ZHAO GANG (US)
FREEMAN JENNIFER C (US)
GAO JU (US)
JUDD ANDREW S (US)
KYM PHILIP R (US)
LYNCH JOHN K (US)
MULHERN MATHEW M (US)
SOUERS ANDREW J (US)
IYENGAR RAJESH R (US)
ZHAO GANG (US)
FREEMAN JENNIFER C (US)
GAO JU (US)
JUDD ANDREW S (US)
KYM PHILIP R (US)
LYNCH JOHN K (US)
MULHERN MATHEW M (US)
SOUERS ANDREW J (US)
| WO2006113919A2 | 2006-10-26 | |||
| WO2006019020A1 | 2006-02-23 |
| US20040224997A1 | 2004-11-11 |
| Filed electronically May 17, 2007 8224WOOS
Claims
What we claim is:
1 A compound of formula (I)
(D, or a phaimaceutically acceptable salt, prodiug, salt of a piodiug, oi a combination thereof, wherein
Q is ~C(=Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R b ), oτ -C(O)O(R b );
R 1 and R 2il , aie each independently hydiogen oi lowei allcyl;
R 2 is allcyl, aryl, heleioaryl, cycloalkyi, cycloalkenyl, oi hcteiocycle; wheiein the aiyl. heteioaiyl. cycloalkyl, cycloalkenyl, and hetetocycle aie each independently fmthei unsubstituted or substituted with 1, 2, 3, 4, oi 5 substituents independently selected From the gioup consisting of alkyl, alkenyl, alkynyl, nitio, -CN, halogen, ethylenedioxy, methylenedioxy, haloalkyi, -OR a , -O-C(O)(R a ), -S(R a ), -S(O)(R b ), -S(O) 2 (R 1 '), -C(O)(R"), -C(0)0(R a ), -N(R tt ) 2 , -N(R a )-C(O)(R a ), -C(0)N(R a ) 2 , ~S(O) 2 N(R a ) 2 , R 4 , -(CR c R d )r0R a , -(CR c R d ),-O-C(O)(R a ), -(CR c R d )rS(R a ), -(CR c R d ) r S(O)(R b ), -(CR c R d ) r S(O) 2 (R b ), -(CR 0 R 11 J 1 -C(O)(R 11 ), -(CR 0 R 1 ^ 1 -C(O)O(R 3 ), -(CR c R d ),-N(R a ) 2t -(CR c R d ) r N(R λ )-C(O)(R :I ), "(CR c R ϋ ),-C(0)N(R :i ) 2! ~(CR c R' ! ),-S(O) 2 N(R a ) 2! and -(CR c R d ),-R 4 ;
R 3 repiesents a substituent group selected from the gioup consisting of alkyl, haloallcyl, -0R a , and halogen; m is 1, 2, 3, 4, or 5; n is O, 1, oi 2;
A and D aie each a monocyclic iing selected fiom the group consisting of phenyl, heteioaiyl, cycloalkyl, and cycloalkenyl; each of which is optionally fin the. substituted with 1 , 2, 3, 4, or 5 substituents as repiesented by T, wheiein each T is independently selected fiorn the group consisting of alkyl, alkenyl, alkynyl, nitio, -CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, -0R e s -O-C(O)(R C ), -S(R e ), -S(O)(R 1 ), -S(O) 2 (R 1 ), -C(O)(R 0 ), -C(0)0(R c ) 5 -N(R U ) 2 , -N(R C )-C(O)(R C ), -C(0)N(R c ) 2s -S(O) 2 N(R^) 2 , -(CR c R d ) r OR B , -(CR c R' ι ) r 0-C(0)(R e ), -(CR c R d ) t -S(R c ), -(CR°R d ) r S(0)(R f ), -(CR^R 11 J 1 -S(O) 2 (R 1 ), Filed electronically May 17, 2007 8224WOO1
-(CR c
R d
VC(O)(R e
), -<CR c
R d
) r
C(O)O(R"), -(CR c
R d
) r
N(R c
) 2
, -(CR c
R d
) r
N(R°)-C(O)(R e
), -(CR c
R d
) r
C(O)N(R°) 2
, and -(CR°R d
) r
S(O) 2
N(R c
) 2
; two adjacent substituents as represented by T, together with the caibon or nitrogen atom to which they are attached, optionally form a monocyclic ring selected fiom the group consisting of phenyl, heteroaryl, cycloalkyl and cycloalkenyl, and each of said monocyclic ring is independently furthei unsubstituted or substituted with 1 , 2, 3. 4 os 5 subsUlncnls independently selected fiom the gioup consisting of alkyl, alkenyl, alkynyl, nitio, -CN, halogen, clhylαiedioxy, mcthylenedioxy, Iwioalkj l, -OR 41
, -O-C(O)(R e
), -S(R 0
), -S(O)(R 1
), -S(O) 2
(R 1
), -C(0)(R c
), -C(O)O(R 0
), -N(R L>
) 2
, -N(R e
)~C(0)(R°), -C(O)N(R 0
),, -S(O),N(R°) 2l
-(CR c
R d
) r
0R c
, -(CR e
R d
) r
0-C(0)(R e
), -(CR c
R ll
),-S(R c
), ~(CR c
R d
) r
S(O)(R f
),
Z is C(O), C(H)(OH), C(alkylXOI-I), O, N(R C ), S(O), S(O) 2 , or CH 2 ;
Y is O, N(CN), S, or C(H)(NO 2 );
W is O oi S;
X iepresenls a substituent group selected from (lie group consisting of -C(O)OR 3 , -C(O)N(R 5 ),, -CN, -C(=NOR 5 )N(R 5 ),, -C(R 6 R 7 JOT-I, -O(O)-N(R 5 )(OR 5 ), and tctiazolyl; with the pi ov iso that when Z is C(O) or C(H)(OH), A and D are phenyl, and X is located on the carbon atom that is adjacent to the caibon atom bearing Z, then X is -CN, -Cf=NOR^)N(R 5 ),, -C(R 6 R 7 )OH, -C(O)-N(R 5 J(OR 5 ), oi tetiazolyl; and with the further proviso that when Z is C(O), A is pyridinyl or pyiϊmidinyl, D is phenyl, and X is located on the caibon atom that is adjacent to the caibon atom bearing Z, then X is not -C(O)OH;
R 5 , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;
R fi and R 7 are independently hydrogen or alkyl, oi R 1 and R 7 together with the carbon atom to which they are attached, form a three- to six-membered, monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;
R 4 , at each occurrence, is independently aryl, heteroaryl, cycloalkyi, cycloalkenyl, or heteiocycle; wherein each R 4 is independently unsubstitiited or substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitio, -CN, halogen, ethyleπedioxy, methylenedioxy, haloalkyl, -0R e , -0-C(0)(R c ), -S(R 0 ), -S(O)(R'), -S(O) 2 (R 1 ), ~C(0)(R e ), -C(0)0(R c ), -N(R C ) 2 , ~N(R c )-C(0)(R e ), -C(0)N(R e ) 2 , -S(O) 2 N(R^) 2 , -(CR c R ll ) r OR g , -(CR^) 1 -O-C(O)(R 0 ), -(CR^) 1 -S(R 0 ), -(CR c R d ) r S(O)(R f ), -(CR 0 RVS(O) 2 (R 1' ), -(CR c R d )rC(0)(R e ), -(CR°R d ) r C(0)0(R e ), -(CR c R d ) r N(R c ) 2 , Filed electronically May 17, 2007 8224WOO!
-(CR c R d ) r N(R q )-C(O)(R e ), -(CR c R d ) r C(O)N{R e ) 2l and -(CR c R d ) r S(O) 2 N{R c ) 2 ;
R a , at each occurrence, is independently hydrogen, alkyl, haloalkyl, R 4 , or -(CR 15 R 1 ^-R 4 ;
R b , at each occuπence, is independently alley], haloalkyl, R 4 , or -(CR 8 R Si ) u -R 4 ;
R c , R d , R g , and R', at each occurrence, ate each independently hydiogen, halogen, alkyl oi haloalkyl; Oi
R g and R 1 ', logelhei wilh the carbon atom Io which lhcy ai e attached, fbi πi a monocyclic, thiee- to six-membeied cycloalkyl ring;
R e , at each occurrence, is independently hydrogen, alkyl oi haloalkyl;
R , at each occurrence, is independently alkyl or haloalkyl; and
U and t, at each occuπence, aie each independently 1 , 2, 3, ot 4
2 The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, salt of a piodiitg, oi a combination Lheicof, wheieiπ
Z is C(O) or C(M)OH;
X is -C(O)OR 5 or -C(O)N(R 5 ),, -CN, oi -C(R r 'R 7 )0H; wilh the proviso that when X is located on the caibon atom adjacent Io the catbon atom bcaiing Z, and λ and D are phenyl, then X is -CN or -C(R 6 R 7 )OH; and with the further pioviso that when X is located on the carbon atom adjacent to the caibon atom beai ing Z, Z is C(O), A is pyiimidinyl or pyiϊdinyl, and D is phenyl, then X is not -C(O)OH; and
R 1 , R 3 , R 5 , R f) , R 7 , Q, A, D, m, and n aie as defined in claim 1
3 The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
Z is C(O);
X is -C(O)OR 5 or -C(O)N(R 5 )?, with the proviso that when X is located on the caibon atom adjacent to the caibon atom bearing Z, then A and D aie not both phenyl, and with the fuithei pioviso that when X is located on the caibon atom adjacent to the carbon atom bearing Z, A is pyiimidinyl or pyiidinyl, and D is phenyl, then X is not -C(O)OH; and
R 1 , R 3 , R\ Q, A, D, m, and n are as defined in claim 1
4. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein Filed electronically May 17, 2007 8224WOO1
Z is C(O);
X is -C(O)OR 5 or -C(O)N(R 5 ) 2 ;
A is phenyl which is further unsubstituted or substituted with 1, 2, 3, 4, oi 5 substituents T; and
D is monocyclic heteioaryl, which is further unsubstituted or substituted with 1 , 2, 3, 4, oi 5 siibslitiicnis T
5 The compound of claim 4, oi a pharmaceutically acceptable sail, piodiug, salt oi a prodiυg, oi a combination thereof, wheiein Q is ~C(=Y)N(R 2 )(R 2a )
6 The compound of claim 5 whcicin X is -C(O)OII
7 The compound oi claim 1 , ot a pharmaceutically acceptable salt, piodiug, salt o( a prodrug, oi a combination thcicoi, wheiein
Z is C(O);
X is -C(R 6 R 7 PII, and
R ! , K 3 , R 6 . R 7 , Q, λ, D, m and n aic as defined in claim 1
S The compound of claim 7, oi a pharmaceutically acceptable salt, piodiug, salt of a prodiug, oi a combination thereof, wherein
A and D aie phenyl, each of which is independently further unsubstituted oi substituted with 1, 2, 3, 4, or 5 substituents T
9 The compound of claim 7, or a pharmaceutically acceptable salt, prodrug, salt of a piodiug, or a combination thereof, wheiein
A is phenyl which is further unsubstituted oi substituted with 1 , 2, 3, 4, oi 5 substituents T; and
D is monocyclic heteioaryl that is fiπthei unsubstituted or substituted with 1 , 2, 3, 4, oi 5 substituents T
10 The compound of claim I , or a pharmaceutically acceptable salt, prodrug, salt of a prodiug, or a combination thereof, wherein
Z is C(H)(OH); Filed electronically May 17, 2007 8224WOO1
X is -C(R 6 R 7 )OH; and
R 1 , R 3 , R 6 , R 7 , Q, A, D, m, and n are as defined in claim 1
1 1 The compound of claim 1 comprising formula (Ia),
Ua), or a phaimaceutically acceptable salt, prodiug, salt of a piodiug, or a combination theieof, wheiein R 1 , R 3 , Q, A, D, Z, X, m, and n aie as defined in claim 1
12 The compound of claim 11, oi a phaimaceutically acceptable salt, piodiug, salt of a piodiug, oi a combination thereof, wherein
Z is C(O);
X is -C(O)OR 5 or -C(O)N(R 5 ) 2 , with the pioviso that A and D aie not both phenyl, and with the furthei proviso that when A is pyrimidinyl oi pyiidinyl, and D is phenyl, then X is not -C(O)OH.
13 The compound of claim 1 1, or a pharmaceutically acceptable salt, piodiug, salt of a piodiug, oi a combination theieof, wheiein
Z is C(O);
X is -C(O)OR 5 oi -C(O)N(R 5 ),;
A is phenyl which is fϊtiihei unsubstituled oi substituted with 1, 2, ϊ, 4, oi 5 substituents T; and
D is monocyclic heteioaryl that is furthei unsubstltuted or substituted with 1 , 2, 3, 4, oi 5 substituents T
14 The compound of claim 1 comprising foimula (If),
(If), oi a pharmaceutically acceptable salt, piodiug, salt ol a prodiug, oi a combination thereof, wheiein R 1 , R 3 , Q, A, D, Z, X, m, and n are as defined in claim 1 Filed electronically May 17, 2007 8224W0O1
15 The compound of claim 14, or a pharmaceutically acceptable salt, prodiug, salt of a prodrug, oi a combination thereof, wherein
Z is C(O);
X is -C(O)OR 5 or -C(O)N(R 5 ) 2 , with the proviso that A and D are not both phenyl, and with the fiii lhci pi oviso that when λ is pyi imidiπyl oi pys idmyl. and D is phenyl, lhcn X is nol - C (O)OH
16 The compound of claim 14, oτ a pharmaceutically acceptable salt, piodnig, salt of a piodiug, O! a combination theieof, whciein
Z is C(O);
X is -C(O)OR 5 or -C(O)N(R 5 ),;
λ is phenyl which is further unsitbsliiutcd oi substituted with 1 , 2, 3, 4, ot 5 substiUienls T; and
D is monocyclic heteioaryl, which is fuithei unsubsti tilted oi substituted with 1 , 2, 3, 4, oi 5 substiluents T
17 The compound ofclaim 1 selected Horn the group consisting of: N-(3-chloiophcnyl)-N t -(4'- f(λ)-hydioxy[(l/? ! 2λ)-2-
(hydioxymethyl)cyclopentylJmethyl] -l ,l'--biphcnyl-4-yl)uiea;
N-(3-chloiophenyl)"N l
-(4 <
-{(5)-hydroxy[(l/? !
27?)-2-
N-(4'-{r(lλ,2λ)-2-(l-hydroxy-l-methylethyl)cyclopentyllcaibonyl}-l,l ! -biphenyl-4- yl)-N'~pheny]urea;
N-(4'- {(5)-hydroxy[( 1 J?,2/ϊ)"2-(hydioxymethyl)cycIopentyl]methyl }- ] , 1 '-biphcnyI-4- yl)-N'-phenylυiea;
N-(4'-{(λ)-hydroxyt(l/? J 2J?)-2-(hydioxymelhyl)cyclopentyl]methyl}-l ,r-biphenyl-4- yl)-N-phenyliuea;
N-(4'- { [( 1 J?,2λ)-2-(hydroxymethyl)cyclopenlyl]methyl }-l , 3 '-biphenyl^-y^-N 1 - phenylurea; methyl (lJϊ,2λ)-2-{4-[5-({[(3-chloiophenyl)amino]caibonyI}amino)thien-2- Filed electronically May 17, 2007 S224WOO1
yl]benzoyl}cyclopentanecarboxylate; methyl (lλ,2/i)-2-(4-{5-[(anilinocarbonyI)amino]thien-2- yl}benzoyl)cyclopentanecaiboxylale; methyl (l/?,2Jϊ)-2-(4-{5-[( {[3-(trifluoiomethyI)phenyl]aτnino}carbonyl)ammo]tliien- 2-yl}benzoyl)cyclopentanecaiboxylate;
(\ R,2R)-2- [4-[5-( ([(3-ehloiOphcnyl)aniino]caibonyl ' j πniino)(hien-2- yljbonzoyl j cyclσpenlanccarboxylie acid;
( l λ,2/?)-2-{4- ! 5-[(aniIinocarbonyl)amino]lhien-2-yI } benzoyl )cyclopenlanecaiboxylic acid;
( l /? 5 2λ)-2-(4- (5-[({ [3-(ti iπιioiomethy1)ρhcnyl]amino) cnιbonyl)amino]thicn-2- yl j bcnzoyl)cyclopeπlanecarboxy1ic acid;
N-(4'-{[(li?,27?)-2-cyanocyclopenty]]caibonyl}-l ,l'-biphenyI"4-yl)-iV-phenylinea; tians-2- {4-[4-( {[(3- ch]oiophenyl)amino]caibonyl}amino)cyclohexyl]bcπzoyl}cyclopenlancca]boxylic acid; meLhyl ( \R,2R)-2-(4- [6-[(anilinocarboπyl)amino]pyridiπ-3- yl] benzoyl)cyclopentanecarboxylate;
Tiaπs~2'[(5- {4-[(anilinocarbonyl)amino]pheny] jpyridtn-2- yl)caibony!]cyclopentaπecarboxylic acid;
Trans-2-[(5- (4-[( {[3-(trifiiioiomelhyl)phenyl]amino] caibonyl)amino]phenyl]pyiidin- 2-yl)caibonyl]cyclopentanecaiboxylic acid;
Tiϊins-2-{{5-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]pyridin-2- yl } carbonyl)cyclopentanecaiboxylic acid;
Trans-2-({5-[4-{{[(2-fluoiophenyl)amiπo]carbonyl}amino)phenyl]pyi i idin-2- yl}carbonyl)cyclopentanecaiboxylic acid;
Tians-2-[(5- {4-[( {[2-fluoiO-5-
(hiflιιoiOmethyl)phenyl]aπiino}caibonyl)aiτιino]phenyl}pyτidin-2- yl)carbonyl]cyclopentanecaiboxylic acid;
Tiaπs-2-[(5- {4-[(phenylacetyl)amino]phenyl}pyridin-2- yl)catbonyl]cyc1opentanecaiboxylic acid;
Ti i ans-2-{[5-(4- f[(2-ethoxyphenyl)acetyl]amino}ρheny!)pyridin-2- yl]caibony]}cyclopentanecaiboxylic acid;
Trans-2-{[5-(4-{[(3,5-dimethylphenyI)acetyl]amino}pheπyl)pyiidin-2- y]]caτbonyl}cyclopentanecaiboxylic acid; Filed electronically May 17, 2007 8224WOO I
Tians-2- { [5-{4- { [(2R)-2-phenylpropanoyi]amino } phenyl)pyridin-2- yljcaibonyl } cyclopentanecarboxylic acid;
Trans-2-{[5-(4-{[fluoto(phenyl)acetyl]amino}phenyl)pyiidin-2- yl]carbonyl} cyclopentanecarboxylic acid;
Trans-2-[{5-{4-[(thieπ-3-ylacetyl)aτnino]phenyl}pyiidin-2- y1)caιbonyI]cyclopenUinecaιboxylie acid;
Trans-2-[(5- |4-[(pyridin-3~ylacclyl)aiiiino]phcπyl ) ρyι idin-2- yi)carbonyl]cyclopentanecarboxylic acid;
Trans-2-{[5-(4-{[(l-phenylcyclopiOpyl)carbonyl]amino}ρhenyl)pyτidin-2- yl]caibonyl] cyclopcnlanecatboxylic acid;
Trans-2-[(5- (4-[(anilinocai i bonyl)amino]-3-f!uoi 1 opheπyl}pyπdiπ-2- yl)caibonyl]cyclopentanecaιboxylic acid;
Trans-2-[{5- l3-fluoio-4-[(pheny]acctyl)amino]phenyl] pyndin-2- yl)caibonyl]cyc]opentanccaiboxylic acid;
Trans-2-( [6'-[(
Trans-N-[2-πιioro-5»(lriπuoiOmethyl)phenyl]-N'-[4-(2- ([(l S,2S}~2-{1 -hydroxy-l - methylelhy])cyclopenty!]catbony] j -1 ,3-thiazol-5-y])phcnyl]urea;
Trans-2-[(5- (4-[{ {[2-πuoio-5-
(trifluoromethy])phenyl]amino}caibonyl)amino]phenyl}th!en-2-yl)carbonyl]cyclobutane carboxylic acid;
Tians-2-[(5- [4-[( { [2-fluoro-5-
(trifluoromethyl)phenyl]amino}caτboπyl)amino]phenyl} -l,3-lhiazol-2- yl)carbonyϊ]cyclopentanecaiboxy!ic acid ;
Tians-2-[(5H3-fluoto-4-[( { [3-
(tiifluoiomethyl)phenyl]amino}carbonyl)amino]phenyl}-l ,3-thiazol-2- yl)carbonyl]cyclopentaπecaiboxylic acid;
Trans-2-t(5-{3-fluoto-4-[( l[2-fluoio-5-
(triflιioromethyl)phenyl]amino}caiboπyl)amino]phenyl}-l,3-thiazo1-2- yl)carbonyl]cyclopentanecatboxylic acid;
Tians-2-[(5- {4-[( { [2-fluoio-5-
(trifluoioraethyl)phenyl]amino}caibonyl)amino]phenyl}-I ,3-thiazol-2- yl)caibonyl]cyclobutane carboxylic acid; and Filed electronically May 17, 2007 8224W0O1
Trans-2-[(5-{3-fluoio-4-[({[3-
(trifluoromethyl)phenyl]amino}caiboπyl)amino]phenyl}thien-2-yl)caiboiiyl]cyclobutane carboxylic acid; or a pharmaceutically acceptable salt, prodrug, or salt of a prodrug thereof.
I S λ method for treating a disosdci selected Horn (lie group consisiing of type 2 diabetes, obesity, elevated plasma triglycerides, metabolic syndrome, non-alcoholic sleaSohcpalilis, and non-alcoholic fatly iiver disease comprising the step of administciing to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof
19 The method of claim 18 further compi isiπg She step of co-adminislcring with one or more pharmaceutical agents selected from the group consisting of DPPIV inhibitor, incretin mimetic, metfoπnin, fenofibrate, limonabant, sibutramine, otlistat, statin, and nicotinic acid
20 A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable cairici
21 A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt theieof, one ot more phaπnaceutical agents selected from the gioup consisting of DPPIV inhibitor, incretin mimetic, metfoπnin, fenofibrate, limonabant, sibutramine, oilislat, statin, and nicotinic acid, in combination with a pharmaceutically acceptable canϊei
22. A method of treating a disorder selected from the group consisting of type 2 diabetes, obesity, elevated plasma triglycerides, metabolic syndrome, non-alcoholic steatohepaiilis, and non-alcoholic fatty liver disease comprising the step of administering to a subject in need theieof a pharmaceutical composition of claim 20.
23. A method for treating a disorder selected from the group consisting of type 2 diabetes, obesity, elevated plasma triglycerides, metabolic syndrome, non-alcoholic steatohepatϊtis, and non-alcoholic fatty livei disease comprising the step of administering to a subject in need thereof a pharmaceutical composition of claim 21 |
Filed electronically May 17, 2007 8224WOOI
Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
Cross Reference to Related Applications The present application claims the benefit of U.S. Provisional Application Number
60/801,890, filed on May 19, 2006, and ILS. Provisional Application Number 60/871 ,043, filed December 20, 2006, both of which are hereby incorporated by refeience in their entirety.
Field of the Invention Compounds that are inhibitors of the diacylglycerol O-acyltransfeiase type 1 (DGAT-
1) enzyme are disclosed Methods of using such compounds to inhibit the activity of diacylglyceiol O-acyltransferase type I and pharmaceutical compositions including such compounds are also encompassed,
Background of the Invention
Tiϊacylglycerides represent the major foim of energy storage in eukaiyotes, and disorders or imbalance in triacylglycerides metabolism are implicated in the pathogenesis and the increased risk for obesity, insulin resistance, type II diabetes, nonalcoholic fatty liver disease and coronary heart disease (Lewis, et al., Endocrine Reviews 23:201 , 2002). Storage of excess triacylglyceiides in lean tissues, such as liver, muscle, and other peripheral tissues, leads to lipid-induced dysfunction in those tissues; thus, reducing fat accumulation in nonadipose sites appears to be of benefit in the treatment of lipotoxicily (linger, R. H Endocrinology, 144: 5159-5165, 2003). Accumulation of excess triacylglycerides in white adipose tissue (WAT) leads to obesity, a condition that is associated with decreased life span, type II diabetes, coronary artery disease, hypertension, stroke, and the development of some cancels (Gmndy, S. M Endocrine 13(2): 155-165, 2000). Obesity is a chronic disease that is highly prevalent in modem society and current pharmacological treatment options are limited, creating a need to develop pharmaceutical agents for the treatment of obesity that are safe and effective. Diacylglycerol O-acyltransfereases (DGATs) are membrane-bound enzymes that catalyze the terminal step of triacylglycerides biosynthesis- Two enzymes that display DGAT activity have been characterized: DGAT-I (diacylglycerol O-acyltransferase type 1) (U.S Pat. No. 6,100,077; Cases, et al, Proσ Nat. Acad. Sci, 95:13018-13023, 1998) and
Filed electronically May 17, 2007 S224WOO!
DGAT-2 (diacyjglyerol O-acyltiansferase type 2) {Cases, et al , J Biol Chem 276:38870- 38876, 2001) DGAT-I and DGAT-2 shaie only 12% sequence identity Significantly, DGAT-I null mice are resistant to diet-induced obesity and have increased sensitivity to insulin and leptin (Smith, et al , Nature Genetics 25:87-90, 2000; Chen and Faiese, Trends Cardiovasc Med 10: 188, 2000; Chen et al , J. Clin Invest 109: 10049, 2002) DGAT-3 deficient mice aie protected against hepatic steatosis, demonstrate incieased energy expenditure, and decieased levels of tissue triacylglycerides In addition to improved hiacylglycerides metabolism, DGAT-I deficient mice also have improved glucose metabolism, with lower glucose and insulin levels following a glucose load, in compaiison Io wild-type mice Partial DGAT-I deficiency in heterozygous DGAT-I+/- animals is sufficient to deliver an intermediate phenotype on body weight, adiposity, and insulin and glucose metabolism when compared to wild type and homozygous litteimates (Chen and Farese, Aiteriosclei Thromb Vase Biol 25:482-486, 2005), and small molecule DGAT-I inhibitors have been repoited to induce weight loss in diet-induced obese (DlO) mice (US 2004/0224997) The phenotypes of DGAT-I deficient mice, and the phaimacological activity repoited with DGAT-I inhibitors suggests that the discoveiy ol small molecules that effectively block the conveision of diacylglycerol to triacylglycerides by inhibiting the DGAT-I enzyme can have utility in the heatment of obesity and othei diseases associated with tiiacylglycciides imbalance
Summary oi the Invention
One aspect of the invention is diiected towards a compound of foimula (I), oi a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
Q is ~C(=Y)N(R 2 )(R 2a ), -C(=W){R b ), -R b , -S(O) 2 (R b ), or -C(O)O(R b ); R ! and R 2a , are each independently hydrogen oi lower alky!;
R 2 is allcyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, oi heterocycle; wherein the aiyl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycle are each independently further unsubstituted or substituted with 1 , 2, 3, 4, or 5 substituents independently selected from the
Filed electronically May 17, 2007 8224WOO1
group consisting of alkyl, alkenyl, alkynyl, nitro, -CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, -OR a , -O-C(O)(R a ), -S(R a ), -S(O)(R b ), ~S(O) 2 (R b ), -C(O)(R 3 ), -C(O)O(R 3 ), -N(R a ) 2 , -N(R a )-C(O)(R a ), -C(0)N(R a ) 3j -S(O) 2 N(R a ) 2 , R 4 , -(CR c R d ),-0R a , -(CR c R d ),-0-C(0)(R a ), -(CR 11 R^ 1 -S(R 3 ), -(CR^) 1 -S(O)(R 13 ), -(CR c R d ) t -S(O) 2 (R b ), -(CR c R d ),-C(O)(R a ), -(CR^) 1 -C(O)O(R 3 ), -(CR c R d ),-N(R a ) 2 , -(CR c R d ) r N(R a )-C(0)(R a ), -(CR c R d ) r C(O)N(R a ) 2 , -(CR e R d ) r S(O) 2 N(R a ) 2 , and -(CR c R d ) r R";
R 3 iepresents a substituent group selected fiom the group consisting of alkyl, haloalkyl, -OR a , and halogen; m is 1, 2, 3, 4, oi 5; n is 0, 1 , Oi 2;
A and D are each a monocyclic ring selected from the gioup consisting of phenyl, heteioaiyl, cycloalkyl, and cycloalkenyl; each of which is optionally fuilhei substituted with 1 , 2, 3, 4, oi 5 substituents as iepresented by T, wherein each T is independently selected from the group consisting of alkyl, alkenyl, alkynyl, nilio, -CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, -OR C , -0-C(O)(R 1"' ), -S(R C ), -S(O)(R r ), -S(O) 2 (R'), -C(O)(R"), -C(O)O(R"), -N(R C ) 2 , -N(R^-C(O)(R"), ~C(0)N(R c ) 2 , -S(O) 2 N(JT) 2 , ~(CR c R d ) r OR 0 , -(CR ς R d ) r 0-C(0)(R e ), -(CR c R d ) r S(R e ), -(CR c R d ),-S(O)(R ( ), -(CR c R d ) r S(O) 2 (R l ), -(CR^) 1 -C(O)(R"), -(CR c R d ) r C(0)0(R c ), -(CR c R d ) r N(R c ) 2 , -(CR c R t! ) r N(R c )-C(0XR ϋ ), -(CR c R d ) r C(O)N(R c ) 2 , and -(CR c R'')rS(O) 2 N(R c ) 2 ; two adjacent substituents as iepresented by T, together with the caibon oi nitrogen atom to which they aic attached, optionally form a monocyclic ting selected fiom the gioup consisting of phenyl, heteioaiyl, cycloaikyl and cycloalkenyl, and each of the monocyclic iing is independently fuither unsubslituted oi substituted with 1, 2, 3, 4 or 5 substituents independently selected fiom the gioup consisting of alkyl, alkenyl, alkynyl, nitro, -CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, -0R e , -O-C(O)(R e ), -S(R e ), -S(O)(R 1 ), -S(O) 2 (R f ), -C(O)(R e ), -C(O)O(R 0 ), -N(R e ) 2 , -N(R e )-C(O)(R c ), -C(0)N(R e ) 2 , -S(O) 2 N(R e ) 2 , -(CR c R d ) ( -0R e , -(CR c R d ) r 0-C(0)(R e ), -(CR c R d )rS(R E ), -(CR c R d )rS(0XR'\ -(CR c R d ),-S(0) 2 (R'), -(CR c R ϋ ) r C(0)(R c ), -(CR c R d ) t -C(0)0(R e ), -(CR c R d )rN(R c ) 2> -(CR c R d ) r N(R e )-C(0)(R c ) > -(CR c R d ) r C(O)N(R e ) 2 , and -(CR c R d )rS(O) 2 N(R e ) 2 ; Z is C(O), C(H)(OH), C(alkyl)(OH), O 5 N(R e ), S(O), S(O) 2 , or CH 2 ;
Y is O, N(CN), S, or C(H)(NO 2 ); W is O or S;
X represents a substituent group selected ftom the group consisting of -C(O)OR 5 ,
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-C(O)N(R 5 ) 2 , -CN, -C(=NOR 5 )N(R 5 ) 2 , -C{R°R 7 )0H, -C(O)-N(R 5 )(OR 5 ), and tetiazolyl; with the proviso that when Z is C(O) or C(H)(OH), A and D are phenyl, and X is located on the carbon atom that is adjacent to the carbon atom bearing Z, then X is -CN, -C(=NOR 5 )N(R 5 ) 2 , -C(R 6 R 7 )OH, -C(O)-N(R 5 XOR 5 ), oi tetrazolyl; and with the further proviso that when Z is C(O), A is pyridinyl or pyrimidinyl, D is phenyl, and X is located on the carbon atom that is adjacent to the carbon atom bearing Z, then X is not -C(O)OH;
R 5 , at each occurrence, is independently hydrogen, alkyl, oi haioalkyl; R 6 and R 7 are independently hydrogen or alkyl, or R 6 and R 7 together with the caibon atom to which they aie attached, form a three- to six-membeied, monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl;
R 1 *, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; wherein each R 4 is independently unsubstituted or 1 substituted with 1 , 2, 3, 4 or 5 sυbstituents independently selected fiom the group consisting of alkyl, alkenyl, alkynyl, nitio, -CN, halogen, ethylenedioxy, methylenedioxy, haioalkyl , -0R e , -0-C(0)(R e ), -S(R 0 ), -S(O)(R 1 ), -S(O) 2 (R 1 ), -C(O)(R 0 ), -C(O)O(R e ), -N(R C ) 2 , -N(R c )-C(0)(R c ), -C(O)N(R°) 2 , -S(O) 3 N(R e ) 2 , -(CR 1 ^rOR 0 , -(CR c R d ) r 0-C(0)(R e ), -(CR c R ll ) r S(R c ), -(CR c R <! ) r S(0)(R f ), -(CR c R d ) 1 -S(0) 2 (R r ), -(CR c R d ) t -C(0)(R e ), -(CR c R d )rC(0)0(R e ), -(CR c R d ) r N(R e ) 2 , -(CR c R d ),-N(R e )-C(0)(R c ), -(CR c R ll ) r C(0)N(R e ) 2 , and -(CR c R d ) r S(O) 2 N(R c ) 2 ;
R a , at each occurrence, is independently hydrogen, alkyl, haioalkyl, R , or -(CR s R h ) ιr R 4 ;
R b , at each occurrence, is independently alkyl, haioalkyl, R 4 , or -(CR g R h ) u -R 4 ; R c , R , R g , and R 1 , at each occurrence, aie each independently hydrogen, halogen, alkyl oi haloalkyl; or
R E and R , together with the carbon atom to which they are attached, form a monocyclic, three- to six-mernbered cycloalkyl ring;
R e , at each occurrence, is independently hydiogen, alkyl or haloalkyl; R f , at each occurrence, is independently alkyl or haloalkyl; and u and t, at each occurrence, are each independently 1, 2, 3, or 4. Another aspect of the invention provides methods of treating various diseases or conditions in a subject, preferably a human, wherein the methods include administering to the subject in need thereof a therapeutically effective amount of a compound of the invention as disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical compositions including a compound of the invention, or a pharmaceutically acceptable salt
Filed electronically May 17, 2007 8224WOO1
thereof, and a pharmaceutically acceptable carrier In another aspect, the invention provides methods of preventing oi treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially elevated triacylglycerides levels, in a subject, especially human, afflicted with such elevated levels, including administering to the subject a therapeutically or prophylactically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a composition as disclosed herein. The invention also relates to novel compounds having therapeutic ability to reduce lipid levels in a subject (for example, mammal), especially triacylglycerides levels. In another aspect, the invention provides pharmaceutical compositions including the compound of the invention as disclosed herein, or a pharmaceutically acceptable salt theieof, and a pharmaceutically acceptable carrier. In one embodiment, the present invention relates to methods of treating various conditions in a subject (for' example, mammal) including the step of administering to the subject a pharmaceutical composition including an amount of the compound of the invention, or a pharmaceutically acceptable salt theieof, that is effective in treating the target condition, and a pharmaceutically acceptable carrier
Detailed Description of the Invention
For a variable that occuis more than one time in any substituent or in the compound of the invention or any othei formulae herein, its definition at each occurrence is independent of its definition at eveiy other occurrence Combinations of substituents are permissible only if such combinations result in stable compounds Stable compounds aie compounds, which can be isolated in a useful degree of purity from a reaction mixture
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated: The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyI, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl. The term "alkyl" as used herein, means a straight or branched chain, saturated hydrocarbon containing from 1 to 10 carbon atoms. The term "lower alkyl" or "Cj-β alkyl" means a straight or branched chain hydrocarbon containing 1 , 2, 3, 4, 5, or 6 carbon atoms. The term "C 1 . 3 alkyl" means a straight or branched chain hydrocarbon containing 1, 2, or 3
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carbon atoms. Representative examples of alkyl include, but aie not limited to, methyl, ethyl, n-piopyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methyl hexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-hepty], n-octyl, n-nonyl, and n-decyl. The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 caibon atoms and containing at least one carbon-carbon tuple bond Representative examples of alkynyl include, but aie not limited, to acetylenyl, 1- piopynyl, 2-piopynyI, 3-butynyI, 2-pentynyl, and I-bυtynyl
The term "aryl" as used herein, means phenyl or a bicyclic aiyl. The bicyclic ary] is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, oi a phenyl fused to a monocyclic cycloalkenyl The phenyl and the bicyclic aryl gτoups of the present invention are unsubstituted oi substituted. The bicyclic aiyl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic aryl Representative examples of the aryl groups include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthaleπyl, and 5,6,7,8-ιelτahydronaphthalenyl .
