(m，2H)，1.48-1.60(m，2H)，1.22-1.46(m，5H)，0.88-1.08(m，2H)，0.74-0.82(m，3H)
8	isopropyl (propane-2-sulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-yl propane-2-sulfonate. HRMS 535.1307 δ 10.13(s, 0.13H), 9.79(s, 0.87H), 8.96(s, 0.14H), 8.31(d, J ═ 7.5Hz, 0.86H), 7.40-7.56(m, 3H), 7.24-7.36(m, 3H), 5.21(qn, J ═ 7.5Hz, 1H), 2.90-3.00(sp, J ═ 6.7Hz, 1H), 1.41(d, J ═ 7.5Hz, 3H), 1.30-1.70(m, 2H)1.15(d, J ═ 6.7Hz, 6H), 0.90-1.08(m, 2H)
8	isopropyl (propane-2-sulfonyl chloride)		9	Phenyl (benzenesulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-yl benzene sulfonate. HRMS 569.1140 δ 10.16(s, 0.37H), 9.83(s, 0.63H), 9.00(s, 0.38H), 8.29(d,J＝8.2Hz，0.62H)，7.60-7.66(m，1H)，7.42-7.48(m，2H)，7.34-7.40(m，4H)，7.20-7.30(m，2H)，6.94-7.02(m，1H)，6.78-6.84(m，1H)，5.10-5.22(m，1H)，1.28-1.48(m，5H)，0.90-1.12(m，2H).
10	benzyl (phenylmethanesulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-ylphenylmethane sulfonate. HRMS 583.1299 δ 10.11(s, 0.23H), 9.78(s, 0.77H), 8.95(s, 0.24H), 8.30(d, J ═ 8.0Hz, 0.76H), 7.44-7.54(m, 3H), 7.34-7.40(m, 4H), 7.28-7.34(m, 4H), 5.14-5.26(m, 1H), 4.44-4.54(m, 2H), 1.35-1.42(m, 3H), 1.14-1.34(m, 2H), 0.80-1.08(m, 2H)	9	Phenyl (benzenesulfonyl chloride)
10	benzyl (phenylmethanesulfonyl chloride)		11	-N(CH₃)₂(dimethylaminosulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-yl dimethyl sulfamate. HRMS 536.1260 δ 10.12(s, 0.76H), 9.78(s, 0.24H), 8.96(s, 0.76H), 8.30(d, J ═ 7.2Hz, 0.24H), 7.40-7.55(m, 3H), 7.27-7.38(m, 3H), 5.12-5.24(m, 1H), 2.42-2.48(m, 6H), 1.32-1.44(m, 5H), 0.82-0.98(m, 2H)
12	-CH₂CF₃(2, 2, 2-trifluoro-ethanesulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } -1, 1' -biphenyl-2-yl 2, 2, 2-trifluoroethanesulfonate. LRMS (M + H)⁺)575.1δ9.89(s，1H)，8.32(d，J＝7.2Hz，1H)，7.43-7.52(m，2H)，7.33-7.40(m，1H)，7.21-7.32(m，3H)，5.33(qn，J＝7.2Hz，1H)，4.21(q，J＝9.1Hz，2H)，1.46-1.56(m，5H)，1.02-1.16(m，2H).	11	-N(CH₃)₂(dimethylaminosulfonyl chloride)
12	-CH₂CF₃(2, 2, 2-trifluoro-ethanesulfonyl chloride)		13	4- (acetylamino) -phenyl (4- (acetylamino) -benzenesulfonyl chloride)	3, 3 '-difluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) -amino]Ethyl } biphenyl-2-yl 4-acetylbenzenesulfonate. MH +626.3

Example 14

3-chloro-3 '-fluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethane

1, 1' -Biphenyl-2-yl trifluoromethanesulfonate radical

Tert-butyl (1R) -1- (4-bromo-2-fluorophenyl) ethylcarbamate (10.04g, 31.55mmol) was dissolved in ethyl acetate and treated with hydrogen chloride gas. A white solid precipitated and the suspension was concentrated under reduced pressure to give (1R) -1- (4-bromo-2-fluorophenyl) -ethanaminium chloride as a white solid, which was used without further purification. Low resolution mass spectrum: (M + H)⁺-NH₃)＝201.1。

(1R) -1- (4-bromo-2-fluorophenyl) ethanaminium chloride (16.50g, 64.83mmol), 1- [ (trifluoroacetyl) amino]Cyclopropanecarboxylic acid (12.78g, 64.83mmol), EDC (12.43g, 64.83mmol) and HOAT (4.41g, 32.41mmol) were dissolved in dimethylformamide (100 mL). To the solution was added triethylamine (6.56g, 64.83 mmol). After 6 hours, the reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over sodium sulfate, filtered under reduced pressure and concentrated to a solid. The solid was purified by silica gel chromatography using 5% methanol/CH₂Cl₂Elution gave N- [ (1R) -1- (4-bromo-2-fluorophenyl) -ethyl]-1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide, which is a white solid. Low resolution mass spectrum: (M + H)⁺)＝399.0。

The above-mentioned compound (6.0g, 15.11mmol), bis (pinacolato) diboron (4.60g, 18.13mmol), potassium acetate (4.45g, 45.32mol) and [1, 1' -bis (diphenylphosphino) ferrocene]Mixture of palladium (II) dichloride (1.234g, 1.511mmol) in DMSO (30ml) at 90 ℃ and N₂The mixture was heated for 1 hour. The mixture was then allowed to cool to room temperature and partitioned between ethyl acetate and water. The organic extracts were washed with water and brine, washed with Na₂SO₄Dried, filtered under reduced pressure and concentrated. The residue was purified by chromatography on silica gel with 0-100% EtOAc and CH₂Cl₂Eluting to obtain N- { (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide, which is a brown solid. Low resolution mass spectrum: (M + H)⁺)＝445.1。¹H NMR(400MHz，CDCl₃) Δ 7.53(d, 1H, 7.5Hz), 7.46(d, 1H, 11.5Hz), 7.23(t, 1H, 7.5Hz), 6.90(br s, 1H), 6.61(br d, 1H), 5.20(qn, 1H), 1-53-1.67(m, 2H), 1.48(d, 3H, 7.0Hz) and 1.06-1.18(m, 2H) ppm.

The above compound (2.00g, 4.50mmol) was dissolved in methanol (5 mL). To the solution was added concentrated hydrochloric acid (5 mL). After 3 hours, the reaction was diluted with DMF and purified by reverse phase chromatography using 95/5H₂O/CH₃CN-5/95 H₂O/CH₃Gradient of CN. The product was lyophilized to give 3-fluoro-4- { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]-cyclopropyl } carbonyl) amino]Ethyl } phenylboronic acid, which is a white solid. Low resolution mass spectrum: (M + H)⁺)＝363.1。

Triethylamine (2.87g, 28.36mmol) was added to 3-chlorobenzene-1, 2-diol (1.025g, 7.09mmol) in CH₂Cl₂(20 mL). It was cooled to-78 ℃ and trifluoromethanesulfonic anhydride (4.00g, 14.18mmol) was added and the reaction allowed to warm to room temperature. After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate. By CH₂Cl₂And (4) extracting. The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oil, which was then adsorbed onto silica gel. It was purified by flash chromatography, eluting with 10% ethyl acetate/hexanes, to give 2-chloro-6- { [ (trifluoromethyl) -sulfonyl]Oxy } phenyl triflate, which is an oil.¹H NMR(400MHz，(CD₃)₂SO)δ7.98(d，J＝8.4Hz，1H)，7.90(d，J＝8.4Hz，1H)，7.76(t，J＝8.4Hz，1H)

Under argon, 3-fluoro-4- { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) amino]Ethyl } -phenylboronic acid (0.050g, 0.138mmol), tetrakis (triphenylphosphine) palladium (0) (0.016g, 0.014mmol) and potassium phosphate (0.035g, 0.166mmol) were added to the dry flask. Coupling 2-chloro-6- { [ (trifluoromethyl) sulfonyl]A solution of oxy } phenyl triflate (0.068g, 1.66mmol) in dioxane (0.33M) was added to the solid and heated to 90 ℃. After 3 hours, the reaction was diluted with methanol, filtered and purified by reverse phase chromatography using 95/5H₂O/CH₃CN-5/95 H₂O/CH₃Gradient of CN. The product was lyophilized to yield the title compound as a solid.¹H NMR(400MHz，(CD₃)₂SO)δ9.80(s，1H)，8.31(d，J＝7.5Hz，1H)，7.76-7.83(m，1H)，7.56-7.63(m，2H)，7.50(t，J＝8Hz，1H)，7.38(dd，J＝10.6Hz，J＝1.5Hz，1H)，7.33(dd，J＝8Hz，J＝1.5Hz，1H)，5.23(qn，J＝7.5Hz，1H)，1.41(d，J＝7.5Hz，3H)，1.29-1.39(m，2H)，0.92-1.07(m，2H)。

Example 15

3 '-fluoro-4' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -

2- { [ (trifluoro-methyl) sulfonyl ] oxy } -1, 1' -biphenyl-3-yl trifluoromethanesulfonate

Under argon, 3-fluoro-4- { (1R) -1- [ ({1- [ (trifluoroacetyl) amino group]Cyclopropyl } carbonyl) amino]Ethyl } -phenylboronic acid (0.050g, 0.138mmol), tris (dibenzylideneacetone) dipalladium (0) (0.013g, 0.014mmol) and cesium carbonate (0.054g, 0.166mmol) were charged to the oven dried flask. Coupling 2-chloro-6- { [ (trifluoromethyl) sulfonyl]To this solid was added a solution of oxy } phenyl triflate (0.068g, 1.66mmol) in dioxane (0.33M) and a solution of tri-tert-butylphosphine (0.007g, 0.035mmol) in dioxane (1.65M) and heated at 85 ℃. After 1.5H, the reaction was diluted with methanol, filtered and purified by reverse phase chromatography using 95/5H₂O/CH₃CN-5/95 H₂O/CH₃Gradient of CN. The product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: c₂₂H₁₆F₁₀N₂O₈S₂Theoretical value: 691.0261, found: 691.0275.¹H NMR(400MHz，(CD₃)₂SO)δ9.80(s，1H)，8.32(d，J＝7.4Hz，1H)，7.86-7.92(m，1H)，7.76-7.81(m，2H)，7.53(t，J＝7.9Hz，1H)，7.37(dd，J＝11Hz，J＝1.7Hz，1H)，7.33(dd，J＝7.9Hz，J＝1.7Hz，1H)，5.24(qn，J＝7.4Hz，1H)，1.41(d，J＝7.4Hz，3H)，1.30-1.37(m，2H)，0.92-1.08(m，2H)。

example 16

(1- (3-fluoro-4- { (1R) -1- [ ({1[ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl }

Phenyl) -2-naphthyl trifluoromethanesulfonate

1-bromo-2-naphthol (2.0g, 8.97mmol) was dissolved in THF (20mL) and the solution was cooled to 0 ℃ in an ice bath. NaH was added to it (60% dispersion in mineral oil, 430mg10.8mmol) followed by MeI (1.2mL, 19.6mmol) and a foam precipitation occurred. The reaction mixture was heated to reflux overnight, cooled to room temperature, and water was added dropwise thereto until a bubble precipitated. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine each 1 time, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% -50% EtOAc/hexanes to give 1-bromo-2-methoxynaphthalene as a solid. LC/MS (ES MS, M + H)⁺Measured value: 238) proton NMR (400MHz, CDCl)₃)δ4.04(s，3H)，7.28(d，J＝9Hz，1H)，7.42(t，J＝7Hz，1H)，7.58(t，J＝6.8Hz，1H)，7.8(dd，J＝9Hz，2H)，8.2(d，J＝8.6Hz，1H)

In a sealed tube, N- { (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide (1g, 2.25mmol), 1-bromo-2-methoxynaphthalene (534mg (2.25mmol), cesium carbonate (1.47g 4.5mmol), and bis (tri-tert-butylphosphine) palladium (0) (6mg 0.1mmol) in anhydrous dioxane (4mL) were stirred at 90 deg.C overnight the reaction was cooled to room temperature, diluted with EtOAc, washed 1 time with water and brine each organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with 0% -50% EtOAc/hexane to give N- { (1R) -1- [ 2-fluoro-4- (2-methoxy-1-naphthyl) phenyl]Ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropane-carboxamide LC/MS (ES MS, M + H)⁺Measured value: 475) proton NMR (400MHz, CDCl)₃)δ1.2(m，J＝2.4Hz，2H)，1.58(d，J＝6.8Hz，3H)，1.7(m，J＝2.9Hz，2H)，3.86(s，3H)，5.33(q，J＝7.2Hz，1H)，6.64(d，J＝8.8Hz，1H)，6.84(s，1H)，7.08-7.19(m，3H)，7.34(m，3H)，7.47(m，J＝4.5Hz，1H)，7.81(m，J＝5Hz，1H)，7.9(d，J＝9Hz，1H)。