The term "cyano" as used herein means a -CN group.
The term "cycloalkyl" or "cycloalkane" as used herein, means a monocyclic or bicyclic cycloalkyl The monocyclic cycloalkyl has three to eight carbon atoms, zero heteroatom and zero double bond. Examples of monocyclic ring systems include cyclopiopyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepiyl, and cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl, or a monocyclic cycloalkyl in which two non-adjacent carbon atoms of the monocyclic cycloalkyl are linked by an alkylene bridge of one, two, or three carbon atoms. The monocyclic and bicyclic cycloalkyjs can be attached to the parent molecular moiety through any substitutable atom contained within the monocyclic and bicyclic cycloalkyl groups The monocyclic and bicyclic cycloalkyl groups of the present invention can be unsubslituted or substituted.
The term "cycloalkenyl" or "cycloalkene" as used herein, means a monocyclic or a bicyclic hydrocarbon ring system, The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteioatom The foui-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The bicyclic cycloalkenyl is a
Fiiecl electronically May ! 7, 2007 S224WOOI
monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group Repiesentative examples of the bicyclic cycloalkenyl gioups include, but are not limited to, 4,5,6, 7-tetrahydio~3aH-indene, octahydronaphthalenyl and 1 ,6-dihydro-pentalene. The monocyclic and the bicyclic cycloalkenyls can be attached to the parent molecular moiety through any substitutable atom contained within the gioups, and can be unsubstituted or substituted
The term "ethylenedioxy" as used herein, means a -0-(CH 2 J 2 -O- group wherein the oxygen atoms of the ethylenedioxy group aie attached to two adjacent carbon atoms of a phenyl or naphthyl moiety, forming a six membeied ring with the phenyl or naphthyl moiety that it is attached to
The term "halo" or "halogen" as used herein, means -Cl, -Br, -I oi -F. The term "haloalkyl" as used herein, means an alley! gioup, as defined herein, in which one, two, three, four, five or six hydrogen atoms aie replaced by halogen. Repiesentative examples of haloalkyl include, but ate not limited to, difluoromethyl, chloiomethyl, 2-fiuoroethyl, tiifluoiomethyl, pentafluoroethyl, and 2-chloiO-3-fluoropentyl
The term "heteiocycle" oi "heterocyclic" as used heiein, means a monocyclic heterocycle, or a bicyclic heterocycle. The monocyclic heteiocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S The three- or four-membeied ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N and S . The five-membered ring contains zeio oi one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two or thiee hetetoatoms selected from the group consisting of O, N and S. The seven- or eight-membered ring contains zero, one, two, or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziiidinyl, diazepanyi, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1 ,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyianyl, pyrazolinyl, pyiazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydiothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomoipholinyl, 1 ,1-dioxidothiomoipholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl The bicyclic heterocycle is a
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monocyclic heterocycle fused to a phenyl gioup, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, a monocyclic heterocycle fused to a monocyclic heteiocycle. Representative examples of bicyclic heterocycles include, but aie not limited to, 1 ,3-benzodithiolyl, benzopyranyl, benzothiopyianyl, 2,3-dihydrobenzofuranyI, 2,3~dihydrobenzothienyl, 2,3-dihydro-lH- indolyl, 2,3-dihydroisoindol-2-yl, 2,3-dihydroisoindo3-3-yl, 1,3-dioxo-lH-isoindolyl, 2- {tiifluoromethyl)-5,6-di3iydroimidazo-[l ,2-a]pyiazin-7(8H)-yl, l -acetyl-2,3-dihydτo-lH- indol-6-yl, 3-(trif!uoiOmethy])-5,6-dihydro[l,2 ) 4]triazolo[4,3-a]pyτazin-7(8H)-yl ) 1 ,2,3,4- tetiahydroisoqιπnolin-2-yI, and 1 ,2,3,4-tehahydroquinolinyl . Tlie monocyclic and bicyclic heteiocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic and bicyclic heterocycles, and can be unsubstituted oi substituted
The term "heteroaryl" as used herein, means a monocyclic heteroaryl, or a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring The five-membered ring contains two double bonds, and at least one heteioatom selected fiom oxygen, sulfur and nitrogen. The six-membered ting contains three double bonds and one, two, three or four nitrogen atoms Representative examples of monocyclic heteroaryl include, but aie not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyiidinyl, pyridazinyl, pyiimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl, The bicyclic heteroaryl is exemplified by a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteioaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, oi a monocyclic heteioaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaiyl fused to a monocyclic heteiocycle. Representative examples of bicyclic heteioaiyl groups include, but not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, 6,7-dihydio- 1 ,3-benzothiazolyl, imidazo[l ,2-σ]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4- d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquino]in-5-yl The monocyclic and the bicyclic heteroaryls are connected to the parent moleculai moiety through any caibon atom or any nitrogen atom contained within the monocyclic and bicyclic heteroaryls, and can be substituted or unsubstituted.
The term "heteioatom" as used herein, means a nitrogen, oxygen or sulfur atom.
The term "methylenedioxy" as used herein, means a -O-{CH 2 )-O- group wherein the
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oxygen atoms of the methyl enedioxy group aie attached to two adjacent carbon atoms of the phenyl or naphthyl ring, forming a five membered ring with the phenyl or naphthyl moiety that it is attached to.
The term "nitro" as used herein, means an -NO 2 group. The term "mammal" includes humans and animals, such as cats, dogs, swine, cattle, horses, and the like.
The term "pharmaceutically acceptable ester," as used herein, iefeis to esters of compounds of the invention which hydro lyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esteis of the invention include Cu, alkyl esteis and Cs -? cycloalkyl esteis, although C M alkyl esters aie preferred. Esters of the compounds of the invention can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydioxy groups by reaction of the compound that contains the hydioxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an aiylcarboxylic acid such as benzoic acid. In the case of compounds containing caiboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the catboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, alkyl inflate, for example with methyl iodide, benzyl iodide, cyclopentyl iodide. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alkylcaiboxylic acid such as acetic acid, or with acid and an arylcaiboxylϊc acid such as benzoic acid .
The term "pharmaceutically acceptable amide," as used herein, refers to non-loxic amides of the invention derived from ammonia, primary Ci. e alkyl amines and secondary Cι_o dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom Amides derived from ammonia, C 1 . 3 alkyl primary amides and C 1 . 2 dialkyl secondary amides are preferred. Amides of the compounds of formula (1), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the caiboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl
Filed electronically May 17, 2007 8224WOO1
carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, foi example with methylamine, diethylaniine, piperidine . They also can be prepaied by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid undei dehydrating conditions as with molecular sieves added The composition can contain a compound of the invention in the form of a pharmaceutically acceptable prodrug.
The term "pharmaceutically acceptable prodrug" or "prodrug" as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the invention can be rapidly transformed in vivo to a parent compound of the invention, for example, by hydrolysis in blood, A thorough discussion is piovided in T. Higuchi and V Stella, Prodrugs as Novel Delivery Systems, V. 14 oi ' the A C S Symposium Series, and in Edward B Roche, ed , Bioreveisible Caπiers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987)
The term "pharmaceutically acceptable carrier" as used herein, means a non-toxic, solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type Examples of therapeutically suitable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like. These therapeutic compositions can be administered parenterally, inlracisiemally, orally, rectally, intraveneously, oi intraperitoneal iy
The term "treatment" or "treating" includes any process, action, application, therapy, or the like, wherein a subject, including human, is provided medical aid with the object of improving the subject's condition, directly or indirectly, oi slowing the progression of a condition or disorder in the subject
Compounds of the invention have the formula (I) as described above. Particular values of variable groups in compounds of formula (I) are as follows. Such values can be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter
In compounds of formula (ϊ), Q is -C(=Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R b ), or
-C(O)O(R 1 ').
Filed electronically May 17, 2007 8224WOO 1
In one embodiment, Q is -C(=Y)N(R 2 ){R 2a ) wherein R 2 , R 2a and Y are as described in the summary R 2a is hydrogen oi lower alkyl, particularly, R 2a is hydrogen or methyl; more particularly, R 2a is hydrogen, R 2 is alky], aryl, heteioaryl, cycloalkyl, cycloalkenyl or heteiocycle; wheiein each of the aryl, heteroaryl, cycloalkyl, cycloalkeny] or heteiocycle is independently unsubstituted or substituted with substituents as described in the summary of the invention In one embodiment, R" is aiyl, heteroaryl or cycloalkyl, for example, R " is phenyl, thienyl, pyridinyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1 ,2,3,4-tettahydronaphthalen-l-yl, wheiein each R 2 is independently further unsubsli tilted or substituted with substituents as described in the summary section Particularly, R 2 is phenyl, cyclohexyl, pyiidinyl or thienyl, each of which is independently unsubstituted or substituted with substituents as described in the summary section, preferably, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cι-e alkyl such as methyl, ethyl, and the like, -OR a wherein R" is Ci-r, alkyl such as methyl, ethyl, and the like, halogen (for example, fluoro, chloro, and the like), and haloalkyl such as tiifluoromethyl. Examples of Y are O, N(CN), S oi C(H)(NO 2 ) In one embodiment, Y is O or S In anolhei embodiment, Y is O
In another embodiment, Q is -C(=W)(R b ) wherein W and R b aie as described in the summary section, W is O or S. In one embodiment, W is 0.. R b is alkyl, haloalkyl, R 4 , or -(CR g R h ) ιr R 4 wheiein R 4 , R g , R h and u are as desciibed in the summary In one embodiment, R b is R 4 , oi -(CR 15 R^ u -R 4 wherein R 4 is aryl or heteoiaryl, each of which is independently unsubstituted oi substituted as described in the summaiy section For example, R 4 is phenyl, thienyl or pyiidinyl, each of which is unsubstiluted or substituted as described in the summary Examples of the substituents on R 4 include, but aie not limited to, Ci-e alkyl such as methyl, ethyl, and the like, -OR a wheiein R ;l is Ci_ 6 alkyl such as methyl, ethyl, and the like, halogen (for example, fluoro, chloro, and the like), and haloalkyl such as trifiuoromethyl In one embodiment, u is 1 , one of II s and R h is hydrogen, and the other is hydrogen, Cu, alkyl such as methyl, and the like, or halogen such as fluoio and the like In another embodiment, u is 1 , and R g and R h , together with the carbon atom to which they are attached, form a monocyclic, three- to six-membeied cycloalkyl ring (for example, cyclopiopyl)
In another embodiment, Q is -R b wherein R b is as described in the summary section. In yet another embodiment, Q is -S(O) 2 (R b ) wherein R b is as described in the summary section.
I l
Fifed electronically May 1 7, 2007 8224WOO1
In yet anothei embodiment, Q is -C(O)O(R b ) wherein R b is as described in the summaiy section.
R ! is hydrogen, or lower alkyl such as, but not limited to, methyl In one embodiment, R 1 is hydrogen A and D are each a monocyclic ring selected fiom the group consisting of phenyl, heteioaryl, cycloalkyl, and cycloalkenyl In one embodiment, A and D are each independently a monocyclic ring selected fiom the gioup consisting of phenyl, heteioaiyl, oi cycloalkyl (for example, cyclohexyl) In anothei embodiment, A and D aie both phenyl In yet another embodiment, A is phenyl and D is monocyclic heteioaryl In yet anothei embodiment, A is monocyclic heteioaryl, and D is phenyl In yet anothei embodiment, A is cycloalkyl and D is phenyl In a further embodiment, A and D aie both monocyclic heteroaryl Each of the rings as represented by A and D is optionally further substituted with 1 , 2, 3, 4, or 5 subsliluents as reptesented by T and T is as described in the summary section Examples of monocyclic heteroaiyl ring include, but are not limited to, pyiidinyl, pyiimidinyl, pyrazinyl, thieny, furanyl, pyπolyl, thiazolyl, isolhiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyiazolyl In one embodiment, the heteioaryl ring is pyiidinyl, thienyl or thiazolyl Examples of the optional stibstitueπls on each of the rings A and D include, but aie not limited to, C K , alkyl such as methyl, ethyl, and the like, halogen such as fluoto, chloro, and the like, and haloalkyl (for example, Irifiuoiomelhyϊ, difluoiomethyl) In one embodiment, A and D aie each independently unsubstituted oi fuithei substituted with 1 oi 2 subslituents T wherein T is halogen (foi example, fluoio) m is 1, 2, ϊ, 4 oi 5 In one embodiment, m is 2, 3 or 4
Z is C(O), C(H)(OH), C(alky])(OH), O, N(R C ), S(O), S(O) 2 oi CII 2 , wherein R c is as described in the summary section. In one embodiment, Z is C(O) or C(H)(OH) In another embodiment, Z is C(O) In yet another embodiment, Z is CH;
X ieptesents a substituent gioup selected ftom the group consisting of -C(O)OR 5 , -C(O)N(R 5 ),, -CN, -C(=NOR 5 )N(R 5 ) 2 , -C(R 6 R 7 )OH, -C(OVN(R 5 )(OR 5 ) and leliazolyl wherein R 5 , R 6 and R 7 are as described in the summary of the invention, with the proviso that when Z is C(O) or C(H)(OH), A and D are phenyl, and X is located on the carbon atom that is adjacent to the carbon atom bearing Z, then X is -CN, -C(=NOR 5 )N(R 5 ) 2 , -C(R 6 R 7 )OH, -C(O)-N(R 5 J(OR 5 ), or tetrazolyl; and with the further pioviso that when Z is C(O) 5 A is pyridinyl or pyrimidinyl, D is phenyl, and X is located on the carbon atom that is adjacent to the carbon atom bearing Z, then X is not -C(O)OH In one embodiment, X is -C(O)OR 5 .
Filed electronically May 17, 2007 8224WOO1
-C(O)N(R 5 )?, -CN, or -C(R 6 R 7 )OH wherein R 5 , R 6 and R 7 are each independently hydrogen or Ci- 6 alkyl (for example, methyl), with the proviso that when X is located on the carbon atom that is adjacent to the carbon atom beating Z, Z is C(O) or C(H)(OH), A and D are phenyl, then X is -CN or -C(R 6 R 7 )OH, and with the further proviso that when Z is C(O), A is pyiidinyl or pyrϊrnidinyl, D is phenyl, and X is located on the caihon atom that is adjacent to the caihon atom bearing Z, then X is not -C(O)OH. In another embodiment, X is -C(O)OH, with the proviso that when X is located on the carbon atom that is adjacent to the caibon atom bearing Z, and Z is C(O) or C(H)(OH), then A and D are not phenyl, and with the further pioviso that when X is located on the carbon atom that is adjacent to the catbon atom bearing Z, Z is C(O), and A is pyiidinyl or pyrimidinyl, then D is not phenyl n is O, 1 oi 2 In one embodiment, n is O.
It is appreciated that the present invention contemplates compounds of formula (I) with combinations of the above embodiments, including particular more particular and preferred embodiments Accordingly, one aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, piodtug, salt of a prodrug, or a combination thereof, wherein Z is C(O) or C(H)(OH), X is -C(O)OR 5 , -C(O)N(R 5 ),, -CN or -C(R 6 R 7 JOH, with the proviso that when X is located on the carbon atom adjacent to the carbon atom bearing Z, A and D aie phenyl, then X is -CN or -C(R 6 R 7 )OH; and with the further proviso that when X is located on the caibon atom adjacent to the carbon atom bearing Z, Z is C(O), A is pyiidinyl or pyrimidinyl, and D is phenyl, then X is not -C(O)OH; and R 1 , R 3 , R 5 , R ( \ R 7 , Q, A, D, m, and n are as described in the summary section. Examples of R 1 are hydiogen and C K , alkyl such as methyl In one embodiment, R 1 is hydrogen In one embodiment, A and D are each independently a monocyclic ring selected from the group consisting of phenyl, heleroaiyl (for example, thienyl, pyiidinyl, and thiazolyl), or cycloalkyl (for example, cyclohexyl). In another embodiment, A and D aie both phenyl. In yet another embodiment, A is phenyl and D is monocyclic heteioaryl (for example, thienyl, pyridinyl, and thiazolyl) In yet another embodiment, A is monocyclic heteioaryl (for example, thienyl, pyiidinyl, and thiazolyl), and D is phenyl In a further embodiment, A and D are both monocyclic heteroaryl (for example, thienyl, pyridinyl, and thiazolyl) Each of the rings as represented by A and D is optionally further substituted with 1, 2, 3, 4, or 5 substituents as represented by T and T is as described in the summary section.
Another aspect of the invention relates to a compound of formula (I), or a
Filed electronically May 17, 2007 8224WOO1
pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein Z is C(O) and X is -C(O)OR 5 oi -C(O)N(R 5 ) 2 , with the proviso that when X is located on the carbon atom adjacent to the carbon atom bearing Z 1 then A and D are not both phenyl, and with the proviso that when A is pyridinyl or pyrimidϊnyl, and D is phenyl, then X is not -C(O)OH, and R 1 , R 3 , R 5 , Q, A, D, m, and n are as described in the summary of the invention. Examples of R 5 include hydrogen and Cu, alkyl such as methyl, and ethyl, In one embodiment, X is -C(O)OH
Of Lhis group of compounds, examples of a subgroup include those wherein A is phenyl, and D is monocyclic heteroaryl, wherein each of A and D is optionally further substituted with 1 , 2, 3, 4, or 5 substitueπts as represented by T, and ϊ, Q, R 1 , R 3 , m, and n are as described in the summary section. Examples of D as a monocyclic heteioaryl ring include, but are not limited to, pyridinyl, pyrϊmidinyl, pyiazinyl, thieny, fiiianyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl, each of which is optionally further' substituted as described herein. In one embodiment, D is pyiidinyl, thienyl oi thiazolyl, each of which is optionally further substituted with 1 , 2, 3, 4, or 1 5 substituents as represented by T and T is as disclosed in the summary. Examples of T include, but are not limited to, Ci -G alkyl such as methyl, ethyl, and the like, halogen such as fluoro, chloro, and the like, and haioalkyl (for example, tiifluorom ethyl or difluoiomethyl). In one embodiment, A and D are each independently unsubstiluted or further' substituted with 1 or 2 substituents T wherein T is halogen (for example, fluoro). Examples of R ! are hydrogen and Cu, alkyl such as methyl In one embodiment, R 1 is hydrogen. In one embodiment, n is 0 Q is -C(-Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R 1 '), or -C(0)0(R b ) wherein Y, W, R 2 , R 2 ' 1 , and R b are as described in the summary. In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wherein Y, R 2 , and R 2 ' 1 are as disclosed in the summary Examples of Y include O, N(CN), S or C(H)NO? In one embodiment, Y is O or S In anothei embodiment, Y is O. In one embodiment, R 23 is hydrogen or 1 methyl. In another' embodiment, R 2rι is hydrogen Examples of R 2 include phenyl, heteroaryl (for example, pyridinyl, pyrimidinyl, pyiazinyl, thieny, furanyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl) and cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1 , 2, 3, 4-tetrahydronaphthalen-I-yl), each of which is independently optionally substituted as described in the summary In one embodiment, R 2 is phenyl, thienyl, pyridinyl, or cyclohexyl, each of which is independently optionally further substituted as described in the summary. Examples of the optional substituents of R 2 include C^ 6 alkyl such as methyl,
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ethyl, and the like, -OR a wherein R a is Cm alkyl such as methyl, ethyl, and the like, halogen (for example, fluoro, chloio, and the like), and haloalkyl such as ttiflυoromethyl In another embodiment, Q is -C(=W)(R b ) wherein W and R b are as disclosed in the summary. In one embodiment, W is O- Examples of R b include R 4 and -(CR^^R 4 wheiein R 4 , R 8 , R h and u are as defined in the surnmaiy Examples of R 4 include aiyl (for example, phenyl) and heteroaiyl, each of which is optionally further substituted as described in the summary In one embodiment, R 4 is phenyl, thienyl, or pyridmyl, each of which is optionally further substituted as described in the summary. Examples of the optional substituenls of R 4 include C i- 6 alkyl such as methyl, ethyl, and the like, -OR a wherein R a is Ci. 6 alkyl such as methyl, ethyl, and the like, halogen (for example, fluoro, chloro, and the like), and haloalkyl such as ttifluoioπiethyl, In one embodiment, u is 1 , one of R g and R h is hydrogen, and the other is hydrogen, C|.(, alkyl such as methyl, and the like, or halogen (for example, fluoro). In anothei embodiment, u is 1 , and R B and R h , together with the carbon atom to which they aie attached, form a monocyclic, three- to six-membered cycloalkyl ring (for example, cyclopiopyl).
Other examples of a subgroup include those wherein both A and D aie monocyclic heteioaryl, wherein each A and D is independently optionally furlhei substituted with 1 , 2, 3, 4, or 5 substituents as represented by T, and T, Q, R ! , R 3 , m, and n aie as described in the summary section. Examples of the monocyclic heteroaryl ring include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thieny, fmanyl, pyirolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyiazolyl, each of which is optionally further substituted as described herein. In one embodiment, A and D aie each independently pyridmyl, thienyl oi thiazolyl, each of which is optionally further substituted with I , 2, 3, 4, oi 5 substituents as represented by T, and T is as disclosed in the summary. Examples of T include, but are not limited to, Cu alkyl such as methyl, ethyl, and the like, halogen such as fluoro, chloro, and the like, and haloalkyl (for example, trifluoiomethyl or difiuoromethyl). In one embodiment, A and D are each independently unsubstituted or further substituted with 1 or 2 substituents T, wherein T is halogen (for example, fluoro). Examples of R 1 are hydrogen and Ci .6 alkyl such as methyl. In one embodiment, R ! is hydrogen. In one embodiment, n is 0. Q is -C(=Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R 1 '), or -C(O)O(R b ) wherein Y, W, R 2 , R 2a , and R b are as described in the summary, In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wherein Y, R 2 , and R 2a are as disclosed in the summary. Examples of Y include O, N(CN), S or C(H)NO 2 . In one embodiment, Y is O or S In anothei embodiment, Y is O. In one
Filed electronically May 17, 2007 8224WOO!
embodiment, R 2a is hydrogen or methyl In another embodiment, R 2a is hydrogen Examples of R 2 include phenyl, heteroaryl (foi example, pyridinyl, pyrimidinyl, pyiazinyl, thieny, furanyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, Oϊ pyrazolyl) and cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl oi 1 , 2, 3, 4-tetrahydionaphthalen-l-yl), each of which is independently optionally further substituted as described in the sumrnaiy In one embodiment, R " is phenyl, thieπyl, pyridinyl, or cyclohexyl, each of which is independently optionally fuithei substituted as described in the summaiy Examples of the optional substitueπts oi R 2 include Ci-& alkyl such as methyl, ethyl, and the like, -OR a wherein R a is Cm alkyl such as methyl, ethyl, and the like, halogen (for example, fjuoio, chloio, and the like), and haloalkyl such as tiifluoiomethyl In anothei embodiment, Q is -C(=W)(R b ) wheiein W and R b aie as disclosed in the summary In one embodiment, W is O Examples of R b include R 4 and -(CR s R h ) u -R 4 wherein R 4 , R s , R h and u ate as defined in the summaiy Examples of R 4 include aiyl (foi example, phenyl) and heteroaryl, each of which is optionally fuilher substituted as desciibed in the summary. In one embodiment, R 4 is phenyl, thienyl, oi pyiidinyl, each of which is optionally fuithe. substituted as desciibed in the summary Examples of the optional substituents of R 4 include C 1 - 6 alkyl such as methyl, ethyl, and the like, -OR 11 wherein R λ is C]. f , alkyl such as methyl, ethyl, and the like, halogen (foi example, fluoio, chloio, and the like), and haloalkyl such as Uifiuoiomelhyl In one embodiment, u is 1 , one of R g and R 1 ' is hydrogen, and the otliei is hydrogen, Ci - 6 alkyl such as methyl, and the like, or halogen (foi example, fluoio) In anothei embodiment, u is 1, and R g and R h , iogethei with the catbon atom to which they are attached, ibim a monocyclic, thiee- to six-membeied cycloalkyl ling (foi example, cyclopropyl)
Yet other examples of a subgroup include those wherein A is cycloalkyl (foi example, cyclohexyl) and D is phenyl, wherein each A and D is independently optionally fiuther substituted with 1, 2, 3, 4, oi 5 substituents as represented by T, and T, Q, R 1 , R 3 , m, and n are as desciibed in the summary section In one embodiment, A is cyclohexyl and D is phenyl, each of which is optionally furthei substituted with 1, 2, 3, 4, or 5 substituents as represented by T, and T is as disclosed in the summary Examples of T include, but are not limited to, Cι_o alkyl such as methyl, ethyl, and the like, halogen such as fluoio, chloro, and the like, and haloalkyl (for example, tiifluoromethyl oi difluoromethyl) In one embodiment, A and D are each independently unsubstituted or further substituted with 1 or 2 substituents T, wherein T is halogen (foi example, fluoro) Examples of R 1 are hydrogen and C|. 6 alkyl
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such as methyl. In one embodiment, R 1 is hydrogen. In one embodiment, n is 0 Q is -C(=Y)N(R 2 )(R 2π ), -C(-W)(R b ), -R b , -S(O) 2 (R b ), or -C(O)O(R b ) wherein Y, W, R 2 , R 2a , and R b are as described in the summary. In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wherein Y, R 2 , and R 2a are as disclosed in the summary, Examples of Y include O, N(CN), S oi C(H)NO 2 In one embodiment, Y is O or S In another embodiment, Y is O- In one embodiment, R 3a is hydiogen or methyl In another embodiment, R 2a is hydrogen Examples of R 2 include phenyl, heteroaryl (for 1 example, pyridinyl, pyrimidinyl, pyiazinyl, thieny, fuianyl, pyπolyl, Ihiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl) and cycloalky] (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1, 2, .3, 4-tetτahydronaphthalen-l-yl), each of which is independently optionally further substituted as described in the summary. In one embodiment, R 2 is phenyl, Ihienyl, pyridinyl, or cyclohexyl, each of which is independently optionally further substituted as described in the summary Examples of the optional substituents of R 2 include Cj.f, alkyl such as methyl, ethyl, and the like, -OR' 1 wherein R a is Cu, alkyl such as methyl, ethyl, and the like, halogen (for example, fiuoro, chloro, and the like), and haloalkyl such as trifluoiomelhyl In another embodiment, Q is -C(=W)(R b ) wherein W and R b aie as disclosed in the summary. In one embodiment, W is O. Examples of R b include R 4 and "(CR g R h ) u -R 4 wherein R 4 , R B , R h and u are as defined in the summary Examples of R 4 include aiyl (for example, phenyl) and heteioaryl, each of which is optionally further substituted as described in the summary. In one embodiment, R 4 is phenyl, thienyl, or pyridinyl, each of which is optionally furthei substituted as described in the summary Examples of the optional substituents of R 4 include C i. 6 alkyl such as methyl, ethyl, and the like, -OR a wherein R a is Q -6 alkyl such as methyl, ethyl, and the like, halogen (for example, fiuoro, chloro, and the like), and haloalkyl such as trifluoromethyl In one embodiment, u is I 5 one of R s and R !l is hydrogen, and the other is hydrogen, Cι- 6 alkyl such as methyl, and the like, or halogen (for example, fiuoro) In another embodiment, u is 1, and R s and R h , together with the carbon atom to which they are attached, form a monocyclic, three- to six-membered cycloalky 1 ring (for example, cyclopropyl).
Yet another aspect of the invention is related to a group of compounds having formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein Z is C(O) and X is -C(R 6 R 7 )OH, and R 1 , R 3 , R 6 , R 7 , Q, A, D, m, and n are as described in the summary of the invention. Examples of R 6 and R 7 include, but are not limited to, hydrogen and methyl In one embodiment, X is -CH 2 OH. In another
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embodiment, X is -C(CH 3 ) 2 OH
Of this gioup of compounds, examples of a subgroup include those wheiein A and D are phenyl wheiein each of the phenyl rings as represented by A and D is independently further unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by T, and T, R 1 , R 3 , Q, m, and n are as described in the summary, Examples of R 1 are hydrogen and Q. G alkyl such as methyl. In one embodiment, R 1 is hydrogen. In one embodiment, n is 0. In one embodiment, A and D are each independently unsubstituted or further substituted with 1 oi 2 substituents T wherein T is halogen (for example, fluoro)
Of this group of compounds, examples of another subgroup include those wherein A is phenyl and D is monocyclic heteroaryl wherein each of the rings as repiesented by A and D is independently further unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by T, and T, R 1 , R 3 , Q, m, and n are as described in the summary Examples of R 1 are hydrogen and C|_ 6 alkyl such as methyl In one embodiment, R 1 is hydrogen In one embodiment, n is 0 Examples of D as a monocyclic heteioaiyl ring are as disclosed heieinabove In one embodiment, D is pyiidinyl, thienyl or thiazolyl, each of which is optionally further substituted as disclosed heieinabove In one embodiment, A and D are each independently unsubstituted or further substituted with 1 or 2 substitueπts T wherein T is halogen (for example, fluoro).
Of this group of compounds, examples of yet another subgroup include those wherein A is monocyclic heteroaryl and D is phenyl wheiein each of the rings as represented by A and D is independently further unsubstituted or substituted with 1 , 2, 3, 4, or 5 substituents as represented by T, and T, R ! , R 3 , Q, m, and n are as described in the summary. Examples of R 1 are hydrogen and Ci- 6 alkyl such as methyl In one embodiment, R 1 is hydrogen In one embodiment, n is 0. Examples of A as a monocyclic heteroaryl ring are as disclosed hereinabove In one embodiment, A is pyiidinyl, thienyl or thiazolyl, each of which is optionally further substituted as disclosed heieinabove. In one embodiment, A and D are each independently unsubstituted oi further substituted with 1 or- 2 substituents T wherein T is halogen (for example, fluoro)
Of this group of compounds, examples of yet another subgroup include those wherein A and D are each a monocyclic heteroaryl wheiein each of the rings as represented by A and D is independently furthei unsubstituted or substituted with 1 , 2, 3, 4, oi 5 substituents as represented by T, and T, R 1 , R 3 , Q 1 m, and n are as described in the summary. Examples of R 1 are hydrogen and Ci- 6 alkyl such as methyl. In one embodiment, R 1 is hydrogen, In one
Filed electronically May 17, 2007 8224WOO1
embodiment, n is 0 Examples of A and D as a monocyclic heteroaryl ring are as disclosed hereinabove. In one embodiment, A and D are each independently pyridinyl, thienyl or thiazolyl, each of which is optionally further substituted as disclosed hereinabove. In one embodiment, A and D are each independently unsubstituted or further substituted with 1 or 2 substituents T wherein T is halogen (for example, fluoro).
Of this group of compounds, examples of yet another subgroup include those wherein A is cycloalkyl (for example, cyclohexyl) and D is phenyl, each of which is independently unsubstituted oi substituted as described in the preceding paragraph Particular values of T 5 R 1 , R 3 , Q, m, and n are as described in the preceding paragiaph.. Yet another aspect of the invention is related to a group of compounds having formula
(I), or a pharmaceutically acceptable salt, prodiug, salt of a prodrug, or a combination thereof, wherein Z is C(H)(OH) and X is -C(R 6 R 7 )OH, and R ! , R 3 , R c , R 7 , Q, A, D, m, and n are as described in the summary of the invention. Examples of R 6 and R 7 include, but are not limited to, hydrogen and methyl. In one embodiment, X is -CH 2 OM. In another embodiment, X is -C(CH 3 J 2 OH
Of this group of compounds, examples of a subgroup include those wherein A and D aie phenyl wherein each of the phenyl rings as represented by A and D is independently further unsubstituted or substituted with 1 , 2, 3, 4, or 5 substituents as repiesented by T, and T, R 1 , R 3 , Q, m, and n are as described in the summary. Examples of R 1 are hydrogen and C|. r, alkyl such as methyl. Jn one embodiment, R 1 is hydiogen. In one embodiment, n is 0. In one embodiment, A and D are each independently unsubstituted or substituted with 1 or 2 subslitueπts T wherein T is halogen (for example, fluoro)
Of this group of compounds, examples of another' subgroup include those wherein A is phenyl and D is monocyclic heteioaryl wherein each of the lings as represented by A and D is independently further unsubstituted or substituted with 1 , 2, 3, 4, or 5 substituents as represented by T, and T, R 1 , R 3 , Q, m, and n are as described in the summary. Examples of R 1 are hydrogen and Cu alkyl such as methyl. In one embodiment, R 1 is hydrogen In one embodiment, n is 0. Examples of D as a monocyclic heteioaryl ring are as disclosed hereinabove In one embodiment, D is pyridinyl, thienyl or thiazolyl, each of which is optionally further substituted as disclosed hereinabove. In one embodiment, A and D are each independently unsubstituted or further substituted with 1 or 2 substituents T wherein T is halogen (for example, fluoro).