The above compound (800mg (1.7mmol) was dissolved in DCM (5mL), the solution was cooled to-78 deg.C, BBr3(3.39mL of a 1.0M solution in DCM) was added dropwise, stirring was continued for 16 h the reaction was concentrated under reduced pressure MeOH (5mL) was added, the solvent was removed under vacuum, the residue was purified by silica gel chromatography eluting with 5% -75% EtOAc in hexanes to give N- { (1R) -1- [ 2-fluoro-4- (2-hydroxy-1-naphthyl) phenyl]Ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide. LC/MS (ES MS, M + H)⁺Measured value: 461) proton NMR (400MHz, CDCl)₃)δ1.17(m，2H)，1.58-1.7(m，5H)，5.09(s，1H)，5.33(q，J＝8.1Hz，1H)，6.61(b，1H)，6.88(s，1H)，7.02-7.2(m，2H)，7.3-7.4(m，3H)，7.44-7.48(t，J＝7.7Hz，2H)，7.81(d，J＝9.1Hz，2H)

The above compound (50mg 0.109mmol) was dissolved in 2mL DCM and TEA (0.02mL (.141mmol) was added, the reaction mixture was cooled to-78 deg.C, after addition of triflic anhydride (0.028mL 0.163mmol) for 10 min, the reaction was allowed to warm to room temperature and quenched with saturated sodium bicarbonate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel chromatography eluting with 5% -70% EtOAc/hexanes to give the title compound, LC/MS (ES MS, M + H)⁺Measured value: 593) proton NMR (400MHz, CDCl)₃)δ1.18(m，2H)，1.60(d，J＝6.8Hz，3H)，1.69(m，2H)，5.3(q，J＝7.1Hz，1H)，6.6(b，1H)，6.87(d，J＝11Hz，1H)，7.1-7.2(m，2H)，7.3-7.69(m，5H)，7.96(t，J＝8.5Hz，2H)。

Example 17

N- (1- { [ ((1R) -1- {3, 3 ' -difluoro-2 ' - [ methyl (methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-

Yl } ethyl) amino ] -carbonyl } cyclopropyl) pyrimidine-5-carboxamide

To a solution of 2-bromo-6-fluoroaniline (500mg, 2.631mmol) in pyridine (2ml) was added methanesulfonic anhydride (1.35g, 7.78mmol) and the mixture was heated to 70 ℃ for 3 h. The solution was adjusted to pH 1 with 1.0N HC1 and treated with CH₂Cl₂(2X 40ml) was extracted. The combined organic extracts were washed with 1.0N HCl (20ml), MgSO₄Dried, filtered under vacuum and concentrated to give the disulfonated product. This material was dissolved in methanol (20ml) and treated with 1.0N NaOH (10ml) for 45 min. Thereafter, the solution was acidified with 1.0N HCl (12ml) in CH₂Cl₂(50+25ml) and brine (10 ml). The combined organic extracts were extracted with MgSO₄Dried, filtered under vacuum and concentrated. The residue was purified by column chromatography using 0-100% EtOAc/CH₂Cl₂Gradient elution to obtain N- (2-bromo-6-fluorophenyl) -methanesulfonamide.¹HNMR(400MHz，CDCl₃) δ 7.41-7.47(m, 1H), 7.16(d, 1H, J ═ 12.5Hz), 7.14-7.17(m, 1H), 6.22(br s, 1H) and 3.27(s, 3H) ppm.

To a solution of the above compound (142mg, 0.530mmol) in methanol (2ml) was added 1.0N trimethylsilyldiazomethane (1ml, 1mmol) in hexane and stirred for 3 hours. Thereafter, trimethylsilyldiazomethane (1ml, 1mmol) was added and stirring continued for an additional 24 hours. The resulting solution was concentrated in vacuo and the residue was purified by column chromatography using 25-100% CH₂Cl₂Elution with hexanes gradient gave N- (2-bromo-6-fluorophenyl) -N-methyl-methanesulfonamide. Low resolution mass spectrum: (M + H)⁺)＝282.0。¹H NMR(400MHz，CDCl₃) δ 7.47(d, 1H, J ═ 8.1Hz), 7.11-7.26(m, 2H), 3.26(s, 3H) and 3.12(s, 3H) ppm.

Mixing the above compound (74mg, 0.2)62mmol), tert-butyl (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]A suspension of ethyl carbamate (92mg, 0.262mmol), tris (dibenzylideneacetone) dipalladium (24mg, 0.026mmol), cesium carbonate (85mg, 0.262mmol) and a solution of 1.0M tri-tert-butylphosphine (63 μ l, 0.063mmol) in dioxane (0.5ml) was heated at 85 ℃ for 1 hour. Thereafter, the reaction mixture was washed with EtOAc (5mL) and NH₄Aqueous Cl (1ml) was diluted and filtered through Gelman Acrodisc. The filtrate was partitioned and the aqueous layer was back-extracted with EtOAc (3 mL). The combined organic extracts were extracted with MgSO₄Dried, filtered under vacuum and concentrated. The residue was purified by column chromatography using 0-20% EtOAc/CH₂Cl₂Eluting to obtain {3, 3 '-difluoro-2' - [ methyl (methylsulfonyl) amino group]-1, 1' -biphenyl-4-yl } methyl carbamic acid tert-butyl ester. Low resolution mass spectrum: (M + H)⁺)＝327.17(-Boc)。¹H NMR(400MHz，CDCl₃) δ 7.34-7.44(m, 2H), 7.12-7.24(m, 4H), 4.95(br s, 1H), 4.41(br s, 2H), 3.08(s, 3H), 2.87(s, 3H) and 1.46(s, 9H) ppm.

HC1 gas was bubbled through a cooled solution of the above compound (68mg, 0.159mmol) in EtOAc (2mL) for 2 minutes. The mixture was stirred at 0 ℃ for 10 minutes and then allowed to warm to room temperature. The resulting mixture was concentrated in vacuo to give {3, 3 '-difluoro-2' - [ methyl- (methylsulfonyl) amino group]-1, 1' -biphenyl-4-yl } methylammonium chloride. Low resolution mass spectrum: (M + H)⁺)＝327.17。1HNMR(400MHz，CDCl₃) δ 8.7(br s, 3H), 7.77(t, 1H, J ═ 7.8Hz), 7.33-7.40(m, 1H), 7.24-7.30(m, 1H), 7.12-7.23(m, 3H), 4.31(br s, 2H), 3.05(s, 3H) and 2.88(s, 3H) ppm.

To the above compound (33mg, 0.091mmol), 1- [ (pyrimidin-5-ylcarbonyl) -amino]To a solution of the cyclopropanecarboxylic acid compound with lithium chloride (1: 1) (23mg, 0.091mmol), EDC (17mg, 0.091mmol) and HOAT (12mg, 0.091mmol) was added triethylamine (13. mu.l, 0.091mmol), and the mixture was stirred at room temperature for 3 days. Thereafter, EDC (17mg, 0.091mmol) and triethylamine (13ul, 0.091mmol) were added and stirring was continued for 30 minutes. The mixture was diluted with DMF (0.75ml)And purified on a Gilson LC using a VYDAC C18 column eluting with 5-95% aqueous acetonitrile. Lyophilization of the desired fraction yielded N- (1- { [ ({3, 3 '-difluoro-2' - [ methyl (methyl-sulfonyl) amino)]-1, 1' -biphenyl-4-yl } methyl) amino]Carbonyl } cyclopropyl) pyrimidine-5-carboxamide, which is a white solid. High resolution mass spectrometry: c₂₄H₂₄F₂N₅O₄Theoretical value of S: 516.1512, found: 516.1508.¹H NMR(400MHz，(CD₃)₂SO) δ 9.38(s, 1H), 9.32(s, 1H), 9.21(s, 2H), 8.62(t, 1H, J ═ 5.9Hz), 7.45-7.53(m, 1H), 7.35-7.43(m, 2H), 7.18-7.25(m, 3H), 4.39(d, 2H), J-5.9Hz, 3.04(s, 3H), 2.85(s, 3H), 1.37-1.43(m, 2H) and 1.05-1.09(m, 2H) ppm.

Example 18

N- (1- { [ ({3, 3 ' -difluoro-2 ' - [ (methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-yl } methyl) amino ]

Carbonyl } -cyclopropyl) pyrimidine-5-carboxamides

The title compound was prepared in a similar manner as described in example 17. High resolution mass spectrometry: c₂₃H₂₂F₂N₅O₄Theoretical value of S: 502.1368, found: 502.1363.¹H NMR(400MHz，(CD₃)₂SO) δ 9.37(s, 1H), 9.31(s, 1H), 9.25(s, 1H), 9.21(s, 2H), 8.62(t, 1H, J ═ 5.8Hz), 7.21-7.48(m, 6H), 4.38(d, 2H, 5.8Hz), 2.66(s, 3H), 1.40(q, 2H, 3.4Hz) and 1.07(q, 2H, 3.4Hz) ppm.

Example 19

N- { (1R) -1- [2 '- ({ [4- (acetylamino) phenyl ] sulfonyl } amino) -3, 3' -difluorobiphenyl-

4-yl ] ethyl } -1- [ (trifluoro-acetyl) amino ] cyclopropanecarboxamide

The title compound was prepared in a similar manner as described in example 17. MS (M + H)⁺626.3)

Example 20

N- {1- [ ({ [2 '- (1, 1-dioxo-1, 2-thiazinan) -2-yl) -3, 3' -difluoro-1, 1-

Biphenyl-4-yl ] methyl } amino) carbonyl ] -cyclopropyl } pyrimidine-5-carboxamide

2-bromo-1-fluoro-3-methoxybenzene (200mg, 0.975mmol), 1, 2-thiazinane 1, 1-dioxide (264mg, 1.951mmol), copper (62mg, 0.975mmol) and potassium carbonate (270mg, 1.951mmol) were mixed and heated to 170C for 5 hours. After this time, the mixture was suspended in methanol (15ml) and vortexed for 18 hours. The mixture was filtered through a Gelman Acrodisc and evaporated in vacuo. The resulting residue was washed with EtOAc (2X 10mL) and NH₄Aqueous Cl (5ml) was partitioned between. The combined organic extracts were extracted with MgSO₄Dried, filtered under vacuum and concentrated. The residue was purified by column chromatography using 0-10% EtOAc/CH₂Cl₂Eluting to obtain 2- (2-fluoro-6-methoxyphenyl) -1, 2-thiazine alkane 1, 1-dioxide. Low resolution mass spectrum: (M + H)⁺)＝260.1。¹HNMR(400MHz，CDCl₃) δ 7.21(dt, 1H, J ═ 8.1 and 4.3Hz), 6.69 to 6.77(m, 2H), 3.88(s, 3H), 3.75 to 8.74(m, 1H), 3.65(dq, 1H, J ═ 4.6, 6.0 and 14Hz), 3.24(dd, 2H, J ═ 5.6 and 7.4Hz), 3.27(quin, 2H, J ═ 6.1Hz), 3.69 (quin, 2H, J ═ 6.1Hz), and so onHz) and 1.78-1.90(m, 2H) ppm.

To the above compound (58mg, 0.224mmol) cooled in a dry ice/acetone bath in CH₂Cl₂(1ml) boron tribromide (224ul, 0.224mmol) was added to the solution and stirred at room temperature overnight. Thereafter, the mixture was treated with methanol (3X 5ml) and concentrated in vacuo to give 2- (1, 1-dioxan-1, 2-thiazinan-2-yl) -3-fluorophenol. Low resolution mass spectrum: (M + H)⁺)＝246.16。1HNMR(400MHz，CDCl₃) δ 7.19(dd, 1H, J ═ 8.4 and 15Hz), 6.81(d, 1H, J ═ 8.4Hz), 6.70(t, 1H, 10Hz), 3.82-3.90(m, 1H), 3.60-3.68(m, 1H), 3.34-3.43(m, 1H), 3.26-3.34(m, 1H), 2.34-2.43(m, 2H), 1.94-2.08(m, 1H) and 1.77-1.89(m, 1H) ppm.

To the above compound (58mg, 0.236mmol) cooled in a dry ice/acetone bath in CH₂Cl₂To a solution in (1ml) was added triethylamine (82. mu.l, 0.473mmol) and trifluoromethanesulfonic anhydride (40. mu.l, 0.236mmol) in that order, and the mixture was stirred at-78 ℃ for 10 minutes, followed by warming to room temperature. The solution was saturated NaHCO₃Treating with aqueous solution and CH₂Cl₂(2X 2ml) was extracted. The combined extracts were concentrated in vacuo and purified by column chromatography using 25-100% CH₂Cl₂Gradient elution with hexane afforded 2- (1, 1-dioxan-1, 2-thiazinan-2-yl) -3-fluorophenyl trifluoromethanesulfonate. Low resolution mass spectrum: (M + H)⁺)＝246.16。¹H NMR(400MHz，CDCl₃) δ 7.41(dt, 1H, J ═ 5.5 and 8.4Hz), 7.20 to 7.24(m, 1H), 7.11(d, 8.4Hz), 4.08 to 4.18(m, 1H), 4.49 to 3.57(m, 1H), 3.35 to 3.44(m, 1H), 3.23 to 3.32(m, 1H), 2.30 to 2.46(m, 2H), 1.98 to 2.13(m, 1H) and 1.84 to 1.94m, 1H) ppm.