Of this group of compounds, examples of yet another subgroup include those wherein
39
FHed electronicnHy May 17, 2007 8224WOO1
A is monocyclic heteroaiyl and D is phenyl wheiein each of the lings as represented by A and D is independently fυithei unsubstituted or substituted with 1 , 2, 3, 4, or 5 substituents as represented by T, and T, R 1
, R 3
, Q, m, and n are as described in the summary Examples of R 1
are hydrogen and
A and D are each a monocyclic heteroaryl wheiein each of the iings as represented by A and D is independently fuithei unsubstituted oi substituted with 1 , 2, 3, 4, oi 5 substituents as represented by T, and T, R 1 , R 3 , Q, m, and n aie as desciibed in the summary Examples of R aie hydrogen and C|.(, alkyl such as methyl In one embodiment, R is hydrogen In one embodiment, n is 0 Examples of A and D as a monocyclic heteroaiyl ring aie as disclosed hereinabove In one embodiment, A and D aie each independently pyiidinyl, thieny] oi thiazolyl, each of which is optionally further substituted as disclosed hereinabove In one embodiment, A and D are each independently unsubstituted oi fuithei substituted with 1 oi 2 substituents T wheiein T is halogen (foi example, fluoio) Of this gtoup of compounds, examples of yet another subgioup include those wherein
A is cycloalkyl (for example, cyclohexyl) and D is phenyl, each of which is independently unsubstituted or substituted as described in the preceding paragraph Pailicular values of " I , R 1 , R , Q, m, and n are as described in the preceding paragiaph
Yet a fuithei aspect of the invention is related to a group of compounds having formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wheiein Z is CH 2 and X is -~C(R 6 R 7 )OH, and R 1 , R 3 , R 6 , R 7 , Q, A, D, m, and n aie as described in the summaiy of the invention Examples of R 6 and R 7 include, but aie not limited to, hydrogen and methyl. In one embodiment, X is -CH 2 OH In another embodiment, X is -C(CH 3 ^OH Of this group of compounds, examples of a subgroup include those wherein A and D are phenyl wherein each of the phenyl rings as represented by A and D is independently further unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by T, and T, R 1 , R 3 , Q, m, and n are as described in the summary Examples of R 1 are hydrogen and Cj.
Filed electronically May 17, 2007 8224WOO l
6 alkyl such as methyl In one embodiment, R ! is hydiogen In one embodiment, n is 0 In one embodiment, A and D aie each independently unsubstituted oi substituted with 1 or 2 substituents T wherein T is halogen (foi example, fluoro) Q is -C(=Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R 1 *), or -C(O)O(R b ) wherein Y, W, R 2 , R 2a , and R b aie as described in the summary In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wherein Y, R 2 , and R 2a are as disclosed in the summary Examples of Y include O, N(CN), S or C(H)NO 2 In one embodiment, Y is O or S In anolhei embodiment, Y is O In one embodiment, R 2j is hydiogen oi methyl In anothei embodiment, R 2a is hydiogen Examples of R " include phenyl, hetetoaryl (foi example, pyiidinyl, pyiimidinyl, pyrazinyl, thieny, furanyl, pyriolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oi pyiazolyl) and cycloalkyl (foi example, cyclopenty], cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1, 2, 3, 4- tetrahydionaphthalen-1-yl), each of which is independently optionally substituted as described in the suinmaiy In one embodiment, R 2 is phenyl, thienyl, pyiidinyl, oi cyclohexyl, each of which is independently optionally substituted as described in the summary Examples of the optional subslituents of R 2 include C|. f , alley! such as methyl, ethyl, and the like, -OR 1 ' vvheiein R π is C] -O alkyl such as methyl, ethyl, and the like, halogen (for example, fluoio, chloio, and the like), and haloalkyl such as iiifluoiomethyl
Yet a furthei aspect oi the invention is related to a group of compounds having formula (I), or a pharmaceutically acceptable salt, piodiug, salt of a ptodπig, or a combination theieof, wherein Z is CO, X is -CN, and R 1 , R 3 , Q, A, D, m, and n are as defined in the summaiy
Of this gioup of compounds, examples oi a subgioup include those wherein A and D aie phenyl wherein each of the phenyl rings as repiesented by A and D is independently fuilhei unsubstituted or substituted with I , 2, 3, 4, oi 5 substituents as iepresented by T, and T, R 1 , R 3 , Q, m, and n aie as described in the summary Examples of R 1 aie hydrogen and C|. a alkyl such as methyl In one embodiment, R 1 is hydrogen In one embodiment, n is 0. In one embodiment, A and D arc each independently unsubstituted oi further substituted with I or 2 substituents T wherein T is halogen (foi example, fluoro) Q is -C(-Y)N(R 2 )(R 2a ), -C(-W)(R b ), -R b , -S(O) 2 (R b ), oi -C(O)O(R b ) wherein Y, W, R 2 , R 2a , and R b aie as described in the summary In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wheiein Y 1 R 2 , and R 2a are as disclosed in the summary Examples of Y include O, N(CN), S or C(H)NO 2 - In one embodiment, Y is O or S In another embodiment, Y is O. In one embodiment, R 2a is hydiogen or methyl In another embodiment, R 2a is hydiogen. Examples of R 2 include
Filed electronically May 17, 2007 8224WOOt
phenyl, heteroaryl (for example, pyridinyl, pyrimidinyl, pyiazinyl, thieny, ήiranyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl) and cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl oi 1, 2, 3, 4~ tetiahydronaphthalen-l-yl), each of which is independently optionally substituted as described in the summary. In one embodiment, R 2 is phenyl, thienyl, pyridinyl, or cyclohexyl, each of which is independently optionally substituted as described in the summary. Examples of the optional substiluents of R " include Ci-G alkyl such as methyl, ethyl, and the like, ~OR a wherein R' 1 is C|.& alkyl such as methyl, ethyl, and the like, halogen (for example, fluoio, chloto, and the like), and haloalkyl such as tiifluoromethyl Another aspect of the invention provides a gioup of compounds having formula (Ia), oi a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
(Ia) wherein R 1 , R 3 , X, Q, Z, A, D, m, and n, are described as in formula (I) in the summary, It is appreciated that particular values of variable groups (for example, R 1 , R 3 , X, Q, Z, A, D, m, and n) in compounds of formula (Ia), embodiments of such groups and combinations of embodiments, including particular, and more paiticiilar embodiments as described hereinabove in formula (I), are also contemplated for compounds of formula (Ia).
Thus, a further aspect of the invention is related to a gioup of compounds of formula (Ia), ot a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein Z is C(O) or C(H)(OH), X is -C(O)OR 5 , -C(O)N(R 5 ) 2 , -CN oi -C(R 6 R 7 )OH, with the proviso that when A and D are phenyl, then X is -CN oi -C{R 6 R 7 )OH; and with the further proviso that when Z is C(O), A is pyridinyl or pyrimidinyl, and D is phenyl, then X is not -C(O)OH; and R 1 , R 3 , R 5 , R 6 , R 7 , Q, A, D, m, and n are as described in the summary section. Examples of R 1 are hydrogen and Ci- 6 alkyl such as methyl. In one embodiment, R 1 is hydrogen. In one embodiment, A and D are each independently a monocyclic ring selected ftom the group consisting of phenyl, heteroaryl (for example, thienyl, pyridinyl, and thiazolyl), or cycloalkyl (for example, cyclohexyl) In another embodiment, A and D aie both phenyl. In yet another embodiment, A is phenyl and D is monocyclic heteroaryl (for example, thienyl, pyridinyl, and thiazolyl). In yet another embodiment, A is monocyclic heteroaryl {for example, thienyl, pyridinyl, and thiazolyl), and D is phenyl. In a further
Filed electronically May 17, 2007 8224WOOt
embodiment, A and D aie both monocyclic heteioaryl (foi example, thienyl, pyridinyl, and thiazolyl) Each of the rings as iepresented by A and D is optionally fliithei substituted with 1 , 2, 3, 4, or 5 substituents as represented by T and T is as described in the summary section.
Another aspect of the invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt, prodrug, salt of a prodiug, oi a combination thereof, whetein Z is C(O) and X is -C(O)OR 5
oi -C(O)N(R S
) 2
, with the proviso that A and D are not both phenyl, and with the proviso that when A is pyiidinyl os pyrimidinyl, and D is phenyl, then X is not -C(O)OH, and R 1
, R 3
, R D
, Q, A, D, m, and n aie as desciibed in the summary of the invention Examples of R a
include hydiogen and
Of this group of compounds, examples of a subgroup include those wherein A is phenyl, and D is monocyclic heteioaiyl, wherein each of A and D is optionally fuithei substituted with 1, 2, 3, 4, or 5 substituents as represented by T, and T, Q, R , m, and n are as desciibed in the summary section Examples of D as a monocyclic heteioaryl ring include, but are not limited to, pyiidinyl, pyrimidinyl, pyiazinyl, thieny, fuianyl, pyπolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl, each of which is optionally further substituted as desciibed heicin In one embodiment, D is pyridinyl, thienyl oi thiazolyl, each of which is optionally fiπlhei substituted with 1 , 2, 3, 4, oi 5 substituents as iepiesented by T and T is as disclosed in the summaiy Examples of T include, but aie not limited to, C|. & alkyl such as methyl, ethyl, and the like, halogen such as fluoio, chloro, and the like, and haloalkyl (for example, hifluoromethyl oi diflυoiom ethyl) In one embodiment, A and D aie each independently unsubstituted oi fuithei substituted with 1 or 2 substituents T wherein T is halogen (for example, fluoio) Examples of R 1 aie hydrogen and Ci-β alkyl such as methyl In one embodiment, R j is hydrogen In one embodiment, n is O Q is -Ct=Y)N(R 2 XR 2 "), -C(=W)(R b ), -R b , ~S(O) 2 (R b ), or -C(0)0(R b ) wherein Y, W, R 2 , R 2a , and R b aie as desciibed in the summary In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wherein Y, R 2 , and R 2li are as disclosed in the summaiy Examples of Y include O, N(CN), S or C(H)NO 2 In one embodiment, Y is O or S In another embodiment, Y is O In one embodiment, R 2a is hydrogen oi methyl In another embodiment, R 2a is hydrogen Examples of R 2 include phenyl, heteroaiyl (foi example, pyiidinyl, pyrimidinyl, pyrazinyl, thieny, furanyl, pyπolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl) and cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1, 2, 3, 4-tetrahydronaphthalen-l-yl), each of which is independently optionally substituted as
Filed electronically May 17, 2007 S224WOO1
described in the summary In one embodiment, R 2
is phenyl, thienyl, pyiidinyl, or cyclohexy], each of which is independently optionally substituted as described in the summary, Examples of the optional substituents of R 2
include
Other examples of a subgroup include those wherein both A and D aie monocyclic heteroaiyl, wherein each A and D is independently optionally further substituted with 1, 2, 3, 4, or 5 substituents as represented by T, and T, Q, R " \ m, and n ate as described in the summary section. Examples of the monocyclic heteroaiyl ring include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thieny, furanyl, pyπolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl, each of which is optionally further substituted as described herein In one embodiment, A and D are each independently pyridinyl, thienyl or thiazolyl, each of which is optionally further substituted with 1 , 2, 3, 4, or 5 substituents as represented by T and T is as disclosed in the summary. Examples of T include, but are not limited to, Ci-e alkyl such as methyl, ethyl, and the like, halogen such as fluoro, chloio, and the like, and haloalkyl (for example, trifluoiomethyl or difiuoromethyl). In one embodiment, A and D are each independently unsubstituted or further substituted with I or 2 substituents T wherein T is halogen (for example, fluoro). Examples of R 1 are hydrogen and C}.& alkyl such as methyl In one embodiment, R 1 is hydrogen In one embodiment, n is 0. Q is -C(=Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R b ), or -C(O)O(R b ) wherein Y, W, R 2 , R 2a , and
Filed electronically May 17, 2007 8224WOO1
R b aie as described in the summary In one embodiment, Q is -C(=Y)N{R 2 )(R 2a ) wherein Y, R 2 , and R 2a are as disclosed in the summary Examples of Y include O, N(CN), S or C(H)NO 2 In one embodiment, Y is O or S In another embodiment, Y is O In one embodiment, R 2a is hydrogen oi methyl In another embodiment, R 2a is hydrogen Examples of R 2 include phenyl, heteroaryl (for example, pyridinyl, pyπmidinyl, pyrazinyl, thieny, fuianyl, pyπolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oi pyiazolyl) and cycloalkyl (foi example, cyclopentyl, cyclohexyl, cycloheplyl, cyciooctyl, adamantyl oi 1 , 2, 3, 4-tci]ahyd!onaphthalen-l-yl), each of which is independently optionally substituted as described in the summary In one embodiment, R 2 is phenyl, thienyl, pyridinyl, or cyclohexyl, each of which is independently optionally substituted as desciibed in the summaiy Examples of the optional substituents of R 2 include C|-& alky] such as methyl, ethyl, and the like, -OR a wherein R a is C | - G alkyl such as methyl, ethyl, and the like, halogen (for example, fluoio, chloio, and the like), and haloalkyl such as trifluosomethyl In another embodiment, Q is -C(=W)(R ) wherein W and R aie as disclosed in the summaiy In one embodiment, W is O Examples of R b include R 4 and -(CR 8 RVR "1 whciein R 4 , R B , R h and u are as defined in the summaiy Examples of R 4 include atyl (fot example, phenyl) and heteioaiyl, each of which is optionally fuithei substituted as described in the summaiy In one embodiment, R J is phenyl, thienyl, oi pyiidinyl, each of which is optionally furthes substituted as described in the summary Examples of the optional substituents of R 4 include Ci - f , alkyl such as methyl, ethyl, and the like, -OR J wheieirs R a is Ci-ή alkyl such as methyl, ethyl, and the like, halogen (for example, fluoio, chloro, and the like), and haloαlkyi such as trifluoromethyl In one embodiment, u is 1 , one of R B and R 1 ' is hydrogen, and the other is hydrogen, CI- G alkyl such as methyl, and the like, or halogen (for example, fluoro) In anothei embodiment, u is 1 , and R g and R 1 ', together with the carbon atom to which they are attached, form a monocyclic, thiee- to six-membered cycloaikyl ring (foi example, cyclopiopyl)
Examples of yet another subgroup include those wherein A is cycloalkyl (for example, cyclohexyl) and D is phenyl, each of which is independently unsubstituted or substituted as desciibed in the preceding paragraph Particular values of T, R 1 , R 3 , Q, m, and n are as described in the preceding paragraph
A further aspect of the invention is related to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein Z is C(O) and m is 3, with the proviso that when A is phenyl, and D is phenyl, then
Filed electronically May 17, 2007 8224WOO!
X is -CN, -C(=NOR S )N(R 5 ) 2) -C(R 6 R 7 )OH, -C(O)-N(R 5 )(OR 5 ), or tetiazolyl, and with the further proviso that when A is pyridinyl oi pyiimidinyl, and D is phenyl, then X is not -C(O)OH Such compound can exist as the cis isomers or tians isomers One embodiment is directed to the trans isomers as represented by formula (Ib). It is understood that the structural drawing of (Ib) encompasses not only one particular trans isomer as depicted in (Ib), but also othei trans isomers (for example, (Ic)), and mixtures lheieof (including racemates)
(Ib) ( |c ) wherein Q, A, D, X, R 1 , R 3 , and n in formula (Ib) and (Ic) are as described in formula (I). It is understood that particular values of the various groups (for example, Q, A, D, X, R ! , R 3 , and n), embodiments and combinations of embodiments of the groups, including particular, and moie particular embodiments as described in formula (I) are also contemplated for compounds of formulae (Ib) and (Ic).
A further aspect of the invention is related to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a piodrug, or a combination theieof, wherein m is 2, and Z is C(O), with the proviso that when A is phenyl, and D is phenyl, then X is -CN, -C(=NOR 5 )N(R 5 ) 2 , -C(R 6 R 7 JOH, -C(O)-N(R 5 )(OR 5 ), oi tetiazolyl, and with the fiulhei proviso that when A is pyridinyl or pyiimidinyl, and D is phenyl, then X is not -C(O)OH Such compound can exist as the cis isomers or tians isomers One embodiment is directed to the tians isomers as iepiesented by formula (Id). It is understood that the structural drawing of (Id) encompasses not only one particulai trans isomer as depicted in (Id), but also other trans isomers (for example, (Ie)), and mixtures thereof (including racemates) .
(I). Il is understood that particular values of the various groups (for example, Q, A, D, X, R 1 , R 3 , and n), embodiments and combinations of embodiments of the groups, including particular, and more particular embodiments as described in formula (I) are also
Filed electronically May 17, 2007 8224WOO 1
contemplated for compounds of formulae (Id) and (Ie)
Thus, examples of compounds of formula (Ib) or (Id) include those wherein X is C(O)O(R 5 ) or C(O)N(R 5 ), wherein R 5 , Q, A, D 1 R 1 , R 3 , and n are as described in the summary, with the proviso that when A is phenyl, then D is not phenyl, and with the further proviso that when A is pyridinyl or pyrimidinyl, and D is phenyl, then and X is not -COOH Examples of R 3 include hydrogen and Cι-& alkyl such as methyl, and ethyl In one embodiment, X is -C(O)OH
Of this group of compounds, examples of a subgroup include those wherein A is phenyl, and D is a monocyclic heteroaiyl, wherein each of A and D is optionally further substituted with 1 , 2, 3, 4, or 5 substituents as repiesented by T, and T, Q, R 1 , R 3 , and n aie as described in the summary section. Examples of D as a monocyclic heteioaryl ring include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thieny, fuianyl, pyπolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl, each of which is optionally further substituted as described herein In one embodiment, D is pyridinyl, thienyl or thiazolyl, each of which is optionally iurtliet substituted with 1, 2, 3, 4, oi 5 substituents as repiesented by T and T is as disclosed in the summary. Examples of T include, but are not limited to, Cu, alkyl such as methyl, ethyl, and the like, halogen such as fluoro, chloro, and the like, and haloalkyl (for example, trifluoromethyl or difluoromethyl) In one embodiment, A and D are each independently unsubstituted oi further substituted with 1 or 2 substituents T wheieiπ T is halogen (for example, fluoro) Examples of R 1 are hydrogen and C|.& alkyl such as methyl In one embodiment, R 1 is hydrogen In one embodiment, n is 0 Q is -Q=Y)N(R 2 XR 23 ), -C(=W)(R b ), -R b , -S(O) 2 (R b ), or -C(O)O(R b ) wheiein Y, W, R 2 , R 2a , and R b are as described in the summary In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wheiein Y, R 2 , and R 2a are as disclosed in the summary. Examples of Y include O, N(CN), S oi C(H)NOi In one embodiment, Y is O or S In another embodiment, Y is O In one embodiment, R 2a is hydrogen or methyl In another embodiment, R 2a is hydrogen Examples of R 2 include phenyl, heteroaiyl (for example, pyridinyl, pyrimidinyl , pyrazinyl, thieny, fuianyl, pyπolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oi pyiazolyl) and cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1 , 2, 3, 4-tetrahydronaphthalen-l-yl), each of which is independently optionally substituted as described in the summary. In one embodiment, R 2 is phenyl, thienyl, pyridinyl, or cyclohexyl, each of which is independently optionally substituted as described in the summary Examples of the optional substituents of R 2 include Cι-6 alkyl such as methyl,
Filed electronically May 17, 2007 S224WOO1
ethyl, and the like, -OR a wheiein R a is C|. & alkyl such as methyl, ethyl, and the like, halogen (for example, fiuoro, chloro, and the like), and haloalkyl such as trifluoiomethyl. In another embodiment, Q is -C(=W)(R b ) wheiein W and R b are as disclosed in the summary In one embodiment, W is O. Examples of R b include R 4 and -(CR g R Sl ) u -R 4 wherein R 4 , R g , R h and u are as defined in the summary Examples of R 4 include aryl (for example, phenyl) and heteroaiyl, each of which is optionally furthei substituted as described in the summary In one embodiment, R 4 is phenyl, thienyl, or pyiϊdinyl, each of which is optionally fuiiher substituted as described in the summaiy. Examples of the optional substituents of R 4 include C i- 6 alkyl such as methyl, ethyl, and the like, -OR a wherein R a is Ci-o alkyl such as methyl, ethyl, and the like, halogen (for example, fiuoro, chloro, and the like), and haloalkyl such as trifluoromethyl. In one embodiment, u is 1, one of R s and R h is hydiogen, and the other is hydrogen, CV<, alkyl such as methyl, and the like, or halogen (for example, fluoio) In another embodiment, u is 1 , and R s and R ', together with the carbon atom to which they are attached, form a monocyclic, three- to six-membeted cycloalkyl ring (for example, cyclopropyl)
Other examples of a subgroup include those wherein both A and D are monocyclic heteroaiyl, wherein each A and D is independently optionally further substituted with 1 , 2, .3, 4, oi 5 substituents as represented by T, and T, Q, R , R " , and n aie as described in the summary section. Examples of the monocyclic heteroaryl ring include, but aie not limited to, pyridinyl, pyrimidinyl, pyrazinyi, thieny, furanyl, pyπolyl, thiazoly], isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl, each of which is optionally further substituted as described herein. In one embodiment, A and D are each independently pyπdinyl, thienyl oi thiazolyl, each of which is optionally fiuther substituted with 1 , 2, 3, 4, or 5 substituents as represented by T and T is as disclosed in the summary Examples of T include, but aie not limited to, Ci-e alkyl such as methyl, ethyl, and the like, halogen such as fluoio, chloxo, and the like, and haloalkyl (for example, tiifluoromethyl or difluoromelhyl) In one embodiment, A and D are each independently unsubstituted oi further substituted with 1 or 2 substituents T wherein T is halogen (for example, fiuoro) Examples of R aie hydrogen and Cι-o alkyl such as methyl. In one embodiment, R 1 is hydrogen. In one embodiment, n is 0 Q is -C(=Y)N(R 2 )(R 2a ), -C(=W)(R b ), -R b , -S(O) 2 (R b ), or -C(O)O(R b ) wheiein Y, W, R 2 , R 2a , and R b are as described in the summaiy. In one embodiment, Q is -C(=Y)N(R 2 )(R 2a ) wherein Y, R 2 , and R 2il are as disclosed in the summary Examples of Y include O, N(CN), S or C(H)NO 2 . In one embodiment, Y is O or S. In another embodiment, Y is O In one
Filed electronically May !7, 2007 S224WOO1
embodiment, R 2a is hydiogen oτ methyl In another embodiment, R 2a is hydrogen. Examples of R 2 include phenyl, heteroaryl (for example, pyridinyl, pyrimidinyl, pytazinyl, thieny, fuianyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oi pyiazolyl) and cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or 1, 2, 3, 4-letiahydronaphthalen-l-yl), each of which is independently optionally substituted as described in the summary In one embodiment, R" is phenyl, Ihienyl, pyridinyl, oi cyclohexyl, each of which is independently optionally substituted as described in the summary, Examples of the optional subslituents of R " include Cι- 6 alkyl such as methyl, ethyl, and the like, -OR a wherein R a is Ci -6 alkyl such as methyl, ethyl, and the like, halogen (for example, fluoio, chloro, and the like), and haloalkyl such as trifluoromethyl In another embodiment, Q is -C(=W)(R b ) wherein W and R b aie as disclosed in the summary. In one embodiment, W is O Examples of R b include R '! and -(CR 8 R 51 VR 4 wherein R 4 , R*% R h and u are as defined in the summary Examples of R 4 include aryl (foi example, phenyl) and heteroaryl, each of which is optionally further substituted as described in the summary In one embodiment, R 4 is phenyl, thienyl, or pyridinyl, each of which is optionally further' substituted as described in the summary Examples of the optional substttueπts of R 4 include C i.( 3 alkyl such as methyl, ethyl, and the like, -OR a wherein R a is Cι- 6 alkyl such as methyl, ethyl, and the like, halogen (for example, fiuoio, chloro, and the like), and haloalkyl such as trifluoromethyl. In one embodiment, u is 1 , one of R B and R 1 is hydrogen, and the other is hydiogen, Ci -6 alkyl such as methyl, and the like, or halogen (for 1 example, fluoio) In another embodiment, u is 1, and R g and R 1 , togethei with the carbon atom to which they are attached, form a monocyclic, three- to six-metnbered cycloalkyl ring (foi example, cyclopropyl)
Yet other examples of a subgroup include those wherein A is cycloalkyl (for example, cyclohexyl) and D is phenyl, wherein each A and D is independently optionally further substituted with 1 , 2, 3, 4, or 5 substituents as represented by T, and T, Q, R , R 3 , and n are as described in the summary section Particular values of T, Q, R 1 , R 3 , and n are as described in the preceding paragraph.
Exemplary compounds of the present invention include, but are not limited to the following:
λ/ ' -(3-chloiOpheny1)--V-(4'-{(λ)-hydroxy[(lλ,2λ)-2- (hy droxymethyl)cycl opentyljmethy 1 } - 1 , l'-b iphenyl -4-yl )u rea; N-(3-chlorophenyl)-N'-(4'-{(S)-hydroxy[(lλ,2/?)-2-
Filed electronically May 17, 2007 8224WOO1
(hydtoxymethyl)cyclopentyl]methyI}-l ,r-biphenyl-4-yl)urea;
N'(3-chlorophenyl}-N i -(4 l -{[(li? ! 27?)-2-{M-iydrOxy~l - niethylethyl)cyclopentyl]caibonyl} - 1 , 1 '-biphenyl-4-yl)uiea;
N-(4 l - {[( lR,2R)-2-{ 1 -hydroxy- 1 -methylethyl)cyclopentyl]carbonyl }- 1 , 1 '-biphenyl-4- yI)-iV-phenylurea;
λ r -(4'-{(,S)-hydioxy[(lλ s 2λ)-2-(hydtoxymethyl)cyclopentyl]melhyl}-l ) l'-biphenyl-4- yl)-W-phenylurea;
N-(4 1 -{(λ)-hydiOxy[(17?,2/?)-2~(hydiOxymethyl)cyc]opentyI]methyl }-l ,l '-biphenyl-4- yl)-N'-phenylurea; N-(4'- { [( 1 λ,2i?)-2-(hydiOxymethyl)cyc]opentyl]methyl}- 1 , 1 '-biphenyl-4-yl)-JV- phenyluiea; methyl (IJ?,2/2)-2-{4-[5-({[(3-chlorophenyl)amino]caτbonyl}amino)t hien-2- yl]benzoyl}cyclopentanecaiboxy1ate; methyl (lJ?,2λ)-2-(4-^5-[(anilinocatbonyl)amino]lhien-2- yl } benzoyl)cyclopeπtanecarboxylate; methyl (lλ J 2i?)-2-(4-{5-[( {[3-(tτifiuoiomethyl)phenyl]amino}carboπyl)amino]thien- 2-yl}benzoyl)cyclopentanecaiboxylate;
( 1 R,2R)-2-{4-[5-( {[(3-chloiophenyl)amino]carbonyl } amino)thien-2- yl]benzoyl}cyclopenlanecarboxylic acid; (l/?,2λ)-2-(4-{5-[(anilinocaibonyI)amino]thien-2-yl }benzoyl)cyc!opentanecaiboxylic acid;
( 1 R,2R)-2-(4- {5-[( { [3-(tiifluoiomethyl)phenyl]amino} carbonyl)amino]thien-2- yl } benzoyl)cyclopentaπecaiboxylic acid;
N-{4 ! -{[(17?,2/i)-2-cyanocyclopentyl]caibony]}-l ,r-biphenyl-4-yl)-N ! -phenylurea; ttans-2-{4-[4-({[(3- chlorophenyl)amino]caibonyl}amino)cyclohexyl]benzoyl}cyclope ntanecaiboxylic acid; methyl ( 1 R,2R)-2-{4- {6-[(aniIinocaibonyl)amino]pyridin-3 - yl } benzoytycyclopentanecarboxylate;
Tmns-2-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyiidin-2- yl)carbonyl]cyclopentanecaτboxylic acid;
Trans-2-[(5-{4-[({[3-{trifluoromethyl)phenyl]amino}caτbo nyl)amino]phenyl}pyiidin- 2-yl)carbonyl]cyclopentanecarboxylic acid;
Trans-2-({5-[4-{{[(3-chlorophenyl)amino]carbonyl}amino)ph enyl]pyiidin-2-
Filed electronically May 17, 2007 8224WOO!
yl } carbonyl)cyclopentanecarboxylic acid;
Trans-2-({5-[4-({[(2-fluoiophenyl)amino]caibonyl}aniino)p lieny]]pyridin-2- yl}caibonyl)cyc!opentanecarboxylic acid;
T.ans-2-[(5-{4-[( {[2-fluoio-5- (tiifluoromelhyl)phenyl]amino}carbonyl)amino]phenyl}pyridin- 2- yl)caibonyl]cyclopenlanecaιboxylic acid;
Tiaπs-2-[(5- {4-[(phenylacetyl)amino]phenylj pyiidm-2- yl)caibonyl]cyclopentanecaiboxylic acid;
Tians-2-{[5-(4-{[(2-ethoxyphenyI)acetyl]amino}phenyl)pyii din-2- yl]caibonyl}cyclopentanecaiboxylic acid;
Tiaπs-2-{[5-(4-{[(3,5-dimethylphenyl)acetyl]amino}phenyl )pyiidin-2- yl]catbonyi}cyclopentanecaiboxylic acid;
Trans-2-{[5-(4--S [(2R)-2-phenylpiopanoyl]amino}phenyl)pyiidin-2- yl]caibonyl } cyclopentanecaiboxylic acid; Tians-2-{[5-(4-{[fluoio(phenyI)acety]Jamino}phenyl)pyπdin-2 - yl]caibonyl}cyclopenlaneca!boxylic acid;
Tιans-2-[(5- {4-[(lhien-3-ylacetyl)amino]pheπyl}pyridin-2- yl)caibonyl]cyclopentanecaiboxylic acid;
Trans-2-[(5--{4-[(pyπdin-3-y]acetyl)amino]phenyl}pyridin -2- yl)caibonyl]cyclopentanecaiboxylic acid;
Trans-2- { [5-(4- { [( 1 -pheπylcyclopropyl)caibonyl]amino } phenyl )pyi idm-2- yl]caτbonyl}cyclopenlanccaiboxylic acid;
Trans-2-[(5-{4-[(anilinocaibonyl)amino]-3-ωuotopheny]}py ridin-2- yl)caibonyl]cyclopentanecaiboxylic acid; Tians-2-[(5-{3-fluoio-4-[(phenylacetyl)amino]phenyl}pyiidin- 2- yl)caibonyl]cyclopentanecaiboxylic acid;
Trans-2-({6'-[({[3-(triflιιoiomethyl)phenyl]amino}caibo nyl)amino]-3,3'-bipyridin-6-- yl}caibonyl)cyclopentanecaiboxylic acid;
Trans-N-[2-f]uoio-5-(ttifIuoromethyl)pheny]]~N r 44-(2-{[(lS,2S)-2-(l-liydioxy-l - methylethyl)cyclopenty]]carbonyl} -1 ,3-thiazoI-5-yl)phenyl]urea;
Trans-2-[(5-{4-[({[2-fluoro-5-
{trifluoromethyl)phenyl]amino}caibonyl)amino]phenyl}thien -2-yl)carbony]]cyclobutane caiboxylic acid;
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Trans-2-I(5- {4-[( {[2-fluoio-5-
(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-l,3- fhiazol-2- yl)caτbonyl]cyclopentanecarboxylic acid ;
Trans-2-[(5- {3-fluoro-4-[( {[> (trifluoiomethyl)phenyl]amino}caibonyl)amino]phenyl}-l ,3-thiazol-2- yl)caibonyl]cyclopentanecaiboxylic acid;
Tians-2-[(5-{3-fluoιo-4-[( {[2-fluoio-5-
(ti iIluoiomethy1)phcnyl]aminoJ caibonyl)amino]phenyl}-i,34hiazol-2- yl)caibony1]cyclopentanecaiboxylic acid; Trans-2-[(5- {4-[( {[2-fluoio-5-
(trifluoromethyl)pheny]]amino}carbonyl)amino]phenyl}-l,3- thiazoI-2- yl)caibonyl]cyclobutane caiboxylic acid; and
Tians-2-[(5- {3-fluoio-4-[( { [3-
(tiifiuoiomethyl)phenyljamino}caibonyl)amino]phenyl}lhien -2-yl)caibonyl]cyclobutane caiboxylic acid; oi a pharmaceutically acceptable salt, piodiug, or salt of a piodnig thereof
Compounds disclosed heiein can contain asymmctiically substituted carbon oi sulfur atom, and accoidingly can exist in, and be isolated in, single steieoisomeis (e g single enantiomer or single diasleieomei), mixtures of stereoisomer (e g any mixture of enanliomeis oi diasteieomers) Ot iacemic mixtures theicol Individual optically-active foπn of the compounds can be prepaied foi example, by synthesis fiom optically-active stalling materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation It is to be understood that the present invention encompasses any racemic, optically-active, steieoisomeric foπn, or mixtures of vaiious proportions thereof, which form possesses properties useful in the inhibition of DGAT-I activity Where the stereochemistty of the chiial centers present in the chemical stiuctuics illustrated hcicin is not specified, the chemical structure is intended to encompass compounds containing either steieoisomei of each chiral center piesent in the compound
Examples of some of the possible stereoisomers of the compounds of this invention are represented by formula (If) and (Ig) It is understood that the structural drawing of (If) encompasses not only one particular trans isomer as depicted in (If), but also othei bans isomers (for example, (Ig)), racemates and mixtures of various proportions of (IQ and (Ig)
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It is understood that particular values of the variable groups (for example, R 1 , R 3 , X, Q, Z, A, D, m, and n), and combinations of embodiments, including preferred, more preferred and most preferred embodiments as described in formula (I) are also contemplated for compounds of formulae (If) and (Ig)
Geometric isomers can exist in the present compounds. The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon nitrogen double bond, a cycloalky] group, or a heterocycloalkyl group Substituents around a carbon-carbon or carbon-nitrogen double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heleiocycloalkyl are designated as being of cis or trans configuration
Within the present invention it is to be understood that compounds disclosed herein can exhibit the phenomenon of tautomerism Thus, the formulae drawings within this specification can represent only one of the possible tautomeric oi stereoisomeric forms It is to be understood that the invention encompasses any tautomeric or stereoisomeric form, and mixtures theieof, and is not to be limited meiely to any one tautomeric or steteoisomeiic foπn utilized within the naming of the compounds or formulae drawings
Synthetic Methods
This invention is intended to encompass compounds of the invention when prepared by synthetic processes or by metabolic processes Preparation of the compounds of the invention by metabolic ptocesses include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
The synthesis of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein the groups R 1 , R 2 , R 2a , R 3 , R 5 , R c , R 7 , R b , Q, X, Z, A, D, m, and n have the meanings as set forth in the summary section unless otherwise noted, is exemplified in Schemes 1 - 10
As used in the descriptions of the schemes and the examples, certain abbreviations are intended to have the following meanings: DMSO for dimethylsulfoxide and RP-HPLC for
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preparative ieverse phase high pressure liquid chromatography
Compounds of general formula (1), (Ia), (Ib) 1 (Ic), (Id), (Ie), (If) or (Ig), wherein Z is C(O) prepared can be prepared using the general procedures as outlined in Scheme 1
Scheme 1
As illustrated in Scheme 1, acids of formula (1) can react with a chlorinating agent in a solvent such as, but not limited to, dichloromethane, at a temperature from about room temperature to about 50° C, to provide acid chlorides of foiimila (2). Non-limiting examples of the chlorinating agents include phosphorus pentachloride, oxalyl chloride, and thionyl chloride with or without catalytic N,N-dimethylformamide, The acid chloride of formula (2) can be treated with compounds of formula (3) wherein X 1 is halogen oi tiiflale, G 1 is hydrogen, and D is phenyl or heteroaryl, in the piesence of Lewis acids such as, but not limited to, aluminum chloride, in a solvent such as, but not limited to, dichloromethane, oi dichloioethane to provide a compound of formula (4). In some instances, the compound of formula (3) can act as the reactant as well as the reaction solvent. The reaction is generally conducted at a temperature ianging from about O 0 C to about 10 0 C.