The above-mentioned compound (60mg, 0.159mmol), (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Tert-butyl ethylcarbamate (56mg, 0.159mmol), tetrakis (triphenyl-phosphine) palladium (18mg, 0.016mmol) and potassium phosphate (23mg, 0.106mmol) were combined in DME (0.5ml) under Ar and heated to 70 deg.C for 18 hours. Thereafter, the mixture was suspended in EtOAc (5mL) and saturated NH₄Cl(1ml) Aqueous solution, and vortexed for 2 minutes. The suspension was filtered through a Gelman Acrodisc. The filtrate was partitioned and the aqueous layer extracted with EtOAc (3 mL). The combined organic extracts were extracted with MgSO₄Dried, filtered under vacuum and concentrated. The residue was purified by column chromatography with 0-5% EtOAc/CH₂Cl₂Gradient elution is carried out to obtain [2 ' - (1, 1-dioxygen bridge-1, 2-thiazine alkane-2-yl) -3, 3 ' -difluoro-1, 1 ' -biphenyl-4-yl]Tert-butyl methylcarbamate. Low resolution mass spectrum: (M + H)⁺)＝353.13(-Boc)。¹HNMR(400MHz，CDCl₃) δ 7.41(t, 1H, J ═ 7.9Hz), 7.34(dt, 1H, J ═ 5.4 and 8.2Hz), 7.10 ═ 7.24(m, 4H), 4.96(br s, 1H), 4.42(d, 2H, J ═ 5.5Hz), 3.47-3.56(m, mlH, 3.32-3.41(m, 1H), 3.18-3.28(m, 1H), 2.86-2.95(m, 1H), 2.14-2.34(m, 2H), 1.65-1.80(m, 1H), 1.46(s, 9H) and 1.33-1.46(m, 1H) ppm.

The above compound was used to prepare the title compound in a similar manner to example 18. High resolution mass spectrometry: c₂₆H₂₆F₂N₅O₄Theoretical value of S: 542.1668, found: 542.1661.¹H NMR(400MHz，(CD₃)₂SO) δ 9.37(s, 1H), 9.32(s, 1H), 9.21(s, 2H), 8.62(1H, 6.1Hz), 7.33-7.49(m, 3H), 7.16-7.24(m, 3H), 4.38(d, 2H, 6Hz), 4.42-5.58(m, 1H), 3.10-3.24(m, 1H), 2.7-2.8(m, 1H), 2.3-2.6(m, 1), 1.96-2.16(m, 2H), 1.54-1.66(m, 1H), 1.41(q, 2H, J ═ 4Hz), 1.26-1.39(m, 1H) and 1.07(q, 2H, J ═ 4Hz) ppm.

Example 21

N- [ (1R) -1- (3, 3 ' -difluoro-2 ' - { [ (trifluoromethyl) sulfonyl ] methyl } -1, 1 ' -biphenyl-4-yl)

Ethyl ] -1- [ (trifluoro-acetyl) amino ] cyclopropanecarboxamide

To a solution of 2-chloro-6-fluorobenzyl alcohol (0.50g, 3.1mmol) in ether (5mL) at-10 deg.C was added trifluoromethanesulfonyl chloride followed by a mixture of triethylamine (0.411mL, 3.88mmol) and trimethyl phosphite (0.458mLm, 3.88mmol)) in ether (5 mL). The resulting mixture was stirred at room temperature for 16 hours and then partitioned between ether and water. The organic extract was extracted with aqueous HCl (0.5N), saturated NaHCO₃Washed with aqueous solution and dried (MgSO)₄). The solvent was evaporated in vacuo to give 2-chloro-6-fluorobenzyl trifluoromethanesulfonic acid ester as an oil.¹HNMR(400MHz，CDCl₃)₂δ 7.38(1H, dt, J ═ 6 and 8Hz)7.28(1H, d, J ═ 8Hz), 7.08(1H, dt, J ═ 1, 8Hz), 5.53(1H, dd, J ═ 1.8 and 11.1Hz), 5.30(1H, dd, J ═ 0.7 and 11.1Hz) ppm.

To a solution of the above compound (0.9g, 3.25mmol) in acetonitrile (12mL) was added 2, 6-lutidine (0.71mL), and the mixture was heated under reflux for 48 hours. The reaction was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ether and washed with 0.5M aqueous HC1 solution, saturated NaHCO₃Aqueous solution and water wash. The organic extract was dried (MgSO)₄) And (4) evaporating in vacuum. The residue was purified by flash chromatography, eluting with a gradient of hexane-50% diethyl ether in hexane to give 1-chloro-3-fluoro-2- { [ (trifluoromethyl) sulfonyl]Methyl } benzene, which is an oil.¹HNMR(400MHz，CDCl₃)₂δ 7.40(1H, dt, J ═ 6 and 8Hz)7.34(1H, d, J ═ 8Hz), 7.08(1H, dt, J ═ 1, 8Hz), 4.80(s, 2H) ppm.

To a solution of the above compound (91mg, 0.34mmol) in dioxane (0.5mL) was added tri-tert-butylphosphine (0.025mL of a 1.65M solution in dioxane, 0.04 mmol). Adding Pd to the solution₂(dba)₃(15.7mg，0.0017mmol)，Cs₂CO₃(134mg, 0.41mmol), followed by addition of (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Tert-butyl ethylcarbamate (130mg, 0.36mmol) was added and the resulting suspension was heated at 80 ℃ for 24 hours. The reaction was cooled to room temperature and diluted with DMF (4mL)And (4) filtering. The resulting filtrate was purified by reverse phase HPLC C-18 using a 5: 95% -95: 5% acetonitrile: gradient elution with 0.1% TFA in water and lyophilization afforded (1R) -1- (3, 3 '-difluoro-2' - { [ (trifluoromethyl) sulfonyl]Methyl } -1, 1' -biphenyl-4-yl) ethylcarbamic acid tert-butyl ester. Low resolution mass spectrum M + -t-BocNH 363.

A solution of the above compound (33mg, 0.068mmol) in EtOAc (5mL) was treated with HC1 gas at 0 deg.C. After 5 min, the solvent was evaporated in vacuo to give (1R) -1- (3, 3 '-difluoro-2' - { [ (trifluoromethyl) sulfonyl group]Methyl } -1, 1' -biphenyl-4-yl) ethanaminium chloride. Low resolution mass spectrometer MH⁺＝380。

To the above-mentioned compound (26mg, 0.062mmol), 1- [ (trifluoroacetyl) amino group]To a solution of cyclopropanecarboxylic acid (1.5mg, 0.069mmol), HOAT (9.4mg, 0.069mmol) in DMF (1mL) was added EDC (13.2mg, 0.069mmol) and triethylamine (0.026mL, 0.187 mmol). The reaction was stirred at room temperature for 16 h, diluted with DMF (1mL), purified by reverse phase HPLC C-18, purified with 5: 95% -95: 5% acetonitrile: gradient elution with water containing 0.1% TFA afforded the title compound, which was lyophilized to give a solid. High resolution mass spectrometry: c₂₂H₁₈F₈N₂O₄S MH + found 559.0951 theoretical value 559.0933.¹H NMR(400MHz，CDCl₃)₂δ 7.48(1H, dt, J ═ 6 and 8Hz)7.33(1H, d, J ═ 8Hz), 7.22(1H, dt, J ═ 1, 8Hz), 7.14(1H, d, J ═ 7.6Hz), 7.12-7.05(2H, m), 7.07m (1H, s), 6.60(1H, d, J ═ 8Hz), 5.26(1H, qn, J ═ 7Hz), 4.61(s, 2H), 1.64(2H, m), 1.15(2H, m) ppm.

Example 22

N- [ (1R) -1- (3, 3 ' -difluoro-2 ' - { [ (trifluoromethyl) sulfonyl ] amino } -1, 1 ' -biphenyl-4-yl)

Ethyl ] -1- [ (trifluoro-acetyl) amino ] cyclopropanecarboxamide

Coupling N- { (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide (1.50g, 3.377mmol), 2-bromo-6-fluoroaniline (401ul, 3.545mmol), tris (dibenzylideneacetone) dipalladium (309mg, 0.338mmol), cesium carbonate (1.10g, 3.377mmol) and 1.65M tri-tert-butylphosphine in dioxane (491ul, 0.810mmol) were suspended in dioxane (15ml), degassed by blowing argon and heated to 90 ℃ for 15 minutes. After this time, the mixture was filtered through a Gelman Acrodisc and the filter was washed with EtOAc (10mL) and methanol (20 mL). The combined filtrates were concentrated in vacuo and the residue was purified by column chromatography using 0-100% EtAOc/CH₂Cl₂Gradient elution to obtain N- [ (1R) -1- (2 ' -amino-3, 3 ' -difluoro-1, 1 ' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide. Low resolution mass spectrum: (M + H)⁺)＝428.2。¹H NMR(400MHz，(CD₃)₂SO) δ 9.79(s, 1H), 8.28(d, 1H, J ═ 7.6Hz), 7.48(t, 1H, J ═ 8.2Hz), 7.19-7.26(m, 2H), 7.02-7.09(m, 1H), 6.89(d, 1H, J ═ 7.6Hz), 6.61-6.68(m, 1H), 5.22-5.29(m, 1H), 1.45-1.57(m, 2H), 1.42(d, 3H, J ═ 7.1Hz) and 0.93-1.08(m, 2H) ppm.

The above compound (50mg, 0.117mmol) was added to CH₂Cl₂The solution in (0.5ml) was cooled with a dry ice/acetone bath and then treated sequentially with diisopropylethylamine (41ul, 0.234mmol) and trifluoromethanesulfonic anhydride (20ul, 0.117mmol), after which it was warmed to room temperature and stirred for 4 hours. The resulting mixture was diluted with methanol, filtered and purified by reverse phase chromatography with a gradient of 5-95% CAN in water. The desired fractions were combined and lyophilized to give the title compound as a white solid. High resolution mass spectrometry: c₂₁H₁₇F₈N₃O₄Theoretical value of S: 560.0885, found: 560.0884.¹H NMR(400MHz，CD₃CN) δ 8.10(s, 1H), 7.52(dt, 1H, J ═ 5.7 and 8.1Hz), 7.41(t, 1H, J ═ 8.1Hz), 7.26-7.33(m, 2H), 7.21(dd, IH, J ═ 1.7 and 8.1Hz), 7.17(dd, 1H, J ═ 1.7 and 11.5Hz), 7.14 to 7.24(m, 1H), 5.26(quin, 1H, J ═ 7.3Hz), 1.46(d, 3H, J ═ 6.9Hz), 1.34 to 1.45(m, 2H), 1.08 to 1.15(m, 1H) and 1.01 to 1.07(m, 1H) ppm.

Example 23

N- (1- { [ ((1R) -1- {3, 3 ' -difluoro-2 ' - [ (methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-yl } ethyl)

Amino carbonyl-cyclopropyl) pyrimidine-5-carboxamides

To N- [ (1R) -1- (2 ' -amino-3, 3 ' -difluoro-1, 1 ' -biphenyl-4-yl) ethyl]-1- [ (trifluoroacetyl) amino group]To a solution of cyclopropanecarboxamide (174mg 0.407mmol) in methanol (2ml) was added 1.0N NaOH (2ml, 2mmol) and stirred at room temperature for 4 days. The mixture was concentrated under vacuum to a volume of 2ml and extracted with dichloromethane (2X 10 ml). The combined extracts were washed with water (1ml) and MgSO₄Drying, filtering and removing the solvent in vacuo to yield 1-amino-N- [ (1R) -1- (2 ' -amino-3, 3 ' -difluoro-1, 1 ' -biphenyl-4-yl) ethyl]Cyclopropanecarboxamide. Low resolution mass spectrum: (M + H)⁺)＝332.3。

To a solution of the above compound (123mg, 0.371mmol) in DMF (2ml) were added 5-pyrimidinecarboxylic acid (46mg, 0.371mmol), HOAT (51mg, 0.371mmol), triethylamine (38mg, 0.371mmol) and EDC (71mg, 0.371mmol), and the mixture was stirred for 18 hours. The mixture was purified directly on Gilson LC using Waters prep pak eluting with a gradient of 5-95% CAN in water over 20 min. Freeze drying the desired fraction, and dissolving the resulting amorphous solid in CH₂Cl₂In the specification, Na is used₂CO₃Washing with aqueous solution of MgSO 2₄Drying, filtering and removing the solvent in vacuo to yield N- [1- ({ [ (1R) -1- (2 '-amino-3, 3' -di)Fluoro-1, 1' -biphenyl-4-yl) ethyl]Amino } carbonyl) cyclopropyl]The title compound is pyrimidine-5-carboxamide. Low resolution mass spectrum: (M + H)⁺)＝438.3。