Alternatively, compounds of formula (4) can be prepared by ieacting compounds of formula (2) with compounds of formula (3) wherein G 1 is a reactive subslituent such as, but not limited to, -ZnI, -B(OR 1O i h wherein R [O i is hydrogen or C^, alkyl, in the piesence of a palladium catalyst.
Compounds of formula (4) can be treated with boronic acids or esteis of formula (5) wherein A is phenyl or heteroaryl, X 3 is NO^, N(H)(P G ) wherein PQ is an amine protecting group, or R 2 N(R')C(-Y)N(R 2a ), and X 2 is -B(OR 1 Oi) 2 wherein R 10 ] is hydrogen or C|. fi alkyl, in the presence of a palladium catalyst, in a solvent such as, but not limited to, toluene, dioxane, N,N-dimethylformamide, N,N»dimethyl acetamide, dimethoxyethane, dimethylsulfoxide, isopropanol, ethanol, water, or mixture thereof, to provide compounds of formula (6) Non-limiting examples of palladium catalyst suitable for the transformation include, tetrakis(triphenylphosphine)paIladium(0), bis(triphenylphospine)palladium (H) chloride, and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (II). The reaction can be facilitated with the addition of a base such as, but not limited to, potassium iodide,
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triethylamine, cesium carbonate, sodium caibonate, potassium phosphate, potassium fluoride, oi thallium ethoxide The reaction is generally conducted at an elevated temperature such as 5O 0 C to about 100 0 C and optionally in a miciowave oven
Compounds of formula (4) can also be treated with stannaries of formula (5) wherein A is phenyl or lieteroaryl, X 3 is as defined heieinabove, and X 2 is -Sn(Cj- O alkyl)j, in the piesence of a palladium catalyst such as, but not limited to, teuakis(tπphenylphospine)palladium (0), and heating, in a solvent such as dioxane, to piovide compounds of formula (6) The transformations can also be effected by healing in a microwave reactor Alternatively, compounds of formula (4) wheiein D is phenyl or heteroaryl, and X 1 is
B(ORioi)i or Sn(C ι-6 alky]).-), can be tieated with compounds of formula (5) wherein A is phenyl or heteroaryl, X 2 is halogen or triflate, and X 3 is as defined hereinabove, using ieaction conditions as described in the preceding paragraphs to provide compounds of foimula (6) While many stannaries and boronic acids oi esteis ate commercially available, compounds of formula (4) and (5) wheiein X 1 and X 2 aie independently B(ORjOi) 2 oi Sn(Cj-O alkyl) 3 can also be prepared by tieating the corresponding halides or triflates, with boionatc esters of formula (R[ O iO) 2 B-B(ORi O i) 2 oi distannanes of foimula ((Ci-G alkylXiSn)?, in the presence of a palladium catalyst, using methodologies that aie known in the ait
Compounds of foimula (6) can also be piepaied from treatment of compounds of formula (2) with compounds of foimttia X 3 -A~D » G ' wheiein X 3 is NO 2 , N(H)(P 0 ) and P 0 is an amine protecting gioup, oi R 2 N(R I )C( ; =Y)N(R 1 ), and G 1 is hydrogen, ZnI or -B(RiOi)' wheiein R ]O ι is hydrogen ot Cι- 6 alkyl, using reaction conditions as desciibed above for the transformation of (2) to (4)
Scheme 2 illustrates geneial procedure for the synthesis of compounds of general formula (I) wherein Z is C(O) and Q is -C(=O)N(R 2a )(R 2 ), -~C(=S)N(R 2a )(R 2 ), or -C(=O)(R b )
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Scheme 2
Compounds of formula (6) wherein X 3 is NO? can be converted to compounds of formula (7) wherein R 1 is hydrogen, by treatment with a reducing agent in a suitable solvent. Examples of reducing agents suitable for' the conversion include, but not limited to, iron in the presence of an acid (for example, acetic acid, ammonium chloride, and the like), oi hydrogen gas and palladium catalyst (e g. 5-10% palladium on caibon, and 20% palladium hydroxide on carbon) Compounds of formula (7) can also be obtained by deprotection of compounds of formula (6) when X 3 is N{R j )Po by means well known in the art. Compounds of Formula (8) wherein R 2;ι is hydrogen, X 4 is O or S can be prepared by reaction of compounds of formula (7) with isocyariates or ' isothiocyaπales of formula R 2 NCX 4 , in a solvent such as, but not limited to, tetrahydrofuran, at about room temperature Compounds of formula (8) wherein R 2a is lower alkyl can be prepared from compounds of formula (8) wherein R 2a is hydrogen by treatment with an alkylating agent of formula (Cι-e alkyl)-X° wherein X 0 is halide, txϊflaέe or 1 alkyl sulfonates or aromatic sulfonates such as p- toluenesulfonate, in the presence of a base, in a solvent Non limiting examples of suitable bases include organic bases (for example lrialkylamines such as triethylamine, diisopiopylethylamine and the like), pyridine, picoline, or tertiary cyclic amines such as N- metliylmorpholine) and inorganic bases (for example, alkali metal hydrides, alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates).
Compounds of foirnula (8a) wherein R j is hydrogen can be obtained fiom their reaction of compounds of formula (7a) with an acid of formula R b C(O)OH using coupling reaction conditions known to one skilled in the art. Compounds of formula (7a) wherein R 1 is H can be converted to compounds of formula (7a) wherein R 1 is alkyl by treatment with an
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alkylating agent as described in the preceding paragraph
Scheme 3
Compounds of formula (10) wherein R 2il and R 1 are hydrogen can be piepared fiom compounds of formula (7a) by heating with compounds of formula (9) in a solvent such as, but not limited to, acetonitτile, at elevated tempeiatuie (for example, 70-150° C, moie generally at about 140° C) in a microwave oven Compounds of formula (9) can be obtained ftom reaction of diphcnyl cyaπocabonimidate with amines of formula R 2 NH 2 , in a solvent such as, but not limited to, acetoπiliile. Compounds of foimula (1 1) wheiein K 2a and R are hydiogen can be obtained by (a) lefluxing (7a) with l ,l-bis(melhylthio)-nitroethylene, and (b) treating the product from step (a) with amines of foimula R 2 NH 2 at ioom tempeiatuie, followed by heating at about 6O 0 C until the reaction is complete
Alternatively, compounds of foimula (10) wheiein R 2a is hydiogen can be piepaied by (a) heating compounds of foimula (7a) with compounds of foimula (i) wheiein G 2 is SCH 3 or 0(C G H S ), and (b) heating compounds of foimula (12) obtained from step (a) with amines of foimula R 2 NH 2
Both compounds of formula (10) and (1 1) wherein R ~a and R aie hydiogen can be alkylated to provide compounds of formula (10) and (1 1) wheiein R 2a and R 1 aic lowei alkyl, using the alkylalion reaction conditions as described in Scheme 2 and an appiopitate alkylating reagent
Compounds of general formula (I) wheiein Z is C(O) and X is -C(R f> R 7 )OII can be synthesized using general procedures as outlined in Scheme 4
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8224WOO1
Scheme 4
Compounds of foimula (13) can be conveited to compounds oi foimula ( 14) wheiein
R b and R 7 aie the same and both aie alley! by (a) selectively ieducing the carbonyl functionality between D and the cycloalkyl gioup with a reducing agent such as sodium boiohydtide at lempeiatute of about 0° C, (b) heating the intermediate from step (a) with about two equivalents of the Giinaid ieagcnt of foimula R 0 MgX 5 wheiein X D is Cl, Bi or I, and (c) treating the intermediate fiorn step (b) with an oxidizing agent such as, but not limited to, pyiidinium chloiochi ornate Transformation of compounds of foimula (14) using icaction conditions as described in Schemes 1 , 2 and 3, piovides compounds of foimula (15)
Scheme 5
Reduction of compounds of foimula (16) to psovide compounds of foimula (17) can be accomplished by treatment with a reducing agent such as, but not limited to, sodium boiohydiide oi lithium aluminum hydride, in a solvent such as tetrahydrofman, at a temperature from about 0° C to about room temperature The diastereomeis obtained aflei isolation can be sepaiated using techniques known in the art, for example, silica gel chromatography Scheme 6
Conversion of compounds of formula (16) to amides of formula (18) can be achieved
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by (a) hydrolyzing compounds of formula (16) wherein R 5 is alkyl, (b) converting the corresponding acids of formula (16) wherein R 5 is hydrogen to an activated ester, for example, by treatment with N-hydioxy succinamide, N~(3-dimeιhylaminopropyl)-N'- ethylcarbodiimide hydrochloride and a base such as, N-methyl morpholine, in a solvent such as, dichloromelhane, and (c) generally without isolation of the activated ester from step (b), treating the activated ester with ammonia The ammonia source used can be ammonium chloride, gaseous ammonia, or ammonia in a suitable solvent such as alcohol, water os dioxaπe.
Treatment of compounds of formula (18) with a dehydiaϋng agent in a suitable solvent provides compounds of formula (19). νon limiting examples of dehydrating agent are phosphorous pentoxide, phosphoryl chloride/pyridine or imidazole, trifluoroacetic anhydride/pyridine, and thionyl chloride
Scheme 7
Tieatment of compounds of formula (21) with compounds of formula (22) or (25) wheiein X fl is hydrogen ot halides, and each R 103 can be the same or different Ci-& alkyl, in the piesence of a strong base such as, but not limited to, lithium diisopropylamide, piovides compounds of formula (23) or (26) respectively. Compounds of formula (22) oi (25) can be obtained from the coπesponding aldehydes by treatment with potassium cyanide and trialkyl silyl halides of formula (Rioa-bSiX 7 wheiein X 7 is halogen.
Reaction of compounds of formula (2.3) and formula (26) with tetiabutyl ammonium fluoride in acidic conditions (such as in the presence of acetic acid) provides compounds of formula (24) and (27) respectively, If desired, compounds of formula (.24) and (27) can be resolved into their respective diastereomers using standard means, for example, via silica gel
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column chromatography
Scheme 8
Compounds of foimula (23) (prepared fiom Scheme 7) wheiein G 3 is -O(alkyl) or alkyl, can be treated with a ieducing agent such as sodium hoiohydride to provide alcohols of formula (28) wherein R 6 and R 7 aie both hydrogen Compounds of formula (28) wherein R 6 and R 7 aie the same and are alkyl, can be obtained from reaction of (23) with about one equivalent of Grignaid reagent of formula R 6 MgX 5 when G 3 is alky], or with at least two equivalents of Grignaid reagent of formula R 6 MgX 5 when G 3 is -O(allcyl). Utilizing the reaction conditions as described in Scheme 7 for the transformation of
(23) to (24) converts compounds of formula (28) to (29)
Scheme 9
Scheme 9 illustrates an alternative method of synthesis for compounds of formula (4) wherein X s is bromide
Compounds of foimula (1) can be transformed into compounds of formula (30) when treated with a reagent such as, but not limited to, N.O-dimethylhydroxylamine hydrochloride or moipholine, and a coupling reagent such as, but not limited to, l-ethyl-3-(3- dimethylaminopropyl)caibodiimide, and in the presence of an auxiliary nucleophile such as, but not limited to, hydroxybenzotriazole, and in the piesence of a base such as, but not limited to, N-methyl morpholine, and in a solvent such as, but not limited to, N 3 N- dimethylformamide. The reaction can be conducted at room temperature The amide of formula (30) can be treated with compounds of formula (3) wherein X 1 is bromide, G 1 is halide, and D is phenyl or heteroaryl, in the presence of a Grignard reagent such as isopropyl magnesium chloride, or an alkyl lithium reagent, such as, but not limited to, n- butyllithium, in a solvent such as, but not limited to, tetrahydrofuran or ether, to provide a
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compound of formula (4). The reaction is generally conducted at a temperature ranging from about -2O 0 C to about 10 0 C
Scheme 10
Compounds of formula (33) or (34) can be treated with 4,4,4 1 ,4 t ,5,5,5',5'~octamethyl~ 2,2'-bi(l,3,2-dioxaboiOlane) in the presence of an iridium catalyst and bipyridine ligand, in a solvent such as, but not limited hexane, octane, mesitylene, toluene, or xylenes, at a temperature from about 80° C to about 120° C, to provide compounds of formula (36) wherein Ri 04 is hydrogen or alkyl Non-limiting examples of catalysts suitable for the transformation include rnethoxybis(3 ,5-cycloocladiene)iridium(I) dime. and chloiobis(cyclooctene)iridium(l) dimer. Non-limiting examples of bipyridine ligands suitable for the transformation include 4,4'~dW-butyl-2 5 2'-bipyπdine, 3,3'-dimeιhyl- bipyridine, 4,4'-dimethyl-bipyridine, 5,5'-dimethyl-bipyiidine, and 4,4'-dimethoxy- bipyridine
Compounds of formula (36) wherein Rio4 is hydrogen or alkyl can be treated with compounds of formula (5) wherein A is phenyl or heteroaryl, X 3 is NO 2 , N(H)(PG) and PG is an amine protecting group, or R 2 N(R 2a )C(=Y)N(R'), and X 2 is halide or triflate using reaction
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conditions as described in Scheme 1, to provide compounds of formula (37)
It is appreciated that the synthetic schemes and specific examples as illustrated in the synthetic examples section are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims
Optimum ieaction conditions and reaction limes fo! each individual step can vaiy depending on the particulai ieactants employed and substiluents piesent in the reactants used
Unless otheiwise specified, solvents, tempeiatiπes and other reaction conditions can be ieadily selected by one of ordinary skill in the ait Specific pioceduies are piovϊded in the
Synthetic Examples section Reactions can be woilced up in the convention mannei, c g by eliminating the solvent from the residue and further purified according to methodologies geneially known in the ait such as, but not limited to, crystallization, distillation, exti action, trituiation and chromatography Unless otherwise desciibed, the stalling materials and ieagents are eithei commercially available or can be prepared by one skilled in the ait fiom commercially available materials using methods described in the chemical litciatuie
Routine experimentations, including appiopiiate manipulation of the ieaction conditions, ieagents and sequence of the synthetic route, protection of any chemical functionality that can not be compatible with the reaction conditions, and depioteclion at suitable point in the reaction sequence of the method are included in the scope of the invention Suitable protecting gioups and the methods for piotecling and depiotecting different substiluents using such suitable protecting gioups are well known to those skilled in the art; examples of which can be found in T Gieene and P WuIs, Protecting Groups in Chemical Synthesis (3 rd ed ), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety Synthesis of the compounds of formula (I), (Ia), (Ib), (Ha) or (lib) can be accomplished by methods analogous to those desciibed in the synthetic schemes described heieinabove and in specific examples
Starting materials, if not commercially available, can be piepaied by piocedures selected fiom standard organic chemical techniques, techniques that aie analogous to the synthesis of known, structurally similai compounds, or techniques that are analogous to the above described schemes oi the proceduies desciibed in the synthetic examples section
When an optically active form of a compound of the invention is required, it can be obtained by carrying out one of the procedures described herein using an optically active
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starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure {such as chromatographic separation, recrystallization or enzymatic resolution) Similaily, when a pure geometric isomer of a compound of the invention is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, oi by resolution of a mixtiπe of the geometric isomeis of the compound or intermediates using a standard proceduie such as chiomalographic sepaiation
Biological Data
Inhibition of DGAT-I
The identification of the compounds of the invention as DGAT-I inhibitors was ieadily achieved using a high throughput screening FlashPlate assay.. In this assay, recombinant human DGAT-3 containing an N-teπninal Hise-epitope tag was produced in the baculoviius expression system Insect cells (e g , 5/9 or High Five) were infected for 24 to 72 hours and collected by centrifugation. Cell pellets were resuspended in homogenization buJTei [250 mSVl sucrose, 10 πiM Tris-HCl (pH 7.4), 1 niM EDTA] and lysed using a homogenization appaiatus, such as a Microfluidizei (single pass, 4° C) Cell debris was removed by centrifυgatioπ at 10,000 x g for .30 mm, and microsomal membranes were collected by ultracentrifugation at 100,000 x g for 30 min
DGAT-I activity was determined as follows: Assay buffer [20 niM HEPES (pH 7 5), 2 niM MgCl 3 , 0.04% BSA] containing 50 μM of enzyme stibstiate (dϊdecanoyl glycerol) and 7 5 μM radiolabeled acyl-CoA substrate. [l- M C]decanoyl-CoA) was added to each well of a phospholipid FlashPlate (PerkinElmer Life Sciences). A small aliquot of membrane (1 μg/well) was added to start the reaction, which was allowed to proceed for 60 min The reaction was terminated upon the addition of an equal volume (100 μL) of isopiopanol. The plates were sealed, incubated overnight and counted the next morning on a TopCount Scintillation Plate Reader (PerkinElmei Life Science) DGAT-I catalyzes the transfer of the radiolabel-ied decanoyl gioup onto the <r/;-3 position of didecanoyl glycerol The resultant radiolabeled tridecanoyl glycerol (tricaprin) preferentially binds to the hydrophobic coating on the phospholipid FlashPlate. The proximity of the radiolabeled product to the solid scintillant incorporated into the bottom of the FlashPlate induced fluor release from the scintillant, which was measured in the TopCount Plate Reader. Various concentrations (e.g.
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0.0001 μM, 0.001 μM, 0.01 μM, 0.1 μM, 1.0 μM, 10,0 μM) of the representative compounds of the invention were added to individual wells prior to the addition of membianes The potencies of DGAT-I inhibition for the compounds of the present invention were determined by calculating the IC 50 values defined as the inhibitor concentration From the sigmoidal dose response curve at which the enzyme activity was inhibited 50%. Compounds of the present invention were effective in inhibiting DGAT-I activity and thus aie useful as therapeutic agents for treating conditions and diseases that me associated with DGAT-I activity.
Table 1 : DGAT-I Inhibition of compounds of the present invention (IC50 nM)
Evaluation of Compound Efficacy on the Reduction of Body Weight in Diet-Induced Obese
Mice
The purpose of this piotocol was to determine the effect of chronic administration of a compound on body weight and other metabolic disease parameters in mice made obese by spontaneous ad libitum consumption of a high-fat diet Diet-induced obesity (DlO) in rodents mimics key aspects of human obesity and metabolic syndrome. DIO mice used in this study have been shown to be hyperiπsulinemic and insulin resistant, hypeileptinemic and leptin resistant, and have marked visceral obesity (for review on DIO mice see Collins et al.,
Physiol, Behav. 81 :243-248, 2004). Individually housed male C57BL/6.I mice were given ad lib access to water and to either a low fat diet (Dl 2450B) or a high-fat content diet (D12492 containing 60% kcal from
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fat, both from Research Diets Inc ., New Brunswick, NJ), for approximately 18 weeks Mice were sham dosed once daily with the study vehicle for 7 days prior to active dosing to acclimate them to handling and oial gavage One day prior to active compound dosing, mice were assigned to groups of equal mean body weight and variance A typical experiment consisted of 80-100 animals, 10 animals per dose including vehicle dosed low-fat and high- fat diet gioiips Body weight and food intake were measured by differential weighing
Representative compounds of the invention were typically dosed at 3, 10, oi 30 mg/kg p o b i d as a formulation in 1 % Tween 80 in watei, and the compounds were considered to be active if a statistically significant reduction in body weight was obseived for the treated animals after a treatment period of at least seven days, relative to vehicle-treated control animals. In this model, representative compounds produced a statistically significant reduction in body weight after a treatment period of at least seven days, relative to vehicle- treated control animals.
Liver triacylglycerides levels from DlO-mice treated with compounds of the invention typically dosed at 3, 10, or 30 mg/kg p.o, b i.d. as a formulation in 1% Tween 80 in water for a treatment period of al least seven days were measured from ethanol exti acted liver samples using Infinity TM reagents (Thermo Electron Corporation, Louisville, CO, USA) Representative compounds of the invention produced a statistically significant reduction in liver triacylglycerides in DIO-mice after a treatment period of at least seven days, relative to vehicle-treated control animals.
An insulin tolerance test was also performed at the end of study in DIO mice after a 4 hour fast Blood glucose levels were monitored via tail snip before and at 30 minute intervals following a single i.p injection of 0 25U/kg insulin (Humulin-R, Lilly) using a Precision PCx glucose monitor (Abbott Laboratories, Abbott Park, IL) Representative compounds of the invention produced a statistically significant reduction in blood glucose in animals that had been treated for at least seven days, relative to vehicle-treated control animals.
The effect of co-dosing representative compounds of the invention with i imonabant was also evaluated in DIO-mice Compounds of the invention were typically dosed at 3, 10, or 30 mg/kg p.o b i d as a formulation in 1% Tween 80 in water and rimonabant was typically co-administered at a dose of 3 or 10 mg/kg p.o q.d as a formulation in l%Tween in water' Compounds were considered to be active if they significantly decreased body weight compared to DIO-mice dosed with rimonabant alone. In this model, representative compounds produced a statistically significant reduction in body weight after a treatment
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period of at least seven days, relative to animals treated with rimonabant alone
The effect of co-dosing representative compounds of the invention with fenofibrate was also evaluated in DIO-mice. Compounds of the invention were typically dosed at 3, 10, or 30 mg/kg p.o. b.i d, as a formulation in 1% Tween 80 in water and fenofibrate was typically co-administered at a dose of 100 mg/kg p.o b i,d as a formulation in l%Tween in vvatei Compounds weie considered to be active if they significantly deci eased body weight compaied to DIO-mice dosed with fenofibialc alone. In this model, representative compounds pioduced a statistically significant reduction in body weight after a liealmenl period of at least seven days, relative to animals treated with fenofibrate alone Compounds of the piesent invention and the pharmaceutically acceptable salts are useful as therapeutic agents, Accordingly, an embodiment of this invention includes a method of treating the various conditions in a subject in need thereof (including mammals) which includes administering to the subject a pharmaceutical composition containing an amount of the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), that is effective in ti eating the target condition, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier
Another aspect of the piesent invention provides a method of treating, delay or prevention of various conditions in a patient (such as mammal, preferably human) that are mediated by DGAT-I , which includes administering to the patient a compound of formula (I), (Ia) 5 (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, or a pharmaceutical composition including the same
Another aspect of the piesent invention provides methods for the prevention, delay or tieatment of obesity and inducing weight loss in an individual which includes administering to the individual a compound of the invention, or its pharmaceutically acceptable salt, prodrug, salt of a prodrug, or 1 a combination thereof. The invention furthei provides a method fot the prevention, delay or' tieatment of obesity and inducing weight loss in an individual which includes administering to the individual a pharmaceutical composition including a compound of the invention, oi its phaimaceutically acceptable salt, prodrug, salt of a prodiug, or a combination thereof, in an amount that is effective in heating obesity or to induce weight loss, and a phaimaceutically acceptable carrier. Yet another aspect of the invention provides a method for preventing weight gain in an individual by administering at least one compound of the invention, oi its pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, in an amount that is sufficient to prevent weight gain,
Filed electronically May 1 7, 2007 8224W0O 1
The present invention also relates to the use of the compounds of this invention for the treatment of obesity-ielated diseases including associated dyslipidemia and othei obesity- and overweight-ielated complications such as, foi example, cholesterol gallstones, gallbladder disease, gout, cancer (e g , colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, and bile duct), menstrual abnormalities, infertility, polycystic ovaries, osteoarthritis, and sleep apnea, as well as foi a numbei of othei pharmaceutical uses associated therewith, such as the iegulation of appetite and Food intake, dyslipidemia, hypeitiiglyceiidemia, metabolic syndiome oi Syndtomc X, type 2 diabetes (non-insulin- dependent diabetes), atheioscleiotic diseases such as heatt failure, hypcilipidemia, hyper cholesteiernia, low HDL levels, hypei tension, caidiovasculai disease {including atherosclerosis, coronary heart disease, coronary aitery disease, and hypertension), cerebrovascular disease such as stroke, and peripheral vessel disease The compounds of this invention can also be useful for heating physiological disordeis related to, for example, iegulalion of insulin sensitivity, inflammatory response, liver steatosis, elevated lives triacylglycerides, non-alcoholic fatty liver disease, non-alcoholic steatohepatilis, plasma triacylglycerides, HDL, LDL and cholesterol levels and the like Metabolic syndiome is chaiacteiized by a group of metabolic iisk factois in one peison Such factois include, but aie not limited to, abdominal obesity, atherogenic dyslipidemia (blood fat disorders such as high triglycerides, low HDL cholesterol and high LDL cholesteiol), elevated blood pressure, insulin resistance (oi glucose intoleiance), prothiombotic state (e g high fibiinogcn or plasminogen activator inhibitor-1 in the blood), and pioinflammaloiy state (e g elevated C- reactive protein in the blood) In one embodiment, the piesent invention provides methods of treating the above listed disorders wherein the methods include the step of administering to a subject in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same The compounds of this invention, or pharmaceutical acceptable salts thereof, or pharmaceutical compositions including the same, ate also useful in lowei ing plasma tπglyceπdes level Thus, in one embodiment, the present invention provides a method foi lowering plasma triglycerides in a subject (including mammal) in need thereof, wheiein the method includes the step of administering to the subject in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same
Compounds of the invention or pharmaceutically acceptable salts thereof, can be
Filed electronically May 17, 2007 8224WOO1
administered alone or in combination (i.e. co-administered) with one or more additional pharmaceutical agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutical agents, as well as administration of the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, and each additional pharmaceutical agent, in its own sepaiaie pharmaceutical dosage formulation For example, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), oi (Ig), oi a pharmaceutically acceptable salt thereof, and a pharmaceutical agent, can be administeied to the patient together, in a single oral dosage composition having a fixed ratio of each active ingredient, such as a tablet or capsule, or each agent can be administered in separate oial dosage formulations.
Where sepaiate dosage formulations are used, compounds of the invention and one or more additional pharmaceutical agents can be administeied at essentially the same time (e g , concurrently) oi at separately staggeicd times (e g., sequentially)
For example, the compounds of the invention can be used in combination with one of moie of the following pharmaceutical agents, including, but are not limited to, anti-obesity drags including /3-3 agonists such as CL-316,243; CB-I antagonists and/or inverse agonists (for example, rimonabant); neuropeptide Y5 inhibitors; appetite suppressants, such as, for example, sibulramine (Meridia© or Reductil©); MCHr 1 antagonists and lipase inhibitors, such as, for example, orlistat (Xenical), and a drug compound that modulates digestion and/or metabolism such as drugs that modulate thermogenesis, lipolysis, gut motility, fat absorption, and satiety
In addition, compounds of the invention can be administered in combination with one or more of the following pharmaceutical agents including PPAR ligands (agonists, antagonists), insulin sectetagogues (for example, sulfonylurea ch ugs and non-suifoπylurea secretogogues), a- glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, and insulin and insulin derivatives Such agents can be administeied prior to, concurrently with, or following administration of the compounds of the invention Insulin and insulin deiivatives include both long and short acting foims and formulations of insulin PPAR ligands can include agonists and/or antagonists of any of the PPAR receptors or combinations thereof. For example, PPAR ligands can include ligands of PPAR-α, PPAR-γ, PPAR-δ or any combination of two oi three of the receptors of PPAR. PPAR ligands
Filed electronically May 17, 2007 8224WOO1
include, for example, rosiglitazone, tioglitazone, and pioglitazone Sulfonylurea drugs include, for example, glyburide, glimepiiide, chlorpropamide, tolbutamide, and glipizide, α- glucosidase inhibitors include acarbose, miglitol, and voglibose. Insulin sensitizers include PPAR-γ agonists such as the glitazones (e g 5 troglitazone, pioglitazone, englitazone, MCC- 555, losiglitazone, and the like) and other ihiazolidinedione and non- thiazolidinedione compounds; biguaπides such as metfoimin and phenfoimin; piotein tyrosine phosphatase- IB (PP-IB) inhibitois; dipeplidyl peptidase IV (DPP-IV) inhibitois, and 1 1 beta -USD inhibitors Hepatic glucose output loweiing compounds include glucagon antagonists and metroπnin, such as Glucophagc and Glucophage XIl Insulin secictagogues include sulfonyliuea and non- sulfonyluiea diugs: GLP-I , GIP, PACAP, secietin, and deiivatives theieof; nalcglinide, meglitinide, repaglinide, glibeiiclamide, glimepiiide, chloipropamide, glipizide GLP-I includes deiivatives of GLP-I with longei half-lives than native GLP-I, such as, for example, fatty-acid dciivatized GLP-I and cxendin
Compounds of the invention can also be used in methods of the invention in combination with one oi moie phaimaceulical agents including, but aie not limited to, HMG- CoA reductase inhibitois, nicotinic acid (for example, Niaspan©), fatty acid loweiing compounds (e g , acipimox); lipid loweiing diugs (e g , stanol estcis, steiol glycosides such as tiqueside, and azetidinones such as czetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants, bile acid ieuptake inhibitors, miciosomal tiiacylglycerides tianspoit inhibitors, and fibiic acid deiivatives LIMG-CoA reductase inhibitois include, foi example, statin such as lovastatin, simvastatin, piavaslatin, fiuvastalin, atoivastatin, livastatin, itavastatin, ceiivastatin, and ZD-4522 Fibric acid deiivatives include, foi example, clofibiate, fenofibiate, bezafibrate, ciprofibrate, beclofibrate, etoiϊbiate, and gemfibrozil Sequestrants include, for example, cholestyramine, colestipol, and dialkylaminoalkyl deiivatives of a cross-linked dextran
Compounds of the invention can also be used in combination with anli- hypci tensive drugs, such as, foi example, jS-blockers and ACF inhibitois Examples of additional anti- hypei tensive agents foi use in combination with the compounds of the picscnt invention include calcium channel blockeis (L-type and T-type; c g , dilliazcm, veiapamil, nifedipine, amlodipine and mybeftadil), diuretics (e g , chlorothiazide, hydiochloiothiazide, flumethiazide, hydioflumethiazide, bendroωumethiazide, methylchloiothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin
Filed electronically May 17, 2007 8224WOO1
inhibitors, ACE inhibitors {e g , captopril, zofenopiil, fosinopril, eπalapiil, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-I receptor antagonists (e g , Iosartan, irbesartan, valsartan), ET receptor antagonists (e g , sitaxsentan, atisentan, neutral endopeptidase (NEP) inhibitois, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e g , omapatiilat and gemopatrilat), and nitrates
The compounds of this invention can also be co-administcied with an incicϋn mimetic such as, but not limited to, cxenatidc
The compounds of this invention can be utilized to achieve the dcsiicd pharmacological effect by administration to a subject in need thereof in an appiopi lately fbi initiated pharmaceutical composition A subject, for example, can be a mammal, including human, in need of treatment for a particular condition or disease There foie the piesent invention includes pharmaceutical compositions which include a theiapeuiically effective amount of a compound identified by the methods described heiein, or a pharmaceutically acceptable salt thcieof, in combination with a pharmaceutically acceptable canici The compounds identified by the methods described hciein can be administered with a pharmaceutically acceptable caπ iei using any effective conventional dosage unit forms, foi example, immediate and timed release preparations, orally, paientcially, topically, oi the like The phaimaceutical compositions can be formulated foi oial administiation in solid or liquid fomi, for paienteral injection oi for rectal administiation L iquid dosage forms foi oial administration of the piesent compounds include formulations of the same as emulsions, microemulsions, solutions, suspensions, syiups, and elixirs In addition to the compounds, the liquid dosage foπns can contain diluents and/or solubilizing or emulsifying agents Besides inert diluents, the oral compositions can include wetting, emulsifying, sweetening, flavoring, and perfuming agents Injectable preparations of the present compounds include sterile, injectable, aqueous and oleaginous solutions, suspensions or emulsions, any of which can be optionally foππulatcd with paientcially suitable diluents, dtspeising, wetting, or suspending agents These injectable picpaiaiions can be sterilized by filiiation through a bactctial-ietaining filtci or formulated with sterilizing agents that dissolve or dispeise in the injectable media Inhibition of DGAT-I by the compounds of the piesent invention can be delayed by using a liquid suspension of crystalline oi amoiphous material with pooi watei solubility The iate of absorption of the compounds depends upon their rate of dissolution, which, in turn, depends on then crystallinity Delayed absorption of a parenterally administered
Filed electronically May 17, 2007 8224WOO1
compound can be accomplished by dissolving or suspending the compound in oil. Injectable depot forms of the compounds can also be prepared by microencapsulating the same in biodegradable polymers. Depending upon the ratio of compound to polymer and the nature of the polymer employed, the rate of release can be controlled. Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions that are compatible with body tissues.
Solid dosage forms fbi oral administration of the present compounds include capsules, tablets, pills, povvdeis, and granules In such forms, the compound is mixed with at least one inert, therapeutically suitable excipient such as a carrier, filler, extender, disintegrating agent, solution retarding agent, wetting agent, absorbent, or lubricant, With capsules, tablets, and pills, the excipient can also contain buffering agents. Suppositoties for rectal administration can be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperature but fluid in the lectum.
The present compounds can be micro-encapsulated with one or more of the cxcipients discussed pieviously The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepaied with coatings and shells such as enteric and release-controlling In these forms, the compounds can be mixed with at least one inert diluent and can optionally include tableting lubricants and aids Capsules can also optionally contain opacifying agents that delay release of the compounds in a desired part of the intestinal tract Transdermal patches have the added advantage of providing controlled delivery of the present compounds to the body. Such dosage fonns are prepared by dissolving oi dispensing the compounds in the proper medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin, and the rate of absorption can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel
The compounds of the invention can be used in the form of pharmaceutically acceptable salts, esters, or amides derived from inorganic or organic acids The term "pharmaceutically acceptable salts, esteis and amides," as used herein, include salts, zwitterions, esteis and amides of compounds of disclosed herein which aie, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower ' animals without undue toxicity, irritation, allergic response, and the like, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
Pharmaceutically acceptable salts are well-known in the art, The salts can be
Filed electronically May 17, 2007 8224WOO1
prepared during the final isolation and purification of the compounds or separately by reacting an amino gioup of the compounds with a suitable acid. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, d.gluconate, glycerophosphate, hernϊsulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, malate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfatc, 3-phcnylpιopionate, piciate, oxalate, pivalate, propionate, succinate, tartrate, trichloroacetic, tiifiuoioacctic, glutamate, para-loluenesulfonale, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The amino groups of the compounds can also be quateinized with alky] chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lainyl, myiistyl, stearyl, and the like.
Basic addition salts can be prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydi oxide, carbonate, or bicaibonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine Quaternary amine salts derived from melhylamine, dimethyϊamine, trimethylamine, triethylamine, diethylamine, ethylaminc, iributlyamine, pyridine, N.N-dimethylaniline. N- methylpiperidine, N-methylmoipholine, dicyclohexylamine, piocaine, dibenzylamine, N ,N- dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethy1enediamine, ethylenediamine, ethanolamine, diethanolamine, pipeiidine, piperazine, and the like, are contemplated as being within the scope of the present invention
Disorders that can be treated or prevented in a patient by administering to the patient, a therapeutically effective amount of compound of the present invention in such an amount and for such time as is necessary to achieve the desired result The term "therapeutically effective amount," refers to a sufficient amount of a compound of the invention to effectively ameliorate disoideis by inhibiting DGAT-I at a reasonable benefil/tisk ratio applicable to any medical treatment The specific theiapeuticaHy effective dose level foi any par ticular patient depends upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, rate of excretion; the duration of the treatment; and drugs used in combination or coincidental therapy.
Filed electronically May 17, 2007 S224WOO1
The total daily dose of the compounds of the present invention necessary to inhibit the action of DGAT-I in single or divided doses can be in amounts, for example, from about 0,01 to 50 mg/kg body weight. In a more preferred range, compounds of the present invention inhibit the action of DGAT-I in a single or divided doses from about 0.05 to 25 mg/kg body weight. Single dose compositions can contain such amounts or subniultiple doses thereof of the compounds of the piesent invention to make up the daily dose. In geneial, treatment iegimens include administration to a patient in need of such treatment Horn about 1 mg to about 1000 mg of the compounds pei day in single or multiple doses
The compounds identified by the methods desciibed herein can be administered as the sole pharmaceutical agent or in combination with one or moie othei pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with anti-obesity, or with known antidiabetic or other indication agents, and the like. Thus, the present invention also includes pharmaceutical compositions which include a thesapeutically effective amount of a compound identified by the methods desciibed herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable caπ iei, and one of moie pharmaceutical agents as disclosed hereinabove.
The piesenl invention is described below in connection with certain preferred embodiments which are not intended to limit its scope. On the contrary, the piesent invention coveis all alternatives, modifications, and equivalents as can be included within the scope of the claims. Routine experimentation, including appropriate manipulation of the reaction conditions, reagents used and sequence of the synthetic route, protection of any chemical functionality that can not be compatible with the ieaction conditions, and deprotection at suitable point in the reaction sequence of the method are included in the scope of the invention Suitable protecting groups and the methods for piotecting and depiotecting different siibstilucnts using such suitable piotecting groups aic well know to those skilled in the art; examples of which can be found in T Gieene and P Wυls, Piotecting Gtoups in Chemical Synthesis (3 rd ed ), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety Synthesis of the compounds of formula (I) can be accomplished by methods analogous to those described above and in the following examples The following examples, which include preferred embodiments, illustiate the preferred practice of the present invention, it being understood that the examples are for the purpose of illustration of certain preferred embodiments and are presented to provide what is believed to be the most
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useful and readily understood description of its procedures and conceptual aspects Finally, the compounds of the invention were named by ACD/ChemSketch version 5.06 (developed by Advanced Chemistry Development, Inc , Toronto, ON, Canada) or were given names consistent with ACD nomenclature.
Examples
Example 1
N-f3-chloiophenyl)-N'-r4'" [f7?)-hvdiOxy[f l J R,2/<!)-2-fhvdtOXvmethyl ' )cvclopentyl1methyl}- 1.r-biρhenyl-4-vnutea and N-(3-chloioi3hcπylViV ! -f4'-lf.yvhvdiOxyrri^.2/;)-2- fhvdroxymetlivDcyclopentylimethyU-I .r-biphenyM-vDurea
Example IA cis-cyclopentane-1.2-dicarboxylic actd To a solution containing ethyl 2-oxocyclohexanecarboxylate (100 g, 0 588 mol) in
300 niL of chloiofoim at 0° C biomine (94 g, 0 588 mo!) was added The mixture was stirred overnight, washed with a saturated sodium bicaibonate solution and brine, dried over aπhydious sodium sulfate, filtered and concentrated under reduced piessurc to remove the solvent The residue was added drop wise to an ice-cold solution containing potassium hydroxide (140 g, 2 50 mol) in 800 mL of water The reaction mixture was stirred for 2 hours and was extracted with diethyl ethci The aqueous phase was acidified with a 4.0 M hydrochloric acid solution and extracted with diethyl ether. The combined ethereal solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a yellow oil, which crystallized on standing to provide to Example IA as colorless crystals
Example I B cyclopentane-1.2-dicaiboxylic anhydride
A solution containing Example I A (56 6 g, 0 358 mol) in 1500 ml- of acetic anhydride was heated at ieflux for 20 hours The excess acetic anhydride was removed by distillation under ieduced pressure. The oily residue was distilled to give Example IB as a colorless oil. 1 H νMR (500 MHz, DMSOd 6 ) δ ppm 1 -07-2.02 (m, 6H) and 3.47-3 55 (m,
2H).
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Example 1C ci s-2 -f methoxyc arbonyl )cyclopentaneearboxyϊi c ac id
Example IB (40.2 g, 286,9 mmol) was dissolved in methanol (250 niL), and the mixture was then heated at 50-55° C under N 2 for 16 hours The ieaction was concentrated under i educed piessitie, and the residue was dried in vacuo to afford the desired product as a coloiless oil 1 H NMR (500 MHz, DMSO-(I 6 ) δ ppm 1 .54-1 61 (m, IH), 1.66-1 76 (m, IH),
1 80-1 91 (m, 4H), 3 95-3 02 (m, 2H), 3.54 (s, 31-1), 12 05 (bi s, I H).
Example ID me thy 1 cis-2 -f 4-bτom obεnzo yl)c yc lop en tanecarboxyl a te Step A:
A solution of Example 1C (30,7 g, 178..3 mmol), SOCI 2 (39 niL, 535 mmol), and N,N-dimethylforτnamide (0 33 mL) in CH2CI 2 (38.3 ml) was stirred at room tempeialure overnight under N?. The solvent was removed by iolary evaporation at < 40° C, and the iesidue was diied in vacuo for 1 hour. Step B:
The intermediate described in step A was dissolved in biomobenzene (1 12.5 mL, 1.067 mol), and AlCh (47,5 g, 357 mmol) was then added portion wise at <5 G C. The reaction mixture tinned dark brown, and was stirred at <5°C for 4 houi under N 2 . 1 H NMR showed that little starting material remained The reaction mixture was then slowly pouted into 700 mL ice-water, and then 350 mL. ethyl acetate was added. After the mixture was stilled for 10 minutes, the aqueous (top) layer' was separated, and extracted with 200 mL ethyl acetate The combined organic layers were washed with water (2 x 350 mL) and saturated NaI-ICO.i solution (70 mL), dried ovei Na 2 SO^, and filtered . Removal of solvent and drying in vacuo provided the desired pioduct, which was used directly in the next step. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1 5S-1 .83 (m, 3H), 1 .91 -2 05 (m, 3Ii), 3 15-3.21 (m, 1 H), 3 37 (s, 3H), 4 13-4. 19 (m, IH), 7 73 (d, ./ = S 59 Hz, 2H), 7 87 (d, J = 8 90 Hz, 2H) .
Example IE tians-2-(4-bromobenzoyI)cyclopentanecarboxylic acid
A solution of NaOH (42.9g, 1 07 mol) in 234 mL water was added to a solution of Example I D (3783 rnrnol) in methanol (234 mL). The reaction mixture was stirred at room
Filed electronically May 17, 2007 8224WOO1
temperature overnight. 1 H NMR showed that little starting material lemained. After 350 mL solvent was removed by rotary evaporation, the mixture was diluted with 350 mL water The aqueous was acidified to pH 6 with concentrated HCl while keeping the internal temperature at < 15 0 C. A precipitate formed, and stirring was continued foi I hour, The solid precipitate was filtered, and iinsed with water The dried filter cake was dissolved in 350 mL ethyl acetate, dried over Na 2 SO 4 , and filtered Removal of solvent and drying in vacuo affoided the title compound . 1 I-I NMR (500 MHz, DMSOd 6 ) δ ppm 1 55-1.85 (m, 4H), 1 .93-2 03 (m, IH), 2 09-2,15 <m, IH), 3.15-3.21 (m, H-I), 4.00-4 06 (m, IH), 7 75 (d, J- 8 59 Hz 1 2H), 7 92 (d, J= S 59 Hz, 2H), 12.21 (br s, IH).
Example IF
( 17?,2/0-2-f4-bromobenzoyl)cvclopentanecarboxylic acid
A mixture of Example IE (27.4 g, 92.2 mmoi) and (R)-(+)-alpha-methyl-benzylamine (5 59 g, 46. 1 mmol) in CH 3 CN (268 mL) was heated to 90-95 α C undei N 2 to piovide a solution The hot solution was allowed to cool slowly with slow staring overnight The crystallized solid was filteied, and iinsed with CHjCN (12 mL) The Filter cake was dried in vacuo to a constant weight. The solid was then dissolved in a hot (95° C) mixiuie of solvent (62 mL ethanol and 124 mL water) undei N 2 . The hot solution was allowed to cool slowly with slow Stirling overnight The solid was filtered, rinsed with 15 mL of 1 :2 ethanol/water, and dried in vacuo to a constant weight The white solid was stirred with IN HCl (120 mL) and ethyl acetate (120 mL) for 10 minutes. The organic layer was separated, washed with water (2 x 48 mL), and dried over Na 2 SO 4 . Removal of solvent and drying in vacuo provided an off-white solid (> 94% ee based on chiral HPLC). Chiral HPLC method: Chimed OJ analytical column, 2:98 ethanol/hexanes (both containing 0 1% hifluoioacetic acid), 1 5 mL/min flow rate, retention times were 18 90 min and 22 18 min for the (S,S) and (R 1 R) isomeis, respectively 1 H NMR (500 MHz, DMSO-do) δ ppm 1 55- 1 85 (m, 4H), 1 93-2 03 (m, I H), 2 09-2. 15 (m, IH), 3.15-3 21 (ni, IH) 1 4 00-4 06 (m, IH), 7 75 (d, ./= S 59 Hz, 2H), 7 93 (d, J= 8 59 Hz, 2H), 12.21 (br s, IH)
Example IG methyl (17?,2.fl)-2-(4-bromobenzoyl)cyclopentaneeaιboxylaιe
A suspension of Example IF (7.96 g, 26. 8 mmol), iodomethane (2,5 mL, 40 2 mmol), and NaHCO 3 (6.75g, 80 4 mmol) in N,N-dimethylformaτnide (94 mL) was stirred at
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room temperature undei N 2 For 16 hours 1 H NMR showed that little starting mateiial remained Water (262 mL) was added to the reaction mixture, and the organics were removed under reduced pressure The aqueous was acidified to pH < 7 by the addition of 1 N HCl, while keeping the internal temperature of the < 15° C Ethyl acetate (300 mL) was added, and the layers were separated The aqueous layer was extracted with ethyl acetate (2x 200 mL) The combined organic layeis weie washed with brine, di ied over Na^SO 4 and concentrated The residue was puiified by chromatography on SiOi gel, cUtling with 0 - 5% ethyl acetate in hexanes, to provide the title compound. 1 Il NMR (500 MHz, DMSOd 0 ) δ ppm 1 59-1.84 (m, 4H), 1 97-2 04 (m, IH), 2,11-2 19 (m, IH), 3 24-3 29 (m, IH), 3 56 (s, 3H), 4.02-4 08 (m, IH), 7.76 (d, ./ = 8.90 Hz, 2H), 7.93 (d, J = 8 59 Hz, 2H)
Example IH methyl (iy?,2/?)-2-[f4 1 -nitio-l ,r-biphenyl-4-yl)caibonyIlcvclopentanecaiboxylate
To an ambient sluiry of Example IG (2 g, 6 4 mmol), 4-nitιophenyl boionic acid (2.1g, 12 S mmol) and KT (1 12 g, 19 3 mmol) in dimelhoxyethane/toluene/ethanol/ϊ-LO
(10/1/6/3 ratio, 30 mL) palladium tetiakis(lripheπylphosphine) (75 nig, 0.06 mmol) in a single portion was added The reaction was heated to 90° C overnight, cooled to ioom lempeialiue, filteied through celite, washed with ethyl acetate, concentrated and puiified on a flash column, elυting with 0 - 15% ethyl acetate in hexanes, to piovide the title compound. 1 H NMR (500 MtIz, DMSOd 6 ) δ ppm 1 .58-1 ,89 (m, 4H), 1 ,99-2 07 (m, IH), 2.16-2 2.3 (m,
IH), 3 24-3.29 (m, IH), 3.58 (s, 3H), 4..1 1-4.18 (m, IH), 7 96 (d, J = S 59 Hz, 2H), 8,06 (d, J
= 8 90 Hz, 2H), 8.14 (d, J = 8.59 Hz, 2H), 8 34 (d, ./ = 8 90 Hz, 2H); MS (ESI) m/z 354 0
Example 11 methyl ( l/? ? 2/?)-2-[(4'-amino-l .r-biphenvJ-4-yl)carbonyHcvclopentanecarboxylate
A mixture of Example I H (2 206 g, 6 24 mmol), iron powdei (1 046 g, 1 S 7 mmol), and NH 1 ]C] (334 mg, 6 24 mmol) in a mixture of solvents (90 ml of ethanol and 25 mL of water) was heated to 85° C undei N 2 for 2 hours, The ieaction mixture was fϊHeied through celite, treated with aqueous saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate The organic layer was washed with brine, dried over Na^SO 4 , filtered and concentrated. The residue was concentrated to provide the title compound without further purification. 1 H NMR (500 MHz, DMSOd 6 ) δ pprn 1.54-1 86 (m, 4H), 1 .98-2.07 (m, IH),
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2.13-2..22 (m, IH), 3.25-129 (m, I H), 3.57 (s, 3H), 4 04-4 10 (m, IH), 5.41 (s, 2H), 6.8ό(d, J = 8 90 Hz, 2H), 7 48 (d, J = 8,59 Hz, 2H), 7..70 (d, J = 8 90 Hz, 2H), 7 98 (d, J = 8,60 Hz, 2H); MS (ESI) m/z 324.0 [M+H] + .
Example U methyl f lJ?,2JO-2- [[4'-f {[O-chioiophenyDaminoicaibonyU amino)-! .1 '-biphenyi-4- y] " [caibonyll cvclopentanccarboxylate
A scintillation vial was charged with Example I I (20 mg, 0 06 mmol), l -chloro-3- isocyanatobenzene (9 mg, 0..07 mmol) and tetiahydiofuran (6 mL) It was placed in a shaker at ioom tempeiatuie overnight Tlie mixture was concenliated and puiified by RP-HPLC (prepai alive reversed-phase chromatography was performed using a Zorbax SB-CIS 7uM 21.2x250 mm column with UV detection analyzed at 220 and 254 nM. Preparative method: (water with 0.1% trifluoioacetic acid and CH 3 CN with 0.1% liifluoroacetic acid gradient) 5- 95% CH 3 CN over 30 minutes at 15 rnL/min.) to provide the title product. 1 H NMR (500 MHz 3 DMSO-dβ) δ ppm 1 56-1 87 (m, 4H), I 00-2 07 (m, IH), 2 16-2 23 (m, IH), 3 30-3 34 (m, IH), 3 58 (s, 3H), 4,09-4, 14 (m, I H), 7 02-7.05 (m, IH), 7.28-7 33 (m, 2H), 7 60 (d, J = S 84 Hz, 2H), 7 72-7 74 (m, 3H), 7 82 (d, ./ - 8,55 Hz, 2H), 8.06 (d, ./ = 8 24 Hz, 2H), 8.96 (d, J= 2.44 Hz, 2H); MS (ESl) m/z 477 [M+H] +
Example IK
N-(3-chlorOphenyl)-N ! -(4'-((^)-hvdioxyl ' (17?,2/?)-2-(hvdiOXvniethyl)cvclopentvilmethyl|- l J'-biphenvI-4-v1)urea and N-(3-chloiOphenyl)-N'-(4'-{(5)-hvdiOχyrf lR,27;)-2-
(hydioxymethvDcyclopentyljmethyl) -3 , i'-biphenγl-4-yl)urea
A 25 mL lound-botlom flask was charged with Example U (48 mg, 0 1 mmol) and leti ahydrafuian (8 mL) Aftei cooling to 0° C, a solution of lithium aluminum hydiide in tetrahydrofuran (0 4 mL of 1 0 M, 0 4 mmol) was added to the reaction flask. The cooling bath was removed, and the reaction stirred at room temperature for 2 hours The reaction was quenched with saturated ammonium chloride solution (10 mL), and the aqueous layer was extracted with ethyl acetate (50 mL) The combined organic layer was dried over Na 2 SCi, concentrated, and purified by RP-HPL.C to provide two diastereomers Retention times of the two diastereomeis were determined by RP-HPLC (Agilent ZORBAX SB-CI S column 5 urn,
4.6 x 250 mm, solvent flow: 1.5 ml / min, stop time: 20 minutes, beginning with 100% H 2 O
(with 0.1% trifluoroacetic acid) for 0-1 min., 1-15 min: 0% CH 3 CN to 100% CH 3 CN, 15 -18
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min: 100% CH 3 CN, 18-19 minutes: 100% to 0% CH 3 CN, 19-20 minutes: 100% H 2 O (with 0 1 % tiifluoroacetic acid) Diasteieomer with retention time = 12.775 minutes had 1 H NMR (500 MHz, DMSOd 6 ) δ ppm 1 35-1 52 (m, 4H), 1 55-1 67 (m, 2H), 1 81-1 89 (m, 2H), 3 08- 3 36 (m, 2H), 4 37 (t, J = 4 91 Hz, IH), 4 50 (t, J = 4 91 Hz, IH), 5 13 (d, / = 4 60 Hz, IH), 7 01-7 03 (m. IH), 7 30 (d, J = 7 67 Hz, 2H), 7 37 (d, / - 8 29 Hz, 2H), 7 53-7 62 (m, 6H), 7 72-7 73 (m, I H), S 84 (s, I H), S 90 (s, IH); MS (ESI) m/z 449 1 [M-II]"; diasteieomer with icLcntion time of 13 082 minutes had 1 II NMR (500 MIIz, DMSO-J 6 ) δ ppm 1 16-1 51 (m, 511), 1 63-1 71 (m, IH), 1 79-1 86 (m, IH), 1 99-2 07 (m, IH), 3 26-3 35 (m, 2H), 4 32 (d, J - 8 28 Hz, IH), 4 79 (bι, s, IH), 5 48 (bi s, IH), 7 01 -7 03 (m, IH), 7 30 (d, J= 7 67 Hz 1 2H), 7 37 (d, J = 8 29 Hz, 2H), 7 52-7 62 (m, 6H), 7 72-7 73 (m, IH), 8 83 (s, IH), 8 89 (s, IH), MS (ESI) m/z 449 1 [M-H] +
Example 2
JV-(3-chloiophenyl )-IΫ-(4'- 1 U 1 R,2R)-2-( 1 -hydioxy-1 -methylethvDcvclopentyllcaibonvU -1.1 '- biphcnyl-4-yl)uιca
Example 2A
(4-biomophenyI)[(lJ?,2/?)-2-(l -hydroxy- l-methylcthyDcvclopentyllmethanone Step A Sodium boiohydiidc (0 25 g, 6 59 raraol) was added in portions to a solution of
Example IG (1 95 g, 6 27 mmol) in tetiahydiofuian (20 niL) and methanol (5 mL) maintained at 0° C The ieaction was allowed to waim to rt over 30 minutes and then stiπed at it foi 1 hoiu The ieaction was quenched by addition of water (50 niL) and extiacted with ethyl acetate The organic exttacls were washed with watci, brine, dried (MgSO-j), filleted and concentrated to a blown oil, which was used in the next step StejiB
Methyl magnesium btomide ( 1 1 ml, 3M solution in diethylethei) was added drop wise to a solution of the cuide pioduct obtained fiom step A in tetrahydiofuian (40 mL) maintained at 0° C The ieaction was allowed to warm up to ioom tcmpeiaiuie overnight and then quenched by caieful addition of watei and aqueous dilute HCl The mixtuie was cxLiacted with ethyl acetate, and the oiganic layers wcic washed with water, brine, dried (MgSO 4 ), filtered and concentrated to a clear oil, which was used as is in the next step Step C
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The pioduct from step B was placed in dichloromethane (30 mL) with silica gel (1 g), and pyridinium chlorochromate (2.02 g, 9 4 mmol) was added at it The reaction was stirred at it for 24h and was then filtered through a pad of silica gel. The filtrate was concentrated and purified by flash chromatography, using 10% ethyl acetate/ hexanes as the eluent, to afford the title compound. 1 H NMR (300 MHz, DMSOd 6 ) δ ppm 0.94 (s, 3H), 1 06 (s, 3H), 1 42-1 .77 (m, 5H), 1 93-2 02 (m, IH), 2 53-2.61 (m, IH), 3 77-3 85 (m, IH), 4 16 (broad s, I H), 7 74 (d, J = S 5 Hz, 2H), 7 94 (d, J= S 5 Hz, 2H)
Example 2B [( lR2R)-2-( 1 -hydroxy- 1 -methvIethyl)cvclopentyl]f4 < -niiiO- 1 , 1 '-biphenyl-4-yI)meUiaiione
4-Nitro phenyl boionic acid (0.69 g, 4 1 mmol) was added to a suspension of Example 2A (0 92 g, 2,94 mmol), potassium fluoride (0 5 Ig, 8 8 mmol), and Ietiakis(uiphenylphosphine)palladium(0) (0 28 g, 0.24 mmol) in a solvent mixtiπe (10: 1 :6:3 ::DME:PhCH3:ethanol, FbO, 40 mL) and degassed with nitrogen for 10 minutes The reaction mixtuie was then heated to 90° C foi 15 houis, cooled, quenched with water (40 mL), and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (MgSO 1 )), concenuated and puiified by Hash chtomalogiaphy, using 30% ethyl acetate/hexanes as eluent, to provide the title compound. 1 H NMR (400 MHz, DMSO-d^) 5 ppm 0 96 (s, 3H), 1 .08 (s, 3H) 1 1 50-1 58 (m, 2H), 1 62-1 67 (m, 2H), 1.73-1 79 (m, IH), 1 99-2 07 (m, 1 H), 2 61-2,66 (q, ./ » 7.7 Hz, 1 H), 3 89-3.92 (m, 1 H), 4 17 (s, 1 H), 7 95 (d, J = 8 6 Hz, 2H), S 04 (d, J= 8.9 Hz, 2H), 8 14 (d, J = 8.6 Hz, 2H), S 35 (d, J = 8.9 Hz, 2H); MS (ESI) m/z 352 1 [M-H] *
Example 2C λ f -f3-chloiOphenvlVλ/'-(4'-{[(lJ?.2/?)-2-(l-hvdtoxy-l -methylethvl)cvclopentvllcaibonyll-l .l '- biphenyl-4-yl)urea Step A
Example 2B (0.6 g, 1 7 mmol) was placed along with iron (0 19g, 3 4 mmol) and ammonium chloride (0 Ig, 1 87 mmol) in ethanol (10 mL) and water (4 mL-) and heated at 90° C for 2 hours The reaction mixture was then cooled, filtered over wet celite, and the filttate diluted with water. The iesultant piecipitatc was filteied, and the filtrate extracted with ethyl acetate. The organic extracts were washed with water and biine, dried (MgS O 4 ), Filtered, concentrated and combined with the solid obtained fiom filtration and carried
Filed electronically May ! 7, 2007 8224WOOi
forward to the next step without further purification. Step B
The crude product from step A (0.4 g, 1 .24 mrnol) was treated with 3-chlorophenyl isocyanate (0 18 mL, 1 48 mmol) in tetrahydrofuran (20 mL) and stirred at room tempeiature for 2 clays. The reaction mixture was quenched with water and extracted with ethyl acetate The organic extracts were washed with water and brine, dried (MgSCi), filtered and concentrated to a yellow solid The crude solid was taken up in methanol, and the resultant slurry filtered to affoid the title compound The filtrate was purified by RP-HPLC (Preparative leversed-phase chromatography was performed using a Zoibax SB-Cl 8 7μM 21 2x250 mm column with UV detection analyzed at 220 and 254 nM . Preparative method: (Water with 0.1% trifluoroacetic acid and CH 3 CN with 0. 1% trifluoioacetic acid gradient) 5- 95% CH 3 CN ovei 30 minutes at 15 mL/min ) to afford an additional crop of the title compound 1 H NMR (400 MHz, DMSOd 6 ) δ ppm 0.96 (s, 3H), 1 .08 (s, 3H), 1.49-1 55 (m, 2H), 1.62-1 .67 (m, 2H), 1 73-1.79 (m, IH), 1 99-2 07 (m, I H), 2 63 (q, 7 = 7 9 Hz 5 IH), 3.89- 3 92 (m, 1 H), 4.15 (s, 1 H), 7.03 (dt, .7 = 2 1 , 6.7, IH), 7 29-7 34 (m, 2H), 7 59 (d, 7 = 8 6 Hz, 2H), 7 71 (d, 7 - 8 9 Hz, 2H), 7 Sl (d, J = 8 6 Hz, 2H), 8.06 (d, 7 = 8,9 Hz, 2M), 8.93 (s, 2H); MS (ESI) m/z 459.2 [M- 17] "
Example 3 λW- \ UlR2R)-2-( 1 -hydroxy- 1 -methylethyDcvclopentylicarbonvH- 1.1 '-biphenyI-4-yl ViY- pheirykπea
Example 3 was prepared using the proceduie described for the synthesis of the intermediate of step B of Example 2C, substituting phenyl isocyanate for 3-choloro phenyl isocyanate 1 H NMR (400 MHz, DMSOd 0 ) δ ppm 0 96 (s, 3H), 1 .08 (s, 3H), 1 ,46-1 56 (m, 2H), 1 59-1 69 (m, 2H), 1 72-1 80 (m, IH), 1 99-2.07 (m, I H), 2 61 {q, J = 7.9 Hz, I H), 3 86- 3.92 (m, I H), 4 17 (s, I H), 6 98 (I, J = 7 3, I H), 7.28 (t, 7 = 7 6 Mz, 2H), 7 47 (d, 7 = 7 6 Hz, 2H), 7.60 (d, 7 = 8 8 Hz, 2H), 7.70 (d, 7 = 8 8 Hz, 2H), 7.80 (d, 7 = 8.5 Hz, 2H), 8 06 (d, 7 = 8 5 Hz, 2H), 8 77 (s, IH), 8.91 (s, IH); MS (ESI) m/z 441 2 [M-H] "
63
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Example 4
^-(4':if . ^-lwdroxy[f lλ,27?)-2-(hydroxymethyl)cvclopenWllmethyl)-lJ'"biphenyl-4- yl)-N- phenylurea and N-(4'-(fi?)-hvdroxyfπ.ff,2J?)-2-fhvdr ι oxymethvπcvclopentyllniethyU-l,r- biphenyl-4-yl)-iV-phenylurea Step A
A solution of Example 14A (44 mg, 0,1 mmol) in tetrahydrofuian (0 4 mL) and methanol (0.1 ml.) at ambient tempeiaturc was tieated with sodium boiohydricϊe (5 mg, 0 13 mmol) The homogeneous yellow solution turned colorless in ten minutes Aftei one hour, the reaction was quenched by slow addition of distilled water, stilted five minutes, then IM H 7 SO4 added and stilted an additional five minutes. The reaction mixluie was then diluted with ethyl acetate, and the aqueous layei basified to pH 10 with IM K2CO3. The layeis weie separated, and the organic extract was washed with brine, dried (νa2Sθ4), filtered and concentrated to give 40 mg of a yellow solid. Step B One half of this yellow solid from Step A (20 mg) was purified by flash silica gel chromatography using a gradient elution of methanol in dichloromethane to afford two diastereomers. The higher' Rf diasteieomer isolated as an off-white solid had 1 H NMR (.300
MHz, DMSOd 6 ) δ ppm 1 1 1 - 1 52 (m, 5 H), 1 59 - 1 72 (m, 1 H) 1 1.83 (s, J=6 78 Hz, 1 H), 1 95 - 2.1 1 (m, I H), 3 2-3 3 (m, 2H), 4.32 (dd, ./=7.97, .3 56 Hz, 1 H), 4 79 (C, ,/=4.75 Hz, 1 H) 1 5 48 (d, /=3.39 Hz, 1 H), 6,97 (d, 7=7.46 Hz, 1 H), 7 24 - 7 32 (m, 2 H), 7 36 (d, ./=8.48 Hz, 2 H), 7 47 (d, J=I 46 FIz, 2 H), 7,50 - 7.64 (m, 6 H), 8.72 (s, 1 H), 8 77 - 8.82 (s, 1 H); MS (ESI, methano]/NH 4 OH) m/z 416 [M] + , 415 [M-H] " Lower R, diasteteomes was isolated as an off-white solid with 1 H NMR (300 MHz, DMSO-d n ) δ ppm 1 29 - 1 53 (m, 4 H) 1 5.3 - 1 69 (m, 2 H) 1 74 - 1 93 (m, 2 H) 3 03 - 3 19 (m. 2 H) 4.38 (t, 7=5 09 Hz, 1 H) 4 44 - 4.54 (m, 1 H) 5 1.3 (d, ./=4 41 Hz, 1 H) 6 97 (t, ./=7.29 Hz, 1 H) 7 24 - 7 32 (in, 2 H) 7 37 (d, J=S 14 Hz, 2 H) 7.46 (d, ./=7.46 Hz, 2 H) 7..51 - 7.65 (m, 6 H) 8 69 (s, 1 H) 8.76 (s, 1 H); MS (ESI 5 methanol/NH 4 OH) m/z 417 [MH-H] + , 415 [M-H] " .