To a solution of the above compound (27mg, 0.062mmol) in pyridine (500ul) was added methanesulfonic anhydride (22mg, 0.123mmol) and heated to 70 ℃ for 2 hours. To this mixture was added additional methanesulfonic anhydride (33mg, 0.186mmol) and heated to 70 ℃ for 18 hours. The mixture was concentrated in vacuo and the resulting oil was purified on a Gilson LC system using a Jupiter column (10u, C18, 300 *) and eluted with a gradient of 5-95% CAN in water. The two title compounds and the bis-mesylate by-product were isolated by freeze-drying the respective fractions. The dimethyl sulfonate salt was dissolved in methanol and treated with 1.0N NaOH and re-purified as described above to give additional title compound as an amorphous solid. Low resolution mass spectrum: (M + H)⁺)＝516.3。

¹H NMR(400MHz，(CD₃OD) δ 9.33(s, 1H), 9.29(s, 1H), 9.24(s, 2H), 8.33(d, J ═ 8.0Hz, 1H), 7.47(t, J ═ 8Hz, 1H), 7.43 to 7.36(m, 1H), 7.28 to 7.16(m, 4H), 5.34(quintet, J ═ 7.1Hz, 1H), 2.73(s, 3H), 1.59 to 1.50(m, 2H), 1.50(d, J ═ 7.1Hz, 2H) and 1.24 to 1.11(m, 2H) ppm.

Example 23A

N- (1- { [ ((1R) -1- {3, 3 ' -difluoro-2 ' - [ ([35S ] methylsulfonyl) amino ] -1, 1 ' -biphenyl-4-yl }

Ethyl) amino ] carbonyl } cyclopropyl) pyrimidine-5-carboxamide

Reacting N- (1- { [ ((1R) -1- {2 ' -amino-3, 3 ' -difluoro-1, 1 ' -biphenyl-4-yl } ethyl) amino]Carbonyl } cyclopropyl) pyrimidine-5-carboxamide (9mg, 0.02mmol) was dissolved in pyridine (10 uL). Distillation under atmospheric pressure in dichloromethane [35S]Methanesulfonyl chloride (40mCi) was brought to a volume of about 50uL and added to the amine solution. The reaction mixture was aged at room temperature for 2 hours, diluted with ethyl acetate (10mL),and extracted with 10% aqueous sodium bicarbonate (2 × 5 mL). The organic phase is concentrated and the residue is purified by preparative HPLC (Zorbax RX C8, 25/75A/B-30/70A/B, A ═ CH₃CN, B ═ 0.1% TFA). After separation, the tracer was purified by preparative HPLC (Luna C8, 25/75A/B-32.5/67.5A/B, a ═ CH₃CN, B ═ 0.1% TFA) was further purified to give the title compound of 75 uCi. The tracer was identified by HPLC (Zorbax SB-phenyl 55/45 MeOH/0.1% HC 1O)₄) As confirmed by co-elution with authentic standards.

Example 24

N- [ (1R) -1- (2-fluoro-4- {1- [ (trifluoromethyl) sulfonyl ] -1, 2, 3, 4-tetrahydroquinolin-8-yl }

Phenyl) ethyl ] -1- [ (trifluoroacetyl) amino ] cyclopropanecarboxamide

In a sealed tube, N- { (1R) -1- [ 2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide (250mg, 0.563mmol), 8-bromoquinoline (117mg, 0.563mmol), cesium carbonate (367mg, 1.13mmol), and bis (tri-tert-butylphosphine) palladium (0) (10mg, 0.03mmol) were stirred in 1mL of anhydrous dioxane at 90 deg.C overnight. The reaction mixture was cooled to room temperature and diluted with w/EtOAc. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 10% -95% EtOAc/hexanes to give (N- [ (1R) -1- (2-fluoro-4-quinolin-8-ylphenyl) ethyl]-1- [ (trifluoroacetyl) -amino]Cyclopropanecarboxamide. ES MS, M + H⁺Measured value: 475. proton NMR (400MHz, CDCl)₃)δ1.2(m，J＝2.4Hz，2H)，1.58(d，J＝6.8Hz，3H)，1.7(m，J＝2.9Hz，2H)，3.86(s，3H)，5.33(q，J＝7.2Hz，1H)，6.64(d，J＝8.8Hz，1H)，6.84(s，1H)，7.08-7.19(m，3H)，7.34(m，3H)，7.47(m，J＝4.5Hz，1H)，7.81(m，J＝5Hz，1H)，7.9(d，J＝9Hz，1H)。

The above compound (40mg, 0.09mmol) was dissolved in 1ml of 1: 1 EtOH/EtOAc and N was blown into the solution for 10 minutes₂. 10% Pd-C catalyst (2mg, 0.016mmol) was added, and the mixture was again purged with air for 10 minutes. The reaction was stirred for 16 hours with a hydrogen balloon attached. The mixture was purged with nitrogen, filtered through celite, washed with 2.0M NH3 in MeOH, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 10% -95% EtOAc/hexanes to provide N- { (1R) -1- [ 2-fluoro-4- (1, 2, 3, 4-tetrahydroquinolin-8-yl) phenyl]Ethyl } -1- [ (trifluoroacetyl) amino group]Cyclopropanecarboxamide. ES MS, M + H⁺Measured value: 450.

the above compound (40mg) was dissolved in 1mL of dichloromethane, and triethylamine (0.014mL, 1.1equiv) was added. The solution was cooled to-78 ℃ and trifluoromethanesulfonic acid (triflic) anhydride (0.018mL, 1.3equiv) was added slowly. After 30 minutes, another 1.3 equivalents of triflic anhydride was added. After an additional 30 minutes, the solution was allowed to warm to room temperature and the reaction was quenched with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel, eluting with 5% -75% EtOAc/hexanes. Further separation was done by preparative TLC on 1mm plates with 10% Et₂O/DCM as eluent gave the title compound. ES MS, M + H⁺Measured value: 582. proton NMR (400MHz, CDCl)₃)δ1.1(m，2H)，1.52(d，J＝7.1Hz，3H)，1.65(m，2H)，1.9(m，1H)，2.5(m，1H)，2.8(m，2H)，3.5(m，1H)，4.2(m，1H)，5.25(q，J＝7Hz，1H)，6.6(d，J＝8.2Hz，1H)，6.8(d，J＝8.2Hz，1H)，7.03-7.09(m，2H)，7.31-7.35(m，2H)。

Claims

1. A compound of formula I:

wherein

R¹And R²Independently selected from hydrogen and C_1-4An alkyl group;

R^3aand R^3bIndependently selected from hydrogen and C optionally substituted by 1 to 5 halogen atoms_1-4An alkyl group;