Example 5 N-(4'-{[(1^.2/?)-2-(hvdiOxymethyl)cyclopentyllmethyl}-l .r-biphenyl-4-yl)-λ / '-phenv]ιπea
A solution of the product from Step A of Example 4 (20 mg, 0.045 mmol) in tetrahydrofuran (0.4 mL) and methanol (0 1 mL) was charged with 20% Pd(OH)2 on carbon
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(10 mg) The reaction was swept with nitrogen and stirred under a hydrogen atmosphere (balloon) for 23 hours at ambient temperature Analysis by LC/MS revealed remaining starting material. Therefoie, the flask was swept with nitrogen, more Pd(OH) 2 on carbon (10 mg) added, swept with nitrogen and stiπed under a hydrogen atmosphere for an additional fourteen hours The reaction was swept with nitrogen for five minutes, the black heterogeneous mixture was filtered through a plug of silica (2g), rinsed with 95/5 dichloromelhane/melhanol and concenUated to give a white solid Purification by (lash silica gel chromatography using giadienl elulion of methanol in dichloiomethane gave the Lille compound as a while solid 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1 .15 - 1.62 (m, 6 H), 1 63 - 1 74 (m, 2 H), 1 .77 - 1 89 (m, 1 H) 1 2 80 (dd, 7=13 39, 5.59 H) 1 , I H), 3 13 - 3.28 (m, 2 H), 4,42 (I 1 J=5 26 Hz, 1 H), 6 97 (t, ,/=7.29 Hz, 1 H) 1 7.20 - 7.33 (m, 4 H), 7 46 (d, >7 46 Hz, 2 H), 7.50 - 7 63 (m, 6 H), 8.71 (s, 1 H), 8 77 (s, 1 H); MS (ESI, meUianol/NH 4 OH) m/z 401 [MH-H] + , 423 [M+Na]+, 399 [M-H] "
Example 6 methyl ( iy?.2/0-2--!4-[5-( ^ [(3~chloiophenyl)aminolcarbonvUamino)lhien-2- yl 1 benzoyl kvclopentanecarboxylate
Example 6 A methyl (li;.2/?)-2-l ' 4-(4 1 4,5.5-tetramelhyl-1.3,2-dioxabotolan-2- vPbenzovHcyclopentanecaiboxylate
To a solution of Example I G (1 9 g, 6 4 mmol), bis(pinacolato)diboron (1 .6 g, 6 4 mmol) and N,N-dimethy1formamide (35 niL) potassium acetate (1 9 g, 19 mmol) and palladium (II) acetate (430 mg, 1 9 mmol) were added. The reaction mixture was heated to 85 0 C for 3 hours, (lien cooled to room lempeialure. The mixture was filleted though a plug of silica gel and rinsed with ethyl acetate The filtrate was concentrated and Fuither purified by flash chromatography (ethyl acetate/Hexane; 1/30) to give rise to pale yellow oil. 1 H NMR
(500 MHz, DMSOd 6 ) δ ppm 1 32 (s, 12H), 1 47-1 88 (m, 4H), 1 99-2.20 (m, 2H), 3 28 (m,
IH), 3 56 (s, 3H), 4.08 (m, I H), 7 82 (d, J = 8 29 Hz, 2H), 7 98 (d, ./ = 8 29 Hz, 2H); MS (DCI/NH 3 ) m/z 359 [M-H-I] +
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Example 6B methyl fl J R,2iϊ ' )-2-f4-(5-ni<τothien-2-yl ' )benzoyl]cvclopentanecarboxylate To an ambient sluπy of 6A (270 rng, 0.75 mmol), 2-brorno-5-nitτo-thiophene (156 mg, 0.75 mmol) and potassium fluoride (130 mg, 2,24 mmol) in dimethyoxyethane/toluene/ethanol/HiO (10/1/6/3 ratio, 3 mL) was added palladium tetτakis(triphenylphosphiπe) (10 mg, 0 0086 mmol) in a single portion The reaction was heated at 90 0 C overnight, cooled Io room iemperatiπe, filtered through celite, washed with ethyl acetate, concent! aled and puiified by flash chromatography on SiO? column (0 - 5% ethyl acetate in hexanes) to provide the title compound as yellow solid 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1 .54-1 87 (m, 4H), 1 99-2 20 (m, 2H), 3 30 (m, IH), 3.57 (s, 3H), 4. 12 (m, 1 H), 7 ,84 (d, ./ = 4.27 Hz, 1 H), 8 ,01 (d, J = 8.54 Hz, 2H), 8 10 (d, J = 8 54 Hz, 2H), 8 23 (d, J = 427 Hz, IH); MS (DCl/NHj) m/z 360 [M+I-lf
Example 6 C methyl (l/?.2j/?)-2-[4-(5-aminolhien-2-yl)bcnzoyllcyclopentanecarbo xylate
A mix tut c of 6B (200 mg, 0..56 mmol), iron powder (188 mg, 3 36 mmol), and NHUCl (30 mg, 0 56 mmol) in a mixture of solvents (8 mL of ethanol and 2 mL of water) was heated at 85° C under N? foi 1 hour The reaction mixture was cooled to about room tempeiature, filtered through celite, washed with ethyl acetate, and concentrated The reaction mixture was basified with saturated NaHCO 3
solution and exti acted with ethyl acetate The oiganic layer was washed with brine, dried over Na^SO^, and filteied. Removal of solvent provided the title compound 1
H NMR (500 MHz 5
DMSO-d 6
) δ ppm 1.52-3.86 (m, 4H), 1.96-2 21 (m, 2H), 3.27 (m, IH), 3 56 (s, 3H), 4.03 (m, IH), 5.93 (d, ■/= 3.99 Hz 5
IH), 6 13 (s 5
2H), 7 25 (d, J = 3.99 Hz, I H), 7 48 (d, J = 8.60 Hz, 2H), 7 88 <d, J = 8 60 Hz, 2H); MS (DCI/NH 3
) m/z
Example 6D methyl (l/^2/?)-2-{4-[5-( {[(3-chlorophenyl)aniino1carbonyl }ammo)thien-2- yllbenzoyllcyclopentanecaiboxylate A scintillation vial was charged with 6C (50 mg, 0.15 mmol), 3-chlorophenyl isocyanate (23 mg, 0 15 mmol) and leliahydiofuran (3 mL), It was placed in a shakei at room temperature for 2 hours. The mixture was concentrated and purified by RP-HPLC (Preparative re versed-phase chromatography was performed using a Zoτbax SB-C 18 7uM
Filed electronically May 17, 2007 S224WOO1
21.2x250 mm column with UV detection analyzed at 220 and 254 nM Preparative method: (water with 0 1% trifluoioacetic acid and CH 3 CN with 0 1% trifluoroacetic acid gradient) 5~ 95% CH 3 CN over 30 minutes at 15 mL/min ) to provide the title product ! H NMR (500 MHz, DMSO-d 6 ) δ ppm 1 65-1 85 (m, 4H), ϊ 97-2.22 (m, 2H), 3 30 (m, IH), 3 57 (s, 3H), 4 07 (m, IH), 6 66 (d, J = 3 97 Hz, I H), 7 06 (m, IH), 7 33 (m, 2H), 7 46 (d, J = 3 97 Hz, IH), 7 71 (d, /= S 85 Hz, 2H), 7 72 (s, I H), 7 98 (d, /= 8 85 Hz, 2H), 9 10 (s, I II), 10 06 (s, IH); MS (DCI/NIIj) m/z 483 [IVH HJ 4
Example 7 methyl (lR2R)-2-(4- [ 5-j fanilinocarbonyl)amino ' |thien-2- ylifaenzovDcyclopεntanecaiboxylate
Example 7 was piepaied using the same procedme as described foi Example 6D substituting phenyl isocyanate foi 3-chlorophenyl isocyaπate H NMR (500 MHz, DMSO- d 6 ) δ ppm 1 65-1 86 (m, 4H), 1 98-2 22 (m, 211), 3 30 (m, IH), 3 57 (s, 3Ii), 4 06 (m, III), 6 62 (d, J = 3 97 Hz, III), 7 01 (t, J = 7 32 Hz 1 IH), 7 31 (ni, 2H), 7 46 (d, / = 3 97 Hz, III), 7 48 (d, / = 7 63 Hz, 2H), 7 70 (d, / = 8 54 1Iz, 2H), 7 98 (d, J = 8 54 Hz, 2H), 8 88 (s, I H), 9 95 (s, 1 H), MS (DCI/NI-Ij) ni/z 449 [M Hl] "1
Example 8 methyl (l/ϊ.2/?)-2-(4-{5-r({[3-(ti ifluoiomcthvl)phenvl]aiτiinol caibony1)amino1thicn-2- yl}benzoyl)cyclopentanecaiboxylate
Example 8 was piepaied using the piocedure as desciibed for Example 6D, substituting 3-tiiflιπomcthyI-phenyl isocyanate for 3-chIoiophenyI isocyanate 1 H NMR (500
MHz, DMSOd 6 ) δ ppm 1 65-1 87 (m, 411), I 98-2 21 (m, 2H), 3 30 (m, IH), 3 57 (s, 3H), 4 07 (m, 1 H), 6 67 (d, J = 3 97 Hz, 1 H), 7 36 (d, J = 1 93 Hz, 1 H), 7 46 (d, J = 3 97 Hz, 1 H),
7 54 (t, / = 7 93 Hz, 1 H), 7 64 (d, / = 8 85 Hz, 1 H), 7 72 (d, ./ = 8 54 Hz, 2H), 7 98 (d, J =
8 54 Hz, 2H), 8 03 (s, IH), 9 27 (s, IH), 10 13 (s, I H); MS (DCI/NH 3 ) m/z 517 [M-HI] +
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Example 9 methyl ( lR.2R)-2- !4-[5-H[Y 3-chIorophenyl)amino " [carbonyUamino)pyridin-2- ylibenzoyl } cyclopentanecaiboxylate
Example 9A methyl n/^2i^)-2-[4-f5-aminopyiidin-2-y1)benzoyl]cyc1opentanccaibox ylate
To an ambient slimy of Example 6λ (0. 100 g, 0.279 mmol), 3-amino-6- bromopyridine (0 048 g, 0 279 mmol) and KF (0 049 g, 0 837 mmol) in dimelhoxyethane/toluene/ethanol/I-LO (10/1/6/3 ratio, 30 ml) was added palladium tetrakis(titphenylphosphine) (5 nig, 0 004 mmol) in a single poition. The reaction was heated at 90° C overnight, cooled to room temperature, filtered through celite, washed with ethyl acetate, concentrated and purified by RP-HPLC (Piepaiative reversed-phase chromatography was performed using a Zorbax SB-C 18 7uM 21 2x250 mm column with UV detection analyzed at 220 and 254 nM, Preparative method: (watei with 0.1% tiifluoroacetic acid and CH 3 CN with 0 1% trifliioraacetic acid gradient) 5-95% CH 3 CN over 30 minutes at 15 mL/miπ ) to provide the title compound MS (ESI) m/z 325 0 [M+H] +
Example 9B methyl dJ?,2/?)-2-{4-[5-f {| ' ( ' 3-chlorophenvπamino1caibonyl)amino ' )pyridin-2- ylJbenzovUcyciopentanecarboxylate
A scintillation vial was charged with Example 9A (5 mg, 0,015 mmol), 3- chlorophenyl isocyanate (3 mg, 0 02 mmol) and tetrahydtofuian (6 niL). It was placed in a shaker at room temperature overnight. The mixture was concentrated and purified by RP- HPLC (Prepaiative reveised-phase chromatography was performed using a Zorbax SB-C 18 7μM 21 .2x250 mm column with UV detection analyzed at 220 and 254 nM Preparative method: (water with 0.1% tiifluoioacetic acid and CH 3 CN with 0 1% tiifluoroacetic acid gradient) 5-95% CH 3 CN over 30 minutes at 15 mL/min ) to provide the title product. 1 H NMR (500 MHz, DMSO-(J 6 ) δ ppm 1.56-1 86 (m, 4H), 2 00 (m, IH), 2 21 (m, IH), 3 30-3.34 (m, I H), 3.58 (s, 3H) 1 4.09-4.14 (m, I H), 7 02-7.05 (m, IH), 7 28-7.33 (m, 2H), 7 40 - 7 44 (m, IH), 7 57 (m, IH), 7 69 (d, J = 8 55 Hz, 2H), 8 09 (d, J = B SS Hz, 2H), 8 21 (m, IH), S 97 (s, I H), 10 16 (s, IH), 10.21 (s, IH); MS (ESI) m/z 478.1 [MH-I-I] + .
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Example 10 (U?,2i?)-2-{4-[5-f lf(3-chlorophenyl ' )amino1carbonyl}amino)thien-2- yljbenzoyl) cyclopentanecarboxylic acid
A scintillation vial was charged with Example 6D (30 mg, 0.06 mmol), lithium hydroxide moπohydrate (10 mg, 0.24 mmol) and a mixed solvent (2 raL of tettaliydrofuran, 1 ml- of FbO) Tt was placed in a shaker at room temperature overnight The mixtiπe was acidified with 10 % HCl, concentiatcd, and pui ified by RP-HPLC (Pt cpat alive reversed- phase chiomatography was performed using a Zorbax SB-CIS 7uM 21 2x250 mm column with UV detection analyzed at 220 and 254 nM Preparative method: (water with 0.1 % lrifluoroacetic acid and CH 3 CN with 0 1% trifluoroacetic acid gradient) 5-95% CH3CN ovei
30 minutes at 15 mL/min ) to provide the title product. 1 M NMR (500 MFIz, DMSOd 6 ) δ ppm 1 64-1 85 (in, 4H), 1.97-2.20 (m, 2H), 3.20 (m, IH), 4 04 (111, I H), 6.65 (ά, J= 3,97 Hz 5
I H) 1 7 06 (m, IH), 7,33 (m, 2H), 7 46 (d, J= 3 97 Hz, I H) 1 7 71 (d, ./ * S 54 Hz, 2H), 7,72 (s,
IH), 7.99 (d, ■/ = S 54 Hz, 2H), 9..09 (s, H-I), 10 05 (s, I H), 12 22 (s, IH); MS (DCI/NH3) m/z 469 [M+H] +
Example 1 1 (17?,2i?)-2-(4-{5-[(aniIinocarbonv])aminolthien-2-yUbenzoyl) cyclopentanecarboxylic acid
Example 1 1 was piepared using the same piocediue as desctibcd fot Example 10 substituting Example 7 for Example 6D. 1 H NMR (500 MHz, DMSO-d fl ) 6 ppm 1 .64-1 85 (m, 4H), 1 97-2 20 (m, 2H), 3.21 (m, IH), 4.03 (m, IH), 6 62 (d, J = 3 97 Hz, IH), 7 01 (111, I H), 7 31 (m, 2H), 7,45 (d, J = 3 97 Hz, IH), 7 48 (d, J = 8 55 Hz 1 2H), 7 70 (d, J = 8.55 Hz, 2H), 7,79 (d, ./ = 8.55 Hz, 2H), 8.87 (s, I H), 9 94 (s, I H), 12 23 (s, IH); MS (DCI/NH3) m/z 435 [M+H] + .
Example 12 ( 17?,2/?)-2-(4- { 5-IY { [ " 3-fti ifluoiomethvDphenyllamino \ carbonγl)amino]thien-2- yllbeiizovDcyclopentanecarboxylic acid
Example 12 was prepared using the same procedure as described for Example 10, substituting Example S for Example 6D 1 H NMR (500 MHz, DMSOd 6 ) 5 ppm 1.64-1 85
(m, 4H), 1.97-2 20 (m, 2H), 3.20 (m, I H), 4 04 (m, I H), 6 67 (d, 7 = 3.97 Hz, IH), 7,36 (d, J
= 7.63 Hz, IH), 7,46 (d, J = 3.97 Hz, IH), 7.54 (d, J/ - 8.23 Hz 1 J 3 = 7.63 Hz, IH), 7.63 (d, J
= 8.23 Hz, I H), 7.72 (d, J = 8.54 Hz, 2H), 7.99 (d, J = 8.54 Hz 1 2H) 1 8.03 (s, IH), 9.26 (s,
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IH), 10.12 (s, IH), 12 22 (s, IH); MS (DCI/NH 3 ) m/z 503 [M+H] +
Example 13 di?,2J<!)-2-ff4'-{[anilino(cvanoimino ' )methyl1amino}-l ,r-biphenvl"4- vDcarbonylicyclopentanecaiboxylic acid
Example I 3A phenyl N'-cyano-N-pheπyiimidocaibamate
Aniline (500 μL., 5,48 mπiol) was combined wilh diplieny] N-cyanocarbonimidate (1 .31 g, 5.48 mmol) and aceionitπle (20 mL) at room tempetalure Aftei 18 houis the iesulling white powdei was collected by filtration, 1 H NMR (300 MHz, DMSO-d 0 ) 5 ppni
7.21 - 7 33 (m, 4 H) 7.37 - 7 49 (m, 6 H) 10 83 (s, 1 H); MS (ESI, melhanoI/NH4OH) m/z
238 [M+H], 260 [M+Na], 236 [M-H].
Example 13B methyl (l/?,2J?)-2-[f4 > -{[anilinofcyanoimino)methvl1aininol -Lr-biphenyl-4- yl)caibonyl]cvclopentanecarboxylale
Example 11 (20 mg, 62 μmol), Example 13A (15 mg, 62 μmol), and acetomtπle (04 mL) wcie combined and heated in the Emiys Optimizer at 140° C foi 20 minutes tin ice The mixture was combined with ethyl acetate (40 mL-), washed with IN aqueous NaOH (1x40 mL), washed with biine (1x40 mL), dried (Na 2 SO 4 ), filtered, and concentialed Piπificalion by flash chromatography (eluting with a gradient of 0 to 100% ethyl acetate in hexane) provided the title compound as a yellow solid, 1 H NMR (300 MHz, DMSO-d fl ) δ ppm 1 56 -
1.70 (m, 2 H) 1 73 - 1.87 (m, 2 H) 2 03 (m, 1 H) 2 16 - 2.24 (m, 1 H) 3 21 - 3 27 (m, 1 H) 3 57 (S 1 3 H) 4 07 - 4.16 (m, 1 H) 7.14 (m, 1 H) 7.31 - 7 38 (m, 4 H) 7 44 (d, ,7=8 48 Hz, 2 H)
7 76 (d, .7=8 48 Hz, 2 H) 7 83 (d, -7=8 48 Hz, 2 H) 8 07 (d, J=SAS Hz, 2 H) 9.59 (s, 2 H); MS
(ESl, methanol/NH4OH) m/z 467 [M+H], 489 [M+Na], 465 [M-H].
Example 13C f lJ?.2/?V2-ff4'- f| ' aniiino(cvanoirnino)nnethvπamino| -l,r-biphenv]-4-
Vi)carbonyl]cvclopentanecaiboxylic acid Example 13B (9 mg, 19 μmol) was dissolved in CH 2 CI 2 (1.5 mL) and cooled in an ice-water bath. Boion trichloride (58 μL, 58 μmol of a IM solution in CH 2 Ci 2 ) was added in
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one portion. The reaction mixtuie was permitted to warm to room temperature as it was stiiϊed overnight. After 22 hours the solution was diluted with ethyl acetate (40 niL) and IM aqueous HCl (40 mL). The layers were separated, and the organic layer was washed with brine (1x40 mL), dried
Example 14 jV-(4'- g [( l.fl,2/ϊV2-cvanocyclopentyl ' |carbonyl| -1 ■ 1 '-biphenyl-4-yl)-N'-phenyliiiea
Example 14A methyl ( 1 R2R)-2-( J4' r [f ani1inocarbonyl)amino]--l .1 '-biphenyl-4- yl] caτbpnyl)cyclopentanecaiboxylate
Example 11 (0.9 g, 2 78 mmol) and phenyl isocyanaie (0 .36 g, 3 06 mmol) weie placed in tehahydiofuran (20 mL) at it, stirred overnight, concentrated and purified by flash chromatography (5%~50% ethyl acetate in Hexane) to provide the title product 1 H NMR
(500 MHz, DMSOd 6 ) δ ppm 1 .56-1.86 (m, 4H), 2.00-2 07 (m, IH), 2 16-2.22 (m, I H), 3 30-
3 35 (m, IH), 3 58 (s, 3H), 4 08-4 14 (m, IH), 6.98 (t, J = 7 4 Hz, IH), 7 29 (t, .7 = 7 7 Hz,
2H), 7 47 (d, J = 7 7 Hz, 2H), 7 60 (d, J = 8 9 Hz, 2H), 7.72 (d, ./ = 8.9 Hz, 2H), 7 82 (d, J =
8.6 Hz, 21-1), 8 05 (d, J = 8 6 Hz, 2H), 8 71 (s, IH), 8 85 (s, I H); MS (ESI) m/z 443 2 [M-I-H] '.
Example 14B ( lJ?.2/g)-2-({4'-[(anilinocarbonyl)amino]-l.r-biphenyl-4-yl}c aibony])cyc1opentane carboxylic acid Example 14A (0.8 g, 1 81 mmol), LiOH (0.38 g, 9 mmol) was stirred at room temperature overnight in 4: 1 tetiahydiofiuan/water mixture (50 mL) It was then adjusted to pH < 7 with 4 M HCL The mixture was concentrated and purified by RP-HPLC (Preparative reversed-phase chromatography was performed using a Zorbax SB-Cl 8 7μM 21.2x250 mm
Filed electronically May 17, 2007 8224WOOi
column with UV detection analyzed at 220 and 254 nM. Preparative method: (water with 0.1% trifluoroacetic acid and CH 3 CN with 0,1% trifluoioacetic acid gradient) 5-95% CH 3 CN over 30 minutes at 15 mL/min.) to provide the title product.. 1 H NMR (500 MHz, DMSOd 0 ) δ ppm 1 58-1.86 (m, 4H), 1.98-2.05 (m, IH), 2.14-2 21 (m, IH), 3 20-3.24 (m, IH), 4.07- 4 12(m, IH), 6 99 (t, J = 7 3 Hz, IH), 7.29(t, J = 8 3 Hz, 2H), 7.48 (d, J = 7 6 Hz, 2H), 7 60 (d, 7 = 8 5 Hz, 2H), 7 72 (d, .7 = 8 5 Hz, 2H), 7.82 (d, ./ = 8.2 Hz, 2H) 1 8 06 (d, 7 = 8 5 Hz, 2H), S 73 (s, IH), S 87 (s, I H), 12 23(s, I H); MS (ESI) m/z 429 1 [M+H] +
Example 14C (!J?.2/ϊV2-( f4'-r(anilinocaibonvε)amino1-l .l '-biplienyl-4- yl \ carbonypcyclopentanecarboxamide
Example 14B (0 12 g, 0.28 mmol) was treated with N-hydioxy succinamide (0 065 g, 0,56 mmol), N-(3-dimethylaminoptopyl)-N'-ethylcaibodiimide hydrochloride (0 107 g, 0 56 mmol) and TV- methyl moψholine (0.16 mL, 1 32 mmol) in dichlosomethaπe (5 mL) and stirred at it for 2h. The solvents wese lemoved on a rotary evaporator and then diluted with a 1 :1 mixture of ethyl acetate and watei (20 ml..). The organic layers were separated, washed with brine, dried (MgSO-O and conceniialed to a while solid The residue was taken up in dioxane (5 mL) and ammonium hydi oxide (0.2 mL, 1 4 mmol) was added to the solution at room tempeiatiπe and stirred foi Ih. The ieaction mixture was filtered and the filtrate concentrated to a white solid that was purified by RP-HPLC (Preparative reversed-phase chromatography was pei formed using a Zorbax SB-CI S 7μM 21 2x250 mm column with UV detection analyzed at 220 and 254 nM Preparative method: (water with 0 1% trifluoroacetie acid and CH 3 CN with 0.1% lrifluoioacetic acid gradient) 5-95% CH 3 CN ovei 30 minutes at 15 mL/min.) to affoid the title compound. 1 H NMR (500 MFIz, DMSO-d 6 ) δ ppm 1 56-1 79 (m, 4H), 1.98-2.04 (m, IH), 2 07-2 1 1 (m, I H), 3.01 -3.06 (m, 3 H), 4 07-4 13 (m, I H), 6.78 (s, IH), 6 98 (t, IH, 7,36 Hz), 7.27-7 31 (m, 3H), 7.47 (d, J = 7 67 Hz, 2H), 7.59 (d, J = 8.90 Hz, 2H), 7 71 (d, J = 8 90 Hz, 2H), 7.80 (d, 7= 8.59 Hz, 2H), 8 02 (d, J = 8 59 Hz, 2H), 8 72 (s, IH), 8 86 (s, I H); MS (ESI) m/z 428 1 [M-I-H] +
Example 14D
N-(4'- { U li? f 2 J /?)-2-cyanocyclopentyl ' |carbonyU-l , 1 '-biphenyl-4-vl)-N'-phenylu-ea
Trifluoroacetic anhydride (0.062 mL, 0.45 mmol) was added drop wise to a solution of Example 14C (0.038 g, 0.09 mmol) in pyridine (1 5 mL) maintained at - 20° C The
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ieaction mixture was allowed to warm up to 0° C, quenched with water and exhacted with ethyl acetate The organic extracts weie washed with water, brine, dried (MgSO.;) and purified by RP-HPLC (Preparative reversed -phase chromatography was performed using a Zorbax SB-Cl 8 7uM 21 .2x250 mm column with UV detection analyzed at 220 and 254 nM. Preparative method: (water with 0 1% trifluoroacetic acid and CH 3 CN with 0 1% trifluoroacetic acid gradient) 5-95% Cϊ-T 3 CN ovei 30 minutes at 15 mL/min .) to affoid the titled compound 1 H NMR (499 MHz, DMSO-d<,) δ ppm 1 56-1 71 (m, 2H), 1 79-1 So (m, IH), 1.874.95 (m, IH), 2 14-2 20 (m, I H), 2 26-2 33 (m, IH), 3.42 (q, ./ = S 2 Hz, IH), 4 23- 4.28 (m, IH), 6.99 (t, J = 7 3, IH), 7 30 (t, J = 7.6 Hz, 2H), 7.47 (d, ./= 7 6 Hz, 2H), 7 61 (d, ./ = 8.S Hz, 2H), 7 74 (d, J = 8.8 Hz, 2H), 7 84 (d, J = 8.5 Hz, 2H), 8.09 (d, ,7 = 8 5 Hz 5 2H), 8.76 (s, IH), 8.90 (s, I H); MS (ESI) m/z 4I0 1 [M-H-I] + .
Example 15
Example 15A
A f -(3-chlorophenyl)-N 1 -(4-phenylcycIohexyl)tiiea
A mixture of 4-phenylcyclohexanone (4 g > 23 mmol), ammonium acetate (18 g, 230 mmol), and sodium cyanoborohydride (1 g, 16 1111110!) in methanol (150 niL) was stirred at loom tcmpciaturc under N 2 foi 16 h. The reaction mixture was filteicd through cclilc, and the filtrate was concentrated to diyness, and then dissolved in tettahydromran (5OmL) To this mixture, 3-chloiophenyl isocyanate (3 g, 20 mmol) was added, stirred at room temperature for 3 hours The reaction was quenched by adding water and product was extiacted with ethyl acetate. The organic layer was washed with brine, and dried over Na 2 SOi) Purification by flash chromatography (ethyl acetate/Hexane, 1/10) afforded the titled compound as while solid 1 H NMR (500 MHz, DMSO-d 0 ) δ ppm 1 .6-1 .70 (m, 6H), 1 .72-1 81 (m, 2H), 2 66 (m,
IH), 3.94 (m, IH), 6.57 (m, I H), 6 94 (m, I H), 7 13-7 33 (m, 7H), 7 71 (d, J = 2. 14 Hz, IH),
8 54 (s, IH); MS (DCI/NH 3 ) m/z 329 [M+Hf.
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Example 15B methyl cis-2~{4-f4-f t]( 3- chlorophenyl)amino]caτbonvl}amino)cvclohexyl]benzoyllcvclop entanecarboxylate Step A
5 A solution of Example 1C (1 g, 5.81 mmol), SOCl 2 (1 3 mL, 17 8 mmol), and N 1 N- dimeihylfoπnamicle (0 01 ml ) in 10 ml. CHiCIo was stiπed al room tempera ture overnight under Ni The solvent was semoved by iolaiy cvapoialion at < 40" C, and (be iesidue was dried in vacuo for 1 hour Step B
I O A round bottom flask was charged with I 5A (100 mg, 0 30 mmol), the intermediate from step A (1 14 mg, 0 60 mmol), aluminum chloride (360 mg, 2.7 mmol), and dichloioethane (5 mL) The reaction mixture was heated to 100 0 C Foi 1 hour under N?, and the solvent was removed by distillation. The reaction mixture was then slowly poiπed into 50 mL of ice water, and then 100 mL of ethyl acetate was added. After the mixture was stiπed
15 for 10 minutes, the aqueous layer was separated, and extracted with 50 ml, of ethyl acetate The combined organic layers were washed with watei (2x50 mL) and saturated NaHCC^ solution (50 mL), dried over NaiSO.), and filicied Removal of solvent piovided etude Example 15B that was finthei purified by using RP-HPLC (Preparative leveised-phase chromatography was performed using a Zoibax SB-Cl 8 7μM 21 2x250 mm column with UV
20 detection analyzed at 220 and 254 iiM. Preparative method: (water with 0 1% trifluoroacetic acid and CH 3 CN with 0,1% trifluoroacetic acid giadicnt) 5-95% CH 3 CN over .30 minutes at 15 mL/min.). 1 H NMR (500 MHz, DMSO-(J 6 ) δ ppm 1 6-2.2 (m, 14H), 2 69 (m, IH), 3,27 (m, IH), 3 66 (s, 3H), 3 94 (m, IH), 4 07 (m, IH), 6.59 (d, J = 7 63 Hz, IH), 6.93 (m, IH), 7.15 (m, IH), 7 25 (m, IH), 7 45 (d, J = 8 24 Hz, 2H), 7 71 (m, I H), 7.96 (d, J = 8 24 Hz,
25 2H), 8.64 (s, IH); MS (DCI/NH 3 ) m/z 483 [M+Hf
Example 15C ttans-2-(4-f4-f {rf3- chloiophenyl)ammolcarbonyl}aτnino)cvclohexyl]benzoyl}cyclop entanecatboxylic acid 30 Example 15C was prepared using the procedure as described for 1 Example 10, substituting Example 15B for Example 6D.. 1 H NMR (500 MHz, DMSOd 6 ) δ ppm 1 6-1 .85 (m, 12H), 1 .96-2,2 {m, 2 H), 2,67 (m, IH), 3.21 (m, IH), 3.94 (rn, IH), 4 05 (m, IH), 6.59 (d,
J= 7 63 Hz, IH), 6,93 (m, IH), 7.15 (m, IH), 7 25 (t, J = 7,94 Hz, IH), 7.44 (d, J= 8 24 Hz,
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2H), 7.71 (m, IH), 7.97 (d, J = 8 24 Hz, 2H), 8 53 (s, I H), 12..20 (s, IH); MS (DCI/NH 3 ) m/z
469 [M+H] + .
Example 16 methyl (\R2R)-2-\(4'-t\l -( cvclohexylaminoV2-nihOvinyl ' ]ammol - 1.1 '-biphenyl-4- yl)caibonyl]cyclopentanecarboxv1ate
To a 10 ml. iound bottom flask, inicimcdiatc I I (30 0 111» , 0 0930 inmol), 1 ,1 - bis(methyUhio)-nitiOeιhylene (16.0 mg, 0 0968 mmol) and 1 ml ol cthanol weic added. The reaction mixture was heated to reflux for 48 hours. After this time, the reaction solution was allowed (o cool to room temperature Cyclohexylamine (50.0 μl_, 0 465 mmol) was added via syringe, and the reaction mixture heated to 60° C for 24 hours. Aftei this time, the reaction solution was cooled to room tempeiature, and the solvent evaporated The iesidue was purified via RP-HPLC (Preparative reversed-phase chromatography was peiformed using a
Zorbax SB-CI S 7uM 21 2x250 mm column with UV detection analyzed at 220 and 254 nM. Prepaiative method: (water with 0 1% Uifhtotoacetic acid and CH 3 CN with 0.1% ttifluoroacetic acid gradient) 5-95% CH3CN ovei 30 minutes at 15 niL/min ) to a f foul the title compound 1 H NMR (400 MHz, DMSO-d ύ ) δ ppm 1 19 - 1 33 (m, 1 H), 1 34 - 1 46 (m, 4
H), 1 54 - 1.65 (m, 2 H), 1 65 - L74 (m, 3 H), 1.74 - 1.80 (m, 2 H), 1 79 - 1.87 (m, 1 H), 1.92
- 2 10 (m, 3 H), 2 14 - 2 25 (m, 1 H), 3 27 - 3 37 (m, 1 H), 3 58 (s, 3 H), 3 76 - 3 83 (in, 1 H), 4 07 - 4 17 (in, 1 H), 6.18 (s, 1 H) 1 7 39 (d, J = 8 59 Hz, 2 H), 7 87 (del, 7 = 14 27, 8 44 Hz, 4
H), 8 09 (d, J- S 59 Hz, 2 H); MS (ESI) m/z 492.2 {M+HJ *
Example 17 methyl ( 17i.2/?)-2-(4- {6-f (aniIinocarbonyl)amino1pyridin-3- yUbenzoyPcyclopentanecaiboxylate
Example 17A (lR.2R)-2-l ' 4-(6-Aniino-pyndin-3-ylVbenzoyl]-cvc]opentanecaiboxylic acid methyl ester
2-Amino-5-(4 s 4,5,5-tetiarnethyl-l ,.3,2-dioxaborolan-2-yl)pyiidine (0.1 1 g, 0 5 mmol) was added to a suspension of Example I G (0 1 g, 0 32 mmol), potassium fluoride (0 06 g, 1 mmol), letrakis(ιtiphenylphosphine)palIadium{G) (0 037 g, 0.032 mmol) in a solvent mixture
(10:l :6:3:dimethoxyethane:toluene:ethanol, H 2 O, 10 ml) and degassed with nitrogen for 10 minutes The reaction mixture was then heated at 90° C for 12 hours, cooled, quenched with
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water (20 mL), extracted with ethyl acetate The oiganic extracts were then washed with watei, brine, dried (MgSO 4 ), filtered, concentrated and purified by flash chromatography using ethyl acetate as eluent to afford the title compound 1 H NMR (499 MHz, DMSO-do) 5 ppm 1.55-1.69 (m, 2H), 1.72-1.87 (m, 2H), 1 99-2..06 (m, I H), 2.15-2.22 (m, IH) 1 3 57 (s, 3H), 4 09 (q, ./ = 9 1 Hz, IH), 6.25 (s, 2H), 6 55 (d, J = 8 2, I H), 7 54-7 57 (in, IH), 7 60- 7 65 (m, 2H), 7 75 (d, 7 = 8 5 Hz 1 2H), 7 81 (dd, J = 2 4, S 5 Hz 1 IH) 1 S 01 (d, J = 8.5 Hz, 2H), S 37 (d, J = 2 -HIz, S II)
Example 17B Methyl f lJ?.2/?)-2-f4-l6-r(anilinocarbonyl)amino1pyridin-3- yUbenzovDcvclopentanecaiboxylate
Example 17A (0.06 g, 0.18 mmol) was placed with phenyl isocyanate (0 03 mL, 0 24 mmol) in teiiahydioiuian (6 mL) and stirred at room tempeialure for 32 houis The reaction mixture was quenched with water, exit acted with ethyl acetate, the organic extracts washed with water, brine, dried (MgSO 4 ), filteicd and concenuated to a white solid The crude solid was taken up in ethyl acetate and the iesulLanl slurry filteicd The fill! ate was purified by flash chromatography elating with 50% ethyl acetate/hexanes Io afford the title compound 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1 59-1 .69 (m, 2H), 1 72-1 89 (m, 2H), 1 99-2 06 (m, IH), 2.15-2 22 (m, IH), 3.ii (q, J = 8.2 Hz, IH), 3 58 (s, 3H), 4 13 (q, 7 = 7 7 Hz, IH), 7 04 (t, ./ = 7 4 Hz, IH), 7 33 (t, J = 8.3, 2H), 7 54 (d, J = 7.7 Hz, 2H), 7 70 (d, ./ = 8 9 Hz, IH), 7 89 (d, J = S 6 Hz, 2H), 8 09 (d, J = 8.6 Hz, 2H), 8 19 (dd, ./ = 2.5, 8.6 Hz, H-I) 8.73 (d, ,/ = 2 5 Hz, IH), 9 58 (s, IH), 10.29 (s, IH); MS (ESI) m/z 444.2 [MH-H] +
Example 18 (lJ l ?,2/i)-2-(4-{6-[(anilinQcaibonyl)aminolpyridin-3-yl}benzoyl) cyclopentanecai ι boxylic acid
Example 17B (0 04 g, 0.09 mmol) was placed with lithium hydroxide monohydiate
(0 02 g, 0,3 mmol) in tetrahydrofuran (4 mL) and water (1 mL) and stiried at room temperature for 2 hours The reaction mixture was then acidified with 3N HCl, extracted with ethyl acetate, oiganic extracts washed with water and brine, dried (MgSOj), filtered and concentrated The solid residue was taken up in ethyl acetate and the slmry was filtered Io isolate the iesidue as the titled compound. 1 H NMR (500 MHz, DMSO-d&) δ ppm 1 57-1 .70
(m, 2H), 1 72-1 87 (m, 2H) 3 1.99-2.06 (m, IH), 2.15-2.22 (m, IH), 3.23 (q, J = 8.2 Hz, IH),
4.11 (q, J = 8.8 Hz, IH), 7.04 (t, / = 7.3 Hz, IH), 7.33 (t, J = 7.6, 2H), 7.54 (d, J = 7.6 Hz,
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2H), 7,70 (d, J = 8.8 Hz, IH), 7 89 (d, J = 8,6 Hz, 2H), 8 11 (d, J = 8.6 Hz 1 2H), 8.19 (dd, J - 2,5, 8 6 Hz, 1 H) 8 7.3 (d, ,/ = 2.5 Hz, 1 H), 9 60 (s, 1 H), 10.31 (s, 1 H), 12.25 {bioad s, 1 H); MS (ESI) m/z 430 1 [IVH-H] +
Example 19 methyl ( 1 R2R)-2- j [4'-f { [f 3-chloi ophenvDaminofcnrbonofhioyl } amino)-! .1 '-biphcnyl-4- y1]caibony1}cyclo)3cn(anccaiboxyla[c
Example 19 was prepared using the proceduic as desciibed FOE Example U substituting 3-chlorophenyl isothiocyanate foi 3-chlorophenyl isocyanate. 1 H NMR (500 MHz, DMSOd 0 ) 5 ppm 1 56-1 SS (m, 4H), 1 99-2.08 (m, I H), 2 16-2 2.3 (m, I H), 3 29-3 35 (m, IH), 3.5S (s, 3H), 4.09-4 15 (m, IH), 7.18 (d, ./ = 7 98 Hz, IH), 7.36 (t, J =7 9S Hz, IH), 7 43 (d, J = 8.29 Hz, IH), 7 64 (d, J = S 60 Hz, 2H), 7 72-7.77 (m, 3H), 7.84 (d, J =S 29 Hz, 2H), 8.07(d, ./ =8 28 Hz, 2H), 9 99 (s, 2H), 10 09 (s, IH); MS (ESI) m/z 493 1 [MH-H] +
Example 20
(\R,2R)-2-{\4'-( { [(3-chloiophenyl)amino1carbonolhioyU amino)- 1.1 '-biphenyl-4- ylicai'bonyUcyciopentanecaiboxylic acid
Example 20 was prepaied using the procedure as desciibed foi Example 10, substituting Example 19 for Example 6D 1 H NMR (500 MHz, DMSOd 6 ) δ ppm 1 56-1 87 (in, 4H), 1 97-2 07 (m, IH), 2 14-2 20 (m, IH), 3 20-3 25 (m, I H), 4 07-4 13 (in, I H), 7 19 (d, 7 = 7.67 Hz, I H), 7 36 (t, J =7 98 Hz, IH), 7 43 (d, 7= 8.60 Hz, H-I), 7.64 (d, J= 8.59 Hz, 2H), 7 72-7.77 (m, 3H), 7,84 (d, 7 =8.59 Hz, 2H), 8.0S (d, 7 =8,29 Hz, 2H), 9 99 (s, 2H), 10 09 (s, IH), 12 19 (br s, I H); MS (ESI) m/z 479. 1 [MH-H] + .
Example 21
Trans-2-[(5-j4-[(anilinocaibonv1)amino1phenyl|pyridin-2- vl)carbonvl]cyclopentanecarboxylic acid
Example 21 A 2-[(5-biomopyridin-2-yl)caibonvHcyclopentanecarboxylic acid
Step One: l-Ethyl-3-[3-(dimethyIamino)piopyl]-caibodiimide hydrochloride (8 01 g, 41.82 mmol) and l~hydroxybenzotriazole hydrate (5.65 g, 41.82 mmol) were sequentially added to
Filed electronically May ! 7, 2007 8224WOO1
a solution of 2-(rnethoxycarbonyl)cyclopentanecarboxylic acid (6,0 g, 34,85 ramol), N, O- dimethylhydroxylaraine hydrochloride (3 74 g, 38.33 mmol) and ν -methyl morpholine (1 1.5 raL, 104,55 mmol) in ν,ν-dimethylformamide (60 rriL) maintained at room temperatuie. After overnight stiiring, the reaction was quenched with water (100 raL) and extracted with ethyl acetate (4 x 150 πiL) The organic extracts were washed with water (5 x 100 ml. ), brine, dried (MgSO s), filtered, and conccntinted to an oil and used as is in step two Step Two:
Lithium hydi oxide monohydiate ( 1.95 g, 47 mmol) was added to a solution of the crude product (4 g, 18 6 mmol) from step one in tetrahydiofuraπ (45 niL) and water ' (15 mL) and the mixtuie stirred at room temperature for 14 horns The reaction was quenched by the addition of 3N hydrochloric acid (reaction adjusted to pH 1) and extracted with ethyl acetate (4 x 150 mL,). The organic extracts wcic washed with water, brine, dried (MgSCi), filtered, and concentrated to an oil and used as is in step three Step Thiee: /vo-Propyl magnesium bromide (2 M solution in terrahydrofuian, 33 ml,, 66 mmol) was added diop wise via an addition Funnel to a solution of 5-bromo-2-iodo-pyιύline (17 g, 60 mmol) in tetrahydrofuian (100 mL) maintained at -20 °C The reaction was allowed to warn) up to 5 0 C oves 2 hours. The reaction was cooled to -15 0 C, a solution of the crude product fiom step two (3 0 g, 15 mmol) in tetiahydrofuran (25 mL) was added drop wise to the mixtuie, and the mixture warmed up to 0° C over 2 hours The reaction was then quenched by addition of saturated aqueous ammonium chloride solution, adjusted to pH 1 with 3N hydrochloric acid, and extracted with ethyl acetate (5 x 150 mL) The organic extracts weie washed with water, brine, dried (MgSO 1 )), filtered, concentrated to an oil and purified by flash chromatography using 10-75 % ethyl acetate/hexanes as the eluent to afford the title compound 1 H NMR (300 MHz, DMSO d ύ ) δ ppm 1 55 - 1.75 (m, 3 H), 1 81 -1 95 (m, 3 H), 3 31 - 3 37 (m, 1 H), 4 34 - 4.22 (m, 1 H), 7.84 (d, J = 6 Hz, 1 H), 8 24 (dd, Jl = 6 Hz, .12 - 3 Hz, i H), 8.84 (d, ./ - 3 Hz, 1 H), 1 1 .95 (broad s, 1 H); MS (ESI) m/z 297 8 [MH-H] +
Example 21 B
Methyl 2-rf5-bromopyridin-2-yl)carbonyl]cvclopeηtanecarboxylate (Trimethylsilyl)diazomethane (2 M solution in hexanes, 4,6 mL, 9.23 mmol) was added drop wise to a solution of Example 21A (2.3 g, 7.69 mmol) in benzene (50 mL) and
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methanol (38 mL) and the mixture stirred at ioom tempeiature for 30 minutes, The reaction was quenched by addition of glacial acetic acid and then concentrated in vacuo. The residue was purified by flash chromatography using 8-30 % ethyl acetate/hex anes as the elueπt to afford the title compound. 1
H NMR (500 MHz, DMSO d 6
) 5 ppm 1.61 - 1 65 (m, 2 H), 1 67 - 1 73 (m, 1 H), 1 80 - 1 85 (m, 1 H), 1 .91 - 2 02 (m, 1 H) 5
2, 10 - 2. 15 (m, 1 H), 3 21 (η, J = S 54 Hz, 1 H), 3 55 (s, 3 H), 4 31 - 4 40 (m, 1 H), 7 94 (dd, Jl = S 54 Hz 1
/.' = 0 61 Hz, 1 H), S 28 CcKl, JI - S 54 Hz, Jl = 2 44 Hz, 1 II), S 88 (dd, Jl = 2 44 Hz, J2 = 0 61 HZ, I II); MS
Example 21C
Tians-methyl 2-{[5-f4-nilroplienyl)pyridii>2-yllcatbonyl)cvclopentaπe caiboxylate
A solution of Example 21B (0 5 g, 1 6 mmol), 4-nitrophenylboionic acid pinacol ester (0.52 g, 2 1 mmol), potassium fluoride (0 28 g, 4.83 mmol) and pailadium- tetιakis(triphenylphosphiπe) (0 19 g, 0 16 mmol) in a solvent mixture of 1 ,2- dimethoxyelhane: ethanol: water: toluene ( 10: 6: 3: 1 , 50 mL) was degassed with nitiogen foi 10 minutes and then heated at 90° C for 15 hoius The ieaction was cooled to ioom tempeiature, quenched with watei (50 mL) and exit acted with ethyl acetate (4 x 100 mL) The organic extracts weie washed with water, brine, dried (MgSO-s), filtered, concentrated to an oil and purified by flash chromatography using 20% ethyl acetale/hexanes as the eluent to afford the title compound 1 I-I NMR (500 MHz, DMSO d 6 ) δ ppm 1 63 - 1 70 (m, 2 H), 1 .73 - 1 79 (in, 1 H), 1.80 - 1.88 (m, 1 H), 2 02 - 2 09 (m, 1 H), 2 15 - 2.21 (m, 1 II), 3 25 (q, J = 8,24 Hz, 1 H), 3.57 (s, 3 H), 4.46 (q, J = 9 15 Hz, 1 H), 8 12 - 8 15 (m, 3 H), 8 38 (d, J= S 85 Hz, 2 H), 8.45 (dd, Jl = 8 24 Hz, Jl = 2 14 Hz, 1 H), 9 17 (d, J= 2.44 Hz, 1 H)
Example 21D
Trans-methyl 2-j [5-(4-aniinophenyl)pyridin-2-yl ' ]carbonvUcvclopentanecarboxylate
A suspension of Example 21C (0 37 g, 1 06 mmol), iron powder (0, 12 g, 2 12 mmol) and ammonium chloiide (0 07 g, 1 .27 mmol) in ethanol (15 mL) and water (5 mL) weie heated at 90° C for' 15 hours. The reaction was cooled to room temperature, and diluted with water 1 and ethyl acetate It was then filtered through a pad of wet celite and the organic layers were separated and washed with watci and biinc, diied (MgSO.)), filtered, and concentrated to affoid the title compound.. 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1,63 - 1 ,70 (m, 2 H), 1.73 -
1.79 (m, 1 H), 1.80 - 1 .88 (m, 1 H), 2 02 - 2 09 (m, 1 H), 2.15 - 2.21 (m, 1 H), 3 25 (q, J =
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8.24 Hz, 1 H), 3 57 (s, 3 H), 4 46 (q, J = 9.15 Hz, 1 H), 8 12 - 8 15 (m, 3 H), 8 38 (d, J= 8.85 Hz, 2 H), 8 45 <dd, Jl = 8 24 Hz, .12 = 2 14 Hz, 1 H), 9.17 (d, J = 2 44 Hz, 1 H).
Example 21 E Tτans-2-[f5"{4-rfani]inocaτbonyl)aminolpheny1|pyridin-2- yl)carbonvTjcvc1oρcntanecarboxy1ic acid Step One
Phenyl isocyanate (0 01 ml, 0.07 nimol) was added to a solution of Example 21D (0 02 g, 0 06 mmol) in tetrahydiofuian (2 niL) and the mixture stirred at room temperature fot 15 hours The reaction was quenched with water, extracted with ethyl acetate, concentrated and purified by leverse phase high piessuie liquid chromatography (RP-HPLC) using a Zoibax SB-Cl 8 7M 21 2x250 mm column with UV detection analyzed at 220 and 254 πM, and eluted with a solvent system containing component A (water with 0.1% trifluoroacetic acid) and component B (acelonitrile with 0 1% tiifluoroacelic acid) with gtadient of 5-95% of component B over 30 minutes at 15 mL/min to isolate the ester. Step Two
Lithium hydroxide (0 02 g) was added to a solution of the estei from step one in lelrahydrofuran (2 niL) and water (1 mL) and the mixtiue sliπed at room tempetatuie for 10 hoiπs The reaction was quenched with 3N hydrochloric acid, extracted with ethyl acetate, dried (MgSO 4 ), filtered, concentrated and puiificd by RP-HPLC (using a Zorbax SB-Cl S 7M 21 2x250 mm column with UV detection analyzed at 220 and 254 nM, and eluted with a solvent system containing component A (watei with 0 1% Irifluoxoacetic acid) and component B (acetonitrile with 0 1% trifiuoioacetic acid) with gradient of 5-95% of component B over 30 minutes at 15 mL/min) to afford the title compound. 1 H NMR (500 MHz, DMSO d ύ ) δ ppm 1 55 - 1 62 (m, 1 H), 1 63 - 1 .70 (m, IH), 1.73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H) 5 1.99 - 2.06 (m, 1 H), 2 14 - 2 21 (m, 1 H), 3.22 (q, J = 8,54 Hz, 1 H), 4.48 (q, J = 8 85 Hz, 1 H), 6.99 (t, J = 7.63 Hz, 1 H), 7 30 (t, J = 7.32 Hz, 2 H), 7 47 (d, J = 9 46 Hz, 2 H), 7.64 (d, J = 8 54 Hz, 2 H), 7.80 (d, J = 8 85 Hz, 2 H), 8 04 (d, J = 8.54 Hz, 1 H), 8 25 (dd, Jl = 8 24 Hz, Jl = 2 45 Hz, 1 H), 8 76 (s, 1 H), 8.93 (s, 1 H), 9 06 (d, J = 1 .83 Hz, 1 H), 12 15 (broad s, 1 H); MS (ESI) m/z 430 2 [M+Hf .
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Example 22 Trans-l-ffS-M-fdp-ftiifluoromethyDphenYliaminolcaibonvDamino jphenyllpyiidin-σ- yDcarbonylicyclopentanecarboxylic acid
The title compound was prepared as described in Example 21 E, substituting 3- tiifloiπomethylphenyl isocyaπate for phenyl isocyanate 1 H NMR (500 MHz, DMSO d ύ ) δ ppm I 55 - 1 62 (m, 1 H), 1 63 - 1 70 (m, I TT), 1 73 - 1 79 (m, I T I) 1 1 80 - 1 88 (m, 1 H), 1 99
- 2 0ό (m, 1 I I) ( 2 14 - 2 21 (in, 3 II), 3 22 (q, ./ = S 54 1 Iz, 1 I I), 4 4S (q, / = S S5 Ik, 1 11),
7 30 - 7 36 (m, 1 H), 7 50 - 7 56 (m, 1 II), 7 59 - 7 63 (m, 1 IT), 7 65 (d, J - 8 S5 Hz, 2 H),
7 80 (d, J = 8 85 Hz, 2 H), 8 03 (s, 1 H), 8 05 (dd, Jl = 8 24 Hz, J 2 = 2 14 Hz, 1 H), 8 27 (dd, Jl = 8 24 Hz, J2 = 2 45 Hz, I H), 9 OS (bioad s, 1 II), 9 17 (bioad s, 1 H), 9 06 (dd, JJ = 2 45
Hz, J2 = 1 S3 Hz, 1 H), 12 1 1 (bioad s, 1 H); MS (CSI) m/z 498 2 [M+H] +
Example 23
Tians-2-( f5-r4-( frf3-chloiophcnyl)amino]caibonyl}aniino)phenyllpyridin-2- ylj caibonvDcyclopentanccaiboxylic acid
The title compound was prcpaicd as desciibcd in Example 2 I E substituting 3- chloiophcnyi isocyanate foi phenyl isocyanate 1 M NMR (500 MHz, DMSO d^ δ ppm 1 55 - 1 62 (m, 1 H), 1 63 - 1 70 (m, IH), 1 73 - 1 79 (m, 1 H), 3 80 - 1 88 (m, 1 H), 1 99 - 2 06 (m,
1 H), 2 14 - 2 21 (m, 1 H), 3 22 (q, J = S 54 Hz, 1 H), 4 48 (q, / = S 85 Hz, 1 H), 7 03 - 7 05 (m, 1 H), 7 28 - 7 34 (m, 2 H), 7 64 (d, J = S 55 Hz, 2 II), 7 73 (m, 1 H), 7 82 (d, / = 8 S5 Hz,
2 II), S 04 (d, J = S 24 Hz, 1 H), 8 27 (dd, Jl = 8 24 Hz, 12 = 2 45 Hz, 1 II), 9.00 (s, 1 H), 9 03 (s, 1 H), 9 06 (d, /= 1 83 Hz 1 1 H), 12 15 (btoad s, 1 H); MS (ESI) m/z 464 2 [M+Hf
Example 24 Trans-2-( {5-f4-( r {r(2-fluorophenyl)amino]carbonyl >amino)phenyl]pytidin-2- yl } carbonvDcyclopentanecaiboxylic acid
The title compound was piepared as described in Example 21 E substituting 2- fluoiophenyl isocyanate for phenyl isocyanate 1 I-I NMR (500 MHz, DMSO (I 6 ) δ ppm 1 55 - 1 62 (m, 1 H), 1 63 - 1 70 (m, IH), 1 73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 99 - 2 06 (m, 1 II), 2 14 - 2 21 (m, 1 H), 3 22 (q, / = 8 54 Hz. 1 H), 4 48 (q, J = 8 85 Hz, 1 M), 7 01 - 7 05 (m, 1 H), 7 16 (d, J = 7 93 Hz, 1 ϊl), 7 26 (dq, Jl = 7 93 Hz, J2 = 1 53 Hz, 1 II), 7.64 (d, J = 8.85 Hz, 2 H), 7.80 (d, J = 8 85 Hz, 2 H), 8 05 (d, J = 8 24 Hz, 1 H), 8 16 (dt, JJ = 8.24 Hz,
J2 = 1 53 Hz, 1 H), 8.27 (dd, Jl = 8 24 Hz, J2 = 2 14 Hz, 1 H), 8 63 (d, J = 2.45 Hz, 1 H),
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9.06 (d, J= 2..13 Hz, 1 H) 1 9 30 (s, 1 H), 12-15 (bioad s, 1 H); MS (ESI) m/z 448.2 [M+Hf .
Example 25 Trans-2-ff 5- \4~U i U-fluoro-S- (trifluoτomethyl)phenyllamino} carbonvDaminolphenyl } pyridin-2- yl)cnrhony11cyc1opentanecarhoxy1ic acid
The I Hie compound was picpαicd as described in Example 21 E substituting 2-fluoio- 5-trifluoiomethylphenyJ isocyanate. 1 H NMR (500 MHz, DMSO J 6 ) δ ppm 1 55 - 1 .62 (m, 1 H), 1..63 - 1 70 (m, IH), 1.73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 99 - 2 06 (m, 1 H), 2 14 - 2 21 (m, 1 H) 1 3 22 (q, J = 8 54 Hz, 1 H), 4 48 (q, J = S 85 Hz 1 I H), 7 40 - 7 43 (m, 1 H), 7 49 - 7 53 (m, 1 H) 1 7 64 (d, J = 8 85 Hz, 2 H), 7 82 (d, J ~ 8 85 Hz, 2 H), 8.06 (d, J = S 24 Hz, 1 H), 8 27 (dd, Jl = 8.24 Hz, J2 = 2. 14 Hz, 1 H), 8 62 (dd, Jl = 7.33 Hz, J2 = 2,14 Hz, 1 H), S..98 (d, ./ = 2 75 Hz, 1 H), 9 07 (d, J = 2.14 Hz 3 1 H), 9.42 (s, I H), 12 15 (bioad s, 1 H); MS (ESI) m/z 516 3 [MH-H] + ,
Example 26 Trans— 2-rf5- |4-r(phenylacetyl)amino1phenyl1 pyiidin-2-vπcaιbonylicvciopcntanecaiboxyHc acid
Step One: Phenyl acetic acid (0..01 g, 0 07 mmol) was added to a solution of Example 21 D (0 02 g, 0.06 mmol), l-cthyl-3-[3-(dimcthylamino)piopyl]-caibodiimidc hydtochloiidc (0,015 g, 0 08 mmol) and 1 hydroxybenzotiiazole hydsate (0.01 g, 0.08 mmol) in N,N~ dimethylformamide (2 mL) and the mixture stiired at room temperature for 15 hours. The reaction was quenched with water, extracted with ethyl acetate, concentrated and purified by reverse phase high pressure liquid chromatography (RP-HPLC) using a Zorbax SB-C 18 7M 21.2x250 mm column with UV detection analyzed at 220 and 254 nM, and eluted with a solvent system containing component A (water with 0 1% trill uoroacetic acid) and component B (acetonitrile with 0.1% trifluoroacetic acid) with gradient of 5-95% of component B over 30 minutes at 15 mL/min to isolate the ester, Step Two
Lithium hydroxide (0 02 g) was added to a solution of the ester from step one in tetrahydrofutan (2 mL) and water (1 mL) and the mixture stiired at room temperature for 10 hours. The reaction was quenched with 3N hydrochloric acid, extracted with ethyl acetate,
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dried (MgSO 4 ), concentrated and purified by RP-HPLC (using a Zorbax SB-Cl 8 7M 21.2x250 mm column with UV detection analyzed at 220 and 254 nM, and eluted with a solvent system containing component A (water with 0, 1% trifluoroacetic acid) and component B (acetonitiile with 0 1% trifluoroacetic acid) with gradient of 5-95% of component B over 30 minutes at 15 mL/min) to afford the title compound 1 H NMR (500 MHz. DMSO d f ) δ ppm 1 54 - 1 62 (m, 1 H), 1 63 - 1 70 (m. I H), 1 73 - 1 70 (m, 1 H). 1 80 - 1 SS (m, 1 I I), 1 93 - 2 0G (m, 1 II), 2 14 - 2 21 (m, 1 II), 3 20 (q, J = S.54 Hz, 1 I I), 3 69 (s, 2 H), 4.48 (q, ■/ = S..S5 Hz, 1 H), 724 - 7.2S (m, 1 H), 7 32 - 7 36 (m, 4 H), 7.7S (d, ./ = 8 84 Hz, 2 H) 1 7 81 (d, J = 8 85 Hz, 2 H), 8 04 (d, J = 8.24 Hz, 1 H), 8 26 (dd, Jl = 8 24 Hz, J2 = 2..14 Hz, 1 H) 1 9.05 (d, J = 1 S3 Hz, 1 H), 10,4 (s, 1 H), 12.1 1 (broad s, 1 H); MS (ESI) m/z 429., 2 [M+H] +
Example 27
Ti ans-2- 11 ' 5-(4- \ [(2-elhoxyphenyDacetyr|amino \ phcnyDpy t idin-2 : yljca-bonvUcycIopentanecaiboxylic acid
The title compound was prepared as described in Example 26, substituting 2- ethoxyphenyl acetic acid fot phenyl acetic acid 1 H NMR (500 MHz, DMSO ti () ) δ ppm 1 26 ([, J = 6.72 Hz, 3 Ii), I 54 - 1 62 (m, 1 H), 1.63 - 1 70 (m, IH), 1 73 - 1 .79 (m, 1 H), 1.80 - I ..S8 (m, 1 H), 1 93 - 2.06 (m, 1 H), 2 ,14 - 2 21 (m, 1 M), 3.20 (q, J = 8 54 Hz, 1 H), 3 65 (s, 2 H), 4 00 (q, J = 6 72 Hz, 2 H), 4 4S (q, J - 8 ,85 Hz, 1 H), 6 86 - 6 91 (m, 1 H), 6 96 (d, J = S 24 Hz, 2 H), 7 78 (d, J = 8.84 Hz, 2 H), 7 Sl (d, J = S 85 Mz, 2 H), 8 ,04 (d, J = 8.24 Hz, 1 H), 8 26 (dd, JJ = 8.24 Hz, J2 = 2 14 Hz, 1 H), 9.05 (d, J = 1 83 Hz, 1 H), 10.27 (s, 3 H) 3 12.1 1 (bioad s, 1 H); MS (ESI) m/z 473.2 [M+Hf
Example 28
Tians— 2-{[5-(4--{ [(3,5-dimethvlph.enyl)acetyl1amino|phenvl)pvridin-2- yljcaibonyl } cyclopentanecarboxylic acid
The title compound was prepaied as described in Example 26, substituting 3,5- dimelhylphenyl acetic acid for phenyl acetic acid. 1 H NMR (500 MHz, DMSO ds) δ ppm 1 54 - 1 62 (m, 1 H), 1 63 - 1 70 (m, I H), 1 73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 93 - 2,06 (m, 1 H), 2 14 - 2 21 (m, 1 H), 2,26 (s, 6 H), 3.20 (q, J = 8.54 Hz, 1 H), 3 59 (s, 2 H), 4.48 (q, J= 8.85 Hz, 1 H), 6 89 (s, 1 H), 6.96 (s, 2 H), 7.77 (d, J= 8.84 Hz, 2 H), 7,81 (d, J = 8.85 Hz, 2 H), 8.04 (d, J= 8 24 Hz, 1 H), 8 26 (dd, Jl = 8 24 Hz, J2 - 2, 14 Hz, 1 H), 9 05 (d,
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J= 1 ,83 Hz, 1 H), 10 34 (S 1 1 H), 12.1 1 (broad s, 1 H); MS (ESl) rn/z 457.2 [M+H] +
Example 29 Trans-2 - { [ 5-f 4- \ [Y 2R)-2~phenylpi opano yll a m ino lphen vPpyr idin-2 - yl1carbonγl}cyclopentanecaτboxylic acid
The title compound was prepared as described in Example 26, substituting (R)-(-)-2- phenyl piopionic acid for phenyl acetic acid H NMR (500 MHz, DMSO ι!ό) δ ppin 1 45 (d, J = 6.72 Hz, 3 H), 1.51 - 1.62 (m, 1 H), 1 63 - 1 70 (m, IH), 1 73 - 1 79 (m, 1 H), 1 80 - 1.88 (m, 1 H), 1.93 - 2 06 (m, 1 H), 2 14 - 2 21 (m, 1 H), 3.20 (q, ,/ = 8.54 Hz, 1 H), 3 86 (q, ./ = 6 72 Hz, 1 H), 4.48 (q, J = 8 85 Hz, 1 H), 7.23 - 7 31 (m, 1 H), 7.33 - 7 36 (m, 2 H), 7.37 - 7.44 (m, 2 H), 7 77 (d, J = 8,84 Hz, 2 H), 7,80 (d, J = 8.85 Hz, 2 H), 8.04 (d, J = 8 24 Hz 1 1 H), 8.26 (dd, Jl = 8 24 Hz, J2 - 2 14 Hz, 1 H), 9 04 (d, ./ = 1 83 Hz, 1 H), 10 27 (s, 1 H), 12 14 (bioad s, 1 H); MS (ESI) m/z 443 2 [MH-H] + .
Example 30
Tians-2- f [5-(4--i [fluoiO(phenyl)acetyllamino|phenvl)pyndiπ-2- yl Icaibonyl ) cyclopentaπecaiboxyl i c ac id
The title compound was prepared as described in Example 26, substituting α- fluoiophenyl acetic acid for phenyl acetic acid. 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1 .54 - 1.62 (m, 3 H), 1 63 - I 70 (m, IH), 1 73 - 1 .79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1.93 - 2..06 (m, 1 H), 2.14 - 2,21 (m, 1 H), 3 20 (q, J = 8 54 Hz, 1 H) 5 448 (q, J = 8 85 Hz, 1 H) 5 ό 06 (s, 0 5 H), 6.15 (s, 0.5 H), 7.43 - 7 50 (m, 3 H) 1 7 52 - 7 63 (m, 2 H), 7 84 (d, J= 8.84 Hz, 2 H), 7 87 (d, J = 8 85 Hz, 2 H), 8 05 (d, J = 8.24 Hz, 1 H), 8.28 (dd, Jl - 8.24 Hz, J2 = 2 14 Hz, 1 H), 9 06 (d, J = 1.83 Hz, 1 H), 10 6 (s, 1 H), 12.13 (broad s, 1 H); MS (ESI) m/z 447 2 [M+H] + .