R^4aand R^4bIndependently selected from hydrogen, halogen, and C optionally substituted with 1-4 groups selected from_1-4Alkyl groups: halogen, OR^a，OC(O)R^a，S(O)_kR^d，OS(O)₂R^dAnd NR and¹R²or is or

R^4aAnd R^4bTogether with the carbon atoms to which they are both attached form an exo-cyclomethylene group optionally substituted with 1-2 groups selected from: c optionally substituted by 1-5 halogen_1-4Alkyl and C_1-4An alkoxy group;

R⁵selected from (1) C_1-6Alkyl, optionally substituted with 1-5 groups independently selected from: halogen, nitro, cyano, OR^a，SR^a，COR^a，SO₂R^d，CO₂R^a，OC(O)R^a，NR^bR^c，NR^bC(O)R^a，NR^bC(O)₂R^a，C(O)NR^bR^c，C_3-8Cycloalkyl, (2) C_3-8Cycloalkyl optionally substituted with 1-5 groups independently selected from halogen, nitro, cyano and phenyl, (3) C_3-6Alkynyl, (4) C optionally substituted with hydroxyethyl_2-6Alkenyl, (5) (CH₂)_k-aryl, optionally substituted with 1 to 3 groups independently selected from: halogen, nitro, cyano, OR^a，SR^a，C(O)₂R^a，C_1-4Alkyl and C_1-3A haloalkyl group; (6) (CH)₂)_k-heterocycle, optionally substituted with 1-3 substituents independently selected from halogen, nitro, cyano, OR^a，SR^a，C_1-4Alkyl and C_1-3Haloalkyl, wherein the heterocycle is selected from (a) a 5-membered heteroaryl ring containing a ring heteroatom selected from N, O and S, and optionally containing up to 3 additional ring nitrogen atoms, wherein the ring is optionally benzo-fused; (b) 6-membered heteroaromatic rings containing 1-3 ring nitrogen atoms and N-oxides thereof, wherein the rings are optionally benzo-fused; and (c) a 5-or 6-membered non-aromatic heterocyclic ring selected from the group consisting of tetrahydrofuranyl, 5-oxo-tetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1, 6-dihydropyridazinyl group, (7) C (O)₂R^aAnd (8) C (O) NR^bR^c；

R^6aSelected from (1) -OSO₂R⁸，(2)-NR^8aSO₂R⁹And (3) -C (R)^8b)(R^8c)SO₂R⁹；

R^6b，R^6cAnd R^6dIndependently selected from (1) hydrogen, (2) halogen, (3) OSO₂R⁸(4) C optionally substituted by 1 to 5 halogen atoms_1-4Alkyl, (5) cyano, (6) nitro, (7) OR^aAnd (8) CO₂R^aOr R when bound to an adjacent carbon atom^6cAnd R^6dTogether with the carbon atom to which they are attached form a 5-to 8-membered saturated or unsaturated ring;

R^8aselected from hydrogen, C optionally substituted by 1-5 halogen atoms_1-4Alkyl, halogen, and CO₂R^aOr when R is^6aAnd R^6bWhen bound to an adjacent atom, R^8aAnd R^6bTogether form a 5-or 6-membered ring;

R⁹Selected from (1) optionally substituted by 1 to 5 halogen atomsSubstituted C_1-4Alkyl, (2) aryl optionally substituted with 1-3 groups independently selected from: halogen, nitro, cyano, NR^a(C)OR^a，OR^a，SR^a，CO₂R^a，C_1-4Alkyl and C_1-3Haloalkyl, and (3) (CH)₂)_k-aryl optionally substituted with 1 to 3 groups independently selected from: halogen, nitro, cyano, NR^aC(O)R^a，OR^a，SR^a，C(O)₂R^a，C_1-4Alkyl and C_1-3Haloalkyl, or

R^dselected from (1) C optionally substituted by 1 to 5 halogen atoms_1-4An alkyl group, a carboxyl group,

(2)C_1-4an alkoxy group,

(3) phenyl optionally substituted with 1-3 groups selected from: halogen, cyano, nitro, OH, C_1-4Alkoxy radical, C_3-6Cycloalkyl and C_1-4Alkyl optionally substituted with 1-5 halogen atoms, and (4) hydrogen;

x is selected from CH and N;

y is selected from C and S ═ O; and

k is selected from 0, 1 and 2.

2. The compound of claim 1, wherein R⁵Selected from pyrimidinyl and C_1-6Alkyl optionally substituted with 1-5 groups independently selected from halogen.

3. The compound of claim 1, wherein Y is C.

4. The compound of claim 1, wherein R^6aIs OSO₂R⁸And R is⁸Selected from the group consisting of 2, 2, 2-trifluoroethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, and dimethylamino; or R^6aIs NHSO₂R⁹And R is⁹Is methyl or trifluoromethyl.

5. The compound of claim 1, wherein R^6bSelected from hydrogen, fluorine, and chlorine.

6. The compound of claim 1, having formula I (2):

wherein X is N or CH, R^3aIs H or C_1-4-alkyl, R⁷Is hydrogen or halogen, R⁵，R^6a，R^6bAnd R^6cHaving the same definition as set forth in claim 1.

7. The compound of claim 6, wherein R^6aIs NHSO₂R⁹；R⁹Is C optionally substituted by 1 to 5 halogen atoms_1-4-alkyl, R^6bIs halogen, and R^6cIs hydrogen or halogen.

8. The compound of claim 10, wherein R^6aIs OSO₂R⁸；R⁸Selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, isopropyl, benzyl, dimethylamino, 2,2, 2-trifluoroethyl, and phenyl; r^6bIs hydrogen or halogen, and R^6cIs hydrogen or halogen.

9. The compound of claim 10, wherein R⁵Is pyrimidinyl or C optionally substituted with 1-5 groups independently selected from halogen_1-4-an alkyl group.

10. A compound selected from

1- ({ [ (1R) -1- (3, 3 ' -difluoro-2 ' - { [ (trifluoromethyl) sulfonyl ] oxy } -1, 1 ' -biphenyl-4-yl) ethyl ] amino } carbonyl) -cyclopropaneammonium trifluoroacetate,

3, 3 ' -difluoro-4 ' - { (1R) -1- [ ({1- [ (trifluoroacetyl) amino ] cyclopropyl } carbonyl) amino ] ethyl } -1, 1 ' -biphenyl-2-ylphenylmethanesulfonate

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

12. 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.

13. The use of claim 30, wherein the pain is post-herpetic neuropathy, osteoarthritis pain, or dental pain.