Example 31 Trans-2-[(5-{4-[(thien-3-ylacetyl)amino]phenvUpyridin-2- vDcaibonyllcyciopentanecaiboxylic acid
The title compound was prepared as described in Example 26, substituting thiophene- 3-acetic acid foi phenyl acetic acid 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1 54 - 1 62 (m, 1
H), 1 63 - 1 70 (m, IH), 1.73 - 1 .79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 93 - 2 06 (m, 1 H), 2 14
- 2 21 (m, 1 H), 3 20 (q, J= 8 54 Hz, 1 H), 3.70 (s, 2 H), 4 48 (q, J= 8,85 Hz 1 1 H), 7.12 (d, ./
= 4.88 Hz, 1 H), 7.35 (d, J= 2 14 Hz, 1 H), 7 50 (dd, J/ = 4.88 Hz, J2 = 2.14 Hz, 1 H), 7.78
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(d, J = 8 84 Hz, 2 H), 7,81 (d, J = 8 85 Hz, 2 H), 8 05 (d, / = 8 24 Hz 1 1 H), 8 26 (dd, Jl = 8-24 Hz, /2 = 2 14 Hz, 1 H), 9 05 (d, / = 1 83 Hz, 1 H), 10 36 (s, 1 H), 12-1 1 (bioad s, 1 H); MS (ESI) m/z 435 1 [M+H] +
Example 32
Ttans-2-| " f5--(4-ffpyridin-3-ylacelv1)amino]phenv1}pyi idin-2- vDcaibonyllcvclopcntanccaiboxylic acid
The title compound was prepared as desciibed in Example 26, substituting pyiidyl-3- acetic acid for phenyl acetic acid 1 H NMR {500 MHz, DMSO d 6 ) 5 ppm 1 54 - 1 62 (m, 1 H), 1 63 - 1 70 (m, IH), 1 73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 93 - 2 06 (m, 1 H), 2 14 - 2 21 (m, I H) 1 3 21 (q, J = 8 54 Hz, 1 H) 5 3 92 (s, 2 H), 4 48 (q, J = 8 85 Hz, 1 H), 7 72 - 1 78 (m, 3 H), 7 83 (d, J = 8 84 Hz, 2 H), 8 05 (d, ,/ - 8 24 Hz, 1 H), 8 15 - 8 19 (m, 1 H), 8.26 (dd, JI = 8 24 Hz, /2 = 2 14 Hz, 1 H), 9 05 (d, ./ = 1 83 Hz, 1 H), 10 52 (s, 1 H), 12 1 1 (bioad s, 1 H); MS (ESI) m/z 430 1 [MH-H] +
Example 33 Tians-2-|j " 5-f4--![(l-phenylcvclopiopy])caibonyl]amino)phenvl)pyiidin-2 - yl " |caibonyUcyclopenιanecatboxylic acid
The title compound was piepaicd as desciibed in Example 26, substituting l-phenyl- 1 -cyclopropane carboxylic acid foi phenyl acetic acid 1 H NMR (500 MHz, DMSO dβ) δ ppm 1 14-1 18 (m, 2 H), 1 47-1 49 (m, 2 H), 1 54 - 1 62 (m, 1 H), I 63 - 1 70 (m, IH) 1 1 73 -
1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 93 - 2 06 (m, 1 H), 2 14 - 2 21 (m, 1 H), 3 20 (q, J =
8 54 Hz, 1 H), 4 48 (q, / = 8 85 Hz, 1 H), 7 28 - 7 31 (m, 1 H), 7 36 - 7 42 (m, 4 H), 7 74 (d,
J = 8 84 Hz, 2 H), 7 78 (d, / = 8 85 Hz, 2 H), 8 04 (d, / = 8 24 Hz, 1 H), 8.26 (dd, // = 8 24 Hz, /2 = 2 14 Hz, 1 H), 9 04 (d, / - 1 83 Hz, ! H), 9 32 (s, 1 H), 12 1 1 (broad s, 1 H); MS
Example 34 Tians-2-[f5-(4-[(anUinocaibonyl)amino1-3-fluorophenvUpyiidin -2- vDcarbonyllcvclopentanecaiboxylic acid
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Example 34A Tians-methyl 2-[(5-{4-[('fe^-butoxycaibonyl)arnino1-3-fluorophenyltpyτid in-2- yl)catbonyl]cyclopentanecaiboxylate
The title compound was prepared as described in Example 21 C, substituting 4-(tert- butoxycaibonyIamino)-3-fluoiophenylboionic acid for 4-nitrophenyiboionic acid piπacol ester 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1 49 (s, 9 H), 1 63 - 1 70 (m, 2 H), 1 73 - 1 79
(m, I Ii), i SO - 1 88 (m, 1 11), 1 97 - 2 05 (m, 1 11), 2 15 - 2 21 (ra, 1 H), 3 25 (q, ./ = S 24
Hz, 1 H), 3 57 (s, 3 H), 4 48 (q, ./= 9 15 Hz, 1 H), 7 63 - 7 69 (m, 1 H), 7 75 - 7 85 (m, 2 H),
8 06 (d, ,/= 8 54 Hz, 1 H), 8 28 - 8 33 (m, 1 H), 9 07 (dd, Jl = 1 3 15 Hz, J2 = 1 83 Hz, 1 H), 9 20 (broad s, 1 H); MS (HSl) m/z 443 1 [M+Ilf
Example 34B
Tians-mcthy] 2-{j " 5-f4-amino-3-fluoιophenyπpyiidin-2-yl]caibonyl)cvclopcntan ecaiboxylate Example 34λ was added to tiifluoioaceϋc acid (7 niL) and dichloiomethane (20 mL) and the miλtuie stiired at loom tempcialuie lbi 2 houts The solvents weie icmoved /// vacuo, the iesiduc was diluted with saluiated sodium hydiogcn caibonale, cxtiacted with ethyl acetate, diicd (MgSθ 4 ), fϊlteied, and concentialed to a blown paste, to affoid the title compound, which was used in the next step without puiifϊcaϋon 1 II NMR (500 MHz, DMSO d 6 ) δ ppm 1 63 - 1 70 (m, 2 H), 1 73 - 1 79 (m, 1 H), 1 80 - 1 SS (ra, 1 H), 1 97 - 2 05 (m, 1 Ii), 2 15 - 2 21 (m, 1 H), 3 22 (q, / = S 24 Hz, I Ii), 3 55 (s, 3 H), 4 46 (q, J = 9 15 Hz, 1 H), 5 60 (s, 2 H), 6 91 (1, J = 8 24 Hz, 1 H), 7 44 (dt, Jl = 7 93 Hz, /2 = 2 13 Hz, 1 H), 7 59 (dd, Jl = 13 15 Hz, JI = 1 83 Hz, 1 H), 7 99 (d, ./ = S 24 Hz, 1 H), 8 19 (dt, .// = 10 99 Hz, Jl = 2 13 Hz, 1 H), 8 99 (s, 1 H); MS (ESI) m/z 343 0 [MH-H] +
Example 34C
Tians-2-[(5--j4-[ ' (anilinocaibonyl)amino1-3-fluoFophe ι nyl}pyiidin-2- ypcaibonyllcvelopentanecaiboxylic acid
T he title compound was piepared as desciibed in Example 2 IE, substituting Example
34B foi Example 21D 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1 55 - 1 62 (m, 1 H), 1 63 - 1 70 (m, I H), 1 73 - 1 79 (m, 1 Ii) 1 1 80 - 1 88 (m, 1 H), 1 99 - 2 06 (m, 1 II), 2 14 - 2 21 (m,
1 H), 3 22 (q, ./ = S 54 Hz, 1 H), 4 48 (q, / - 8 85 Hz, 1 H), 7 01 (t, J = I 63 Hz, 1 M), 7 32 (t,
/ = 7 63 Hz, 2 Ii), 7 47 (d, J- 7 63 Hz, 2 H), 7 69 (dd, Jl = 8 54 Hz, /2 = 1 83 Hz, 1 H), 7 85
(dd, Jl = 12 51 Hz, J2 = 2 13 Hz, 1 H), 8 06 (d, J= 8 23 Hz, 1 H), 8 31 (dd, J7 - 8 24 Hz, J2
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= 2 13 Hz, 1 H), 8 36 <t, J = 8 54 Hz, 1 H), 8 76 (d, J = 2 45 Hz, 1 H), 9 10 (d, ./ = 2 14 Hz 1 1 H), 9 15 (s, 1 H), 12 15 (bioad s, 1 H); MS (ESI) m/z 448 1 [M+H] +
Example 35 Trans-2-[f5-{3-fluoro-4-j ' fphenylacetyl)amino1phenyl)pyridin-2- ypcarbonylicyciopentanecaiboxylic acid
The title compound w as ptepuicd as described in Example 26, substituting Example 34B fox Example 21D 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1 55 - 1 62 (m, 1 H), I 63 -
1 70 (m, IH), 1 73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 1 99 - 2 06 (m, 1 H), 2 14 - 2 21 (m, 1 H), 3 20 (q, J = 8 54 Hz 1 1 H) 3 3 7S (s, 2 H), 4 48 (q, J = S 85 Hz, 1 H), 7 24 - 7 30 (m, 1
H), 7 31 - 7 37 (m, 4 H), 7 67 (dd, Jl = 8 54 Hz, /2 = 1 83 Hz, 1 H), 7 83 (dd, // = 12 51 Hz, J2 = 2 13 Hz, 1 H), 8 06 (d, J = S 23 Hz, 1 H), 8 08 - S 13 (m, 1 H), 8 32 (dd, Jl = 8 24 Hz, J2 = 2 13 Hz, I H), 9 10 (d, J = 2 14 Hz, 1 H), 10 15 (s, 1 H), 12 15 (bioad s, 1 H); MS (ESI)
Example 36
Tians-2-( 16'-[Y [ [3-f Ii ifluoiomethyOphenyliamino] caiboπyI)amino]-3.3'-bipytidin-6- yllcaibonvDcyclopentanecarboxylic acid
Example 36A
Tians-methyl 2-[ " f6'-amino-3.3'-bipyiidin-6-yl)caibonv11cyclopentanecaiboxyla ie
The title compound was piepaicd as described in Example 21 C, substituting 2- aminopyridine-5-boionic acid pinacol ester for 4-nϊtrophenylboionic acid pinacol ester 1 H
NMR (500 MHz, DMSO d 6 ) δ ppm 1 63 - 1 70 (m, 2 H), 1 73 - 1 79 (m, 1 H), 1 80 - 1 88 (m, 1 H), 2 02 - 2 09 (m, 1 H), 2 15 - 2 21 (m, 1 H), 3 22 (q, J = 8 24 Hz, 1 H), 3 56 (s, 3 H), 4 44
(q, / = 9 15 Mz, 1 H), 6 37 (s, 2 H), 6 58 (d, J = 8 85 Hz, 1 H), 7 89 (dd, JJ = 8 54 Hz, J2 =
245 Hz, 1 H), 800 (d, J= 854 Hz, 1 H), 819 (dd, /7 = 823 Hz, J2 = 245 Hz, 1 H), 845 (d, /=244 Hz, 1 II), 899 (d, /= 153 Hz, 1 H)
Example 36B
Tians-2-(6'-(3-(3-(Trinuoiomethyl)phenyl)uieido)-3.3'-bip yndine-6- caibonyDcyclopentanecatboxylic acid The title compound was prepared as described in Example 2 IE, substituting Example
Filed electronically May 1 7, 2007 8224WOO 1
36A foi Example 2 ID, and substituting 3-tiifluoromethylphenyl isocyanate foi phenyl isocyanate. 1 H NMR (500 MHz, DMSO d 6 ) δ ppm 1.55 - 1 .62 (rn, 1 H), 1 ,63 - 1 70 (m, IH), 1 .73 - 1.79 (m, 1 H), 1.80 - 1.88 (m, 1 H), 1.99 - 2.06 (m, 1 H), 2 14 - 2.21 (m, 1 H), 3 22 (q, J = 8 54 Hz, 1 H), 4.48 (q, J = 8.85 Hz, 1 H), 7.38 (d, J= 7 93 Hz, 1 H), 7.57 (t, ./ = 8.24 Hz, 1 H), 7.68 (d, J= 9.15 Hz, 1 H), 7 75 (d, J = 8 85 Hz, 1 H), 8.07 - 8.11 (m, 2 H), 8.28 (dd, J/ = S 85 Hz, J2 - 2 44 Hz, 1 H), 8 35 (dd, .// = 8 85 Hz, J2 = 2 45 Hz, 1 H), 8 83 (d, .7 = 2 14 Hz, 1 H), 9 12 (d, J = 2 14 Hz 1 1 11), 9 75 (s, 1 H), 10.56 (s, 1 H), 12 1 1 (broad s, 1 H); MS (ESI) m/z 499.2 [MH-H] + ,
Example 37
Trans-N-r2-fluoto-5-(ti-ifluoiomethyl)phenvn-N'-r4-f 2- \ \2-( 1 -hydroxy- 1 - methylethyπcyclopentyllcaibonyll-U-thiazol-S-yDphenyl^urea
Example 37A j ftø; /-butylfdimclhyi)silyl ' joxy 1 , f 1.3 -thiazol-2-yl^ace toni U ile
To a solution of fhiazole-2-caibaldehyde (1 3 g, 1 1 5 mmol) in aceloπittilc (38 ml.) at ambient temperatuie, potassium cyanide (2 86 g, 44 0 mmol), leti-butylchlorodimethylsilane (2.08 g, 13.8 mmol), and zinc(II) iodide (0.055 g, 0 173 mmol) wete added. After 16 houis, the ieaction was filtered and concentialed under reduced pressure. The crude residue was puiified by chromatography on silica gel, eluting with hexane, to afford the title compound MS (ESI) m/z 255 [MH-H] +
Example 37B Trans 2-(2-acerylcvclopentyl)-2-(tert-butyldimeihylsilyloxy)-2-(th iazol-2-yl)acetonitiile
To a cold (-78 0 C) solution of Example 37A (1 .0 g, 3.92 mmol) in tetrahydiofiiian (10 niL), lithium diisopropylamide (8.62 mL, 4 31 mmol, 0.5 M in tehahydrofuran) vvas added over five minutes After 30 minutes, 1-cyclopentenylethanone (0,476 mL, 4.31 mmol) was added drop wise The reaction was stilted foi an additional 30 minutes and was quenched by the addition of saturated aqueous ammonium chloride (20 mL) and ethyl acetate (20 mL)
The layers were separated, and the aqueous was extracted with additional ethyl acetate (2 x 20 mL). The combined oiganic layers were dried with anhydrous sodium sulfate, filtered, and concentiated under reduced pressure The crude iesidue vvas purified by chromatography on silica gel, eluting with a gradient of 5% ethyl acetate in hexane to 25% ethyl acetate in hexane, to afford the title compound. 1 H NMR (300 MHz, DMSO-c?<j) δ ppm -0.15 (s, 3 H),
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0 17 (s, 3 H), 1 46-1 68 (m, 4 H), 1 77 (s, 3 H), 1 75-1 82 (m, 1 H), 1 87-1 98 (m, 1 H), 2 59 (ddd, J = 10 2, 6 8, and 6 8 Hz, 1 H), 2 69 (ddd, J = 6 8, 6 8, and 3.4 Hz, 1 H), 7 72 (d, 7= 3 0 Hz, 1 H), 7 75 (d, J= 3 O Hz, IH)
Example 37C Trans Ufe; /-butylfdimethyl)silyl1oxyl [2-f l-hvdioxy-l-methv1ethyl)cyclopentv11L3-t1iiazo]-
2-ylaceioniu ile
Tυ a cυld (0° C) solution of Example 37B (0 682 g, 1 S7 mmol) in lcimh> diohπan (9 ml), melhylmagnesum biomide {1 67 mL, 2 34 mol, 1 4 M in tehahydiofuian) was added Aftei 15 minutes, the ieaction was quenched by the addition of saturated aqueous ammonium chloiide (15 ml) and ethyl acetate (15 mL) The layeis wcie sepaiated, and the aqueous Iayei was extiacled with additional ethyl acetate (2 x 15 mL) The combined oiganic layeis were diied with anhydious sodium sulfate, filteied, and concentiated undei ieduced piessuie The crude iesidue was puiificd by chiomatogiaphy on silica gel, eluting with 5% ethyl acetate in hexane to 35% ethyl acetate in hcxanc, to affoid the title compound MS (EST) m/z 381 [M+H] +
Example 37D Tians-f 27?)- { [tei /-butyl(dimethyl)silyl |oxy ] \2-{ 1 -hydi oxy- 1 -melhylcthyDcyclopentyllfS- iodo-1.3-thiazol-2-yl)acetonitule
To a cold (-78 0 C) solution of Example 36C (0 592 g, 1 56 mmol) in tclrahydiofuran (8 mL), n-butyllilhium (1 38 mL, 3 43 mol, 2 4S M in hexane) was added λftci 15 minutes, a solution of iodine (0 476 g, 1 87 mmol) in tcliahydiofuian (2 mL) was added diop wise Aftei 5 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloiide (20 mL) and ethyl acetate (20 mL) The layers were sepaiated and the aqueous Iayei was extracted with additional ethyl acetate (2 x 20 mL) The combined organic layeis were dried with anhydious sodium sulfate, filtered, and concentiated under ieduced pressure to afford the title compound, which was used in the subsequent step without further pur ification MS (ESI) m/z 507 [M+Hj !
Example 37E Trans-[2-(l -hydi oxy- l-mcthylet]wl)cyclopentyl](5-iodo-1.3-thiazo1-2-yl)methanone
To a solution of Example 37D (0 791 g, 1 56 mmol) at ambient tempeialiπe in a solvent mixtiπe of tehahydiofuian (5 mL) and acetic acid (0 5 mL), letrabutyl ammonium fluoride (1 72 mL, 1 72 mmol, 1 0 M in tettahydrofuian) was added Aftei 3 hours, the
Filed electronically May ! 7, 2007 S224WOO1
reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate (10 mL) and ethyl acetate (10 ml-) The layeis were separated, and the aqueous was extracted with additional ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound, which was used in the subsequent step without further purification. MS (ESI) m/z 36G [M+H] +
Example 37F Trans-| ~ 2-( 1 -hydioxy- 1 -methylethvDcycIopentylif 5-f4-nitiophenvl)- 1 ,3-lhiazol-2- yl " |methanone A solution of Example 37E (0 330 g, 0 904 mmol), 4-nitiophenylboionic acid (0 21 1 g, 2 70 mmol), potassium fluoride (0 157 g, 2,70 mmol), and bis{triphenylphosphine)pal1adium(ll) dichloride ( 0.065 g, 0 090 mmol) in a mixtuie of 1 ,2- dimethoxyethane/methanol (1 : 1 , 3 mL)was heated to 80° C for 16 horns The reaction was cooled to ioom temperature, and saturated aqueous ammonium chloride (5 mL) and ethyl acetate (5 mL) wetc added. The layers wcie scpatated, and the aqueous layer was exttacted with additional ethyl acetate (2 x 5 mL) The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced presstne The crude iesidue was purified by chiomatogtaphy on silica gel, eluting with 50% ethyl acetate in hexane, to afford the title compound MS (ESl) m/z 361 [M+H] +
Example 37G Tians-[5-f4-aminophenyl V 1.3-thiazol-2-vnr2-(l -hydroxy-1 - methylethyl)cyclopentyl]methanone
To a solution of Example 37F (0.150 g, 0 417 mmol) and ammonium chloride (0.023 g, 0.417 mmol) in a solvent mixture of ethanol (4 mL) and water (1 mL) was added iron powder (0 056 g, 1 04 mmol) The mixture was heated at 80° C for 8 horns. The reaction was then cooled to room temperature and quenched by the addition of satuiated aqueous sodium hydrogen carbonate (10 mL) and ethyl acetate (10 mL) The layers were sepaialed, and the aqueous was extracted with additional ethyl acetate (2 x 10 mL), The combined organic layeis vveie dried with anhydrous sodium sulfate, filtered, and concentiaied under reduced pressuie to afford the title compound, which was used in the subsequent step without further purification . MS (ESl) m/z 331 [MH-H] + .
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Example 37H Tians-N-| " 2-fluoro-5-ftrifluoromethvπphenyl]-N'-[4-f2-fr2-f l-hvdioxy-l- nietlwlethyπcvclopentylicarbonyO-l J-thiazol-S-vDphenyliuiea
To a solution of Example 37G (0 123 g, 0 373 mmol) at ambient temperature in tetrahydrofuran (3 ml) was added 2-iliioro-5-trifluoramethy1phenyl isocyanate (0 054 mL,
0 373 mmol) After 1 hoiπ, the reaction was coπcentialcd undei icduccd picssure The ciiidc icsidue w as purified by chiϋmutυguphy on silica gel, cliiling with elhvi ace La Ie, iυ allbsd the title compound 1 H NMR (300 MHz, DMSO-r/<s) δ ppm LOO (s, 3 II), 1 07 (s, 3 H), 1 56-1 69
(m, 4 H), 1 75-1 80 (m, 1 H) 3 1 97-2 04 (m, 1 H), 2 53 (q, J = 8 5 Hz, 1 H), 4 09 (q, 7 = 8 5 Hz, 1 II), 4 21 (s, 1 H), 7 33 (d, ,/ = 7 6 Hz, 1 H), 7 53 (t, .7 = 7 9 Hz, 1 H), 7 60 (d, J = S 9
Hz, 2 II), 7 75 (d, J = S 9 Hz, 2 H), 8 02 (s, 1 H), S 45 (s, 1 II), 9 10 (s, 1 H), 9 1 3 (s, 1 H);
MS (ESI) ra/z 536 [M+H] 1
Example 38 Tians-2-| (5- i4-[({[2-fluoio-5-fUifluoiomeLhyl)phenyl |amino| catbonyl)amino]phcnvU thien-
2-yI)carbonyl]cyclobπtaπe carboxylic acid
Example 38A
Cis-2-(methoxyeaibonvl)cvclobulanc caiboxylic acid A solution of 3~oxabicyclo[3 2 0]heptane-2,4-dione ( 1 65 g, 13 1 mmol) in methanol
(20 mL) was heated to 60° C for 16 hours The reaction was then concentrated iindei i educed piessuie (o afford the title compound MS (ESI) m/z 159 [M+Ilf
Example 38B Trans-methyl 2~l " (5-bromothien-2-yl)carbonyl ' ]cvc]obutanecarboxylate
To solution of Example 3SA (1 0 g, 6 5 mol) in a solvent mixture of dichloromethane (1 1 mL ) and N,N-dimelhylfoimamide (0 25 mL ) at ambient tempeiatuse, thionyl chloride (1 44 mL, 19 7 mmol) was added λftei 6 houis, the reaction was concentrated under reduced pressure The iesidue was dissolved in 2-bromothiophene (3 8 mL, 39 0 mmol) and cooled to 0° C Aluminum Uichloride (1 73 g, 13 mmol) was added in a single poition with vigoious stirring Aftei 3 houis, the reaction was quenched by the slow addition of water (20 mL) and ethyl acetate (20 mL) The layers weie separated, and the aqueous was extracted with additional ethyl acetate (2 x 10 mL) The combined organic layeis were dried with
Filed electronically May 17, 2007 8224WOO1
anhydrous sodium sulfate, filteied, and concentrated under reduced pressure The residue was purified by chromatography on silica gel, eluting with 10% ethyl acetate in hexane, to afford the title compound. MS (ESI) m/z 305 [M+H] +
Example 3SC
N-f2-fluoro-5-(ti'ifluoiOmethyl)pheny11-A f '-r4-f4.4.5.5-tetramethv1-1 .3.2-dioxaboiolan-2- yl)phcny1]ιuca
To an ambient solution of 4-(4,4,5 s 5-lettamethyl-l ,3 1 2-dioxaboio!an-2-yl)aniline (2 0 g, 9 13 mmol) in tetrahydrofuran (30 mL), 2-f!uoro-5-trifluoiOmethy]phenyl isocyanate (1.32 mL, 9.13 mmol) was added. After 1 hour, the mixture was conceπhated under i educed piessure to afford the title compound as a white solid MS (ESF) m/z 425 [M+H] +
Example 38JD Trans-2-[(5- ι {4-[( f [2-fluoiO-5-(tnflιioromethyl)pheηyI]amino] caibony1)amino1phenyl ' | thie8i- 2-yl)caibonyl]cyciobutane caiboxylic acid
A solution of Example 3SB (0.072 g, 0 236 mmol), Example 38C (0 100 g, 0 236 mmol). cesium fluoiidc (0.108 g, 0 0 708 mmol), and tetrakis(tripheny]phosphine)palladium(0) (0 027 g, 0.024 mmol) in a solvent mixture of 1 ,2- dimethoxyethane (0.5 mL) and methanol (0 5 mL) was heated to 90° C for \ 6 horns The reaction was then cooled to ioom temperature and diluted with ethyl acetate (5 mL) and water (5 mL) The layers were separated, and the aqueous was extracted with additional ethyl acetate (2 x 10 mL) The combined organic layeis were dried with anhydrous sodium sulfate, filteied, and concentrated under reduced pressuie to yield the intermediate ester To the crude ester dissolved in tetiahydrofuran (0 6 mL) and methanol (0 3 mL) was added 2N sodium hydroxide (0 2 mL) The ieaction was stirred at room temperature for 2 hours and was then acidified to pH 1 with 10% hydrochloric acid After addition of ethyl acetate (5 mL), the layeis were separated, and the aqueous was extracted with additional ethyl acetate (2 x 5 mL ). The combined organic layeis were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The residue was purified via RP-HPLC (pieparative leversed-phase high piessuie liquid chiomatogiaphy) using a Zotbax SB-CI S 7M 21 .2x250 mm column with UV detection analyzed at 220 and 254 iiM (piepaiative method: water with 0 1% trifluoioacetic acid and acetonitrile with 0 1% trifluoroacetic acid gradient 5-95% acetonihile over 30 minutes at 15 mL/minutes) to afford the title compound
Fiieci electronically May 17, 2007 8224WOO1
as a white solid 1 H NMR (300 MHz, DMSO-cfc) δ ppm 2 06-2 28 (m, 4 H), 3 38-3 42 (m, 1 H), 4 17-4,25 (m, 1 H), 7 39-7 44 (m, 1 H), 7 50 (d, J = 10 8 Hz, 1 H), 7 55-7 58 (m, 3 H), 7 74 (d, ./ = 8 5 Hz, 1 H), 7 90 (d, J = 4 1 Hz, 1 H), 8-61 (dd, J = 7 1 and 1 7 Hz, 1 H), 8 96 (br s, 1 H), 9 42 (s, 1 H), 12 37 (s, 1 H); MS (ESI) m/z 507 [M+H] + .
Example 39
Tians-2-| ' (5- |4-[( I [2-fluoio-5-(ti ill uoιomethvl)phcnyl]amino! cιubϋnvπaminϋl phenyl ! -1.3- thiazol-2-yI) c ai bony 1 " I c yc lopenlanecai boxy 1 i c ac id
Example 39A
Trans-2-(1.3-Lliiazol-2-ylcaibonyl)cvclopcntanccaiboxylic acid
To a 20 mL vial with scievv cap, letiahydio-lH-cyclopenta[c]fιπan-l,3(3aH)-dione
(1000 mg, 7 14 mmol) and teliahydiofutan (8 mL) weie added Thiazol-2-ylzmc(II) bromide
(17 mL, 8 5 mmol, 0 5 M in tetiahydiofuian) was added diop wise followed by Ieliakis(uiphenylphosphine)palladium(0) (400 mg, 0 36 mmol) The vial was scaled and the mixtiπc stiπcd at 80° C overnight The reaction was cooled to room tcmpeiatine and diluted with diethyl cthci (25 mL) and 2 5M sodium hydioxide (25 mL) The iaycis wcie scpaiatcd, and the aqueous layci was acidified to pH 1 with coπcentialcd hydiochloi ic acid The aqueous layei was cxtiacted with diethyl cthei (2 x 25 mL), and the combined oiganic layeis weie dticd ovei sodium sulfate, filleted, and concentrated to affoid the title compound MS
(ESl) rn/z 226 [M+H] f
Example 39B
Trans-methyl-2-π ,3-thiazol-2-ylcaibonyl)cvclopenlanecaiboxylale To a 50 mL flask, Example 39A (1718 mg, 7 627 mmol), iodornethane (2 37 mL, 38 134 mmol), potassium carbonate (2100 mg, 15 253 mmol), and N,N~dimethylfoimamide (10 mL) were added The solution was stilted at ioom temperature for 48 houis The reaction was then diluted with diethyl ether (50 mL) and watei (50 mL) The layeis were separated, and the organic was washed with water (1 x 25 mL) and brine (1 x 25 mL), dried over sodium sulfate, filtered, and concentiated to afford the title compound MS (ESI) m/z 240 [MH-H] ' '
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Example 39C Trans-methy 1-2- 1 [ 5-(4 ,4 , 5 ,5 -tetramethy 1 - 1.3 ,2-di oxaborol a n-2-yl )- 1 ,3 -th i azol-2- yl 1 carbonyl ) cyclopentanecaiboxylate
To a 25 mL flask, chloro-bis-cyclooctene-iridium (I) dimer (11 mg, 0.013 mmol), di- /-biitylpyridine (7 mg, 0 025 mmol), 4,4,4',4',5,5,5' ! 5'-octamethyI-2,2 I -bi(l ,3,2-dioxaboroIane)
(425 ing, 1 674 mmol), and ocUinc (5 mL) weie added The teaclion was stirred and heated to 50° C foi 30 minutes Example 39B (200 mg, 0 S37 mmol) in octane (5 ml.) was added. and the solution was stirred at 80° C foi 16 hours. The reaction was cooled to room temperature and directly purified by chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, to afford the title compound MS (ESl) m/z 366 [M+H] +
Example 39D
Tians-2-[f5- { " 4-[f {[2-fluQiO : 5-(ti ι ifluoiOmethyl)phenyl1amino) caibonyl)aiτiino|phcnyl | -1.3- thiazo1-2-vl)caibonyl]cyclopentanecarboxy1ic acid To a 5 mL microwave reaction vessel, Example 39C (7 mg, 0.019 mmol), Example 44
(8 mg, 0 019 mmol), cesium fluoride (9 mg, 0 058 mmol), Ie(rakis(tiiphenylphosphinc)palladium(0) (2 mg, 0 002 mmol), 1,2-dimethoxyethaπc (3 ml..), and methanol( 2 mL) were added The reaction was heated to 150° C foi 5 minutes under microwave irradiation (Peisonal Chemistry Microwave). The solution was concentiated, taken up in methanol (2 mL), filtered thiough a plug of celite, and purified by RP-HPLC (Piepaiative reversed-phase high pressure liquid chromatography) using a Zotbax SB-Cl 8 7M 21 .2x250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0 1% irifluoroacelic acid and acetonitrile with 0 1% trifluotoacetic acid gradient 5-95% acetonitrile over 30 minutes at 15 ml/minutes) to give an intermediate ester. The ester was dissolved in methanol (2 mL) and 2.5M sodium hydroxide (23 μL) The resulting solution was stirred at room temperature for 16 hours. The solution was acidified to pH 1 with 6N hydrochloric acid, and diluted with ethyl acetate (5 mL) and water (5 mL) The organic layer was washed with brine (1 x 5 mL), dried over anhydrous sodium sulfate, filtered, and concentiated under reduced pressure to afford the title compound. 1 H NMR (300 MHz, methanol-^) δ ppm I 75 - 1 .86 (m, 3 H), 1 .88 - 2.01 (m, 1 H), 2 05 - 2 I S (m, 1 H), 2.24 - 2 34 (m, 1 H), 3 33 - 3 36 (m, 1 H), 4 26 - 4 34 (m, 1 H), 4 87 (s, 3 H), 7 29 - 7.38 (m, 2 H), 7,58 - 7.63 (m, 2 H), 7.68 - 7.74 (m, 2 H), 8 27 (s, 1 H), 8 61 (d, J = 6.44 Hz, 1 H); MS (ESI) m/z 522 [M+H] + .
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Example 40 Tians-2-[(5-l3-fluoto-4-[f {[3-(trifluoiomethyl)phenyl1amino)carbonyl)amino1phenvU-U- thiazol-2-vl)carbonyl " [cyclopentanecarboxyIic acid
The title compound was prepared as described in Example 39D, substituting Example 45 for l-(2-fluoro-5-(ti 1 ifluoromethyl)phenyl)-3-(4-iodophenyl)uτea. 1 H NMR (300 MHz, methanol-r/.,) δ ppm 1 76 - 1 86 fm, 3 H), ϊ S9 - 2 01 (m, 1 H) 1 2 12 (s, 1 H), 2 28 (s, 1 H),
3 34 - 3 43 (in, 1 H), 4 29 (s, 1 11), 4.76 (s, 3 II), 7 33 (s, 1 II), 7 46 - 7.49 (m, 1 H), 7 51 -
7.64 (m, 3 H), 7 94 (s, 1 H), 8 26 - 8.34 (m, 2 H); MS (ESl) m/z 522 [M+H] + .
Example 41
Trans-2-rf5-{3-πuoio-4-rf f r2-fluoro-5- ftπfluoiomethyl)phenyl]aminolcaibonyl)aminolphenvU-l,3-thia zol-2- ypcaibonylicvclopentanecarboxylic acid
The title compound was prepared as desciibed in Example 39D, substituting Example 46 foi l -(2-fluoi-o-5-{liiπuoiomethyl)pheny1)-3-(4-iodophenyl)uiea 1 I-I NMR (300 MHz, methanol-^) δ ppm 1 76 - 1 87 (m, 3 H), 1 92 - 1 .99 (m, 1 H), 2.0S - 2 16 (m, 1 H), 2 26 - 2.33 (m, 1 H), 3 21 - 3 27 (m, 1 H). 4 26 - 4.34 (m, 1 H), 4 73 - 4 75 (m, 3 H), 7 32 - 7 34 (m, 3 H) 5 7.35 (d, J= 1 36 Hz, 1 H), 7 54 - 7 58 (m, 1 H), 7 61 (dd, J = 1 1.87, 2.03 Hz, 1 H), S 30 (s, 1 H) 1 8.36 (t, ./= S 48 Hz, 1 H), 8 62 - S 66 (m, 1 H); MS (ESI) m/z 540 [M-KHf
Example 42
Ttans 7 2 r [( ' 5--i4-rf {f2-fluoio-5-( ' ti ι iωuoiometliyl)phenyl1amino 1 fCarbonyπamiiio]phenyl }-1.3- thiazol-2-vl)carbonyl]cvclobutane carboxylic acid
Example 42A
Trans-2-f 1.3-thiazol-2-yIcaibonyl)cyclobutane caiboxylic acid The title compound was prepared as desci ibed in Example 39A, substituting 3- oxabicyclo[3 2 0]heptane-2,4-dione for tetrahydιo-lH-cyclopenta[c]fιπan-l ,3(3aH)-diorie MS (APCl) m/z 212[M-M-I] + Example 42B
Tians-methyl-2-f 1.3-lhiazol-2-ylcarbonyDcyclobutanecaiboxylate The title compound was prepared as desciibed in Example 39B, substituting Example 42A for Example 39A. MS (APCI) m/z 226 [M+H] + ,
Filed electronically May 17, 2007 8224W0O1
Example 42C
Trans-methyl -2- i r5-(4.4.5,54etraniethyl- 13.2-dioxaborolan-2-:yl)-l ,3-thiazol-2- ylicaibonvUcyclobutanecarboxylate The title compound was prepared as described in Example 39C, substituting Example
42B for Example 39B MS (ESI) m/z 352[M+H] +
Example 42D
Tians-σ-l ' fS-M-Cf lβ-fliioro-S-ftTiωuoromethvDphenvnarninolcarbonvDaminQiphe nvU-I J- ihiazoi-Z-yDcarboπyilcyclobutane cπiboxylic acid
The title compound was prcpaied as described in Example 39D 3 substituting Example
42C for Example .39C 1 H NMR (300 MHz, methanol-^) δ ppm 2.19 - 2 29 (m, 2 H) 1 2 32 -
2 39 (m, 2 H), 3 53 - 3 63 (ra, 1 H), 4 42 - 4 52 (m, 1 H), 4 87 (s, 3 H), 7.32 (t, J = S 82 Hz, 2
H), 7 55 - 7.62 (m, 2 H), 7 67 - 7 72 (m, 2 H), 8 24 (s, 1 Ii), 8.5S - 8.63 (m, 1 H); MS (ESI)
Example 43
Tians-2-[f5- [3-fluoio-4-ff f[3-(tiifluθiomethy1)phcnyl1amino]-carbonyl)απiino]ρhcny lUhicn-
2-yl)carbonyl]cyclobutanc carboxylic acid
Example 43 A
Trans-methyl 2-[f5-{4-ff/gri'-btitoxycarbonyl)amino|-3-f1uoiOphenvlUhien- 2- vDcaibonylicyclobutanecarboxylate
To a 5 mL microwave reactor vial, 4-(teit-butoxycarbonylamino)-3- fiuoiophenylboronic acid (250 nig, 0.980 mmol), Example 38B (297 mg, 0.980 mmol), cesium fluoiide (447 mg, 2 94 mmol), tetrakis(triphenylphosphine)palladium(0) (1 13 mg, 0 098 mmol), 1 ,2-dimethoxyethane (3 mL), and methanol (2 mL) were added The reaction was heated to 150 0 C for 5 minutes under microwave irradiation (Personal Chemistry Microwave). The reaction was concentrated, and the crude residue was puiified by chromatography on silica gel, eluting with 15% ethyl acetate in hexanes, to afford the title compound. 1 H NMR (300 MHz, DMSO-r/*) δ ppm 1.46 - 1 51 {m, 9 H), 2.09 - 2.20 (m, 3 H), 2 22 - 2.30 (m, 1 H), 3 44 - 3.57 (m, 1 H), 3 59 - 3 62 (m, 3 H), 4.20 - 4.29 (m, 1 H), 7 54 (dd, J=S 31, 1 86 Hz, 1 H) 1 7 64 - 7 72 (m, 2 H), 7 76 (t, J= 8 48 Hz, 1 H), 7 90 (d, J = 4,07 Hz, 1 H), 9 21 (s, I H).
Filed electronically May 17, 2007 8224WOO1
Example 43 B Tians-melhyl-2-{f5-(4-ammo-3-fluoiophenyl)thien-2-yl]carbonv πcyclobutanecarboxy1ate
To a 25 mL flask, Example 43A (210 mg, 0 485 mmol), dichloromethane (10 mL), and trifluoioacetic acid (2 mL) were added The solution was stirred at room temperature for 3 hows, and washed with vvatei (2 x 5 mL), saturated sodium hydrogen carbonate (2 x 5 mL), brine (1 x 5 ml), dried over sodium sulfate, filleted, and concentrated Io alToκl the title compound MS (λPCI) m/z 434 [M-MT] +
Example 43C Tιans-methvI-2-Tf5- f 3-flιioiO-4-rf > f B-
(triflupiomethyl)phenyl1aminol caibonyl)aminolphcnyl] thien-2- yDcaibonyllcyclobutanecarboxylate
To a 4 mL vial, Example 43B (160 mg, 0 48 mmol), l-isocyaπato-3- (Innuoromcthyl)benzene (67 μL, 0.4S mmol), and tetiahydiofuran (2 mL) were added. The vial was sealed and the mix line suited at 60 0 C foi 16 houis The solution was conceπtiated to alϊoid the title compound MS (APCI) m/z 521 [M+H] +
Example 43 D Trans-2-[(5- j3-i1uoio-4-l ' ( !r3-(tnπuoiomethyl)phcnyl]aminolcarbony])amiπo]phenylUhien - 2-yl)caibonyl]cyclobutane catboxylic acid
To a 4 mL vial, Example 43C (150 mg, 0 28S mmol), methanol (2 mL.), and 2.5M sodium hydi oxide (0 35 mL) were added The solution was stirred at room temperature foi 16 hours The solution was acidified to pH 1 with 6M hydrochloric acid, and diluted with ethyl acetate (5 mL) and water' (5 mL) The layeis were separated, and the oiganics were washed with brine (1 x 5 mL), dried over sodium sulfate, filleted, and concentrated under' reduced pressure. The residue was purified by RP-HPLC (preparative reversed -phase high pressure liquid chromatography) using a Zoibax SB-CI S 7M 21 2x250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0 1% trifluoroacetic acid and acetonitrile with 0.1% trifluoroacetic acid gradient 5-95% acetonihile over 30 minutes at 15 mL/minules) to afford the title compound. 1 H NMR (300 MHz, methanol-^) δ ppm 2 19 - 2 34 (m, 4 H), 3.46 - 3 55 (m, 1 H), 4 20 - 4 29 (m, 1 H), 4.80 - 4.91 (m, 3 H), 7.27 - 7.33 (m, 1 H), 7.45 (d, J = 4.07 FIz, 1 H) 1 7.48 - 7 62 (m, 4 H), 7 76 - 7.84 (m, 1 H), 7.94 (s, 1 H), 8.23 - 8 29 (m, 1 H); MS (ESI) m/z 507 [M+H] + .
Filed electronically May 17, 2007 8224WOOi
Example 44 l~(2-fluoro-5-(tτifluoromethyl)phenyl)-3-f4-iodophenyl)urea l-fluoto-2-isocyanato-4*(tiifluoromethyl)benzene (2 00 grams, 9 75 mmol) was dissolved in 10 raL of tetrahydrofuran, and 4-iodoaniline (2 14 grams, 9 75 mmol) was added The reaction vessel was heated to 65°C foi 3 horns Aftei this time, the reaction mixiuic w as cooled (o ioom tempci nluie, and the solvcnS cvapouited Io affoid llic title compound
Example 45 l-f2-fluoτo-4-iodophenylV3-f3-( ' tiifiιιoiomethyl)phenyl ' )ιuea l -isocyanato-3-(Uinuoiomcthy1)benzcnc (59 0 μL, 0 422 mmol) was dissolved in 4 mL ol tctiahydiofuran, and 2-fluoio-4-iodoanilinc (0 100 gtams, 0 422 mmol) was added The icaclion vessel was heated to 65° C for 3 hoius λftei this time, the icaction mix tine was cooled to ioorn tempciatiue, and the solvent evapotated to aifoid the title compound
Example 46 l -f2-fluoio-4-iodophenyl)-3-f2-flιioio-5-fttiflυoiomelhyl)p henyl)ιiica l -fluoio-2-isocyanato-4-(Uif!uoiomethyl)benzenc (305 μL, 2 1 1 mmol) was dissolved in 5 mL ol tetiahydrofutan, and 2-fluoio4-iodoanilinc (0 500 giams, 2 1 1 mmol) was added The reaction vessel was healed to 65° C for 3 hoiπs Aftet this lime, the icaction mixture was cooled to loom tempeialiue, and the solvent was evapoiated to affoid a solid that was tiiturated in boiling hexanes to afford the title compound
It is understood that the foregoing detailed description and accompanying examples are rneiely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents Vaiious changes and modifications including, but not limited to, those relating to the chemical strυctiues, substituents, deiivatives, intermediates, syntheses, formulations and/oi methods of use of the invention, can be made without departing from the spirit and scope thereof